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

Tracking Information
First Submitted Date ICMJE	April 15, 2014
First Posted Date ICMJE	April 17, 2014
Last Update Posted Date	July 17, 2018
Actual Study Start Date ICMJE	May 16, 2014
Estimated Primary Completion Date	October 31, 2018 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: March 2, 2018)	MTD of talazoparib and temozolomide, defined as the maximum dose at which fewer than one-third of patients experience dose limiting toxicities (Phase I Part A1) [ Time Frame: 28 days ]In addition to determination of the MTD or RP2D, a descriptive summary of all toxicities will be reported.; Objective response in patients with Ewing sarcoma or peripheral PNET assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 and criteria for CNS tumors (Phase I Part A2) [ Time Frame: Up to 24 months ]All disease responses will be reported descriptively.; Pharmacokinetic (PK) parameters of talazoparib (Phase I Part A) [ Time Frame: Pre-dose, 1, 2, 4, 8, and 24 hours on day 1 and on day 5 or 6 of course 1 ]A descriptive analysis will be performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).; Best response of disease to talazoparib plus temozolomide in Ewing sarcoma or peripheral PNET patients determined according to RECIST v1.1 (Phase II Parts B and C) [ Time Frame: From the start of the treatment until disease progression/recurrence, assessed up to 24 months ]; Best response of disease to talazoparib plus temozolomide in patients with ALL using the leukemia rating scale and peripheral blood counts (Phase II Parts B and C) [ Time Frame: From the start of the treatment until disease progression/recurrence, assessed up to 24 months ]; Incidence of toxicities, graded using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 (Phase II Parts B and C) [ Time Frame: Up to 30 days ]Described separately.
Original Primary Outcome Measures ICMJE; (submitted: April 16, 2014)	MTD of PARP inhibitor BMN-673 and temozolomide, defined as the maximum dose at which fewer than one-third of patients experience dose limiting toxicities (DLT) (Phase I Part A1) [ Time Frame: 28 days ]In addition to determination of the MTD or RP2D, a descriptive summary of all toxicities will be reported.; Objective response in patients with Ewing sarcoma or peripheral PNET assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 and criteria for CNS tumors (Phase I Part A2) [ Time Frame: Up to 24 months ]All disease responses will be reported descriptively.; Pharmacokinetic (PK) parameters of PARP inhibitor BMN-673 (Phase I Part A) [ Time Frame: Pre-dose, 1, 2, 4, 8, and 24 hours on day 1 and on day 5 or 6 of course 1 ]A descriptive analysis will be performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).; Best response of disease to PARP inhibitor BMN-673 plus temozolomide in Ewing sarcoma or peripheral PNET patients determined according to RECIST v1.1 (Phase II Parts B and C) [ Time Frame: From the start of the treatment until disease progression/recurrence, assessed up to 24 months ]; Best response of disease to PARP inhibitor BMN-673 plus temozolomide in patients with ALL using the leukemia rating scale and peripheral blood counts (Phase II Parts B and C) [ Time Frame: From the start of the treatment until disease progression/recurrence, assessed up to 24 months ]; Incidence of toxicities, graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (Phase II Parts B and C) [ Time Frame: Up to 30 days ]Described separately.
Change History	Complete list of historical versions of study NCT02116777 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE	Not Provided
Original Secondary Outcome Measures ICMJE	Not Provided
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Talazoparib and Temozolomide in Treating Younger Patients With Refractory or Recurrent Malignancies
Official Title ICMJE	A Phase 1/2 Study of BMN 673, an Oral Poly(ADP-Ribose) Polymerase Inhibitor, Plus Temozolomide in Children With Refractory or Recurrent Malignancies
Brief Summary	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	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 and recurrent acute lymphoblastic leukemia (ALL). (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.
Study Type ICMJE	Interventional
Study Phase	Phase 1; Phase 2
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Adult Solid Neoplasm; Childhood Solid Neoplasm; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Central Nervous System Neoplasm; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Malignant Solid Neoplasm; Refractory Central Nervous System Neoplasm
Intervention ICMJE	Other: Laboratory Biomarker Analysis Correlative studies; Other: Pharmacological Study Correlative studies; Drug: Talazoparib Given PO Other Names: BMN 673 BMN-673; Drug: Temozolomide Given PO Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac
Study Arms	Experimental: Treatment (talazoparib, temozolomide); 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.; Interventions: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Talazoparib; Drug: Temozolomide
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Active, not recruiting
Estimated Enrollment ICMJE; (submitted: May 19, 2016)	148
Original Estimated Enrollment ICMJE; (submitted: April 16, 2014)	172
Study Completion Date	Not Provided
Estimated Primary Completion Date	October 31, 2018 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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 and Part C) Patients must be > than 12 months and =< 30 years of age at the time of study enrollment; Body surface area (for Parts A, B and C): 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) Acute lymphoblastic leukemias (ALL): patients must have 2nd or greater relapse of pre-B ALL or T-cell ALL; patients may not have refractory disease Patients with ALL must have had histologic verification of the malignancy at the most recent relapse, including immunophenotyping to confirm diagnosis; 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 Phase 2 (Part C): Acute lymphoblastic leukemias (ALL): patients with ALL must have an M3 marrow with or without extramedullary site of relapse OR an M2 bone marrow with an extramedullary site of relapse; patients with CNS 3 status are not eligible for enrollment; 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) Acute lymphoblastic leukemias (ALL) (Part C): Patients with leukemia who relapse while receiving standard maintenance chemotherapy will not be required to have a waiting period before enrollment onto this study Patients who relapse while they are not receiving standard maintenance therapy, must have fully recovered from all acute toxic effects of prior therapy; at least 14 days must have elapsed after the completion of cytotoxic therapy, with the exception of hydroxyurea Note: cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of BMN 673 Note: patients with leukemia are permitted to receive intrathecal chemotherapy, including methotrexate or cytarabine; intrathecal therapy should be restricted to days 15 and 22 of each 28 day cycle 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 and Part C: 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; Patients on Part C with acute lymphoblastic leukemia: platelet count >= 20,000/mm^3 (may receive platelet transfusions); these patients must not be known to be refractory to red cell or platelet transfusion; 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; Patients on Part C with ALL: bilirubin (sum of conjugated + unconjugated) =< 1.5 x ULN for age; Patients on Part C with ALL: SGPT (ALT) =< 225 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L; Patients on Part C with ALL: 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; For Part C (Phase 2): recurrent ALL patients with CNS 3 status 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 and Part C): 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
Sex/Gender	Sexes Eligible for Study: All
Ages	13 Months to 30 Years (Child, Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT02116777
Other Study ID Numbers ICMJE	NCI-2014-00804; NCI-2014-00804 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); ADVL1411 ( Other Identifier: COG Phase I Consortium ); ADVL1411 ( Other Identifier: CTEP ); UM1CA097452 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	National Cancer Institute (NCI)
Study Sponsor ICMJE	National Cancer Institute (NCI)
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Eric Schafer COG Phase I Consortium
PRS Account	National Cancer Institute (NCI)
Verification Date	June 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP