Modufolin (6R 5,10-Methylenetetrahydrofolate) and Pemetrexed for Neoadjuvant Rectal Cancer Treatment

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by Isofol Medical AB
Sponsor:
Information provided by (Responsible Party):
Isofol Medical AB
ClinicalTrials.gov Identifier:
NCT01397305
First received: May 25, 2011
Last updated: September 10, 2013
Last verified: September 2013
  Purpose

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.


Condition Intervention Phase
Rectal Cancer
Drug: [6R] 5,10-methylenetetrahydrofolate
Drug: Pemetrexed
Phase 1
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Isofol Medical AB:

Primary Outcome Measures:
  • 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:

    1. CTC grade 4 lasting >= 7 days, or febrile neutropenia
    2. CTC grade 4 thrombocytopenia or grade 3 with bleeding.
    3. 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).


Secondary Outcome Measures:
  • 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


Estimated Enrollment: 52
Study Start Date: April 2011
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: [6R] 5,10-methylenetetrahydrofolate
    10, 50 or 100 mg/m2 IV on day 1, day 8 day and day 15 of each 21-day cycle. 3 cycles.
    Other Names:
    • Modufolin
    • 6R-MTHF
    • ISO-901
    Drug: Pemetrexed
    500 mg/m2 IV on day 1 of each 21-day cycle. 3 cycles.
    Other Names:
    • ly 231514
    • multitargeted antifolate
    • pemetrexed
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pathological/ cytological diagnosis of adenocarcinoma of the rectum. Patients must have operable rectal cancer that is amenable to surgery.
  • No prior therapy for rectal cancer
  • Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1
  • Adequate organ function
  • Patient compliance and geographic proximity that allow adequate follow-up
  • For women: Must be surgically sterile, postmenopausal, or compliant with a medically approved contraceptive regimen during and for 3 months after treatment; must have a negative serum or urine pregnancy test and must not be lactating.
  • For men: Must be surgically sterile or compliant with a contraceptive regimen during and for 3 months after treatment.
  • Estimated life expectancy of at least 12 weeks
  • Signed informed consent
  • At least 18 years of age

Exclusion Criteria:

  • Concurrent administration of any other anti-tumor therapy.
  • Treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.
  • Serious concomitant systemic disorders (e.g., active infection including HIV, cardiac disease) that in the opinion of the investigator would compromise the patient's ability to complete the study.
  • Have previously completed or withdrawn from this study or any other study investigating pemetrexed.
  • Are pregnant or breast-feeding.
  • Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
  • History of significant neurological or mental disorder, including seizures or dementia.
  • Inability to interrupt aspirin or other nonsteroidal anto-inflammatory drugs (NSAIDs)
  • Presence of clinically relevant third-space fluid collection that cannot be controlled by drainage or other procedures prior to study entry.
  • Inability or unwillingness to be given 5,10-methylenetetrahydrofolate, vitamin B12 or dexamethasone.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01397305

Contacts
Contact: Anders G Rabbe +46707646500 anders.rabbe@isofolmedical.com

Locations
Sweden
Sahlgrenska University Hospital Recruiting
Göteborg, Sweden, 416 85
Contact: Hillevi Björkqvist, RN    +46313436657    hillevi.bjorkqvist@vgregion.se   
Principal Investigator: Bengt Gustavsson, PhD, MD         
Sponsors and Collaborators
Isofol Medical AB
Investigators
Principal Investigator: Bengt G Gustavsson, PhD, MD Sahlgrenska University Hospital, Sweden
  More Information

No publications provided

Responsible Party: Isofol Medical AB
ClinicalTrials.gov Identifier: NCT01397305     History of Changes
Other Study ID Numbers: ISO-MC-091
Study First Received: May 25, 2011
Last Updated: September 10, 2013
Health Authority: Sweden: Medical Products Agency

Keywords provided by Isofol Medical AB:
Digestive System Diseases
Gastrointestinal Diseases
5,10-methylenetetrahydrofolate
neoadjuvant therapy
pemetrexed
Neoplasms
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Rectal Diseases
Intestinal Diseases
Pemetrexed
Pharmacologic Actions
Therapeutic Uses
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Antimetabolites, Antineoplastic
Antimetabolites

Additional relevant MeSH terms:
Digestive System Diseases
Gastrointestinal Diseases
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Intestinal Diseases
Rectal Diseases
Antimetabolites
Pemetrexed
Antimetabolites, Antineoplastic
Antineoplastic Agents
Folic Acid Antagonists
Tetrahydrofolates
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses
Enzyme Inhibitors
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 20, 2014