Clinical Trial 23154

• Overview

  Study Title:

  A Prospective, Multicenter, Randomized, Open-Label, Phase II Study of Salvage BCL2i Plus CLAG-M in Relapsed or Refractory Acute Myeloid Leukemia

  Objective:

  Primary Objective: Compare MRD-negative remission between treatment arms. Secondary Objectives: Estimate and descriptively compare: Event-Free survival (EFS): defined as failure to achieve morphologic remission, failure to achieve MRD-negative remission, relapse from MRD-negative remission, or death from any cause. This applies to both transplanted and non-transplanted patients. Overall response rate (ORR): a composite of complete remission (CR), complete remission with partial hematologic recovery (CRh), complete remission with incomplete blood count recovery (CRi), morphologic leukemia-free state (MLFS), partial remission (PR). Rate of composite complete remission (CR) and complete remission with partial/incomplete blood count recovery (CRh/CRi). This endpoint directly addresses the secondary objectives and will help to establish an early efficacy signal with this treatment combination. The definition of CR and CRi is based on the European LeukemiaNet 2022 Response Criteria. Rate of CRMRD- and durability of CRMRD-. Logistic regression will be used to calculate the odds ratio (OR) for MRD-negative CR. Overall survival (OS) based on treatment arm starting from treatment initiation with venetoclax and CLAG-M vs CLAG-M to death or last follow-up if alive at last follow-up. This endpoint directly addresses the secondary objectives and will help establish an early efficacy signal. The Kaplan-Meier method of survival analysis will be used in this assessment. EFS and OS in patients who achieved MRD-negative remission vs patients without MRD-negative remission. Outcomes after allogeneic stem cell transplantation (HSCT) in patients with CLAG-M + venetoclax versus CLAG-M alone and based on MRD status. 30- and 60-day mortality after treatment. Treatment-related toxicities. Rate of transition to allogeneic HSCT at anytime. Time to ANC/Platelet Recovery. Time to First Composite Complete Remission. Time to best response. Endpoints across clinical and molecular subgroups.

• Treatments

  Therapies:

  Chemotherapy (NOS); Therapy (NOS)

  Medications:

  Cladribine (); Cytarabine (Cytosine Arabinoside); G-CSF (); GDC-0199 (Venetoclax); Novantrone (mitoxantrone); Venetoclax (); mitoxantrone ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Provision of signed and dated informed consent form.
  • Ability to understand and stated willingness to comply with all study procedures and availability for the duration of the study.
  • Adults aged >=18 years to 80 years.
  • Patients with documented refractory or relapsed AML: Refractory disease is defined as failure to achieve CR (i.e., = 5% blasts in the marrow or peripheral blood, extramedullary disease.
  • Secondary AML arising out of MDS previously treated with HMA, HMA + venetoclax (if > 3 months from venetoclax exposure), and/or 1 cycle of induction chemotherapy.
  • Extramedullary AML with marrow involvement is allowed as long as concurrent medullary AML is present.
  • ECOG performance status > Participants must have adequate organ function.
  • Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Testing is not mandatory.
  • For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
  • Participants with a history of hepatitis C virus (HCV) infection must have been treated and have an undetectable HCV viral load. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. Testing is not mandatory.
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 4 months after completion of study drug administration.
  • Other inclusion criteria may apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Venetoclax-refractory disease or recent venetoclax exposure > Prior treatment with a high-dose cytarabine-containing regimen (e.g., no prior CLAG/FLAG/MEC/CLIA/HAM, etc.).
  • Allogeneic stem cell transplant in the past 3 months.
  • Less than 14 days from last AML-directed therapy or five half-lives, whichever is shorter, not including hydroxyurea.
  • Known history of prior TP53 mutation (results from any myeloid mutation panel are not required for screening eligibility).
  • Active CNS involvement by AML.
  • WBC count >=25k at the time study treatment begins.
  • Uncontrolled intercurrent systemic illness that would limit compliance.
  • Concurrent malignancy in addition to AML that requires active treatment with some exceptions.
  • Immunosuppressive therapy in the past 14 days except for prednisone at > Participants who have not recovered from adverse events (Aes) due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1), with the exception of alopecia.
  • Participants who are receiving any other investigational agents.
  • Participants with psychiatric illness/social situations that would limit compliance with study requirements.
  • Patients with active heart disease that limits the use of mitoxantrone or recent (> Pregnant women are excluded from this study because venetoclax, cladribine, and cytarabine are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these drugs, breastfeeding should be discontinued.
  • Other exclusion criteria may apply.

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