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Decitabine and Talazoparib in Treating Patients with Untreated Relapsed, or Refractory Acute Myeloid Leukemia

Trial Status: Active

This phase I / II trial studies best dose and side effects of decitabine and talazoparib and how well they work in treating patients with acute myeloid leukemia that is untreated, has come back, or does not respond to treatment. Decitabine and talazoparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Inclusion Criteria

  • Diagnosis of AML based on 2008 World Health Organization (WHO) criteria; AML may be de novo, following a prior hematologic disorder, including MDS or Philadelphia chromosome-negative myeloproliferative neoplasm, and/or therapy-related
  • PHASES 1 AND 2: patient participants with AML that has relapsed after, or is refractory to, first-line therapy, with or without subsequent additional therapy, and are currently considered unfit for, or unlikely to respond to, cytotoxic chemotherapy
  • PHASE 2 ONLY: Patient participants previously untreated for AML who are considered unfit for cytotoxic chemotherapy by virtue of performance status, comorbidities, advanced age and/or low likelihood of response based on disease characteristics, or who decline cytotoxic induction chemotherapy
  • Patient participants who have undergone autologous stem cell transplantation (autoSCT) are eligible provided that they are >= 4 weeks from stem cell infusion
  • Patient participants who have undergone allogeneic SCT (alloSCT) are eligible if they are >= 60 days from stem cell infusion, have no evidence of graft versus host disease (GVHD) > grade 1, and are >= 2 weeks off all immunosuppressive therapy
  • Previous cytotoxic chemotherapy must have been completed at least 3 weeks and radiotherapy at least 2 weeks prior to day 1 of treatment on the study, and all adverse events (excluding alopecia) due to agents administered more than 4 weeks earlier should have recovered to < grade 1; participants with hematologic malignancies are expected to have hematologic abnormalities at study entry; hematologic abnormalities that are thought to be primarily related to leukemia are not considered to be toxicities (adverse events [AE]) and do not need to resolve to < grade 1
  • Prior DNA methyl transferase inhibitor administration (azacitidine, decitabine or guadecitabine) for AML or for antecedent MDS is allowed if this clinical trial is considered the best treatment option, but azacitidine, decitabine or guadecitabine must have been stopped at least 3 weeks prior to day 1 of treatment on the study
  • Participants are required to stop receiving myeloid growth factors at least 1 week (Neupogen) or 2 weeks (Neulasta) before starting treatment on the study
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 2 months
  • Total bilirubin within normal institutional limits unless thought due to hemolysis or to Gilbert’s syndrome
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
  • Creatinine within normal institutional limits; OR creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal
  • Female participants of childbearing potential must have a negative pregnancy test, and female participants of childbearing potential and male participants must agree to use adequate contraception * Decitabine has been assigned to pregnancy category D by the Food and Drug Administration (FDA); pregnant women must not take decitabine and female participants must immediately stop taking decitabine and inform their doctor if they become pregnant during treatment; decitabine is expected to result in adverse reproductive effects and can cause fetal harm when administered to a pregnant woman; in preclinical studies in mice and rats, decitabine was teratogenic, fetotoxic, and embryotoxic * Studies in pregnant animals to evaluate the effect of talazoparib on pregnancy have not been performed * Women of child-bearing 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 that she is pregnant while she or her partner is participating in this study, she should inform the treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of decitabine and talazoparib administration * It is not known whether decitabine is excreted in human milk; similarly, studies in lactating animals to evaluate the effect of talazoparib have not been performed, and thus, it is not known whether talazoparib is excreted in human milk; therefore, breast-feeding should be stopped during decitabine and talazoparib treatment
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • Patients with acute promyelocytic leukemia
  • Patients with active central nervous system leukemia or requiring maintenance intrathecal chemotherapy
  • Patients receiving concurrent chemotherapy, radiation therapy, or immunotherapy for AML
  • Patients receiving any other investigational agents
  • Hyperleukocytosis with > 50,000 blasts/ul; hydroxyurea for blast count control is permitted before starting treatment, but must be stopped prior to starting treatment on the study; patients will be withdrawn from the study if > 50,000 blasts/ul occur or recur > 14 days after starting treatment on the study
  • Active, uncontrolled infection; patients with infection controlled with antibiotics are eligible
  • Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that per investigator’s judgment would limit compliance with study requirements
  • Patients who are pregnant or nursing
  • Patients who have had chemotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) or radiotherapy within 2 weeks for antecedent malignancies prior to entering the study, or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to decitabine or talazoparib
  • Known human immunodeficiency virus (HIV) infection * HIV-positive patients are at increased risk of lethal infections when treated with marrow suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  • Previous treatment with talazoparib

California

Los Angeles
USC / Norris Comprehensive Cancer Center
Status: ACTIVE
Contact: Suraj Chandwani

Maryland

Baltimore
University of Maryland / Greenebaum Cancer Center
Status: ACTIVE
Contact: Maria R. Baer
Phone: 410-328-8708
Email: mbaer@umm.edu

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 doses of combined decitabine intravenously (IV) daily for 5 days and talazoparib orally daily continuously in patient participants with refractory or relapsed acute myeloid leukemia (AML). (Phase 1)

II. To determine the safety of decitabine and talazoparib combination therapy in newly diagnosed AML patient participants unfit for intensive chemotherapy. (Phase 2)

III. To determine the efficacy of decitabine and talazoparib combination therapy in newly diagnosed AML patient participants unfit for intensive chemotherapy. (Phase 2)

IV. To determine the safety of decitabine and talazoparib combination therapy in patient participants with relapsed and refractory AML. (Phase 2)

V. To determine the efficacy of decitabine and talazoparib combination therapy in patient participants with relapsed and refractory AML. (Phase 2)

VI. To explore the safety of decitabine and talazoparib therapy in AML patient participants previously treated with a deoxyribonucleic acid (DNA) methyltransferase inhibitor (azacitidine, decitabine or guadecitabine) for AML or for antecedent myelodysplastic syndrome (MDS). (Phase 2)

VII. To explore the efficacy of decitabine and talazoparib therapy in AML patient participants previously treated with a DNA methyltransferase inhibitor (azacitidine, decitabine or guadecitabine) for AML or for antecedent MDS. (Phase 2)

VIII. To determine treatment duration, disease-free survival (DFS) and overall survival (OS) for each of the three patient participant cohorts. (Phase 2)

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity while on protocol therapy. (Phase 1)

II. To explore pharmacodynamic effects of decitabine IV daily for 5 days every 28 days and talazoparib orally daily continuously in patient participants with relapsed or refractory AML. (Phase 1)

III. To explore cytogenetic and molecular predictors of response to decitabine and talazoparib combination therapy. (Phase 1)

IV. To explore biomarker correlates of response. (Phase 2)

V. To explore pharmacodynamic correlates of response. (Phase 2)

OUTLINE: This is a phase I, dose-escalation study of followed by a phase II study.

Patients receive decitabine IV over 1 hour on days 1-5 and talazoparib orally (PO) daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks and then every 6 months.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
University of Maryland / Greenebaum Cancer Center

Principal Investigator
Maria R. Baer

  • Primary ID 1565GCC
  • Secondary IDs NCI-2017-00417
  • Clinicaltrials.gov ID NCT02878785