Talazoparib and Temozolomide in Treating Younger Patients With Refractory or Recurrent Malignancies

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of talazoparib and temozolomide and to see how well they work in treating younger patients with tumors that have not responded to previous treatment (refractory) or have come back (recurrent). Talazoparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving talazoparib together with temozolomide may work better in treating younger patients with refractory or recurrent malignancies.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of temozolomide when combined with a dose of talazoparib (BMN 673) given once daily for 5 days after a one day dose of BMN 673 administered orally (either once daily or twice daily), every 28 days to children with refractory or recurrent solid tumors. (Phase I) II. To define and describe the toxicities of BMN 673 given with temozolomide administered on this schedule. (Phase I) III. To characterize the pharmacokinetics of BMN 673 and temozolomide when given in combination to children with refractory or recurrent cancer. (Phase I) IV. To define the antitumor activity of BMN 673 when given with temozolomide in recurrent/refractory Ewing sarcoma.(Phase II) SECONDARY OBJECTIVES: I. To preliminarily define the antitumor activity of BMN 673 and temozolomide in pediatric patients with recurrent or refractory solid tumors within the confines of a phase I study. II. To explore possible predictive biomarkers in archival tumor tissue from Ewing sarcoma patients in Phase II. OUTLINE: This is a phase I, dose-escalation study followed by a phase II study. Patients receive talazoparib orally (PO) once daily (QD) or twice daily (BID) on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days.

Official Title
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A Phase 1/2 Study of BMN 673, an Oral Poly(ADP-Ribose) Polymerase Inhibitor, Plus Temozolomide in Children With Refractory or Recurrent Malignancies

Conditions
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Adult Solid Neoplasm, Childhood Solid Neoplasm, Recurrent Childhood Central Nervous System Neoplasm, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Malignant Solid Neoplasm, Refractory Central Nervous System Neoplasm

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Drug: Talazoparib
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: Phase 1 (Part A) Patients must be > than 12 months and =< 21 years of age at the time of study enrollment Phase 2 (Part B) Patients must be > than 12 months and =< 30 years of age at the time of study enrollment Body surface area (for Parts A and B): Patients must have a body surface area (BSA) of >= 0.42 m^2 at the time of study enrollment Diagnosis: Phase 1 (Part A) Solid tumors (Part A1): patients with relapsed or refractory solid tumors including central nervous system (CNS) tumors without bone marrow involvement are eligible; patients must have had histologic verification of malignancy at original diagnosis or relapse except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG) Ewing sarcoma or peripheral primitive neuroectodermal tumor (PNET) (Part A2): patients with relapsed or refractory Ewing sarcoma or peripheral PNET without bone marrow involvement will be eligible for Part A2 if there are no available slots on Part A1; these patients will be enrolled at one dose level below the dose level at which patients on Part A1 are actively enrolling, or at the starting dose level (dose level 1) if dose escalation has not yet occurred; patients must have had histologic verification of malignancy at original diagnosis or relapse Phase 2 (Part B) Ewing sarcoma or peripheral PNET: patients with relapsed or refractory Ewing sarcoma or peripheral PNET are eligible; patients must have had histologic verification of malignancy at original diagnosis or relapse Phase 2 (Part C) Disease status: Phase 1 (Part A): Patients must have either measurable or evaluable disease Phase 2 (Part B): Ewing sarcoma or peripheral PNET: patients must have measurable disease Therapeutic options: patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; Note: neurologic deficits in patients with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score Patients who have received prior therapy with a temozolomide-based regimen are eligible; Note: patients who have progressed on a poly adenosine diphosphate ribose polymerase (PARP) inhibitor and temozolomide regimen are not eligible for Part A of the study Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy Myelosuppressive chemotherapy: Solid tumors (Part A and Part B): at least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea) Hematopoietic growth factors: at least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair Biologic (anti-neoplastic agent): at least 7 days after the last dose of a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair Immunotherapy: at least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines Monoclonal antibodies: at least 3 half-lives of the antibody after the last dose of a monoclonal antibody Radiation therapy (XRT): at least 14 days after local palliative XRT (small port); at least 42 days must have elapsed if other substantial bone marrow (BM) radiation; patients with prior total body irradiation (TBI), craniospinal XRT and/or >= 50% radiation of the pelvis are not eligible Stem cell infusion without TBI: no evidence of active graft vs. host disease and at least 84 days must have elapsed after transplant or stem cell infusion PARP inhibitor exposure: Part A: Patients who have received prior therapy with a PARP inhibitor, with the exception of BMN 673, are eligible; however, patients who have progressed on a PARP inhibitor and temozolomide regimen are not eligible Part B: Patients who have previously been exposed to a PARP inhibitor are not eligible For patients with solid tumors without known bone marrow involvement: peripheral absolute neutrophil count (ANC) >= 1000/mm^3 For patients with solid tumors without known bone marrow involvement: platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) For patients with solid tumors without known bone marrow involvement: hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) All patients enrolled on Part A of the study must be evaluable for hematologic toxicity Patients on Part B of the study with known bone marrow metastatic disease will be eligible for the study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a maximum serum creatinine (mg/dL) based on age/gender as follows: 1 to < 2 years: 0.6 2 to < 6 years: 0.8 6 to < 10 years: 1 10 to < 13 years: 1.2 13 to < 16 years: 1.5 for males, 1.4 for females >= 16 years: 1.7 for males, 1.4 for females Patients on Part A and Part B: bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age Patients on Part A and Part B: serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L Patients on Part A and Part B: serum albumin >= 2 g/dL All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines For patients enrolling on Part B: tissue blocks or slides must be sent; if tissue blocks or slides are unavailable, the Study Chair must be notified prior to enrollment Exclusion Criteria: Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible Patients who are currently receiving another investigational drug are not eligible Patients who are currently receiving other anti-cancer agents are not eligible (except leukemia patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy); patients with acute lymphoblastic leukemia may receive intrathecal therapy Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial Patients must be able to swallow capsules whole Patients who have an uncontrolled infection are not eligible Patients who have received a prior solid organ transplantation are not eligible Patients with prior TBI, craniospinal XRT and/or those with >= 50% radiation of the pelvis are not eligible Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible Patients with known hypersensitivity to temozolomide or dacarbazine are not eligible Phase 1 (Part A): patients who have progressed on a PARP inhibitor and temozolomide regimen are not eligible Phase 2 (Part B): patients who have previously been exposed to a PARP inhibitor are not eligible Phase 1 (Part A): patients with known bone marrow involvement are not eligible

