Abstract A93: Safety, efficacy and pharmacokinetics of two schedules of navitoclax (ABT-263) in combination with irinotecan: Preliminary results of an open-label phase 1 study.
Authors: Tolcher Anthony W. , LoRusso Patricia , Rosen Lee , de Oliveira Moacyr Ribeiro , Waring Jeffrey F. , Rudersdorf Niki , Patel Raina , Brasher Carol Ann , Busman Todd , Cui Yue , Yang Jianning , Holen Kyle 
Published: June 2012

Abstract
Introduction: Navitoclax (Nav), a novel BH3 mimetic that binds with high affinity and inhibits antiapoptotic Bcl-2 family proteins, enhances chemotherapy activity by lowering the apoptotic threshold. Preclinically, navitoclax enhanced irinotecan (Ir) efficacy in colon, gastric, pancreatic, and small cell lung cancer tumor models.
Methods: This phase 1 study in cancer patients (pts), assessed safety, pharmacokinetics (PK), and tumor activity of Nav in combination with Ir on 2 different schedules. Eligible pts had an ECOG performance score of ≤2 and a malignancy refractory to standard therapy. Pts were assigned to 1 of 2 dosing schedules. A continual reassessment method for dose escalation was used. Pts were assigned to 21-day (D)-cycle dosing schedules, either 3-week (Q3W) (Nav D1–3 [18 off]; Ir D1) or weekly (W) (Nav D1–3 and D8–10 [11 days off]; Ir D1 and D8). Oral Nav was dosed once daily starting at 150 mg in both schedules; Ir was dosed intravenously over 90 min at 180, 250 or 350 mg/m2 (Q3W), and over 45 min at 75 or 100 mg/m2 (W). PK was assessed for Nav and Ir; safety was assessed per NCI-CTCAE v3.0; disease response/progression was assessed per standard of care for each tumor type (RECIST, PSA, CEA, CA-125, etc).
Results: 31 pts (15 women, 16 men) were enrolled; median age (range) 58 years (31–73); median (range) prior therapies was 4 (1–17). The most common adverse events (Q3W and W) that were Nav-related, irrespective of relationship to Ir, were diarrhea 77% (86% and 71%), nausea 45% (50% and 41%), vomiting 39% (29% and 47%), fatigue 32% (21% and 41%), and febrile neutropenia 26% (36% and 18%). Dose-limiting toxicities (DLT) (Q3W and W) were reported by 11 pts (6 and 5), and included febrile neutropenia 7 pts (5 and 2), diarrhea 7 pts (4 and 3), fatigue 2 pts (0 and 2), and colitis 1 pt (1 and 0). The recommended phase 2 dose (RPTD) in the W schedule was Nav 150 mg and Ir 75 mg/m2. The lowest level explored on the Q3W schedule (Nav 150 mg and IR 180 mg/m2) was determined to be not tolerable and therefore the highest administrated dose exceeded a maximum tolerated dose (MTD). Tumor response is available for 17 pts (Q3W and W); 2 had a partial response (1 Merkel cell carcinoma and 1 colon cancer; neither pt had received prior Ir), 6 had stable disease (2 and 4), 9 had progressive disease (PD) (5 and 4). Objective response rate was 6.5% [95% CI: 0.8, 21.4]. 19 pts discontinued treatment due to PD, 7 due to AEs, 3 withdrew consent, and 1 due to DLT (1 pt is still on study). Median [95% CI] time on study (Q3W and W) was 25 days [10, 32] (25 days [3, 32], 26 days [3, 53]). Preliminary results indicate no apparent PK interaction between Nav and Ir. The average SN-38 exposure appeared to be higher in pts with DLTs. After febrile neutropenia was observed in the first dose level explored, the study was amended to include only those pts with functional UGT1A1 enzyme activity. The frequency of UGT1A1 genotypes (%) was *1/*1 (32); *1/*28 (52); *28/*28 (13); *28/*37 (3).
Conclusions: The RPTD in the W schedule was Nav 150 mg and Ir 75 mg/m2. The Q3W schedule had a high rate of toxicities and an MTD was not identified. Despite limiting enrollment to those with functional UGT1A1 enzyme activity, the SN-38 exposures remained highly variable and may have contributed to the high rate of toxicities observed. The 2 tumor responses were notable in this highly chemotherapy-refractory pt population.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A93.