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Talazoparib in Combination with Chemotherapy for the Treatment of Pediatric Patients with Relapsed or Refractory AML, the PARPAML Trial
Trial Status: active
This phase I trial tests the safety, side effects, best dose and effectiveness of talazoparib in combination with chemotherapy in treating pediatric patients with acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Talazoparib is a poly (ADP-ribose) polymerase (PARP) inhibitor. PARP is a protein that helps repair damaged deoxyribonucleic acid (DNA). Blocking PARP may prevent cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Gemcitabine is a chemotherapy drug that blocks the cells from making DNA and may kill cancer cells. Topotecan is in a class of medications called topoisomerase I inhibitors. It works by killing cancer cells. Giving talazoparib in combination with chemotherapy may be safe, tolerable and/or effective in treating pediatric patients with relapsed or refractory AML.
Inclusion Criteria
AML or acute leukemia of ambiguous lineage (acute undifferentiated leukemia or mixed phenotype acute leukemia) and have (a) refractory leukemia, defined as persistent leukemia after at least two courses of induction chemotherapy, OR (b) relapsed leukemia, defined as ≥ 1% blasts in the bone marrow OR rising minimal residual disease (MRD) by flow cytometry on two or more serial samples. If an adequate bone marrow sample cannot be obtained, subjects may be enrolled if there is unequivocal evidence of leukemia with ≥ 5% blasts in the peripheral blood
Subjects must have fully recovered from the acute effects of all prior therapy, including that they have no evidence of acute graft versus host disease (GVHD)
Age ≤ 21 years
Male or female of reproductive age must agree to the use of contraception for the duration of the study
Lansky ≥ 50 for subjects who are ≤ 16 years old and Karnofsky ≥ 50% for subjects who are > 16 years old
Direct bilirubin ≤ 2 x institutional upper limit of normal (ULN)
Normal creatine for age or a calculated creatinine clearance of ≥ 60 mL/min/1.73 m^2
* < 6 months: male 0.4, female 0.4
* 6 months to 1 year: male 0.5, female 0.5
* 1 to < 2 years: male 0.6, female 0.6
* 2 to < 6 years: male 0.8, female 0.8
* 6 to < 10 years: male 1.0, female 1.0
* 10 to < 13 years: male 1.2, female 1.2
* 13 to < 16 years: male 1.5, female 1.4
* > 16 years: male 1.7, female 1.4
Left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25
Ability to understand and the willingness of subject or parent/guardian (if ≤ 18 years of age) to personally sign the written institutional review board (IRB) approved informed consent document
Exclusion Criteria
Uncontrolled infection. Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines are acceptable
Pregnant
Breast-feeding
Subject has any of the following:
* Down syndrome
* Acute promyelocytic leukemia (APL)
* Juvenile myelomonocytic leukemia (JMML)
* Bone marrow failure syndrome
Additional locations may be listed on ClinicalTrials.gov for NCT05101551.
I. To determine a tolerable combination of talazoparib in combination with chemotherapy (topotecan plus gemcitabine) in pediatric subjects with relapsed or refractory acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage.
SECONDARY OBJECTIVES:
I. To measure pharmacokinetics (PK) of talazoparib in combination with topotecan and gemcitabine.
II. To estimate the overall response rate to the combination of talazoparib with chemotherapy in pediatric subjects with relapsed or refractory AML.
EXPLORATORY OBJECTIVE:
I. To determine if responders to treatment with PARP inhibitors can be predicted through biomarkers, cytogenetic features, and gene signature profiling.
OUTLINE: This is a dose-escalation study of talazoparib followed by dose-expansion study.
Patients on dose level 1 receive talazoparib orally (PO) once daily (QD) on days 1-5. Patients on dose levels 2-5 receive talazoparib PO twice daily (BID) on day 1 then QD on days 2-5. Patients on dose level 5 also receive talazoparib QD on days 15-19. All patients receive topotecan intravenously (IV) on days 1-5 and gemcitabine IV on day 1. Treatment continues for a single 28-day course in the absence of disease progression or unacceptable toxicity. Patients in the dose-expansion portion of the study may receive an additional course.
Patients also receive standard of care methotrexate, hydrocortisone and cytarabine intrathecally (IT) with leucovorin at 24 and 30 hours after IT on day 1. For patients with overt central nervous system (CNS) leukemia, IT therapy may be repeated twice weekly until cerebrospinal fluid (CSF) is free of blast cells.
Additionally, patients undergo an X-ray and skin biopsy during screening, echocardiography (ECHO) or multigated acquisition (MUGA) scans during screening and on study, and lumbar puncture, bone marrow aspiration with or without biopsy, and collection of blood samples throughout the trial.
After completion of study treatment, patients are followed up at 30 days and then yearly for 2 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationStanford Cancer Institute Palo Alto
