Oxaliplatin + Fluorouracil for Colorectal Cancer

Overseen by Arjun Mittra

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Arjun Mittra

Must not be taking: Investigational drugs

Disqualifiers: BRAF mutation, Appendiceal tumors, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of intraperitoneal oxaliplatin and fluorouracil in treating patients with colorectal cancer that has spread to the peritoneal cavity (peritoneal metastasis). Oxaliplatin is in a class of medications called platinum-containing antineoplastic agents. It damages the cell's DNA and may kill cancer cells. Fluorouracil stops cells from making DNA and it may kill cancer cells. Both oxaliplatin and fluorouracil are approved by the Food and Drug Administration to treat patients with colorectal cancer, however administration of these drugs directly into the area between the muscles and organs in the abdomen (intraperitoneal) for the treatment of peritoneal metastases is experimental. Giving oxaliplatin and fluorouracil directly into the peritoneal space may be a safe and effective way of treating patients with peritoneal metastases from colorectal cancer.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop your current medications. However, if you are on anticoagulation or antiplatelet agents, you may need to hold them for surgical procedures, as decided by your doctor.

What data supports the effectiveness of the drug combination of Oxaliplatin and Fluorouracil for colorectal cancer?

Research shows that adding Oxaliplatin to Fluorouracil (5-FU) therapy improves survival rates in patients with advanced colorectal cancer. This combination has become a standard treatment due to its enhanced effectiveness compared to 5-FU alone, leading to longer disease-free survival and increased overall survival in patients. ^{1 2 3 4 5}

Is the combination of Oxaliplatin and Fluorouracil safe for humans?

The combination of Oxaliplatin and Fluorouracil (5-FU) is generally safe for treating colorectal cancer, but it can cause some side effects. Oxaliplatin may lead to increased diarrhea, mouth sores, and temporary nerve problems, which can be managed by adjusting the dose or taking precautions. Rarely, 5-FU can cause confusion or seizures, but these are uncommon. ^{1 6 7 8 9}

What makes the drug combination of Oxaliplatin and Fluorouracil unique for colorectal cancer?

This drug combination is unique because Oxaliplatin and Fluorouracil (5-FU) work together to enhance their effectiveness against colorectal cancer, especially in patients who have not responded to 5-FU alone. Additionally, Oxaliplatin is administered directly into the abdominal cavity (intraperitoneal), which can target cancer cells more directly compared to standard intravenous methods. ^{1 2 10 11 12}

Research Team

Arjun Mittra

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with colorectal cancer that has spread to the lining of the abdomen (peritoneal metastasis). They should not have had certain previous treatments, must be expected to live at least 6 months, and have good organ function. Women who can bear children need a negative pregnancy test and agree to use contraception.

Inclusion Criteria

Anticipated life expectancy of ≥ 6 months

I am willing to use birth control during and for 9 months after the study.

I haven't had systemic therapy for metastatic colorectal cancer but may have had adjuvant chemotherapy over 6 months ago.

Exclusion Criteria

I do not have any severe illnesses that could interfere with the study.

I have severe liver disease with complications like confusion or fluid in the abdomen.

I have moderate to severe numbness, tingling, or pain in my hands or feet.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive intraperitoneal oxaliplatin and fluorouracil over 1-2 hours on days 1 and 15 of each cycle. Cycles repeat every 4 weeks for up to 16 weeks.

16 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up includes monitoring for adverse events and disease progression.

30 days

1 visit (in-person)

Long-term Follow-up

Participants with confirmed disease progression or who start a new anti-cancer therapy are followed up every 12 weeks until death, withdrawal of consent, or end of study.

Every 12 weeks until end of study

Treatment Details

Interventions

• Fluorouracil (Anti-metabolites)
• Intraperitoneal Oxaliplatin (Alkylating agents)

Trial Overview The trial tests intraperitoneal oxaliplatin and fluorouracil's safety, side effects, and best dose. These drugs are given directly into the abdominal space in patients with peritoneal metastases from colorectal cancer. This method is experimental despite both drugs being FDA-approved for colorectal cancer treatment.

Participant Groups

Group I: Treatment (oxaliplatin, 5FU) Experimental Treatment 8 Interventions

Patients undergo placement of indwelling IP port for chemotherapy infusion. Patients receive oxaliplatin and 5FU over 1-2 hours via IP infusion on days 1 and 15 of each cycle. Cycles repeat every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo diagnostic laparoscopy, biopsy, CT/MRI, and collection of blood samples at screening and on study and undergo collection of IP fluid samples on study.

Fluorouracil is already approved in Canada for the following indications:

Approved in Canada as 5-Fluorouracil for:

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

Who Is Running the Clinical Trial?

Arjun Mittra

Lead Sponsor

Trials

1

Recruited

20+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study involving 206 patients with advanced colorectal carcinoma who had previously failed 5-FU-based therapy, the addition of oxaliplatin to 5-FU +/- folinic acid resulted in a 25.5% objective response rate, demonstrating its efficacy as a salvage therapy.

The median overall survival for patients receiving oxaliplatin combined with 5-FU +/- FA was 9.6 months, indicating that this treatment can provide significant benefits for patients resistant to prior fluoropyrimidine therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxaliplatin added to 5-fluorouracil-based therapy (5-FU +/- FA) in the treatment of 5-FU-pretreated patients with advanced colorectal carcinoma (ACRC): results from the European compassionate-use program. Brienza, S., Bensmaïne, MA., Soulié, P., et al.[2020]

Oxaliplatin shows effectiveness as a standalone treatment for colorectal cancer, both in patients who have not received chemotherapy and those who have progressed after 5-fluorouracil (5-FU) treatment.

The combination of oxaliplatin with UFT (uracil plus tegafur) and oral calcium folinate has the potential to enhance treatment outcomes for advanced colorectal cancer, leveraging the known synergy between oxaliplatin and 5-FU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxaliplatin and UFT/oral calcium folinate for advanced colorectal carcinoma. Hoff, PM., Pazdur, R.[2018]

Adjuvant therapy using 5-fluorouracil/leucovorin (5-FU/LV) regimens and capecitabine has significantly improved 3-year disease-free survival rates in stage III colorectal cancer patients, indicating its efficacy in early disease stages.

The addition of oxaliplatin to 5-FU-based regimens has been confirmed to enhance disease-free survival, establishing it as a standard treatment alongside other chemotherapy options for colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid evolution in colorectal cancer: therapy now and over the next five years. de Gramont, A.[2007]

Fluorouracil has been effectively used for over 20 years to alleviate symptoms in patients with metastatic colorectal carcinoma, but researchers are exploring ways to enhance its effectiveness.

Prolonged infusion of fluorouracil, combined with leucovorin, improves its ability to inhibit cancer cell replication, potentially leading to better response and survival rates in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of metastatic colorectal carcinoma. Recent advances in use of fluorouracil. Treat, J., Joseph, RR.[2019]

In a study of 267 patients with stage III colorectal cancer treated with the mFLOX regimen, the 2-year disease-free survival rate was 74.9%, indicating that the combination of oxaliplatin and bolus 5-FU is effective in a community setting, similar to clinical trial results.

However, the study found a higher risk of death in patients over 70 years old, suggesting that adjuvant oxaliplatin should be used cautiously, particularly in older patients, due to a significant incidence of Grade ≥3 toxicities, including diarrhea and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of a Modified FLOX Adjuvant Regimen for Patients With Stage III Colorectal Cancer Treated in the Community. Protásio, BM., Matutino, A., Lage, LV., et al.[2018]

Oxaliplatin is an effective treatment for advanced colorectal cancer, showing activity as both a first- and second-line therapy, and is well tolerated when combined with fluorouracil/leucovorin.

Unlike other platinum-based drugs, oxaliplatin has a lower risk of kidney and ear damage, but it can cause acute and chronic neurosensory symptoms, which are manageable and reversible upon stopping the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of oxaliplatin in the treatment of colorectal cancer. Haller, DG.[2018]

The combination of oxaliplatin (OXA) with 5-fluorouracil (5-FU) and leucovorin (LV) alongside concurrent radiotherapy was found to be feasible and effective in treating 22 patients with unresectable rectal cancer, leading to a median overall survival of 19.5 months.

Despite some reported toxicities, including diarrhea and neutropenia, the treatment was manageable, with 12 out of 16 patients undergoing successful surgeries, indicating a promising approach for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiochemotherapy with short daily infusion of low-dose oxaliplatin, leucovorin, and 5-FU in T3-T4 unresectable rectal cancer: a phase II IATTGI study. Carraro, S., Roca, EL., Cartelli, C., et al.[2019]

In a study of 9 Korean patients with advanced colorectal cancer, the pharmacokinetics of oxaliplatin showed higher maximum concentration ratios in total plasma compared to other ethnic groups, indicating potential differences in drug metabolism.

The plasma concentrations of 5-fluorouracil (5-FU) varied significantly among patients, suggesting that individual responses to treatment may differ widely, which could impact overall antitumor efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of oxaliplatin and 5-fluorouracil administered in combination with leucovorin in Korean patients with advanced colorectal cancer. Cho, HK., Lee, ES., Lee, JW., et al.[2018]

The combination of oxaliplatin with 5-fluorouracil and folinic acid (known as FOLFOX) is more effective than the alternative treatment (IFL) for first-line therapy in advanced colorectal cancer, showing superior median survival rates and tumor response, while also having fewer severe side effects except for increased peripheral neuropathy.

For second-line treatment, FOLFOX is a reasonable option for patients who cannot use irinotecan, and adding bevacizumab to the FOLFOX regimen may provide additional survival benefits after progression on initial therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of oxaliplatin combined with 5-fluorouracil and folinic acid in the first- and second-line treatment of advanced colorectal cancer. Jonker, D., Rumble, RB., Maroun, J.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Oxaliplatin added to 5-fluorouracil-based therapy (5-FU +/- FA) in the treatment of 5-FU-pretreated patients with advanced colorectal carcinoma (ACRC): results from the European compassionate-use program. [2020]

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

Oxaliplatin and UFT/oral calcium folinate for advanced colorectal carcinoma. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Rapid evolution in colorectal cancer: therapy now and over the next five years. [2007]

4. Hungary pubmed.ncbi.nlm.nih.gov

[The modern treatment of colorectal cancer. Present and future]. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Treatment of metastatic colorectal carcinoma. Recent advances in use of fluorouracil. [2019]

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

Safety and Efficacy of a Modified FLOX Adjuvant Regimen for Patients With Stage III Colorectal Cancer Treated in the Community. [2018]

7. Switzerland pubmed.ncbi.nlm.nih.gov

The confused cancer patient: a case of 5-fluorouracil-induced encephalopathy. [2021]

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

Safety of oxaliplatin in the treatment of colorectal cancer. [2018]

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

Oxaliplatin: a new therapeutic option in colorectal cancer. [2022]

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

Radiochemotherapy with short daily infusion of low-dose oxaliplatin, leucovorin, and 5-FU in T3-T4 unresectable rectal cancer: a phase II IATTGI study. [2019]

11. Germany pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of oxaliplatin and 5-fluorouracil administered in combination with leucovorin in Korean patients with advanced colorectal cancer. [2018]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Role of oxaliplatin combined with 5-fluorouracil and folinic acid in the first- and second-line treatment of advanced colorectal cancer. [2021]