title: 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.
abstract: 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 500 mg/m(2) in the neoadjuvant treatment of patients with rectal cancer.
  
  
  METHODS
  Adult patients (≥18 years) with resectable rectal adenocarcinoma were allocated to [6R]-MTHF doses of 500, 100, 50, and 10 mg/m(2) in combination with pemetrexed 500 mg/m(2). [6R]-MTHF was administered as an intravenous (i.v.) bolus injection 1 week prior to the first dose of pemetrexed and then once weekly for 9 weeks; pemetrexed was administered by i.v. infusion once every 21 days 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, 10 mg/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 100 mg/m(2) once weekly in combination with pemetrexed 500 mg/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.
authors.affiliation: Department of Surgery, University of Gothenburg, Sahlgrenska University Hospital/Östra Institute of Clinical Sciences, Gothenburg, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Gustavsson
authors.affiliation: Department of Surgery, University of Gothenburg, Sahlgrenska University Hospital/Östra Institute of Clinical Sciences, Gothenburg, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Carlsson
authors.affiliation: Department of Surgery, University of Gothenburg, Sahlgrenska University Hospital/Östra Institute of Clinical Sciences, Gothenburg, Sweden.
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Swartling
authors.affiliation: Department of Surgery, University of Gothenburg, Sahlgrenska University Hospital/Östra Institute of Clinical Sciences, Gothenburg, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Kurlberg
authors.affiliation: Department of Surgery, University of Gothenburg, Sahlgrenska University Hospital/Östra Institute of Clinical Sciences, Gothenburg, Sweden.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Derwinger
authors.affiliation: Department of Surgery, University of Gothenburg, Sahlgrenska University Hospital/Östra Institute of Clinical Sciences, Gothenburg, Sweden.
authors.forename: Hillevi
authors.initials: H
authors.lastname: Björkqvist
authors.affiliation: Department of Surgery, University of Gothenburg, Sahlgrenska University Hospital/Östra Institute of Clinical Sciences, Gothenburg, Sweden.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Odin
authors.affiliation: PharmaGenesis London, 9 Whitehall, 4th Floor, London, SW1A 2DD, UK. fernando.gibson@pharmagenesis.com.
authors.forename: Fernando
authors.initials: F
authors.lastname: Gibson
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000601:surgery; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D000068437:Pemetrexed / Q000627:therapeutic use; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000601:surgery; D013763:Tetrahydrofolates / Q000627:therapeutic use
chemical_list: D013763:Tetrahydrofolates; D000068437:Pemetrexed; C013123:5,10-methylenetetrahydrofolic acid
keywords: Antifolates; Endogenous folate; Neoadjuvant therapy; Pemetrexed; Phase 1 trial; Rectal cancer; [6R]-5,10-methylene tetrahydrofolate