Clinical Trials /

Study of Biomarker-Based Treatment of Acute Myeloid Leukemia

NCT03013998

Description:

This screening and multi-sub-study Phase 1b/2 trial will establish a method for genomic screening followed by assigning and accruing simultaneously to a multi-study "Master Protocol (BAML-16-001-M1)." The specific subtype of acute myeloid leukemia will determine which sub-study, within this protocol, a participant will be assigned to evaluate investigational therapies or combinations with the ultimate goal of advancing new targeted therapies for approval. The study also includes a marker negative sub-study which will include all screened patients not eligible for any of the biomarker-driven sub-studies.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia
  • Official Title: A Master Protocol for Biomarker-Based Treatment of AML (The Beat AML Trial)

Clinical Trial IDs

  • ORG STUDY ID: BAML-16-001
  • NCT ID: NCT03013998

Conditions

  • Previously Untreated Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Samalizumab (BAML-16-001-S1)BAML-16-001-S1
BI 836858 (BAML-16-001-S2)BAML-16-001-S2
Daunorubicin (BAML-16-001-S1)BAML-16-001-S1
Cytarabine (BAML-16-001-S1)BAML-16-001-S1
Azacitidine (BAML-16-001-S2)BAML-16-001-S2
AG-221 (BAML-16-001-S3)EnasidenibBAML-16-001-S3
Azacitidine (BAML-16-001-S3)BAML-16-001-S3
Entospletinib (BAML-16-001-S4)GS-9973, ENTOBAML-16-001-S4
Azacitidine (BAML-16-001-S4)BAML-16-001-S4
Entospletinib (BAML-16-001-S5)GS-9973, ENTOBAML-16-001-S5
Decitabine (BAML-16-001-S5)BAML-16-001-S5
Entospletinib (BAML-16-001-S6)GS-9973, ENTOBAML-16-001-S6
Azacitidine (BAML-16-001-S6)BAML-16-001-S6
Daunorubicin (BAML-16-001-S6)BAML-16-001-S6
Cytarabine (BAML-16-001-S6)BAML-16-001-S6
Pevonedistat (BAML-16-001-S9)TAK-924, MLN4924BAML-16-001-S9
Azacitidine (BAML-16-001-S9)BAML-16-001-S9
AG-120 (BAML-16-001-S16)BAML-16-001-S16
Azacitidine (BAML-16-001-S16)BAML-16-001-S16
Gilteritinib (BAML-16-001-S8)BAML-16-001-S8
Decitabine (BAML-16-001-S8)BAML-16-001-S8

Purpose

This screening and multi-sub-study Phase 1b/2 trial will establish a method for genomic screening followed by assigning and accruing simultaneously to a multi-study "Master Protocol (BAML-16-001-M1)." The specific subtype of acute myeloid leukemia will determine which sub-study, within this protocol, a participant will be assigned to evaluate investigational therapies or combinations with the ultimate goal of advancing new targeted therapies for approval. The study also includes a marker negative sub-study which will include all screened patients not eligible for any of the biomarker-driven sub-studies.

