PMID- 26189513
OWN - NLM
STAT- MEDLINE
DCOM- 20160627
LR  - 20181113
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Print)
IS  - 0167-6997 (Linking)
VI  - 33
IP  - 5
DP  - 2015 Oct
TI  - 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.
PG  - 1078-85
LID - 10.1007/s10637-015-0272-0 [doi]
AB  - BACKGROUND: Modufolin(R) ([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.
FAU - Gustavsson, Bengt
AU  - Gustavsson B
AD  - Department of Surgery, University of Gothenburg, Sahlgrenska University 
      Hospital/Ostra Institute of Clinical Sciences, Gothenburg, Sweden.
FAU - Carlsson, Goran
AU  - Carlsson G
AD  - Department of Surgery, University of Gothenburg, Sahlgrenska University 
      Hospital/Ostra Institute of Clinical Sciences, Gothenburg, Sweden.
FAU - Swartling, Torbjorn
AU  - Swartling T
AD  - Department of Surgery, University of Gothenburg, Sahlgrenska University 
      Hospital/Ostra Institute of Clinical Sciences, Gothenburg, Sweden.
FAU - Kurlberg, Goran
AU  - Kurlberg G
AD  - Department of Surgery, University of Gothenburg, Sahlgrenska University 
      Hospital/Ostra Institute of Clinical Sciences, Gothenburg, Sweden.
FAU - Derwinger, Kristoffer
AU  - Derwinger K
AD  - Department of Surgery, University of Gothenburg, Sahlgrenska University 
      Hospital/Ostra Institute of Clinical Sciences, Gothenburg, Sweden.
FAU - Bjorkqvist, Hillevi
AU  - Bjorkqvist H
AD  - Department of Surgery, University of Gothenburg, Sahlgrenska University 
      Hospital/Ostra Institute of Clinical Sciences, Gothenburg, Sweden.
FAU - Odin, Elisabeth
AU  - Odin E
AD  - Department of Surgery, University of Gothenburg, Sahlgrenska University 
      Hospital/Ostra Institute of Clinical Sciences, Gothenburg, Sweden.
FAU - Gibson, Fernando
AU  - Gibson F
AD  - PharmaGenesis London, 9 Whitehall, 4th Floor, London, SW1A 2DD, UK. 
      fernando.gibson@pharmagenesis.com.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150721
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Tetrahydrofolates)
RN  - 04Q9AIZ7NO (Pemetrexed)
RN  - 0SXY5ET48B (5,10-methylenetetrahydrofolic acid)
SB  - IM
MH  - Adenocarcinoma/*drug therapy/surgery
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/adverse 
      effects/*therapeutic use
MH  - Dose-Response Relationship, Drug
MH  - Drug Administration Schedule
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - *Neoadjuvant Therapy
MH  - Pemetrexed/therapeutic use
MH  - Rectal Neoplasms/*drug therapy/surgery
MH  - Tetrahydrofolates/therapeutic use
PMC - PMC4768212
OTO - NOTNLM
OT  - Antifolates
OT  - Endogenous folate
OT  - Neoadjuvant therapy
OT  - Pemetrexed
OT  - Phase 1 trial
OT  - Rectal cancer
OT  - [6R]-5,10-methylene tetrahydrofolate
EDAT- 2015/07/21 06:00
MHDA- 2016/06/28 06:00
PMCR- 2015/07/21
CRDT- 2015/07/21 06:00
PHST- 2015/03/25 00:00 [received]
PHST- 2015/07/07 00:00 [accepted]
PHST- 2015/07/21 06:00 [entrez]
PHST- 2015/07/21 06:00 [pubmed]
PHST- 2016/06/28 06:00 [medline]
PHST- 2015/07/21 00:00 [pmc-release]
AID - 10.1007/s10637-015-0272-0 [pii]
AID - 272 [pii]
AID - 10.1007/s10637-015-0272-0 [doi]
PST - ppublish
SO  - Invest New Drugs. 2015 Oct;33(5):1078-85. doi: 10.1007/s10637-015-0272-0. Epub 
      2015 Jul 21.