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An Extended Feasibility Phase I/II Study of Methylenetetrahydrofolate (Arfolitixorin) and Pemetrexed Single Agent, Given as Neoadjuvant Treatment in Patients With Resectable Rectal Cancer

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ClinicalTrials.gov Identifier: NCT01397305
Recruitment Status : Completed
First Posted : July 19, 2011
Last Update Posted : September 9, 2020
Sponsor:
Information provided by (Responsible Party):
Isofol Medical AB

Tracking Information
First Submitted Date  ICMJE May 25, 2011
First Posted Date  ICMJE July 19, 2011
Last Update Posted Date September 9, 2020
Actual Study Start Date  ICMJE April 14, 2011
Actual Primary Completion Date October 16, 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 18, 2011)
Feasibility of Pemetrexed Prior to Surgery [ Time Frame: 3 cycles (21-day cycles) ]
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 10, 2013)
  • Pathological Complete Response (pCR) [ Time Frame: Surgery following 3 cycles (21-day cycles) of chemotherapy ]
  • Number of Participants Receiving Sphincter Saving Surgery [ Time Frame: Surgery following 3 cycles (21-day cycles) of chemotherapy ]
  • Evaluation of qualitative and quantitative toxicities [ Time Frame: Start of study treatment until last postoperative visit. Expected average 16 weeks. ]
    Bleeding, anastomosis, leakage, serious infection.
  • [6R] 5,10-methylenetetrahydrofolate tissue concentration determination [ Time Frame: Surgery following 3 cycles (21-day cycles) of chemotherapy ]
  • 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. ]
    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. ]
    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 ]
    Plasma samples will be collected prior to study treatment, and at 10 minutes, 1, 2 and 4 hours after study treatment
Original Secondary Outcome Measures  ICMJE
 (submitted: July 18, 2011)
  • Pathological Complete Response (pCR) [ Time Frame: Surgery following 3 cycles (21-day cycles) of chemotherapy ]
  • Number of Participants Receiving Sphincter Saving Surgery [ Time Frame: Surgery following 3 cycles (21-day cycles) of chemotherapy ]
  • Evaluation of qualitative and quantitative toxicities [ Time Frame: Start of study treatment until last postoperative visit. Expected average 16 weeks. ]
    Bleeding, anastomosis, leakage, serious infection.
  • [6R] 5,10-methylenetetrahydrofolate tissue concentration determination [ Time Frame: Surgery following 3 cycles (21-day cycles) of chemotherapy ]
  • 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. ]
    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. ]
    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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE An Extended Feasibility Phase I/II Study of Methylenetetrahydrofolate (Arfolitixorin) and Pemetrexed Single Agent, Given as Neoadjuvant Treatment in Patients With Resectable Rectal Cancer
Official Title  ICMJE An Extended Feasibility Phase I/II Study of Methylenetetrahydrofolate and Pemetrexed Single Agent, Given as Neoadjuvant Treatment in Patients With Resectable Rectal Cancer
Brief Summary The purpose of this study is to determine whether an optimal dose of [6R] 5,10-methylenetetrahydrofolate (arfolitixorin) in combination with pemetrexed are effective in pre-operative treatment of patients with resectable rectal cancer.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Rectal Cancer
Intervention  ICMJE
  • Drug: [6R] 5,10-methylenetetrahydrofolate (arfolitixorin)
    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:
    • Modufolin
    • 6R-MTHF
    • ISO-901
    • arfolitixorin
  • Drug: Pemetrexed
    500 mg/m2 IV on day 1 of each 21-day cycle. 3 cycles.
    Other Names:
    • ly 231514
    • multitargeted antifolate
Study Arms  ICMJE Experimental: Modufolin and Pemetrexed
Modufolin ( [6R] 5,10-methylenetetrahydrofolate) and Pemetrexed
Interventions:
  • Drug: [6R] 5,10-methylenetetrahydrofolate (arfolitixorin)
  • Drug: Pemetrexed
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 4, 2015)
24
Original Estimated Enrollment  ICMJE
 (submitted: July 18, 2011)
52
Actual Study Completion Date  ICMJE October 16, 2014
Actual Primary Completion Date October 16, 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01397305
Other Study ID Numbers  ICMJE ISO-MC-091
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Isofol Medical AB
Study Sponsor  ICMJE Isofol Medical AB
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Bengt G Gustavsson, PhD, MD Sahlgrenska University Hospital, Sweden
PRS Account Isofol Medical AB
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP