Abstract C242: A phase 1/1b dose escalation study of iniparib as a single agent and in combination with gemcitabine/carboplatin in patients with advanced solid tumors.
Authors: Mita Monica , Baffa Raffaele , Charpentier Eric , Lockhart Craig A. , Morris John C. , Rixe Olivier , Sarantopoulos John , Ramanathan Ramesh 
Published: August 2014

Abstract
Background: Iniparib (I) is a novel anticancer agent initially thought to be a poly (ADP-ribose) polymerase (PARP) inhibitor. Recent preclinical data suggest that iniparib does not inhibit PARP at pharmacologically-relevant concentrations. The initial Phase 1 did not identify any dose limiting toxicity (DLT) and the dose of 5.6 mg/kg used in further development was based on a PK/PD model for PARP inhibition. This new Phase 1 study was designed to determine a maximum tolerated dose (MTD) based on DLT occurrence for single agent iniparib and in combination with gemcitabine and carboplatin (GC).
Patients and Methods: Patients with advanced cancer and ECOG performance status (PS) 0-2 with no standard therapeutic option or for whom GC could be considered an adequate treatment were enrolled in this trial. In the Phase 1 portion, patients received escalating doses of single agent iniparib starting at 15 mg/kg in a 3+3 design. In the Phase 1b, two different regimens of GC and iniparib were evaluated (GC2+I: carboplatin AUC2, gemcitabine 1,000 mg/m2 and iniparib on Days 1 and 8 every 21 days; and GC5+I: carboplatin AUC5 on Day 1, gemcitabine at 1,000 mg/m2 and iniparib both on Days 1 and 8 in a 21-day cycle). At the MTD, the cohort was expanded by 12 patients. Safety, pharmacokinetics, pharmacodynamics, and antitumor effects were also evaluated.
Results: Of the 59 patients (M/F= 18/41; ECOG 0/1-2=21/38) enrolled in this study, 29 received single agent iniparib (15 mg/kg=3; 20 mg/kg=16; 26 mg/kg=10); 23 received GC2+I (15 mg/kg=3; 20 mg/kg=20) and 7 were treated in the GC5+I arm at 15 mg/kg. DLT in the phase 1 was G3 transient increase in blood pressure during the iniparib infusion in 4 patients treated at 26 mg/kg. Nine patients at 20 mg/kg (5 in Phase 1 and 4 in Phase 1b) experienced also transient non-DLT hypertension. In most cases HTN was managed by interrupting the infusion; infusions were completed after blood pressure normalization. No patient was discontinued due to it. DLT for GC2+I was G4 thrombocytopenia in 3 patients. GC5+I at 15 mg/kg was considered non-tolerable due to G4 hematological toxicity in 2/5 patients. One ovarian cancer patient treated with iniparib single agent at 26 mg/kg for longer than 18 months had a durable (9 months) partial response (PR). Ten PRs were recorded in combination with GC.
Conclusions: The MTD of iniparib single agent and in combination with GC2 is 20 mg/kg weekly. Hypertension during the infusion has been identified as a characteristic DLT. The MTD of GC5+I is below 15mg/kg of iniparib weekly due to hematological toxicity. The GC2+I regimen demonstrated manageable tolerability.
ClinicalTrials.gov identifier: NCT01455532
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C242.
Citation Format: Monica Mita, Raffaele Baffa, Eric Charpentier, Craig A. Lockhart, John C. Morris, Olivier Rixe, John Sarantopoulos, Ramesh Ramanathan. A phase 1/1b dose escalation study of iniparib as a single agent and in combination with gemcitabine/carboplatin in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C242.