Explore the vast range of titles available.

In a randomized trial of perioperative nivolumab as compared with chemotherapy, 18-month event-free survival was 70% in the nivolumab group and 50% in the chemotherapy group at 2-year median follow-up.

Parsaclisib, a potent, selective, next‐generation PI3Kδ inhibitor, has shown clinical benefit in patients with relapsed or refractory B‐cell lymphoma. We undertook a phase Ib study (CITADEL‐111) evaluating safety, pharmacokinetics, and efficacy of parsaclisib in Japanese patients with relapsed or refractory B‐cell malignancies. Patients received oral parsaclisib daily for 8 weeks then once weekly (10‐mg dose, n = 3; 20‐mg dose, n = 14). Pharmacokinetic samples were collected on days 1, 8, and 15, and efficacy was monitored according to Lugano criteria. At data cut‐off (August 14, 2020), 6 patients (35.3%) remained on study treatment and 11 (64.7%) discontinued due to progressive disease (9 [52.9%]) or adverse events (2 [11.8%]). Median duration of treatment was 8.3 (range, 0.3–24.4) months. The most commonly reported nonhematologic adverse events were constipation (6 [35.3%]), nausea, and pyrexia (each 4 [23.5%]). Five patients (29.4%) experienced treatment‐emergent new or worsening decreased neutrophils to grade 3 or 4. No treatment‐emergent worsening in aminotransferase elevations to grade 3 or 4 were observed. Ten patients (58.8%) required dose interruption and 5 (29.4%) dose reduction. Body weight–normalized parsaclisib exposure was comparable between Japanese and Western patients. Objective response rate was 100% in follicular lymphoma (9 of 9 patients, including complete response in 2 patients [22.2%]) and marginal zone lymphoma (2 of 2 patients), and 16.7% in diffuse large B‐cell lymphoma (1 of 6 patients). Results observed in Japanese patients with relapsed or refractory follicular or marginal zone lymphoma support further clinical development of parsaclisib in these patient populations. We undertook a phase Ib study (CITADEL‐111) evaluating safety, pharmacokinetics, and efficacy of the potent and selective PI3Kδ inhibitor parsaclisib in Japanese patients with relapsed or refractory B‐cell malignancies. Objective response rate was 100% in follicular lymphoma (9 of 9 patients, including complete response in 2 patients [22.2%]) and marginal zone lymphoma (2 of 2 patients), and 16.7% in diffuse large B‐cell lymphoma (1 of 6 patients). Results observed in Japanese patients with relapsed or refractory follicular or marginal zone lymphoma support further clinical development of parsaclisib in these patient populations.

In the randomized phase III CheckMate 77T study, perioperative nivolumab showed statistically significant and clinically meaningful improvement in event‐free survival (EFS) vs. placebo in patients with resectable, non‐metastatic non‐small cell lung cancer (NSCLC). Here, we report efficacy and safety outcomes in the Japanese subpopulation. Adults with resectable stage IIA–IIIB NSCLC were randomized 1:1 to neoadjuvant nivolumab plus chemotherapy or chemotherapy plus placebo every 3 weeks for ≤ 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for ≤ 13 cycles. Assessments included EFS (primary endpoint), pathological complete response (pCR), major pathological response (MPR), and safety. A total of 68 Japanese patients were randomized to perioperative nivolumab ( n = 40) or placebo ( n = 28). At 24.9 months' median follow‐up, median EFS was not reached (NR; 95% CI: 21.4–NR) with perioperative nivolumab vs. 12.1 (95% CI: 8.1–NR) months with placebo (hazard ratio, 0.46 [95% CI: 0.22–0.95]); 18‐month EFS rates were 76.6% vs. 42.9%, respectively. The pCR rate (95% CI) was 42.5% (27.0%–59.1%) with perioperative nivolumab vs. 0% (0%–12.3%) with placebo (odds ratio [OR], not available); MPR rate (95% CI) was 52.5% (36.1%–68.5%) vs. 7.1% (0.9%–23.5%), respectively (OR, 14.37; 95% CI: 3.00–68.82). Grade 3–4 treatment‐related and surgery‐related adverse events with perioperative nivolumab vs. placebo occurred in 55.0% vs. 39.3% and 16.7% vs. 19.2% of patients. Consistent with the global population, perioperative nivolumab improved EFS, pCR, and MPR vs. placebo in the Japanese subpopulation, with no new safety signals reported, supporting its use in Japanese patients with resectable NSCLC. Trial Registration: ClinicalTrials.gov identifier, NCT04025879

