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PANTHER: A phase 3, randomized, controlled, open-label, clinical study of pevonedistat plus azacitidine vs. single-agent azacitidine as first-line treatment for patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), or low-blast acute myelogenous leukemia (AML)

Description

The purpose of this study is to determine whether the combination of pevonedistat and azacitidine improves overall response rate and whether the combination of pevonedistat and azacitidine improves event-free survival when compared with single-agent azacitidine. The drug being tested in this study is called pevonedistat. Pevonedistat is being tested to treat people with higher-risk MDS, CMML and low-blast AML as a combination treatment with azacitidine. This study will look at the overall survival, event-free survival and response to treatment in people who take pevonedistat and azacitidine when compared to people who take single-agent azacitidine.

Status

Accepting new patients

Primary Study Objective(s)

The objectives of this study are:

  • To determine whether the combination of pevonedistat and azacitidine improves overall response rate by cycle six when compared with single-agent azacitidine (Overall response in patients with HR MDS or CMML is defined as CR+PR; overall response in patients with low-blast AML is defined as CR+complete remission with incomplete blood count recovery [CRi]+PR.)
  • To determine whether the combination of pevonedistat and azacitidine improves event-free survival when compared with single-agent azacitidine (An event is defined as death or transformation to AML in patients with MDS or CMML, whichever occurs first, and is defined as death in patients with low-blast AML.)

Core eligibility

Note: This is only a partial list of eligibility criteria.

Including patients who:

  • Have morphologically confirmed diagnosis of MDS, non-proliferative CMML (i.e., with white blood cell [WBC] <13,000/μL) or low-blast AML
  • Have MDS or CMML and must also have one of the following prognostic risk categories, based on the Revised International Prognostic Scoring System:
    • Very high (>6 points)
    • High (>4.5-6 points)
    • Intermediate (>3-4.5 points): a patient determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of >=5% bone marrow myeloblasts
  • Have Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2
  • Have AML (20 percent to 30 percent blasts) with treatment-related mortality score >=4 for intensive, induction chemotherapy as calculated using the simplified model described by Walter and coworkers

Calculation of TRM score:

    • 0 for (age <61 years), +2 for (age 61-70 years), +4 for (age >71 years)
    • + 0 for (PS=0), +2 for (PS=1), +4 for (PS >1)
    • + 0 for (platelets <50), +1 for (platelets >50)
Excluding patients who:
  • Have had previous treatment for higher-risk MDS or low-blast AML with chemotherapy or other antineoplastic agents including hypomethylating agent such as decitabine or azacitidine. Previous treatment is permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given within eight weeks before the first dose of study drug.
  • Have 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.
  • Is eligible for intensive chemotherapy and/or allogeneic stem cell transplantation. 
    • The reason a participant is not eligible for intensive chemotherapy and/or allogeneic stem cell transplantation may consist of one or more of the following factors:
      • Older than 75
      • Comorbidities
      • Inability to tolerate intensive chemotherapy (e.g., patients with AML with 20 percent to 30 percent blasts and TRM ≥4
      • Physician decision (e.g., lack of available stem cell donor).
      • The reason a participant is not eligible should be documented in the electronic case report form

  • Have either clinical evidence of or history of central nervous system involvement by AML
  • Have active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia
  • Is diagnosed or treated for another malignancy within two years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease
  • Have nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection.
  • Have prothrombin time (PT) or aPTT >1.5× upper limit of normal (ULN) or active uncontrolled coagulopathy or bleeding disorder. Participants therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment
  • Have known human immunodeficiency virus (HIV) seropositive
  • Have known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection (Note: Participants who have isolated positive hepatitis B core antibody [i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody] must have an undetectable hepatitis B viral load)
  • Have known hepatic cirrhosis or severe preexisting hepatic impairment
  • Have known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), and/or myocardial infarction within six months before first dose, or severe pulmonary hypertension
  • Have treatment with strong cytochrome P 3A inducers within 14 days before the first dose of pevonedistat