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

A. M. Traynor, J. Kolesar, R. M. Marnocha, J. C. Eikhoff, D. B. Alberti, N. Takebe, G. Wilding, G. Liu and W. R. Schelman
Journal of clinical oncology, Vol.29(15_suppl), pp.3040-3040
05/20/2011
DOI: 10.1200/jco.2011.29.15_suppl.3040
url
https://doi.org/10.1200/jco.2011.29.15_suppl.3040View
Published (Version of record) Open Access

Abstract

Abstract only Background: AT-101 (AT) is an oral BH3 mimetic that lowers the apoptotic threshold by inhibiting heterodimerization of Bcl-2, Bcl-xL, Mcl-1 and Bcl-W, up-regulating pro-apoptotic proteins noxa and puma and inhibiting angiogenesis. Synergistic anti-tumor activity as been observed in vitro with EP in combination with agents that suppress Bcl-2 expression. This study was conducted to determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic (PK) profile and preliminary anti-tumor activity of AT and EP. Methods: Adult pts with relapsed or refractory advanced solid tumors received AT orally BID days (D) 1-3, P IV D 1, and E IV D 1-3 of a 21-D cycle. We previously reported the MTD without pegfilgrastim (F) was AT 20 mg BID, P 60 mg/m2, and E 100 mg/m2 (Leal, JCO 2009; 27(15S), e13502). Pts were enrolled in 3 additional dose levels (DL) with F support (6 mg SQ day 4): DL1a (AT 30 mg, P 60 mg/m2, and E 100 mg/m2), DL2a (AT 30 mg, P 60 mg/m2, and E 120 mg/m2), and DL3a (AT 40 mg, P 60 mg/m2, and E 120 mg/m2). Results: 12 additional pts were enrolled: 8 men, 4 women. Tumor types: 4 non-small cell lung cancer (NSCLC), 1 ES-SCLC, 2 esophageal, 2 high-grade (HG) neuroendocrine, 1 prostate, 1 adrenocortical, 1 gallbladder. No dose limiting toxicities occurred. Grade 3/4 treatment-related toxicities included: 2 pts with diarrhea (1 at DL1a and 1 at DL3a), and 1 episode, each, of increased ALT (DL1a), hypokalemia (DL1a), fatigue (DL2a), neutropenia (DL2a), anemia (DL3a), hypophosphatemia (DL3a), and pulmonary embolism (DL3a). Dose-proportional PK was observed with a mean AT t1/2 of 3.32 hr (range 2.86-3.94). No PK interactions were observed between the agents. Two pts with NSCLC and 1 with HG neuroendocrine tumor had a PR. Conclusions: The MTD with F was established at AT 40 mg BID D1-3, P 60 mg/m2 D1, and E 120 mg/m2 D1 of a 21 D cycle. F support permitted standard doses of EP without dose limiting neutropenia. Anti-tumor activity was observed in NSCLC and HG neuroendocrine tumor. Accrual to an MTD expansion cohort of pts with untreated ES-SCLC is ongoing. This study was supported by NCI UO1 CA062491, SAIC 25XS097, and 1ULRR025011.

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