A dose-escalating and pharmacodynamic study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (triapine) and radiation in patients with locally advanced pancreas cancer.

Abstract

e14558 Background: Pancreas cancer is a leading cause of cancer death in the US. Chemoradiation, a standard therapy for patients with locally advanced pancreas cancer (LAPCA), has resulted in modest improvement in outcome. Triapine, an inhibitor of the M2 subunit of ribonucleotide reductase, was shown to be a radiosensitizer in preclinical and early clinical studies. Methods: This is a dose escalation trial with three dose levels of triapine (24 mg/m2, 48 mg/m2, 72 mg/m2) administered concurrently with a total of 50.4 Gy of radiation in 28 fractions. Patients with LAPCA were given triapine intravenously over 2 hours, within 30 minutes of radiation, every Monday Wednesday and Friday, every other week for 5 ½ weeks. The primary endpoint was to determine the maximum tolerated dose (MTD) of triapine in combination with radiation. Secondary endpoints included response and radiographic correlates with dynamic contrast enhanced (DCE) MRI. Results: Eleven patients were treated. Three patients were non-evaluable (NE) for the primary endpoint due to disease progression prior to completion of therapy (2) or other (1). Four patients (1 NE) were enrolled at dose level 1, 3 patients at dose level 2, and 4 patients (2NE) at dose level 3 with the fourth patient still undergoing treatment. A fifth and last patient is scheduled to begin treatment at dose level 3, which is the highest planned dose level. No DLTs have been observed so far. The only related grade 3 toxicity was thrombocytopenia in 1 patient at dose level 2. Two of ten (20%) patients evaluable for response achieved a PR. One patient underwent successful surgical resection after therapy. mPFS is 4 months (95% CI 1-10) and mOS 7.5 months (95% CI 3-15.8). DCE MRI was shown to be a potential early predictor for response to therapy in LAPCA. Conclusions: The combination of triapine and radiation is safe and tolerable in patients with LAPCA with evidence of preliminary activity. DCE MRI is a potentially useful imaging tool to predict early response to therapy in patients with LAPCA and deserves further investigation. Final results including the recommended phase II dosing will be presented at the meeting.