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Wang X, Li S, Lin X, Lu Y, Mao C, Ye Z, Li X, Koh TS, Liu J, Liu J, Ma X, Cheng J, Ning G, Yan Z, Hou Z. Evaluation of tracer kinetic parameters in cervical cancer using dynamic contrast-enhanced MRI as biomarkers in terms of biological relevance, diagnostic performance and inter-center variability. Front Oncol 2022; 12:958219. [PMID: 36324571 PMCID: PMC9620719 DOI: 10.3389/fonc.2022.958219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/04/2022] [Indexed: 11/18/2022] Open
Abstract
Objectives This study assessed the clinical value of parameters derived from dynamic contrast-enhanced (DCE) MRI with respect to correlation with angiogenesis and proliferation of cervical cancer, performance of diagnosis and reproducibility of DCE-MRI parameters across MRI scanners. Materials and Methods A total of 113 patients with cervical carcinoma from two centers were included in this retrospective study. The DCE data were centralized and processed using five tracer kinetic models (TKMs) (Tofts, Ex-Tofts, ATH, SC, and DP), yielding the following parameters: volume transfer constant (Ktrans), extravascular extracellular volume (Ve), fractional volume of vascular space (Vp), blood flow (Fp), and permeability surface area product (PS). CD34 counts and Ki-67 PI (proliferation index) of cervical cancer and normal cervix tissue were obtained using immunohistochemical staining in Center 1. Results CD34 count and Ki-67 PI in cervical cancer were significantly higher than in normal cervix tissue (p<0.05). Parameter Ve from each TKM was significantly smaller in cervical cancer tissue than in normal cervix tissue (p<0.05), indicating the higher proliferation of cervical cancer cells. Ve of each TKM attained the largest AUC to diagnose cervical cancer. The distributions of DCE parameters for both cervical cancer and normal cervix tissue were not significantly different between two centers (P>0.05). Conclusion Parameter Ve was similar to the expression of Ki-67 in revealing the proliferation of tissue cells, attained good performance in diagnosis of cervical cancer, and demonstrated consistent findings on measured values across centers.
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Affiliation(s)
- Xue Wang
- Department of Radiology, The Second Affiliated Hospital and Yuying Children′s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shujian Li
- Department of Magnetic Resonance Imaging (MRI), The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xianhui Lin
- Department of Pathology, The Second Affiliated Hospital and Yuying Children′s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yi Lu
- Department of Radiology, The Second Affiliated Hospital and Yuying Children′s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chuanwan Mao
- Department of Radiology, The Second Affiliated Hospital and Yuying Children′s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhijun Ye
- Department of Radiology, The Second Affiliated Hospital of Sichuan University, Chengdu, China
| | - Xuesheng Li
- Department of Radiology, The Second Affiliated Hospital of Sichuan University, Chengdu, China
| | - Tong-San Koh
- Department of Oncologic Imaging, National Cancer Center, Singapore, Singapore
- The department of Jiangsu Key Laboratory of Medical Optics, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore, Singapore
| | - Jie Liu
- Department of Magnetic Resonance Imaging (MRI), The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingjing Liu
- Department of Magnetic Resonance Imaging (MRI), The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoyue Ma
- Department of Magnetic Resonance Imaging (MRI), The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingliang Cheng
- Department of Magnetic Resonance Imaging (MRI), The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Gang Ning
- Department of Radiology, The Second Affiliated Hospital of Sichuan University, Chengdu, China
| | - Zhihan Yan
- Department of Radiology, The Second Affiliated Hospital and Yuying Children′s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zujun Hou
- Department of Radiology, The Second Affiliated Hospital and Yuying Children′s Hospital of Wenzhou Medical University, Wenzhou, China
- Jiangsu Key Laboratory of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
- *Correspondence: Zujun Hou,
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Zhu M, Molina JR, Dy GK, Croghan GA, Qi Y, Glockner J, Hanson LJ, Roos MM, Tan AD, Adjei AA. A phase I study of the VEGFR kinase inhibitor vatalanib in combination with the mTOR inhibitor, everolimus, in patients with advanced solid tumors. Invest New Drugs 2020; 38:1755-1762. [PMID: 32328844 DOI: 10.1007/s10637-020-00936-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 04/07/2020] [Indexed: 11/26/2022]
Abstract
Purpose Combining small-molecule inhibitors of different targets was shown to be synergistic in preclinical studies. Testing this concept in clinical trials is, however, daunting due to challenges in toxicity management and efficacy assessment. This study attempted to evaluate the safety and efficacy of vatalanib plus everolimus in patients with advanced solid tumors and explore the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies as a predictive biomarker. Patients and Methods This single-center, phase I trial containing 70 evaluable patients consisted of a dose escalation proportion based on the traditional "3 + 3" design (cohort IA and IB) and a dose expansion proportion (cohort IIA and IIB). Toxicity was evaluated using the Common Terminology Criteria of Adverse Events. Antitumor activity was assessed using the Modified Response Evaluation Criteria in Solid Tumors. Results The maximum tolerated doses were determined to be vatalanib 1250 mg once daily or 750 mg twice daily in combination with everolimus 10 mg once daily. No treatment-related death occurred. The most common toxicities were hypertriglyceridemia, hypercholesterolemia, fatigue, vomiting, nausea and diarrhea. There was no complete response. Nine patients (12.9%) had partial response (PR) and 41 (58.6%) had stable disease (SD). Significant antitumor activity was observed in neuroendocrine tumors with a disease-control rate (PR + SD) of 66.7% and other tumor types including renal cancer, melanoma, and non-small-cell lung cancer. Conclusions The combination of vatalanib and everolimus demonstrated reasonable toxicity and clinical activity. Future studies combining targeted therapies and incorporating biomarker analysis are warranted based on this phase I trial.
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Affiliation(s)
- Mojun Zhu
- Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA
| | | | - Grace K Dy
- Roswell Park Cancer Institute, Buffalo, NY, 14263, USA
| | - Gary A Croghan
- Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA
| | - Yingwei Qi
- Dignity Health Medical Foundation, San Francisco, CA, 94107, USA
| | - James Glockner
- Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA
| | | | | | - Angelina D Tan
- Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA
| | - Alex A Adjei
- Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
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A Comparative Study of Two-Compartment Exchange Models for Dynamic Contrast-Enhanced MRI in Characterizing Uterine Cervical Carcinoma. CONTRAST MEDIA & MOLECULAR IMAGING 2019; 2019:3168416. [PMID: 31897081 PMCID: PMC6925719 DOI: 10.1155/2019/3168416] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 10/14/2019] [Indexed: 12/13/2022]
Abstract
A variety of tracer kinetic methods have been employed to assess tumor angiogenesis. The Standard two-Compartment model (SC) used in cervix carcinoma was less frequent, and Adiabatic Approximation to the Tissue Homogeneity (AATH) and Distributed Parameter (DP) model are lacking. This study compares two-compartment exchange models (2CXM) (AATH, SC, and DP) for determining dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters in cervical cancer, with the aim of investigating the potential of various parameters derived from 2CXM for tumor diagnosis and exploring the possible relationship between these parameters in patients with cervix cancer. Parameters (tissue blood flow, Fp; tissue blood volume, Vp; interstitial volume, Ve; and vascular permeability, PS) for regions of interest (ROI) of cervix lesions and normal cervix tissue were estimated by AATH, SC, and DP models in 36 patients with cervix cancer and 17 healthy subjects. All parameters showed significant differences between lesions and normal tissue with a P value less than 0.05, except for PS from the AATH model, Fp from the SC model, and Vp from the DP model. Parameter Ve from the AATH model had the largest AUC (r = 0.85). Parameters Fp and Vp from SC and DP models and Ve and PS from AATH and DP models were highly correlated, respectively, (r > 0.8) in cervix lesions. Cervix cancer was found to have a very unusual microcirculation pattern, with over-growth of cancer cells but without evident development of angiogenesis. Ve has the best performance in identifying cervix cancer. Most physiological parameters derived from AATH, SC, and DP models are linearly correlated in cervix cancer.
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4
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Wang F, Molina J, Satele D, Yin J, Lim VS, Adjei AA. A phase I study of the vascular endothelial growth factor inhibitor Vatalanib in combination with Pemetrexed disodium in patients with advanced solid tumors. Invest New Drugs 2018; 37:658-665. [PMID: 30382439 DOI: 10.1007/s10637-018-0690-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 10/25/2018] [Indexed: 02/07/2023]
Abstract
Introduction Vatalanib is an oral receptor tyrosine kinase inhibitor that blocks all known VEGF, PDGF, and c-Kit receptors. This phase I study evaluated the safety, tolerability, and biologic activity of the combination of vatalanib with pemetrexed disodium in patients with advanced solid tumors. Methods Patients were administered escalating twice daily doses of vatalanib in combination with pemetrexed disodium in 21-day cycles. A dose expansion cohort was enrolled to further define the maximum tolerated dose (MTD) and further evaluate efficacy. Results A total of 29 patients were enrolled in the study (dose escalation, 9; dose expansion, 20). Dose-limiting toxicities included grade 4 thrombocytopenia (6.9%) and febrile neutropenia, anorexia, constipation, and dehydration. Other common adverse events were fatigue (75%), nausea (66%), vomiting (48%), oral mucositis (31%) and diarrhea (28%). The majority of these toxicities were Grade 1-2. The MTD was reached at vatalanib 250 mg twice daily continuously combined with pemetrexed disodium 500 mg/m2 day 1. Overall, 2 patients (6.9%) had partial responses, 8 (27.6%) had stable disease for at least 4 cycles, 5 had progressive disease (17.2%) and 5 went off study before disease assessment. Conclusion The combination of vatalanib with pemetrexed disodium was feasible, but not well tolerated. The modest efficacy results are consistent with other results obtained from combinations of chemotherapy and a large number of VEGF tyrosine kinase inhibitors. This combination should not be developed further unless predictive biomarkers can be identified.
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Affiliation(s)
- Fen Wang
- Department of Oncology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Julian Molina
- Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, United States
| | - Daniel Satele
- Department of Health Sciences Research, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, United States
| | - Jun Yin
- Department of Health Sciences Research, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, United States
| | - Vun-Sin Lim
- Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, United States
| | - Alex A Adjei
- Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, United States.
