Study of Talazoparib in Combination With Chemotherapy in Relapsed Pediatric AML to Determine Safety and Efficacy
- Conditions
- Acute Myeloid Leukemia
- Interventions
- Registration Number
- NCT05101551
- Lead Sponsor
- Jennifer Lauren Kamens
- Brief Summary
This is a Phase 1, open label, multicenter, dose finding study with dose expansion intended to evaluate the safety and tolerability of talazoparib in combination with conventional chemotherapy. Preliminary estimates of efficacy will be obtain through a dose expansion cohort receiving the maximum tolerated dose from the dose escalation phase of the study.
This study aims to determine the safety of talazoparib in combination with conventional chemotherapy and to establish the maximum tolerated dose of all 3 drugs when given in combination. A preliminary estimate of efficacy through a dose expansion phase is a secondary aim.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 34
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Aged ≤ 21 years.
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Acute myeloid leukemia (AML) OR acute leukemia of ambiguous lineage (acute undifferentiated leukemia or mixed phenotype acute leukemia), specified as either refractory (persistent leukemia after at least 2 courses of induction chemotherapy) or relapsed, and further defined as any one of the criteria below:
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Bone marrow specimen ≥ 5% leukemic blasts by flow, as assessed by Hematologics Inc.
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A single bone marrow specimen with at least 2 tests demonstrates ≥ 1% leukemic blasts by flow cytometry (as assessed by Hematologics Inc), AND at least one of the following:
- Karyotypic abnormality with at least 1 metaphase similar or identical to diagnosis
- FISH abnormality identical to one present at diagnosis
- PCR or NGS-based demonstration of leukemogenic lesion identical to diagnosis
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Rising MRD > 0.1% by flow cytometry on ≥ 2 serial samples, as assessed by Hematologics Inc.
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If an adequate bone marrow sample is not obtained, subjects may be enrolled if there is unequivocal evidence of leukemia based on ≥ 5% blasts in the peripheral blood
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> 60 days has passed since hematopoietic stem cell transplant.
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Patients who have undergone previous allogeneic stem cell transplantation who are otherwise eligible must also be without evidence of any active graft versus host disease (GVHD), and off calcineurin inhibitors for at least 28 days (four weeks) prior to therapy. A physiologic dose of prednisone up to 3 mg/m2 (and a maximum of 7.5 mg) or equivalent other steroid dose is allowable.
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A minimum of 14 days has passed since completion of myelosuppressive therapy or gemtuzumab ozogamicin and all nonhematologic toxicities have resolved to Grade 0 or 1.
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A minimum of 24 hours has elapsed since the patient has completed any low-dose or non-myelosuppressive therapy (e.g., hydroxyurea or low-dose cytarabine (up to 100 mg/m2).
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Lansky (subjects ≤ 16 years old) or Karnofsky (subjects > 16 years old) score ≥ 50.
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WBC ≤ 50,000/uL. This may be achieved using cytoreductive therapy such as hydroxyurea or low-dose cytarabine (up to 100 mg/m2/dose)
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Total bilirubin ≤ 2.0 x institutional upper limit of normal (ULN) for age.
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AST/ALT ≤ 5 x ULN for age
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Left ventricular ejection fraction ≥ 40% or ECHO shortening fraction ≥ 25%.
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Estimated serum creatinine ≥ 60 mL/min/1.73m2
- Patients receiving or planning to receive ANY concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy or biologic therapy.
- Patients with down syndrome.
- Patients with Acute Promyelocytic leukemia (APL) or Juvenile Myelomonocytic Leukemia (JMML).
- Patients with Bone Marrow Failure Syndrome.
- Pregnant subjects or those unwilling to use an effective method of birth control.
- Female subjects with infants who do NOT agree to abstain from breastfeeding.
- Inability or unwillingness of legal guardian/representative to give written informed consent.
- Patients with uncontrolled systemic fungal, bacterial, viral or other infection.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Talazoparib with topotecan and gemcitabine Gemcitabine Talazoparib will be administered orally on Days 1 to 5 concurrently with topotecan and a single dose of gemcitabine on Day 1 of 28 day cycle for 1 or 2 cycles. Subjects on dose level 5 will receive an additional 5 day treatment course of talazoparib on days 15-19. Talazoparib with topotecan and gemcitabine Talazoparib Talazoparib will be administered orally on Days 1 to 5 concurrently with topotecan and a single dose of gemcitabine on Day 1 of 28 day cycle for 1 or 2 cycles. Subjects on dose level 5 will receive an additional 5 day treatment course of talazoparib on days 15-19. Talazoparib with topotecan and gemcitabine Topotecan Talazoparib will be administered orally on Days 1 to 5 concurrently with topotecan and a single dose of gemcitabine on Day 1 of 28 day cycle for 1 or 2 cycles. Subjects on dose level 5 will receive an additional 5 day treatment course of talazoparib on days 15-19.
- Primary Outcome Measures
Name Time Method Dose limiting toxicity (DLT). 28 days after starting therapy (ie, single course of therapy). Patient safety is assessed as dose limiting toxicity (DLT). The outcome is the number of DLT events. A DLT event is defined as:
* Hematologic DLT - Failure to recover peripheral ANC to \> 200/µL or non-transfusion-dependent platelets to \> 20,000/µL by Day 43 from the start of Cycle 1 of chemotherapy will be considered a DLT, unless the delay in count recovery is due to another identifiable factor
* Non-Hematologic DLT-Any ≥ Grade 4 non-hematological organ toxicity, including Hy's Law case is a DLT with the following exceptions:
* Grade 4 infection or fever ≤ 7 days in duration.
* Grade 4 electrolyte or laboratory abnormalities correctable with supportive therapy or that resolve to \< Grade 3 within 72 hours.
* Grade 4 elevation in hepatic transaminases that resolves to ≤ Grade 2 within 7 days.
* Grade 4 tumor lysis syndrome must resolve in ≤ 7 days without evidence of end-organ damage.
- Secondary Outcome Measures
Name Time Method Objective Response (OR) 28 days Objective response includes all participants that achieve complete or partial response, and assessed for all participants treated at the maximum tolerated dose.
* Complete remission: Bone marrow MRD \< 5% by flow cytometry, ANC ≥ 500/μL AND platelets ≥ 50,000/μL,without transfusions,No extramedullary disease
* Complete remission without hematologic recovery: Bone marrow MRD \< 5% by flow cytometry, One of ANC ≥ 500/μL OR platelets ≥ 50,000/μL,without transfusions, No extramedullary disease
* Partial response: Decrease of at least 50% of blasts by MRD and ≥ 5% to 25% blasts by flow cytometry.Enrolled patients with fewer than 5% blasts by MRD are not evaluable for PR.
* No response: No change in clinical or laboratory status.For patients with \< 5% of blasts at enrollment, no response is defined as failure to achieve MRD negative CR or MRD negative CRi.
* Progressive Disease: Deterioration of initial disease status
* MRD negative: \< 0.05% of leukemic blasts by flow cytometry.
Related Research Topics
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Trial Locations
- Locations (9)
Phoenix Children's Hospital
🇺🇸Phoenix, Arizona, United States
Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States
City of Hope
🇺🇸Duarte, California, United States
Stanford University
🇺🇸Stanford, California, United States
Cincinnati Children's Hospital
🇺🇸Cincinnati, Ohio, United States
Pennsylvania State University Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
University of Wisconsin Carbone Cancer Center
🇺🇸Madison, Wisconsin, United States