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

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

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Malignant Solid Neoplasm; Childhood Solid Neoplasm; Recurrent Childhood Central Nervous System Neoplasm; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Adult Solid Neoplasm; Refractory Central Nervous System Neoplasm
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Temozolomide; Drug: Talazoparib

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.(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: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Children's Hospital of Alabama
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Francisco, California, United States, 94158
      • UCSF Medical Center-Mission Bay
    • San Francisco, California, United States, 94143
      • UCSF Medical Center-Parnassus
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta - Egleston
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Lurie Children's Hospital-Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota/Masonic Cancer Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 30 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (talazoparib, temozolomide): Phase 1; (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; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Temozolomide; Given PO; Other Names: Temodar; SCH 52365; Temodal; Temcad; Methazolastone; RP-46161; Temomedac; TMZ; 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; Drug: Talazoparib; Given PO; Other Names: BMN 673; BMN-673
Experimental: Treatment (talazoparib, temozolomide): Phase 2; (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; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Temozolomide; Given PO; Other Names: Temodar; SCH 52365; Temodal; Temcad; Methazolastone; RP-46161; Temomedac; TMZ; 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; Drug: Talazoparib; Given PO; Other Names: BMN 673; BMN-673

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Eric S Schafer, COG Phase I Consortium

Publications and helpful links

General Publications

• Schafer ES, Rau RE, Berg SL, Liu X, Minard CG, Bishop AJR, Romero JC, Hicks MJ, Nelson MD Jr, Voss S, Reid JM, Fox E, Weigel BJ, Blaney SM. Phase 1/2 trial of talazoparib in combination with temozolomide in children and adolescents with refractory/recurrent solid tumors including Ewing sarcoma: A Children's Oncology Group Phase 1 Consortium study (ADVL1411). Pediatr Blood Cancer. 2020 Feb;67(2):e28073. doi: 10.1002/pbc.28073. Epub 2019 Nov 14.

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2014
• Primary Completion (Actual): December 31, 2018
• Study Completion (Actual): December 31, 2018

Study Registration Dates

• First Submitted: April 15, 2014
• First Submitted That Met QC Criteria: April 16, 2014
• First Posted (Estimate): April 17, 2014

Study Record Updates

• Last Update Posted (Actual): March 26, 2021
• Last Update Submitted That Met QC Criteria: March 1, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Disease Attributes; Neoplasms, Neuroepithelial; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Neoplasms; Recurrence; Sarcoma, Ewing; Nervous System Neoplasms; Central Nervous System Neoplasms; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Poly(ADP-ribose) Polymerase Inhibitors; Temozolomide; Talazoparib
• Other Study ID Numbers: NCI-2014-00804 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UM1CA097452 (U.S. NIH Grant/Contract); ADVL1411 (Other Identifier: CTEP)