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

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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Rectal Cancer	Drug: [6R] 5,10-methylenetetrahydrofolate (arfolitixorin); Drug: Pemetrexed	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Actual Study Start Date: April 14, 2011
• Actual Primary Completion Date: October 16, 2014
• Actual Study Completion Date: October 16, 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Modufolin and Pemetrexed; Modufolin ( [6R] 5,10-methylenetetrahydrofolate) and Pemetrexed	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

Outcome Measures

Primary Outcome Measures :

1. 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).

Secondary Outcome Measures :

1. Pathological Complete Response (pCR) [ Time Frame: Surgery following 3 cycles (21-day cycles) of chemotherapy ]
2. Number of Participants Receiving Sphincter Saving Surgery [ Time Frame: Surgery following 3 cycles (21-day cycles) of chemotherapy ]
3. 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.
4. [6R] 5,10-methylenetetrahydrofolate tissue concentration determination [ Time Frame: Surgery following 3 cycles (21-day cycles) of chemotherapy ]
5. 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.
6. 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.
7. 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

Locations

Sweden

Sahlgrenska University Hospital

Göteborg, Sweden, 416 85

Sponsors and Collaborators

Isofol Medical AB

Investigators

• Principal Investigator: Bengt G Gustavsson, PhD, MD; Sahlgrenska University Hospital, Sweden

More Information

• Responsible Party: Isofol Medical AB
• ClinicalTrials.gov Identifier: NCT01397305
• Other Study ID Numbers: ISO-MC-091
• First Posted: July 19, 2011
• Last Update Posted: September 9, 2020
• Last Verified: September 2020

Keywords provided by Isofol Medical AB:

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

Additional relevant MeSH terms:

Rectal Neoplasms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases; Pemetrexed; Antineoplastic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors