Phase I dose escalation study of CVM-1118, a novel anti-vascular mimicry agent, in patients with advanced cancers.

Abstract

2580 Background: CVM-1118 is an oral NCE that demonstrated potent anti-tumor effects in several tumor xenograft models, via multiple MOAs including induction of cancer cell cycle arrest and apoptosis, and reducing vasculogenic mimicry (VM) network formation in cancer cells, providing a promising therapeutic means in the treatment of malignant tumors that have metastatic potential. Methods: Patients with advanced tumors are being enrolled into 2 ongoing open-label Phase I dose escalation studies in both US (CVM-001) and Taiwan (CVM-002) to evaluate ethnic differences in drug responses. CVM-1118 capsules are administrated orally QD/BID in a 28-day cycle for 4 cycles. The primary objectives are to evaluate the safety, tolerability and pharmacokinetics (PK) and establish the Recommended Phase 2 Dose (RP2D). The secondary objective is to evaluate the therapeutic response after receiving treatment. Beyond 4 cycles, patients showing clinical benefit with CVM-1118 may enter extension cohort to continue the treatment. Results: To date, 28 pts (16 M/12 F)received CVM-1118 across 6 dose levels (50 to 800 mg daily). Median number of days was 52 (range 2 to 135). For CVM-001, 2 DLTs (grade 5 dehydration and grade 3 fatigue) were reported at cohort 6 (800 mg/daily) and the MTD is currently under evaluation. For CVM-002, 3 cohorts (100 to 400 mg/daily) have been completed without DLT. Enrolment to cohort 5 (600 mg/daily) is in progress. From both studies, the most common drug-related AEs included manageable diarrhea, nausea, and vomiting. Rapid oral absorption was observed with Tmax < 2 hr. Bioconversion to active metabolite, CVM-1125, occurred rapidly and the drug exposure increased with increasing dose levels. However, patients in US study showed higher drug exposure than those in Taiwan study. Two patients at 200 mg/daily cohort in Taiwan completing 4-cycle treatment and showing stable disease continued into extension cohort with higher dose. Conclusions: In this ongoing study, Asian patients in Taiwan appear to have better tolerance for CVM-1118 than those in US, likely due to lower drug exposure at same dose level, and some patients have experienced clinical benefit. Clinical trial information: NCT02507544; NCT02703298.