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Wong ALA, Sundar R, Wang TT, Ng TC, Zhang B, Tan SH, Soh TIP, Pang ASL, Tan CS, Ow SGW, Wang L, Mogro J, Ho J, Jeyasekharan AD, Huang Y, Thng CH, Chan CW, Hartman M, Iau P, Buhari SA, Goh BC, Lee SC. Phase Ib/II randomized, open-label study of doxorubicin and cyclophosphamide with or without low-dose, short-course sunitinib in the pre-operative treatment of breast cancer. Oncotarget 2018; 7:64089-64099. [PMID: 27577069 PMCID: PMC5325427 DOI: 10.18632/oncotarget.11596] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Accepted: 08/08/2016] [Indexed: 01/05/2023] Open
Abstract
Background Prolonged anti-angiogenic therapy destroys tumor vasculature, whereas vascular-normalizing doses may enhance intra-tumoral drug delivery. We hypothesize that low-dose, short-course sunitinib normalizes vasculature, enhancing chemotherapy efficacy. Patients and Methods In phase Ib, treatment-naïve breast cancer patients received four cycles of pre-operative doxorubicin/cyclophosphamide, with sunitinib before each cycle. The optimal dose of sunitinib leading to tumor vessel normalization on immunohistochemistry was identified. In phase II, subjects were randomized to chemotherapy alone or chemotherapy plus sunitinib at the recommended phase II dose (RP2D). Primary endpoint was pathological complete response (pCR) rate. Tumor and functional imaging biomarkers were evaluated serially. Results In phase Ib (n=9), sunitinib 12.5 mg daily for 7 days before each chemotherapy was established as RP2D. In phase II, patients receiving chemotherapy plus sunitinib (n=24) had similar pCR rates (5.0% versus 4.3%, p=1.00), but a higher incidence of chemotherapy dose delays (33.3% versus 8.7%, p=0.04), compared to those receiving chemotherapy alone (n=25). The addition of sunitinib to chemotherapy significantly increased vascular normalization index (VNI) and decreased lymphatic vessel density (D2-40) on immunohistochemistry [VNI:25.50±27.94% versus 49.29±31.84%, p=0.034; D2-40:3.29±2.70 versus 1.29±1.54, p=0.014, baseline versus post-cycle 1], and improved perfusion on DCE-MRI (Ktrans:12.6±9.6 mL/100 g/min versus 16.3±10.7 mL/100 g/min, baseline versus post-cycle 1, p=0.015). Conversely, immunohistochemical and DCE-MRI parameters were not significantly altered by chemotherapy alone. Conclusion Low-dose, short-course sunitinib prior to anthracycline-based chemotherapy in breast cancer patients did not improve pCR and increased chemotherapy dose delays. However, the addition of sunitinib induced compelling pharmacodynamic evidence of vascular normalization. Further studies with alternative cytotoxic regimens should be explored.
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Affiliation(s)
- Andrea L A Wong
- Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.,Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.,Cancer Science Institute, National University of Singapore, Singapore
| | - Raghav Sundar
- Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.,Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore
| | - Ting-Ting Wang
- Cancer Science Institute, National University of Singapore, Singapore
| | - Thian-C Ng
- Clinical Imaging Research Centre, National University of Singapore, Singapore
| | - Bo Zhang
- Clinical Imaging Research Centre, National University of Singapore, Singapore
| | - Sing-Huang Tan
- Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.,Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore
| | - Thomas I P Soh
- Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.,Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore
| | - Angela S L Pang
- Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.,Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore
| | - Chee-Seng Tan
- Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.,Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore
| | - Samuel G W Ow
- Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.,Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore
| | - Lingzhi Wang
- Cancer Science Institute, National University of Singapore, Singapore.,Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore
| | - Jannet Mogro
- Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore
| | - Jingshan Ho
- Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.,Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore
| | - Anand D Jeyasekharan
- Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.,Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.,Cancer Science Institute, National University of Singapore, Singapore
| | - Yiqing Huang
- Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.,Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore
| | - Choon-Hua Thng
- Department of Diagnostic Imaging, National Cancer Centre, Singapore
| | - Ching-Wan Chan
- Department of Surgical Oncology, National University Cancer Institute, National University Health System, Singapore
| | - Mikael Hartman
- Department of Surgical Oncology, National University Cancer Institute, National University Health System, Singapore
| | - Philip Iau
- Department of Surgical Oncology, National University Cancer Institute, National University Health System, Singapore
| | - Shaik A Buhari
- Department of Surgical Oncology, National University Cancer Institute, National University Health System, Singapore
| | - Boon-Cher Goh
- Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.,Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.,Cancer Science Institute, National University of Singapore, Singapore.,Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore
| | - Soo-Chin Lee
- Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.,Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.,Cancer Science Institute, National University of Singapore, Singapore
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6
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Tyrosine Kinase Inhibitor, Vatalanib, Inhibits Proliferation and Migration of Human Pterygial Fibroblasts. Cornea 2018. [PMID: 28644233 DOI: 10.1097/ico.0000000000001268] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
PURPOSE Vatalanib is a small-molecule tyrosine kinase inhibitor. We investigated the effects of vatalanib on the proliferation and migration of cultured human pterygial fibroblasts (HPFs). METHODS Pterygium tissues were obtained after pterygium excision surgery and subjected to primary culture. HPFs were treated with vatalanib at various concentrations. Mitomycin C (MMC) was used as a positive control. Cell proliferation and migration assays were used to investigate the effects of vatalanib. Cell death was measured using flow cytometry analysis. Western blot analysis was performed to identify signaling molecules associated with the response to vatalanib. RESULTS Vatalanib inhibited both proliferation and migration of HPFs in a dose-dependent manner. Cell proliferation was significantly suppressed by vatalanib (10 and 100 μM) and MMC (0.004% and 0.04%) treatments. Migration assays revealed significant HPF delay when treated with vatalanib (1, 10, and 100 μM) and MMC (0.004% and 0.04%) compared with that in a negative control. Cell death analysis showed that high concentrations of vatalanib (100 μM) and MMC (0.004% and 0.04%) decreased cell numbers. Western blot analysis of vatalanib-treated cells showed vascular endothelial growth factor and transforming growth factor-β significantly reduced, but there was no alteration in p53 protein levels in HPFs. CONCLUSIONS These results indicate that vatalanib significantly suppressed the proliferation and migration of HPFs by decreasing vascular endothelial growth factor and transforming growth factor-β. Vatalanib showed less toxicity than that of MMC. Based on these results, vatalanib may potentially serve as a new adjuvant treatment after pterygium excision surgery.
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Morotti M, Dass PH, Harris AL, Lord S. Pharmacodynamic and Pharmacokinetic Markers For Anti-angiogenic Cancer Therapy: Implications for Dosing and Selection of Patients. Eur J Drug Metab Pharmacokinet 2018; 43:137-153. [PMID: 29019020 DOI: 10.1007/s13318-017-0442-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Angiogenesis is integral to tumour growth and invasion, and is a key target for cancer therapeutics. However, for many of the licensed indications, only a modest clinical benefit has been observed for both monoclonal antibody and small-molecule tyrosine kinase inhibitor anti-angiogenic therapy. Pre-clinical and clinical studies have attempted to evaluate circulating, imaging, genomic, pharmacokinetic, and pharmacodynamic markers that may aid both the selection of patients for treatment and define dosing. Correct dosing is likely to be critical in the context of vascular normalization to allow better delivery of concomitant anti-cancer therapy and novel imaging techniques hold much promise in the early evaluation of pharmacodynamic response to improve efficacy.
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Affiliation(s)
- Matteo Morotti
- Hypoxia and Angiogenesis Group, Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK.
- Department of Gynaecology Oncology, University of Oxford, Oxford, UK.
- Department of Oncology, Churchill Hospital, University of Oxford, Oxford, OX3 9DU, UK.
| | - Prashanth Hari Dass
- Department of Oncology, Churchill Hospital, University of Oxford, Oxford, OX3 9DU, UK
| | - Adrian L Harris
- Hypoxia and Angiogenesis Group, Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK
- Department of Oncology, Churchill Hospital, University of Oxford, Oxford, OX3 9DU, UK
| | - Simon Lord
- Hypoxia and Angiogenesis Group, Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK
- Department of Oncology, Churchill Hospital, University of Oxford, Oxford, OX3 9DU, UK
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Yan Y, Sun X, Shen B. Contrast agents in dynamic contrast-enhanced magnetic resonance imaging. Oncotarget 2018; 8:43491-43505. [PMID: 28415647 PMCID: PMC5522164 DOI: 10.18632/oncotarget.16482] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Accepted: 03/15/2017] [Indexed: 12/19/2022] Open
Abstract
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a noninvasive method to assess angiogenesis, which is widely used in clinical applications including diagnosis, monitoring therapy response and prognosis estimation in cancer patients. Contrast agents play a crucial role in DCE-MRI and should be carefully selected in order to improve accuracy in DCE-MRI examination. Over the past decades, there was much progress in the development of optimal contrast agents in DCE-MRI. In this review, we describe the recent research advances in this field and discuss properties of contrast agents, as well as their advantages and disadvantages. Finally, we discuss the research perspectives for improving this promising imaging method.
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Affiliation(s)
- Yuling Yan
- Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, Heilongjiang, China.,TOF-PET/CT/MR Center, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Xilin Sun
- Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, Heilongjiang, China.,TOF-PET/CT/MR Center, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang, China.,Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University School of Medicine, Stanford, California, USA
| | - Baozhong Shen
- Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, Heilongjiang, China.,TOF-PET/CT/MR Center, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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9
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Sartore-Bianchi A, Ricotta R, Cerea G, Maugeri M, Siena S. Rationale and Clinical Results of Multi-target Treatments in Oncology. Int J Biol Markers 2018; 22:77-87. [DOI: 10.1177/17246008070221s410] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
During the last 10 years, the concept of targeted biological therapy for the treatment of cancer has emerged. Targeted agents entered clinical practice only recently, and the first drugs with demonstrated clinical efficacy were mainly inhibitors of the ErbB family of receptors (i.e., EGFR and HER-2), either monoclonal antibodies (MAbs) or tyrosine kinase inhibitors (TKIs). After the proof of concept for the clinical efficacy and tolerability of these selective agents, it was conceived that most tumors will depend on more than one signaling pathway for their growth and survival. As a consequence, different strategies were pursued to inhibit multiple signaling pathways or multiple steps in the same pathway, either by the development of multi-targeted agents or the combination of single targeted drugs. The recent FDA and EMEA approval of sorafenib and sunitinib, both multi-targeted TKIs, marked the coming of age of this new generation of drugs. Now a whole new wave of multi-targeted compounds is moving into clinical trials, raising in the minds of investigators important questions about the best strategies to pursue in their use and many doubts about their differences and the seeming redundancies in the pipelines of pharmaceutical companies. This review will deal with the rationale underlying the multi-targeted approach and with the available clinical experience with multi-targeted agents, especially focusing on molecules with anti-EGFR mechanisms of action.
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Affiliation(s)
- A. Sartore-Bianchi
- The Falck Division of Medical Oncology, Ospedale Niguarda Ca’ Granda, Milan - Italy
| | - R. Ricotta
- The Falck Division of Medical Oncology, Ospedale Niguarda Ca’ Granda, Milan - Italy
| | - G. Cerea
- The Falck Division of Medical Oncology, Ospedale Niguarda Ca’ Granda, Milan - Italy
| | - M.R. Maugeri
- The Falck Division of Medical Oncology, Ospedale Niguarda Ca’ Granda, Milan - Italy
| | - S. Siena
- The Falck Division of Medical Oncology, Ospedale Niguarda Ca’ Granda, Milan - Italy
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10
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Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol 2017; 52:117-124. [PMID: 29229461 DOI: 10.1016/j.semcancer.2017.12.002] [Citation(s) in RCA: 328] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 12/02/2017] [Accepted: 12/07/2017] [Indexed: 12/11/2022]
Abstract
The critical role of angiogenesis in promoting tumor growth and metastasis has been well established scientifically, and consequently blocking this pathway as a therapeutic strategy has demonstrated great clinical success for the treatment of cancer. The holy grail however, has been the identification of patients who derive significant survival benefit from this class of agents. Here we attempt to delineate the diverse mechanisms related to anti-VEGF including its role as an anti-vascular, anti-angiogenic or an anti-permeability factor and review the most promising predictive biomarkers interrogated in large clinical trials, that identify patients who may derive significant survival advantage with VEGF inhibition. Lastly, we describe the function of VEGF as an immunomodulator and illustrate the evidence for anti-VEGF in reprogramming the tumor milieu from an immunosuppressive to an immune permissive microenvironment in human cancers, thus elucidating the role of anti-VEGF as an optimal combination partner for immune checkpoint inhibitors.
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Affiliation(s)
- Priti S Hegde
- Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
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11
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Tolcher A. Dose determination for molecularly targeted therapies: Much Ado About Nothing. Cancer 2017; 123:1298-1300. [PMID: 28182254 DOI: 10.1002/cncr.30584] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 12/28/2016] [Accepted: 01/04/2017] [Indexed: 11/07/2022]
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12
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Deng J, Wang Y. Quantitative magnetic resonance imaging biomarkers in oncological clinical trials: Current techniques and standardization challenges. Chronic Dis Transl Med 2017; 3:8-20. [PMID: 29063052 PMCID: PMC5627686 DOI: 10.1016/j.cdtm.2017.02.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Indexed: 12/21/2022] Open
Abstract
Radiological imaging plays an important role in oncological trials to provide imaging biomarkers for disease staging, stratifying patients, defining dose setting, and evaluating the safety and efficacy of new candidate drugs and innovative treatment. This paper reviews the techniques of most commonly used quantitative magnetic resonance imaging (qMRI) biomarkers (dynamic contrast enhanced, dynamic susceptibility contrast, and diffusion weighted imaging) and their applications in oncological trials. Challenges of incorporating qMRI biomarkers in oncological trials are discussed including understanding biological mechanisms revealed by MRI biomarkers, consideration of rigorous trial design and standardized implementation of qMRI protocols.
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Affiliation(s)
- Jie Deng
- Department of Medical Imaging, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.,Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Yi Wang
- Department of Radiology, Peking University People's Hospital, Beijing, 100044, China
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13
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Xu X, Li L, Zhou Z, Sun W, Huang Y. Dual-pH responsive micelle platform for co-delivery of axitinib and doxorubicin. Int J Pharm 2016; 507:50-60. [DOI: 10.1016/j.ijpharm.2016.04.060] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 04/22/2016] [Accepted: 04/23/2016] [Indexed: 12/14/2022]
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14
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van den Boogaart VEM, de Lussanet QG, Houben RMA, de Ruysscher D, Groen HJM, Marcus JT, Smit EF, Dingemans AMC, Backes WH. Inter-reader reproducibility of dynamic contrast-enhanced magnetic resonance imaging in patients with non-small cell lung cancer treated with bevacizumab and erlotinib. Lung Cancer 2016; 93:20-7. [PMID: 26898610 DOI: 10.1016/j.lungcan.2015.12.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 12/16/2015] [Accepted: 12/25/2015] [Indexed: 10/22/2022]
Abstract
UNLABELLED Objectives When evaluating anti-tumor treatment response by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) it is necessary to assure its validity and reproducibility. This has not been well addressed in lung tumors. Therefore we have evaluated the inter-reader reproducibility of response classification by DCE-MRI in patients with non-small cell lung cancer (NSCLC) treated with bevacizumab and erlotinib enrolled in a multicenter trial. MATERIALS AND METHODS Twenty-one patients were scanned before and 3 weeks after start of treatment with DCE-MRI in a multicenter trial. The scans were evaluated by two independent readers. The primary lung tumor was used for response assessment. Responses were assessed in terms of relative changes in tumor mean trans endothelial transfer rate (K(trans)) and its heterogeneity in terms of the spatial standard deviation. Reproducibility was expressed by the inter-reader variability, intra-class correlation coefficient (ICC) and dichotomous response classification. RESULTS The inter-reader variability and ICC for the relative K(trans) were 5.8% and 0.930, respectively. For tumor heterogeneity the inter-reader variability and ICC were 0.017 and 0.656, respectively. For the two readers the response classification for relative K(trans) was concordant in 20 of 21 patients (k=0.90, p<0.0001) and for tumor heterogeneity in 19 of 21 patients (k=0.80, p<0.0001). CONCLUSIONS Strong agreement was seen with regard to the inter-reader variability and reproducibility of response classification by the two readers of lung cancer DCE-MRI scans.
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Affiliation(s)
- Vivian E M van den Boogaart
- Department of Pulmonary Diseases, Viecuri Medical Center, Tegelseweg 210, 5912 BL Venlo, The Netherlands; Department of Pulmonary Diseases, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
| | - Quido G de Lussanet
- Department of Radiology, Medical Center Zuiderzee, Ziekenhuisweg 100, 8233AA Lelystad, The Netherlands.
| | - Ruud M A Houben
- Department of Radiation-Oncology (Maastro), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 3035, 6202 NA Maastricht, The Netherlands.
| | - Dirk de Ruysscher
- Department of Radiation-Oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.
| | - Harry J M Groen
- Department of Pulmonary Diseases, University of Groningen and University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
| | - J Tim Marcus
- Physics and Medical Technology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
| | - Egbert F Smit
- Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
| | - Anne-Marie C Dingemans
- Department of Pulmonary Diseases, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
| | - Walter H Backes
- Department of Radiology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
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15
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Sung YS, Park B, Choi Y, Lim HS, Woo DC, Kim KW, Kim JK. Dynamic contrast-enhanced MRI for oncology drug development. J Magn Reson Imaging 2016; 44:251-64. [PMID: 26854494 DOI: 10.1002/jmri.25173] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Accepted: 01/15/2016] [Indexed: 12/17/2022] Open
Abstract
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a promising tool for evaluating tumor vascularity, as it can provide vasculature-derived, functional, and quantitative parameters. To implement DCE-MRI parameters as biomarkers for monitoring the effect of antiangiogenic or vascular-disrupting treatment, two crucial elements of surrogate endpoint, ie, validation and qualification, should be satisfied. Although early studies have shown the accuracy and reliability of DCE-MRI parameters for evaluating treatment-driven vascular alterations, there have been an increasing number of studies demonstrating the limitations of DCE-MRI parameters as surrogate endpoints. Therefore, in order to improve the application of DCE-MRI parameters in drug development, it is necessary to establish a standardized evaluation method and to determine the correct therapeutics-oriented meaning of individual DCE-MRI parameter. In this regard, this article describes the biophysical background and data acquisition/analysis techniques of DCE-MRI while focusing on the validation and qualification issues. Specifically, the causes of disagreement and confusion encountered in the preclinical and clinical trials using DCE-MRI are presented in detail. Finally, considering these limitations, we present potential strategies to optimize implementation of DCE-MRI. J. Magn. Reson. Imaging 2016;44:251-264.
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Affiliation(s)
- Yu Sub Sung
- Department of Radiology, Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Center for Bioimaging of New Drug Development, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Bumwoo Park
- Department of Radiology, Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Center for Bioimaging of New Drug Development, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yoonseok Choi
- Center for Bioimaging of New Drug Development, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Hyeong-Seok Lim
- Center for Bioimaging of New Drug Development, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Dong-Cheol Woo
- Department of Radiology, Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Center for Bioimaging of New Drug Development, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Kyung Won Kim
- Department of Radiology, Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Center for Bioimaging of New Drug Development, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jeong Kon Kim
- Department of Radiology, Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Center for Bioimaging of New Drug Development, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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Salem A, O'Connor JPB. Assessment of Tumor Angiogenesis: Dynamic Contrast-enhanced MR Imaging and Beyond. Magn Reson Imaging Clin N Am 2016; 24:45-56. [PMID: 26613875 DOI: 10.1016/j.mric.2015.08.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Dynamic contrast-enhanced (DCE) MR imaging is used increasingly often to evaluate tumor angiogenesis and the efficacy of antiangiogenic drugs. In clinical practice DCE-MR imaging applications are largely centered on lesion detection, characterization, and localization. In research, DCE-MR imaging helps inform decision making in early-phase clinical trials by showing efficacy and by selecting dose and schedule. However, the role of these techniques in patient selection is uncertain. Future research is required to optimize existing DCE-MR imaging methods and to fully validate these biomarkers for wider use in patient care and in drug development.
