Metastatic Colorectal CancerPhase 1/2NCT04126655
Modelle 001, TS-inhibition in Colorectal Liver Metastases Comparing Arfolitixorin and Calciumfolinate
A Phase 1/2 study testing Arfolitixorin in people with Metastatic Colorectal Cancer, run by Vastra Gotaland Region at 1 site in Sweden.
Trial summary
A study that is blinded to the patient and the investigator where the combination of Arfolitixorin + 5-FU is compared to Calciumfolinate + 5-FU. The patients will be randomised and will receive the above described combination as IV bolus injections, peroperatively in conjuction with collection of the first tissue… Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- Metastatic Colorectal Cancer
- What is being tested?
- Arfolitixorin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteSweden
- Study dates
- 5 Feb 2020to Nov 2021
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 7.3.1 Inclusion criteria
- Patients must sign an informed consent document.
- At least two liver metastases secondary to CRC. Patients must have removable metastases amenable to surgery.
- Performance status of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG). Performance Status scale. (See Protocol Attachment 1.)
- For women: Must be surgically sterile, postmenopausal, or compliant with a contraceptive regimen during and for 3 months after treatment. Fertile women must have a negative serum or urine pregnancy test (within 7 days before enrolment) and must not be lactating.
- For men: Must be surgically sterile or compliant with a contraceptive regimen during and for 3 months after treatment.
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- Patient legally competent and able to communicate effectively with the study personnel as judged by the investigator.
- Patient likely to co-operate during the study.
- Patients must be at least 18 years of age.
Who cannot join
- Concurrent administration of any other anti-tumour therapy minimum 3 weeks before surgery according to clinical practise.
- 2. Treatment within the last 30 days with a drug/device that has not received regulatory approval for any indication at the time of study entry.
- 3. Any intake of medication, which could influence folate, and vitamin B12 status, within 30 days of surgery.
- 4. 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.
- 5. Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
- 6. Patients with a high risk of postoperative liver failure due to advanced liver metastatic load.
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- 7. Pregnancy. 8. History of significant neurological or mental disorder, including seizures or dementia.
- 9. Presence of clinically relevant (i.e., detectable by physical examination) third-space fluid collection (e.g., ascites, pleural effusion) that cannot be controlled by drainage or other procedures prior to study entry.
- 10. Known hypersensitivity to 5-FU and or Calciumfolinate/Arfolitixorin.
Trial locations and contacts
1 site in 1 country.
Sweden1 site, 1 recruiting
- Recruiting
Sahlgrenska University Hospital
Gothenburg, 41345
Helena Taflin, MD, PhD, +46700824799, helena.taflin@vgregion.se
About this study
Official title: A Randomised Phase II Study Investigating Two Doses of Arfolitixorin Compared to Calciumfolinate Together With 5- Fluorouracil on TS Inhibition in Tumour and Adjacent Hepatic Tissue for Patients With Liver Metastases From Colorectal Cancer
A study that is blinded to the patient and the investigator where the combination of Arfolitixorin + 5-FU is compared to Calciumfolinate + 5-FU. The patients will be randomised and will receive the above described combination as IV bolus injections, peroperatively in conjuction with collection of the first tissue sample.
A low dose (30 mg) and a high dose (120) mg of Arfolitixorin will be used in order to investigate the relation between dose of Arfolitixorin and TS-inhibition.
Read the detailed description
Arfolitixorin ([6R] 5,10-methylenetetrahydrofolate) is a folate based biomodulator designed to replace leucovorin. Arfolitixorin is the key active metabolite of leucovorin (LV) and does in contrast to LV not require enzymatic metabolic activation. In clinical practice, LV is administered in the form of Calciumfolinate. A hypothesis is therefore that patients which are not capable of metabolizing LV could have a better antitumoral effect with Arfolitixorin administration. The antitumoural effect could be measured as inhibition of the enzyme thymidylate synthase, an enzyme essential for DNA synthesis.
Primary objective The primary objective is to compare the properties of Arfolitixorin and Calciumfolinate together with 5-fluorouracil (5-FU) on thymidylate synthase (TS) (i.e. measured as thymidylate synthase inhibition) in tumour and adjacent liver tissue in patients with liver metastases from colorectal cancer receiving a peroperative intravenous administration of Arfolitixorin or Calciumfolinate.
Secondary objectives To study safety in terms of adverse events and laboratory measurements; haematology and clinical chemistry.
To explore differences in pharmacokinetics of folates and folate metabolites in plasma.
To study gene expression in tumour and adjacent hepatic tissue and its correlation to tissue concentration.
To investigate the relation between the levels of deoxyuridine (dU) in plasma with the amount of TS inhibition in tumour tissue, in order to evaluate dU as a surrogate marker for TS-inhibition.
