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Lin C, Lin P, Yao H, Liu S, Lin X, He R, Teng Z, Zuo X, Li Y, Ye J, Zhu G. Modulation of YBX1-mediated PANoptosis inhibition by PPM1B and USP10 confers chemoresistance to oxaliplatin in gastric cancer. Cancer Lett 2024; 587:216712. [PMID: 38364962 DOI: 10.1016/j.canlet.2024.216712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/29/2024] [Accepted: 02/05/2024] [Indexed: 02/18/2024]
Abstract
Gastric cancer (GC) is a common malignant tumor of the digestive tract, and chemoresistance significantly impacts GC patients' prognosis. PANoptosis has been associated with oxaliplatin-induced cell death. However, the direct regulatory role of YBX1 in cellular chemoresistance through PANoptosis remains unclear. In this study, we investigated the impact of YBX1 on regulating PANoptosis and its influence on the resistance of gastric cancer cells to oxaliplatin. Through overexpression and silencing experiments, we assessed YBX1's effect on proliferation and PANoptosis regulation in gastric cancer cells. Additionally, we identified PPM1B and USP10 as interacting proteins with YBX1 and confirmed their influence on YBX1 molecular function and protein expression levels. Our results demonstrate that YBX1 suppresses PANoptosis, leading to enhanced resistance of gastric cancer cells to oxaliplatin. Furthermore, we found that PPM1B and USP10 play critical roles in regulating YBX1-mediated PANoptosis inhibition. PPM1B directly interacts with YBX1, causing dephosphorylation of YBX1 at serine 314 residue. This dephosphorylation process affects the deubiquitination of YBX1 mediated by USP10, resulting in decreased YBX1 protein expression levels and impacting PANoptosis and oxaliplatin resistance in gastric cancer cells. Additionally, we discovered that the 314th amino acid of YBX1 has a profound impact on its own protein expression abundance, thereby affecting the functionality of YBX1. In conclusion, our study reveals the significance of PPM1B-mediated dephosphorylation of YBX1 and USP10-mediated deubiquitination in regulating PANoptosis and sensitivity to oxaliplatin in gastric cancer cells. These findings offer a potential therapeutic strategy for patients with oxaliplatin-resistant gastric cancer.
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Affiliation(s)
- Chunlin Lin
- Department of Gastrointestinal Surgery 2 Section, Institute of Abdominal Surgery, Key Laboratory of Accurate Diagnosis and Treatment of Cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350000, China; National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Penghang Lin
- Department of Gastrointestinal Surgery 2 Section, Institute of Abdominal Surgery, Key Laboratory of Accurate Diagnosis and Treatment of Cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350000, China
| | - Hengxin Yao
- Department of Gastrointestinal Surgery 2 Section, Institute of Abdominal Surgery, Key Laboratory of Accurate Diagnosis and Treatment of Cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350000, China
| | - Songyi Liu
- Department of Gastrointestinal Surgery 2 Section, Institute of Abdominal Surgery, Key Laboratory of Accurate Diagnosis and Treatment of Cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350000, China
| | - Xiang Lin
- Department of Gastrointestinal Surgery 2 Section, Institute of Abdominal Surgery, Key Laboratory of Accurate Diagnosis and Treatment of Cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350000, China
| | - Ruofan He
- Department of Gastrointestinal Surgery 2 Section, Institute of Abdominal Surgery, Key Laboratory of Accurate Diagnosis and Treatment of Cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350000, China
| | - Zuhong Teng
- Department of Gastrointestinal Surgery 2 Section, Institute of Abdominal Surgery, Key Laboratory of Accurate Diagnosis and Treatment of Cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350000, China
| | - Xinyi Zuo
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350000, China
| | - Yuxuan Li
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350000, China
| | - Jianxin Ye
- Department of Gastrointestinal Surgery 2 Section, Institute of Abdominal Surgery, Key Laboratory of Accurate Diagnosis and Treatment of Cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China; National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
| | - Guangwei Zhu
- Department of Gastrointestinal Surgery 2 Section, Institute of Abdominal Surgery, Key Laboratory of Accurate Diagnosis and Treatment of Cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China; National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
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Zhang X, Jia D, Wang Y, Wen F, Zhang X. Engineering glutathione-responsive near-infrared polymeric prodrug system for fluorescence imaging in tumor therapy. Colloids Surf B Biointerfaces 2021; 206:111966. [PMID: 34293577 DOI: 10.1016/j.colsurfb.2021.111966] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 06/30/2021] [Accepted: 07/01/2021] [Indexed: 01/14/2023]
Abstract
The release and biodistribution of drugs in the body have an important impact on tumor diagnosis and treatment. Near-infrared (NIR) fluorescent active fluorophores with good photostability are used to detect drug release and perform in vivo imaging. Here, we developed a glutathione-responsive NIR prodrug POEGMA-b-P(CPT-CyOH) (PCC) for effective cancer diagnosis and treatment, whereby the camptothecin (CPT) and NIR fluorophore CyOH in PCC are connected by disulfide bonds. In vitro experiments confirmed that PCC was quickly taken up by cells. The high concentration of tumor intracellular glutathione caused the cleavage of the PCC disulfide bonds, leading to the release of the chemotherapeutic drug CPT, indicating that PCC can promote apoptosis. Moreover, owing to the fluorescent properties of CyOH, PCC was successfully used for in vivo imaging to observe the drug penetration and enrichment capabilities in tumors. Finally, PCC successfully inhibited tumor growth, indicating that the prodrug has a good anti-tumor effect. This work provides new strategies for chemical drug delivery and precise cancer treatment.
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Affiliation(s)
- Xiaoli Zhang
- Pediatric Research Institute, Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, Guangdong 518038, PR China
| | - Die Jia
- School of Materials and Energy, Southwest University, Chongqing, 400715, PR China
| | - Yuxin Wang
- Pediatric Research Institute, Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, Guangdong 518038, PR China
| | - Feiqiu Wen
- Pediatric Research Institute, Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, Guangdong 518038, PR China.
| | - Xingliang Zhang
- Pediatric Research Institute, Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, Guangdong 518038, PR China.
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Bordonaro R, Calvo A, Auriemma A, Hollebecque A, Rubovszky G, Saunders MP, Pápai Z, Prager G, Stein A, André T, Argilés G, Cubillo A, Dahan L, Edeline J, Leger C, Cattan V, Fougeray R, Amellal N, Tabernero J. Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study. ESMO Open 2021; 6:100270. [PMID: 34547581 PMCID: PMC8453191 DOI: 10.1016/j.esmoop.2021.100270] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 08/13/2021] [Accepted: 08/20/2021] [Indexed: 02/07/2023] Open
Abstract
Background In preclinical studies trifluridine/tipiracil (FTD/TPI) plus oxaliplatin (Industriestrasse, Holzkirchen, Germany) sensitised microsatellite stable (MSS) metastatic colorectal cancer (mCRC) to anti-programmed cell death protein-1; the addition of oxaliplatin or bevacizumab (F Hoffmann- la ROCHE AG, Kaiseraugst, Switzerland) enhanced the antitumour effects of FTD/TPI. This study aimed to investigate the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab (Uxbridge business Park, Uxbridge, United Kingdom) in patients with mCRC who had progressed after at least one prior line of treatment. Patients and methods In 14-day cycles, patients received FTD/TPI 35 mg/m2 (twice daily, days 1-5) plus oxaliplatin 85 mg/m2 (day 1), and, on day 1, either bevacizumab 5 mg/kg (cohort A) or nivolumab 3 mg/kg (cohort B). Patients in Cohort B had confirmed MSS status. Results In total, 54 patients were enrolled: 37 in cohort A and 17 in cohort B. Recruitment in cohort B was stopped early due to the low response rate (RR) observed at interim analyses of efficacy. The most common adverse events (AEs) in cohort A were neutropenia/decreased neutrophils (75.7%), nausea (59.5%), vomiting (40.5%), diarrhoea (37.8%), peripheral sensory neuropathy (37.8%), fatigue (35.1%) and decreased appetite (35.1%). In cohort B, the most common AEs were neutropenia/decreased neutrophils (70.6%), diarrhoea (58.8%), nausea (47.1%), vomiting (47.1%), fatigue (47.1%), asthenia (41.2%), paraesthesia (41.2%), thrombocytopenia/decreased platelets (35.3%) and decreased appetite (35.3%). Confirmed objective RR was 17.1% in cohort A and 7.1% in cohort B; the corresponding values for median progression-free survival in the two cohorts were 6.3 and 6.0 months. Conclusion FTD/TPI plus oxaliplatin and bevacizumab or nivolumab had an acceptable safety profile and demonstrated antitumour activity in previously treated patients with mCRC.
This study evaluated the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab in mCRC patients. FTD/TPI plus oxaliplatin in combination with bevacizumab or nivolumab had an acceptable and manageable safety profile. Antitumour activity was observed following treatment with FTD/TPI plus oxaliplatin and bevacizumab. Despite a modest RR with the addition of nivolumab, survival data were promising in these poor-prognosis patients.
