Despite limited RCTs, neoadjuvant chemotherapy (NAC) shows promise for resectable pancreatic adenocarcinoma (rPAC). Few prospective results are available on completing the full therapeutic sequence and oncologic outcomes with NAC.

The PANACHE01-PRODIGE48 phase II trial randomly assigned 153 patients with rPAC (2:2:1) to four cycles of NAC (modified leucovorin, fluorouracil, irinotecan, and oxaliplatin [mFOLFIRINOX], arm 1; leucovorin, fluorouracil, and oxaliplatin [FOLFOX], arm 2) or up-front surgery (control) across 28 French centers (February 2017-July 2020). The primary objective was to evaluate the feasibility and efficacy of these NAC regimens. Two binary primary end points included 1-year overall survival (OS) postrandomization and the rate of patients completing the full therapeutic sequence. Event-free survival (EFS) assessed time to failure, defined as progression before surgery, unresectable/metastatic disease at surgery, recurrence, or death.

The primary objective was achieved for arm 1. In the intention-to-treat population, 70.8% (90% CI, 60.8 to 79.6) and 68% (90% CI, 55.5 to 78.8) completed the therapeutic sequence in arm 1 and arm 2, respectively. Within 12 months postrandomization, 84.3% (90% CI, 75.3 to 90.9) and 71.4% (90% CI, 59.0 to 81.8) of the patients were alive in arm 1 and arm 2, respectively. Treatment was safe and well-tolerated in both NAC arms. Arm 2 was stopped after interim analysis for lack of efficacy (H0 rejection for 1-year OS). One-year EFS rates were 51.4% (95% CI, 41.0 to 64.3), 43.1% (95% CI, 31.3 to 59.5), and 38.7% (95% CI, 24.1 to 62.0) in arm 1, arm 2, and control arm, respectively.

The feasibility and efficacy of mFOLFIRINOX in the perioperative setting are confirmed concerning therapeutic sequence completion and oncologic outcomes, supporting ongoing trials (PREOPANC3, Alliance AO21806). Further research is needed to identify patients who benefit from NAC (ClinicalTrials.gov identifier: NCT02959879; EudraCT: 2015-001851-65).

Basket trials test a single therapeutic treatment on several patient populations under one master protocol. A desirable adaptive design feature is the ability to incorporate new baskets to an ongoing trial. Limited basket sample sizes can result in reduced power and precision of treatment effect estimates, which could be amplified in added baskets due to the shorter recruitment time. While various Bayesian information borrowing techniques have been introduced to tackle the issue of small sample sizes, the impact of including new baskets into the borrowing model has yet to be investigated. We explore approaches for adding baskets to an ongoing trial under information borrowing. Basket trials have pre-defined efficacy criteria to determine whether the treatment is effective for patients in each basket. The efficacy criteria are often calibrated a-priori in order to control the basket-wise type I error rate to a nominal level. Traditionally, this is done under a null scenario in which the treatment is ineffective in all baskets, however, we show that calibrating under this scenario alone will not guarantee error control under alternative scenarios. We propose a novel calibration approach that is more robust to false decision making. Simulation studies are conducted to assess the performance of the approaches for adding a basket, which is monitored through type I error rate control and power. The results display a substantial improvement in power for a new basket, however, this comes with potential inflation of error rates. We show that this can be reduced under the proposed calibration procedure.

Inhibition of the programmed cell death protein 1-programmed death-ligand 1 (PD-1-PD-L1) axis results in a modest objective response rate (ORR) in recurrent/metastatic head and neck squamous cell carcinoma. This study aimed to evaluate whether the addition of metronomic chemotherapy and a single fraction of radiotherapy could synergistically operate with anti-PD-L1 treatment.

We conducted a phase I-II study evaluating avelumab (10 mg/kg intravenously every 2 weeks), low-dose cyclophosphamide (50 mg/day, fixed dose, without treatment breaks), and a single fraction of radiotherapy (8 Gy) to one lesion. The phase II portion of the study followed Simon's two-stage optimal design. A total of 6 patients were enrolled in phase I, and 20 patients were accrued and analyzed in phase II before determining progression to the second stage (51 patients). The primary endpoint was ORR. Further, a panel of circulating cytokines was analyzed to explore potential toxicity and/or efficacy markers.

Between January 2019 and June 2020, 20 patients were enrolled. In phase I, only one dose-limiting toxicity was observed among the six patients, allowing progression to phase II. At the end of stage I, five objective responses (2 complete responses and 3 partial responses) were recorded, failing to meet the threshold of six responses required to reject the null hypothesis. The median progression-free survival and overall survival were 3.0 and 9.2 months, respectively. Treatment was well tolerated. Low baseline levels of transforming growth factor-beta (TGF-β) and/or interleukin (IL)-4 were associated with a higher risk of immune-related adverse events (irAEs), whereas high baseline levels of IL-6 and vascular endothelial growth factor (VEGF) correlated with poor outcomes.

Our results did not achieve the ORR threshold required to reject the null hypothesis in this cohort of unselected patients with relapsed/metastatic head and neck cancer. IL-6 and VEGF were associated with overall survival, whereas TGF-β and IL-4 correlated with irAEs.

KO-947, a potent, intravenously administered, extracellular signal-regulated kinase (ERK) inhibitor, has demonstrated activity in preclinical models. This phase I trial of KO-947 evaluated maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with relapsed/refractory solid tumors.

This multicenter, open-label, dose-escalation study evaluated KO-947 0.45-11.3 mg/kg in three schedules. Schedules 1 (0.45-5.4 mg/kg, 1- to 2-hour infusion) and 2 (4.8-9.6 mg/kg, 4-hour infusion) were administered once weekly on a 28-day cycle. Schedule 3 (3.6-11.3 mg/kg, 4-hour infusion) was administered on days 1, 4, and 8 (and on days 11 and 15 for two patients) on a 21-day cycle. The primary objective was determination of MTD and/or recommended phase II dose. Safety analysis included adverse events of special interest (AESIs), namely ocular toxicities and infusion-related reactions (e.g. hypotension, corrected QT interval prolongation). Results from the dose-escalation portion of the phase I study are presented due to trial termination before preplanned cohort expansion cohorts.

