Chemotherapy Combination for Cancer

(I-FLOAT Trial)

Overseen By Daniel Catenacci, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Chicago

Must be taking: Pancreatic enzymes

Disqualifiers: Prior radiation, Inflammatory bowel, Neuropathy, others

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

Compensation: Varies

Number of Visits: 8

Duration: 4 months

54 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of the proposed study is to establish the safety of combining irinotecan chemotherapy with 5-FU, leucovorin/folinic acid, oxaliplatin, and docetaxel (abbreviated as the I-FLOAT study of gFOLFOXIRITAX) chemotherapies (leucovorin/folinic acid is a vitamin to make 5-FU work well).

Will I have to stop taking my current medications?

The trial suggests that patients taking certain medications that interact with irinotecan should try to switch to other drugs if possible. It doesn't specify a complete stop of all current medications, but you should discuss your specific medications with the trial team.

What data supports the effectiveness of the chemotherapy drug combination for cancer?

Research shows that the combination of oxaliplatin, 5-fluorouracil (5-FU), and leucovorin is effective in treating colorectal cancer, with high response rates and improved survival times. Additionally, the FOLFIRINOX regimen, which includes oxaliplatin, irinotecan, fluorouracil, and leucovorin, has been effective in treating pancreatic cancer. ^{1 2 3 4 5}

Is the chemotherapy combination treatment generally safe for humans?

The chemotherapy drugs 5-Fluorouracil, Irinotecan, Oxaliplatin, and Leucovorin have been studied for safety in humans, showing some common side effects like diarrhea, nausea, and neuropathy (nerve damage), but these are generally manageable. Supportive measures and dose adjustments help control these side effects, indicating that the treatment is generally safe with proper management. ^{6 7 8 9 10}

What makes the chemotherapy combination of 5-Fluorouracil, Docetaxel, Irinotecan, Leucovorin, and Oxaliplatin unique for cancer treatment?

This chemotherapy combination is unique because it combines several drugs that have shown effectiveness in treating advanced colorectal cancer, with irinotecan being particularly active. The combination aims to enhance the effectiveness of 5-Fluorouracil by using leucovorin to boost its activity, while also incorporating other potent agents like docetaxel and oxaliplatin to potentially improve treatment outcomes. ^{9 11 12 13 14}

Research Team

Daniel Catenacci, MD

Principal Investigator

University of Chicago Medicine

Eligibility Criteria

This trial is for adults with certain advanced gastrointestinal cancers who have a life expectancy over 3 months, good organ function, and no severe neuropathy or uncontrolled bleeding. They must not be pregnant or breastfeeding, haven't had major surgery recently, and can't have had prior chemotherapy for metastatic disease.

Inclusion Criteria

My blood counts and liver/kidney functions are within the required ranges.

Negative serum or urine B-hCG pregnancy test at screening for patients of childbearing potential

I am willing to change my current medications to avoid interactions with irinotecan.

Exclusion Criteria

I have had radiation therapy for cancer before.

I have not had major surgery in the last 4 weeks.

I have experienced mild to severe diarrhea.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the gFOLFOXIRITAX regimen, including irinotecan, 5-FU, leucovorin, oxaliplatin, and docetaxel, with genotype-guided dosing of irinotecan

4 months

8 doses administered

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• 5-Fluorouracil
• Docetaxel
• Irinotecan
• Leucovorin
• Oxaliplatin

Trial Overview The I-FLOAT study tests the safety of combining multiple chemotherapies: Irinotecan with 5-Fluorouracil (5-FU), Leucovorin (a vitamin to enhance 5-FU's effect), Oxaliplatin, and Docetaxel in patients with specific types of gastrointestinal cancers.

Participant Groups

Group I: Low Risk UGT1A1 genotype Experimental Treatment 5 Interventions

Group II: Intermediate Risk UGT1A1 genotype Experimental Treatment 5 Interventions

Group III: High Risk UGT1A1 genotype Experimental Treatment 5 Interventions

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

Approved in European Union as 5-FU for:

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

Approved in United States as 5-FU for:

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

Approved in Canada as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer

Approved in Japan as 5-FU for:

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

Who Is Running the Clinical Trial?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Findings from Research

In a review of 61 patients with pancreatic adenocarcinoma treated with FOLFIRINOX, the regimen demonstrated clinical effectiveness with a median overall survival of 13.5 months, despite significant adverse events and dose modifications in over half of the treatment cycles.

The most common severe side effect was neutropenia, affecting 19.7% of patients, but there were no therapy-related deaths, indicating that while FOLFIRINOX can cause serious side effects, it remains a viable treatment option for both metastatic and locally advanced disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-institutional experience with FOLFIRINOX in pancreatic adenocarcinoma. Peddi, PF., Lubner, S., McWilliams, R., et al.[2022]

Oxaliplatin, a new platinum analog, shows high effectiveness in treating metastatic colorectal cancer, particularly when used in combination with 5-FU and leucovorin, which has led to its approval in Europe for first- and second-line treatments.

This ongoing compassionate-use study aims to provide oxaliplatin to patients in the United States who have no adequate second- or third-line therapy options available, highlighting the urgent need for safety data and FDA approval for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxaliplatin with 5-FU or as a single agent in advanced/metastatic colorectal cancer. Mitchell, EP.[2018]

Oxaliplatin, when used in combination with 5FU and leucovorin, shows significantly higher response rates in previously untreated patients, achieving objective response rates between 51% and 66% and improving overall survival to 16-19 months.

The combination therapy not only enhances efficacy but may also reduce dose-limiting toxicities, such as sensory neurotoxicity, and has enabled some patients with initially unresectable metastases to undergo complete surgical removal of metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Oxaliplatin in combination with 5-fluoro-uracil and folinic acid as treatment of metastatic colorectal cancer]. André, T., Louvet, C., Maindrault-Goebel, F., et al.[2018]

Capecitabine, an oral fluoropyrimidine, has been shown to achieve superior response rates and equivalent overall survival compared to traditional intravenous 5-FU plus leucovorin in metastatic colorectal cancer, making it a preferred treatment option.

Recent trials, including the Xeloda Adjuvant Chemotherapy Trial (X-ACT), confirm that capecitabine is at least as effective and safer than IV 5-FU/LV for adjuvant treatment in patients with resected stage III colon cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral capecitabine: bridging the Atlantic divide in colon cancer treatment. Van Cutsem, E., Verslype, C., Tejpar, S.[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]

In a study of 50 patients with nonmetastatic colorectal cancer, adverse reactions were more frequent with the XELOX regimen (capecitabine combined with oxaliplatin), particularly neurotoxicity, thrombocytopenia, and neutropenia, compared to capecitabine monotherapy.

The type of capecitabine formulation (innovative vs. generic) did not significantly affect the safety profile; instead, the chemotherapy scheme used was the main factor influencing the occurrence of adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine safety profile, innovative and generic adjuvant formulation of nonmetastatic colorectal cancer. Sánchez-Gundín, J., Torres-Suárez, AI., Fernández-Carballido, AM., et al.[2020]

Chemotherapy agents like fluorouracil and oxaliplatin can cause significant side effects in colorectal cancer treatment, but strategies like therapeutic drug monitoring and chronomodulation have shown promise in reducing these adverse effects in clinical trials.

Supportive measures, including specific medications and schedule adjustments, are essential for managing side effects such as myelosuppression and nausea, emphasizing the need for individualized patient care and teamwork among healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of chemotherapy-induced adverse effects in the treatment of colorectal cancer. Jansman, FG., Sleijfer, DT., de Graaf, JC., et al.[2018]

A 42-year-old woman with metastatic breast cancer experienced allergic reactions to capecitabine, leading to its discontinuation, but she tolerated fluorouracil without any adverse effects during treatment.

Fluorouracil can be safely used in patients with mild allergic reactions to capecitabine, as demonstrated by this case where the patient had no complications after switching treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluorouracil for allergic reactions to capecitabine. Liu, CY.[2017]

Irinotecan has shown significant activity against advanced colorectal cancer when combined with traditional chemotherapy agents like fluorouracil, leading to clinical responses including complete remissions in patients.

The combination therapies have acceptable toxicity profiles, with neutropenia and delayed diarrhea being the most common side effects, indicating that irinotecan could be a safe option for treatment, although further large-scale phase III studies are needed to confirm its benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European experience with irinotecan plus fluorouracil/folinic acid or mitomycin. Khayat, D., Gil-Delgado, M., Antoine, EC., et al.[2018]

A phase II study involving 43 patients with advanced gastrointestinal tumors showed that capecitabine combined with either irinotecan or oxaliplatin is effective in treating colorectal and other GI cancers, demonstrating significant clinical activity as both first-line and salvage therapy.

