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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

Primary Purpose

Rectal Cancer

Status

Completed

Phase

Phase 1

Locations

Sweden

Study Type

Interventional

Intervention

[6R] 5,10-methylenetetrahydrofolate (arfolitixorin)

Pemetrexed

About this trial

This is an interventional treatment trial for Rectal Cancer focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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Have previously completed or withdrawn from this study or any other study investigating pemetrexed.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.

Sites / Locations

Sahlgrenska University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Modufolin and Pemetrexed

Arm Description

Modufolin ( [6R] 5,10-methylenetetrahydrofolate) and Pemetrexed

Outcomes

Primary Outcome Measures

Feasibility of Pemetrexed Prior to Surgery

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).

Secondary Outcome Measures

Pathological Complete Response (pCR)

Number of Participants Receiving Sphincter Saving Surgery

Evaluation of qualitative and quantitative toxicities

Bleeding, anastomosis, leakage, serious infection.

[6R] 5,10-methylenetetrahydrofolate tissue concentration determination

Correlation between 5,10-methylenetetrahydrofolate and HCy levels in blood

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.

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

Plasma samples will be collected prior to study treatment, and at 10 minutes, 1, 2 and 4 hours after study treatment

Full Information

NCT ID

NCT01397305

First Posted

May 25, 2011

Last Updated

September 7, 2020

Sponsor

Isofol Medical AB

1. Study Identification

Unique Protocol Identification Number

NCT01397305

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2020

Overall Recruitment Status

Completed

Study Start Date

April 14, 2011 (Actual)

Primary Completion Date

October 16, 2014 (Actual)

Study Completion Date

October 16, 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Isofol Medical AB

4. Oversight

Data Monitoring Committee

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Rectal Cancer

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

24 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Modufolin and Pemetrexed

Arm Type

Experimental

Arm Description

Modufolin ( [6R] 5,10-methylenetetrahydrofolate) and Pemetrexed

Intervention Type

Drug

Intervention Name(s)

[6R] 5,10-methylenetetrahydrofolate (arfolitixorin)

Other Intervention Name(s)

Modufolin, 6R-MTHF, ISO-901, arfolitixorin

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Pemetrexed

Other Intervention Name(s)

ly 231514, multitargeted antifolate

Intervention Description

500 mg/m2 IV on day 1 of each 21-day cycle. 3 cycles.

Primary Outcome Measure Information:

Title

Feasibility of Pemetrexed Prior to Surgery

Description

Time Frame

3 cycles (21-day cycles)

Secondary Outcome Measure Information:

Title

Pathological Complete Response (pCR)

Time Frame

Surgery following 3 cycles (21-day cycles) of chemotherapy

Title

Number of Participants Receiving Sphincter Saving Surgery

Time Frame

Surgery following 3 cycles (21-day cycles) of chemotherapy

Title

Evaluation of qualitative and quantitative toxicities

Description

Bleeding, anastomosis, leakage, serious infection.

Time Frame

Start of study treatment until last postoperative visit. Expected average 16 weeks.

Title

[6R] 5,10-methylenetetrahydrofolate tissue concentration determination

Time Frame

Surgery following 3 cycles (21-day cycles) of chemotherapy

Title

Correlation between 5,10-methylenetetrahydrofolate and HCy levels in blood

Description

Time Frame

Samples taken prior before study treatment, during 3 cycles of chemotherapy and after completion of study treatment. Expected average 20 weeks.

Title

Correlation of folate gene polymorphisms and gene signature profiling with clinical outcome and toxicity profiles.

Description

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.

Title

Pharmacokinetic parameters of [6R] 5,10-mTHF, 5-formyl-THF, 5-methyl-THF and THF calculated from plasma

Description

Plasma samples will be collected prior to study treatment, and at 10 minutes, 1, 2 and 4 hours after study treatment

Time Frame

Calculated on Day1 and Day15 after cycle 1 and 3

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bengt G Gustavsson, PhD, MD

Organizational Affiliation

Sahlgrenska University Hospital, Sweden

Official's Role

Principal Investigator

Facility Information:

Facility Name

Sahlgrenska University Hospital

City

Göteborg

ZIP/Postal Code

416 85

Country

Sweden

12. IPD Sharing Statement

Learn more about this trial

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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