All 61 enrolled patients (schedules 1/2, n = 34, schedule 3, n = 27) discontinued treatment, mostly owing to disease progression (88% and 67%). The MTD for schedule 1 was 3.6 mg/kg; the maximum administered doses for schedules 2 and 3 were 9.6 and 11.3 mg/kg, respectively. Treatment-related adverse events occurred in 88% of patients in schedules 1/2, and 92% in schedule 3; most common were blurred vision (schedules 1/2, 50.0%; schedule 3, 33.3%). AESIs occurred in 50% of patients in schedules 1/2, and 82% in schedule 3. In all schedules, the best overall response was stable disease.

Intravenous KO-947 had a generally tolerable safety profile with minimal gastrointestinal toxicity compared with oral administration of other ERK inhibitors.

Mirvetuximab soravtansine-gynx (MIRV) is a first-in-class, folate receptor alpha (FRα)-targeting antibody-drug conjugate with United States Food and Drug Administration approval for FRα-positive platinum-resistant ovarian cancer. PICCOLO is a phase II, global, open-label, single-arm trial of MIRV as third-line or greater (≥3L) treatment in patients with FRα-positive (≥75% of cells with ≥2+ staining intensity) recurrent platinum-sensitive ovarian cancer (PSOC).

Participants received MIRV (6 mg/kg adjusted ideal body weight every 3 weeks) until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. Primary endpoint was investigator-assessed objective response rate (ORR). Key secondary endpoint was investigator-assessed duration of response (DOR). Additional endpoints included investigator-assessed progression-free survival (PFS), overall survival (OS), and safety. Analyses of subgroups by disease characteristics (e.g. platinum-free interval) and treatment history [e.g. prior bevacizumab and poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitor (PARPi) treatment] were exploratory.

Seventy-nine participants were enrolled and efficacy assessable. The primary endpoint was met; ORR was 51.9% [95% confidence interval (CI) 40.4% to 63.3%]. Median DOR was 8.25 months (95% CI 5.55-10.78 months) and median PFS was 6.93 months (95% CI 5.85-9.59 months). OS was not mature at data cut-off. ORR was 45.8% (95% CI 32.7% to 59.2%) in participants with PD while on/within 30 days of prior PARPi (n = 59) and 60.0% (95% CI 14.7% to 94.7%) in those without PD with prior PARPi (n = 5). No new safety signals occurred; most common treatment-emergent adverse events (TEAEs) were gastrointestinal, neurosensory, and resolvable ocular events. TEAEs led to discontinuation in 13 participants (16%) and death in 2 participants (3%).

MIRV as ≥3L treatment in heavily pretreated recurrent FRα-positive PSOC demonstrated notable efficacy and tolerable safety, including among those with prior PD on or within 30 days of PARPi (NCT05041257).

It is well known a basket trial consisting of multiple cancer types has the potential of borrowing strength across the baskets defined by the cancer types, leading to an efficient design in terms of sample size and trial duration. The treatment effects in those baskets are often heterogeneous and categorized by the cancer types being sensitive or insensitive to the treatment. Hence, the assumption of exchangeability in many existing basket trials may be violated, and there is a need to design trials without this assumption. In this paper, we simplify the constrained hierarchical Bayesian model for latent subgroups (CHBM-LS) for two classifiers to deal with the potential heterogeneity of treatment effects due to the single classifier of the cancer type. Different baskets are aggregated into subgroups using a latent subgroup modeling approach. The treatment effects are similar and exchangeable to facilitate information borrowing within each latent subgroup. Applying the simplified CHBM-LS approach to the real basket trials where baskets defined by only cancer types shows better performance than other available approaches. Further simulation study also demonstrates this CHBM-LS approach outperforms other approaches with higher statistical power and better-controlled type I error rates under various scenarios.

MITO-RT3/RAD (NCT04593381) is a prospective multicenter phase 2 trial designed to assess the effectiveness and safety of stereotactic body radiation therapy (SBRT) in patients who received diagnoses of oligometastatic ovarian cancer. In this report, we provide the results of the trial in the setting of lymph node disease.

The primary endpoint was the complete response (CR) rate, secondary endpoints included local control (LC), progression-free survival (PFS), overall survival, treatment-free interval, and toxicity rates. The sample size was based on a previous study reporting an average 70.0% CR with SBRT. The study was powered to detect an improvement in the CR rate from 70.0% to 85.0%, with an α error of 0.05 (one-side) and a β error of 0.1.

The study met its primary endpoint of a statistically significant improvement in CR. One hundred thirty-five patients with 249 lesions were enrolled across 15 institutions from May 2019 to November 2023. CRs were observed in 194 lesions (77.9%), partial responses in 40 (16.1%), stable disease in 14 (5.6%), and progressive disease in 1 lesion (0.4%). The objective response rate was 94%, with an overall clinical benefit rate of 99.6%. CR lesions exhibited a significantly higher LC rate than partial or not responding lesions (12-month LC: 92.7% vs 63.1%, P < .001). The 12-month actuarial rates for PFS and for overall survival were 36.6% (CR, 38.3% vs not-CR, 18.8%; P, .022) and 97.2% (CR, 97.8% vs not-CR, 93.8%; P, .067), respectively. The 12-month actuarial rate for treatment-free interval was 52.7% (CR, 58.4% vs not-CR, 24.4%; P, .004). CR was substantially associated with higher PFS (P, .036) and treatment-free interval (P, .006) rates in the univariate analysis. Twenty-three patients (17.0%) experienced mild acute toxicity. Late toxicity was reported in 9 patients (6.7%), mostly grade 1.

This trial confirms the efficacy of ablative SBRT, with minimal toxicity observed. SBRT offered a high CR rate, promising long-term outcomes, and a significant systemic therapy-free survival period for complete responders.

MET exon14 skipping mutations (METex14) is an established actionable driver oncogene of non-small-cell lung cancer (NSCLC). While ensartinib is a known second-generation tyrosine kinase inhibitor with primary activity against ALK translocation, it is also classified as a type Ia MET inhibitor. We have previously shown anti-tumor activity against METex14 positive NSCLC both in vivo and in vitro. The EMBRACE trial aims to evaluate the clinical efficacy and safety of ensartinib for treatment of METex14 positive NSCLC.

