Clinical Trials /

Single Agent Decitabine in TP53 Mutated Relapsed/Refractory Acute Myeloid Leukemia

NCT03063203

Description:

In this study, the investigators seek to determine whether decitabine therapy can improve outcomes, specifically overall survival this selected subset of acute myeloid leukemia (AML) patients with the poorest prognosis based on refractoriness to induction treatment and high risk genetic mutations.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Single Agent Decitabine in TP53 Mutated Relapsed/Refractory Acute Myeloid Leukemia
  • Official Title: An Open Label, Multicenter, Phase II Trial Testing Single Agent Decitabine in TP53 Mutated Relapsed/Refractory Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 201703089
  • NCT ID: NCT03063203

Conditions

  • Acute Myeloid Leukemia
  • Acute Myeloid Leukemia, Relapsed, Adult

Interventions

DrugSynonymsArms
Decitabine5-aza-2'-deoxycytidineDecitabine

Purpose

In this study, the investigators seek to determine whether decitabine therapy can improve outcomes, specifically overall survival this selected subset of acute myeloid leukemia (AML) patients with the poorest prognosis based on refractoriness to induction treatment and high risk genetic mutations.

Trial Arms

NameTypeDescriptionInterventions
DecitabineExperimentalCycle 1: All patients will receive decitabine 20 mg/m^2 IV infusion per day over one hour on Days 1-10 of a 28-day cycle Cycle 2: Patients with bone marrow blast counts < 5% may receive decitabine 20 mg/m^2 IV infusion per day over one hour on Days 1-5 of a 28-day cycle. All other patients will receive decitabine 20 mg/m^2 IV infusion per day over one hour on Days 1-10 of a 28-day cycle. Cycle 3 and subsequent cycles: All patients will receive 20 mg/m^2 IV infusion per day over one hour on Days 1-5 of the 28-day cycle
  • Decitabine

Eligibility Criteria

        Inclusion Criteria:

          -  TP53 mutant relapsed/refractory AML following 7+3 (or similar cytarabine containing
             induction chemotherapy for AML) disease detected by one of the following methods:

               -  bone marrow blasts > 5%, or

               -  Hematologics flow cytometry assay (threshold > 0.5%) (alternative equivalent
                  assay may be substituted), or

               -  Persistent cytogenetic abnormality (e.g. del5, del17p, etc), by FISH or
                  conventional karotyping, or

               -  Persistent TP53 mutation (at least 5 variant reads with at least 50x coverage).

          -  Patients with > 10% blasts on a day +14 bone marrow biopsy following 7+3 may either be
             enrolled or may be treated with a course of standard re-induction (e.g. 5+2 or
             similar) and then re-evaluated for response. Eligible patients will meet any of the
             above criteria on a subsequent biopsy.

        The presence of a TP53 mutation should be determined by Genoptix (or institutional
        preferred equivalent assay) for all patients. Detection of a TP53 mutation at the time of
        initial diagnosis is sufficient for enrollment. Detection of a TP53 mutation in either the
        peripheral blood or bone marrow is adequate for enrollment.

          -  Bone marrow and organ function as defined below:

               -  Peripheral white blood cell count < 50,000/mcl (patients may receive hydroxyurea
                  as necessary for cytoreduction),

               -  Total bilirubin < 1.5 x upper limit of normal,

               -  AST and ALT < 2.5 x upper limit of normal,

               -  Serum creatinine < 2.0 x upper limit of normal, and,

          -  At least 18 years of age.

          -  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

          -  Ability to understand and willingness to sign an IRB approved written informed consent
             document (or that of legally authorized representative, if applicable

          -  Performance status ≤ 3

        Exclusion Criteria:

          -  Prior treatment with either decitabine or azacitidine.

          -  Acute promyelocytic leukemia with PML-RARA or t(15;17).

          -  Active HIV, Hepatitis B, or Hepatitis C infection.

          -  Concurrent illness including, but not limited to, ongoing uncontrolled infection,
             symptomatic NYHA class 3 or 4 congestive heart failure, unstable angina pectoris, or
             cardiac arrhythmia.

          -  Radiation therapy within 14 days of enrollment.

