Phase 2 Study of Voreloxin (Formerly Known as SNS-595) as Single Agent Therapy for Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia (AML): Preliminary Safety and Clinical Responses (The REVEAL-1 Study).

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. Voreloxin demonstrated single agent activity in a phase 1 study of relapsed/refractory hematologic malignancies (ASH 2007). Preliminary results of an ongoing phase 2 study of voreloxin in newly diagnosed elderly (≥ age 60) AML patients are reported. The study is known as the REVEAL-1 (Response Evaluation in Elderly AML-1) study.

Objectives:

1. assess the overall remission rate (CR plus CRp)

2. establish safety and tolerability of voreloxin in this patient population

3. assess pharmacokinetics

4. assess secondary markers of efficacy (leukemia-free survival, overall survival, duration of remission/response), assess both 30- and 60-day all-cause mortality, and

5. determine whether ex vivo activity of voreloxin is predictive of response.

Methods: Open label phase 2 two-stage study design; 9 CR/CRp are required within the first 30 evaluable patients to complete study enrollment. Eligibility: newly diagnosed AML (either de novo or from an antecedent hematologic disorder, AHD) in patients age 60 and older with a minimum of 1 adverse risk factor (age older than 70, AML from AHD, intermediate or poor risk cytogenetics, or ECOG performance status of 2). Study treatment is voreloxin given by IV push within 10 minutes at a dose of 72 mg/m² weekly X 3 doses. Patients achieving a CR or CRp after induction or reinduction may receive up to 2 additional courses of voreloxin as consolidation. Response evaluation is per IWG criteria. PK analyses for voreloxin were performed during cycle 1 on a subset of patients. Ex vivo sensitivity to voreloxin of baseline bone marrow samples was evaluated using the CellTiter-Glo® proliferation assay.

Results: To date, 15 patients have been enrolled and treated. Preliminary data are available for 9 patients who have completed induction. Demographics: 7 males (78%) and 2 females, median age 75 years (range: 60–84). ECOG PS was 0 in 33%, 1 in 44% and 2 in 11% of patients. Three patients had AHD (2 MDS and 1 t-AML) and cytogenetics were intermediate in 7 patients, unclassified in 1 patient, and not performed for 1 patient. Of the 9 evaluable patients who have completed induction and had a day 22 bone marrow biopsy, 6 patients had a day 22 bone marrow blast count < 5% (3 of these patients have a CR and 3 patients are in count recovery). As of 01-Aug-2008, there have been 2 deaths occurring within 60 days of the start of voreloxin therapy: one due to sigmoid volvulus and one due to neutropenic sepsis. Grade 3+ related AEs reported in 2 patients included: neutropenia, thrombocytopenia, leukopenia, and nausea. Study results are too preliminary to further assess safety profile or calculate other efficacy endpoints, PK, or PD.

Conclusion: Voreloxin demonstrates preliminary clinical activity as a single agent for treating newly diagnosed elderly (age ≥ 60) AML patients. This single agent phase 2 study is continuing to enroll. A phase 1b study of combination voreloxin plus cytarabine in relapsed/refractory AML is also in progress.