This is a multicenter single arm phase II investigator-initiated study that enrolled METex14 positive lung cancer after failing first line chemotherapy and/or immunotherapy. Eligible patients received ensartinib 225 mg orally once daily in a continuous 28-day treatment cycle until disease progression, unacceptable side effect, or death. Primary endpoint was investigator-assessed objective response rate (ORR), and the secondary end point included disease control rate (DCR), progression-free survival (PFS), duration of response (DoR) and safety profiles. The study was registered with the Chinese Clinical Trial Registry (ChiCTR2100048767).

From July 2021 to February 2024, a total of 31 patients were enrolled and received ensartinib. Median follow-up time of the 30 evaluable patients was 9.2 months (95% Confidence Interval [CI], 6.3-not estimable). The ORR was 53.3% (16/30; 95% CI, 35.5-71.2) and DCR was 86.7% (26/30; 95% CI, 74.5-98.8). Median PFS was 6.0 months (95% CI, 3.0-8.8) and median DoR was 7.9 months (95% CI, 4.8-8.7). Adverse events (AEs) were reported in 24 patients (80%), with 7 (23.3%) of grade 3. The most common AEs were rash (14/30, 46.7%), followed by anemia (7/30, 23.3%), increased ALT (7/30, 23.3%), increased AST (7/30, 23.3%), and pruritus (6/30, 20%). No serious adverse events or treatment-related deaths occurred. Importantly, the exploratory ctDNA analysis indicates that clearance of circulating tumor DNA (ctDNA) at four weeks treatment was associated with more favorable treatment outcomes comparing with patients having positive ctDNA.

Ensartinib has a promising anti-tumor activity and manageable safety in previously treated patients with METex14 positive lung cancer.

This work was supported by the National Natural Science Foundation of China [82370028, 82422001] and the CSCO-MET Aberrant Solid Tumor Research Grant [Y-2022METAZMS-0066].

The optimal scheduling of PD-1 inhibitors with neoadjuvant chemotherapy in patients with early triple-negative breast cancer is unknown. We aimed to investigate the activity of two differing schedules of neoadjuvant nivolumab initiation with 12 weeks of carboplatin and paclitaxel for this patient population.

Neo-N is an investigator-initiated, non-comparative, open-label, randomised, phase 2 trial conducted at 12 hospitals in Australia, one in New Zealand, and one in Italy. Participants had to be aged 18 years or older; have an Eastern Cooperative Oncology Group performance status of 0-1, clinical stage I (cT1cN0) or II (cT1cN1, cT2cN0-1, or cT3cN0), oestrogen receptor expression of less than 1%, and progesterone receptor expression of less than 10%; had to be HER2 negative; and have previously untreated operable breast cancer with adequate organ function. Participants were stratified according to age and randomly assigned (1:1) centrally using a computer-generated sequence with a minimisation algorithm to either nivolumab 240 mg then 2 weeks later nivolumab 360 mg and carboplatin AUC5 every 3 weeks with concurrent paclitaxel 80 mg/m2 once per week for 12 weeks (lead-in group) or concurrent nivolumab 360 mg and carboplatin AUC5 every 3 weeks with once per week paclitaxel 80 mg/m2 for 12 weeks then 240 mg nivolumab 2 weeks later (concurrent group). Data were collected from registration until the 100-day safety follow-up visit, and survival follow-up continues. The primary endpoint was pathological complete response (ypT0/Tis ypN0) at the time of surgery, analysed in each group separately and in all patients who received at least one dose of all three study treatment (modified intention-to-treat population). The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12619001308189, and EudraCT, 2019-003465-18, and is ongoing.

Between July 6, 2020, and April 1, 2022, 124 participants were enrolled and 14 were ineligible. 110 participants were randomly assigned and 108 were included in the modified intention-to treat analysis (53 in the lead-in group and 55 in the concurrent group). Median follow-up was 12 months (IQR 7-18). All patients were female with a median age of 49 years (IQR 43-60). 18 (17%) patients had clinically node-positive disease; 37 (34%) had clinical stage I, 70 (65%) had stage II, and one (1%) had stage III disease. The pathological complete response rate was observed in 27 (51% [39-63]) of 53 patients in the nivolumab lead-in group and in 30 (55% [43-66]) of 55 in the concurrent group. Treatment-related grade 3-4 adverse events occurred in 70 (65%; 32 [60%] of 53 in the lead-in group and 38 [69%] of 55 in the concurrent group) of 108 patients, with the most common being decreased neutrophil count (25 [47%] of 53 in the lead-in group vs 28 [53%] of 55 in the concurrent group), anaemia (six [11%] vs ten [19%]), and increased alanine aminotransferase (three [6%] vs three [6%]). Serious adverse events were reported in 16 (30%) patients in the lead-in group and 26 (47%) in the concurrent group. Treatment-related serious adverse events occurred in seven (13%) patients in the lead-in group and 20 (36%) in the concurrent group. No treatment-related deaths occurred during the study.

While this study did not support the hypothesis that lead-in nivolumab before chemotherapy was associated with a pathological complete response advantage, high pathological complete response rates were reached supporting shorter duration, non-anthracycline regimens in patients with newly diagnosed triple-negative breast cancer. Future trials are warranted to compare this regimen with the current standards of care.

Breast Cancer Trials and Bristol Myers Squibb.

The Mann-Whitney-Wilcoxon test, often referred to as the Mann-Whitney U test or Wilcoxon rank-sum test, is a non-parametric statistical test used to compare two independent groups when the dependent variable is ordinal or continuous but not normally distributed. It's particularly useful for small sample sizes or when the assumptions of parametric tests, such as the t-test, are violated, including cases where the data is skewed. This study focuses on the Mann-Whitney-Wilcoxon test for ordinal data, which frequently arises in biomedical research when the proportional odds assumption does not hold. Currently, there are no optimal two-stage randomized clinical trial designs utilizing the Mann-Whitney-Wilcoxon test. To address this research gap, our study proposes optimal two-stage designs based on the Mann-Whitney-Wilcoxon test. We demonstrate the application of these designs through illustrative examples and evaluate their operating characteristics.

