Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in combination with gemcitabine and docetaxel in non-small cell and small cell lung cancers.

TPS3189 Background: Arginine is essential to neoplastic growth and development, yet many cancer cells do not express argininosuccinate synthetase (ASS1), an enzyme necessary to produce arginine. ADI-PEG 20 is a microbial enzyme that degrades arginine causing arginine auxotrophy in cancer cells that are ASS1 negative. Preclinical data suggests that ADI-PEG 20 in combination with docetaxel (D), resulted in increased expression of hENT, the transporter for gemcitabine (G) as well upregulation of dCK to trap G inside of cancer cells. A phase II trial of ADI-PEG 20, G and D was shown to be a safe and efficacious combination in soft tissue sarcoma (STS). We are conducting a phase I/II trial examining the safety, tolerability, to determine the recommended phase II dose (R2PD) and evaluate the efficacy of this combination in patients with previously treated metastatic non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) with an alternative dosing regimen than that used in STS based on the mechanism of action. Methods: Eligible pts include previously treated metastatic NSCLC and SCLC with performance status 0-1 with adequate organ function. Pts are excluded if previously treated with G; however, prior use of docetaxel is permitted. Up to 12 patients will be enrolled in an open-label phase I trial with a 3 + 3 dose escalation design with ADI-PEG 20 in combination with G and D. Primary objectives of the phase I portion are to determine the safety, tolerability and recommend phase II dose (RP2D) of combination ADI-PEG 20, G and D. Pts will be treated with ADI-PEG 20 intramuscularly at 36mg/m 2 on day -7 of cycle 1 and then on days 1, 8, and 15 of each subsequent cycle with dose-escalated G (600, 750, 900 mg/m 2 ) on day 2 and D (60, 75, 75 mg/m 2 ) on day 1 of each 21-day cycle for up to 8 cycles then will continue with combination therapy at provider discretion for up to 34 cycles. The phase II will consist of two cohorts (NSCLC and SCLC) receiving the triplet treatments at the RP2D determined during phase I. Primary objective of the phase II portion is to determine the objective response rate (ORR) in each cohort. Phase II uses a Simon optimal two-stage design per cohort for ORR with a minimum of 12 patients and a maximum of 36 patients per cohort. In the phase I, patient accrual at the maximum tolerated dose level is nearing completion and ADI-PEG in combination with G and D will be further evaluated in the phase II with separate cohorts for NSCLC and SCLC. Clinical trial information: NCT05616624 .