Phase I study of amonafide + cytosine arabinoside (AraC) in patients with poor risk acute myeloid leukemia (AML)

Abstract

6602 Background: Amonafide (Am) is an ATP independent topoisomerase 2 inhibitor that in prior clinical studies demonstrated activity in breast cancer (18–25% response rate (RR)) and prostate cancer (12% RR) with the dose limiting AE being myelosuppression. Prior studies evaluated single agent Am in AML; in one study a complete response (CR) rate of 24% (4/17) was observed. This cohort dose-escalation study was designed to evaluate Am in combination with conventional dose AraC in patients (pts) with poor risk AML. Methods: 26 pts with relapsed AML (n=8), 2° AML (n=15) or CML in blast crisis (BC) (n=3) were treated with AraC 200 mg/m2/day CIV x 7 days plus a fixed dose of Am IV over 2 hrs daily x 5 days. Pts were treated at Am doses of 600 mg/m2/d (n=6), 800 mg/m2/d (n=5) and 700 mg/m2/d (n=15). Median patient age was 67 years (range 30–82). Results: All 26 pts were evaluable for safety. The dose limiting toxicity (DLT) was painful mucositis and erythematous rash in 3/5 pts at 800 mg/m2/d. The MTD of Am when given together with AraC in this regimen was 700 mg/m2/d. 5 early deaths occurred on study; 1 additional pt was discontinued for worsening clinical condition. Among all pts the CR rate was 10/26 (38%). 2 additional pts with AML secondary to MDS were noted to have partial remissions. Of the 10 pts with CR, 3 were diagnosed with 2° AML from MDS, 2 with 2° AML from previous radiotherapy and/or chemotherapy, 4 with relapsed AML, and 1 with CML BC. The CRs occurred in 5/15 pts with 2° AML, 4/8 pts with relapsed AML, and 1/3 pts with CML BC. The median CR duration following Am + AraC therapy (and consolidation therapy for some pts) was 5 months; 2 pts remained disease free for >2 years. Conclusions: The combination of Am + AraC demonstrated antileukemic activity in poor risk AML pts with an acceptable safety profile. The MTD of Am is 700 mg/m2/d x 5 days when combined with conventional dose AraC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Xanthus Life Sciences Xanthus Life Sciences