Talazoparib will be administered orally on day 1 either once or twice per day depending on the dose level of the enrolled patient. Both oral talazoparib and IV irinotecan will then be administered daily, on days 2-6. Each cycle will last 21 days. Filgrastim or peg-filgrastim will be given following the last dose of chemotherapy.
Arm A is closed to enrollment.

Once the maximum tolerated doses (MTDs) for talazoparib and irinotecan are determined, a second arm of the study will open administering talazoparib, irinotecan and temozolomide. Talazoparib will be given orally, days 1-6. Intravenous irinotecan and oral temozolomide will be given days 2-6. Filgrastim or peg-filgrastim will be given following the last dose of chemotherapy.

Childhood Solid Tumors

Given orally once or twice on day 1 (depending on the dose level), then daily on days 2-6.

Talazoparib

Given intravenously daily, days 2-6 immediately following the talazoparib dose.

Irinotecan

Given orally daily. Dose to be determined after MTD established with talazoparib plus irinotecan.

Temozolomide

Given subcutaneously (SubQ) once per day starting 24-36 hours after last dose of chemotherapy and continuing until post-nadir ANC is >2,000/μL, unless peg-filgrastim is given.

Filgrastim

Given subcutaneously (SubQ) once per day starting 24-36 hours after last dose of chemotherapy and continuing until post-nadir ANC is >2,000/μL, unless filgrastim is given.

Peg-filgrastim

St. Jude Children's Research Hospital

Talazoparib Plus Irinotecan With or Without Temozolomide in Children With Refractory or Recurrent Solid Malignancies

A Phase I Study of Talazoparib (BMN 673) Plus Irinotecan With or Without Temozolomide in Children With Refractory or Recurrent Solid Malignancies

This study is a traditional dose escalation study using a standard 3+3 phase I design to define the MTD. Six or more dose levels will be evaluated for the combination of talazoparib and irinotecan. Each cycle will last 21 days with talazoparib given daily on days 1-6 and irinotecan given daily on days 2-6.

Dose-limiting toxicities defined in the first cycle of the combination of talazoparib and irinotecan will be summarized for patients treated at each dose level with DLTs type and grade.

Once the MTD is defined for the combination of talazoparib plus irinotecan in Arm A, then temozolomide will be added to make a triple drug combination, talazoparib plus irinotecan and temozolomide. This is a traditional dose escalation study using a standard 3+3 phase I design to define the MTD. Six or more dose levels will be evaluated for the combination of talazoparib plus irinotecan and temozolomide. Each cycle will last 21 days with talazoparib given daily on days 1-6 and irinotecan and temozolomide given daily on days 2-6.

DLT defined in the first cycle of the combination of talazoparib plus irinotecan and temozolomide will be summarized for patients treated at each dose level with DLTs type and grade.

We will provide summary statistics for the best overall response (complete response, partial response, stable disease and progressive disease) of patients experienced during treatment.

A population average value and variance will be reported for week 1 of course 1

BioMarin Pharmaceutical

Alliance Pharma

Pfizer

Niraparib (capsule) and temozolomide (capsule) will be taken together.

Niraparib will be taken orally and irinotecan will be administered intravenously.

Niraparib and temozolomide will be taken orally. Irinotecan will be administered intravenously.

Ewing Sarcoma

niraparib

Children's Hospital of Los Angeles

National Cancer Institute

University of Michigan

Seattle's Children Cancer Center

University College London Hospital

ESP1/SARC025 Global Collaboration: A Phase I Study of a Combination of the PARP Inhibitor, Niraparib and Temozolomide and/or Irinotecan Patients With Previously Treated, Incurable Ewing Sarcoma

ESP1/SARC025 Global Collaboration: A Phase I Study of a Combination of the PARP Inhibitor, Niraparib and Temozolomide and/or Irinotecan in Patients With Previously Treated,Incurable Ewing Sarcoma

Dose limiting toxicity describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. The maximum tolerated dose is the highest dose of a drug or treatment that does not cause unacceptable side effects.

The percentage of patients whose tumor shrinks or disappears after treatment

The time from starting treatment until disease progression

The time from tumor response to disease progression

Sarcoma Alliance for Research through Collaboration

Olaparib, taken orally twice per day on days 1-7 (week 1) of each cycle Temozolomide, taken orally once per day on days 1-7 (week 1) of each cycle for patients with Ewing sarcoma

Olaparib, taken orally twice per day on days 1-7 (week 1) of each cycle Temozolomide, taken orally once per day on days 1-7 (week 1) of each cycle Irinotecan, given by IV once per day on days 1-7 of each cycle

Olaparib, taken orally twice per day on days 1-7 (week 1) of each cycle Temozolomide, taken orally once per day on days 1-7 (week 1) of each cycle for patients with Rhabdomyosarcoma

Rhabdomyosarcoma

Tablets to be taken on an empty stomach twice a day.

Olaparib

Tablets to be taken on an empty stomach before bedtime.

