Phase 1 dose de-escalation trial of the endogenous folate [6R]-5,10-methylene tetrahydrofolate in combination with fixed-dose pemetrexed as neoadjuvant therapy in patients with resectable rectal cancer.

• Background Modufolin® ([6R]-5,10-methylene tetrahydrofolate; [6R]-MTHF) is an endogenous biomodulator that is being developed as an alternative to leucovorin, a folate prodrug used in the treatment of colorectal cancer. The objective of this phase 1 dose de-escalation trial was to estimate the minimum tolerated dose of [6R]-MTHF to be used in combination with pemetrexed 500mg/m(2) in the neoadjuvant treatment of patients with rectal cancer. Methods Adult patients (≥18years) with resectable rectal adenocarcinoma were allocated to [6R]-MTHF doses of 500, 100, 50, and 10mg/m(2) in combination with pemetrexed 500mg/m(2). [6R]-MTHF was administered as an intravenous (i.v.) bolus injection 1week prior to the first dose of pemetrexed and then once weekly for 9weeks; pemetrexed was administered by i.v. infusion once every 21days for three cycles. Results Twenty-four patients (mean [SD] age, 63.1 [12.9] years) were enrolled in the study. A total of 72 treatment-related adverse events (AEs) were reported, of which the most common were fatigue (n=17; 23.6%), nausea (n=10; 13.9%), and diarrhea (n=5; 6.9%). The incidence of treatment-related AEs by [6R]-MTHF dose level (500, 100, 50, 10mg/m(2)) was 11.1% (n=8), 13.9% (n=10), 45.8% (n=33), and 29.2% (n=21), respectively. There were no dose-limiting toxicities, and only two (2.8%) treatment-related AEs were grade 3 in severity. Of the 11 serious AEs reported, none were considered to be related to [6R]-MTHF treatment. Conclusions The results of this phase 1 study indicate that the estimated minimum tolerated dose of [6R]-MTHF was 100mg/m(2) once weekly in combination with pemetrexed 500mg/m(2). The low toxicity profile of [6R]-MTHF supports its further evaluation as a component of systemic chemotherapy in the management of colon and rectal cancer.

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MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kirurgi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Surgery (hsv//eng)

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