Clinical Trials /

Improving Risk Assessment of AML With a Precision Genomic Strategy to Assess Mutation Clearance

NCT02756962

Description:

The investigators will prospectively determine whether the relapse-free and overall survival in patients who have cleared their leukemia-associated mutations treated with standard consolidation chemotherapy is superior to what is expected based on historical controls. The investigators will also prospectively determine the relapse-free and overall survival of patients who have not cleared their mutations. Because the relapse rate of patients with persistent mutations is expected to be high, treatment with either standard of care consolidation therapy alone or alloSCT will be permitted, at the discretion of the treating physician.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Improving Risk Assessment of AML With a Precision Genomic Strategy to Assess Mutation Clearance
  • Official Title: Improving Risk Assessment of AML With a Precision Genomic Strategy to Assess Mutation Clearance

Clinical Trial IDs

  • ORG STUDY ID: 201606003
  • NCT ID: NCT02756962

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
CytarabineAra-C, Cytosar-U, Tarabine-PFS, AraCCohort A: HiDAC
MidostaurinCohort A: HiDAC

Purpose

The investigators will prospectively determine whether the relapse-free and overall survival in patients who have cleared their leukemia-associated mutations treated with standard consolidation chemotherapy is superior to what is expected based on historical controls. The investigators will also prospectively determine the relapse-free and overall survival of patients who have not cleared their mutations. Because the relapse rate of patients with persistent mutations is expected to be high, treatment with either standard of care consolidation therapy alone or alloSCT will be permitted, at the discretion of the treating physician.

Trial Arms

NameTypeDescriptionInterventions
Cohort A: HiDACExperimentalAt the time of diagnostic bone marrow biopsy, samples will be clinically sequenced Patients who have clearance of their leukemia-associated mutations, defined as a LAM VAF <2.5% will be assigned to the high-dose cytarabine consolidation (HiDAC) arm. HiDAC = Standard regimen of cytarabine 1.5 g/m^2 or 3 g/m^2 over 2-3 hours twice a day on Days 1, 3, & 5 of each 28 day cycle for 3-4 cycles. For patients with the FLT3-ITD or a FLT3-TKD mutation, therapy with the FDA-approved FLT3 inhibitor midostaurin is permitted at the discretion of the treating physician.
  • Cytarabine
  • Midostaurin
Cohort B: Investigator's choice (HiDAC, AlloSCT)ExperimentalAt the time of diagnostic bone marrow biopsy, samples will be clinically sequenced Patients who have persistent leukemia-associated mutations, defined as a LAM VAF ≥2.5% will be assigned to the investigator's choice arm. Patients assigned to this arm may received either HiDAC or AlloSCT. HiDAC = Standard regimen of cytarabine 1.5 g/m^2 or 3 g/m^2 over 2-3 hours twice a day on Days 1, 3, & 5 of each 28 day cycle for 3-4 cycles. The source of stem cell product, donor selection, conditioning regimen, graft-versus-host-prophylaxis, and supportive care will be at the discretion of the treatment physician For patients with the FLT3-ITD or a FLT3-TKD mutation, therapy with the FDA-approved FLT3 inhibitor midostaurin is permitted at the discretion of the treating physician.
  • Cytarabine
  • Midostaurin

Eligibility Criteria

        Inclusion Criteria:

          -  Age 18-60 years.

          -  Considered to be suitable intensive (cytotoxic) induction candidates.

          -  Has previously untreated, de novo, non-M3 AML with intermediate-risk disease
             (Intermediate-I or Intermediate-II) as defined by ELN criteria OR normal cytogenetics
             (after analysis of 20 or more metaphases) with mutated NPM1 without FLT3-ITD.
             Monoallelic CEBPA mutations are not considered favorable risk and are therefore
             eligible.

