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NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) plus Intravenous Irinotecan
Michael Cecchini1, Zenta Walther2, Wei Wei3
1Department of Internal Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut.
Purpose:
Veliparib is a PARP inhibitor (PARPi) with activity in BRCA 1/2/PALB2-deficient tumors. Preclinical observations reveal topoisomerase inhibitors like irinotecan are synergistic with PARPi irrespective of homologous recombination deficiency (HRD), potentially expanding the role for PARPi.
Experimental Design:
NCI 7977 was a multicohort phase I clinical trial evaluating the safety and efficacy of multiple dose schedules of veliparib with irinotecan for solid tumors. In the intermittent veliparib cohort, escalating doses of veliparib were given twice daily at dose level (DL) 1 (50 mg) and DL 2 (100 mg) days 1-4 and 8-11 with irinotecan 100 mg/m2 days 3 and 10 in 21-day cycles.
Results:
Fifteen patients enrolled, 8 of 15 (53%) received ≥4 prior systemic treatments. At DL1, 1 of 6 patients experienced a dose-limiting toxicity (DLT) of diarrhea. At DL2, 9 patients were treated, with 3 unevaluable for DLT, and 2 of 6 evaluable patients experienced a DLT of grade 3 neutropenia. Irinotecan 100 mg/m2 and veliparib 50 mg twice daily was the MTD. No objective responses were observed, although 4 patients had progression-free survival >6 months.
Conclusions:
The MTD of intermittent veliparib is 50 mg twice daily days 1-4 and 8-11 with weekly irinotecan 100 mg/m2 days 3 and 10 every 21 days. Multiple patients experienced prolonged stable disease irrespective of HRD and prior irinotecan. However, due to the toxicities with higher dose intermittent veliparib and irinotecan, this schedule was determined too toxic for further development and the arm was closed prematurely.
Significance:
The combination of intermittent veliparib with weekly irinotecan was deemed too toxic for further development. Future PARPi combinations should focus on agents with nonoverlapping toxicities to improve tolerability. The treatment combination showed limited efficacy with prolonged stable disease observed in multiple heavily pretreated patients, but no objective responses were seen.
Insights
This study found that combining veliparib (a PARP inhibitor) with irinotecan was too toxic for further development, despite some patients experiencing stable disease. Future research should explore PARP inhibitor combinations with better tolerability.
Area of Science:
- Oncology
- Clinical Pharmacology
Background:
- Veliparib, a PARP inhibitor (PARPi), shows activity in BRCA-deficient tumors.
- Preclinical data suggest synergy between PARPi and topoisomerase inhibitors like irinotecan, regardless of homologous recombination deficiency (HRD).
Purpose of the Study:
- To evaluate the safety and efficacy of veliparib combined with irinotecan in a phase I clinical trial (NCI 7977).
- To determine the maximum tolerated dose (MTD) of intermittent veliparib and irinotecan in patients with solid tumors.
Main Methods:
- A multicohort phase I trial administered escalating doses of veliparib (50 mg or 100 mg twice daily) on days 1-4 and 8-11 with irinotecan (100 mg/m²) on days 3 and 10 of 21-day cycles.
- Dose-limiting toxicities (DLTs) were assessed to determine the MTD.
Main Results:
- The MTD was determined to be veliparib 50 mg twice daily with irinotecan 100 mg/m².
- Grade 3 neutropenia and diarrhea were observed as DLTs.
- No objective responses were noted, though four patients achieved progression-free survival exceeding 6 months.
Conclusions:
- The combination of intermittent veliparib and weekly irinotecan was found to be too toxic for further clinical development.
- Future PARPi combinations require agents with non-overlapping toxicities to improve patient tolerability.
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