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Affiliation(s)
- Ahmed Salem
- Cancer Research UK and EPSRC Cancer Imaging Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK
| | - James P B O'Connor
- Cancer Research UK and EPSRC Cancer Imaging Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK. james.o'
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17
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Bruce JY, LoRusso PM, Goncalves PH, Heath EI, Sadowski E, Shalinsky DR, Zhang Y, Traynor AM, Breazna A, Ricart AD, Tortorici M, Liu G. A pharmacodynamically guided dose selection of PF-00337210 in a phase I study in patients with advanced solid tumors. Cancer Chemother Pharmacol 2016; 77:527-38. [PMID: 26791870 DOI: 10.1007/s00280-016-2958-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 01/05/2016] [Indexed: 12/29/2022]
Abstract
PURPOSE PF-00337210 is an oral, highly selective vascular endothelial growth factor receptor (VEGFR) inhibitor. We evaluated a composite of biomarkers in real time to identify the recommended phase 2 dose (RP2D) and preliminary anticancer activity of PF-00337210. PATIENTS AND METHODS Patients (Pts) with advanced cancers were treated once (QD) or twice daily (BID) with escalating doses. Acute effects on tumor perfusion and vascularity were assessed using DCE-MRI, weekly BP readings, soluble VEGFR-2, and hemoglobin levels. RESULTS Forty-six pts were treated with 0.67-9 mg QD and 4-6 mg BID of PF-00337210. Nineteen pts (41%) previously received VEGF/VEGFR inhibitors. Two pts had dose-limiting toxicity (DLT) at 9 mg QD (troponin I increase and hypertension). The MTD at QD dose was 8 mg. Common drug-related adverse events were hypertension, fatigue, proteinuria, and nausea. Hypertension incidence and intensity corresponded with dose, but was well controlled with medication. Two confirmed partial responses and minor regressions (>10 to <30% reduction in target lesions) were noted. Complete DCE-MRI was acquired in 21 pts (20 evaluable for vascular response). Ten pts were vascular responders, including 5/6 pts at BID doses. Greatest modulation of soluble VEGFR-2 was at 6 mg BID. The maximum change from baseline in diastolic BP was higher at BID doses. There were no significant differences for systolic BP and hemoglobin levels. CONCLUSIONS PF-00337210 has profound VEGFR inhibition effects at well-tolerated doses. Antitumor activity and VEGF inhibition effects were observed across BID doses. The RP2D was 6 mg BID.
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Affiliation(s)
- Justine Yang Bruce
- Wisconsin Institute for Medical Research, University of Wisconsin Carbone Cancer Center, Room 7105, 1111 Highland Avenue, Madison, WI, 53705, USA.
| | - Patricia M LoRusso
- Karmanos Cancer Institute, Wayne State University, 4100 John R Street, Detroit, MI, 48201, USA
| | - Priscila H Goncalves
- Karmanos Cancer Institute, Wayne State University, 4100 John R Street, Detroit, MI, 48201, USA
| | - Elisabeth I Heath
- Karmanos Cancer Institute, Wayne State University, 4100 John R Street, Detroit, MI, 48201, USA
| | - Elizabeth Sadowski
- E3/366 Clinical Science Center, Department of Radiology, University of Wisconsin SMPH, 600 Highland Avenue, Madison, WI, 53792-3252, USA
| | - David R Shalinsky
- Department of Pharmacology, Pfizer, Inc., 235 E. 42nd Street, New York, NY, 10017, USA
| | - Yanwei Zhang
- Department of Statistics, Pfizer Inc., 610 Main Street, Cambridge, MA, 02139, USA
| | - Anne M Traynor
- Wisconsin Institute for Medical Research, University of Wisconsin Carbone Cancer Center, Room 3103, 1111 Highland Avenue, Madison, WI, 53705, USA
| | - Aurora Breazna
- Department of Biostatistics, Pfizer, Inc., 235 E. 42nd Street, New York, NY, 10017, USA
| | - Alejandro D Ricart
- Department of Biotechnology and Oncology Research, Pfizer, Inc., 235 E. 42nd Street, New York, NY, 10017, USA
| | - Michael Tortorici
- Department of Clinical Pharmacology, Pfizer, Inc., 235 E. 42nd Street, New York, NY, 10017, USA
| | - Glenn Liu
- Wisconsin Institute for Medical Research, University of Wisconsin Carbone Cancer Center, Room 7105, 1111 Highland Avenue, Madison, WI, 53705, USA
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Gohlke BO, Overkamp T, Richter A, Richter A, Daniel PT, Gillissen B, Preissner R. 2D and 3D similarity landscape analysis identifies PARP as a novel off-target for the drug Vatalanib. BMC Bioinformatics 2015; 16:308. [PMID: 26403354 PMCID: PMC4582733 DOI: 10.1186/s12859-015-0730-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 09/08/2015] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Searching for two-dimensional (2D) structural similarities is a useful tool to identify new active compounds in drug-discovery programs. However, as 2D similarity measures neglect important structural and functional features, similarity by 2D might be underestimated. In the present study, we used combined 2D and three-dimensional (3D) similarity comparisons to reveal possible new functions and/or side-effects of known bioactive compounds. RESULTS We utilised more than 10,000 compounds from the SuperTarget database with known inhibition values for twelve different anti-cancer targets. We performed all-against-all comparisons resulting in 2D similarity landscapes. Among the regions with low 2D similarity scores are inhibitors of vascular endothelial growth factor receptor (VEGFR) and inhibitors of poly ADP-ribose polymerase (PARP). To demonstrate that 3D landscape comparison can identify similarities, which are untraceable in 2D similarity comparisons, we analysed this region in more detail. This 3D analysis showed the unexpected structural similarity between inhibitors of VEGFR and inhibitors of PARP. Among the VEGFR inhibitors that show similarities to PARP inhibitors was Vatalanib, an oral "multi-targeted" small molecule protein kinase inhibitor being studied in phase-III clinical trials in cancer therapy. An in silico docking simulation and an in vitro HT universal colorimetric PARP assay confirmed that the VEGFR inhibitor Vatalanib exhibits off-target activity as a PARP inhibitor, broadening its mode of action. CONCLUSION In contrast to the 2D-similarity search, the 3D-similarity landscape comparison identifies new functions and side effects of the known VEGFR inhibitor Vatalanib.
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Affiliation(s)
- Bjoern-Oliver Gohlke
- Structural Bioinformatics Group, Charite - University Medicine Berlin & ECRC, Lindenberger Weg 80, 13125, Berlin, Germany.
| | - Tim Overkamp
- Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University Berlin, Berlin, Germany.
| | - Anja Richter
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Antje Richter
- Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University Berlin, Berlin, Germany.
| | - Peter T Daniel
- Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University Berlin, Berlin, Germany. .,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. .,Clinical and Molecular Oncology, Max Delbrück Center for Molecular Medicine, 13125 Berlin-Buch, Berlin, Germany.
| | - Bernd Gillissen
- Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University Berlin, Berlin, Germany. .,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Robert Preissner
- Structural Bioinformatics Group, Charite - University Medicine Berlin & ECRC, Lindenberger Weg 80, 13125, Berlin, Germany. .,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Wang X, Owzar K, Gupta P, Larson RA, Mulkey F, Miller AA, Lewis LD, Hurd D, Vij R, Ratain MJ, Murry DJ. Vatalanib population pharmacokinetics in patients with myelodysplastic syndrome: CALGB 10105 (Alliance). Br J Clin Pharmacol 2015; 78:1005-13. [PMID: 24838014 DOI: 10.1111/bcp.12427] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 05/12/2014] [Indexed: 12/14/2022] Open
Abstract
AIMS Vatalanib is an oral anti-angiogenesis agent that inhibits vascular endothelial growth factor receptor tyrosine kinases, which in patients showed auto induction of metabolism and variability in pharmacokinetic (PK) disposition. The objective was to characterize the population PK and time-dependent change in vatalanib clearance and assess exposure-toxicity relationship in patients with myelodysplastic syndrome (MDS). METHODS This was an open-label phase II study of vatalanib in MDS patients receiving 750-1250 mg once daily in 28-day cycles. Serial blood samples were obtained and plasma vatalanib concentrations measured by HPLC. Population PK analysis was performed using nonmem 7.2 with FO estimation since FOCE failed. The final model was evaluated using goodness-of-fit plots, bootstrap analysis, and visual predictive check. RESULTS Pharmacokinetic data were complete for 137 patients (86 M, 51 F), of median age 70 years (range 20-91). A one-compartment model with lagged first-order absorption and time-dependent change in oral clearance was fitted to the vatalanib plasma concentration versus time data. The population means for pre-induction and post-induction oral clearance were 24.1 l h(-1) (range: 9.6-45.5) and 54.9 l h(-1) (range: 39.8-75.6), respectively. The apparent oral clearance increased 2.3-fold, (range: 1.7-4.1-fold) from first dose to steady state. Our data did not identify a significant relationship of the predefined covariates with vatalanib pharmacokinetics, although power to detect such a relationship was limited. CONCLUSIONS Vatalanib pharmacokinetics were highly variable and the extent of auto induction was not determined to correlate with any of the pre-defined covariates.
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Gaumann AKA, Kiefer F, Alfer J, Lang SA, Geissler EK, Breier G. Receptor tyrosine kinase inhibitors: Are they real tumor killers? Int J Cancer 2015; 138:540-54. [PMID: 25716346 DOI: 10.1002/ijc.29499] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 02/13/2015] [Indexed: 12/11/2022]
Abstract
Inhibiting tumor growth by targeting the tumor vasculature was first proposed by Judah Folkman almost 40 years ago. Since then, different approaches and numerous drugs and agents have been developed to achieve this goal, either with the aim of inhibiting tumor neoangiogenesis or normalizing the tumor vasculature. Among the most promising therapeutic targets are receptor tyrosine kinases (RTKs), some of which are predominantly expressed on tumor endothelial cells, although they are sometimes also present on tumor cells. The majority of RTK inhibitors investigated over the past two decades competes with ATP at the active site of the kinase and therefore block the phosphorylation of intracellular targets. Some of these drugs have been approved for therapy, whereas others are still in clinical trials. Here, we discuss the scientific basis, current status, problems and future prospects of RTK inhibition in anti-tumor therapy.