Study population:
Thirty adult patients with colorectal cancer and liver metastases, indicated for surgical removal will be randomised.
- Conditions
- Metastatic Colorectal Cancer
- Being tested
- Arfolitixorin
- Keywords
- Colorectal cancer,, Liver metastases, 5-FU, Arfolitixorin, Calciumfolinate, TS-inhibtion
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ArfolitixorinDrug
Also called Calciumfolinate
Per operative administration of 5-FU with Arfolitixorin or Calciumfolinate
| Study group | Role | What they receive |
|---|---|---|
| Arfolitixorin. | Experimental | Drug: Arfolitixorin Drug: 5-FU Per operative i.v. bolus injection of Arfolitixorin in combination with 5-FU Receives: Drug: Arfolitixorin |
| Calciumfolinate. | Active comparator | Drug: Calciumfolinate Drug: 5-FU Per operative i.v. bolus injection of Calciumfolinate in combination with 5-FU Receives: Drug: Arfolitixorin |
What is being measured
The primary outcome is the main question the study is designed to answer.
TS inhibition i tumour tissue
The primary objective is to compare the TS-inhibtion capacity of the combination Arfolitixorin/5-FU in contrast to Calciumfolinate/5-FU in tumour, adjacent liver parenchyma and plasma in patients with liver metastases from colorectal cancer
Measured: Biopsies will be collected during liver surgery
TS inhibition in adjacent liver parenchyma
The primary objective is to compare the TS-inhibtion capacity of the combination Arfolitixorin/5-FU in contrast to Calciumfolinate/5-FU in adjacent liver in patients with liver metastases from colorectal cancer
Measured: Biopsies will be collected during live surgery
TS inhibition in plasma
The primary objective is to compare the TS-inhibtion capacity of the combination Arfolitixorin/5-FU in contrast to Calciumfolinate/5-FU in plasma in patients with liver metastases from colorectal cancer
Measured: Blood samples will be collected according to a sampling schedule during 24 hours after the bolus injection.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Oct 2019
- Study start5 Feb 2020
- Primary completionOct 2021 (estimated)
- Study completionNov 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metastatic Colorectal CancerStudies of the same condition, open and under way.
- More trials run by Vastra Gotaland RegionThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- A total of 30 patients will be included in the study and will be equally randomised in three steps. In the first phase, six patients will receive a reduced dose 5-FU; 250 mg / m², of which three patients will be randomized to additional Calciumfolinate and three patients will be randomized to additional Arfolitixorin. P When all six patients have been followed up in the context of visits consultation, a clinical safety evaluation (SE) of all AE, and SAE will be performed by two independent physicians If the responsible physicians finds that it is safe that the study will continue, we intend to increase the dose of 5-FU 500 mg / m, after which additional 12 patients will be included. After inclusion of 6 patients receiving 5-FU 500 mg /m² in combination with Arfolitixorin in the dose of 30mg/m2 a dose adjustment will take place and the last 12 patients will be randomised to either Calciumfolinate 60 mg/m2 or Arfolitixorin 120 /m2.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Vastra Gotaland Region
- Sponsor type
- Other government
- Collaborators
- Isofol Medical AB
- Responsible party
- Sponsor
- Investigators
- Helena Taflin, MD, PhD, Principal investigator, Vastra Gotaland Region
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04126655
- Sponsor's protocol ID
- 2016-005052-25
- Other IDs
- 2016
- Status last verified
- Aug 2020
- First submitted
- 4 Oct 2019
- Last updated
- 27 Aug 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomised Phase II Study Investigating Two Doses of Arfolitixorin Compared to Calciumfolinate Together With 5- Fluorouracil on TS Inhibition in Tumour and Adjacent Hepatic Tissue for Patients With Liver Metastases From Colorectal Cancer
- ClinicalTrials.gov ID
- NCT04126655
- Acronym / sponsor ID
- 2016-005052-25
- Conditions
- Metastatic Colorectal Cancer
- Keywords
- Colorectal cancer,, Liver metastases, 5-FU, Arfolitixorin, Calciumfolinate, TS-inhibtion
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- Vastra Gotaland RegionOther government
- Collaborators
- Isofol Medical AB
- Study start
- 5 Feb 2020 (actual)
- Primary completion
- Oct 2021 (estimated)
- Study completion
- Nov 2021 (estimated)
- First posted
- 15 Oct 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
A study that is blinded to the patient and the investigator where the combination of Arfolitixorin + 5-FU is compared to Calciumfolinate + 5-FU. The patients will be randomised and will receive the above described combination as IV bolus injections, peroperatively in conjuction with collection of the first tissue sample.
A low dose (30 mg) and a high dose (120) mg of Arfolitixorin will be used in order to investigate the relation between dose of Arfolitixorin and TS-inhibition.
