A Phase I Pharmacokinetic, Pharmacogenomic Trial Of Weekly Amonafide In Patients (Pts) With Solid Tumors.

2023 Background: Amonafide (AMF) is a topoisomerase II inhibitor previously tested in clinical trials, predominantly with a daily x 5 administration schedule. AMF is extensively metabolized by N-acetyltransferase 2 to N-acetylamonafide (AAMF), an active metabolite which demonstrates nearly equipotent activity to the parent compound. Previous trials indicated a relationship between AMF related neutropenia and acetylator phenotype. Methods: Dose escalation was initiated at 400 mg/m2 IV on days 1, 8, and 15 every 28 days. Blood samples were obtained for acetylator genotyping, but initially the results were not prospectively determined. Due to dose-limiting toxicities (DLT) encountered at 500 mg/m2, genotype results were obtained prospectively and subsequent pts were dosed by genotype (slow [S] vs intermediate/rapid [I/R]). Blood and urine samples for pharmacokinetics (PK) were obtained with the first dose of AMF. Results: 26 pts (14F/12M; median age 65, range 32–74; median PS 1;acetylator status: S =11; I/R = 15; common tumor types: ovarian [5], prostate [3], breast [3], colon [3]) have been enrolled at doses of 400 and 500 mg/m2. Myelosuppression consisting of ANC and platelet nadirs preventing Day 15 dosing has been the DLT. Non-hematologic toxicities include nausea/vomiting, phlebitis, and infusion-related symptoms. PK analyses confirm the marked difference in drug exposure between S and I/R acetylators as determined by genotype. The mean AAMF/AMF AUC ratio for S vs I/R acetylators is 0.66 (range 0.28 - 1.31) vs 2.75 (range 1.2 - 5.98) [p = 0.00008]. Percent change of ANC for I/R at the 400 mg/m2 dose level was 78% vs 55% for S at 500 mg/m2 (p = 0.02). Antitumor activity has been noted in prostate cancer (declining PSA; 400 mg/m2; S), ovarian cancer (declining CA125; 400 mg/m2; I/R), and GIST (decreased lymph nodes; 500 mg/m2; S). Conclusions: Determination of pt acetylator status via genotyping allows pts to receive amonafide doses that are tailored to their drug metabolism. Weekly amonafide is well tolerated in S acetylators, and the recommended phase II dose is 500 mg/m2 weekly x 3 q4weeks. Enrollment for I/R acetylators continues at 320 mg/m2. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ChemGenex Bristol-Myers Squibb; Chemgenex; GlaxoSmithKline; ILEX GlaxoSmithKline; ILEX Aventis; Bristol-Myers Squibb; GlaxoSmithKline ChemGenex