A Phase I study of intravenous PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors

Abstract

Purpose To evaluate the safety, tolerability, pharmacokinetics, and efficacy of the intravenously administered pan-PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors.MethodsA Phase I open-label study in Japanese patients with advanced or refractory solid tumors was carried out. Patients received a single intravenous dose of either copanlisib 0.4 mg/kg or copanlisib 0.8 mg/kg, dosed intermittently on days 1, 8, and 15 of a 28-day cycle. Safety was monitored throughout the study. Plasma copanlisib levels were measured for pharmacokinetic analysis. ResultsTen patients were enrolled and treated; three received copanlisib 0.4 mg/kg and seven received copanlisib 0.8 mg/kg. Overall, median duration of treatment was 6.2 weeks. No patients treated at 0.4 mg/kg experienced a dose-limiting toxicity, and the maximum tolerated dose in Japanese patients was determined to be 0.8 mg/kg. Adverse events were recorded in all ten patients; the most common were hyperglycemia, hypertension, and constipation. Copanlisib pharmacokinetic exposures displayed near dose-proportionality, with no accumulation. No patients achieved a complete or partial response, and disease control rate was 40.0%.ConclusionsCopanlisib was well tolerated in Japanese patients with advanced or refractory solid tumors, and the maximum tolerated dose was determined to be 0.8 mg/kg. Copanlisib demonstrated near dose-proportional pharmacokinetics and preliminary disease control, warranting further investigation.Clinical trial registration numberNCT01404390.

Phase I study of taselisib in Japanese patients with advanced solid tumors or hormone receptor‐positive advanced breast cancer

“…Stage 2 results also showed good safety and preliminary efficacy of taselisib in combination with fulvestrant, particularly in the case of the patient who had a PR, whose duration of response was >600 days, suggesting promising efficacy for this combination. The common treatment‐related AE observed in this stage of the study were diarrhea, stomatitis, rash, dry skin, and colitis, which are similar to the AE observed in stage 1 and in global Phase I studies of taselisib monotherapy and in studies of other PI3K inhibitors . All the treatment‐related SAE were considered manageable and patients recovered or improved with appropriate treatment and interruption or reduction of taselisib dosing.…”

“…The results from stage 1 suggested that taselisib had good tolerability, with the common treatment-related AE being diarrhea, rash, stomatitis, headache, and decreased appetite; these were consistent with AE seen in the previous taselisib global Phase I study 14 and studies of other PI3K inhibitors. [15][16][17][18] All treatment-related SAE resolved or improved with dosage reduction, interruption, or discontinuation of treatment. Taselisib monotherapy was associated with 2 PR, all of which were in patients with PIK3CA-mutated tumors.…”

“…The common treatment-related AE observed in this stage of the study were diarrhea, stomatitis, rash, dry skin, and colitis, which are similar to the AE observed in stage 1 and in global Phase I studies of taselisib monotherapy 14 and in studies of other PI3K inhibitors. [15][16][17][18] All the treatment-related SAE were considered manageable and patients recovered or improved with appropriate treatment and interruption or reduction of taselisib dosing. Overall pharmacokinetic profile of taselisib, when given as a single dose or as repeated doses, was similar to that of taselisib monotherapy in this and other studies.…”

Targeting PI3K in cancer: mechanisms and advances in clinical trials

“…The most common treatment-related AEs included nausea and transient hyperglycemia [126]. In a phase I study among Japanese patients with advanced or refractory solid tumor, MTD of 0.8 mg/kg was also observed; the most frequent AEs were hyperglycemia, hypertension, and constipation [127]. A phase I, dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine (CisGem) recommended copanlisib 0.8 mg/kg for patients with advanced cancer.…”

Quantitative structure‐selectivity relationship (QSSR)‐based molecular insight into the cross‐reactivity and specificity of chemotherapeutic inhibitors between PI3Kα and PI3Kβ

“…The compound possesses a small size that can be well compatible with the active sites of both the 2 kinase isoforms. In contrast, the larger inhibitor Copanlisib () was suggested to have a strong selectivity for PI3K β over PI3K α ( S = −0.34 < 0).…”