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Affiliation(s)
- R Bordonaro
- Azienda Ospedaliera ARNAS Garibaldi, Catania, Italy.
| | - A Calvo
- Gregorio Marañon University General Hospital, Madrid, Spain
| | - A Auriemma
- Azienda Ospedaliera Universitaria Integrat, University of Verona, Verona, Italy
| | - A Hollebecque
- Drug Development Department, Gustave Roussy Cancer Campus, Villejuif, France
| | - G Rubovszky
- Department of Medical Oncology and Clinical Pharmacology, National Institute of Oncology Hungary, Budapest, Hungary
| | | | - Z Pápai
- Department of Medical Oncology, Duna Medical Centre, Budapest, Hungary
| | - G Prager
- Comprehensive Cancer Centre Vienna, Medical University Vienna, Austria
| | - A Stein
- UKE Universitätsklinikum Hamburg-Eppendorf KMTZ, Hamburg, Germany
| | - T André
- Sorbonne Université et Hôpital Saint-Antoine, Service d'Oncologie Médicale, Paris, France
| | - G Argilés
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain
| | - A Cubillo
- Medical Oncology, Hospital Universitario Madrid Sanchinarro Centro Integral Oncologico Clara Campal, Madrid, Spain
| | - L Dahan
- Aix Marseille University; Assistance Publique Hôpitaux de Marseille, Centre d'Essais Précoces en Cancérologie de Marseille CLIP, Marseille, France
| | - J Edeline
- Department of Medical Oncology, Centre Eugene Marquis, ARPEGO network, Rennes, France
| | - C Leger
- Institut de Recherches Internationales Servier, Suresnes, France
| | - V Cattan
- Institut de Recherches Internationales Servier, Suresnes, France
| | - R Fougeray
- Institut de Recherches Internationales Servier, Suresnes, France
| | - N Amellal
- Institut de Recherches Internationales Servier, Suresnes, France
| | - J Tabernero
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain; UVic-UCC, IOB-Quiron, Barcelona, Spain
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Cecchini M, Kortmansky JS, Cui C, Wei W, Thumar JR, Uboha NV, Hafez N, Lacy J, Fischbach NA, Sabbath KD, Gomez CM, Sporn JR, Stein S, Hochster HS. A phase 1b expansion study of TAS-102 with oxaliplatin for refractory metastatic colorectal cancer. Cancer 2020; 127:1417-1424. [PMID: 33351187 DOI: 10.1002/cncr.33379] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/10/2020] [Accepted: 11/09/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND TAS-102, a novel antimetabolite, is approved for treatment of refractory metastatic colorectal cancer (CRC). This study sought to determine whether the addition of TAS-102 to oxaliplatin (TAS-OX) was safe and effective in metastatic CRC previously treated with oxaliplatin. METHODS This investigator-initiated, open-label, single-arm phase 1b study enrolled patients with metastatic CRC previously treated with 5-fluorouracil, irinotecan, and oxaliplatin. In dose escalation, TAS-102 was given at 3 dose levels: 25, 30, and 35 mg/m2 twice daily on day 1 to day 5 with 85 mg/m2 oxaliplatin on day 1 in 14-day cycles. The primary endpoint of dose escalation was the recommended dose for expansion, and in dose expansion, the primary endpoint was overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). RESULTS Forty-one patients were treated with TAS-OX. No dose-limiting toxicities were observed in the 11 patients treated in escalation. The recommended dose for expansion was 35 mg/m2 TAS-102 twice daily on day 1 to day 5 in combination with 85 mg/m2 oxaliplatin on day 1 in 14-day cycles. In the intention-to-treat population, the ORR was 2.4% (95% CI, 0%-12.9%) with 1 of 41 patients having a partial response, although 12 (29%) had tumor shrinkage. The median progression-free survival was 2.7 months (95% CI, 2.4-4.8 months) and median overall survival was 6.8 months (95% CI, 5.7-10 months). CONCLUSIONS TAS-OX is safe with no unexpected toxicities at standard doses of each agent. The combination did not result in a clinically meaningful ORR, although progression-free survival and overall survival were encouraging in this heavily pretreated population. LAY SUMMARY For metastatic colorectal cancer, the treatment combination of TAS-102 and oxaliplatin was found to be well-tolerated and revealed no unexpected side effects. Twelve of 41 patients had reductions in the size of their tumor, and the study treatment delayed the time to tumor growth as opposed to what would be expected.
