Individualized 5-FU Dosing for Gastrointestinal Cancer

(FOXRegimen Trial)

Overseen By Research Nurse

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Dartmouth-Hitchcock Medical Center

Disqualifiers: Prior chemotherapy, DPD deficiency, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

Duration: 12 weeks

36 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single-arm clinical trial to evaluate the feasibility of a chemotherapy regimen using adaptive, individualized dose escalation of 5-FU chemotherapy for patients who have good tolerance of the initial dose. Study participants will also receive oxaliplatin chemotherapy together with 5-FU, at standard doses. The goal of the study is to examine the feasibility and effectiveness of this approach, using individualized dose escalation of 5-FU in patients who do not have serious side effects at lower doses.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you have received certain types of chemotherapy in the past six months, you may not be eligible to participate.

What data supports the effectiveness of the drug 5-FU for gastrointestinal cancer?

Research shows that adjusting the dose of 5-FU based on individual patient needs can improve outcomes in colorectal cancer, which is a type of gastrointestinal cancer. This suggests that personalized dosing of 5-FU might also be effective for other gastrointestinal cancers. ^{1 2 3 4 5}

Is 5-FU generally safe for humans?

5-FU (Fluorouracil) has been used in various cancer treatments and is generally considered safe when used correctly, though it can cause side effects like neutropenia (low white blood cell count) and vomiting. Studies have shown that high doses can be used safely with precautions, such as combining with other drugs to reduce toxicity. ^{1 6 7 8 9}

What makes the drug 5-FU unique for gastrointestinal cancer treatment?

The drug 5-FU is unique for gastrointestinal cancer treatment because it involves individualized dosing, which means the amount given is tailored to each patient to improve effectiveness and reduce side effects. This approach considers individual differences in how patients respond to the drug, potentially leading to better outcomes. ^{1 8 10 11 12}

Research Team

Gabriel A. Brooks

Principal Investigator

Dartmouth-Hitchcock Medical Center

Eligibility Criteria

This trial is for adults with advanced gastrointestinal cancers, including colorectal and non-colorectal types. Participants must be in good physical condition (ECOG 0-1) and have not received certain chemotherapies recently. They can't join if they are pregnant, breastfeeding, have specific blood or liver issues, drug dependencies, or other serious health conditions.

Inclusion Criteria

I am fully active or can carry out light work.

My cancer is advanced and cannot be removed by surgery.

Clinically appropriate staging imaging of the chest, abdomen, and pelvis performed within 30 days prior to registration

Exclusion Criteria

I have previously received oxaliplatin or fluoropyrimidine chemotherapy.

I haven't had chemotherapy in the last 6 months, except to make radiation work better.

My cancer is known to have a mismatch repair deficiency.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the FOX regimen, which includes oxaliplatin and 5-FU with adaptive dose escalation over Cycles 1-6

12 weeks

6 cycles, each 14 days long

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Long-term follow-up

Progression-free survival is assessed up to 12 months from Cycle 1 Day 1

12 months

Treatment Details

Interventions

• 5-FU
• FOX dose-escalation algorithm
• Oxaliplatin

Trial Overview The study tests a personalized dose increase of the chemotherapy drug 5-FU for patients who handle an initial dose well. It's combined with standard doses of oxaliplatin to see if this method is feasible and effective without causing severe side effects.

Participant Groups

Group I: Study Arm Experimental Treatment 1 Intervention

All patients in this single-study arm will be exposed to the FOX regimen, an adaptively dose-escalated chemotherapy regimen. The FOX regimen is comprised of oxaliplatin 85 mg/m2 IV on Day 1; leucovorin calcium 350 mg IV on Day 1; and infusional 5-FU IV over 46 hours (Days 1 and 2) - starting at a dose of 2,400 mg/m2 and adaptively adjusted toward a maximum dose of 3,200 mg/m2 over Cycles 2-4 using a clinical algorithm.

5-FU is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Approved in European Union as Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Skin cancer

Approved in Canada as Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Approved in Japan as Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

Dartmouth-Hitchcock Medical Center

Lead Sponsor

Trials

548

Recruited

2,545,000+

Findings from Research

The maximum-tolerated dose (MTD) of 5-fluorouracil (5-FU) in combination with fixed doses of docetaxel and cisplatin for treating advanced gastric cancer was determined to be 1,750 mg/m², with a favorable safety profile as less than 10% of patients experienced severe toxicities.

Among 19 patients evaluated for treatment response, the overall response rate was 26%, increasing to 39% in those who had not received prior chemotherapy, suggesting that this regimen is effective and warrants further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I dose-escalating study of 24-h continuous infusion of 5-fluorouracil in combination with weekly docetaxel and cisplatin in patients with advanced gastric cancer. Wang, B., Zhang, W., Hong, X., et al.[2018]

In a study of 115 colorectal cancer patients undergoing 5-FU-based chemotherapy, those who experienced disease recurrence had significantly lower plasma concentrations of 5-FU, indicating that pharmacokinetics may play a crucial role in treatment outcomes.

Completing all 6 cycles of chemotherapy without dose modifications was identified as the only independent risk factor for improved disease-free survival, highlighting the importance of adherence to treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5-fluorouracil pharmacokinetics predicts disease-free survival in patients administered adjuvant chemotherapy for colorectal cancer. Di Paolo, A., Lencioni, M., Amatori, F., et al.[2022]

In a study of 570 patients with stage III colorectal cancer, three different administration types of 5-fluorouracil (5-FU) in FOLFOX treatment showed similar disease-free survival (DFS) and overall survival (OS) rates, indicating comparable efficacy.

While all treatment regimens were manageable in terms of toxicity, the modified FOLFOX-6 group experienced more grade 1-2 adverse events like thrombocytopenia and neuropathy, suggesting that while efficacy is similar, side effects may vary among the different regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The comparison of FOLFOX regimens with different doses of 5-FU for the adjuvant treatment of colorectal cancer: a multicenter study. Akdeniz, N., Kaplan, MA., Uncu, D., et al.[2021]

In a study of 20 patients with metastatic colorectal cancer, those who had their 5-fluorouracil (5-FU) doses adjusted based on pharmacokinetic monitoring (Group A) showed a median overall survival of 34 months, compared to 14 months for those with conventional dosing (Group B).

The objective response rate was higher in the pharmacokinetically monitored group (63%) compared to the conventional group (33%), suggesting that individualized dosing may enhance treatment effectiveness without increasing severe toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Individual Dose Adjustment of 5-Fluorouracil Based on Pharmacokinetic Monitoring May Improve the Outcome of FOLFOX for Metastatic Colorectal Cancer]. Muneoka, K., Shirai, Y., Sasaki, M., et al.[2016]

In a phase II study involving 36 patients with advanced colorectal cancer, the combination of trimetrexate, fluorouracil (5FU), and leucovorin resulted in a 50% overall response rate, with 7% achieving a complete response and 43% a partial response.

While the treatment showed significant efficacy, gastrointestinal toxicity was a major concern, with 58% of patients experiencing severe diarrhea and 34% severe nausea, although these side effects were deemed manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of trimetrexate, fluorouracil, and leucovorin for advanced colorectal cancer. Blanke, CD., Kasimis, B., Schein, P., et al.[2017]

In a study involving 60 patients with advanced gastric cancer, high-dose infusional 5-FU showed a low incidence of severe toxicity compared to the EAP regimen, particularly with fewer cases of neutropenia and thrombocytopenia.

However, the efficacy of high-dose 5-FU was low, with only a 10% confirmed response rate, suggesting it is not suitable as a standalone treatment, and further research should explore higher doses or combinations with other drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bimonthly 24 h infusion of high-dose 5-fluorouracil vs EAP regimen in patients with advanced gastric cancer. A randomized phase II study. Popov, IP., Jelić, SB., Krivokapić, ZV., et al.[2021]

In a study involving 31 patients with advanced colorectal cancer, the addition of oxaliplatin to the 5-fluorouracil (5FU) treatment regimen did not significantly change the pharmacokinetics of 5FU, indicating that oxaliplatin can be safely combined without altering 5FU's effectiveness.

Both the standard and modified de Gramont regimens showed consistent 5FU plasma concentration levels, suggesting that oxaliplatin does not interfere with the absorption or metabolism of 5FU in these treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lack of pharmacokinetic interaction between 5-fluorouracil and oxaliplatin. Joel, SP., Papamichael, D., Richards, F., et al.[2018]

High-dose 5-fluorouracil (5FU) combined with allopurinol can be safely administered to advanced gastrointestinal cancer patients, as evaluated in a study of 20 patients.

This combination aims to enhance the therapeutic index of 5FU while minimizing toxicity to normal tissues, making it a promising approach in chemotherapy for gastrointestinal cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[5-fluorouracil in high doses. Principles and toxicity]. Fleischer, I., Wainstein, R., Milano, MC.[2013]

In a study involving 294 colorectal cancer patients, the treatment with raltitrexed (Tomudex) was found to be more toxic and resulted in shorter progression-free survival compared to the LV5FU2 and low-dose LV5FU2 treatments.