Plitidepsin is a cyclic depsipeptide of marine origin in clinical development in cancer patients. Previously, some depsipeptides have been linked to increased cardiac toxicity. Clinical databases were searched for cardiac adverse events (CAEs) that occurred in clinical trials with the single-agent plitidepsin. Demographic, clinical and pharmacological variables were explored by univariate and multivariate logistic regression analysis. Forty-six of 578 treated patients (8.0%) had at least one CAE (11 patients (1.9%) with plitidepsin-related CAEs), none with fatal outcome as a direct consequence. The more frequent CAEs were rhythm abnormalities (n = 31; 5.4%), mostly atrial fibrillation/flutter (n = 15; 2.6%). Of note, life-threatening ventricular arrhythmias did not occur. Myocardial injury events (n = 17; 3.0%) included possible ischemic-related and non-ischemic events. Other events (miscellaneous, n = 6; 1.0%) were not related to plitidepsin. Significant associations were found with prostate or pancreas cancer primary diagnosis (p = 0.0017), known baseline cardiac risk factors (p = 0.0072), myalgia present at baseline (p = 0.0140), hemoglobin levels lower than 10 g/dL (p = 0.0208) and grade ≥2 hypokalemia (p = 0.0095). Treatment-related variables (plitidepsin dose, number of cycles, schedule and/or total cumulative dose) were not associated. Electrocardiograms performed before and after plitidepsin administration (n = 136) detected no relevant effect on QTc interval. None of the pharmacokinetic parameters analyzed had a significant impact on the probability of developing a CAE. In conclusion, the most frequent CAE type was atrial fibrillation/atrial flutter, although its frequency was not different to that reported in the age-matched healthy population, while other CAEs types were rare. No dose-cumulative pattern was observed, and no treatment-related variables were associated with CAEs. Relevant risk factors identified were related to the patient’s condition and/or to disease-related characteristics rather than to drug exposure. Therefore, the current analysis supports a safe cardiac risk profile for single-agent plitidepsin in cancer patients.

SummaryBackground Plocabulin (PM060184) is a novel marine-derived microtubule inhibitor that acts as an antitumor agent. This first-in-human study evaluated dose-limiting toxicities (DLT) to define the maximum tolerated dose (MTD) and phase II recommended dose (RD) of plocabulin given as a 10-min infusion on Day (D) 1, D8 and D15 every four weeks. Patients and methods Forty-four patients with advanced solid tumors received plocabulin following an accelerated titration design. Results Plocabulin was escalated from 1.3 mg/m2 to 14.5 mg/m2, which was defined as the MTD. No RD was confirmed, because frequent dose delays and omissions resulted in low relative dose intensity (66%) at the 12.0 mg/m2 expansion cohort. The main DLT was grade 3 peripheral sensory neuropathy (PSN); other DLTs were grade 4 tumor lysis syndrome, grade 4 cardiac failure and grade 3 myalgia. Toxicities were mainly mild to moderate, and included abdominal pain, myalgia, fatigue, nausea, and vomiting. Myelosuppression was transient and manageable. Plocabulin had a half-life of ~4 h and a wide diffusion to peripheral tissues. Antitumor response was observed in cervix carcinoma and heavily pretreated metastatic non-small cell lung cancer patients, and disease stabilization (≥3 months) in patients with colorectal, thymic, gastrointestinal stromal and breast tumors, among others. The clinical benefit rate was 33%. Conclusion The main DLT of plocabulin was PSN, as anticipated for a tubulin-binding agent. Since encouraging antitumor activity was observed, efforts to improve toxicity and to find the RD were planned in other trials evaluating D1&D8 and D1-D3 plus D15-D17 schedules.

Summary Objective To determine the recommended dose for phase II trials of elisidepsin (PM02734, Irvalec®) in combination with erlotinib in patients with advanced malignant solid tumors. Methods Open-label, dose-escalating, phase I study of intravenous elisidepsin administered weekly (days 1, 8 and 15) over 3 h as a flat dose (FD) and daily oral erlotinib, every 3 weeks. A pharmacokinetic analysis was done on blood samples collected around the first elisidepsin infusion. Results Thirty patients were treated across six different dose levels (DLs) ranging from elisidepsin 0.33–2.25 mg/erlotinib 100–150 mg. Two patients had dose-limiting toxicities: grade 3 bilirubin increase (DL3: 0.75 mg/150 mg) and a dose omission for > 2 weeks due to grade 3 alanine aminotransferase increase (DL6: 2.25 mg/100 mg). The daily erlotinib dose was escalated to 150 mg at DL2-DL5, but decreased to 100 mg at DL6, as most grade 3 toxicities were related to this agent only. The most frequent toxicities were transaminase increases (related to elisidepsin), and rash, pruritus and diarrhea (related to erlotinib). No objective responses were observed. Despite no overlapping toxicities, the combination was declared unfeasible due to frequent elisidepsin dose delays. The pharmacokinetics of elisidepsin/erlotinib was not significantly different from that of each agent alone. Conclusion The difficulty in combining elisidepsin with the standard dose of erlotinib (150 mg), together with the lack of antitumor activity, made the combination unattractive for further development. The trial was closed without having determined a recommended dose.