Research into novel therapies for rare, immune-mediated inflammatory diseases (IMIDs) faces significant challenges, including small patient populations, complex clinical trial design and difficulties in patient recruitment. Patients with Behçet's disease (BD), idiopathic inflammatory myopathies (IIM) and IgG4-related disease (IgG4-RD) typically undergo treatment involving prolonged administration of high-dose glucocorticoids and immunosuppressants. Both are associated with an increased risk of infection. Additionally, glucocorticoids carry long-term toxicity risks. Thus, there is an urgent need to develop more targeted and effective anti-inflammatory treatments. Given the activation of the type 1 interferon pathway in BD, IIM and IgG4-RD, inhibition of the Janus kinase (JAK) STAT pathway emerges as a promising therapeutic strategy. The Drug Rediscovery in IMIDs (DRIMID) consortium aims to conduct a prospective pilot basket trial to investigate the effects of filgotinib, a JAK1 preferential inhibitor approved for ulcerative colitis and rheumatoid arthritis, on disease activity, quality of life and safety in patients with refractory BD, IIM and IgG4-RD.

In this investigator-initiated, multicentre, open-label phase 2 study, up to 60 patients with rare IMIDs will be enrolled for a 26-week treatment period with filgotinib 200 mg once daily. The trial consists of two stages, each involving a consecutively treated cohort of up to 20 patients per disease. An interim analysis is conducted between these stages, where the trial will proceed only in diseases showing potential effectiveness. Baseline, 3-month and 6-month assessments will include data on quality of life, disease activity, corticosteroid toxicity and biomarkers. The coprimary endpoints are disease activity and quality of life across and within each disease.

The study received approval from the Medical Research Ethics Committee in Utrecht, Netherlands. A Data Safety Monitoring Board has been established to monitor the trial's safety and progress.

NCT06285539.

In preclinical experiments, cyclic fasting-mimicking diets (FMDs) showed broad anticancer effects in combination with chemotherapy. Among different tumor types, triple-negative breast cancer (TNBC) is exquisitely sensitive to FMD. However, the antitumor activity and efficacy of cyclic FMD in TNBC patients remain unclear. Here, we show that a severely calorie-restricted, triweekly, 5-day FMD regimen results in excellent pathologic complete response (pCR) rates (primary endpoint) and long-term clinical outcomes (secondary endpoints) when combined with preoperative chemotherapy in 30 patients with early-stage TNBC enrolled in the phase 2 trial BREAKFAST. Bulk and single-cell RNA sequencing analysis revealed that highly glycolytic cancer cells, myeloid cells, and pericytes from tumors achieving pCR undergo a significant, early downmodulation of pathways related to glycolysis and pyruvate metabolism. Our findings pave the wave for conducting larger clinical trials to investigate the efficacy of cyclic FMD in early-stage TNBC patients and to validate early changes of intratumor glycolysis as a predictor of clinical benefit from nutrient restriction. This study was registered at Clinicaltrials.gov (NCT04248998).

Immune cells within the lymphoma tumor microenvironment promote immune evasion and are rational therapeutic targets. Alemtuzumab targets CD52 expressed on malignant B-cells and infiltrating nonmalignant T-cells. We evaluated the safety and efficacy of alemtuzumab with DA-EPOCH-R in 48 patients with relapsed/refractory aggressive B-cell lymphoma. Febrile neutropenia occurred in 18% of cycles and serious infections in 21% of patients. Responses were observed in 30 (62%) patients, including 12 (80%) patients with classical HL and 3 (75%) patients with T-cell/histiocyte-rich large B-cell lymphoma (THRLCL). Seventeen (35%) patients achieved complete responses, and 12 (25%) were bridged to consolidation. The 2-year progression-free survival (PFS) and overall survival were 22.1% (95% CI, 11.5-34.7%) and 45.2% (95% CI, 34.3-58.9%), respectively. The 2-year PFS for HL and THRLCL patients was 35% and 50%, respectively. Alemtuzumab can be safely combined with DA-EPOCH-R in relapsed/refractory aggressive B-cell lymphomas and can induce durable responses in patients with T-cell-rich microenvironments.

Background: Oral disorders (ODs) in palliative care (PC) are highly prevalent and significantly impact patients' quality of life (QoL). Nevertheless, evidence-based management recommendations are lacking. Several natural products are safe, well-accepted, and effective for mucosal conditions. Objective: The study aimed to evaluate the efficacy of a propolis-based product combined with basic oral hygiene in preventing and treating ODs. Design: A prospective, open-label, single-center phase II study was performed. Adult patients in PC with cancer or noncancer diagnoses, who were conscious, able to swallow, with a life expectancy of more than one week, were recruited. Results: ODs' improvement or maintenance of oral health was observed in 89.6% of cases. Severity of ODs significantly decreased (p < 0.001), along with reductions in oropharyngeal pain (p = 0.002) and dysgeusia (p < 0.001). Meal comfort, completion, and QoL improved; acceptability was excellent. Conclusions: The protocol was safe, well-accepted, and effective for ODs in adult patients in PC. Study registration: The study protocol was prospectively registered at ClinicalTrials.gov: NCT04911335.

Molecular alterations in the PI3K/AKT and Ras/Raf/MEK/ERK pathways are frequently observed in patients with endometrial cancers. However, mTOR inhibitors, such as temsirolimus, have modest clinical benefits. In addition to inducing metabolic changes in cells, metformin activates AMPK, which in turn inhibits the mTOR pathway. In this phase 1 clinical trial we hypothesized that combining metformin with temsirolimus would potentiate the antitumor activity against advanced or recurrent endometrial cancer.

The dose-expansion cohort used a Simon Minimax two-stage design. The objectives of the endometrial cancer expansion cohort were to evaluate the clinical tumor response, as indicated by the objective response and clinical benefit rates, as well as an ongoing safety assessment of the combination treatment.

Forty patients were enrolled in this study. The most common treatment-related adverse events (reported in 32 patients) were hypertriglyceridemia (n = 14), diarrhea (n = 13), mucositis (n = 13), anorexia (n = 12), and anemia (n = 10). The grade 3 adverse events were 2 instances each of anemia and thrombocytopenia and 1 instance each of mucositis, fatigue, weight loss, hypokalemia, hypophosphatemia, and increased aspartate aminotransferase and alanine transaminase levels. Among the 33 patients evaluable for response, objective response was seen in two (6 %; both partial responses), and 13 (39 %) patients had stable disease, including 11 for ≥4 months, representing a clinical benefit rate of 39 %.

The results of this single-center clinical trial showed that, in patients with advanced or recurrent endometrial cancer, metformin can be safely added to temsirolimus providing limited response without added safety concerns.

NCT01529593.