The combination therapies exhibited an excellent safety profile, with manageable grade 3/4 toxicities primarily limited to diarrhea, and no severe myelosuppression observed, indicating that these regimens are safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of capecitabine/irinotecan and capecitabine/oxaliplatin in advanced gastrointestinal cancers. Jordan, K., Kellner, O., Kegel, T., et al.[2019]

A sequential combination therapy using docetaxel, followed by flavopiridol, and then 5-fluorouracil (5-FU) showed maximum cytotoxicity against HCT116 colon cancer cells, significantly inhibiting tumor growth and promoting apoptosis.

In xenograft models, this treatment schedule not only delayed tumor growth but also improved survival rates, emphasizing the importance of administration timing in enhancing the efficacy of these chemotherapeutic agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of sequential treatment of HCT116 colon cancer monolayers and xenografts with docetaxel, flavopiridol, and 5-fluorouracil. Guo, J., Zhou, AW., Fu, YC., et al.[2018]

In a study using the KPL-4 human breast cancer model, combining docetaxel with oral fluoropyrimidines (5'-dFUrd or tegafur) significantly enhanced tumor growth inhibition and reduced serum IL-6 levels compared to either treatment alone.

The combination treatment also decreased the expression of thymidine phosphorylase in tumors, suggesting that docetaxel may enhance the effectiveness of fluoropyrimidines while also potentially alleviating cancer-related cachexia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined effects of docetaxel and fluoropyrimidines on tumor growth and expression of interleukin-6 and thymidine phosphorylase in breast cancer xenografts. Yamamoto, S., Kurebayashi, J., Kurosumi, M., et al.[2019]

5-Fluorouracil (5-FU) is the primary treatment for colorectal cancer, and its effectiveness can be enhanced by combining it with agents like leucovorin, which has shown improved response rates and potential survival benefits compared to 5-FU alone.

Recent trials indicate that infusional regimens of 5-FU are the least toxic and may be more effective, leading to better quality of life for patients, with future research focusing on optimizing these delivery methods for maximum benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomodulation of Fluorouracil in colorectal cancer. Ardalan, B., Luis, R., Jaime, M., et al.[2019]

Infusional 5-fluorouracil combined with leucovorin shows a higher response rate and better toxicity profile compared to the standard bolus regimen, although it does not improve median survival rates in metastatic colorectal cancer.

Ongoing studies are exploring new drug combinations with 5-fluorouracil, such as oxaliplatin and CPT-11, which may offer improved efficacy over the current standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Developments in fluoropyrimidine therapy for gastrointestinal cancer. Van Cutsem, E., Peeters, M.[2019]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Multi-institutional experience with FOLFIRINOX in pancreatic adenocarcinoma. [2022]

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

Oxaliplatin with 5-FU or as a single agent in advanced/metastatic colorectal cancer. [2018]

3. France pubmed.ncbi.nlm.nih.gov

[Oxaliplatin in combination with 5-fluoro-uracil and folinic acid as treatment of metastatic colorectal cancer]. [2018]

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

Oral capecitabine: bridging the Atlantic divide in colon cancer treatment. [2018]

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

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

6. Spain pubmed.ncbi.nlm.nih.gov

Capecitabine safety profile, innovative and generic adjuvant formulation of nonmetastatic colorectal cancer. [2020]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Management of chemotherapy-induced adverse effects in the treatment of colorectal cancer. [2018]

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

Fluorouracil for allergic reactions to capecitabine. [2017]

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

European experience with irinotecan plus fluorouracil/folinic acid or mitomycin. [2018]

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

Phase II trial of capecitabine/irinotecan and capecitabine/oxaliplatin in advanced gastrointestinal cancers. [2019]

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

Efficacy of sequential treatment of HCT116 colon cancer monolayers and xenografts with docetaxel, flavopiridol, and 5-fluorouracil. [2018]

12. Germany pubmed.ncbi.nlm.nih.gov

Combined effects of docetaxel and fluoropyrimidines on tumor growth and expression of interleukin-6 and thymidine phosphorylase in breast cancer xenografts. [2019]

13. England pubmed.ncbi.nlm.nih.gov

Biomodulation of Fluorouracil in colorectal cancer. [2019]

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

Developments in fluoropyrimidine therapy for gastrointestinal cancer. [2019]