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Affiliation(s)
- Michael Cecchini
- Department of Internal Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut
| | - Jeremy S Kortmansky
- Department of Internal Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut
| | - Can Cui
- Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut
| | - Wei Wei
- Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut
| | - Jaykumar Ranchobdhai Thumar
- Department of Internal Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut
| | - Nataliya V Uboha
- Hematology-Oncology Section, Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin
| | - Navid Hafez
- Department of Internal Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut
| | - Jill Lacy
- Department of Internal Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut
| | - Neal A Fischbach
- Department of Internal Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut
| | - Kert D Sabbath
- Department of Internal Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut
| | - Christina M Gomez
- Department of Internal Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut
| | - Jonathan Reed Sporn
- Department of Internal Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut
| | - Stacey Stein
- Department of Internal Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut
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Reddy TP, Khan U, Burns EA, Abdelrahim M. Chemotherapy rechallenge in metastatic colon cancer: A case report and literature review. World J Clin Oncol 2020; 11:959-967. [PMID: 33312889 PMCID: PMC7701909 DOI: 10.5306/wjco.v11.i11.959] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 10/01/2020] [Accepted: 10/19/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the third leading cause of cancer-related death in males and females in the United States. Approximately, 20%-22% of patients have metastatic disease at the time of presentation, and 50%-60% will develop metastasis over the course of their disease. Despite advances in systemic therapies, there remains a paucity of effective third- and later-line therapies for patients with ongoing disease progression. However, rechallenging chemo-resistant CRC tumors with previously administered therapies is an emerging concept that may be a life-prolonging option for heavily treated metastatic colorectal cancer (mCRC).
CASE SUMMARY A 41-year-old man with no previous medical history initially presented with worsening diffuse abdominal tenderness. Computed tomography was significant for a splenic flexure mass and hepatic lesions concerning for metastatic disease. He underwent a colectomy with anastomosis. Postoperative pathology was diagnostic for moderately to well-differentiated adenocarcinoma (T4bN1bM1a). He received adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX), but therapy was discontinued due to the development of atrial fibrillation. Additional workup indicated a carcinoembryonic antigen level of 508.2 ng/mL, and mutational analysis found that the tumor was microsatellite instability-high and KRAS/BRAF wild-type. He was started on irinotecan with oxaliplatin (IROX), and bevacizumab (14 cycles), developed disease progression, was transitioned to FOLFOX and cetuximab, and then eventually three cycles of pembrolizumab. Following disease progression, he was rechallenged with IROX therapy, as he previously responded well to oxaliplatin-based therapy. The IROX rechallenge provided this patient with a ten-month survival benefit, decreased metastatic burden, and marked improvement in his clinical condition.
CONCLUSION Rechallenge of previous lines of well-tolerated systemic chemotherapy regimens may be a valuable therapeutic strategy in patients with heavily-treated mCRC.
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Affiliation(s)
| | - Usman Khan
- Department of Medical Oncology, Houston Methodist Hospital Cancer Center, Houston, TX 77030, United States
| | - Ethan Alexander Burns
- Department of Medical Oncology, Houston Methodist Hospital Cancer Center, Houston, TX 77030, United States
| | - Maen Abdelrahim
- Department of Medical Oncology, Houston Methodist Hospital Cancer Center, Houston, TX 77030, United States
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center. Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute and Weill Cornell Medical College, Houston, TX 77030, United States
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Varghese AM, Cardin DB, Hersch J, Benson AB, Hochster HS, Makris L, Hamada K, Berlin JD, Saltz LB. Phase I Study of Trifluridine/Tipiracil Plus Irinotecan and Bevacizumab in Advanced Gastrointestinal Tumors. Clin Cancer Res 2020; 26:1555-1562. [PMID: 31924737 DOI: 10.1158/1078-0432.ccr-19-2743] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 11/22/2019] [Accepted: 01/07/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan in patients with advanced gastrointestinal tumors, and evaluated the safety, pharmacokinetics, and antitumor activity of the FTD/TPI, irinotecan, and bevacizumab triplet combination in previously treated metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Dose escalation (3+3 design) in advanced gastrointestinal tumors was followed by expansion in mCRC. During dose escalation, patients received FTD/TPI (20-35 mg/m2 twice daily; days 1-5 of a 14-day cycle) and irinotecan (120-180 mg/m2; day 1). During expansion, the MTD of FTD/TPI and irinotecan plus bevacizumab (5 mg/kg; day 1) was administered. RESULTS Fifty patients (26 across six dose-escalation cohorts and 24 in the expansion phase) were enrolled. Two dose-limiting toxicities (fatigue and neutropenia) were observed in the dose-escalation phase, and MTD was defined as FTD/TPI 25 mg/m2 twice daily plus irinotecan 180 mg/m2. In the expansion phase, 83% (20/24) experienced any-cause grade ≥3 adverse events (AEs) with the triplet combination, most frequently neutropenia (42%), leukopenia (25%), and diarrhea (12%). AEs of any-cause led to dosing interruptions, modifications, and discontinuations in 29%, 17%, and 4% of patients, respectively. No treatment-related deaths occurred. Three patients (12%) experienced partial responses and 16 (67%) patients had stable disease lasting >4 months. The median progression-free survival was 7.9 months (95% confidence interval, 5.1-13.4 months). CONCLUSIONS Tolerability and activity observed in this phase I trial support further investigation of the FTD/TPI-irinotecan-bevacizumab combination in previously treated mCRC.
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Affiliation(s)
| | - Dana B Cardin
- Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
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