Details

Details

Title A Phase 2, Randomized, Controlled, Open-Label, Clinical Study of the Efficacy and Safety of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Low-Blast Acute Myelogenous Leukemia

IRB MLNM1915

CC 16-190

Hospital Main Campus

Phase Phase 2

Disease Leukemia - Acute Myeloid (AML), Leukemia - Chronic Myelomonocytic (CMML), Myelodisplastic Syndrome (MDS)

Drug Azacitidine, Pevonedistat

Description

Description

Primary Objective
  • To determine in patients with HR MDS, CMML, and low-blast AML whether the combination of pevonedistat and azacitidine improves event-free survival (EFS) when compared to single-agent azacitidine; for patients with HR MDS or CMML, an event is defined as death or transformation to AML; for patients with low-blast AML, an event is defined as death or disease progression, see Section 7.4.21).
Secondary Objectives
  • To determine in patients with HR MDS, CMML, and low-blast AML whether the combination of pevonedistat and azacitidine improves overall survival (OS) when compared to single-agent azacitidine.
  • To determine in patients with HR MDS, CMML and low-blast AML whether the combination of pevonedistat and azacitidine improves 6-month and 1-year survival rates when compared to single-agent azacitidine.
  • To determine in patients with HR MDS and CMML whether the combination of pevonedistat and azacitidine delays time to AML transformation when compared to single-agent azacitidine.
  • To determine in patients with HR MDS, CMML, and low-blast AML whether the combination of pevonedistat and azacitidine, when compared to single-agent azacitidine, improves the rate of: CR, CR plus partial remission (CR+PR), and/or overall response. Overall response in HR MDS and CMML is defined as CR+PR+hematologic improvement [HI]); overall response in low-blast AML is defined as CR+PR.
  • To determine in patients with HR MDS, CMML and low-blast AML whether the combination of pevonedistat and azacitidine, when compared to single-agent azacitidine, improves the rate of CR, CR+PR, as well as the ORR by Cycle 4.
  • To determine in patients with HR MDS, CMML, and low-blast AML whether the combination of pevonedistat and azacitidine, when compared to single-agent azacitidine, improves duration of CR, CR+PR, and/or overall response.
  • To determine in patients with HR MDS, CMML, and low-blast AML whether the combination of pevonedistat and azacitidine improves time to first CR or PR when compared to single-agent azacitidine.
  • To determine in patients with HR MDS, CMML, and low-blast AML whether the combination of pevonedistat and azacitidine delays time to subsequent therapy when compared to single-agent azacitidine. Subsequent therapy is defined as agent(s) with antileukemic/anti-MDS activity (eg, cytarabine, anthracyclines, purine analogues, and hypomethylating agents other than azacitidine). Patients who discontinue study treatment to receive single-agent azacitidine off study would not be counted as receiving subsequent therapy.
  • To determine in patients with HR MDS, CMML, and low-blast AML whether the combination of pevonedistat and azacitidine improves rate of transfusion independence when compared to single-agent azacitidine. RBC or platelet transfusion independence requires that the patient receive no RBC or platelet transfusions, respectively, for a period of at least 8 weeks.
  • To determine in patients with HR MDS, CMML and low-blast AML whether the combination of pevonedistat and azacitidine reduces the percent of patients who have at least one inpatient hospital admission(s) related to HR MDS, CMML, or low-blast AML when compared to single-agent azacitidine.
  • To determine in patients with HR MDS, CMML and low-blast AML whether the combination of pevonedistat and azacitidine delays time to PD, relapse after CR or PR, or death when compared to single-agent azacitidine.
  • To evaluate in patients with HR MDS, CMML and low-blast AML, the safety of the combination of pevonedistat and azacitidine when compared to single-agent azacitidine.
  • To collect in patients with HR MDS, CMML, and low-blast AML, plasma concentration-time data for pevonedistat to contribute to future population PK analyses of pevonedistat.
Exploratory Objectives
  • To determine in patients with HR MDS, CMML and low-blast AML whether the combination of pevonedistat and azacitidine improves bone marrow blast reduction by Cycle 2 and Cycle 4 when compared to single-agent azacitidine.
  • To evaluate in patients with HR MDS, CMML and low-blast AML, the potential relationship between baseline molecular characteristics of the tumor (such as cytogenetic abnormalities and somatic mutations), circulating serum biomarkers (including miRNAs, proteins, and metabolites), and changes in gene expression and epigenetic modifications (between Screening and specified postdose time points) with the efficacy and/or safety of the combination of pevonedistat and azacitidine.
  • To evaluate in patients with HR MDS, CMML and low-blast AML, the potential relationship between germline polymorphisms (such as in proteasome pathway genes) and the efficacy and/or safety of the combination of pevonedistat and azacitidine.
  • To evaluate in patients with HR MDS, CMML and low-blast AML, potential mechanisms of treatment-emergent resistance, such as somatic mutations in NEDD8-activating enzyme subunits and key signaling pathways, or change in pathway activity, in tumors from patients who initially respond to therapy and then exhibit PD.
  • To assess in patients with HR MDS, CMML and low-blast AML, the effect on HRQOL of the combination of pevonedistat and azacitidine compared with single-agent azacitidine.
  • To explore in patients with HR MDS, CMML, and low-blast AML, potential relationships between polymorphic variations in genes encoding drug metabolizing enzymes (DME) or transporters that may be implicated in pevonedistat disposition and exposure to pevonedistat.
Inclusion Criteria

