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
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
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).
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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)
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.
United States: Food and Drug Administration
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