Trial Arms

NameTypeDescriptionInterventions
BAML-16-001-S1ExperimentalThis is an open-label Phase 1b/2 clinical study of Samalizumab given in addition to standard induction chemotherapy/consolidation, followed by Samalizumab maintenance, in newly diagnosed acute myeloid leukemia. Patients that are marker negative, as defined based on the Beat AML Master Protocol assignment or with CBF karyotype/interphase cytogenetics/molecular testing defined by presence of t(8;21)(q22;q22) or the molecular equivalent RUNX1/RUNX1T1 fusion transcript or inv(16)(p13q22) or t(16;16)(p13;q22) or the molecular equivalent CBFB/MYH11 fusion transcript based on the Beat AML will receive Samalizumab in combination with induction therapy followed by Samalizumab maintenance.
  • Samalizumab (BAML-16-001-S1)
  • Daunorubicin (BAML-16-001-S1)
  • Cytarabine (BAML-16-001-S1)
BAML-16-001-S2ExperimentalThis is an open-label Phase 1b/2 clinical study of BI 836858 given in combination with azacitidine, followed by BI 836858 plus azacitidine maintenance, in newly diagnosed acute myeloid leukemia. The target population is assigned by the Beat AML Master Protocol (the "umbrella" study). Eligible patients will have previously untreated acute myeloid leukemia, age greater than or equal to 60, with any 1 of the following: mutated TET2, IDH1, IDH2, or WT1, or "marker negative" as defined by the overall Beat AML umbrella protocol.
  • BI 836858 (BAML-16-001-S2)
  • Azacitidine (BAML-16-001-S2)
BAML-16-001-S3ExperimentalThis is a phase 2 clinical trial to assess the feasibility and efficacy of a stepwise approach to the treatment of IDH2-mutant AML. On day 1 of the trial, all enrolled participants will be initiated on therapy with the IDH2 inhibitor AG-221 for IDH2 R140 and R172-mutant patients. The dosing will be based on phase 1 experience of AG-221, which has established 100 mg daily as a safe and tolerated dose, with preliminary suggestion of efficacy. These will be administered continuously in 28 day cycles. Hydroxyurea will be allowed for the purposes of cytoreduction.
  • AG-221 (BAML-16-001-S3)
  • Azacitidine (BAML-16-001-S3)
BAML-16-001-S4ExperimentalThis is a 2 cohort phase 1b/2 clinical trial to assess the feasibility and efficacy of entospletinib (ENTO) stepwise approach to the treatment of patients with balanced translocations of MLL identified cytogenetically (Cohort 1) and patients with MLL-partial tandem duplications identified molecularly (Cohort 2). All enrolled participants will be initiated on monotherapy with ENTO 400 mg PO BID. This dose will be administered continuously in 28 day cycles.
  • Entospletinib (BAML-16-001-S4)
  • Azacitidine (BAML-16-001-S4)
BAML-16-001-S5ExperimentalThis is a phase 2 clinical trial to assess the feasibility and efficacy of a stepwise approach to the treatment of patients with TP53 mutations (identified molecularly) with/without complex karyotype (Cohort A) or complex karyotype (3 or greater metaphase abnormalities without TP53) (Cohort B). All enrolled participants will be initiated on entospletinib 400 mg orally twice daily. This dose will be administered continuously in 28 day cycles.
  • Entospletinib (BAML-16-001-S5)
  • Decitabine (BAML-16-001-S5)
BAML-16-001-S6ExperimentalThe study is an open-label phase 2 study of entospletinib in older AML patients with NPM1+/FLT3ITD- AML. It includes 2 Cohorts: patients 1) age <75 years; 2) have ECOG performance status of 0-1, and 3) are willing to receive 7 + 3 intensive chemotherapy (Cohort A); and patients who do not meet criteria for Cohort A (Cohort B). In Cohort A, entospletinib lead-in is administered on days 1-5 as a single agent (Cycle 0) and is then given daily with IV daunorubicin (days 1-3 for Cycle 1) and cytarabine (days 1-7 for Cycle 1). If a second induction is required, it is given with IV daunorubicin (days 1-2 for Cycle 2) and cytarabine (days 1-5 for Cycle 2). In Cohort B, for subjects receiving monotherapy, entospletinib is given daily for every 28 day cycle until the subject meets criteria for treatment discontinuation; for subjects receiving combination therapy, entospletinib is administered daily on days 1-28 as a single agent (Cycle 1) with azacitidine on days 1-7 of subsequent 28 day cycles
  • Entospletinib (BAML-16-001-S6)
  • Azacitidine (BAML-16-001-S6)
  • Daunorubicin (BAML-16-001-S6)
  • Cytarabine (BAML-16-001-S6)
BAML-16-001-S9ExperimentalThis is an open-label phase 2 clinical trial of a stepwise approach to the treatment of patients with TP53 mutation AML. On day 1, all enrolled participants will be initiated on therapy with pevonedistat (20 mg/m2) day 1, 3 and 5 together with azacitidine (75 mg/m2 days 1-7 or day 1-5 then day 8, 9) every 28 days. During cycle 1, patients with rapidly progressive disease or severe organ dysfunction, not correctable by hydroxyurea cytoreduction will not be eligible to continue. Those patients who achieved a response, defined as complete response or complete response with incomplete blood count recovery, by the end of cycle 4 will continue on pevonedistat and azacitidine until disease progression, unacceptable toxicity, or 12 cycles of therapy. After 12 months of combined therapy, pevonedistat will be continued until progression of disease, unacceptable toxicity, or up to 2 years of total therapy.
  • Pevonedistat (BAML-16-001-S9)
  • Azacitidine (BAML-16-001-S9)
BAML-16-001-S16ExperimentalThis is an open-label phase 2 clinical study to assess the feasibility and efficacy of a combination based approach to the treatment of IDH1 mutant AML. On day 1 of the trial, all enrolled participants will be initiated on therapy with the IDH1 inhibitor AG-120 given daily together with azacitidine (days 1-5 and 8-9 or 7 consecutive days 1-7) in 28 day cycles for IDH1 mutant patients. Those patients who have achieved a response, defined as complete response or complete response with incomplete blood count recovery, by the end of cycle 6, will continue on combination therapy for a total of 12 cycles and then patients will go onto receive monotherapy with AG-120 until disease progression or unacceptable side effects that mandate discontinuation of therapy. Patients who cannot complete 12 cycles of azacitidine may proceed onto monotherapy with AG-120.
  • AG-120 (BAML-16-001-S16)
  • Azacitidine (BAML-16-001-S16)
BAML-16-001-S8ExperimentalThis is an open-label Phase 2/1b clinical study of gilteritinib as a single agent stratified into 2 cohorts in phase 2 portion based upon dominant versus non-dominant FLT3 mutation status. Cohort 1, Dominant FLT3, will include patients with either FLT3-ITD with allelic ratio of ≥0.5 stratified based upon the prioritization schema of the master trial; FLT3-TKD with highest variant allele frequency among mutations studied for stratification; or FLT3-TKD with second highest variant allele frequency in setting of DNMT3A, TET2, ASXL1, BCORL1, JAK2, and SF3B1 or other spliceosome family member. Cohort 2, non-dominant FLT3, will include the remainder of patients with FLT3-ITD or FLT3-TKD stratified based upon the master umbrella study protocol. For the phase 1b portion, gilteritinib will be given in combination with decitabine for non-responding patients to test the efficacy of gilteritinib in combination with decitabine in elderly AML with FLT3 mutation.
  • Gilteritinib (BAML-16-001-S8)
  • Decitabine (BAML-16-001-S8)

