NALIRIFOX for Small Bowel Cancer

Overseen By Tiago Biachi de Castria, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Tiago Biachi de Castria

Must not be taking: CYP3A inhibitors, CYP2C8 inducers

Disqualifiers: CNS metastases, Gastrointestinal disorders, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 12

Duration: 24 weeks

36 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires participants to stop using strong inhibitors or inducers of certain enzymes (CYP3A, CYP2C8, and UGT1A1) at least 1-2 weeks before joining. If you're on these medications, you may need to stop them, but it's best to discuss with your doctor.

What data supports the effectiveness of the drug NALIRIFOX for small bowel cancer?

The components of NALIRIFOX, such as liposomal irinotecan, oxaliplatin, and 5-fluorouracil, have shown effectiveness in treating other types of cancer like pancreatic and colorectal cancer. These drugs have been studied in various combinations and have demonstrated some success in slowing cancer progression and improving survival in these conditions. ^{1 2 3 4 5}

Is NALIRIFOX generally safe for humans?

NALIRIFOX, which includes drugs like 5-fluorouracil, leucovorin, nanoliposomal irinotecan, and oxaliplatin, has been studied for safety in various cancers. Common side effects include diarrhea, nausea, vomiting, and neuropathy (nerve damage), but these are generally manageable with supportive care and dose adjustments. ^{1 4 6 7 8}

How is the NALIRIFOX drug unique for treating small bowel cancer?

NALIRIFOX is unique because it combines nanoliposomal irinotecan, which is a special form of the drug irinotecan that may improve delivery to cancer cells, with other chemotherapy agents like oxaliplatin, 5-fluorouracil, and leucovorin. This combination is being explored for small bowel cancer, a condition with no standard chemotherapy regimen, potentially offering a new treatment option. ^{1 4 9 10 11}

What is the purpose of this trial?

The study regimen will be administered on an outpatient basis and all medications are administered intravenously (IV). Subjects will receive treatment on Day 1 and Day 15 of each 28-day cycle consisting of the following: nanoliposomal irinotecan at 50 mg/m2, followed by oxaliplatin 60 mg/m2, followed by leucovorin at 400 mg/m2 30 minutes after completion of oxaliplatin, followed by 5-FU 2400 mg/m2 60 minutes after leucovorin completion. Subjects will receive up to 6 cycles of NALIRIFOX then based on response and per physician discretion, de-escalated maintenance treatment with NALIRIFOX minus oxaliplatin may continue. Subjects will continue de-escalated maintenance treatment until progression per RECIST 1.1, intolerable toxicity or physician/subject choice to discontinue.

Research Team

Tiago Biachi de Castria, MD, PhD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

This trial is for adults with advanced small bowel cancer that can't be surgically removed. Participants must have measurable disease, adequate organ function, and no prior chemotherapy for metastatic disease. They cannot join if they've had recent surgery or radiation, significant heart disease, another active cancer, or known allergies to the drugs being tested.

Inclusion Criteria

Subjects infected with HIV must meet specific criteria.

Electrocardiogram (ECG) without any clinically significant findings.

I have taken a pregnancy test recently and it was negative.

Exclusion Criteria

My cancer started in the ampulla or appendix.

Pregnant or breastfeeding.

I have a serious stomach or intestine condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive NALIRIFOX treatment on Day 1 and Day 15 of each 28-day cycle for up to 6 cycles

24 weeks

12 visits (in-person)

De-escalated Maintenance

Based on response, participants may continue with NALIRIFOX minus oxaliplatin until progression or intolerable toxicity

Until progression or intolerable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Treatment Details

Interventions

• 5 fluorouracil
• Leucovorin
• Nanoliposomal irinotecan
• Oxaliplatin

Trial Overview The study tests a combination of four IV drugs (NALIRIFOX): nanoliposomal irinotecan, oxaliplatin, leucovorin, and 5-FU given every two weeks in a 28-day cycle. After six cycles of full treatment, patients may receive maintenance therapy without oxaliplatin if their doctor agrees.

Participant Groups

Group I: NALIRIFOX and De-escalated maintenance Experimental Treatment 4 Interventions

Cycle 1 to Cycle 6: NALIRIFOX Subjects will receive treatment on Day 1 and Day 15 of each 28-day cycle consisting of the following: nanoliposomal irinotecan at 50 mg/m2, followed by oxaliplatin 60 mg/m2, followed by leucovorin at 400 mg/m2 30 minutes after completion of oxaliplatin, followed by 5-FU 2400 mg/m2 60 minutes after leucovorin completion. Patients will receive up to 6 cycles of NALIRIFOX. Cycle 7+: De-escalated Maintenance: Based on response to Cycles 1-6 and per physician discretion, de-escalated maintenance treatment with NALIRIFOX minus oxaliplatin may continue as de-escalated maintenance treatment until progression per RECIST 1.1, intolerable toxicity or physician/subject choice to discontinue.

Who Is Running the Clinical Trial?

Tiago Biachi de Castria

Lead Sponsor

Trials

1

Recruited

40+

H. Lee Moffitt Cancer Center and Research Institute

Collaborator

Trials

576

Recruited

145,000+

Ipsen

Industry Sponsor

Trials

358

Recruited

74,600+

David Loew

Ipsen

Chief Executive Officer since 2020

BA in Business Administration and MBA from the University of St. Gallen, Switzerland

Sandra Silvestri

Ipsen

Chief Medical Officer since 2023

MD, PhD

Findings from Research

The mFOLFOXIRI regimen, a combination of 5-fluorouracil, oxaliplatin, and irinotecan, was found to be safe for patients with advanced colorectal cancer, with no treatment-related deaths reported despite some serious adverse events like intestinal perforation and neutropenia.