This first-in-human, phase I clinical trial was designed to determine the dose-limiting toxicities (DLTs) and the dose for phase II trials (P2D) of elisidepsin (PM02734) administered as a 30-min or as a 3-h intravenous infusion every 3 weeks (q3wk). Between March 2006 and April 2011, 53 patients with advanced malignant solid tumors were enrolled and treated with elisidepsin on the two different q3wk infusion schedules: 22 (30-min) and 31 (3-h), respectively. Doses evaluated ranged from 0.1 to 1.6 mg/m 2 (30-min q3wk) and from 2.0 to 11.0 mg flat dose (FD) (3-h q3wk). In the 30-min q3wk schedule, transient grade 3/4 increases in hepatic transaminases were the DLT, which appeared at the highest doses tested (from 1.1 to 1.6 mg/m 2 ). No DLTs were observed on the 3-h schedule at doses up to 11.0 mg q3wk. Common adverse events were grade 1/2 pruritus, nausea, fatigue and hypersensitivity. Of note, myelotoxicity was not observed. Plasma maximum concentration and total drug exposure increased linearly with dose. Prolonged (≥3 months) disease stabilization was observed in pretreated patients with pleural mesothelioma ( n  = 1) in the 30-min q3wk arm, and with colorectal adenocarcinoma ( n  = 3), esophagus adenocarcinoma, endometrium adenocarcinoma, pleural mesothelioma, and head and neck carcinoma ( n  = 1 each) in the 3-h q3wk arm. In conclusion, elisidepsin doses of 1.1 mg/m 2 (equivalent to a FD of 2.0 mg) and 11.0 mg FD are the dose levels achieved for further phase II trials testing the 30-min q3wk and 3-h q3wk schedules, respectively.

Summary PM00104 (Zalypsis®) is a new synthetic alkaloid with potent cytotoxic activity against tumor cell lines. This phase I clinical trial determined the maximal tolerated dose (MTD) and recommended dose (RD) for phase II trials of PM00104 administered as a 1-hour intravenous (i.v.) infusion weekly for three consecutive weeks resting every fourth week (d1,8,15 q4wk). Forty-nine patients with advanced solid malignancies received PM00104 following a toxicity-guided, accelerated, dose-escalation design. Doses evaluated ranged from 0.07 to 3.0 mg/m 2 . Dose-limiting toxicities (DLTs) appeared at the highest doses tested and comprised grade 3 diarrhea and grade 4 lipase increase at 2.0 mg/m 2 ; grade 1 thrombocytopenia and grade 2 neutropenia with two infusion omissions, grade 3 fatigue and grade 4 febrile neutropenia at 2.5 mg/m 2 ; and grade 3/4 fatigue, grade 4 neutropenia lasting >5 days and grade 4 thrombocytopenia at 3.0 mg/m 2 . RD was established at 2.0 mg/m 2 . PM00104-related adverse events at the RD were mostly grade 1/2, with fatigue, nausea and vomiting as the most common. Transient and manageable myelosuppression and transaminase increases were also reported. Main pharmacokinetic parameters increased linearly with dose. Disease stabilization lasting ≥3 months was found in 4 patients with cervical carcinoma, colorectal adenocarcinoma, lachrymal adenoid carcinoma, and bladder carcinoma ( n  = 1 each). In conclusion, PM00104 2.0 mg/m 2 1-hour, d1,8,15 q4wk showed a positive risk-benefit ratio, which has supported its further evaluation in three ongoing phase II clinical trials.

Summary Objective To determine the maximum tolerated dose and the recommended dose (RD) for phase II trials of elisidepsin (Irvalec®) in combination with carboplatin or gemcitabine. Methods Open-label, dose-escalating, two-arm, uncontrolled, phase I study. Patients received carboplatin on Day (D) 1, followed by elisidepsin on D1 and D8, every 3 weeks, or gemcitabine on D1 and D15, followed by elisidepsin on D1 and D15, every 4 weeks. A pharmacokinetic analysis was done from blood samples collected during the first treatment infusion. Results Fifteen patients were treated with carboplatin/elisidepsin at doses from 4 AUC/1.0 mg flat dose (FD) to 5 AUC/2.5 mg FD. Two patients had dose-limiting toxicities (DLTs) at 5 AUC/2.0 mg, a dose delay >2 weeks due to grade-2 ALT increase and grade-3 thrombocytopenia, and a D8 infusion omission due to grade-3 ALT increase. The RD was established at 4 AUC/1.0 mg. Toxicity consisted mainly of mild-moderate anorexia, fatigue, and nausea. Twenty-two patients were treated with gemcitabine/elisidepsin at doses from 1,000 mg*m 2 /1.0 mg FD to 1,250 mg*m 2 /7.5 mg FD. Two patients had DLTs at 1,250 mg*m 2 /7.5 mg, both a D15 dose omission due to grade-2 ALT increase. The RD was defined at 1,250 mg*m 2 /5.0 mg. Toxicity consisted mainly of mild-moderate fatigue, pruritus, erythema, and myalgia. No objective response was observed. No relevant pharmacokinetic interaction was detected. Conclusion Infra-optimal doses of elisidepsin and carboplatin and a lack of antitumor activity despite using active drug concentrations in combination with gemcitabine do not warrant further clinical development for these two combinations.