Veliparib and Topotecan Hydrochloride in Treating Patients With Solid Tumors, Relapsed or Refractory Ovarian Cancer, or Primary Peritoneal Cancer
Adult Solid Neoplasm
Recurrent Ovarian Carcinoma
Recurrent Primary Peritoneal Carcinoma
Other: Laboratory Biomarker Analysis
Other: Pharmacogenomic Study
Other: Pharmacological Study
Drug: Topotecan Hydrochloride
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I/II Trial of ABT-888, an Inhibitor of Poly (ADP-ribose) Polymerase (PARP), and Topotecan (TPT) in Patients With Solid Tumors (Phase I) and Relapsed or Refractory Ovarian Cancer or Primary Peritoneal Cancer (Phase II) After Prior Platinum Containing First-Line Chemotherapy|
- MTD of topotecan hydrochloride and veliparib, determined according to incidence of dose-limiting toxicity (DLT), graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I) [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]The number and severity of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized. The grade 3+ adverse events will also be described and summarized in a similar fashion. Toxicity incidence by BRCA mutation will also be evaluated for the patients enrolled in the expanded Phase I MTD cohort. Frequency distribution, graphical techniques, and other descriptive measures will form the basis of these analyses.
- Proportion of tumor responses, defined as a CR or PR as assessed using RECIST [ Time Frame: Up to 48 weeks (12 courses) ] [ Designated as safety issue: No ]The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner (1987).
- Adverse events, graded using NCI CTCAE version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.
- Duration of response [ Time Frame: The date at which the patient's earliest best objective status is first noted to be either a CR or PR to the earliest date progression is documented, assessed up to 5 years ] [ Designated as safety issue: No ]
- Overall survival [ Time Frame: The time from registration to death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]The distribution of survival time will be estimated using the method of Kaplan-Meier.
- PFS [ Time Frame: The time from registration to the earliest date of documentation of disease progression or death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]The distribution of PFS will be estimated using the method of Kaplan-Meier.
- Time to treatment failure [ Time Frame: The time from the date of registration to the date at which the patient is removed from treatment due to progression, adverse events, or refusal, assessed up to 5 years ] [ Designated as safety issue: No ]
|Study Start Date:||October 2009|
|Estimated Primary Completion Date:||June 2018 (Final data collection date for primary outcome measure)|
Experimental: Treatment (veliparib and topotecan hydrochloride)
Patients receive veliparib PO on days 1-3, 8-10, and 15-17 (veliparib is omitted on days 1-3 of course 2) and topotecan hydrochloride IV over 30 minutes on days 2, 9, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studiesOther: Pharmacogenomic Study
Other Name: PHARMACOGENOMICOther: Pharmacological Study
Correlative studiesDrug: Topotecan Hydrochloride
Other Names:Drug: Veliparib
I. To determine the maximum tolerated dose of the combination of ABT-888 (veliparib) and weekly topotecan (topotecan hydrochloride) in adult patients with advanced solid tumors. (Phase I) II. To identify any anti-tumor activity of this treatment combination, as assessed by objective response in patients with advanced solid tumors. (Phase I) III. To assess the confirmed response rate for patients with epithelial ovarian cancer or primary peritoneal carcinoma treated with the combination of ABT-888 and weekly topotecan.
IV. To assess the toxicity of the combination of ABT-888 and weekly topotecan in patients with epithelial ovarian cancer or primary peritoneal carcinoma. (Phase II)
I. To identify any pharmacokinetic interactions between ABT-888 and topotecan. (Phase I and II) II. Phase I MTD: to provide preliminary view as to difference in response and toxicity based on BRCA mutation status. (Phase I) III. To determine whether topotecan stimulates adenosine diphosphate (ADP)-ribose polymer formation in circulating peripheral blood mononuclear cells. (Phase I) IV. To determine whether ABT-888 inhibits basal or topotecan-stimulated ADP-ribose polymer formation. (Phase I) V. To determine whether topotecan stimulates ADP-ribose polymer formation in circulating tumor cells and whether ABT-888 modulates this. (Phase II) VI. To assess differences in the toxicity and/or efficacy of this regimen based on BRCA 1/2 mutational status. (Phase II) VII. To determine whether pretreatment tumor cell levels of topoisomerase I, poly ADP-ribose polymerase (PARP), BRCA1, BRCA2, XRCC1, tyrosyl-deoxyribonucleic acid (DNA) phosphodiesterase 1 (TDP1), P-glycoprotein or breast cancer resistance protein (BCRP) predict response to this regimen. (Phase II) VIII. To identify, in an exploratory manner, any transcriptional profiles that may predict response to this regimen. (Phase II)
OUTLINE: This is a phase I, dose escalation study of veliparib and topotecan hydrochloride followed by a phase II study.
Patients receive veliparib orally (PO) on days 1-3, 8-10, and 15-17 (veliparib is omitted on days 1-3 of course 2) and topotecan hydrochloride intravenously (IV) over 30 minutes on days 2, 9, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 3 months (Phase I) or every 3 or 6 months for 5 years (Phase II).
Please refer to this study by its ClinicalTrials.gov identifier: NCT01012817
|United States, Arizona|
|Mayo Clinic in Arizona|
|Scottsdale, Arizona, United States, 85259|
|United States, Florida|
|Mayo Clinic in Florida|
|Jacksonville, Florida, United States, 32224-9980|
|United States, Minnesota|
|Rochester, Minnesota, United States, 55905|
|Principal Investigator:||Michael Menefee||Mayo Clinic|