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Affiliation(s)
- Andreas K A Gaumann
- Institute of Pathology Kaufbeuren-Ravensburg, Kaufbeuren, Germany
- Institute of Pathology, University of Regensburg, Medical Center, Regensburg, Germany
| | - Friedemann Kiefer
- Mammalian Cell Signaling Laboratory, Max Planck Institute for Molecular Biomedicine, Münster, North Rhine-Westphalia, Germany
| | - Joachim Alfer
- Institute of Pathology Kaufbeuren-Ravensburg, Kaufbeuren, Germany
| | - Sven A Lang
- Department of Surgery, University of Regensburg, Medical Center, Regensburg, Germany
| | - Edward K Geissler
- Department of Surgery, University of Regensburg, Medical Center, Regensburg, Germany
| | - Georg Breier
- Institute of Pathology, Technical University Dresden, Dresden, Germany
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3D-QSAR study of tetrahydro-3H-imidazo[4,5-c]pyridine derivatives as VEGFR-2 kinase inhibitors using various charge schemes. Arch Pharm Res 2015; 38:1434-42. [DOI: 10.1007/s12272-015-0554-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 01/06/2015] [Indexed: 11/27/2022]
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Perfusion parameters of dynamic contrast-enhanced magnetic resonance imaging predict outcomes of hepatocellular carcinoma receiving radiotherapy with or without thalidomide. Hepatol Int 2014; 9:258-68. [PMID: 25788178 DOI: 10.1007/s12072-014-9557-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Accepted: 06/21/2014] [Indexed: 12/29/2022]
Abstract
BACKGROUND To correlate between signal parameters using dynamic contrast-enhanced magnetic resonance imaging (DCEMRI) and outcomes of hepatocellular carcinoma (HCC) receiving radiotherapy with or without concomitant thalidomide. METHODS DCEMRI was performed in advanced HCC patients undergoing radiotherapy with or without concomitant thalidomide. Initial first-pass enhancement slopes (slope) and peak enhancement ratios (peak) were measured over an operator-defined region of interest over tumor and non-tumor liver parenchyma. The perfusion parameters were correlated with clinical outcomes. The study was registered with ClinicalTrials.gov. (identifier NCT00155272). RESULTS Forty-three patients were evaluable. There were 18 partial responses (PRs), 5 minimal responses (MRs), 17 stable diseases (SDs), and 3 progressive diseases (PDs). Baseline perfusion parameters as well as slope at 14 days of radiotherapy were higher in patients with PR or MR compared to SD or PD (0.81 ± 0.29 vs. 0.49 ± 0.34, p < 0.01; 0.39 ± 0.15 vs. 0.28 ± 0.16, p = 0.02; 0.97 ± 0.38 vs. 0.46 ± 0.26, p < 0.01; respectively). Multivariate analysis revealed perfusion parameters over liver parenchyma, but not over tumor, and independently predicted progression-free and overall survival (182 ± 33 vs. 105 ± 26 days, p = 0.01; 397 ± 111 vs. 233 ± 19 days, p = 0.001 respectively). For 22 patients receiving concomitant thalidomide, the perfusion parameters were not significantly different from those receiving radiotherapy alone. CONCLUSIONS Signal parameters of DCEMRI over tumor and liver parenchyma correlated with tumor response and survival, respectively, in HCC patients receiving radiotherapy.
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Dragovich T, Laheru D, Dayyani F, Bolejack V, Smith L, Seng J, Burris H, Rosen P, Hidalgo M, Ritch P, Baker AF, Raghunand N, Crowley J, Von Hoff DD. Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001). Cancer Chemother Pharmacol 2014; 74:379-87. [PMID: 24939212 DOI: 10.1007/s00280-014-2499-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Accepted: 05/24/2014] [Indexed: 02/06/2023]
Abstract
PURPOSE Vatalanib (PTK 787/ZK22584) is an oral poly-tyrosine kinase inhibitor with strong affinity for platelet-derived growth factor and vascular endothelial growth factor (VEGF) receptors. We conducted an open-label, phase II multicenter therapeutic trial investigating the efficacy and tolerability of vatalanib in patients with metastatic or advanced pancreatic cancer who failed first-line gemcitabine-based therapy. METHODS Vatalanib treatment consisted of a twice daily oral dosing using a "ramp-up schedule," beginning with 250 mg bid during week 1,500 mg bid during week 2, and 750 mg bid on week three and thereafter. The primary objective of this study was to evaluate the 6-month survival rate. RESULTS Sixty-seven patients were enrolled. The median age was 64, and 66% (N = 43) had only one prior regimen. Common grade 3/4 adverse events included hypertension (20%; N = 13), fatigue (17%; N = 11), abdominal pain (17%; N = 11), and elevated alkaline phosphatase (15%; N = 10). Among the 65 evaluable patients, the 6-month survival rate was 29% (95% CI 18-41%) and the median progression-free survival was 2 months. Fifteen patients survived 6 months or more. Two patients had objective partial responses, and 28% of patients had stable disease. Changes in biomarkers including soluble VEGF and vascular endothelial growth factor receptor did not correlate with response to drug. CONCLUSION Vatalanib was well tolerated as a second-line therapy and resulted in favorable 6-month survival rate in patients with metastatic pancreatic cancer, compared with historic controls.
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Affiliation(s)
- T Dragovich
- Banner MD Anderson Cancer Center, 1900 N. Higley Road, Gilbert, AZ, 85234, USA,
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Inomata A, Nakano-Ito K, Fujikawa Y, Sonoda J, Hayakawa K, Ohta E, Taketa Y, Van Gessel Y, Akare S, Hutto D, Hosokawa S, Tsukidate K. Brunner's gland lesions in rats induced by a vascular endothelial growth factor receptor inhibitor. Toxicol Pathol 2014; 42:1267-74. [PMID: 24499803 DOI: 10.1177/0192623313520350] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Vascular endothelial growth factor (VEGF) receptor tyrosine kinase (RTK) inhibitors are reported to cause reversible mucosal hyperplasia (adenosis) in the duodenum of rats; however, the pathogenesis is not fully elucidated. Using lenvatinib, a VEGF RTK inhibitor, we characterized the histologic time course of this duodenal change in rats. At 4 weeks, there was degeneration and necrosis of Brunner's gland epithelium accompanied by neutrophil infiltration around the affected glands. At 13 weeks, the inflammation was more extensive, and Brunner's gland epithelium was attenuated and flattened and was accompanied by reactive hyperplasia of duodenal epithelium. At 26 weeks, the changes became more severe and chronic and characterized by marked cystic dilation, which extended to the external muscular layer. These dilated glands exhibited morphological characteristics of duodenal crypt epithelium, suggestive of replacement of disappeared Brunner's glands by regenerative duodenal crypt epithelial cells. Similar changes were not present in similar time course studies in dog and monkey studies, suggesting that this is a rodent- or species-specific change. Based on the temporal progression of Brunner's gland lesion, we identify degeneration and necrosis of the Brunner's glands as the primary change leading to inflammation, cystic dilatation, and regeneration with cells that are morphologically suggestive of duodenal crypt epithelium.
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Affiliation(s)
| | | | | | - Jiro Sonoda
- Drug Safety Tsukuba, Eisai, Tsukuba, Ibaraki, Japan
| | - Kazuhiro Hayakawa
- Preclinical Safety Research Laboratories, Kawashima Division, Sunplanet, Kagamigahara, Gifu, Japan
| | - Etsuko Ohta
- Drug Safety Tsukuba, Eisai, Tsukuba, Ibaraki, Japan
| | | | | | - Sandeep Akare
- Drug Safety Andover, Eisai, Andover, Massachusetts, USA
| | - David Hutto
- Drug Safety Andover, Eisai, Andover, Massachusetts, USA
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Ahluwalia MS, Patel M, Peereboom DM. Role of tyrosine kinase inhibitors in the management of high-grade gliomas. Expert Rev Anticancer Ther 2014; 11:1739-48. [DOI: 10.1586/era.11.166] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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Bitting RL, Healy P, Creel PA, Turnbull J, Morris K, Wood SY, Hurwitz HI, Starr MD, Nixon AB, Armstrong AJ, George DJ. A phase Ib study of combined VEGFR and mTOR inhibition with vatalanib and everolimus in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 2013; 12:241-50. [PMID: 24685058 DOI: 10.1016/j.clgc.2013.11.020] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 11/01/2013] [Accepted: 11/08/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND Vatalanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), whereas everolimus inhibits mammalian target of rapamycin (mTOR). Combination therapy with VEGFR and mTOR inhibitors has not been well tolerated to date but may have efficacy in renal cell carcinoma (RCC). PATIENTS AND METHODS A phase Ib study of vatalanib and everolimus was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety, and tolerability of the combination. A dose-expansion cohort of 20 patients with metastatic RCC was studied to further define toxicity and preliminary efficacy in patients with RCC. RESULTS We evaluated 32 patients over 3 dose levels and a dose-expansion cohort. The most common toxicities of any grade were proteinuria, fatigue, hypertriglyceridemia, nausea, and vomiting. Dose-limiting toxicities (DLTs) included severe hypertension, diarrhea, neutropenia, mucositis, and fatigue. The MTD for the combination was vatalanib 1000 mg daily and everolimus 5 mg daily. In all patients, median overall survival (OS) was 16.3 months. In patients with RCC, median progression-free survival (PFS) was 5.8 months, and OS was 16.5 months. OS was significantly better in treatment-naive patients (25.1 months) compared with patients who had received previous vascular endothelial growth factor (VEGF)-targeted therapy (6.3 months). Seven of 24 (29.2%) evaluable patients demonstrated a partial response, and an additional 15 patients exhibited stable disease. Long-term tolerability (> 1 year) was demonstrated in 19% of patients. CONCLUSION Relevant doses of vatalanib and everolimus were achieved in combination, with expected toxicities. A substantial number of patients with RCC achieved an objective response in the treatment-naive setting, with prolonged tolerability and survival. Further comparative phase II/III studies of specifically targeted VEGF and mTOR inhibitor combinations may be warranted in patients with RCC.
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Affiliation(s)
- Rhonda L Bitting
- Duke Cancer Institute, Duke University Medical Center, Durham, NC
| | - Patrick Healy
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC
| | - Patricia A Creel
- Duke Cancer Institute, Duke University Medical Center, Durham, NC
| | - James Turnbull
- Duke Cancer Institute, Duke University Medical Center, Durham, NC
| | - Karla Morris
- Duke Cancer Institute, Duke University Medical Center, Durham, NC
| | - Sarah Yenser Wood
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC
| | - Herbert I Hurwitz
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC; Duke Cancer Institute, Duke University Medical Center, Durham, NC
| | - Mark D Starr
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC
| | - Andrew B Nixon
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC; Duke Cancer Institute, Duke University Medical Center, Durham, NC
| | - Andrew J Armstrong
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC; Division of Urology, Department of Surgery, Duke University Medical Center, Durham, NC; Duke Cancer Institute, Duke University Medical Center, Durham, NC
| | - Daniel J George
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, NC; Duke Cancer Institute, Duke University Medical Center, Durham, NC.
