A Phase I trial of the sulfonylhydrazine alkylator, VNP40101M (101M), administered weekly in patients (pts) with metastatic cancer

Abstract

2060 Background: 101M demonstrated broad anti-tumor effects in murine models and was active against selected alkylator-resistant cell lines. In an initial phase I trial, the MTD was 305 mg/m2 IV q6 weeks, and the DLT was delayed grade (gr) 3 thrombocytopenia. This phase I trial was designed to determine the safety and MTD of 101M administered by short IV infusion weekly x 3. A secondary objective was to measure effects on alkylguanine transferase (AGT) in PBMC. Methods: A cycle was 3 consecutive weeks of dosing. New cycles could begin on day 29 if neutrophils ≥ 1500/μL and platelets ≥ 75k/μL. The dose of 101M was escalated in cohorts of 3–6 pts. Results: Four, 6, 5, and 6 pts were entered to the following dose levels (DL): 80, 100, 125, and 155 mg/m2/week. Thirteen were male; median age was 54 (range 18–72); and ECOG performance status was 0 in 11 pts and 1 in 10 pts. No tumor type was represented by more than 3 pts. Eighteen pts had received ≥ 2 prior chemoRx regimens; 20 had received an alkylator or platinum; 14 had prior radiation. No gr 2–4 non-heme toxicities were observed. Hematologic toxicities for the first 2 cycles are shown in the following table: Platelet and neutrophil nadirs occurred at a median of 33 and 52 days, respectively. Cumulative but mild and reversible thrombocytopenia/neutropenia was observed in the pt receiving 5 cycles w x 3 q4w. PBMC AGT depletion was not observed at any DL. Conclusions: The MTD is 100–125 mg/m2weekly x 3. Most patients can receive 2 or more cycles on a q4w schedule. Dose intensity appears increased compared to the single dose q6w schedule. Some evidence of anti-tumor effect was observed. Phase II trials with the weekly schedule are warranted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Vion Pharmaceuticals Vion Pharmaceuticals Vion Pharmaceuticals Vion Pharmaceuticals