Inclusion Criteria

  1. Male or female patients 18 years or older.
  2. Morphologically confirmed diagnosis of MDS, nonproliferative CMML (ie, with WBC <20,000/μL), or low-blast AML based on 1 of the following:

  3. French-American-British (FAB) Classifications [4]:
    • Refractory anemia with excess blasts (RAEB - defined as having 5% to 20% myeloblasts in the bone marrow).
    • CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
    OR

    World Health Organization (WHO) Classifications [5]:

    • Refractory anemia with excess blasts-1 (RAEB-1 - defined as having 5% to 9% myeloblasts in the bone marrow).
    • Refractory anemia with excess blasts-2 (RAEB-2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood).
    • Chronic Myelomonocytic Leukemia-2 (CMML-2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood).
    • Chronic Myelomonocytic Leukemia-1 (Although CMML-1 is defined as having <10% myeloblasts in the bone marrow and/or <5% blasts in the blood, these patients may enroll only if bone marrow blasts ≥5%).
    • WHO-defined AML with 20% to 30% myeloblasts in the bone marrow (defined in this protocol as "Low-Blast AML") and < 30% myeloblasts in peripheral blood who are considered by investigator to be appropriate for azacitidine-based therapy.

  4. ECOG performance status of 0 to 2 (see Section 15.1).
  5. Clinical laboratory values within the following parameters within 3 days before the first dose of study drug:
    • Albumin >2.7 g/dL.
    • Total bilirubin <upper limit of normal (ULN) except in patients with Gilbert's syndrome. Patients with Gilbert's syndrome may enroll if direct bilirubin ≤ 1.5 x ULN of the direct bilirubin.
    • ALT and AST <2.5 x ULN.
    • Creatinine clearance >50 mL/min (see Section 15.2).
    • Hemoglobin >8 g/dL. Patients may be transfused to achieve this value. Elevated indirect bilirubin due to post-transfusion hemolysis is allowed.
  6. For CMML patients: WBC count <20,000/μL before administration of the first dose of study drug on Cycle 1 Day 1; patients must have been off hydroxyurea for at least 1 week prior to WBC count assessment.
  7. Ability to undergo the study-required bone marrow sample collection procedures.
  8. Suitable venous access for the study-required blood sampling (ie, including PK and biomarker sampling).
  9. Female patients who:
    • Are postmenopausal for at least 1 year before the Screening visit, or
    • Are surgically sterile, or
    • If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, or
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.) Male patients, even if surgically sterilized (ie, status postvasectomy), who:
      • Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or
      • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)
  10. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
Exclusion Criteria

Exclusion Criteria

  1. Previous treatment with decitabine or azacitidine or other hypomethylating agent.
  2. Therapy-related MDS, CMML, or low-blast AML associated with previous cytotoxic chemotherapy (eg, alkylating agents, topoisomerase inhibitors).
  3. Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis.
  4. Eligible for allogenic stem cell transplantation.
  5. Patients with MDS, CMML, or low-blast AML, whose only site of disease is extramedullary, eg, the skin.
  6. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures or could limit patient expected survival to less than 6 months.
  7. Treatment with any investigational products within 14 days before the first dose of any study drug.
  8. Known hypersensitivity to mannitol.
  9. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.
  10. Major surgery within 14 days before first dose or a scheduled surgery during study period; insertion of a venous access device (eg, catheter, port) is not considered major surgery.
  11. Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection.
  12. Life-threatening illness unrelated to cancer.
  13. Prothrombin time (PT) or aPTT > 1.5 ULN or active uncontrolled coagulopathy or bleeding disorder.
  14. Known human immunodeficiency virus (HIV) seropositive.
  15. Known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Patients who have isolated positive hepatitis B core antibody (ie, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load.
  16. Known hepatic cirrhosis or severe pre-existing hepatic impairment.
  17. Known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association [NYHA] Class III or IV; see Section 15.3), and/or myocardial infarction within 6 months prior to first dose, or severe pulmonary hypertension. As an example, well-controlled atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion.
  18. Treatment with strong CYP3A inhibitors or inducers (see Section 15.4) within 14 days before the first dose of pevonedistat.
  19. Systemic antineoplastic therapy or radiotherapy for other conditions within 12 months before the first dose of any study drug, except for hydroxyurea.
  20. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.