In terms of efficacy, the regimen showed a promising overall response rate of 63.8% in patients with metastatic colorectal cancer, with significantly better outcomes for those who completed more than four cycles of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Analysis on safety and preliminary efficacy of dose-modified regimen of 5-fluorouracil plus oxaliplatin and irinotecan (FOLFOXIRI) in advanced colorectal cancer]. Cai, Y., Deng, R., Hu, H., et al.[2018]

In a study of 36 patients with advanced colorectal cancer who had previously been treated with fluoropyrimidines, the combination of irinotecan and oxaliplatin showed a 42% overall response rate, indicating significant antitumor activity.

The treatment was generally well-tolerated, with manageable side effects; severe hematologic toxicity was rare, and the most common nonhematologic issues were nausea and diarrhea, suggesting that this regimen could be a viable option for patients with progressive disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer. Scheithauer, W., Kornek, GV., Raderer, M., et al.[2018]

Liposomal irinotecan (Irinophore C™) demonstrated significant efficacy as a single agent in treating colorectal cancer, delaying tumor growth more effectively than the combination with 5-fluorouracil (5-FU).

The combination of IrC™ and 5-FU resulted in increased toxicity and altered pharmacokinetics of 5-FU, suggesting that while IrC™ is a promising treatment, its use with 5-FU may complicate treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of colorectal cancer using a combination of liposomal irinotecan (Irinophore C™) and 5-fluorouracil. Hare, JI., Neijzen, RW., Anantha, M., et al.[2021]

The study established the maximum tolerated dose (MTD) for the combination treatment NALIRIFOX in patients with metastatic pancreatic ductal adenocarcinoma, with 32 out of 56 patients receiving the MTD, indicating a manageable safety profile despite some patients experiencing severe treatment-related adverse events.

Patients treated with NALIRIFOX showed a median progression-free survival of 9.2 months and overall survival of 12.6 months, suggesting that this treatment regimen may be effective for this difficult-to-treat cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line liposomal irinotecan with oxaliplatin, 5-fluorouracil and leucovorin (NALIRIFOX) in pancreatic ductal adenocarcinoma: A phase I/II study. Wainberg, ZA., Bekaii-Saab, T., Boland, PM., et al.[2021]

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]

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]

In a study of 20 patients with advanced small bowel adenocarcinoma, chemotherapy combining 5-fluorouracil (5-FU) with platinum compounds showed a 21% overall response rate, with median progression-free survival of 8 months and overall survival of 14 months, indicating moderate efficacy and tolerability.

The combination of 5-FU and irinotecan demonstrated promising results, with 50% of patients achieving disease stabilization and one patient experiencing a complete biological response, suggesting that this combination warrants further investigation as a first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination chemotherapy in advanced small bowel adenocarcinoma. Locher, C., Malka, D., Boige, V., et al.[2022]

The combination of FOLFOXIRI (oxaliplatin, irinotecan, fluorouracil, and leucovorin) with the biologic agent panitumumab has shown improved outcomes in metastatic colorectal cancer (mCRC) patients, based on randomized clinical trial results.

While FOLFOXIRI combined with bevacizumab has extensive data from large trials, its true benefit is still uncertain as it hasn't been tested in a randomized setting, highlighting the need for further research to confirm its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFOXIRI plus biologics in advanced colorectal cancer. García-Alfonso, P., Torres, G., García, G., et al.[2020]

In a phase II study involving 24 patients with metastatic or recurrent small bowel adenocarcinoma, the mFOLFOX6 chemotherapy regimen demonstrated a 1-year progression-free survival (PFS) rate of 23.3%, indicating some efficacy as a first-line treatment.

The treatment was generally well tolerated, with no treatment-related deaths reported, although significant side effects included neutropenia (38%) and anemia/peripheral neuropathy (25%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of 5-fluorouracil/L-leucovorin/oxaliplatin (mFOLFOX6) in Japanese patients with metastatic or unresectable small bowel adenocarcinoma. Horimatsu, T., Nakayama, N., Moriwaki, T., et al.[2022]

References

1. China pubmed.ncbi.nlm.nih.gov

[Analysis on safety and preliminary efficacy of dose-modified regimen of 5-fluorouracil plus oxaliplatin and irinotecan (FOLFOXIRI) in advanced colorectal cancer]. [2018]

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

Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer. [2018]

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

Treatment of colorectal cancer using a combination of liposomal irinotecan (Irinophore C™) and 5-fluorouracil. [2021]

4. England pubmed.ncbi.nlm.nih.gov

First-line liposomal irinotecan with oxaliplatin, 5-fluorouracil and leucovorin (NALIRIFOX) in pancreatic ductal adenocarcinoma: A phase I/II study. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Post-gemcitabine therapy for patients with advanced pancreatic cancer - A comparative review of randomized trials evaluating oxaliplatin- and/or irinotecan-containing regimens. [2022]

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

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

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

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

8. England pubmed.ncbi.nlm.nih.gov

Biweekly oxaliplatin plus irinotecan and folinic acid-modulated 5-fluorouracil: a phase II study in pretreated patients with metastatic colorectal cancer. [2018]

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

Combination chemotherapy in advanced small bowel adenocarcinoma. [2022]

10. England pubmed.ncbi.nlm.nih.gov

FOLFOXIRI plus biologics in advanced colorectal cancer. [2020]

11. Japan pubmed.ncbi.nlm.nih.gov

A phase II study of 5-fluorouracil/L-leucovorin/oxaliplatin (mFOLFOX6) in Japanese patients with metastatic or unresectable small bowel adenocarcinoma. [2022]