The low-dose LV5FU2 regimen showed comparable efficacy to standard LV5FU2 and high-dose 5FU, suggesting it could be a more manageable and cost-effective option for treating metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised trial comparing three different schedules of infusional 5FU and raltitrexed alone as first-line therapy in metastatic colorectal cancer. Final results of the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 trial. Ducreux, M., Bouche, O., Pignon, JP., et al.[2014]

The sensitivity to 5-fluorouracil (5-FU) in colorectal cancer patients varies significantly, with individual AUC(IR50) values ranging from less than 100 to over 1000 microg hr/ml, indicating that some patients may respond poorly to this treatment.

Achieving the individual AUC(IR50) is associated with significantly better relapse-free survival, suggesting that personalized chemotherapy duration based on 5-FU sensitivity could enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study to predict optimal duration of chemotherapy with fluoropyrimidine by multi-point collagen gel droplet embedded drug sensitivity test. Tokunaga, Y., Sasaki, H., Ohnishi, T.[2013]

The study determined that the maximum tolerated dose of oral eniluracil/5-fluorouracil (5-FU) in combination with oxaliplatin is 10.0/1.0 mg/m² twice daily for 16 days, with dose-limiting toxicities including vomiting and diarrhea.

Among 23 patients with advanced gastrointestinal malignancies, the treatment resulted in a 26% objective tumor response rate, with a median duration of response lasting 15.3 weeks, although 96% of patients experienced some level of neurotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A dose-escalating study of oral eniluracil/5-fluorouracil plus oxaliplatin in patients with advanced gastrointestinal malignancies. Yip, D., Karapetis, C., Strickland, AH., et al.[2020]

In a review of 19 cancer patients with inflammatory bowel disease (IBD) treated with fluorouracil (5FU)-based chemotherapy, 53% experienced severe diarrhea, indicating a significant risk of exacerbation during treatment.

Despite the high incidence of severe diarrhea, many patients tolerated the chemotherapy well, suggesting that while there is an increased risk, not all patients will experience severe side effects, and predicting toxicity based on IBD activity is not reliable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of inflammatory bowel disease on the ability of patients to tolerate systemic fluorouracil-based chemotherapy. Tiersten, A., Saltz, LB.[2017]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Phase I dose-escalating study of 24-h continuous infusion of 5-fluorouracil in combination with weekly docetaxel and cisplatin in patients with advanced gastric cancer. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

5-fluorouracil pharmacokinetics predicts disease-free survival in patients administered adjuvant chemotherapy for colorectal cancer. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

The comparison of FOLFOX regimens with different doses of 5-FU for the adjuvant treatment of colorectal cancer: a multicenter study. [2021]

4. Japan pubmed.ncbi.nlm.nih.gov

[Individual Dose Adjustment of 5-Fluorouracil Based on Pharmacokinetic Monitoring May Improve the Outcome of FOLFOX for Metastatic Colorectal Cancer]. [2016]

5. United States pubmed.ncbi.nlm.nih.gov

Phase II study of trimetrexate, fluorouracil, and leucovorin for advanced colorectal cancer. [2017]

6. United States pubmed.ncbi.nlm.nih.gov

Bimonthly 24 h infusion of high-dose 5-fluorouracil vs EAP regimen in patients with advanced gastric cancer. A randomized phase II study. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Lack of pharmacokinetic interaction between 5-fluorouracil and oxaliplatin. [2018]

8. Argentina pubmed.ncbi.nlm.nih.gov

[5-fluorouracil in high doses. Principles and toxicity]. [2013]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Randomised trial comparing three different schedules of infusional 5FU and raltitrexed alone as first-line therapy in metastatic colorectal cancer. Final results of the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 trial. [2014]

10. Greece pubmed.ncbi.nlm.nih.gov

Study to predict optimal duration of chemotherapy with fluoropyrimidine by multi-point collagen gel droplet embedded drug sensitivity test. [2013]

11. England pubmed.ncbi.nlm.nih.gov

A dose-escalating study of oral eniluracil/5-fluorouracil plus oxaliplatin in patients with advanced gastrointestinal malignancies. [2020]

12. United States pubmed.ncbi.nlm.nih.gov

Influence of inflammatory bowel disease on the ability of patients to tolerate systemic fluorouracil-based chemotherapy. [2017]