Parsaclisib in Japanese patients with relapsed or refractory B-cell lymphoma (CITADEL-111): A phase Ib study.

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.

First-in-human phase I study of the microtubule inhibitor plocabulin in patients with advanced solid tumors.

Background 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.

Phase I, dose-escalating study of elisidepsin (Irvalec(®)), a plasma membrane-disrupting marine antitumor agent, in combination with erlotinib in patients with advanced malignant solid tumors.

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.

First-in-human, phase I study of elisidepsin (PM02734) administered as a 30-min or as a 3-hour intravenous infusion every three weeks in patients with advanced solid tumors.

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.

Phase I study of carboplatin in combination with PM00104 (Zalypsis®) in patients with advanced solid tumors.

This phase I trial determined the recommended dose for phase II trials (RD) of carboplatin 1-h intravenous (i.v.) infusion followed by PM00104 1-h i.v. infusion on Day 1 every 3 weeks (q3wk) in adult patients with advanced solid tumors. A toxicity-guided, dose-escalation design was used. Patients were stratified and divided into heavily (n = 6) or mildly pretreated (n = 14) groups. Transient grade 4 thrombocytopenia (in one heavily and three mildly pretreated patients) was the only dose-limiting toxicity (DLT) observed. Carboplatin AUC3-PM00104 2.0 mg/m(2) was the RD in both groups. At this RD, the carboplatin AUC was equal to ~60 % the target AUC used in other combinations, and the PM00104 dose intensity was 56-67 % of the value achieved at the RD for single-agent PM00104 given as 1-h infusion q3wk. Most treatment-related adverse events were grade 1/2. They mainly consisted of gastrointestinal and general symptoms, such as fatigue, anorexia, mucosal inflammation or nausea. Transient neutropenia (50 % of patients) and thrombocytopenia (33-38 %) were the most common severe hematological abnormalities; their incidence was higher than with single-agent PM00104. No pharmacokinetic drug-drug alterations occurred. Partial response was found in one patient with triple negative breast cancer pretreated with paclitaxel/bevacizumab. Three patients with colorectal cancer, head and neck cancer, and tumor of unknown origin had disease stabilization for ≥3 months. In conclusion, no optimal dose was reached due to overlapping myelosuppression despite stratification according to prior treatment. Therefore, this carboplatin plus PM00104 combination was not selected for further clinical research.

Phase II clinical trial of PM00104 (Zalypsis(®)) in urothelial carcinoma patients progressing after first-line platinum-based regimen.

PURPOSE: This exploratory phase II clinical trial evaluated the antitumor activity, safety profile and pharmacokinetics of PM00104 (Zalypsis(®)) 3 mg/m(2) 1 h every 3-week intravenous infusion in patients with advanced and/or metastatic urothelial carcinoma progressing after first-line platinum-based chemotherapy. METHODS: The primary efficacy end point was the disease control rate (DCR), defined as the percentage of patients with confirmed objective response or progression-free at 3 months, according to the response evaluation criteria in solid tumors. RESULTS: In a first stage (n = 19 patients evaluable for efficacy), only one patient achieved DCR (stable disease as best response and progression-free survival of 3.1 months). According to the 2-stage design used, the primary efficacy objective was unmet, and therefore, the trial was finalized without opening the second stage. The most common adverse events related to PM00104 were fatigue, anorexia, nausea, troponin I increase and neutropenia, which were transient and manageable with dose modifications or administration delays. Mean PK results (Cmax = 48.57 µg/l and area under the curve (AUC) = 154.97 h µg/l) were similar to those observed in a previous phase I trial evaluating the same dose and schedule. Few troponin I concentrations were higher than 0.10 ng/ml, and none of them were related to parameters of PM00104 exposure such as AUC or Cmax. CONCLUSIONS: No recommendation is given for further evaluation of PM00104 as single-agent treatment of patients with pretreated advanced and/or metastatic urothelial carcinoma. No new safety signals were observed.

Phase I study of elisidepsin (Irvalec®) in combination with carboplatin or gemcitabine in patients with advanced malignancies.

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.

Phase I study of PM00104 (Zalypsis®) administered as a 1-hour weekly infusion resting every fourth week in patients with advanced solid tumors.

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.

Complete and sustained objective response per RECIST to Irvalec (PM02734) in undifferentiated large cell esophageal adenocarcinoma: A case report and a review of the literature.

Undifferentiated large cell carcinoma is a rare entity in esophageal cancer and very few data are available in the literature on this uncommon histological subtype. We report a case of a 58-year-old Caucasian male previously treated with cisplatin/5-fluorouracil, docetaxel and carboplatin/plitidepsin who received treatment with a novel antitumor agent, Irvalec (PM02734), as fourth line. The patient received treatment from July 2006 to July 2009, a total of 49 cycles, at a dose of 2.4 mg/m(2) as a 24-hour infusion every 3 weeks. He did not present severe complications or unplanned or cumulative toxicities. Complete and durable response according to RECIST was reported. He was alive at the last follow-up on March 2012.

Plitidepsin has a safe cardiac profile: a comprehensive analysis.

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.