P3-16-08: A Phase 2, Randomized Open-Label Study of Iniparib, Administered Either Weekly or Twice-Weekly in Combination with Gemcitabine Plus Carboplatin in Patients with mTNBC.
Authors: Diéras V , Bonnefoi H , Alba E , Awada A , Coudert B , Pivot X , Gligorov J , Jäger A , Gianni L , Lindeman G , Pham N , Su Y , Gao G , Mery-Mignard D , Paridaens R , Verweij J 
Published: June 2012

Abstract
Background
Iniparib (BSI-201) is an investigational anticancer agent whose precise mechanism of action is under active investigation. In breast cancer cell lines and xenograft models of triple-negative breast cancer (TNBC), iniparib exhibits anti-proliferative activity and potentiates the cell cycle effects of some DNA damaging agents. In a randomized, open-label phase 2 study in pts with metastatic TNBC (mTNBC), iniparib combined with gemcitabine (G) and carboplatin (C) (GC) improved efficacy outcomes compared with GC alone. A confirmatory phase 3 study with GCI failed to meet pre-specified criteria for PFS and OS; however, an exploratory subset analysis demonstrated a potential benefit amongst 2nd/3rd line pts (O'Shaughnessy et al. ASCO 2011). Here we report results of a randomized phase 2 study (NCT01045304) in pts with mTNBC, which assesses efficacy and pharmacokinetics (PK) of iniparib administered either biw or qw in combination with GC.
Patients and methods: Eligible pts (N=163; median age 49 yrs) had documented and measurable TNBC, ECOG PS 0–1, normal organ/marrow function, and had received ≤2 prior chemotherapy (CT) regimens for metastatic disease. Pts were randomized (1:1) to receive G (1,000 mg/m2, IV, d 1, 8) plus C (AUC 2, IV, d 1, 8) and iniparib either biw (5.6 mg/kg, IV d 1,4,8,11) or qw (11.2 mg/kg, IV d 1,8) on a 21 d cycle. Pts were stratified according to prior CT for mTNBC (0 vs. 1–2). The primary efficacy endpoint was overall response rate (ORR; CR + PR); secondary endpoints included: clinical benefit rate (CBR; CR + PR + SD for 24 weeks), PFS, OS and PK.
Results: At the time of analysis, 23% of patients were still on treatment. The median number of cycles administered per patient was 6 in both arms; exposure to iniparib was identical. Safety data are not fully validated. All pts experienced at least 1 treatment emergent adverse event (TEAE). Grade (Gr) ≥3 TEAEs occurred in 94% and 85% of pts in the biw and qw arms, respectively. TEAEs Gr ≥3 occurring in ≥5% of pts regardless of relationship to study drug (biw vs qw) are as follows: blood and lymphatic 71% vs 67%; hepatobiliary 7.5% vs 9.8%; asthenia/fatigue 7.5% vs 11%; GI 8.8% vs 8.5%; infections 7.5% vs 3.7%; respiratory, thoracic and mediastinal 5% vs 8.5%, metabolism and nutrition 4% vs 6%. For response data see table.

No major difference was observed in drug exposure (based on AUC within one cycle) between the two dosing regimens.
Conclusion: Dosing of GCI on a qw schedule produced a similar ORR to that obtained with the biw schedule. A comparable safety profile in both arms, and consistency with results of previous studies, suggests that the weekly combination of GCI may be an appropriate schedule for further studies evaluating this combination. OS and PFS data are not yet mature; updated efficacy and safety data will be presented.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-08.