Detailed description
Arfolitixorin ([6R] 5,10-methylenetetrahydrofolate) is a folate based biomodulator designed to replace leucovorin. Arfolitixorin is the key active metabolite of leucovorin (LV) and does in contrast to LV not require enzymatic metabolic activation. In clinical practice, LV is administered in the form of Calciumfolinate. A hypothesis is therefore that patients which are not capable of metabolizing LV could have a better antitumoral effect with Arfolitixorin administration. The antitumoural effect could be measured as inhibition of the enzyme thymidylate synthase, an enzyme essential for DNA synthesis.
Primary objective The primary objective is to compare the properties of Arfolitixorin and Calciumfolinate together with 5-fluorouracil (5-FU) on thymidylate synthase (TS) (i.e. measured as thymidylate synthase inhibition) in tumour and adjacent liver tissue in patients with liver metastases from colorectal cancer receiving a peroperative intravenous administration of Arfolitixorin or Calciumfolinate.
Secondary objectives To study safety in terms of adverse events and laboratory measurements; haematology and clinical chemistry.
To explore differences in pharmacokinetics of folates and folate metabolites in plasma.
To study gene expression in tumour and adjacent hepatic tissue and its correlation to tissue concentration.
To investigate the relation between the levels of deoxyuridine (dU) in plasma with the amount of TS inhibition in tumour tissue, in order to evaluate dU as a surrogate marker for TS-inhibition.
Study population:
Thirty adult patients with colorectal cancer and liver metastases, indicated for surgical removal will be randomised.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
- Model description
- A total of 30 patients will be included in the study and will be equally randomised in three steps. In the first phase, six patients will receive a reduced dose 5-FU; 250 mg / m², of which three patients will be randomized to additional Calciumfolinate and three patients will be randomized to additional Arfolitixorin. P When all six patients have been followed up in the context of visits consultation, a clinical safety evaluation (SE) of all AE, and SAE will be performed by two independent physicians If the responsible physicians finds that it is safe that the study will continue, we intend to increase the dose of 5-FU 500 mg / m, after which additional 12 patients will be included. After inclusion of 6 patients receiving 5-FU 500 mg /m² in combination with Arfolitixorin in the dose of 30mg/m2 a dose adjustment will take place and the last 12 patients will be randomised to either Calciumfolinate 60 mg/m2 or Arfolitixorin 120 /m2.
| Arm | Type | Receives |
|---|---|---|
| Arfolitixorin. | Experimental | Drug: ArfolitixorinDrug: Arfolitixorin Drug: 5-FU Per operative i.v. bolus injection of Arfolitixorin in combination with 5-FU |
| Calciumfolinate. | Active comparator | Drug: ArfolitixorinDrug: Calciumfolinate Drug: 5-FU Per operative i.v. bolus injection of Calciumfolinate in combination with 5-FU |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 7.3.1 Inclusion criteria
Key exclusion criteria (9 listed)
- Concurrent administration of any other anti-tumour therapy minimum 3 weeks before surgery according to clinical practise.
- 2. Treatment within the last 30 days with a drug/device that has not received regulatory approval for any indication at the time of study entry.
- 3. Any intake of medication, which could influence folate, and vitamin B12 status, within 30 days of surgery.
- 4. 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.
- 5. Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ArfolitixorinAlso: CalciumfolinatePer operative administration of 5-FU with Arfolitixorin or Calciumfolinate | Drug | Arfolitixorin., Calciumfolinate. |
Primary outcome
TS inhibition i tumour tissue
Time frame: Biopsies will be collected during liver surgery
The primary objective is to compare the TS-inhibtion capacity of the combination Arfolitixorin/5-FU in contrast to Calciumfolinate/5-FU in tumour, adjacent liver parenchyma and plasma in patients with liver metastases from colorectal cancer
TS inhibition in adjacent liver parenchyma
Time frame: Biopsies will be collected during live surgery
The primary objective is to compare the TS-inhibtion capacity of the combination Arfolitixorin/5-FU in contrast to Calciumfolinate/5-FU in adjacent liver in patients with liver metastases from colorectal cancer
TS inhibition in plasma
Time frame: Blood samples will be collected according to a sampling schedule during 24 hours after the bolus injection.
The primary objective is to compare the TS-inhibtion capacity of the combination Arfolitixorin/5-FU in contrast to Calciumfolinate/5-FU in plasma in patients with liver metastases from colorectal cancer
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Aug 2020.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Helena Taflin, MD, PhD principal investigator
Vastra Gotaland Region
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Arfolitixorin in people with Metastatic Colorectal Cancer, run by Vastra Gotaland Region at 1 site in Sweden.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 27 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Helena Taflin, MD, PhD (+4631342100, helena.taflin@vgregion.se), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
TS inhibition i tumour tissue (time frame: Biopsies will be collected during liver surgery). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Aug 2020.