Irinotecan + FOLFOX Chemotherapy for Rectal Cancer

(JANUS Trial)

Recruiting at 710 trial locations

Overseen By J. Joshua Smith, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Alliance for Clinical Trials in Oncology

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Pregnancy, Upper rectal tumors, 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

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

312 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing different treatments in patients with advanced rectal cancer to see which one is more effective at shrinking the tumor or stopping its growth, potentially avoiding surgery.

Will I have to stop taking my current medications?

The trial requires that you stop taking any strong CYP3A4 inhibitors or inducers (types of drugs that affect how your body processes other medications) at least 14 days before starting the study treatment.

What data supports the effectiveness of the drug combination Irinotecan and Oxaliplatin for rectal cancer?

Research shows that the combination of Irinotecan and Oxaliplatin is effective in treating advanced colorectal cancer, which is similar to rectal cancer. Studies have found that these drugs work well together and can be used as a first-line treatment, meaning they are often the first choice for treating this type of cancer. ^{1 2 3 4 5}

Is the combination of Irinotecan and Oxaliplatin safe for humans?

The combination of Irinotecan and Oxaliplatin, used in chemotherapy for colorectal cancer, has been associated with various side effects such as myelosuppression (reduced bone marrow activity), diarrhea, nausea, and neurotoxicity (nerve damage). While these drugs can be effective, they may cause significant toxicity, and managing these side effects is important for patient safety. ^{6 7 8 9 10}

How is the drug Irinotecan + FOLFOX different for rectal cancer treatment?

The combination of Irinotecan and FOLFOX, which includes oxaliplatin, is unique because it combines multiple chemotherapy agents that work together to improve outcomes in colorectal cancer, especially when other treatments have failed. This regimen is notable for its synergistic effects and non-overlapping side effects, potentially offering better response rates compared to standard treatments. ^{1 11 12 13 14}

Research Team

J. Joshua Smith, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults with stage II-III rectal cancer, located within 12cm of the anal verge, who haven't had chemotherapy or radiation for colorectal cancer in the last 5 years. They must be healthy enough to participate (ECOG <=2), not pregnant or nursing, and willing to use effective contraception. People with certain heart conditions, HIV on effective treatment, and those not on strong CYP3A4 inhibitors/inducers are eligible.

Inclusion Criteria

I can take care of myself but might not be able to do heavy physical work.

Platelet count >= 100,000/mm

My kidney function, measured by creatinine levels or clearance, is within the normal range.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Radiation

Participants receive long-course chemoradiation therapy

5-6 weeks

Weekly visits (in-person)

Chemotherapy

Participants receive either FOLFOX or CAPOX regimen in Group I, or FOLFIRINOX regimen in Group II

8-12 weeks

Bi-weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Regular visits (in-person and virtual)

Treatment Details

Interventions

• Irinotecan
• Oxaliplatin

Trial Overview The study tests if adding Irinotecan to standard FOLFOX chemotherapy after long-course radiation improves complete response rates and organ preservation in advanced-stage rectal cancer patients compared to using FOLFOX alone.

Participant Groups

Group I: Group II (LCRT, FOLFIRINOX) Experimental Treatment 10 Interventions

Patients receive long-course chemoradiation therapy on study and then receive FOLFIRINOX regimen consisting of leucovorin IV, fluorouracil IV, irinotecan IV, and oxaliplatin IV on study. Patients undergo CT scan, MRI scan, and blood specimen collection throughout the trial. Patients undergo sigmoidoscopy throughout the trial and biopsy during screening.

Group II: Group I (LCRT, FOLFOX or CAPOX) Active Control 9 Interventions

Patients receive long-course chemoradiation therapy on study and then receive either: FOLFOX regimen consisting of leucovorin IV, fluorouracil IV, and oxaliplatin IV or CAPOX consisting of capecitabine PO, and oxaliplatin IV on study. Patients undergo CT scan, MRI, and biospecimen collection throughout the trial. Patients also undergo sigmoidoscopy throughout the trial and biopsy during screening.

