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

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

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.

Study Overview

• Status: Terminated
• Conditions: Acute Myeloid Leukemia; Acute Myeloid Leukemia, Relapsed, Adult
• Intervention / Treatment: Drug: Decitabine; Procedure: Bone marrow biopsy/aspirate; Procedure: Peripheral blood draw; Procedure: Skin biopsy; Procedure: Buccal swab

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Decitabine; 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; 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.; Other Names: 5-aza-2'-deoxycytidine; Procedure: Bone marrow biopsy/aspirate; 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; Procedure: Peripheral blood draw; -Baseline, Cycle 1 Day 10, Cycle 1 Day 28, Cycle 2 Day 28, Cycle 3 Day 28, and Progression/Relapse; Procedure: Skin biopsy; 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; Procedure: Buccal swab; -Baseline (if skin biopsy declined) and Cycle 2 Day 28

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Cancer Institute (NCI); National Institutes of Health (NIH); Janssen Pharmaceuticals
• Investigators: Principal Investigator: John Welch, M.D., Ph.D., Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): July 14, 2017
• Primary Completion (Actual): February 13, 2021
• Study Completion (Actual): March 16, 2022

Study Registration Dates

• First Submitted: February 20, 2017
• First Submitted That Met QC Criteria: February 20, 2017
• First Posted (Actual): February 24, 2017

Study Record Updates

• Last Update Posted (Actual): June 2, 2022
• Last Update Submitted That Met QC Criteria: May 9, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine
• Other Study ID Numbers: 201911185-1001; 3P50CA171963-06S1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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