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

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ClinicalTrials.gov Identifier: NCT02756962
Recruitment Status : Recruiting
First Posted : April 29, 2016
Last Update Posted : September 11, 2019
Sponsor:
Collaborators:
The Leukemia and Lymphoma Society
American Society of Hematology
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Cytarabine Procedure: Allogeneic stem cell transplant Procedure: Bone marrow aspiration Procedure: Punch skin biopsy Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 43 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Improving Risk Assessment of AML With a Precision Genomic Strategy to Assess Mutation Clearance
Actual Study Start Date : July 6, 2016
Estimated Primary Completion Date : July 31, 2024
Estimated Study Completion Date : July 31, 2024


Arm Intervention/treatment
Experimental: Cohort A: HiDAC
  • At 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.
Drug: Cytarabine
Other Names:
  • Ara-C
  • Cytosar-U
  • Tarabine-PFS
  • AraC

Procedure: Bone marrow aspiration
  • Baseline
  • Approximately 30 days after cytotoxic induction therapy
  • End of treatment

Procedure: Punch skin biopsy
  • The first will be obtained with the initial blood and bone marrow collections, whenever possible.
  • The second will be obtained at the time of re-biopsy to confirm remission.

Experimental: Cohort B: Investigator's choice (HiDAC, AlloSCT)
  • At 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.
Drug: Cytarabine
Other Names:
  • Ara-C
  • Cytosar-U
  • Tarabine-PFS
  • AraC

Procedure: Allogeneic stem cell transplant
Other Name: AlloSCT

Procedure: Bone marrow aspiration
  • Baseline
  • Approximately 30 days after cytotoxic induction therapy
  • End of treatment

Procedure: Punch skin biopsy
  • The first will be obtained with the initial blood and bone marrow collections, whenever possible.
  • The second will be obtained at the time of re-biopsy to confirm remission.




Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. Overall survival (OS) of Cohort A compared intermediate risk historical control group [ Time Frame: Up to 5 years ]
    Overall survival is the time from enrollment on study until death from any cause.

  2. Relapse free survival (RFS) of Cohort B [ 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.

  3. Overall survival (OS) of Cohort B [ Time Frame: Up to 5 years ]
    Overall survival is the time from enrollment on study until death from any cause.

  4. Compare relapse free survival of Cohort A to Cohort B [ 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.

  5. Compare overall survival of Cohort A to Cohort B [ Time Frame: Up to 5 years ]
    Overall survival is the time from enrollment on study until death from any cause.

  6. Compare relapse free survival of Cohort A to Cohort B [ Time Frame: 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.

  7. Compare overall survival of Cohort A to Cohort B [ Time Frame: 1 year ]
    Overall survival is the time from enrollment on study until death from any cause.

  8. Relapse free survival of Cohort B patients who receive alloSCT [ 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.

  9. Overall survival of Cohort B patients who receive alloSCT [ Time Frame: Up to 5 years ]
    Overall survival is the time from enrollment on study until death from any cause.

  10. Relapse free survival of Cohort B patients who do not receive alloSCT [ 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.

  11. Overall survival of Cohort B patients who do not receive alloSCT [ Time Frame: Up to 5 years ]
    Overall survival is the time from enrollment on study until death from any cause.

  12. 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 ]
    • 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.

  13. 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 ]

    --LAM VAF = Leukemia Associated Mutations variant allele frequency

    -Overall survival is the time from enrollment on study until death from any cause.




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02756962


Contacts
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Contact: Meagan Jacoby, M.D., Ph.D. 314-454-8304 mjacoby@wustl.edu

Locations
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United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States, 32608
Contact: Christopher Cogle, M.D.    352-733-0972      
Principal Investigator: Christopher Cogle, M.D.         
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Meagan Jacoby, M.D., Ph.D.    314-454-8304    mjacoby@wustl.edu   
Principal Investigator: Meagan Jacoby, M.D., Ph.D.         
Sub-Investigator: Timothy Ley, M.D.         
Sub-Investigator: David Spencer, M.D., Ph.D.         
Sub-Investigator: Camille Abboud, M.D.         
Sub-Investigator: John DiPersio, M.D., Ph.D.         
Sub-Investigator: Todd Fehniger, M.D., Ph.D.         
Sub-Investigator: Armin Ghobadi, M.D.         
Sub-Investigator: Brad Kahl, M.D.         
Sub-Investigator: Iskra Pusic, M.D.         
Sub-Investigator: Mark Schroeder, M.D.         
Sub-Investigator: Keith Stockerl-Goldstein, M.D.         
Sub-Investigator: Geoffrey Uy, M.D.         
Sub-Investigator: Ravi Vij, M.D.         
Sub-Investigator: Matthew Walter, M.D.         
Sub-Investigator: Lukas Wartman, M.D.         
Sub-Investigator: John Welch, M.D., Ph.D.         
Sub-Investigator: Peter Westervelt, M.D., Ph.D.         
Sub-Investigator: Tanya Wildes, M.D.         
Sub-Investigator: Terrence Wong, M.D.         
Sub-Investigator: Jack Baty, B.A.         
United States, New York
University of Rochester Recruiting
Rochester, New York, United States, 14642
Contact: Eric Huselton, M.D.    585-276-3017      
Principal Investigator: Eric Huselton, M.D.         
Sponsors and Collaborators
Washington University School of Medicine
The Leukemia and Lymphoma Society
American Society of Hematology
Investigators
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Principal Investigator: Meagan Jacoby, M.D., Ph.D. Washington University School of Medicine

Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT02756962     History of Changes
Other Study ID Numbers: 201606003
First Posted: April 29, 2016    Key Record Dates
Last Update Posted: September 11, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Cytarabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs