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

Phase 2

Active, not recruiting

• Conditions: Acute Myeloid Leukemia
• Interventions: Drug: Cytarabine; Procedure: Bone marrow aspiration; Procedure: Allogeneic stem cell transplant; Procedure: Punch skin biopsy; Device: ClinSeq

• Registration Number: NCT02756962
• Lead Sponsor: Washington University School of Medicine

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2016-04-27
• Study First Submitted QC: 2016-04-27
• Study First Posted: 2016-04-29
• Study Start: 2016-07-06
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-24
• Last Update Posted: 2024-10-28
• Primary Completion: 2029-07-31
• Study Completion: 2029-07-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 107

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A: HiDAC	Bone marrow aspiration	* 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.
Cohort A: HiDAC	Punch skin biopsy	* 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.
Cohort A: HiDAC	ClinSeq	* 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.
Cohort B: Investigator's choice (HiDAC, AlloSCT)	Allogeneic stem cell transplant	* 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.
Cohort B: Investigator's choice (HiDAC, AlloSCT)	Bone marrow aspiration	* 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.
Cohort B: Investigator's choice (HiDAC, AlloSCT)	Punch skin biopsy	* 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.
Cohort B: Investigator's choice (HiDAC, AlloSCT)	ClinSeq	* 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.
Cohort A: HiDAC	Cytarabine	* 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.
Cohort B: Investigator's choice (HiDAC, AlloSCT)	Cytarabine	* 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.

Primary Outcome Measures

Name	Time	Method
Relapse free survival of Cohort A compared to intermediate risk historical control group	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 Outcome Measures

Name	Time	Method
Overall survival (OS) of Cohort A compared intermediate risk historical control group	Up to 5 years	Overall survival is the time from enrollment on study until death from any cause.
Overall survival (OS) of Cohort B	Up to 5 years	Overall survival is the time from enrollment on study until death from any cause.
Relapse free survival (RFS) of Cohort B	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.
Relapse free survival of Cohort B patients who receive alloSCT	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.
Overall survival of Cohort B patients who receive alloSCT	Up to 5 years	Overall survival is the time from enrollment on study until death from any cause.
Relapse free survival of Cohort B patients who do not receive alloSCT	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.
Compare overall survival of Cohort A to Cohort B	1 year	Overall survival is the time from enrollment on study until death from any cause.
Compare relapse free survival of Cohort A to Cohort B	1 year	* 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.
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	--LAM VAF = Leukemia Associated Mutations variant allele frequency; -Overall survival is the time from enrollment on study until death from any cause.
Overall survival of Cohort B patients who do not receive alloSCT	Up to 5 years	Overall survival is the time from enrollment on study until death from any cause.
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	* 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.

Trial Locations

Locations (3)

University of Florida; 🇺🇸 Gainesville, Florida, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

University of Rochester; 🇺🇸 Rochester, New York, United States