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

Study Overview
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Brief Summary
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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.

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

Conditions
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Acute Myeloid Leukemia, Acute Myeloid Leukemia, Relapsed, Adult

Intervention / Treatment
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* Drug: Decitabine
* Procedure: Bone marrow biopsy/aspirate
* Procedure: Peripheral blood draw
* Procedure: Skin biopsy
* Procedure: Buccal swab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: TP53 mutant AML. The presence of a TP53 mutation should be determined by Genoptix (or institutional preferred equivalent assay). Detection of a TP53 mutation at the time of initial diagnosis is sufficient for enrollment at the time of relapsed/refractory disease. Detection of a TP53 mutation in either the peripheral blood or bone marrow is adequate for enrollment. Alternatively, patients who have not had TP53 mutation analysis performed, but who have > 20% TP53 positive cells by immunohistochemistry detected on a bone marrow aspirate may also be enrolled,29 provided that mutation analysis is requested at the time of enrollment. 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) determined by Genoptix (or institutional preferred equivalent assay). 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. 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 or an investigational agent Acute promyelocytic leukemia with PML-RARA or t(15;17). History of 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 7 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 (other than AML) requiring active therapy or diagnosed within the last year, with the exception of non-melanoma skin cancer which can be treated or in situ malignancies (such as cervical, breast, prostate, etc.) Currently receiving any other investigational agents. Known central nervous system (CNS) leukemia or testicular involvement of 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Decitabine<br>Cycle 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 | Drug: Decitabine<br>* After 2 cycles, patients with progressive disease or relapse (a clear progression with at least >20% bone marrow blasts and an increase of at least 50% from prior biopsy) should be removed from protocol and proceed to salvage treatment according to center preference Transplant eligible patients who achieve CR, CRc, or CRi, after 3 cycles with a suitable donor will proceed to conditioning regimen and transplant Transplant eligible patients with PR after 3 cycles may be removed from protocol and proceed to salvage treatment according to center preference Transplant eligible patients with a suitable donor who achieve mLFS, CR, CRc, or CRi, may proceed to transplant after at 3 cycles Transplant ineligible patients with (CR, CRc or CRi, PR) will continue on maintenance doses Transplant ineligible patient with SD after cycle 4 may be removed from protocol and proceed to alternative treatment or continue on protocol according to treating physician's preference.<br>* Other names: 5-aza-2'-deoxycytidine;Procedure: Bone marrow biopsy/aspirate<br>* Baseline, Cycle 1 Day 10, Cycle 1 Day 28, Cycle 2 Day 28, Cycle 3 Day 28, and Progression or relapse Biopsy/aspirate on Cycle 1 Day 10 is for participants enrolled at Washington University only Biopsy/aspirate on Cycle 2 Day 28 is at the discretion of the treating physician<br>Procedure: Peripheral blood draw<br>* -Baseline, Cycle 1 Day 10, Cycle 1 Day 28, Cycle 2 Day 28, Cycle 3 Day 28, and Progression/Relapse<br>Procedure: Skin biopsy<br>* Optional but if refuse skin biopsy then participant can provided buccal swab There is no required time frame for this sample - it may have been collected months or even years prior to the first dose of decitabine If WBC at time of enrollment is >30,000/µl, skin biopsy should be collected at the time of C1D28 bone marrow biopsy or thereafter<br>Procedure: Buccal swab<br>* -Baseline (if skin biopsy declined) and Cycle 2 Day 28<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival of Participants With TP53 Mutation | Overall survival (OS) is defined as the time from enrollment to death due to any cause. For a patient who is not known to be alive at the end of study follow up, observation of OS is censored on the date the patient was last known to be alive To be evaluable for this outcome measure the participant would have to have received at least one dose of decitabine | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Responding TP53 Mutated Patients (CR, CRi) | 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) | 12 weeks | 
| Time to Stem Cell Transplant Among Participants Who Are Suitable Candidates for Transplant and Have an Identified Donor | Document the number of days that it takes each participant to reach transplant Transplant eligible participants are those who achieve complete remission (CR), cytogenetic complete remission (CRc), complete remission with incomplete hematologic recovery (CRi), or morphologic leukemia free state (mLFS) per 2017 ELN AML Recommendations. | 12 weeks | 
| Median Time to Leukemia Relapse (TTLR) in Non-transplant Patients | -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. | 2 years | 
| Event-free Survival (EFS) | -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. | 2 year | 
| Average Number of Hospital Days | -Document number of hospital days that each participant stays and obtain average for all evaluable participants | During cycles 1 and 2 (60 days) | 
| Response Compared Between Patients With Morphologically Evident Disease Versus Patients With Molecularly Detected Disease at the Time of Enrollment | Morphologically evident disease (>5% blasts by cytomorphology) Molecularly detected disease (disease detected with flow cytometry, cytogenetic, or mutational analysis if ≤ 5% blasts by cytomorphology) Response will be assessed according to the 2017 European LeukemiaNet (ELN) Acute Myeloid Leukemia (AML) recommendations | Through 12 weeks | 
| Survival Compared Between Patients With Morphologically Evident Disease Versus Patients With Molecularly Detected Disease at the Time of Enrollment | Morphologically evident disease (>5% blasts by cytomorphology) Molecularly detected disease (disease detected with flow cytometry, cytogenetic, or mutational analysis with ≤ 5% blasts by cytomorphology) | 2 years | 
| Response Compared Between Patients With de Novo AML Versus Patients With Secondary AML Versus Patients With Treatment-related AML | -Response will be assessed according to the 2017 European LeukemiaNet (ELN) Acute Myeloid Leukemia (AML) recommendations | Through 12 weeks | 
| Survival Compared Between Patients With de Novo AML Versus Patients With Secondary AML Versus Patients With Treatment-related AML |  | 2 years | 
| 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 | -Response will be assessed according to the 2017 European LeukemiaNet (ELN) Acute Myeloid Leukemia (AML) recommendations | 12 weeks | 
| 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 |  | 2 years | 
| Median Number of Hospital Stays | -Document number of hospital days that each participant stays and obtain median for all evaluable participants | During cycles 1 and 2 (60 days) |