Clinical and pharmacokinetic (PK) findings in a phase I study of 7-t-butyldimethylsilyl-10-hydroxycamptothecin (AR-67) in patients with refractory solid tumors

Abstract

2534 Background: AR-67 is a 3rd generation camptothecin analog selected for development based on the high in vitro stability of its pharmacologically active lactone form and high potency in preclinical models. This report describes the initial phase I study of intravenous AR-67 in adults with refractory solid tumors. Methods: AR-67 was infused over 1 hour for 5 days of a 21-day cycle using an accelerated titration phase I trial design. PK was performed on the 1st and 4th day of cycle 1. AR-67 was assayed with a validated chromatography method. Toxicity and response were assessed using NCI CTC (v3) grading scale and RECIST. Results: In total, 26 patients were treated at 9 dose levels (mg/m2/day): 1.2 (n=2), 1.67 (n=3), 2.34 (n=3), 3.2 (n=3); 4.5 (n=1), 6.3 (n=1), 7.5 (n=7), 8.9 (n=4) and 12.4 (n=2). Median age 62 (range 31–79), 15M/11F, median prior therapies 3 (range 1 to 6). Tumor types included: colorectal (8), non-small cell lung (NSCLC) (4), small cell lung (3), soft tissue sarcoma, (3), head and neck (2), prostate (2), and other (4). 21 subjects completed 2 or more cycles of therapy, 5 subjects received 1 cycle of therapy and had rapid disease progression (1 received 2d of drug prior to PD), 1 subject is still under treatment after 9 cycles. DLTs were observed in 5 patients: 2 of 2 at 12.4 mg/m2/day (Gr 4 febrile neutropenia, Gr 3 fatigue); 2 of 4 at 8.9 mg/m2/day (Gr 4 thrombocytopenia), 1 of 7 at 7.5 mg/m2/day (Gr 4 thrombocytopenia). Common C1 worst-grade drug related toxicities (CTC I/II % vs III/IV %): Hg (27/8), WBC (11/19), ANC (19/8), platelets (19/12), fatigue (15/8) insomnia (8/0), flushing (15//0), constipation (8/0), nausea (23/0), ALT elevation (12/0), hiccups (8/0). Antitumor activity, assessed by development of PR and SD, was observed in NSCLC, SCLC, colon and bladder cancer. The lactone form was predominant in plasma (>85% of AUC) at all time points. Clearance was constant with increasing dose and exposure (AUC) correlated with toxicity. Conclusions: AR-67 has superior lactone stability compared to approved analogs, has a predictable toxicity profile that did not include diarrhea and has activity in NSCLC. The RP2D is 7.5 mg/m2/day for 5 days of a 21-day cycle. This work was supported by R21-CA-123867 and Arno Therapeutics. [Table: see text]