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A phase II study of the oral VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK222584) in myelodysplastic syndrome: Cancer and Leukemia Group B study 10105 (Alliance). Invest New Drugs 2013; 31:1311-20. [PMID: 23700288 DOI: 10.1007/s10637-013-9978-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Accepted: 05/08/2013] [Indexed: 01/15/2023]
Abstract
BACKGROUND Angiogenesis is implicated in the pathophysiology and progression of myelodysplastic syndromes (MDS). Vatalanib (PTK787/ZK222584; Novartis and Schering AG) inhibits receptor tyrosine kinases of vascular endothelial growth factor, platelet derived growth factor and c-Kit. We examined whether vatalanib induces hematological responses in MDS and/or delays progression to acute myeloid leukemia (AML) or death. METHODS Two cohorts were studied. Vatalanib 1250 mg orally was given once daily (cohort 1) or 750-1250 mg once daily in an intra-patient dose escalating schedule (cohort 2) in 28-day cycles to 155 patients with MDS; 142 patients were evaluable for response and 153 for toxicity. RESULTS The median age was 70.5 years; 51 % had low risk (International Prognostic Scoring System {IPSS} Low/Intermediate-1) and 32 % had high risk (IPSS Intermediate-2/High) MDS. Hematological improvement was achieved in 7/142 (5 %) patients; all 7 were among the 47 patients able to remain on vatalanib for at least 3 months (hematological improvement achieved in 15 % of these 47 patients). For patients with low risk and high risk MDS, respectively, median progression-free survivals were 15 and 6 months, median times to transformation to AML were 28 and 6 months, and median overall survivals were 36 and 10 months. The most frequent non-hematological adverse events grade ≥ 2 were fatigue, nausea or vomiting, dizziness, anorexia, ataxia, diarrhea, and pain. Two deaths (one intra-cerebral hemorrhage and one sudden death) were possibly related to vatalanib. CONCLUSIONS Vatalanib induces improvement in blood counts in a small proportion of MDS patients. Clinical applicability is limited by side effects.
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Brander D, Rizzieri D, Gockerman J, Diehl L, Shea TC, Decastro C, Moore JO, Beaven A. Phase II open label study of the oral vascular endothelial growth factor-receptor inhibitor PTK787/ZK222584 (vatalanib) in adult patients with refractory or relapsed diffuse large B-cell lymphoma. Leuk Lymphoma 2013; 54:2627-30. [PMID: 23488610 DOI: 10.3109/10428194.2013.784969] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
PTK787/ZK222584 (vatalanib), an orally active inhibitor of vascular endothelial growth factor receptors (VEGFRs), was evaluated in this phase II study of 20 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients received once-daily PTK787/ZK222584 at a target dose of 1250 mg. Eighteen patients were evaluable for response: one patient had a complete response (CR), six patients had stable disease but subsequently progressed, 10 patients had progressive disease by three cycles and one subject withdrew before response evaluation. The patient who attained a CR underwent autologous stem cell transplant and remains disease-free 76 months after study completion. There were no grade 4 toxicities. Grade 3 thrombocytopenia occurred in 20% and grade 3 hypertension occurred in 10%. There were no episodes of grade 3 proteinuria. In conclusion, PTK787/ZK222584 was well tolerated in a heavily pretreated population of patients with DLBCL, although its therapeutic potential as a single agent in DLBCL appears limited.
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Affiliation(s)
- Danielle Brander
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke Cancer Institute , Durham, NC , USA
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3D-QSAR Study on a Series of VEGFR-2 Kinase Inhibitors: 3-Pyrrole Substituted Indolin-2-Ones Compounds. J CHEM-NY 2013. [DOI: 10.1155/2013/374804] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Kieran MW, Kalluri R, Cho YJ. The VEGF pathway in cancer and disease: responses, resistance, and the path forward. Cold Spring Harb Perspect Med 2012; 2:a006593. [PMID: 23209176 DOI: 10.1101/cshperspect.a006593] [Citation(s) in RCA: 152] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Antiangiogenesis was proposed as a novel target for the treatment of cancer 40 years ago. Since the original hypothesis put forward by Judah Folkman in 1971, factors that mediate angiogenesis, their cellular targets, many of the pathways they signal, and inhibitors of the cytokines and receptors have been identified. Vascular endothelial growth factor (VEGF) is the most prominent among the angiogenic cytokines and is believed to play a central role in the process of neovascularization, both in cancer as well as other inflammatory diseases. This article reviews the biology of VEGF and its receptors, the use of anti-VEGF approaches in clinical disease, the toxicity of these therapies, and the resistance mechanisms that have limited the activity of these agents when used as monotherapy.
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Affiliation(s)
- Mark W Kieran
- Department of Pediatric Medical Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
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Gauler TC, Besse B, Mauguen A, Meric JB, Gounant V, Fischer B, Overbeck TR, Krissel H, Laurent D, Tiainen M, Commo F, Soria JC, Eberhardt WEE. Phase II trial of PTK787/ZK 222584 (vatalanib) administered orally once-daily or in two divided daily doses as second-line monotherapy in relapsed or progressing patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). Ann Oncol 2012; 23:678-687. [PMID: 21617019 DOI: 10.1093/annonc/mdr255] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2023] Open
Abstract
BACKGROUND The objective of this multicenter, prospective uncontrolled phase II trial was to determine efficacy, safety and tolerability of vatalanib, an oral angiogenesis inhibitor targeting all known vascular endothelial growth factor receptors, in the second-line treatment of non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with stage IIIB/IV NSCLC-proven tumor progression during or after one platinum-based chemotherapy regimen received a fixed dose of 1250 mg vatalanib either once-daily dosing (QD) or two divided daily dosing (TDD: 500 mg a.m. + 750 mg p.m.) until disease progression or unacceptable toxicity. Primary end point was the disease control rate (DCR) at 12 weeks. RESULTS Fifty-four and 58 patients were enrolled to the QD and TDD arms. DCR at 12 weeks was 35% in the QD and 37% in the TDD arm. The best overall response included one (2%) patient with confirmed partial response with QD and three (5%) with TDD. Median progression-free survival and overall survival were 2.1/7.3 months in the QD arm and 2.8/9.0 months with TDD arm. This therapy showed a moderate toxicity profile for the majority of patients. CONCLUSIONS In the chosen patient population, vatalanib QD and TDD dosing demonstrated potential benefits in tumor size reduction, DCR, and survival.
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Affiliation(s)
- T C Gauler
- Department of Medicine (Cancer Research), West German Tumor Center, University Hospital of University Duisburg-Essen, Essen, Germany.
| | - B Besse
- Institut Gustave Roussy, Villejuif, France
| | - A Mauguen
- Institut Gustave Roussy, Villejuif, France
| | | | | | - B Fischer
- University Medical Center of the Johannes Gutenberg University Mainz, Mainz
| | | | - H Krissel
- Bayer Healthcare Pharmaceuticals, Berlin, Germany
| | - D Laurent
- Bayer Healthcare Pharmaceuticals, Berlin, Germany
| | | | - F Commo
- Institut Gustave Roussy, Villejuif, France
| | - J C Soria
- Institut Gustave Roussy, Villejuif, France
| | - W E E Eberhardt
- Department of Medicine (Cancer Research), West German Tumor Center, University Hospital of University Duisburg-Essen, Essen, Germany
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Huang Z, Mayr NA, Lo SS, Grecula JC, Wang JZ, Jia G, Yuh WT. Characterizing at-Risk Voxels by Using Perfusion Magnetic Resonance Imaging for Cervical Cancer during Radiotherapy. ACTA ACUST UNITED AC 2012; 4:254-259. [PMID: 23638244 DOI: 10.4172/1948-5956.1000151] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The number of voxels with low signal intensity (Low DCE voxels) might be potentially related to treatment failure, which might be associated with the tumor oxygenation status. Our goal was to investigate whether at-risk voxels can be used to predict treatment outcome during radiation therapy for cervical cancer. 80 patients with Stage IB2-IVB cervical cancer were included. Four sequential MRI scans were performed at pre-RT, every 2-2.5 weeks during RT, and post-radiotherapy. 3D volumetric data including tumor regression and tumor perfusion from dynamic contrast enhanced MRI (DCE-MRI) were analyzed. Based on the signal intensity (SI) curves of the DCE-MRI, the low-DCE tumor voxels was obtained for individual patients. The predictive power of low DCE voxels in predicting the treatment outcomes was evaluated by Kaplan-Meier survival analysis. Correlation of low DCE voxels with hemoglobin (Hgb) was checked by Pearson Correlation. The actuarial local control rate and survival rate in the patient group with a small number of low DCE voxels were 89.7% and 76.9%, compared with 75.6% and 51.2% in the patient group with a big number of low DCE voxels for the MRI study #1, and 94.1% and 80.4% compared with 62.1% and 34.5% for the MRI study #2, and 95.7% and 78.7% compared with 63.6% and 42.4% for the MRI study #3, respectively. Low DCE voxels were significantly correlated with Hgb. At-risk voxels can be used to predict the outcomes and help understand tumor heterogeneity of response to RT. The Hgb level and tumor perfusion during RT influence the radioresponsiveness and survival in cervical cancer patients.
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Affiliation(s)
- Zhibin Huang
- Department of Radiation Oncology, East Carolina University, Greenville, NC 27834, USA
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Affiliation(s)
- Andrew S Chi
- Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
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Vatalanib in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (CALGB 30107). Lung Cancer 2011; 76:393-6. [PMID: 22197613 DOI: 10.1016/j.lungcan.2011.11.014] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2011] [Revised: 11/16/2011] [Accepted: 11/20/2011] [Indexed: 12/16/2022]
Abstract
INTRODUCTION The Cancer and Leukemia Group B (CALGB) conducted a multi-center phase II trial to evaluate the efficacy and safety of vatalanib in previously untreated patients with malignant mesothelioma and to evaluate potential biomarkers of disease response (CALGB 30107). METHODS Treatment consisted of vatalanib 1250 mg given orally once daily. CT scans were obtained at baseline and every 6 weeks thereafter. Baseline serum levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), thrombospondin-1 (TSP-1), and mesothelin were obtained. The primary endpoint was 3-month progression-free survival (PFS). RESULTS Forty-seven patients enrolled at 19 centers. The median age was 75 years, and the majority of patients (79%) had an ECOG performance status of 1. Tumors were classified as epithelial (77%), sarcomatoid (10%), or mixed (9%) histology. Toxicity was mild; the most common grade 3/4 adverse events were neutropenia (2%), nausea (15%), elevated alanine aminotransferase (11%), hypertension (2%), and gastrointestinal bleeding (2%). Partial responses were observed in 6% of patients and stable disease in 72% of patients. The 3-month PFS rate was 55% (95% CI: 40%, 68%). The median PFS was 4.1 months. Median overall survival was 10.0 months. There was no correlation between serum levels of VEGF, PDGF, TSP-1, or mesothelin and treatment response, PFS, or survival. CONCLUSIONS Vatalanib as a single agent with this dose and schedule does not warrant further study in this disease.
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Tolcher AW. The evolution of phase I trials in cancer medicine: a critical review of the last decade. CHINESE JOURNAL OF CANCER 2011; 30:815-20. [PMID: 22059910 PMCID: PMC4013329 DOI: 10.5732/cjc.011.10133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The advent of targeted therapies, combined with an unsustainable rate of failure in oncology drug development, has resulted in a number of new approaches to clinical trials. Early clinical trials are no exception, with efforts to improve the eventual success rate of late stage trials through evolving phase I trial methodologies, the addition of extensive pharmacodynamic studies, and early adoption of patient selection strategies. Unfortunately, some of these new approaches have met with mixed results. Furthermore, no clear metrics are available to determine whether these designs are more successful than previous strategies. This review examines the evolution of phase I trials and draws upon several examples of strategies that have been successful as well as those that have not, and outlines a pragmatic approach to phase I trials as our understanding of the molecular biology of individual malignancies emerges.
