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

NCT03063203 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: 201911185-10013P50CA171963-06S1
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (12)

• Percentage of Responding TP53 Mutated Patients (CR, CRi)

  12 weeks

• Time to Stem Cell Transplant Among Participants Who Are Suitable Candidates for Transplant and Have an Identified Donor

  12 weeks

• Median Time to Leukemia Relapse (TTLR) in Non-transplant Patients

  2 years

• Event-free Survival (EFS)

  2 year

• Average Number of Hospital Days

  During cycles 1 and 2 (60 days)

Study Arms (1)

Decitabine

EXPERIMENTAL

* 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; Procedure: Bone marrow biopsy/aspirate; Procedure: Peripheral blood draw; Procedure: Skin biopsy; Procedure: Buccal swab

Interventions

Decitabine 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.

Also known as: 5-aza-2'-deoxycytidine

Decitabine

Bone marrow biopsy/aspirate 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

Decitabine

Peripheral blood draw PROCEDURE

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

Decitabine

Skin biopsy 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

Decitabine

Buccal swab PROCEDURE

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

Decitabine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Janssen Pharmaceuticals: collaborator
• National Institutes of Health (NIH): collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Links

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

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Recurrence

Interventions

Decitabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: John Welch, M.D., Ph.D.
• Organization: Washington University School of Medicine

jwelch@wustl.edu

314-362-2626

Study Officials

• John Welch, M.D., Ph.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 20, 2017
• First Posted: February 24, 2017
• Study Start: July 14, 2017
• Primary Completion: February 13, 2021
• Study Completion: March 16, 2022
• Last Updated: June 2, 2022
• Results First Posted: March 18, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)