Eligibility Criteria

        Inclusion Criteria:

          -  Adults, age 60 years or older at the time of diagnosis

          -  Subjects or their legal representative must be able to understand and provide written
             informed consent

          -  Cohort Inclusion Criteria - Group A: Subjects must have previously untreated acute
             myeloid leukemia (AML) according to the WHO classification with no prior treatment
             other than hydroxyurea. Prior therapy for myelodysplastic syndrome (MDS),
             myeloproliferative syndromes (MPD), or aplastic anemia is permitted but not with
             hypomethylating agents.

          -  Cohort Inclusion Criteria - Group B: Subjects must have relapsed or refractory AML
             according to the WHO classification. For study purposes, refractory AML is defined as
             failure to ever achieve CR or recurrence of AML within 6 months of achieving CR;
             relapsed AML is defined as all others with disease after prior remission. (Group B is
             not currently recruiting.)

        Exclusion Criteria:

          -  Isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement with
             AML to enter the study)

          -  Acute promyelocytic leukemia

          -  Symptomatic central nervous system (CNS) involvement by AML

          -  Signs of leukostasis requiring urgent therapy

          -  Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis

          -  Patients with psychological, familial, social, or geographic factors that otherwise
             preclude them from giving informed consent, following the protocol, or potentially
             hamper compliance with study treatment and follow-up

          -  Any other significant medical condition, including psychiatric illness or laboratory
             abnormality, that would preclude the patient participating in the trial or would
             confound the interpretation of the results of the trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of patients for whom molecular, immunophenotypic, and/or biochemical studies are completed in < 7 calendar days for assignment of treatment
Time Frame:7 days
Safety Issue:
Description:The feasibility of completing molecular, genetic, immunophenotypic, and biochemical testing for assignment of therapy will be assessed based on the proportion of patients for whom testing is completed within 7 days of the registration sample arriving at the laboratory

Secondary Outcome Measures

Measure:Proportion of patients enrolled on this trial that ultimately will be assigned and go onto an assigned therapy
Time Frame:7 days
Safety Issue:
Description:
Measure:Dynamic changes in clonal architecture over time in acute myeloid leukemia patients receiving targeted therapies
Time Frame:time of diagnosis, remission (complete response or complete response with incomplete blood count recovery), 1 year of treatment, and relapse
Safety Issue:
Description:
Measure:Relationships between baseline functional status and response rate or progression-free survival based on graphical comparison (eg, side-by-side boxplots or Kaplan-Meier plots)
Time Frame:Up to 5 years
Safety Issue:
Description:Assessments of functional status will include Eastern Cooperative Oncology Group Performance Status. Assessment of clinical response will be made according to International Working Group criteria. Relationships will be explored graphically (eg, side-by-side boxplots or Kaplan-Meier plots), where estimates with confidence intervals will be presented as the primary method of analysis due to the limited number of patients.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Beat AML, LLC

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