Study of Vosaroxin or Placebo in Combination With Cytarabine in Patients With First Relapsed or Refractory AML (VALOR)

• Complete Remission (CR) Rate Based on Modified International Working Group (IWG) Criteria. [ Time Frame: Up to 5 years or duration of study ]
  Group A (Vosaroxin + cytarabine) patient CR as compared to Group B (placebo + cytarabine) patient CR. Complete remission (CR) is typically defined using IWG criteria as bone marrow blast count of less than 5% with adequate recovery of peripheral blood counts.
• All Cause Mortality [ Time Frame: 30 Days ]
  Vosaroxin + cytarabine mortality versus placebo + cytarabine mortality
• All Cause Mortality [ Time Frame: 60 Days ]
  Vosaroxin + cytarabine mortality versus placebo + cytarabine mortality

• Overall Remission (OR) Rate Based on the IWG Response Criteria [ Time Frame: Up to 5 years or the duration of the study ]

  Group A patient OR compared to Group B patient OR

  Overall Remission includes Complete Remission (CR), Complete Remission with incomplete platelet recovery (CRp), Complete Remission with incomplete blood count recovery (CRi), and Partial Remission (PR). Complete remission means bone marrow blast count of less than 5% with adequate recovery of peripheral blood counts as typically defined by the IWG. Both CRi and CRp refer complete remission but with incomplete blood count and platelet recovery, respectively. PR, or partial remission, refers to remission in which bone marrow contains blast counts between 5 and 25 percent.

• Event Free Survival (EFS) [ Time Frame: Up to 5 years or duration of study ]
• Leukemia-Free Survival (LFS) [ Time Frame: Up to 5 years or the duration of the study ]
  Durability of remission (CR) assessed by LFS

The study includes additional objectives to ones listed above as Outcome Measures. These additional objectives also compared treatment groups in the following:

CR + CRp rate, defined as CR + CRp based on modified IWG response criteria.

Combined CR rate (CR+CRp+CRi).

Percentage of patients who have post-treatment (subsequent) transplantation.

Percentage of patients who received subsequent non-protocol therapy (including transplantation).

Safety and tolerability.

In keeping with FDA guidance for adaptive trial designs, the study incorporated an independent DSMB (Drug Safety Monitoring Board) to address potential uncertainty concerning the true treatment affect between the treatment groups and to address a deterioration of power from a small difference. Sunesis remained blinded and had no involvement in the interim data analysis, interpretation, or adaptive design. Based on the results of the interim data analysis the DSMB recommended an increase in the target number of deaths from 375 in 450 patients to 562 in 675 patients which based on a 5% dropout rate increased enrollment from 475 to 712.

The primary analysis was performed when the target number of deaths had been achieved based on a permuted block randomization procedure, stratified by disease status (refractory, first relapse with duration of first CR or CRp ≥ 90 days and < 12 months, or first relapse with duration of first CR or CRp ≥ 12 months and ≤ 24 months), age (< 60 years or ≥ 60 years), and geographic location (US or outside US). The study included periods of screening, treatment / hematologic recovery, post-treatment follow-up, and long-term follow-up for survival.

Follow-up was monthly during the first year, every 2 months during the second year, and every 3 months thereafter until death, withdrawal of consent, or loss to follow-up, whichever occurred first. Long-term follow-up began for all patients when the required number of deaths for primary analysis had been met; thereafter, survival data were collected every 4 months until death, withdrawal of consent, or loss to follow-up, whichever occurred first.

The long term follow-up for this study continues at this time and the September 2014 date reflects database lock for primary analyses reflected in the Results Section. During long term follow-up Sunesis is not collecting Adverse Events.

• Drug: vosaroxin + cytarabine

  Vosaroxin days 1 and 4: 90 mg/m2 for induction 1; 70 mg/m2 for all other cycles

  Cytarabine 1 g/m2 daily on days 1-5 (IDAC)

• Drug: placebo + cytarabine

  Placebo days 1 and 4: volume matched to vosaroxin

  Cytarabine 1 g/m2 daily on days 1-5 (IDAC)

  Other Name: control

• Experimental: Group A: vosaroxin + cytarabine
  vosaroxin (short IV infusion within 10 minutes) on days 1 and 4: cytarabine on days 1 through 5; a maximum of 2 cycles of Induction and 2 cycles for Consolidation
  Intervention: Drug: vosaroxin + cytarabine
• Placebo Comparator: Group B: placebo + cytarabine
  placebo (short IV infusion within 10 minutes and volume matched to vosaroxin) on days 1 and 4: cytarabine on days 1 through 5; a maximum of 2 cycles of Induction and 2 cycles for Consolidation
  Intervention: Drug: placebo + cytarabine

Inclusion Criteria:

• Provided signed, written informed consent
• At least 18 years of age
• Had a diagnosis of AML according to World Health Organization (WHO) classification
• First relapsed or refractory AML (refractory to initial induction therapy) with at least 5% blasts by bone marrow or aspirate or 1% blasts in peripheral blood with additional requirements for relapsed or refractory
• Had an ECOG score of 0-2
• Had adequate liver and renal function as indicated by certain laboratory values
• Had adequate cardiac function (left ventricular ejection fraction at least 40% by multiple gated acquisition scan or ECG)
• Nonfertile or agreed to use an adequate method of contraception until 30 days after the last treatment
• Had any clinically significant nonhematologic toxicity after prior chemotherapy recovered to Grade 1 per NCI-CTCAE

Exclusion Criteria:

• Had acute promyelocytic leukemia
• Had more than 2 cycles of induction therapy for AML
• Had completed a single cycle of treatment containing a total dose of 5 g/m2 or more of cytarabine within 90 days before randomization
• Refractory to or relapsed within the previous 3 months after therapy with an IDAC- or HIDAC-containing regimen
• Had received a hematopoietic stem cell transplant (HSCT) within the previous 90 days
• Had received active immunosuppressive therapy for graft-versus-host disease (GVHD) within 2 weeks before study start
• Had any other severe concurrent disease, or have a history of serious disease involving the heart, kidney, liver, or other organ system
• Had evidence of central nervous system involvement of active AML
• Had other active malignancies (including other hematologic malignancies) or been diagnosed with other malignancies within the last 12 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia
• Had an active, uncontrolled infection
• Had received any other investigational therapy within 14 days or not recovered from acute affects of the other investigational therapy
• Had received prior or current hydroxyurea or medications to reduce blast count within 24 hours before randomization
• Had received previous treatment with vosaroxin
• Pregnant or lactating
• Had any other medical, psychological, or social condition that may interfere with consent, study participation, or follow-up
• Had known HIV seropositivity