/aims. Pseudoxanthoma Elasticum (PXE, OMIM 264800) is an autosomal, recessive, metabolic disorder characterized by progressive ectopic calcification in the skin, the vasculature and Bruch's membrane. Variants in the ABCC6 gene are associated with low plasma pyrophosphate (PPi) concentration. There is currently no reference treatment for this chronic debilitating disease.

PROPHECI (PyROphosPHate supplementation to fight ECtopIc calcification in PseudoXanthoma Elasticum) is the first phase II, randomized, double-blind, placebo-controlled clinical trial (NTC 04868578) to evaluate the efficacy and safety of a daily oral PPi salt supplementation to attenuate and/or stabilize the progression of ectopic calcification in PXE patients. The primary endpoint is the change in arterial calcification volume quantified by non-contrast CT scan between baseline and 12 months of treatment. Secondary endpoints include the safety and efficacy of daily oral PPi administration on ocular and skin lesions and the evaluation of patients' quality of life.

The PROPHECI trial aims to provide safety and efficacy data on the use of daily oral PPi to reduce or stabilize ectopic calcification in PXE. It also aims to validate the best markers to include in the design of future trials for the treatment of PXE and other parent diseases.

Trial registration number: NCT04868578. References can be found on the ClinicalTrials.gov website: https://clinicaltrials.gov/study/NCT04868578?cond=Pseudoxanthoma%20Elasticum&intr=pyrophosphate&rank=2.

Immune checkpoint inhibition (ICI) has fundamentally changed cancer treatment. However, only a minority of patients with metastatic triple negative breast cancer (TNBC) benefit from ICI, and the determinants of response remain largely unknown. To better understand the factors influencing patient outcome, we assembled a longitudinal cohort with tissue from multiple timepoints, including primary tumor, pre-treatment metastatic tumor, and on-treatment metastatic tumor from 117 patients treated with ICI (nivolumab) in the phase II TONIC trial. We used highly multiplexed imaging to quantify the subcellular localization of 37 proteins in each tumor. To extract meaningful information from the imaging data, we developed SpaceCat, a computational pipeline that quantifies features from imaging data such as cell density, cell diversity, spatial structure, and functional marker expression. We applied SpaceCat to 678 images from 294 tumors, generating more than 800 distinct features per tumor. Spatial features were more predictive of patient outcome, including features like the degree of mixing between cancer and immune cells, the diversity of the neighboring immune cells surrounding cancer cells, and the degree of T cell infiltration at the tumor border. Non-spatial features, including the ratio between T cell subsets and cancer cells and PD-L1 levels on myeloid cells, were also associated with patient outcome. Surprisingly, we did not identify robust predictors of response in the primary tumors. In contrast, the metastatic tumors had numerous features which predicted response. Some of these features, such as the cellular diversity at the tumor border, were shared across timepoints, but many of the features, such as T cell infiltration at the tumor border, were predictive of response at only a single timepoint. We trained multivariate models on all of the features in the dataset, finding that we could accurately predict patient outcome from the pre-treatment metastatic tumors, with improved performance using the on-treatment tumors. We validated our findings in matched bulk RNA-seq data, finding the most informative features from the on-treatment samples. Our study highlights the importance of profiling sequential tumor biopsies to understand the evolution of the tumor microenvironment, elucidating the temporal and spatial dynamics underlying patient responses and underscoring the need for further research on the prognostic role of metastatic tissue and its utility in stratifying patients for ICI.

Polyclonal autologous T cells that are epigenetically reprogrammed through mTOR inhibition and IFN-α polarization (RAPA-201) represent a novel approach to the adoptive T cell therapy of cancer. Ex vivo inhibition of mTOR results causes a shift towards T central memory (TCM) whereas ex vivo IFN-α promotes type I cytokines, with each of these functions known to enhance the adoptive T cell therapy of cancer. Rapamycin-resistant T cells polarized for a type II cytokine phenotype were previously evaluated in the allogeneic transplantation context.

The clinical trial (NCT04176380) evaluated RAPA-201 therapy in combination with fludarabine-sparing low-dose host conditioning for the treatment of patients with relapsed, refractory multiple myeloma (RRMM).

From December 2020 to December 2022, 14 patients with RRMM received a median of three RAPA-201 infusions (median dose, 80×106 cells). RAPA-201 drug products (DPs) were: polyclonal; enriched for TCM cells; reduced for immune checkpoint expression, including PD1, CD73, and LAIR1; and preferentially secreted Th1 cytokines. The median chemotherapy dose administered per cycle was 1,817 mg total for cyclophosphamide (range, 1,100-2,200) and 2.35 mg/M2 for pentostatin (range, 0-16). Nine of 14 patients (64%) achieved disease remission, with eight partial responses and one stringent complete response. Median progression-free survival was 6.0 months (range, 2.1 to>16.8 months). There were no toxicities of any grade attributable to RAPA-201, including no cytokine release syndrome and no immune effector cell-associated neurotoxicity syndrome. Only 4 of 14 patients (29%) had a serious adverse event (≥ grade 3) of any attribution.

Consistent with our hypothesis, ex vivo manufacturing using mTOR inhibition and IFN-α polarization consistently yielded a novel RAPA-201 DP that possessed a desirable phenotype relative to cytokine phenotype, memory status, and checkpoint expression. RAPA-201 recipients had preservation of T cell counts and Th1 cytokine secretion yet had increased T cell receptor clonality that associates with antitumor responses in the setting of monoclonal antibody checkpoint therapy. RAPA-201 therapy overcomes previous barriers to effective autologous polyclonal T-cell therapy, as it is feasible to manufacture, exquisitely safe to administer, and mediates remission in patients with RRMM.

ClinicalTrials.gov: NCT04176380.

Amivantamab, an EGFR-MET bispecific antibody, is approved for multiple indications in EGFR-mutated advanced NSCLC as monotherapy or combined with other agents. Intravenous amivantamab is associated with a 67% infusion-related reaction (IRR) rate.