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Affiliation(s)
- Anthony W Tolcher
- Breast Department of Clinical Research, South Texas Accelerated Research Therapeutics, San Antonio, TX 78229, USA.
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Koh TS, Thng CH, Hartono S, Tai BC, Rumpel H, Ong AB, Sukri N, Soo RA, Wong CI, Low ASC, Humerickhouse RA, Goh BC. A comparative study of dynamic contrast-enhanced MRI parameters as biomarkers for anti-angiogenic drug therapy. NMR IN BIOMEDICINE 2011; 24:1169-1180. [PMID: 21432928 DOI: 10.1002/nbm.1680] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2010] [Revised: 12/16/2010] [Accepted: 01/01/2011] [Indexed: 05/30/2023]
Abstract
The aim of the present study was to compare three tracer kinetics methods for the analysis of dynamic contrast-enhanced (DCE) MRI data, namely the generalized kinetics model, the distributed-parameter model and the initial area under the tumor tracer curve (IAUC) method, in a Phase I study of an anti-angiogenic drug ABT -869; and to explore their utility as biomarkers. Twenty-eight patients with a range of tumors formed the study population. DCE MRI performed at baseline and 2 weeks post-treatment was analyzed using all three methods, yielding percentage changes for various tracer kinetics parameters. Correlation analyzes were performed between these parameters and in relation to drug exposure. The association of these parameters with time-to-progression was examined using receiver-operating characteristic and Kaplan-Meier curves. Significant correlation with drug exposure was found for the following parameters: normalized IAUC (IAUC(norm)), fractional interstitial volume v(e), fractional intravascular volume v(1) and permeability PS. However, only v(e) and PS were effective in predicting late progression. A decrease in v(e) of more than 1.7% and a decrease in PS of more than 25.1% observed at 2 weeks post-treatment could be associated with late progression. All three tracer kinetics methods have biomarker potential for assessing the effects of anti-angiogenic therapy.
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Affiliation(s)
- Tong San Koh
- Department of Oncologic Imaging, National Cancer Center, Singapore.
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Kim KB, Chesney J, Robinson D, Gardner H, Shi MM, Kirkwood JM. Phase I/II and pharmacodynamic study of dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma. Clin Cancer Res 2011; 17:7451-61. [PMID: 21976540 DOI: 10.1158/1078-0432.ccr-11-1747] [Citation(s) in RCA: 104] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Dovitinib (TKI258) is an orally available inhibitor of fibroblast growth factor (FGF), VEGF, and platelet-derived growth factor receptors. This phase I/II dose-escalation study was conducted to evaluate the safety, pharmacodynamics, and preliminary efficacy of dovitinib in the treatment of advanced melanoma. EXPERIMENTAL DESIGN Patients with advanced melanoma resistant or refractory to standard therapies or for whom no standard therapy was available were enrolled. Dovitinib was administered at doses ranging from 200 to 500 mg/d. RESULTS Forty-seven patients were enrolled. The most frequently reported adverse events were fatigue (77%; grade ≥3, 28%), diarrhea (77%; grade ≥3, 11%), and nausea (77%; grade ≥3, 9%). Six dose-limiting toxicities were observed in the 400-mg and 500-mg dose cohorts, which consisted of grade 3 nausea, fatigue, and diarrhea and grade 4 fatigue events. The maximum tolerated dose was 400 mg/d. The best tumor response was stable disease, which was observed in 12 patients. Increases in plasma FGF23, VEGF, and placental growth factor and decreases in soluble VEGF receptor 2 were noted during the first cycle of treatment, consistent with FGF receptor (FGFR) and VEGF receptor (VEGFR) inhibition. Dynamic contrast-enhanced MRI analysis showed a dose-dependent decrease in tumor blood flow and vascular permeability with dovitinib therapy. A decrease in FGFR phosphorylation was observed in paired tumor biopsy samples from a patient treated with dovitinib at a dose of 400 mg/d. CONCLUSIONS At a dose of 400 mg/d, dovitinib showed an acceptable safety profile and limited clinical benefit and inhibited FGFR and VEGFR.
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Affiliation(s)
- Kevin B Kim
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
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An Algorithm for the Management of Hypertension in the Setting of Vascular Endothelial Growth Factor Signaling Inhibition. Clin Colorectal Cancer 2011; 10:151-6. [DOI: 10.1016/j.clcc.2011.03.021] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2010] [Revised: 01/03/2011] [Accepted: 01/24/2011] [Indexed: 11/18/2022]
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Is VEGF a predictive biomarker to anti-angiogenic therapy? Crit Rev Oncol Hematol 2011; 79:103-11. [DOI: 10.1016/j.critrevonc.2010.07.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2010] [Revised: 06/23/2010] [Accepted: 07/14/2010] [Indexed: 01/02/2023] Open
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Klümpen HJ, Samer CF, Mathijssen RH, Schellens JH, Gurney H. Moving towards dose individualization of tyrosine kinase inhibitors. Cancer Treat Rev 2011; 37:251-60. [DOI: 10.1016/j.ctrv.2010.08.006] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2010] [Revised: 08/13/2010] [Accepted: 08/17/2010] [Indexed: 12/11/2022]
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Spigel D, Jones S, Hainsworth J, Infante J, Greco FA, Thompson D, Doss H, Burris H. A phase I trial to determine the safety of imatinib in combination with vatalanib in patients with advanced malignancies. Cancer Invest 2011; 29:308-12. [PMID: 21469980 DOI: 10.3109/07357907.2011.568567] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The role of tyrosine kinase inhibitors (TKIs) in the treatment of advanced malignancies is well established. Imatinib and vatalanib are oral TKIs with different mechanisms of action. This trial sought to establish the safety, tolerability, and maximum tolerated dose (MTD) of the two agents in combination. Secondary objectives included determination of potential pharmacologic interactions among vatalanib and imatinib and observation of antitumor activity. Patients with biopsy-proven advanced refractory solid tumors were enrolled in this single-center dose-escalation trial. Patients initially received imatinib and vatalanib once daily following a 14-day run-in period of daily oral vatalanib only, and were observed for a full 28-day treatment cycle prior to dose escalation. An amendment divided the vatalanib dose into two daily doses and gradually escalated the dose over a 2-3 week period. Patients continued combination therapy until disease progression or intolerable toxicity. Forty-five patients were enrolled between September 2004 and November 2007. As of September 2009, a total of 247 cycles of treatment had been administered (range: 1 -44+, median = 2 ). The MTD was determined to be vatalanib 1250 mg daily and imatinib 400 mg daily. Thirty-five patients (78%) were evaluable for response; 2 patients achieved PR, while 14 patients had SD ( 10 had stable disease ≥ 6 cycles). The combination of vatalanib and imatinib was well tolerated. Twice-daily vatalanib dosing improved tolerability and ease of full-dose administration. These results suggest that vatalanib-containing combinations may be active and tolerable, warranting further study.
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Affiliation(s)
- David Spigel
- The Sarah Cannon Research Institute, Nashville, Tennessee 37203, USA
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Sobrero AF, Bruzzi P. Vatalanib in Advanced Colorectal Cancer: Two Studies With Identical Results. J Clin Oncol 2011; 29:1938-40. [DOI: 10.1200/jco.2010.33.2429] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
| | - Paolo Bruzzi
- Istituto Nazionale per la ricerca sul Cancro, Genova, Italy
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Joensuu H, De Braud F, Grignagni G, De Pas T, Spitalieri G, Coco P, Spreafico C, Boselli S, Toffalorio F, Bono P, Jalava T, Kappeler C, Aglietta M, Laurent D, Casali PG. Vatalanib for metastatic gastrointestinal stromal tumour (GIST) resistant to imatinib: final results of a phase II study. Br J Cancer 2011; 104:1686-90. [PMID: 21540861 PMCID: PMC3111164 DOI: 10.1038/bjc.2011.151] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Vatalanib (PTK787/ZK 222584) inhibits a few tyrosine kinases including KIT, platelet-derived growth factor receptors (PDGFRs) and vascular endothelial growth factor receptors (VEGFRs). We report efficacy and safety results of vatalanib in advanced gastrointestinal stromal tumour (GIST) resistant to imatinib or both imatinib and sunitinib. PATIENTS AND METHODS Forty-five patients whose metastatic GIST had progressed on imatinib were enrolled. Nineteen (42.2%) patients had received also prior sunitinib. Vatalanib 1250 mg was administered orally daily. RESULTS Eighteen patients (40.0%; 95% confidence interval (CI), 25.7-54.3%) had clinical benefit including 2 (4.4%) confirmed partial remissions (PR; duration, 9.6 and 39.4 months) and 16 (35.6%) stabilised diseases (SDs; median duration, 12.5 months; range, 6.0-35.6+ months). Twelve (46.2%) out of the 26 patients who had received prior imatinib only achieved either PR or SD compared with 6 (31.6%, all SDs) out of the 19 patients who had received prior imatinib and sunitinib (P=0.324). The median time to progression was 5.8 months (95% CI, 2.9-9.5 months) in the subset without prior sunitinib and 3.2 (95% CI, 2.1-6.0) months among those with prior imatinib and sunitinib (P=0.992). Vatalanib was generally well tolerated. CONCLUSION Vatalanib is active despite its narrow kinome interaction spectrum in patients diagnosed with imatinib-resistant GIST or with imatinib and sunitinib-resistant GIST.
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Affiliation(s)
- H Joensuu
- Department of Oncology, University Central Hospital of Helsinki, Haartmaninkatu 4, Helsinki FIN-00029, Finland.
