Phase Ib trial of cabazitaxel and tasquinimod in men with heavily pretreated metastatic castration resistant prostate cancer (mCRPC): The CATCH trial.

Abstract

190 Background: Cabazitaxel resistance develops within a few months of treatment initiation in most men with mCRPC in post-docetaxel, and thus combination therapy with other active agents may improve outcomes. Tasquinimod is an oral immunomodulatory agent with anti-angiogenic and anti-tumor in preclinical models of PC and clinical activity in phase II and III trials. Methods: We conducted a phase I dose escalation trial of cabazitaxel plus tasquinimod in men with mCRPC. Cabazitaxel was dosed at 25 mg/m2 every 3 weeks with low dose prednisone and PEG-filgrastim support, and tasquinimod dose levels included 0.25, 0.5, and 1.0 mg, using a 3 week within-patient dose escalation for dose levels 2 and 3, starting all patients at 0.25 mg once daily. The primary objective was to define the recommended phase II dose (RP2D) based on safety and dose limiting toxicity. Preliminary efficacy (PSA decline, PFS) and pharmacokinetic interactions were key secondary objectives. Results: We enrolled 25 men with mCRPC who had failed docetaxel across 3 dose levels. Median PSA at entry was 220 ng/dl. The RP2D was 0.5 mg tasquinimod based on excess DLTs (2 of 3 men) observed at dose level 3 (1.0 mg) including grade 3 sensory neuropathy and grade 3 atrial fibrillation). Dose level 2 was expanded to 14 men, where 3 DLTs were observed: grade 3 fatigue, grade 4 febrile neutropenia, and grade 3 liver function test abnormalities. The proportion of men with a > 30% PSA decline was 63% (95% CI: 41%, 81%). The median composite PFS was 8.5 months (95% CI 4.2-16.4 months) based on 12 PFS events. The median number of cycles of cabazitaxel was 6 (range 1-13), with 6 men receiving > 10 cycles. Best overall RECIST responses (CR+PR) were observed in 3 men (12%), stable disease in 12 (48%). No unexpected adverse events were observed and no pharmacokinetic interactions were observed. Conclusions: The RP2D was cabazitaxel 25 mg/m2 with prednisone and PEG-filgrastim every 3 weeks with tasquinimod 0.25 mg once daily for 3 weeks followed by 0.5 mg. Preliminary evidence of efficacy over cabazitaxel alone is based on observed PSA response and PFS data, and a substantial number of men were progression free beyond 10 cycles with good tolerability. Clinical trial information: NCT01513733.