SNS-595 Demonstrates Clinical Responses in a Phase 1 Study in Acute Leukemia.

SNS-595 is a replication-dependent DNA damaging agent that causes irreversible G2 arrest and rapid apoptosis. A secondary mechanism for SNS-595 is a unique inhibition of topoisomerase (topo) II that causes highly selective DNA damage with low dependence on topo II for its potent anti-tumor activity. SNS-595 is in phase 1 and 2 clinical trials in hematologic and solid malignancies, with clinical responses in AML, ovarian cancer, NSCLC and SCLC. We initiated an escalating-dose phase 1 trial of SNS-595, administered as a weekly x 3 (Arm A) or twice weekly x 2 bolus (Arm B), in patients (pts) with advanced or refractory acute leukemias.

Objectives:

1. establish safety, tolerability and MTD of SNS-595 given on 2 schedules;

2. characterize PK;

3. assess clinical activity;

4. explore potential biomarkers

Methods: SNS-595 was administered as a slow IV push on days 1, 8, 15 (Arm A) or days 1, 4, 8, 11 (Arm B). Minimum cycle length was 42 days (Arm A) and 39 days (Arm B). Additional cycles were permitted if pts achieved stable disease or better. The starting dose was 18 mg/m² weekly on Arm A, and 9 mg/m² twice weekly on Arm B and escalated by cohort. PK analyses for SNS-595 were performed during cycle 1. Pre- and post-dose bone marrow aspirates were obtained from a subset of pts to assess biomarkers.

Results: To date, 49 pts have been enrolled and are evaluable, Arm A: 25 pts, Arm B: 24 pts, 31 males and 18 females with a median age of 65 years. Diagnoses included AML (43 pts), ALL (4 pts), and 1 pt each with acute lymphoblastic leukemia and acute biphenotypic leukemia. Most pts had relapsed/refractory leukemia from prior therapy (median 3 prior regimens (range 1–7)). Dose escalation has proceeded to 90mg/m²/d (Arm A) and dose-limiting toxicity (DLT) of Grade (G) 3 mucositis was observed in 3 pts on Arm B at the 50mg/m² dose level. Five additional pts were accrued at 40mg/m² on Arm B, the likely recommended phase 2 dose for Arm B. To date, 2/11 pts at 40mg/m² have G3 mucositis (Arm B); 3 DLTs have been observed on Arm A - G4 myelosuppression at the 27mg/m² weekly dose (also had progressive disease), prolonged myelosuppression at the 50mg/m² weekly dose, and bowel obstruction at the 72mg/m² weekly dose. Non-DLTs included nausea/vomiting and diarrhea; drug-related G3 & 4 events were limited to stomatitis (3 pts) and diarrhea (1 pt). Blast reduction (>95%) and response is associated with time above a threshold concentration of SNS-595; evidence of DNA-damage induced by SNS-595 is detectable post-dose. Clinical activity - reductions in marrow blasts to ≤5% - was noted at doses at or above 50mg/m² (5 pts in Arm A) and 40mg/m² (1 pt in Arm B). Complete Responses (CR) have been observed at the 50mg/m² dose level (Arm A, 1 pt) and at the 40mg/m² level (Arm B, 1 pt). A 3^rd pt with AML and splenomegally achieved partial response at the 50mg/m² dose level (Arm B) and had G3 mucositis. In addition, 1 pt with AML and splenomegally (at 72 mg/m² Arm A) achieved clinical benefit with reduction in splenomegaly and blast counts.

Conclusion: SNS-595 appears to be well-tolerated in pts with advanced leukemias, with preliminary signs of clinical activity as measured by CR and decreases in leukemic blasts. The likely recommended phase 2 dose in Arm B is 40mg/m² twice weekly x 2 and further accrual to Arm A continues.