PARPAML: Relapsed Pediatric AML to Determine the Safety and Efficacy of the PARP Inhibitor Talazoparib in Combination With Conventional Chemotherapy
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Talazoparib with topotecan and gemcitabine Talazoparib will be administered orally on Days 1 to 5 concurrently with topotecan and a single dose of gemcitabine on Day 1 of each 28 day cycle for 1 cycle. |
Drug: Talazoparib
Talazoparib will be administered in escalating doses based on current dose level.
Dose Level 1: 400 µg/m2/dose once daily
Dose Level 2: 600 µg/m2/dose BID on Day 1, then daily on Days 2 to 5
Dose Level 3: 600 µg/m2/dose BID on Day 1, then daily on Days 2 to 5
Dose Level 4: 600 µg/m2/dose BID on Day 1, then daily on Days 2 to 5
Dose Level 5: 600 ug/m2/dose BID on Day 1, then daily on Days 2 to 5 and 15 19
Drug: Topotecan
Administered IV route on Days 1 to 5. Recommended dose based on this study is 4 mg/m2/dose.
Drug: Gemcitabine
Single dose (IV) of gemcitabine on Day 1 of each 28 day cycle for 1 cycle.
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Outcome Measures
Primary Outcome Measures
- Dose limiting toxicity (DLT). [28 days28 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 a Grade 3, 4, or 5 event, with the exception of following Grade 3 4 events. Infection and/or fever Elevation in liver enzymes Changes in blood electrolyte levels for > 24 hours. Changes in blood sugar for > 24 hours. Fatigue and/or nausea (Grade 3 only). Vomiting and/or diarrhea (Grade 3 only) ≤ 7 days Hypotension associated with sepsis or infusion reaction Mucositis (Grade 3 only) ≤ 14 days Anorexia (Grade 3 only) Hypertension (Grade 3 only) Enterocolitis, typhlitis, or colitis (Grade 3 only) Gastric hemorrhage, gastric ulcer, gastritis, and/or upper GI bleed (Grade 3 only) Glucose intolerance (Grade 3 only) Leukoencephalopathy and/or seizures (Grade 3 only) Any Grade 3 event secondary to an infectious process or thrombocytopenia Other Grade 3 events resolving ≤ 48 hours
Secondary Outcome Measures
- Objective Response (OR) [28 days.]
Objective response (OR) is a collective term representing all participants that achieve a complete response or partial response, and will be assessed for all participants treated at the maximum tolerated dose, including the Dose Expansion cohort. Response will be defined as below: Complete remission (CR) or complete remission without hematologic recovery (CRi): Bone marrow MRD <0.1% by flow cytometry Complete response (CRM) or without hematologic recovery (CRMi): Bone marrow MRD 0.1 to 5% by flow cytometry Partial response (PR): A decrease of at least 50% in the percentage of morphologic blasts and 5% to 25% blasts by flow cytometry No response (NR): No change in clinical or laboratory status Progressive Disease (PD): Deterioration of initial disease status The outcome will be reported as the number of participants that achieve OR, ie, a CR, CRi, CRM, CRMi, or PR. The outcome is a number without dispersioni.
Eligibility Criteria
Criteria
Inclusion Criteria:
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- 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 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.
Exclusion Criteria:
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- Uncontrolled infection. Infections controlled on concurrent anti microbial agents are acceptable, and anti microbial prophylaxis per institutional guidelines are acceptable.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Stanford University | Stanford | California | United States | 94305 |
Sponsors and Collaborators
- Stanford University
Investigators
- Principal Investigator: Jennifer L Kamens, MD, Stanford Universiy
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IRB 59562
- PEDSHEMAML0008