Massachusetts General Hospital

Boston Children's Hospital

Brigham and Women's Hospital

Dana-Farber Cancer Institute

St. Jude's Children's Research Hospital

Phase I Study of Olaparib and Temozolomide for Ewings Sarcoma or Rhabdoomyosarcoma

Phase I Study of Olaparib and Temozolomide in Adult Patients With Recurrent/Metastatic Ewing's Sarcoma or Rhabdomyosarcoma Following Failure of Prior Chemotherapy

Determine the Maximum Tolerated Dose of combine oral administration of olaparib and temozolomide.

Evaluate the safety and tolerability of combination olaparib/temozolomide as defined by CTC version 4.0

Observe objective response in tumor dimensions to olaparib/temozolomide therapy as determined by RECIST 1.1, time of progression free survival (PFS) and overall survival (OS)

Patients will undergo tumor biopsies before and after starting olaparib and temozolomide therapy. Genomic DNA and RNA will be isolated from these samples and slides will be made to identify specific protein levels. The investigators will assess homologous repair status by measuring gammaH2AX and Rad51 focus formation by immunofluorescence. Biomarkers for apoptosis and DNA repair that the investigators plan to analyze include but are not limited to BRCA1, MRE11A, NBS1, TDG, XPA, Rad50, 53BP1, CHEK2, and MK2.

Edwin Choy, MD

Prinicipal Investigator

Patients receive veliparib PO BID on days 1-7 and temozolomide PO on days 1-5.

Patients receive placebo PO BID on days 1-7 and temozolomide as in Arm I.

Patients receive veliparib PO BID on days 1-7 and temozolomide PO on days 1-5.
Laboratory Biomarker Analysis: Correlative studies
Temozolomide: Given PO
Veliparib: Given PO

Arm I (Veliparib and Temozolomide)

Patients receive placebo PO BID on days 1-7 and temozolomide as in Arm I.
Laboratory Biomarker Analysis: Correlative studies
Placebo: Given PO
Temozolomide: Given PO

Arm II (Placebo and Temozolomide)

Total

Sex: Female, Male

Race (NIH/OMB)

Compared across the two arms using a Fisher exact test.

Progression-free Survival, Calculated as the Proportion of Patients Alive and Without Evidence of Disease

Corresponding exact two-sided 95% confidence intervals will be calculated and reported in both arms of the study. Comparisons between treatment arms will be performed using Fisher-exact test.

Overall Response (ORR) by RECIST 1.1 Criteria

Estimated in each treatment group using Kaplan-Meier method. Group comparisons will be performed using log-rank test.

Overall Survival

Tabulated According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. Summary level.

Number of Participants With Adverse Events

Fisher's exact test will be used to correlate response and log-rank test to correlate with progression free survival and overall survival.

BRCA1 Expression, Assessed by Immunohistochemistry

Correlated with outcome in the two treatment arms.

Changes in Plasma Markers

Wilcoxon test will be used to compare the percentage increase of gammaH2AX positive cells between the two treatment groups.

GammaH2AX Levels

Results will be expressed as binary variables. Associations with objective response, with progression free survival and with overall survival will be tested using Fisher's exact test and log-rank test, respectively.

MGMT Expression, Assessed by Immunohistochemistry

The number of CTCs will be correlated with PFS and OS using Cox proportional hazards model. The change in CTCs will be correlated with radiographic response. The number of CTCs at baseline will be correlated with patient characteristics (disease burden, location of metastases, and progression at existing sites or new sites of disease). The number of CTC will be explored as a continuous variable and the presence of a threshold predictive of the outcome will be investigated.

Number of Circulating Tumor Cells

PARP-1 Expression

Presence of MGMT Promoter Methylation, Assessed by the EpiTyper Assay

PTEN Expression, Assessed by Immunohistochemistry

RAD51 Expression, Assessed by Immunohistochemistry

Overall Study

Dr. Charles Rudin

Recurrent Small Cell Lung Carcinoma

Laboratory Biomarker Analysis

Placebo

Veliparib

Moffitt Cancer Center

Emory University/Winship Cancer Institute

Johns Hopkins Bayview Medical Center

Johns Hopkins University/Sidney Kimmel Cancer Center

Washington University School of Medicine

Memorial Sloan-Kettering Cancer Center

UNC Lineberger Comprehensive Cancer Center

Case Western Reserve University

M D Anderson Cancer Center

Virginia Commonwealth University/Massey Cancer Center

Temozolomide With or Without Veliparib in Treating Patients With Relapsed or Refractory Small Cell Lung Cancer

A Multi-Center, Randomized, Double-Blind Phase II Study Comparing ABT-888, a PARP Inhibitor, Versus Placebo With Temozolomide in Patients With Relapsed Sensitive or Refractory Small Cell Lung Cancer

ribose/sarcoma

Talazoparib Plus Irinotecan With or Without Temozolomide in Children With Refractory or Recurrent Solid Malignancies

ESP1/SARC025 Global Collaboration: A Phase I Study of a Combination of the PARP Inhibitor, Niraparib and Temozolomide and/or Irinotecan Patients With Previously Treated, Incurable Ewing Sarcoma

Phase I Study of Olaparib and Temozolomide for Ewings Sarcoma or Rhabdoomyosarcoma

Temozolomide With or Without Veliparib in Treating Patients With Relapsed or Refractory Small Cell Lung Cancer

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