          -  Has undergone cytotoxic induction therapy

          -  In a morphologic complete remission with incomplete blood count recovery, or
             morphologic complete remission post-induction after no more than 2 induction cycles as
             defined by revised IWG criteria

          -  Patients at Washington University must be enrolled in HRPO# 201011766 ("Tissue
             Acquisition for Analysis of Genetic Progression Factors in Hematologic Diseases").This
             is not a requirement for secondary sites. However, secondary sites must provide
             informed consent forms that document that permission for whole genome, whole exome,
             and/or genome wide sequencing, and data sharing among institutions, was obtained.
             Because we will be also be sequencing non-diseased (normal) tissue, the informed
             consent forms must explicitly ask if patients wish to be informed, (or in the case of
             their death, their next-of-kin) if a deleterious mutation is identified in their
             non-diseased tissue, as this may be heritable.

          -  Women of childbearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control, abstinence) prior to study entry and for
             the duration of study participation. Should a woman become pregnant or suspect she is
             pregnant while participating in this study, she must inform her treating physician
             immediately.

          -  Able to understand and willing to sign an IRB approved written informed consent
             document.

          -  Willing to comply with the treatment assignment:

               -  Intent to proceed with HiDAC consolidation for LAM VAF <2.5%

               -  Intent to proceed with either HiDAC consolidation or allogeneic stem cell
                  transplantation, at the discretion of the treating physician, for LAM ≥2.5%

        Exclusion Criteria:

          -  Diagnosis acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA.

          -  Therapy-related AML (defined as occurrence of AML due to prior exposure to
             chemotherapy or radiation for malignancy).

          -  Secondary AML (defined as development of AML in patients with an antecedent
             hematological malignancy).

          -  Has a medical or psychosocial conditions that would prevent study compliance.

          -  Known seropositivity for or active viral infection with human immunodeficiency virus
             (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients who are
             seropositive because of hepatitis B vaccine are eligible.

          -  History of allergic reaction to compounds of similar chemical or biologic composition
             to cytarabine.

          -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
             pregnancy test within 3 days of signing consent.
      
Maximum Eligible Age:60 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Relapse free survival of Cohort A compared to intermediate risk historical control group
Time Frame:Up to 5 years
Safety Issue:
Description:Relapse-free survival is the time from study enrollment (morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) is required) until documented disease relapse, or death from any cause. CR=Defined as morphologic leukemia-free state, defined as less than 5% blasts in aspirate with marrow spicules and a count of ≥200 nucleated cells and no blasts with Auer rods or any persistence of extramedullary disease. In addition, ANC >1000/μl and platelet count of ≥100,000/μl. Patient must be independent of transfusions. No duration requirement for this designation. CRi=Defined as morphologic complete recovery with the exception of neutropenia <1000/μl or thrombocytopenia <100,000/μl.

