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

NCT ID: NCT03063203

Last Updated: 2022-06-02

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 17 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-07-14
• Study Completion Date: 2022-03-16

Brief Summary

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.

Conditions

Acute Myeloid Leukemia; Acute Myeloid Leukemia, Relapsed, Adult

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Decitabine

Intervention Type: DRUG

• 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.

Bone marrow biopsy/aspirate

Intervention Type: PROCEDURE

• 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

Peripheral blood draw

Intervention Type: PROCEDURE

-Baseline, Cycle 1 Day 10, Cycle 1 Day 28, Cycle 2 Day 28, Cycle 3 Day 28, and Progression/Relapse

Skin biopsy

Intervention Type: PROCEDURE

• 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

Buccal swab

Intervention Type: PROCEDURE

-Baseline (if skin biopsy declined) and Cycle 2 Day 28

Interventions

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.

Intervention Type: DRUG

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

Intervention Type: PROCEDURE

Peripheral blood draw

-Baseline, Cycle 1 Day 10, Cycle 1 Day 28, Cycle 2 Day 28, Cycle 3 Day 28, and Progression/Relapse

Intervention Type: 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

Intervention Type: PROCEDURE

Buccal swab

-Baseline (if skin biopsy declined) and Cycle 2 Day 28

Intervention Type: PROCEDURE

Other Intervention Names

5-aza-2'-deoxycytidine

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Janssen Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

John Welch, M.D., Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Locations

Washington University School of Medicine

St Louis, Missouri, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Related Links

http://www.siteman.wustl.edu

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

Other Identifiers

3P50CA171963-06S1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

201911185-1001

Identifier Type: -

Identifier Source: org_study_id