          -  Chemotherapy administration in the 14 days preceding enrollment with the exception of
             hydroxyurea, which can be continued until Cycle 2. A washout period for oral tyrosine
             kinase inhibitors (e.g. Jakafi, etc) is not required, although tyrosine kinase
             inhibitors therapy must be discontinued prior to enrollment.

          -  Malignancies requiring active therapy, with the exception of basal cell or squamous
             cell carcinoma of the skin which can be treated with local resection only or carcinoma
             in situ of the cervix.

          -  Currently receiving any other investigational agents.

          -  Known central nervous system (CNS) leukemia.

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to decitabine or other agents used in the study.

          -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
             urine pregnancy test within 7 days of study entry.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival
Time Frame:1 year
Safety Issue:
Description:-Overall survival is defined as the date of first dose of study drug to the date of death from any cause. Patients still alive at the time of the final analysis will be right-censored.

Secondary Outcome Measures

Measure:Proportion of responding patients (CR, CRi)
Time Frame:12 weeks
Safety Issue:
Description:Complete remission (CR) - Defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count >1.0 x 109/L (1,000/μL); platelet count >100 x 109/L (100,000/μL). Complete remission with incomplete hematologic recovery (CRi): All CR criteria except for residual neutropenia - <1.0 x 109/L (1,000/μL) or thrombocytopenia -<100 x 109/L (100,000/μL)
Measure:Time to transplant
Time Frame:12 weeks
Safety Issue:
Description:-Document the number of days that it takes each participant to reach transplant
Measure:Proportion of patients who are able to undergo stem cell transplantation
Time Frame:12 weeks
Safety Issue:
Description:-Document whether each participant is able to undergo stem cell transplantation to come up with proportion who are able to reach this milestone
Measure:Median time to leukemia relapse (TTLR) in non-transplant patients
Time Frame:2 years
Safety Issue:
Description:-Recurrence/morphologic relapse - Defined as relapse following complete remission is defined as reappearance of blasts in the blood or the finding of ≥ 5% blasts in the bone marrow, not attributable to any other cause. New dysplastic changes is considered relapse. If there are no blasts in the peripheral blood and 5-20% blasts in the bone marrow, bone marrow biopsy should be repeated in > 1 week to confirm relapse.
Measure:Event-free survival (EFS)
Time Frame:2 year
Safety Issue:
Description:-Event-free survival is defined as the interval from the date of first dose of study drug to date of treatment failure, recurrence, death due to any cause, or loss to follow up.
Measure:Average number of hospital days
Time Frame:During cycles 1 and 2 (60 days)
Safety Issue:
Description:-Document number of hospital days that each participant stays and obtain average for all evaluable participants
Measure:Response compared between patients with morphologically evident disease versus patients with molecularly detected disease at the time of enrollment
Time Frame:12 weeks
Safety Issue:
Description:Morphologically evident disease (>5% blasts by cytomorphology) Molecularly detected disease (disease detected with flow cytometry, cytogenetic, or mutational analysis with ≤ 5% blasts by cytomorphology
Measure:Survival compared between patients with morphologically evident disease versus patients with molecularly detected disease at the time of enrollment
Time Frame:2 years
Safety Issue:
Description:Morphologically evident disease (>5% blasts by cytomorphology) Molecularly detected disease (disease detected with flow cytometry, cytogenetic, or mutational analysis with ≤ 5% blasts by cytomorphology
Measure:Response compared between patients with de novo AML versus patients with secondary AML versus patients with treatment-related AML
Time Frame:12 weeks
Safety Issue:
Description:-Will be described using contingency tables
Measure:Survival compared between patients with de novo AML versus patients with secondary AML versus patients with treatment-related AML
Time Frame:2 years
Safety Issue:
Description:-Will be described using Kaplan-Meier methods and compared by log-rank test
Measure:Response compared between patients with presence of cytogenetic abnormalities in addition to TP53 mutations versus patients with absence of cytogenetic abnormalities in addition to TP53 mutations
Time Frame:12 weeks
Safety Issue:
Description:-Will be described using contingency tables
Measure:Survival compared between patients with presence of cytogenetic abnormalities in addition to TP53 mutations versus patients with absence of cytogenetic abnormalities in addition to TP53 mutations
Time Frame:2 years
Safety Issue:
Description:-Will be described using Kaplan-Meier methods and compared by log-rank test

Details

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

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