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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method of administering chemotherapy to individuals with advanced gastrointestinal cancers, such as those in the stomach or esophagus. It aims to adjust the dose of a drug called 5-FU (Fluorouracil) to determine if increasing the dose for those who tolerate it well enhances treatment outcomes. Participants will also receive another chemotherapy drug, oxaliplatin, at standard levels. Suitable candidates include those with advanced gastrointestinal cancer who have not previously undergone certain types of chemotherapy and can manage daily activities effectively. As an unphased trial, this study provides a unique opportunity to explore innovative treatment options for advanced cancer.

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 prior data suggests that this chemotherapy regimen is safe for gastrointestinal cancer patients?

Research has shown that chemotherapy with 5-FU and oxaliplatin is generally well-tolerated. Studies have found 5-FU to be safe for use in several types of cancer, such as colon and stomach cancer. However, some individuals might experience serious side effects, including heart problems. Monitoring for these side effects is crucial, especially for those with conditions that increase their risk.

Oxaliplatin is often combined with 5-FU and leucovorin to treat advanced colorectal cancer. Common side effects of oxaliplatin include numbness or tingling in the fingers and toes, known as nerve damage, and a decrease in blood cells, which can lead to infections. Although these side effects can be serious, they are known and carefully managed during treatment.

The trial under consideration involves adjusting the dose of 5-FU based on patient tolerance. This approach starts with a lower dose, increasing it only if no serious side effects occur. This careful method helps ensure patient safety while determining the most effective dose. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this treatment for gastrointestinal cancer because it uses an individualized dosing strategy for 5-FU, which is different from the traditional fixed dosing methods. This adaptive approach involves adjusting the 5-FU dose based on a clinical algorithm, allowing it to be tailored to each patient's needs while aiming to maximize effectiveness and minimize side effects. Additionally, the regimen combines 5-FU with oxaliplatin and leucovorin calcium to enhance the overall treatment potency. These features could potentially lead to improved outcomes for patients compared to standard treatments.

What evidence suggests that this individualized 5-FU dosing regimen could be effective for gastrointestinal cancer?

Research has shown that personalized dosing of 5-FU can improve outcomes for patients with gastrointestinal cancer. In this trial, all participants will receive the FOX regimen, which includes adaptively dose-escalated 5-FU. Studies have found that adjusting the 5-FU dose to fit the patient can significantly enhance treatment effectiveness, sometimes improving results by 49.6% to 212%. This means that tailoring the dose based on patient tolerance enhances treatment efficacy. Along with 5-FU, oxaliplatin is included in the treatment plan. Research indicates that combining oxaliplatin with 5-FU extends the time patients live without cancer recurrence. This combination has successfully helped many patients live longer without the cancer returning. ^{6 7 8 9 10}

Who Is on the Research Team?

Gabriel A. Brooks

Principal Investigator

Dartmouth-Hitchcock Medical Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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 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]

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]

Citations

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5-FU therapeutic drug monitoring as a valuable option to ... Our analysis confirms that the use of BSA-guided dosing results in highly variable 5-FU exposure and strongly suggests that PK-guided dosing can improve ...

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Determining the optimal 5-FU therapeutic dosage in ... It was found that the AUC of 5-FU was 34.16±14.83mg·h/L in this cohort of study. The immunohistochemical analysis revealed 38.96% and 81.82% positive staining ...

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Pharmacokinetically guided algorithm of 5-fluorouracil ... In the included studies, the PKG algorithms significantly improved the clinical response rate of colorectal cancer patients by 49.6%–212%, ...

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Safety and efficacy of weekly 5-fluorouracil/folinic acid ... Conclusion: These data show excellent tolerance and efficacy of the FUFOXIRI regimen in both mCRC and GC. Therefore, FUFOXIRI is a promising backbone for future ...

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Real-world safety data and differentiation of second-line ... This study examined the proportion of patients (pts) with mPDAC treated with 5-FU-based regimens in the 2L setting who experienced AEs during treatment.

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Fluorouracil (intravenous route, injection route) Fluorouracil belongs to the group of medicines known as antimetabolites. It is used to treat cancer of the colon, rectum, breast, stomach, and pancreas.

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3965252 This label may not be the latest approved by FDA ... No fluorouracil dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in ...