Oxaliplatin is already approved in European Union, United States, Canada, Japan, Switzerland, China for the following indications:

Approved in European Union as Eloxatin for:

• Colorectal cancer

Approved in United States as Eloxatin for:

• Colorectal cancer

Approved in Canada as Eloxatin for:

• Colorectal cancer

Approved in Japan as Eloxatin for:

• Colorectal cancer

Approved in Switzerland as Eloxatin for:

• Colorectal cancer

Approved in China as Ai Heng for:

• Colorectal cancer

Who Is Running the Clinical Trial?

Alliance for Clinical Trials in Oncology

Lead Sponsor

Trials

521

Recruited

224,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

In a meta-analysis of 7 studies involving 2095 participants, oxaliplatin combined with 5-fluorouracil and leucovorin showed a higher response rate and a median overall survival advantage of 2.04 months compared to irinotecan with the same regimen.

Irinotecan was associated with higher rates of gastrointestinal side effects like nausea and diarrhea, while oxaliplatin led to more frequent cases of neurotoxicity and myelosuppression, indicating different safety profiles for the two treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan or oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer: a meta-analysis. Liang, XB., Hou, SH., Li, YP., et al.[2018]

In a randomized phase II trial involving 80 patients with advanced colorectal cancer, the combination of irinotecan and oxaliplatin (IRINOX) showed a 52.5% partial response rate with a median duration of 7.2 months, indicating its efficacy as a first-line treatment.

The IRINOX regimen had manageable toxicity levels, with significant side effects including neutropenia and diarrhea, but overall survival times were comparable to the standard treatment arm, suggesting it is a viable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II trial evaluating safety and efficacy of an experimental chemotherapy regimen (irinotecan + oxaliplatin, IRINOX) and two standard arms (LV5 FU2 + irinotecan or LV5 FU2 + oxaliplatin) in first-line metastatic colorectal cancer: a study of the Digestive Group of the Fédération Nationale des Centres de Lutte Contre le Cancer. Bécouarn, Y., Senesse, P., Thézenas, S., et al.[2020]

In a study of 92 patients with advanced colorectal cancer, the combination of oxaliplatin and irinotecan showed a significantly higher response rate (43.5% vs. 19.6%) and longer progression-free survival (7.1 months vs. 5.0 months) compared to raltitrexed, indicating its effectiveness as a first-line treatment.

While the combination therapy resulted in more side effects, including neutropenia and gastrointestinal issues, adjusting the irinotecan dose improved tolerance, suggesting that oxaliplatin/irinotecan can be a beneficial treatment option with manageable toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized multicenter phase II trial of oxaliplatin plus irinotecan versus raltitrexed as first-line treatment in advanced colorectal cancer. Scheithauer, W., Kornek, GV., Raderer, M., et al.[2018]

In a study of 145 patients with unresectable or recurrent colorectal cancer, those treated with a combination of 5-fluorouracil, irinotecan, and oxaliplatin had a significantly longer median survival time of 31.6 months compared to 18.4 months for those treated with only two of the drugs.

The order of administration of irinotecan and oxaliplatin did not affect survival outcomes, suggesting that the full three-drug regimen is more important for improving patient survival than the sequence in which the drugs are given.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The validity of full administration of 5-fluorouracil, irinotecan, and oxaliplatin to unresectable or recurrent colorectal cancer]. Ishibashi, K., Okada, N., Ishiguro, T., et al.[2018]

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]

The IROX regimen, which combines oxaliplatin and irinotecan, was found to be less effective than the FOLFOX regimen, with lower response rates (36% vs 43%) and shorter time to progression (6.7 months vs 9.2 months).