The phase 2 SKIPPirr study (NCT05663866) enrolled participants with EGFR-mutated (exon 19 deletion or exon 21 L858R) advanced NSCLC after progression on osimertinib and platinum-based chemotherapy who received intravenous amivantamab plus oral lazertinib (amivantamab-lazertinib), a third-generation tyrosine kinase inhibitor. Aiming to mitigate IRRs, four independent prophylactic approaches were evaluated using Simon's two-stage design with an expansion stage if a cohort passed both stages: oral dexamethasone 4 mg twice daily given on cycle (C) 1 day (D) -1 (two doses); oral dexamethasone 8 mg twice daily given on C1D-2, C1D-1, and the morning of C1D1 (five doses); oral montelukast 10 mg once daily given on C1D-4, C1D-3, C1D-2, C1D-1, and C1D1 (five doses); subcutaneous methotrexate 25 mg (one dose) given anytime between C1D-7 and C1D-3. The primary end point was C1D1 IRR incidence.

As of June 24, 2024, 68 participants were treated across all cohorts. The dexamethasone 8 mg cohort passed stages 1 and 2 proceeding to the expansion stage, with 24 additional participants treated. At C1D1, nine of 40 participants (22.5%) experienced IRRs, resulting in an approximately threefold decrease versus historical data (67.4%). By the end of C3, 10 of 41 participants (24.4%) in the dexamethasone 8 mg cohort experienced IRRs (grades 1-2, except one grade 3 on C2D1). Amivantamab-lazertinib's safety and efficacy were consistent with previous reports.

Prophylaxis with 8 mg oral dexamethasone meaningfully reduced IRRs and can be readily implemented in clinical practice.

Disease-modifying treatments (DMTs) are a major unmet need in Parkinson disease (PD). To date, trials investigating DMT candidates in PD most often used a randomized controlled trial (RCT) design. Unfortunately, RCTs to date have not led to a breakthrough, in part because of the large sample sizes and length of follow-up required. In the interest of testing DMT candidates in a more efficient manner, it may be worthwhile to perform futility trials, which are smaller clinical trials that have originally been developed as phase 2 trials in oncology and more recently been used in progressive multiple sclerosis. In this investigation, we used original, patient-level data from DATATOP and PRECEPT, 2 large RCTs in early PD, to explore the feasibility of using the Simon 2-Stage futility trial design in early PD.

This is a post hoc analysis of original, patient-level data from the DATATOP and PRECEPT RCTs in early PD. In our analyses, we use descriptive statistics, survival analysis, and binary logistic regression to explore thresholds of change in the Unified Parkinson Disease Rating Scale (UPDRS) motor score as the primary outcome measure, length of follow-up, inclusion and exclusion criteria, and projected sample sizes for Simon 2-Stage futility trials in early PD. We also performed bootstrapping experiments to illustrate the ability of trials using the Simon 2-Stage futility design to identify selegiline as nonfutile and tocopherol as futile.

PRECEPT included 806 participants (mean age 59.7 years, SD 10.3, 64.4% male), and DATATOP included 800 participants (mean age 61.1 years, SD 9.5, 64.4% male). Our analyses suggest that futility trials using the Simon 2-Stage methodology are feasible in PD. We propose a 5-point worsening on the UPDRS motor score as the primary outcome measure and a length of follow-up of 12 months. Trial simulations based on these data suggest the required sample size for such clinical trials to be lower than 200 participants.

Based on our analysis of DATATOP and PRECEPT, phase 2 clinical trials using the Simon 2-Stage methodology are feasible in PD and may offer an opportunity to expedite the discovery of promising treatments in early PD.

PD-L1 is overexpressed by dendritic cells in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing on androgen receptor pathway inhibitors. We tested whether checkpoint blockade could enhance antitumor activity in mCRPC.

In a multicenter open-label noncomparative randomized phase II study, patients with mCRPC treated with ≤1 prior cytotoxic chemotherapy, with measurable disease and progression on abiraterone and/or enzalutamide, were randomized to durvalumab 1,500 mg intravenously every 4 weeks ±4 doses of tremelimumab 75 mg intravenously. The primary endpoint was objective response (OR) by iRECIST using a Simon two-stage design. Correlative testing included PD-L1/cluster designation 8 IHC on baseline tumor biopsies and deep targeted sequencing of plasma cell-free DNA.

Fifty-two patients were enrolled. Median age was 70 years (range, 50-83 years), and 52% had prior taxane therapy for mCRPC. In stage I, 13 patients were randomized to durvalumab with no OR observed. Durvalumab + tremelimumab advanced to stage II with 39 patients enrolled (receiving a median three cycles, range 1-53). Durvalumab + tremelimumab-related adverse events were mainly ≤ grade 2 but led to discontinuation in seven patients. There were seven ORs [19.4% (95% confidence interval: 8.2%-36.0%); intention to treat 17.9% (95% confidence interval: 7.5%-33.5%)]. Five responding tumors were PD-L1-positive and two exhibited DNA damage repair defects. Responses were observed without high tumor mutational burden or other genomic indices of immunotherapy sensitivity.

Durvalumab + tremelimumab is active in mCRPC, but patient selection remains a challenge. Further studies to develop predictive biomarkers are warranted.

The goal of phase II clinical trials is to evaluate the therapeutic efficacy of a new drug. Some investigators want to use the time-to-event endpoint as the primary endpoint of the phase II study to see the improvement of the therapeutic efficacy of a new drug in median survival time. Recently, median event time test (METT) has been proposed to provide a simple and straightforward rule which compares the observed median survival time with the prespecified threshold. However, median survival time would not be observed during the trial if the drug performs well and indeed cures most patients or if the accrual rate is so fast. To address the issues in clinical practice, we first propose a percentile event time test (PETT), which generalizes METT to any percentile of the survival time, and develop data-driven monitoring for phase II clinical trial designs based on PETT. We evaluate the performance of the method through simulations and illustrate the proposed method with a trial example.

Making the go/no-go decision is critical in Phase II (or Ib) clinical trials. The conventional decision-making framework based on a binary hypothesis testing has been gradually replaced by the TODeM (Triple Outcome Decision-Making) which has three zones of outcomes: go, no-go, and consider. The TODeM provides more flexibility in decision-making with considering both of statistical significance and clinical relevance. However, Bayesian methods (e.g. EXNEX, MUCE, etc.) for the information borrowing are still based on the binary decision-making framework. We propose a new decision-making process G-TODeM (Generalized Triple Outcome Decision-Making) to apply those Bayesian methods with information borrowing across different cohorts to the TODeM framework. Essentially, the information borrowed from other cohorts can shrink the consider zone of the inference cohort.

