Study of Talazoparib in Combination With Chemotherapy in Relapsed Pediatric AML to Determine Safety and Efficacy (PARPAML)
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ClinicalTrials.gov Identifier: NCT05101551 |
Recruitment Status :
Recruiting
First Posted : November 1, 2021
Last Update Posted : April 15, 2024
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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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Acute Myeloid Leukemia | Drug: Talazoparib Drug: Topotecan Drug: Gemcitabine | Phase 1 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 34 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | A Phase I Protocol for Relapsed Pediatric AML to Determine the Safety and Efficacy of the PARP Inhibitor Talazoparib in Combination With Chemotherapy |
Actual Study Start Date : | February 23, 2023 |
Estimated Primary Completion Date : | March 2026 |
Estimated Study Completion Date : | March 2026 |
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 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.
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Drug: Talazoparib
Talazoparib will be administered in escalating doses based on current dose level.
Other Name: Talzenna Drug: Topotecan Administered IV route on Days 1 to 5
Other Name: Hycamtin Drug: Gemcitabine Single dose (IV) of gemcitabine on Day 1 of each 28 day cycle for 1 cycle.
Other Names:
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- Dose limiting toxicity (DLT). [ Time Frame: 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 > 500/µL or non-transfusion-dependent platelets to > 25,000/µL by Day 42 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.
- Objective Response (OR) [ Time Frame: 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, One of ANC < 500/μL OR 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.
- No response: No change in clinical or laboratory status.For patients with < 5% of blasts, 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.
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Ages Eligible for Study: | up to 21 Years (Child, Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- 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:
- 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
- Rising MRD > 0.1% by flow cytometry on ≥ 2 serial samples, as assessed by Hematologics Inc.
- 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
- > 60 days has passed since hematopoietic stem cell transplant.
- 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.
- 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.
- 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).
- Lansky (subjects ≤ 16 years old) or Karnofsky (subjects > 16 years old) score ≥ 50.
- WBC ≤ 50,000/uL. This may be achieved using cytoreductive therapy such as hydroxyurea or low-dose cytarabine (up to 100 mg/m2/dose)
- Total bilirubin ≤ 2.0 x institutional upper limit of normal (ULN) for age.
- AST/ALT ≤ 5 x ULN for age
- Left ventricular ejection fraction ≥ 40% or ECHO shortening fraction ≥ 25%.
- Estimated serum creatinine ≥ 60 mL/min/1.73m2
Exclusion Criteria:
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05101551
Contact: Sophia Brodsky | (650)721-4087 | sophia.brodsky@stanford.edu |
United States, Arizona | |
Phoenix Children's Hospital | Recruiting |
Phoenix, Arizona, United States, 85016 | |
Contact: Chris Oless, MD 602-933-0920 coless@phoenixchildrens.com | |
Principal Investigator: Michael Henry, MD | |
United States, Arkansas | |
Arkansas Children's Hospital | Recruiting |
Little Rock, Arkansas, United States, 72202 | |
Contact: Kevin Bielamowicz, MD 501-364-4405 kjbielamowicz2@uams.edu | |
Principal Investigator: Kevin J Bielamowicz, MD | |
United States, California | |
City of Hope | Recruiting |
Duarte, California, United States, 91010 | |
Contact: Lindsey Murphy, MD 626-218-0948 lmurphy@coh.org | |
Principal Investigator: Lindsey Murphy, MD | |
Stanford University | Recruiting |
Stanford, California, United States, 94305 | |
Contact: Sophia Brodsky 650-721-4087 sophia.brodsky@stanford.edu | |
Principal Investigator: Jennifer Kamens | |
Sub-Investigator: Tanja Gruber | |
Sub-Investigator: Norman Lacayo | |
United States, Pennsylvania | |
Pennsylvania State University Hershey Medical Center | Recruiting |
Hershey, Pennsylvania, United States, 17033-0850 | |
Contact: Valerie Brown, MD, PhD 717-531-6012 vbrown1@hmc.psu.edu | |
Principal Investigator: Valerie Brown, MD, PhD | |
United States, Tennessee | |
St. Jude Children's Research Hospital | Recruiting |
Memphis, Tennessee, United States, 38105 | |
Contact: Jeffrey E Rubnitz, MD 901-595-2615 Jeffrey.Rubnitz@STJUDE.org | |
Principal Investigator: Jeffrey E Rubnitz, MD | |
United States, Utah | |
University of Utah | Recruiting |
Salt Lake City, Utah, United States, 84108 | |
Contact: Spencer Mangum, MD 801-662-4700 Spencer.Mangum@hsc.utah.edu | |
Principal Investigator: Spencer Mangum, MD | |
United States, Wisconsin | |
University of Wisconsin - American Family Children's Hospital | Not yet recruiting |
Madison, Wisconsin, United States, 53792 | |
Contact: Rebecca Richards, MD | |
Principal Investigator: Rebecca Richards, MD |
Principal Investigator: | Jennifer L Kamens, MD | Stanford Universiy |
Responsible Party: | Jennifer Lauren Kamens, Instructor Pediatrics - Hematology/Oncology, Stanford University |
ClinicalTrials.gov Identifier: | NCT05101551 |
Other Study ID Numbers: |
IRB-66573 PEDSHEMAML0008 ( Other Identifier: OnCore ) POE22-01 ( Other Identifier: POETIC study number ) Pro00060706 ( Other Identifier: Advarra IRB number ) |
First Posted: | November 1, 2021 Key Record Dates |
Last Update Posted: | April 15, 2024 |
Last Verified: | April 2024 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
PARP Inhibitor |
Gemcitabine Topotecan Talazoparib Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action |
Antineoplastic Agents Topoisomerase I Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Poly(ADP-ribose) Polymerase Inhibitors |