Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer.

The selective MEK1/2 inhibitor pimasertib has shown anti-tumour activity in a pancreatic tumour model. This phase I/II, two-part trial was conducted in patients with metastatic pancreatic adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m2 ) in 28-day cycles to identify the recommended phase II dose (RP2D) of pimasertib. In the phase II part, patients were randomised to pimasertib (RP2D) or placebo plus weekly gemcitabine (n = 88) to investigate progression-free survival (PFS), overall survival (OS) and safety. The RP2D was determined to be 60 mg BID. PFS and OS outcomes did not indicate any treatment benefit for pimasertib over placebo in combination with gemcitabine (median PFS 3.7 and 2.8 months, respectively, HR = 0.91, 95% CI: 0.58-1.42: median OS 7.3 vs. 7.6 months, respectively). KRAS status did not influence PFS or OS. The incidence of grade ≥3 adverse events was 91.1% and 85.7% for pimasertib/gemcitabine and placebo/gemcitabine respectively, but there was a higher incidence of ocular events with pimasertib/gemcitabine (28.9% vs. 4.8% for placebo/gemcitabine). In conclusion, no clinical benefit was observed with first-line pimasertib plus gemcitabine compared with gemcitabine alone in patients with mPaCa.

A randomized phase II trial of pemetrexed plus irinotecan (ALIRI) versus leucovorin-modulated 5-FU plus irinotecan (FOLFIRI) in first-line treatment of locally advanced or metastatic colorectal cancer.

BACKGROUND: This multicenter, randomized trial compared overall response rate between pemetrexed plus irinotecan (ALIRI) and leucovorin-modulated 5-fluorouracil plus irinotecan (FOLFIRI) in patients with advanced colorectal cancer. Secondary objectives included overall and progression-free survival, duration of response, toxicities, and biomarkers. PATIENTS AND METHODS: ALIRI patients received pemetrexed 500 mg/m(2) and irinotecan 350 mg/m(2) with vitamin supplementation on day 1 of each 21-day cycle. FOLFIRI patients received irinotecan 180 mg/m(2) on days 1, 15, 29; on days 1, 2, 15, 16, 29, 30, patients received leucovorin 200 mg/m(2), bolus 5-fluorouracil 400 mg/m(2), and 5-fluorouracil 600 mg/m(2) as 22-hour infusion. RESULTS: Of 132 patients randomly assigned, 130 patients (64 = ALIRI, 66 = FOLFIRI) received > or =1 dose of treatment. Response rates (ALIRI = 20.0%, FOLFIRI = 33.3%) were not significantly different between arms (p = 0.095). Progression-free survival was 5.7 months for ALIRI and 7.7 months for FOLFIRI (p < 0.001). Neutropenia, fatigue, diarrhea, nausea, and vomiting were the major toxicities. There were 5 drug-related deaths (ALIRI = 4, FOLFIRI = 1). Biomarker analysis failed to reveal that any of the 18 preselected genes were clearly associated with tumor response. CONCLUSIONS: Neither efficacy nor safety improved on the ALIRI arm compared to the FOLFIRI arm. Progression-free survival on FOLFIRI was significantly longer compared to ALIRI. Potential biomarkers capable of predicting response to either regimen in advanced or metastatic colorectal carcinoma need further characterization.