Secondary Outcome Measures

Measure:Overall survival (OS) of Cohort A compared intermediate risk historical control group
Time Frame:Up to 5 years
Safety Issue:
Description:Overall survival is the time from enrollment on study until death from any cause.
Measure:Relapse free survival (RFS) of Cohort B
Time Frame:Up to 5 years
Safety Issue:
Description:Relapse-free survival is the time from study enrollment (morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) is required) until documented disease relapse, or death from any cause. CR=Defined as morphologic leukemia-free state, defined as less than 5% blasts in aspirate with marrow spicules and a count of ≥200 nucleated cells and no blasts with Auer rods or any persistence of extramedullary disease. In addition, ANC >1000/μl and platelet count of ≥100,000/μl. Patient must be independent of transfusions. No duration requirement for this designation. CRi=Defined as morphologic complete recovery with the exception of neutropenia <1000/μl or thrombocytopenia <100,000/μl.
Measure:Overall survival (OS) of Cohort B
Time Frame:Up to 5 years
Safety Issue:
Description:Overall survival is the time from enrollment on study until death from any cause.
Measure:Compare relapse free survival of Cohort A to Cohort B
Time Frame:Up to 5 years
Safety Issue:
Description:Relapse-free survival is the time from study enrollment (morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) is required) until documented disease relapse, or death from any cause. CR=Defined as morphologic leukemia-free state, defined as less than 5% blasts in aspirate with marrow spicules and a count of ≥200 nucleated cells and no blasts with Auer rods or any persistence of extramedullary disease. In addition, ANC >1000/μl and platelet count of ≥100,000/μl. Patient must be independent of transfusions. No duration requirement for this designation. CRi=Defined as morphologic complete recovery with the exception of neutropenia <1000/μl or thrombocytopenia <100,000/μl.
Measure:Compare overall survival of Cohort A to Cohort B
Time Frame:Up to 5 years
Safety Issue:
Description:Overall survival is the time from enrollment on study until death from any cause.
Measure:Compare relapse free survival of Cohort A to Cohort B
Time Frame:1 year
Safety Issue:
Description:Relapse-free survival is the time from study enrollment (morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) is required) until documented disease relapse, or death from any cause. CR=Defined as morphologic leukemia-free state, defined as less than 5% blasts in aspirate with marrow spicules and a count of ≥200 nucleated cells and no blasts with Auer rods or any persistence of extramedullary disease. In addition, ANC >1000/μl and platelet count of ≥100,000/μl. Patient must be independent of transfusions. No duration requirement for this designation. CRi=Defined as morphologic complete recovery with the exception of neutropenia <1000/μl or thrombocytopenia <100,000/μl.
Measure:Compare overall survival of Cohort A to Cohort B
Time Frame:1 year
Safety Issue:
Description:Overall survival is the time from enrollment on study until death from any cause.
Measure:Relapse free survival of Cohort B patients who receive alloSCT
Time Frame:Up to 5 years
Safety Issue:
Description:Relapse-free survival is the time from study enrollment (morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) is required) until documented disease relapse, or death from any cause. CR=Defined as morphologic leukemia-free state, defined as less than 5% blasts in aspirate with marrow spicules and a count of ≥200 nucleated cells and no blasts with Auer rods or any persistence of extramedullary disease. In addition, ANC >1000/μl and platelet count of ≥100,000/μl. Patient must be independent of transfusions. No duration requirement for this designation. CRi=Defined as morphologic complete recovery with the exception of neutropenia <1000/μl or thrombocytopenia <100,000/μl.
Measure:Overall survival of Cohort B patients who receive alloSCT
Time Frame:Up to 5 years
Safety Issue:
Description:Overall survival is the time from enrollment on study until death from any cause.
Measure:Relapse free survival of Cohort B patients who do not receive alloSCT
Time Frame:Up to 5 years
Safety Issue:
Description:Relapse-free survival is the time from study enrollment (morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) is required) until documented disease relapse, or death from any cause. CR=Defined as morphologic leukemia-free state, defined as less than 5% blasts in aspirate with marrow spicules and a count of ≥200 nucleated cells and no blasts with Auer rods or any persistence of extramedullary disease. In addition, ANC >1000/μl and platelet count of ≥100,000/μl. Patient must be independent of transfusions. No duration requirement for this designation. CRi=Defined as morphologic complete recovery with the exception of neutropenia <1000/μl or thrombocytopenia <100,000/μl.
Measure:Overall survival of Cohort B patients who do not receive alloSCT
Time Frame:Up to 5 years
Safety Issue:
Description:Overall survival is the time from enrollment on study until death from any cause.
Measure:Relapse free survival of patients with a LAM VAF <1.0% treated in Cohort A compared to intermediate risk historical control group
Time Frame:Up to 5 years
Safety Issue:
Description:LAM VAF = Leukemia Associated Mutations variant allele frequency Relapse-free survival is the time from study enrollment (morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) is required) until documented disease relapse, or death from any cause. CR=Defined as morphologic leukemia-free state, defined as less than 5% blasts in aspirate with marrow spicules and a count of ≥200 nucleated cells and no blasts with Auer rods or any persistence of extramedullary disease. In addition, ANC >1000/μl and platelet count of ≥100,000/μl. Patient must be independent of transfusions. No duration requirement for this designation. CRi=Defined as morphologic complete recovery with the exception of neutropenia <1000/μl or thrombocytopenia <100,000/μl.
Measure:Overall survival of patients with a LAM VAF <1.0% treated in Cohort A compared to intermediate risk historical control group
Time Frame:Up to 5 years
Safety Issue:
Description:--LAM VAF = Leukemia Associated Mutations variant allele frequency -Overall survival is the time from enrollment on study until death from any cause.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

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