Diffuse midline glioma (DMG) continues to be an aggressive brain stem cancer among children and young adults. It has a dismal prognosis, with less than 10% of patients alive two years after diagnosis. Radiotherapy has been demonstrated to be effective, albeit transient. Hence, radiotherapy is considered a cornerstone in the treatment. Reirradiation has, in retrospective studies, shown promising overall survival and palliative effect, but no pan-European consensus for reirradiation exists. The REMIT (Reirradiation of diffuse Midline glioma paTients) protocol evaluates safety and the palliative efficacy of reirradiation of patients with DMG (clinicaltrials.gov NCT06093165). Patients included in the protocol will be followed with 1) performance status (Karnofsky or Lansky), 2) toxicity monitored with Common Terminology Criteria for Adverse Events (CTCAE), 3) motor and functioning skill with PEDI-CAT (The Pediatric Evaluation of Disability Inventory) and 4) quantification of corticosteroid use. Furthermore, the impact on quality of life and well-being will be assessed qualitatively with interviews as well as with the Pediatric Quality of Life Inventory (PedsQl) Cancer Module questionnaire. The protocol also includes dose accumulation and contouring studies to assess standardization as well as a prescreening log to address selection bias of patients. The safety and palliative efficacy of reirradiation in DMG will be prospectively evaluated, including qualitative patient reported outcomes, through the REMIT protocol. REMIT is planned to open for inclusion in 2024.

Oncoplastic breast-conserving surgery (OBCS) improves satisfaction in patients who would fare otherwise sub-optimal cosmetic outcomes while bringing challenges in tumor-bed identification during adjuvant radiotherapy. The ultra-hypofractionated breast radiotherapy further shortens treatment sessions from moderately hypofractionated regimens. To circumscribe the difficulty in tumor-bed contouring and the additional toxicity from larger boost volumes, the authors, propose to move forward with the boost session preoperatively from the adjuvant radiation part. Thus, the present study aims to evaluate the feasibility of a new treatment paradigm of preoperative primary-tumor boost before breast-conserving surgery (BCS) or OBCS followed by adjuvant ultra-hypofractionated whole-breast irradiation (u-WBRT) for patients with early-stage breast cancer.

There was a phase II study. Patients younger than 55 years old, with a biopsy confirmed mono-centric breast cancer, without lymph node involvement were enrolled. A preoperative primary-tumor boost was given by a single 10 Gy in 1 fraction, and BCS or OBCS was conducted within 2 weeks afterwards. Adjuvant u-WBRT (26 Gy/5.2 Gy/5 f) was given in 6 weeks postoperatively without any boost, after the full recovery from surgery. Surgical complications and patient-reported outcomes, as assessed via Breast-Q questionnaires, were documented. A propensity score matching approach was employed to identify a control group at a 1:1 ratio for BREAST-Q outcomes comparison.

From May 2022 to September 2023, 36 patients were prospectively enrolled. Surgical complications were observed in seven cases (19.4%), including three cases with Clavien-Dindo (CD) grade 1-2 and four cases with CD grade 3 complications. All but four patients (11.1%) started the planned u-WBRT within 1 week after the predefined due dates postoperatively (≤49 days). Four patients (11.1%) developed grade 2 radiodermatitis after chemotherapy initiation. Compared to the study group, the control patients reported higher scores in chest physical well-being ( P =0.045) and in their attitudes towards arm swelling ( P =0.01). No significant difference was detected in the other of domains (Satisfaction with Breasts, Sexual and Psychosocial Well-Being, and Adverse Effects of Radiation). With a median follow-up period of 9.8 months (2.4-18.9 months), none had any sign of relapse.

This Phase II clinical trial confirmed the technical and safety feasibility of a novel radiation schedule in patients undergoing BCS or OBCS. According to the BREAST-Q questionnaire, patients who underwent novel radiation schedules reported lower satisfaction in chest physical well-being. A randomized controlled trial is necessary to further investigate these findings. Additionally, long-term follow-up is required to assess oncological outcomes.

Preliminary data suggest promising activity of loncastuximab tesirine in follicular lymphoma, and synergistic activity between rituximab-induced cytotoxicity and loncastuximab tesirine. In this study, we evaluated loncastuximab tesirine combined with rituximab for second-line and later treatment of follicular lymphoma.

We did a single-arm, investigator-initiated, phase 2 trial at Sylvester Comprehensive Cancer Center in Miami, FL, USA. We recruited patients aged 18 years or older with histologically confirmed relapsed or refractory follicular lymphoma (grade 1-3A) treated with one or more lines of therapy and presenting with progression or relapse of disease within 24 months (POD24) after the first line of treatment, one or more Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria, or second relapse, and with an Eastern Cooperative Oncology Group performance status of 0-2. Intravenous loncastuximab tesirine was administered on day 1 of a 21-day cycle, at 0·15 mg/kg for two cycles, then 0·075 mg/kg thereafter. Intravenous rituximab was administered on day 1 of cycle 1, at 375 mg/m2 for four once-weekly doses, followed by one dose every 8 weeks on cycles 5, 6, and 7. At week 21, patients with a complete response discontinued loncastuximab tesirine and received two more doses of rituximab once every 8 weeks. Patients with a partial response at week 21 continued both agents for 18 more weeks. The primary endpoint was complete response rate at week 12 assessed by the Lugano 2014 classification in patients who had received at least three doses of loncastuximab tesirine. The safety analysis included all patients who received one or more doses of loncastuximab tesirine. The trial is registered with ClinicalTrials.gov, NCT04998669, and is ongoing (open to recruitment); the data cutoff for this analysis was Sept 13, 2024.

Between Jan 28, 2022, and June 3, 2024, we enrolled 39 patients (median age 68 years [IQR 58-77]; 21 [54%] male patients and 18 [46%] female patients). All patients presented with one or more GELF criteria (n=36 [92%]) or POD24 after the first line of treatment (n=20 [51%]) at baseline. As of Sept 13, 2024, the median follow-up was 18·2 months (95% CI 12·0-19·3). Week 12 complete response rate was 67% (n=26 of 39). The most common grade 3 or worse treatment-emergent adverse events (TEAEs) were lymphopenia (eight [21%] of 39 patients) and neutropenia (five [13%] patients; one of whom had a serious grade 3 TEAE of febrile neutropenia that was considered to be related to study treatment). Generalised and peripheral oedema was predominantly grade 1-2 and all cases of oedema were treatable with diuretics. Serious TEAEs that were considered to be related to study drugs occurred in four (10%) of 39 patients. No fatal TEAEs occurred.

