A phase I study of temsirolimus in combination with gemcitabine in previously untreated metastatic pancreatic cancer.

Abstract

296 Background: The PI3K/mTOR/Akt pathway has been demonstrated to be active in pancreatic cancer, and preclinical data in mouse xenograft models has suggested possible synergy between gemcitabine and temsirolimus, an inhibitor of the mTOR pathway. The objective of this Phase I study was to assess toxicity and tolerability of gemcitabine and temsirolimus combination therapy in patients with newly diagnosed metastatic pancreatic cancer. Methods: The study was conducted with a modified, 3+3 phase I design for dose escalation. Patients in cohort 1 received temsirolimus at a fixed dose of 10mg IV on days 1,8,15, and 22, while gemcitabine was administered at 800mg/m2 IV on days 1 and 15 of each 28 day cycle. Results: Between November 2007 and September 2008, 9 patients were enrolled in the trial, with a median age of 56. 6/9 patients were male, and all enrolled patients had a performance status of 1. One patient discontinued prior to starting treatment. 5 of the 8 patients receiving at least one infusion of gemcitabine and temsirolimus were removed from the study for toxicities associated with treatment. There were two episodes of Grade 4 neutropenia, and multiple Grade 3 toxicities, including cytopenias (neutropenia, leukopenia, and lymphopenia), elevated liver function tests, hyperglycemia, hypophosphatemia, diarrhea, and allergic reaction. There were no partial or complete responses observed. One patient demonstrated stable disease, receiving 6 cycles; this patient developed grade 3 neutropenia, requiring a dose delay and subsequent 20% dose reductions for temsirolimus and gemcitabine. No patients were enrolled after the first cohort, and no patients remain on study. In the 8 patients who began the study, the median time on study was 22 days, and overall survival was 126 days from study administration (range 88-416 days). Conclusions: This is the first published report of a human study involving gemcitabine and temsirolimus, which was associated with substantial toxicity in patients with advanced, previously untreated pancreatic cancer precluding further exploration of this combination.