1-methylpropyl-2-imidazolyl-disulfide and Pancreatic-Neoplasms

This study evaluated PX-12, a novel small molecule inhibitor of the proto-oncogene (Trx-1), in patients with previously treated advanced pancreatic cancer (APC).. PX-12 (54 or 128 mg/m²) was administered by 3-hour IV infusion daily × 5 days every 21 days (n = 17). Patients were randomized to either 54 or 128 mg/m² and then stratified based on CA 19-9 level (≥ 1,000 vs. < 1,000 U/ml) and SUV values on PET scans (≥ 7.0 vs. <7.0). The primary endpoint was based on a progression-free survival (PFS) at 4 months in ≥ 40% of patients, and required 40 patients in each arm. An amendment required elevated Trx-1 levels (> 18 ng/ml) as an entry criteria after the first 17 patients were accrued.. Plasma Trx-1 levels were elevated in 3/28 (11%) patients screened for study. The grade of the expired metabolite odor was higher in the 128 mg/m² arm. Therapy was well tolerated, and Grade ≥ 3 adverse events were uncommon. The best response was stable disease in 2 patients. There was no consistent decrease in SUV, Trx-1 levels or CA 19-9 levels with therapy. No patients had a PFS of >4 months. Median PFS and survival were 0.9 months (95% CI 0.5-1.2) and 3.2 months (95% CI 2.4-4.2), respectively.. Due to the lack of significant antitumor activity and unexpectedly low baseline Trx-1 levels, the study was terminated early. PX-12 does not appear to be active in unselected patients with previously treated APC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease Progression; Disease-Free Survival; Disulfides; Dose-Response Relationship, Drug; Female; Gemcitabine; Humans; Imidazoles; Infusions, Intravenous; Male; Middle Aged; Pancreatic Neoplasms; Proto-Oncogene Mas; Survival; Thioredoxins; Treatment Outcome