A Phase 3, Randomized, Controlled, Double-Blind, Multinational Clinical Study of the Efficacy and Safety of Vosaroxin and Cytarabine versus Placebo and Cytarabine in Patients with First Relapsed or Refractory Acute Myeloid Leukemia (VALOR)

Summary

Partcipants will be assigned to a treatment group randomly (i.e. by chance, like flipping a coin) by a computer. About half the participants will receive vosaroxin and cytarabine, and the other half will receive placebo and cytarabine.

They will be randomly assigned to one of the following two treatment groups:


* Vosaroxin Days 1 and 4: 90 mg/m2 induction 1; 70 mg/m2 all other cycles
with
Cytarabine 1 g/m2 daily on days 1-5

– OR –


* Placebo Days 1 and 4: volume matched to vosaroxin
with
Cytarabine 1 g/m2 daily on days 1-5

Treatment Cycles
During this study, partcipants may complete up to 4 cycles of therapy that can include 2 cycles of induction therapy, called induction 1 and induction 2, and up to 2 cycles of consolidation therapy, called consolidation 1 and consolidation 2. A cycle is typically 2 to 8 weeks, with 5 days of treatment followed by at least 9 days and up to 51 days without treatment to allow your blood cells to recover. In some cases, induction cycles can be as long as 12 weeks.

If it is determined that the participant has a complete remission or complete remission with incomplete platelet recovery (numbers 1 or 2) after induction 1 or induction 2 participant may receive consolidation 1 treatment. After consolidation 1, consolidation 2 treatment will be given if medically indicated.

If participant has a complete remission with incomplete neutrophil or platelet recovery (number 3), and, after extra time, neutrophils, platelets or both do not recover enough to receive consolidation treatment, they will go into the study follow-up phase so that information about their health, remission status, and future AML treatments can be collected for 3 years or longer.

If the participant does not have a complete remission, but their leukemia has decreased by about half after Induction 1:
If it is medically indicated that leukemia has decreased by about half but is still present, they may receive induction 2 treatment. After induction 2, if complete remission or complete remission with incomplete platelet recovery (in other words, your leukemia is in remission) patient may receive consolidation 1 and consolidation 2 treatment.

If participant does not have a complete remission, and your leukemia gets worse or does not improve enough after Induction 1, they will not be eligible for more treatment under this study protocol and they will be taken off study treatment because the study drugs did not help their leukemia. They will then go into the study follow-up phase so that information about their health and future AML treatments can be collected for 3 years or longer.

Participant Eligibility

1. Able to understand and provide written informed consent and Health Insurance
Portability and Accountability Act (HIPAA) authorization, as appropriate
2. At least 18 years of age
3. Diagnosis of acute myeloid leukemia (AML) by World Health Organization (WHO)
classification
4. Relapsed or refractory AML with at least 5% blasts by bone marrow biopsy or
aspirate, or at least 1% blasts in peripheral blood, and meeting the following criteria:

First Relapsed (must meet (a), (b), and (c)):
a) Relapse occurred at least 90 days to 24 months after the first CR or CRp
(b) The first CR or CRp had to result from no more than 2 cycles of cytotoxic chemotherapy
and at least 1 cycle had to include an anthracycline (or anthracenedione) and
cytarabine-based regimen
(c) The re-emergence of at least 5% leukemic blasts in bone marrow is not attributable to other
causes, regardless of new or recurrent dysplastic changes or extramedullary disease, or the
re-emergence of at least 1% blasts in the peripheral blood is not attributable to other causes
such as regenerating marrow
The date of relapse is the date of the first bone marrow examination that demonstrated the
re-emergence of at least 5% leukemic blasts, or is the date of the first peripheral blood test that
demonstrated at least 1% blasts not attributable to other causes such as regenerating marrow.
Allowed
• Unlimited cycles/regimens of consolidation for first CR or CRp
• Transplantation for AML (allogeneic or autologous) allowed unless within 90 days of randomization
• Maintenance therapy with hypomethylating or biologic agents until first relapse

Refractory (must meet either (e) and (g) or (f) and (g)):
(e) Persistent AML was documented by bone marrow biopsy or aspirate at least 28 days after day 1 of the first induction cycle of 1 or 2 cycles of cytotoxic chemotherapy
(f) Re-emergence of at least 5% leukemic blasts in bone marrow or at least 1% blasts in peripheral blood is not attributable to other causes such as regenerating marrow, and was less than 90 days after the first CR or CRp
(g) Prior induction therapy had to include no more than 2 cycles of cytotoxic chemotherapy. At least 1 induction cycle must have consisted of an anthracycline (or anthracenedione) and cytarabine combination with a reasonable schedule/dose of anthracycline in the judgment of the investigator

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (Table 9)
6. Local clinical laboratory values as follows:
• Serum creatinine ≤ 2.0 mg/dL
• Total bilirubin ≤ 1.5 × the upper limit of normal (ULN), unless due to Gilbert’s syndrome
• Aspartate aminotransferase (AST) ≤ 2.5 × ULN
• Alanine aminotransferase (ALT) ≤ 2.5 × ULN
7. Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)
8. Clinically significant nonhematologic toxicity after prior chemotherapy has recovered to grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
9. Females must be surgically or biologically sterile or postmenopausal (amenorrheic for at least 12 months) or if of childbearing potential, must have a negative urine or serum pregnancy test within 14 days before randomization, and must agree to use an adequate method of contraception during the study until 30 days after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 30 days after the last treatment