A Phase I Dose-Escalation Study of Oral ABT-888 (NSC #737664) Plus Intravenous Irinotecan (CPT-11, NSC#616348) Administered in Patients With Advanced Solid Tumors
I. To determine the optimal biologic dose (OBD) for poly (ADP-ribose) polymerase (PARP)
inhibition using irinotecan (irinotecan hydrochloride) (once weekly intravenously in 2 of 3
weeks), in combination with ABT-888 (twice daily orally for 2 of 3 weeks).
II. To determine the recommended phase II dose (RP2D) for irinotecan (once weekly
intravenously in 2 of 3 weeks), in combination with ABT-888 (twice daily orally for 2 of 3
weeks), determined by evaluating the feasibility, safety, dose limiting toxicities and the
maximally tolerated dose.
III. To determine the safety profile of irinotecan in combination with ABT-888: the
incidence of adverse events (AEs) and clinically significant changes in laboratory tests,
electrocardiograms (ECGs), and vital signs.
IV. To determine the safety profile of irinotecan in combination with ABT-888 at the
recommended phase II dose: the incidence of adverse events (AEs) and clinically significant
changes in laboratory tests, ECGs, and vital signs.
I. To determine the pharmacokinetic (PK) profile of ABT-888. II. To determine the PK profile
of irinotecan (CPT-11) both as a single agent and in combination with ABT-888.
III. To determine the tumor response as assessed by the Response Evaluation Criteria in
Solid Tumors (RECIST).
I. Pharmacodynamic (PD) biomarker response: PARP inhibition in peripheral blood mononuclear
cells (PBMC) by measurement of PAR levels. (Dose escalation portion) II. DNA damaging
effects of irinotecan and the combination of irinotecan with ABT-888: levels of γ-H2AX and
Rad51 formation in tumor tissue. (Dose escalation portion) III. Relevance of CYP2C9 and 2C19
polymorphisms, UGT1A1 polymorphism, and ABCG2 polymorphism to the pharmacokinetics of
irinotecan and/or ABT-888. (Dose escalation portion) IV. To explore whether a positive
γ-H2AX response in tumor tissue at 4-6 hrs is reflected in CTCs between 8-24 hrs but not at
4-6 hrs, as predicted. (Expansion portion) V. To explore whether PARP inhibition increases
γH2AX response of CTCs to plasma drug by 4-6 hrs after CPT-11 administration. (Expansion
portion) VI. To explore whether PARP inhibition increases γ-H2AX response of tumor cells to
tissue drug level, as indicated by CTCs at 8-24 hrs after CPT-11. (Expansion portion) VII.
To explore when the γ-H2AX response peak in CTCs occurs, indicating a response in tumor.
(Expansion portion) VIII. To explore whether there is a tumor switch between gamma-H2AX and
ERCC1-mediated repair in the presence of PARP inhibition, (i.e., repeat initial PBMC and
tumor findings). (Expansion portion) IX. To perform analysis of CTCs at day 15 to help guide
alteration in ABT-888 drug administration schedule (continuous administration). (Expansion
portion) X. To sequence the genome and transcriptome from both normal and tumor tissue from
each study patient in the expansion cohort to evaluate point mutations, structural changes
and copy number events. (Expansion portion) XI. To evaluate the damaging effects of
irinotecan and the combination of irinotecan with ABT-888 by examining levels of Rad51
formation in tumors. (Expansion portion) XII. To evaluate the percentage of BCSC in serial
breast tumor biopsies before and after irinotecan alone and after 1 cycle of treatment with
the combination of irinotecan and ABT-888. (Expansion portion) XIII. To perform molecular
profiling of the tumor cell and BCSC populations before and after irinotecan alone and after
1 cycle of treatment with the combination of irinotecan and ABT-888. (Expansion portion)
XIV. To compare Rad51 foci in ALDH+ stem cell populations to the bulk tumor cells.
OUTLINE: This is a dose-escalation study of ABT-888.
Patients receive irinotecan hydrochloride IV over 90 minutes on days 1 and 8 and oral
ABT-888 twice daily on days 0-14 (days 3-14 of course 1 only). Courses repeat every 21 days
in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed periodically for 30 days.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Optimal biological dose of study drugs, defined as the maximal decrease in PAR
Up to day 9 of course 1
Barbara Ann Karmanos Cancer Institute
United States: Food and Drug Administration
|Barbara Ann Karmanos Cancer Institute||Detroit, Michigan 48201|
|Dana-Farber Cancer Institute||Boston, Massachusetts 02115|
|University of Maryland Greenebaum Cancer Center||Baltimore, Maryland 21201|