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Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer.

ABSTRACT: BACKGROUND:Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-?/? activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo. METHODS:A phase I, open-label, dose-escalation study to evaluate the safety, tolerability and recommended phase II dose (RP2D) of copanlisib with gemcitabine or with cisplatin plus gemcitabine (CisGem) in patients with advanced malignancies, including an expansion cohort in patients with biliary tract cancer (BTC) at the RP2D of copanlisib plus CisGem. Copanlisib and gemcitabine were administered on days 1, 8 and 15 of a 28-day cycle; maximum tolerated dose (MTD) and RP2D of copanlisib were determined. Copanlisib plus CisGem was administered on days 1 and 8 of a 21-day cycle; pharmacokinetics and biomarkers were assessed. RESULTS:Fifty patients received treatment as follows: dose-escalation cohorts, n=16; copanlisib plus CisGem cohort, n=14; and BTC expansion cohort, n=20. Copanlisib 0.8?mg?kg-1 plus gemcitabine was the MTD and RP2D for both combinations. Common treatment-emergent adverse events included nausea (86%), hyperglycaemia (80%) and decreased platelet count (80%). Copanlisib exposure displayed a dose-proportional increase. No differences were observed upon co-administration of CisGem. Response rates were as follows: copanlisib plus gemcitabine, 6.3% (one partial response in a patient with peritoneal carcinoma); copanlisib plus CisGem, 12% (one complete response and three partial responses all in patients with BTC (response rate 17.4% in patients with BTC)). Mutations were detected in PIK3CA (1 out of 43), KRAS (10 out of 43) and BRAF (2 out of 22), with phosphate and tensin homologue protein loss in 41% (12 out of 29). CONCLUSIONS:Copanlisib plus CisGem demonstrated a manageable safety profile, favourable pharmacokinetics, and potentially promising clinical response.

SUBMITTER: Kim RD

PROVIDER: S-EPMC5830590 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer.

Kim R D RD Alberts S R SR Peña C C Genvresse I I Ajavon-Hartmann A A Xia C C Kelly A A Grilley-Olson J E JE

British journal of cancer 20180118 4

<h4>Background</h4>Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α/δ activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo ...[more]

PMID: 29348486

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Project description:PurposeLenalidomide have both immunomodulatory and anti-angiogenic properties which could confer anti-cancer effects. The aim of this study was to assess the feasibility of combining lenalidomide with the standard treatment gemcitabine in pancreatic cancer patients with advanced disease.Patients and methodsEligible patients had locally advanced or metastatic adenocarcinoma of the pancreas. Patients received lenalidomide days 1-21 orally and gemcitabine 1000 mg/m2 intravenously (days 1, 8 and 15), each 28 day cycle. Three cohorts of lenalidomide were examined (Cohort I = 15 mg, Cohort II = 20 mg and Cohort III = 25 mg daily). The maximum tolerated dose (MTD) of lenalidomide given in combination with gemcitabine was defined as the highest dose level at which no more than one out of four (25%) subjects experiences a dose-limiting toxicity (DLT). Patients should also be able to receive daily low molecular weight heparin (LMWH) (e.g. dalteparin 5000 IU s.c. daily) as a prophylactic anticoagulant for venous thromboembolic events (VTEs). Twelve patients (n = 4, n = 3 and n = 5 in cohort I, II and III, respectively) were enrolled in this study.ResultsMedian duration of treatment was 11 weeks (range 1-66), and median number of treatment cycles were three (range 1-14). The only DLT was a cardiac failure grade 3 in cohort III. Frequent treatment-related adverse events (AEs) (all grades) included neutropenia, leucopenia and fatigue (83% each, but there was no febrile neutropenia); thrombocytopenia (75%); dermatological toxicity (75%); diarrhea and nausea (42% each); and neuropathy (42%).DiscussionThis phase I study demonstrates the feasibility of the combination of lenalidomide and gemcitabine as first-line treatment in patients with advanced pancreatic cancer. The tolerability profile demonstrated in the dose escalation schedule of lenalidomide suggests the dosing of lenalidomide to be 25 mg daily on days 1-21 with standard dosing of gemcitabine and merits further evaluation in a phase II trial.Trial registrationClinicalTrials.gov NCT01547260.

Dataset Information

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer.

Publications

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer.

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