CBT-1 in combination with doxorubicin in patients with metastatic, unresectable sarcomas who previously progressed on doxorubicin.

Abstract

TPS11077 Background: The response rates of advanced soft tissue sarcomas (STS) to single-agent, first-line anthracycline are typically less than 25%. P-glycoprotein 1 (P-gp), a cell membrane drug efflux pump, is believed to be a resistance mechanism in STS. CBT-1 is a small molecule, orally administered, P-gp antagonist currently under clinical development. This is a multi-institutional open label phase I study of CBT-1 in combination with doxorubicin in patients with anthracycline-refractory sarcoma. The study is designed to determine a maximum tolerable dose (MTD), recommended phase II dose (RP2D), and the safety/tolerability of the combination of CBT-1 and doxorubicin. The study will evaluate anti-cancer activity as a secondary objective as measured by Disease Control Rate (DCR; complete response [CR] + partial response [PR] + stable disease [SD]) at 12 weeks. Objective Response Rate (ORR; CR+PR) and Progression Free Survival (PFS) will be monitored. Correlative studies include assessment of pharmacokinetic and pharmacodynamicendpoints. Methods: Patients 18 years or older with locally advanced metastatic, unresectable STS, prior progression on ≤ 150 mg/m2 of doxorubicin (or another anthracycline equivalent), ECOG PS ≤ 1 and normal organ function, are eligible for this study. Dosing includes fixed doxorubicin (37.5 mg/m2 IV day 5 and day 6) and escalation of oral CBT-1 on days 1-7 of a 21 day cycle. This study follows a standard 3+3 phase I design where dose escalation will occur if < 0/3 or 1/6 patients experience a dose-limiting toxicity (DLT). Tumor assessments are conducted at Week 6 and Week 12. For patients with response or stable disease, treatment is allowed to continue for 4-5 cycles to a maximum of 450 mg/m2 lifetime doxorubicin exposure. Once RP2D is defined, an additional 10 patients will be enrolled into the dose expansion phase. To date, Cohorts 1 (50 mg CBT-1) and 2 (100 mg CBT-1) have been completed with one DLT of grade 4 neutropenia lasting longer than 7 days in Cohort 1. Enrollment to Cohort 3 began December 2018.