Final results of a phase Ib trial of PR104, a pre-prodrug of the bioreductive prodrug PR104A, in combination with gemcitabine (G) or docetaxel (D) in patients with advanced solid tumors.

Abstract

2554 Background: PR104 is a nitrogen mustard pre-prodrug activated by hypoxia or the reductase AKR-1C3. When activated, PR104 exerts cytotoxicity through DNA crosslinking. Preclinical studies support combining PR104 with G or D. The MTD of single agent Q3wk PR104 is 1100 mg/m2 with dose-limiting toxicity (DLT) of neutropenia. Methods: Patients (pts) for which treatment with single agent G or D was considered reasonable were eligible. PR104 was combined with either G (800 mg/m2) or D (60 or 75 mg/m2) in 4 separate groups. Grp A received PR104 + G on days 1 and 8; Grp B received PR104 + D (60 mg/m2) on day 1; Grp C received PR104 + D (60 mg/m2) on day 1 with GCSF; Grp D received PR104 + D (75 mg/m2) on day 1 with GCSF. All groups were retreated on a 21 day cycle. Plasma pharmacokinetics was assessed with cycle 1. At selected sites tumor hypoxia was evaluated with F18-fluoro-misonidazole positron emission tomography (FMISO-PET). Results: 42 pts: 23 F/19 M; median age 61 (range 27-87); median of 2 prior chemotherapy regimens (range 0-3); NSCLC (10 pts), pancreatic and prostate (4 pts each), sarcoma and melanoma (3 pts each), and other solid tumors (18 pts) received a median of 3 treatment cycles (range 1-23). Grps A (6 pts) and B (6 pts), defined MTDs for PR104 at ≤200 mg/m2 with myelotoxicity as DLT. Grp C (21 pts) defined an MTD of 770 mg/m2 for PR104. The DLTs in 2/6 pts at 1,100 mg/m2 were grade 4 thrombocytopenia and grade 3 fatigue. Two pts had a partial response (nasopharyngeal and H&N cancer) and 10 pts (5 with NSCLC) had stable disease (≥6 cycles). Grp D (6 pts restricted to ≤1 prior chemotherapy) received PR104 at 770 mg/m2 + D at 75 mg/m2 with GCSF, no DLT were observed. PR104 was rapidly converted to the alcohol PR104A and further metabolized to the glucuronide PR104G and the cytotoxic hydroxylamine PR104H. Tumor hypoxia was detectable in 11/17 baseline scans. Conclusions: The MTD ofPR104 with G or D in the absence of concomitant GCSF is ≤200 mg/m2. With GCSF, PR104 can be administered at a dose of 770 mg/m2 (70% of its single agent MTD) with D (60 or 75 mg/m2). A randomized phase II trial of PR104 + D (60mg/m2) with GCSF was initiated in relapsed NSCLC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Proacta Proacta Proacta Proacta