Loncastuximab tesirine with rituximab showed clinically meaningful activity in relapsed or refractory follicular lymphoma, and had a manageable safety profile.

ADC Therapeutics and Sylvester Comprehensive Cancer Center.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) remains a significant hurdle for patients with EGFR-mutated non-small cell lung cancer (NSCLC), particularly those lacking the EGFRT790M. IMpower 150 study demonstrated promising efficacy for a combination of immune-chemotherapy and bevacizumab in patients with EGFR-mutated NSCLC.

This open-label, single-arm, phase II trial evaluated the efficacy and immune cell profile of the modified regimen combining atezolizumab, bevacizumab (7.5 mg/kg) and chemotherapy in patients with EGFR-mutated NSCLC following TKI failure. The primary endpoint was objective response rate (ORR). The re-biopsy tissue specimens and serial peripheral blood samples were collected to analyse the immune cell profile and tumour microenvironments.

22 EGFR-mutant NSCLC patients participated in this study. The ORR was 42.9%, with a disease control rate (DCR) of 100%. Median progression-free survival (PFS) was 6.3 months. Patients with programmed death-ligand 1 (PD-L1) expression ≥1% exhibited significantly higher ORR (75 vs. 23.1%; p = .032) and longer PFS (14.0 vs. 6.1 months; p = .022) compared with those with PD-L1 expression < 1%. Grade ≥ 3 adverse events occurred in 40.9% of patients. Higher peritumour nature killer (NK) cell infiltration and lower peripheral helper T cell counts before treatment were associated with favourable ORR and longer PFS, respectively. After disease progression, the proportion of S100A9+ myelod-derived suppressor cells (MDSCs) increased, while regulatory T cells decreased.

This modified combination regimen may be a promising therapeutic option for EGFR-mutant NSCLC patients with TKI resistance, especially those with PD-L1-positive tumours. Furthermore, immune cell profiling may aid in identifying patients who may benefit from this approach.

The combination regimen yielded promising efficacy in NSCLC patients after EGFR-TKI resistance, particularly those with PD-L1-positive tumours. Higher peritumour NK cell and lower peripheral helper T cell were associated with favourable ORR and longer PFS, respectively. After disease progression, the proportion of S100A9+ MDSC increased, but Treg cells decreased.

In oncology, Phase II studies are crucial for clinical development plans as such studies identify potent agents with sufficient activity to continue development in the subsequent Phase III trials. Traditionally, Phase II studies are single-arm studies, with the primary endpoint being short-term treatment efficacy. However, drug safety is also an important consideration. In the context of such multiple-outcome designs, predictive probability-based Bayesian monitoring strategies have been developed to assess whether a clinical trial will provide enough evidence to continue with a Phase III study at the scheduled end of the trial. Therefore, we propose a new simple index vector to summarize the results that cannot be captured by existing strategies. Specifically, we define the worst and most promising situations for the potential effect of a treatment, then use the proposed index vector to measure the deviation between the two situations. Finally, simulation studies are performed to evaluate the operating characteristics of the design. The obtained results demonstrate that the proposed method makes appropriate interim go/no-go decisions.

We present a single-arm, phase II, neoadjuvant trial with the oncolytic virus talimogene laherparepvec (T-VEC) in 18 patients with difficult-to-resect cutaneous basal cell carcinomas. The primary end point, defined as the proportion of patients, who after six cycles of T-VEC (13 weeks), become resectable without the need for plastic reconstructive surgery, was already achieved after stage I (9 of 18 patients; 50.0%); thus the study was discontinued for early success. The objective response rate was 55.6% and the complete pathological response rate was 33.3%. Secondary end points included safety, relapse-free survival and overall survival, time to occurrence of new basal cell carcinomas and biological read outs. Only mild adverse events occurred. The 6-month relapse-free survival and overall survival rates were 100%. In two patients a new basal cell carcinoma was diagnosed. T-VEC led to a significant increase in cytotoxic T cells (P = 0.0092), B cells (P = 0.0004) and myeloid cells (P = 0.0042) and a decrease in regulatory T cells (P = 0.0290) within the tumor microenvironment. Together, neoadjuvant T-VEC represents a viable treatment option for patients with difficult-to-resect basal cell carcinomas (EudraCT no. 2018-002165-19).

Gastric cancer, as the fifth most diagnosed malignancy and the fourth leading cause of cancer-related death globally, remains a significant health concern. The potential effect of the programmed death-1 (PD-1) inhibitor, when used alongside chemotherapy and antiangiogenic agents in neoadjuvant therapy for gastric cancer, has yet to be explored in the published literature. This study aims to evaluate the efficacy and safety of the S-1 plus oxaliplatin (SOX) regimen when combined with apatinib and camrelizumab (SOXAC) as neoadjuvant therapy for patients with locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. A single-arm, open-label, single-center phase II clinical trial has been designed to evaluate the safety and efficacy of the SOXAC regimen as neoadjuvant therapy for patients diagnosed with locally advanced gastric or GEJ adenocarcinoma (cT2-3N + M0 or T4NxM0). Eligible patients are to receive 2 cycles of SOXAC and 1 cycle of SOX regimen with camrelizumab (SOXC) as neoadjuvant therapy prior to radical surgery, and 3 cycles of SOXC as postoperative adjuvant therapy. The primary endpoint is major pathological remission (MPR), while secondary endpoints include pathological complete response (pCR) rate, R0 resection rate, objective response rate (ORR), operation-related outcomes, and safety. The SOX regimen remains a leading choice for neoadjuvant chemotherapy in Eastern countries. Recent studies suggest that combining chemotherapy, targeted agents, and immune checkpoint inhibitors can enhance the antitumor immune response. This phase II clinical trial seeks to assess the safety and efficacy of the SOXAC regimen as neoadjuvant therapy for patients with locally advanced resectable gastric or GEJ adenocarcinoma, while also exploring the correlation between biomarkers and efficacy.Trial Registration Chinese Clinical Trial Registry (ChiCTR): ChiCTR2200062285 ( https://www.chictr.org.cn/ ).