Voreloxin (formerly known as SNS-595) in Combination with Cytarabine Demonstrates Preliminary Clinical Responses in a Phase 1 Study in Relapsed/Refractory Acute Myeloid Leukemia.

Background: Voreloxin (formerly SNS-595) is a first-in-class replication-dependent DNA damaging agent that causes apoptosis by DNA intercalation and inhibition of topoisomerase II. A previous phase 1 study of single-agent voreloxin demonstrated acceptable safety and strong signs of clinical activity in patients with relapsed/refractory hematologic malignancies (ASH 2007), where MTD was found to be 72 mg/m2 weekly x 3 and 40 mg/m2 twice weekly x 4. In nonclinical models, the combination of voreloxin and cytarabine demonstrated enhanced activity. Preliminary results of an ongoing phase 1b study of combination voreloxin plus cytarabine in relapsed/refractory AML patients are reported. Objectives: 1. establish safety, tolerability and MTD of escalating doses of voreloxin combination with continuous infusion cytarabine, 2. characterize voreloxin PK in the setting of cytarabine given as a continuous intravenous infusion (CIV) 3. assess clinical activity 4. explore markers of patient response 5. evaluate ex vivo voreloxin sensitivity in bone marrow as a predictor of response. Methods: Open label, doseescalation phase 1b study with a starting dose of voreloxin of 10 mg/m2 (given on days 1,4) in combination with 400 mg/m2/day CIV cytarabine for five days. Dose-limiting toxicities (DLTs) were assessed during cycle 1. PK analyses for voreloxin were performed during cycle 1. Pre- and post-dose PBMC were obtained to evaluate modulation of DNA damage response markers as correlates of patient response. Ex vivo sensitivity to voreloxin of baseline bone marrow samples was evaluated using the CellTiter-Glo® proliferation assay. Clinical response was determined based on IWG criteria. Patients could receive up to 2 courses of induction, and patients achieving CR or CRp could receive up to 2 courses as consolidation. At MTD, an additional cohort of patients will be enrolled to further assess safety. Results: To date, 26 patients have been enrolled and 24 have received treatment. Demographics: 16 males, 8 females, median age 61.4 years (range 30 – 74.5 yrs). Disease status: 17 of 24 treated patients had relapsed disease. Median number of prior therapies was 2 (Range 0–4). Two patients had prior allogeneic stem cell transplant. Dose escalation has proceeded to 80 mg/m2/dose (cohort 6). Safety: a single DLT has been observed (grade 5 septic shock in one patient treated at 70 mg/m2). Grade 3+ related non hematologic AEs ≥ 5% incidence: infections (23%). Grade 3+ hematologic toxicities have been consistent with past experience and include febrile neutropenia, anemia, and thrombocytopenia. The most common reason for early study termination was disease progression. Voreloxin pharmacokinetics were unaffected by cytarabine compared with the single agent phase 1 study. Preliminary clinical responses are listed below in Table 1. Conclusion: Voreloxin given in combination with continuous infusion cytarabine is generally well-tolerated, with encouraging signs of activity in patients with relapsed/refractory AML. Dose escalation continues. Table 1: Clinical Responses by Cohort | Cohort | Voreloxin Dose | Treated/Enrolled | DLTs | Responses | |:------:| -------------- | ---------------- | ---- | --------- | | 1 | 10 | 4/4 | | | | 2 | 20 | 3/4 | | 1 CR | | 3 | 34 | 4/4 | | 2 CR | | 4 | 50 | 6/6 | | 2 CR | | 5 | 70 | 7/8 | 1 | 2 CR |