Modufolin (6R 5,10-Methylenetetrahydrofolate) and Pemetrexed for Neoadjuvant Rectal Cancer Treatment
The purpose of this study is to determine whether an optimal dose of [6R] 5,10-methylenetetrahydrofolate (Modufolin) in combination with pemetrexed are effective in pre-operative treatment of patients with resectable rectal cancer.
Drug: [6R] 5,10-methylenetetrahydrofolate
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||An Extended Feasibility Phase I/II Study of Methylenetetrahydrofolate and Pemetrexed Single Agent, Given as Neoadjuvant Treatment in Patients With Resectable Rectal Cancer|
- Feasibility of Pemetrexed Prior to Surgery [ Time Frame: 3 cycles (21-day cycles) ] [ Designated as safety issue: Yes ]
Feasibility is defined as the ability to receive the total planned dose of pemetrexed (i.e., 1500 mg/m) administered over a period of no more than 9 weeks. Feasibility is measured as absence of the following toxicities:
- CTC grade 4 lasting >= 7 days, or febrile neutropenia
- CTC grade 4 thrombocytopenia or grade 3 with bleeding.
- CTC grade 3 nonhematologic toxicity (excluding nausea and vomiting, isolated CTC grade 3 ALT or AST that returns to the patient's pretreatment CTC grade within 3 weeks, or grade 3 fatigue lasting <7 days).
- Pathological Complete Response (pCR) [ Time Frame: Surgery following 3 cycles (21-day cycles) of chemotherapy ] [ Designated as safety issue: No ]
- Number of Participants Receiving Sphincter Saving Surgery [ Time Frame: Surgery following 3 cycles (21-day cycles) of chemotherapy ] [ Designated as safety issue: No ]
- Evaluation of qualitative and quantitative toxicities [ Time Frame: Start of study treatment until last postoperative visit. Expected average 16 weeks. ] [ Designated as safety issue: Yes ]Bleeding, anastomosis, leakage, serious infection.
- [6R] 5,10-methylenetetrahydrofolate tissue concentration determination [ Time Frame: Surgery following 3 cycles (21-day cycles) of chemotherapy ] [ Designated as safety issue: No ]
- Correlation between 5,10-methylenetetrahydrofolate and HCy levels in blood [ Time Frame: Samples taken prior before study treatment, during 3 cycles of chemotherapy and after completion of study treatment. Expected average 20 weeks. ] [ Designated as safety issue: No ]Blood samples are taken before start of study treatment, in conjunction with start of every study drug cycle, and after completed study treatment. HCy measurements performed using HPLC. 5-10-methylenetetrahydrofolate is measured in tissue biopsies (tumor and adjacent mucosa) sampled in conjunction with surgery. The tissue is collected before start of study treatment, during and after completed study treatment. 5,10-methylenetetrahydrofolate levels are measured using LC/MS/MS.
- Correlation of folate gene polymorphisms and gene signature profiling with clinical outcome and toxicity profiles. [ Time Frame: Tissue to be collected from tumor and adjacent mucosa before start of study treatment, during and after completed study treatment. Expected average 20 weeks. ] [ Designated as safety issue: No ]RT-PCR will be used to measure and determine the gene expression levels of the genes FPGS (Folylpolyglutamate synthase) and GGH (Gamma-glutamyl hydrolase). This translational research will be compared with the clinical outcome and toxicity profiles of patients.
- Pharmacokinetic parameters of [6R] 5,10-mTHF, 5-formyl-THF, 5-methyl-THF and THF calculated from plasma [ Time Frame: Calculated on Day1 and Day15 after cycle 1 and 3 ] [ Designated as safety issue: No ]Plasma samples will be collected prior to study treatment, and at 10 minutes, 1, 2 and 4 hours after study treatment
|Study Start Date:||April 2011|
|Primary Completion Date:||November 2014 (Final data collection date for primary outcome measure)|
Experimental: Modufolin and Pemetrexed
Modufolin ( [6R] 5,10-methylenetetrahydrofolate) and Pemetrexed
Drug: [6R] 5,10-methylenetetrahydrofolate
10, 50, 100, 200, and 500 mg/m2 IV on day 1, day 8 day and day 15 of each 21-day cycle. 3 cycles.
Other Names:Drug: Pemetrexed
500 mg/m2 IV on day 1 of each 21-day cycle. 3 cycles.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01397305
|Sahlgrenska University Hospital|
|Göteborg, Sweden, 416 85|
|Principal Investigator:||Bengt G Gustavsson, PhD, MD||Sahlgrenska University Hospital, Sweden|