Clinical Trial 23750

• Overview

  Study Title:

  Phase 3 Randomized, Double-blind, Placebo-controlled Studies Assessing Ziftomenib in Combination with Either Standard of Care Nonintensive (Venetoclax+Azacitidine) or Intensive (7+3) Therapy in Patients with Untreated NPM1 Mutated or KMT2A Rearranged Acute Myeloid Leukemia

  Summary:

  Ziftomenib is an investigational drug in development for the treatment of patients with acute myeloid leukemia (AML) with certain genetic alterations. This protocol has 3 separate arms that will investigate the benefits and risks of adding ziftomenib to standard-of-care (SOC) drug treatments in patients who have AML with certain genetic mutations. Both newly diagnosed and relapsed refractory patients with AML will be assigned to different cohorts based on specific study criteria and physician discretion. The purpose of this study is to assess the safety, tolerability, and early signs of efficacy of ziftomenib in combination with SOC drugs to treat AML.

  Objective:

  Nonintensive Therapy Study (Ven+Aza) Primary and Secondary Objectives: Primary Objectives: To evaluate the effect of ziftomenib combined with SOC ven+aza on patient survival in untreated NPM1-m AML. To determine the efficacy of ziftomenib combined with SOC ven+aza in untreated NPM1-m AML. Secondary Objectives: To determine the rate of measurable residual disease (MRD) negativity achieved with ziftomenib combined with SOC ven+aza in untreated NPM1-m AML. To evaluate CR/CRh as an additional measure of efficacy of ziftomenib in combination with SOC ven+aza in untreated NPM1-m AML. To evaluate additional measures of efficacy of ziftomenib in combination with SOC ven+aza in untreated NPM1-m AML. To characterize the safety and tolerability of ziftomenib in combination with SOC ven+aza in untreated NPM1-m AML. To characterize the pharmacokinetics (PK) of ziftomenib and ven in the setting of SOC ven+aza in untreated NPM1-m AML. To evaluate if ziftomenib in combination with SOC ven+aza improves fatigue, physical functioning, role functioning, and tolerability based on patient-reported outcome (PRO) measures in untreated NPM1-m AML. Intensive Therapy Study (7+3) Primary and Secondary Objectives: Primary Objectives: To evaluate the effect of ziftomenib combined with SOC 7+3 on patient EFS in untreated NPM1-m and KMT2A-r AML. To determine the efficacy of ziftomenib combined with SOC 7+3 in untreated NPM1-m AML. Secondary Objectives: To evaluate the effect of ziftomenib combined with SOC 7+3 on patient survival in untreated NPM1-m and KMT2A-r AML. To evaluate additional measures of clinical activity of ziftomenib in combination with SOC 7+3 in untreated NPM1-m and KMT2A-r AML. To characterize the safety and tolerability of ziftomenib in combination with SOC 7+3 in untreated NPM1-m and KMT2A-r AML. To characterize the PK of ziftomenib when administered with SOC 7+3 in untreated NPM1-m and KMT2A-r AML. To evaluate if ziftomenib in combination with SOC 7+3 improves fatigue, physical functioning, role functioning, and tolerability based on PRO measures in untreated NPM1-m and KMT2A-r AML.

• Treatments

  Therapies:

  Chemotherapy (NOS); Therapy (NOS); menin-KMT2A interaction inhibitor

  Medications:

  Azacitidine (5-azacitidine); Cytarabine (Cytosine Arabinoside); Daunomycin (daunorubicin); GDC-0199 (Venetoclax); Venetoclax (); Ziftomenib/Placebo (); daunorubicin ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Patients must have a documented NPM1 mutation or KMT2A rearrangement and have either newly diagnosed or relapsed/refractory AML.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
  • Adequate liver, renal, and cardiac function according to protocol defined criteria.
  • A female of childbearing potential must agree to use adequate contraception as well as a double barrier method from the time of screening through 180 days following the last dose of study intervention. A male of childbearing potential must agree to use abstinence or use a double barrier method of contraception from the time of screening through 180 days following the last dose of study intervention.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Diagnosis of either acute promyelocytic leukemia or blast phase chronic myeloid leukemia.
  • Known history of BCR-ABL alteration.
  • Advanced malignant hepatic tumor.
  • Administration of live attenuated vaccines within 14 days prior to, during, or after treatment until B-cell recovery.
  • Active central nervous system (CNS) involvement by AML.
  • Clinical signs/symptoms of leukostasis or WBC > 25,000 / microliter. Hydroxyurea and/or leukapheresis and/or up to 2 doses of cytarabine if used per institutional SOC for control of leukocytosis are permitted to meet this criterion.
  • Not recovered to Grade ≤1 (NCI-CTCAE v5.0) from all nonhematological toxicities except for alopecia.
  • Known clinically active human immunodeficiency virus, active hepatitis B or active hepatitis C infection.
  • For newly diagnosed cohorts: received prior chemotherapy for leukemia, except hydroxyurea and/or leukapheresis and/or up to 2 doses of cytarabine per institutional standards to control leukocytosis, or prior treatment with all-transretinoic acid for initially suspected acute promyelocytic leukemia.
  • For relapsed/refractory cohorts: received chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy that is considered to be investigational > Uncontrolled intercurrent illness including, but not limited to, cardiac illness as defined in the protocol.
  • Mean QT interval corrected for heart rate by Fredericia's formula (QTcF): Arm A and Arm B: >480 ms on triplicate ECGs. Arm C: >450 ms on triplicate ECGs.
  • Uncontrolled infection.
  • Women who are pregnant or lactating.
  • An active malignancy and currently receiving chemotherapy for that malignancy or disease that is uncontrolled/progressing.
  • Patients who have active GVHD requiring >0.5 mg/kg prednisone or any new or increase in immunosuppressants in the prior 2 weeks for GVHD treatment.

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