A phase I study of r-(-)-gossypol (AT-101, NSC 726190) in combination with cisplatin (P) and etoposide (E) in patients with advanced solid tumors and extensive-stage small cell lung cancer (ES-SCLC).

Abstract

e13030 Background: AT-101 [R-(-)-gossypol acetic acid] (AT) is an orally administered BH3 mimetic that lowers the threshold for apoptosis by direct binding to Bcl-2, Bcl-xL, Mcl-1, and Bcl-W. Combinations of AT and cytotoxic drugs demonstrated synergistic antitumor effects in vitro and in vivo SCLC models. We completed a dose-escalation study of AT in combination with cisplatin and etoposide (EP), in which neutropenia was dose- limiting. The objectives of this study were to determine the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) of AT when combined with EP with pegfilgrastim (F) in patients with advanced solid tumors. Methods: Standard phase I eligibility criteria were used. Prior therapy with Bcl2-inhibitors was not allowed. We previously reported the MTD without F established at AT 20 mg BID days (D) 1-3, P 60 mg/m2 D 1, E 100 mg/m2 D 1-3 every 21 days (Leal, JCO 2009; 27(15S), e13502). Patients were enrolled in 3 additional dose levels (DL) with F support (6 mg SQ D 4): DL1a (AT 30 mg BID, P 60 mg/m2, E 100 mg/m2), DL2a (AT 30 mg BID, P 60 mg/m2, E 120 mg/m2), and DL3a (AT 40 mg BID, P 60 mg/m2, E 120 mg/m2). Results: 12 patients were enrolled: 8 men, 4 women. Tumor types: 4 non-small cell lung cancer (NSCLC), 1 ES-SCLC, 2 esophageal, 2 neuroendocrine, 1 prostate, 1 adrenocortical, 1 gallbladder. No dose limiting toxicities occurred. Grade 3/4 treatment-related toxicities included: 2 episodes of diarrhea (1 DL1a, 1 DL3a), and 1, each, of elevated ALT (DL1a), hypokalemia (DL1a), fatigue (DL2a), neutropenia (DL2a), anemia (DL3a), hypophosphatemia (DL3a), and pulmonary embolism (DL3a). Two patients with NSCLC and 1 with neuroendocrine had a PR. Pharmacokinetic data will be available for presentation. Conclusions: The MTD/RP2D with F support was established at AT 40 mg BID on D 1-3, P 60 mg/m2 D 1, and E 120 mg/m2 D 1-3 every 21 days. F support permits full doses of cytotoxics to be administered. Antitumor activity was observed in patients with lung cancer and neuroendocrine tumor. Accrual to an MTD expansion cohort of patients with untreated ES- SCLC is ongoing. This study was supported by NCI UO1 CA062491, SAIC 25XS097, and 1ULRR025011. No significant financial relationships to disclose.