NCT02756962Active, not recruitingPhase 2
Improving Risk Assessment of AML With a Precision Genomic Strategy to Assess Mutation Clearance
Washington University School of Medicine3 sites in 1 country107 target enrollmentStarted: July 6, 2016Last updated:
Conditions
Interventions
Drugs
Trial Snapshot
- Phase
- Phase 2
- Status
- Active, not recruiting
- Enrollment
- 107
- Locations
- 3
- Primary Endpoint
- Relapse free survival of Cohort A compared to intermediate risk historical control group
Study Overview
Brief Summary
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 60 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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 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.
Arms & Interventions
Cohort A: HiDAC
Experimental
- At the time of diagnostic bone marrow biopsy, samples will be clinically sequenced via ClinSeq
- 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. Can be replaced by Onureg with permission from PI.
- 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.
Intervention: Cytarabine (Drug)
Cohort A: HiDAC
Experimental
- At the time of diagnostic bone marrow biopsy, samples will be clinically sequenced via ClinSeq
- 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. Can be replaced by Onureg with permission from PI.
- 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.
Intervention: Bone marrow aspiration (Procedure)
Cohort A: HiDAC
Experimental
- At the time of diagnostic bone marrow biopsy, samples will be clinically sequenced via ClinSeq
- 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. Can be replaced by Onureg with permission from PI.
- 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.
Intervention: Punch skin biopsy (Procedure)
Cohort A: HiDAC
Experimental
- At the time of diagnostic bone marrow biopsy, samples will be clinically sequenced via ClinSeq
- 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. Can be replaced by Onureg with permission from PI.
- 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.
Intervention: ClinSeq (Device)
Cohort B: Investigator's choice (HiDAC, AlloSCT)
Experimental
- At the time of diagnostic bone marrow biopsy, samples will be clinically sequenced via ClinSeq
- 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. Can be replaced by Onureg with permission from PI.
- 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.
Intervention: Cytarabine (Drug)
Cohort B: Investigator's choice (HiDAC, AlloSCT)
Experimental
- At the time of diagnostic bone marrow biopsy, samples will be clinically sequenced via ClinSeq
- 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. Can be replaced by Onureg with permission from PI.
- 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.
Intervention: Allogeneic stem cell transplant (Procedure)
Cohort B: Investigator's choice (HiDAC, AlloSCT)
Experimental
- At the time of diagnostic bone marrow biopsy, samples will be clinically sequenced via ClinSeq
- 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. Can be replaced by Onureg with permission from PI.
- 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.
Intervention: Bone marrow aspiration (Procedure)
Cohort B: Investigator's choice (HiDAC, AlloSCT)
Experimental
- At the time of diagnostic bone marrow biopsy, samples will be clinically sequenced via ClinSeq
- 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. Can be replaced by Onureg with permission from PI.
- 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.
Intervention: Punch skin biopsy (Procedure)
Cohort B: Investigator's choice (HiDAC, AlloSCT)
Experimental
- At the time of diagnostic bone marrow biopsy, samples will be clinically sequenced via ClinSeq
- 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. Can be replaced by Onureg with permission from PI.
- 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.
Intervention: ClinSeq (Device)
Outcomes
Primary Outcomes
Relapse free survival of Cohort A compared to intermediate risk historical control group
Time Frame: Up to 5 years
* 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 Outcomes
- Overall survival (OS) of Cohort A compared intermediate risk historical control group(Up to 5 years)
- Overall survival (OS) of Cohort B(Up to 5 years)
- Relapse free survival (RFS) of Cohort B(Up to 5 years)
- Relapse free survival of Cohort B patients who receive alloSCT(Up to 5 years)
- Overall survival of Cohort B patients who receive alloSCT(Up to 5 years)
- Relapse free survival of Cohort B patients who do not receive alloSCT(Up to 5 years)
- Compare overall survival of Cohort A to Cohort B(1 year)
- Compare relapse free survival of Cohort A to Cohort B(1 year)
- Overall survival of patients with a LAM VAF <1.0% treated in Cohort A compared to intermediate risk historical control group(Up to 5 years)
- Overall survival of Cohort B patients who do not receive alloSCT(Up to 5 years)
- Relapse free survival of patients with a LAM VAF <1.0% treated in Cohort A compared to intermediate risk historical control group(Up to 5 years)
Investigators
Study Sites (3)
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