Ages Eligible for Study
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Minimum Age: 13 Months
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (talazoparib, temozolomide): Phase 1<br>(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Drug: Talazoparib<br>* Given PO<br>* Other names: BMN-673;Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|
| Experimental: Treatment (talazoparib, temozolomide): Phase 2<br>(Part B): Relapse/Refractory EWS or PNET Patients receive MTD from Phase 1 portion of study. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Drug: Talazoparib<br>* Given PO<br>* Other names: BMN-673;Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants With Dose Limiting Toxicities to Determine the Maximum Tolerated Dose of Temozolomide and Talazoparib Combination Therapy | The Maximum Tolerated Dose (MTD) reflects the highest dose of Talazoparib (BMN 673) when combined with a dose of temozolomide that did not cause a Grade 3 or higher toxicity in children with refractory or recurrent solid tumors. | 28 days | 
| All Cycle 1 Toxicities >=Grade 3 | The number of patients with at least one toxicity (DLT or non-DLT) in cycle 1 that is at least possibly attributable to study agent | Up to 28 days | 
| T Max of Talazoparib | Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs. | Cycle 1 Day 1 pre-dose, and 1, 2, 4, 8 and 24 hours after the first talazoparib dose. | 
| C Max of Talazoparib | Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs. | Cycle 1 Day 1 pre-dose, and 1, 2, 4, 8 and 24 hours after the first talazoparib dose. | 
| AUC of Talazoparib | Median with minimum and maximum for the area under the drug concentration over time curve. | Cycle 1 Day 1 pre-dose, and 1, 2, 4 and 8 hours after the first talazoparib dose | 
| Accumulation Half-life of Talazoparib in Combination With Temozolomide. | Median with minimum and maximum for the time required for the serum concentration to fall to 50% of its starting dose. | Cycle 1 Day 1 pre-dose, and 1, 2, 4 and 8 hours after the first talazoparib dose. Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose | 
| T Max of Talazoparib in Combination With Temozolomide | Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs. | Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose | 
| C Max of Talazoparib in Combination With Temozolomide | Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs. | Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose | 
| AUC of Talazoparib in Combination With Temozolomide | Median with minimum and maximum area under the drug concentration over time curve | Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose | 
| Clearance of Talazoparib in Combination With Temozolomide | Median with minimum and maximum for the rate of elimination of the drug. | Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose | 
| Accumulation Ratio of Talazoparib in Combination With Temozolomide | Median with minimum and maximum of the accumulation ratio. | Cycle 1 Day 1 pre-dose, and 1, 2, 4 and 8 hours after the first talazoparib dose. Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose | 
| Half-life of Temozolomide in Combination With Talazoparib | Median with minimum and maximum for the time required for the serum concentration to fall to 50% of its starting dose. | Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose | 
| T Max of Temozolomide in Combination With Talazoparib | Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs. | Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose | 
| C Max of Temozolomide in Combination With Talazoparib | Median with minimum and maximum for the maximum (peak) serum concentration. | Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose | 
| AUC of Temozolomide in Combination With Talazoparib | Median with minimum and maximum for the area under the drug concentration over time curve. | Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose. | 
| Clearance of Temozolomide in Combination With Talazoparib | Median with minimum and maximum for the rate of elimination of the drug. | Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose | 
| Number of Ewing/Peripheral PNET Participants in Phase 2 With Complete Response (CR) or Partial Response (PR) | Frequency of Ewing sarcoma and peripheral PNET participants with Complete Response (CR) or Partial Response (PR) per the Response Evaluation Criteria In Solid Tumors (RECIST) | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Solid Tumor Patients With Complete Response (CR) or Partial Response (PR) | Frequency of solid tumor participants with Complete Response (CR) or Partial Response (PR) per the Response Evaluation Criteria In Solid Tumors (RECIST) | Up to 24 months |