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Burris H, Stephenson J, Otterson GA, Stein M, McGreivy J, Sun YN, Ingram M, Ye Y, Schwartzberg LS. Safety and pharmacokinetics of motesanib in combination with panitumumab and gemcitabine-Cisplatin in patients with advanced cancer. JOURNAL OF ONCOLOGY 2011; 2011:853931. [PMID: 21559248 PMCID: PMC3087488 DOI: 10.1155/2011/853931] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2010] [Accepted: 02/12/2011] [Indexed: 02/04/2023]
Abstract
Purpose. The aim of this study was to assess the safety and tolerability of motesanib (an orally administered small-molecule antagonist of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and Kit) when administered in combination with panitumumab, gemcitabine, and cisplatin. Methods. This was an open-label, multicenter phase 1b study in patients with advanced solid tumors with an ECOG performance status ≤1 and for whom a gemcitabine/cisplatin regimen was indicated. Patients received motesanib (0 mg [control], 50 mg once daily [QD], 75 mg QD, 100 mg QD, 125 mg QD, or 75 mg twice daily [BID]) with panitumumab (9 mg/kg), gemcitabine (1250 mg/m(2)) and cisplatin (75 mg/m(2)) in 21-day cycles. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Results. Forty-one patients were enrolled and received treatment (including 8 control patients). One of eight patients in the 50 mg QD cohort and 5/11 patients in the 125 mg QD cohort experienced DLTs. The maximum tolerated dose was established as 100 mg QD. Among patients who received motesanib (n = 33), 29 had motesanib-related adverse events. Fourteen patients had serious motesanib-related events. Ten patients had motesanib-related venous thromboembolic events and three had motesanib-related arterial thromboembolic events, two of which were considered serious. One patient had a complete response and nine had partial responses as their best objective response. Conclusions. The combination of motesanib, panitumumab, and gemcitabine/cisplatin could not be administered consistently and, at the described doses and schedule, may be intolerable. However, encouraging antitumor activity was noted in some cases.
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Affiliation(s)
- Howard Burris
- Sarah Cannon Research Institute, Nashville, TN 37203, USA
| | - Joe Stephenson
- Cancer Center of the Carolinas, Greenville, SC 29605, USA
| | | | - Mark Stein
- Robert Wood Johnson University Hospital, UMDNJ, New Brunswick, NJ 08903, USA
| | | | | | | | - Yining Ye
- Amgen Inc., South San Francisco, CA 94080, USA
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Koh DM, Padhani AR. Functional magnetic resonance imaging of the liver: parametric assessments beyond morphology. Magn Reson Imaging Clin N Am 2011; 18:565-85, xii. [PMID: 21094456 DOI: 10.1016/j.mric.2010.07.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
There is growing interest in exploring and using functional imaging techniques to provide additional information on structural alterations in the liver, which often occur late in the disease process. This article presents a summary of the different functional MR imaging techniques currently in use, focusing on dynamic contrast-enhanced MR imaging, diffusion-weighted MR imaging, MR spectroscopy, in- and oppose-phase MR imaging, and T2*-weighted imaging. For each technique, the biologic underpinning for the technique is explained, the clinical applications surveyed, and the challenges for their application enumerated. Developing and less frequently used techniques such as MR elastography, blood oxygenation level dependent imaging, dynamic susceptibility contrast-enhanced MR imaging, and diffusion-tensor imaging are reviewed. The challenges widespread adoption of functional MR imaging and the translation of such techniques to high field strengths are also discussed.
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Affiliation(s)
- Dow-Mu Koh
- Department of Radiology, Royal Marsden Hospital, Downs Road, Sutton SM2 5PT, UK.
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Hecht JR, Trarbach T, Hainsworth JD, Major P, Jäger E, Wolff RA, Lloyd-Salvant K, Bodoky G, Pendergrass K, Berg W, Chen BL, Jalava T, Meinhardt G, Laurent D, Lebwohl D, Kerr D. Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol 2011; 29:1997-2003. [PMID: 21464406 DOI: 10.1200/jco.2010.29.4496] [Citation(s) in RCA: 135] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE PTK787/ZK 222584 (PTK/ZK; vatalanib), an orally active, multitargeted angiogenesis inhibitor, has shown tolerability and promising activity in early-phase studies, which led to a phase III trial in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4). PATIENTS AND METHODS Patients (N = 1,168) with previously untreated metastatic colorectal cancer were randomly assigned 1:1 to receive FOLFOX4 plus PTK/ZK or placebo (ClinicalTrials.gov identifier: NCT00056459). Stratification factors included WHO performance status (0 v 1 or 2) and serum lactate dehydrogenase (LDH; ≤ v > 1.5× the upper limit of normal). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and overall response rate (ORR). RESULTS PFS, OS, and ORR were not statistically improved with PTK/ZK (P > .05). Median PFS by central review was 7.7 months with PTK/ZK versus 7.6 months with placebo (hazard ratio [HR], 0.88; 95% CI, 0.74 to 1.03; P = .118); median OS was 21.4 months with PTK/ZK versus 20.5 months with placebo (HR, 1.08; 95% CI, 0.94 to 1.24; P = .260). In an exploratory post hoc analysis of PFS in patients (n = 158 per arm) with high serum LDH, a potential marker of hypoxia, PFS was longer with PTK/ZK versus placebo (7.7 v 5.8 months, respectively; HR, 0.67; 95% CI, 0.49 to 0.91; P = .009). CONCLUSION Although the efficacy objectives of this study were not met, a subgroup of patients who may potentially benefit from small-molecule vascular endothelial growth factor receptor inhibitor therapy has been identified and further research is warranted.
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Affiliation(s)
- J Randolph Hecht
- David Geffen School of Medicine at University of California, Los Angeles, Santa Monica, CA 90404, USA.
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Gauthier M, Leguerney I, Thalmensi J, Chebil M, Parisot S, Peronneau P, Roche A, Lassau N. Estimation of intra-operator variability in perfusion parameter measurements using DCE-US. World J Radiol 2011; 3:70-81. [PMID: 21512654 PMCID: PMC3080053 DOI: 10.4329/wjr.v3.i3.70] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2010] [Revised: 03/02/2011] [Accepted: 03/09/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate intra-operator variability of semi-quantitative perfusion parameters using dynamic contrast-enhanced ultrasonography (DCE-US), following bolus injections of SonoVue®.
METHODS: The in vitro experiments were conducted using three in-house sets up based on pumping a fluid through a phantom placed in a water tank. In the in vivo experiments, B16F10 melanoma cells were xenografted to five nude mice. Both in vitro and in vivo, images were acquired following bolus injections of the ultrasound contrast agent SonoVue® (Bracco, Milan, Italy) and using a Toshiba Aplio® ultrasound scanner connected to a 2.9-5.8 MHz linear transducer (PZT, PLT 604AT probe) (Toshiba, Japan) allowing harmonic imaging (“Vascular Recognition Imaging”) involving linear raw data. A mathematical model based on the dye-dilution theory was developed by the Gustave Roussy Institute, Villejuif, France and used to evaluate seven perfusion parameters from time-intensity curves. Intra-operator variability analyses were based on determining perfusion parameter coefficients of variation (CV).
RESULTS: In vitro, different volumes of SonoVue® were tested with the three phantoms: intra-operator variability was found to range from 2.33% to 23.72%. In vivo, experiments were performed on tumor tissues and perfusion parameters exhibited values ranging from 1.48% to 29.97%. In addition, the area under the curve (AUC) and the area under the wash-out (AUWO) were two of the parameters of great interest since throughout in vitro and in vivo experiments their variability was lower than 15.79%.
CONCLUSION: AUC and AUWO appear to be the most reliable parameters for assessing tumor perfusion using DCE-US as they exhibited the lowest CV values.
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Gounder MM, Maki RG. Molecular basis for primary and secondary tyrosine kinase inhibitor resistance in gastrointestinal stromal tumor. Cancer Chemother Pharmacol 2011; 67 Suppl 1:S25-43. [PMID: 21116624 PMCID: PMC3275340 DOI: 10.1007/s00280-010-1526-3] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2010] [Accepted: 11/10/2010] [Indexed: 02/08/2023]
Abstract
Small molecule kinase inhibitors have irrevocably altered cancer treatment. March 2010 marks the 10th anniversary of using imatinib in gastrointestinal stromal tumors (GIST), a cardinal example of the utility of such targeted therapy in a solid tumor. Before imatinib, metastatic GIST was frustrating to treat due to its resistance to standard cytotoxic chemotherapy. Median survival for patients with metastatic GIST improved from 19 to 60 months with imatinib. In treating patients with GIST, two patterns of tyrosine kinase inhibitor resistance have been observed. In the first, ~9-14% of patients have progression within 3 months of starting imatinib. These patients are classified as having primary or early resistance. Median progression-free survival (PFS) on imatinib is approximately 24 months; patients with later progression are classified as having secondary or acquired resistance. Primary studies and a meta-analysis of studies of imatinib in GIST patients have identified prognostic features that contribute to treatment failure. One of the strongest predictors for success of therapy is KIT or PDGFRA mutational status. Patients with KIT exon 11 mutant GIST have better response rates, PFS, and overall survival compared to other mutations. A great deal has been learned in the last decade about sensitivity and resistance of GIST to imatinib; however, many unanswered questions remain about secondary resistance mechanisms and clinical management in the third- and fourth-line setting. This review will discuss the role of dose effects, and early and late resistance to imatinib and their clinical implications. Patients intolerant to imatinib (5%) and those who progress on imatinib are treated with sunitinib. The mechanism of resistance to sunitinib is unknown at this time but is also appears related to growth of clones with secondary mutations in KIT. Third- and fourth-line treatments of GIST and with future treatment strategies are also discussed.
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Affiliation(s)
| | - Robert G. Maki
- Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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Zweifel M, Padhani AR. Perfusion MRI in the early clinical development of antivascular drugs: decorations or decision making tools? Eur J Nucl Med Mol Imaging 2010; 37 Suppl 1:S164-82. [PMID: 20461374 DOI: 10.1007/s00259-010-1451-z] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Classically, the first step in the clinical development of drugs in oncology involves assessments of dose limiting toxicity (DLT) and maximum tolerated dose (MTD). New paradigms are needed for antiangiogenic drugs and vascular disrupting agents (VDAs) as they are active at doses well below the MTD and as single agents their use might not translate into anti-tumour efficacy. MRI is able to assess the antivascular effects of antivascular drugs via changes in functional kinetic parameters; however, the usefulness of MRI in decision making has been questioned by many. OBJECTIVES Our aim is to review the experience of using dynamic contrast-enhanced MRI (DCE-MRI) in early clinical development of vascular directed anticancer therapies over the last decade. Thirty-nine phase I and II studies including data on more than 700 patients have been published as abstracts and/or papers, documenting DCE-MRI changes after the administration of antiangiogenic drugs and VDAs. DISCUSSION Perfusion MRI is helpful in assessing whether mechanistic goals are achieved, in assisting dose selection for phase II studies, in selecting subpopulations enriched for response and in predicting patient benefit. Imaging tools are increasingly available. Future challenges for imaging include correlation with clinical measures of efficacy and determining relationships with blood and serum biomarkers.
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Affiliation(s)
- Martin Zweifel
- Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, Middlesex, UK
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