While IROX had a similar toxicity profile to FOLFOX, older patients (over 70 years) experienced higher rates of severe toxicities, indicating that caution is needed when using IROX in this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated efficacy and toxicity analysis of irinotecan and oxaliplatin (IROX) : intergroup trial N9741 in first-line treatment of metastatic colorectal cancer. Ashley, AC., Sargent, DJ., Alberts, SR., et al.[2013]

In a study of 162 colorectal cancer patients, specific genetic markers (like the T allele of ABCB1C1236T and GSTT1 gene copies) were linked to a lower risk of severe side effects from irinotecan, such as asthenia and diarrhea.

For patients treated with oxaliplatin, having one or two T variants of the ERCC1 SNP was associated with a reduced risk of neutropenia, suggesting that these biomarkers can help tailor treatments to minimize toxicity and improve patient quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential toxicity biomarkers for irinotecan- and oxaliplatin-containing chemotherapy in colorectal cancer. Cortejoso, L., García, MI., García-Alfonso, P., et al.[2018]

The maximum tolerated doses (MTDs) for oxaliplatin (OXA) and irinotecan (IRI) in a triplet regimen were determined to be 110 mg/m² and 200 mg/m², respectively, with dose-limiting toxicities (DLTs) including grade 4 neutropenia and severe diarrhea observed in some patients.

The recommended doses for the biweekly regimen were established as OXA 110 mg/m² and IRI 175 mg/m² on day 1, followed by folinic acid and 5-fluorouracil on day 2, showing a response rate of 27.5% in patients with advanced colorectal cancer, indicating potential efficacy for further evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxaliplatin plus irinotecan and leucovorin-modulated 5-fluorouracil triplet regimen every other week: a dose-finding study in patients with advanced gastrointestinal malignancies. Comella, P., Casaretti, R., De Rosa, V., et al.[2020]

FOLFOXIRI treatment significantly improves response rates and progression-free survival in metastatic colorectal cancer patients compared to the standard FOLFIRI regimen, with odds ratios indicating a 2.04 times higher response rate and hazard ratios showing a 28% reduction in progression and death risk.

However, while FOLFOXIRI offers these benefits, it also comes with increased toxicity compared to FOLFIRI, although it does not significantly raise the risk of anemia, fatigue, or febrile neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review of FOLFOXIRI chemotherapy for the first-line treatment of metastatic colorectal cancer: improved efficacy at the cost of increased toxicity. Montagnani, F., Chiriatti, A., Turrisi, G., et al.[2018]

In a phase I-II trial involving 34 patients with advanced colorectal cancer, the combination of irinotecan and oxaliplatin showed an overall response rate of 44%, indicating significant efficacy in treating this patient population.

The study found no pharmacokinetic interactions between irinotecan and oxaliplatin, and established a recommended dosing regimen that could be used as a front-line therapy to achieve rapid disease control and facilitate potential surgical interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxaliplatin plus irinotecan and FU-FOL combination and pharmacokinetic analysis in advanced colorectal cancer patients. Gil-Delgado, MA., Bastian, G., Guinet, F., et al.[2019]

In a phase II trial involving 14 patients with metastatic colorectal cancer, a combination of oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin resulted in a 23% partial response rate and 69% stable disease, indicating some efficacy of the treatment.

However, the regimen was associated with significant toxicity, including a grade 5 event and multiple grade 4 events, leading to the study's closure for further enrollment due to safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of oxaliplatin/irinotecan/5-fluorouracil/leucovorin for metastatic colorectal cancer. McWilliams, RR., Goetz, MP., Morlan, BW., et al.[2018]

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 study of 54 patients with fluorouracil-resistant colorectal cancer, the combination of irinotecan followed by oxaliplatin showed a high response rate of 49%, with a median response duration of 6.5 months and overall survival of 15 months.

The treatment was well tolerated, with manageable side effects; the most common grade 3 side effects included nausea/vomiting (11%), diarrhea (18%), and neutropenia (7%), indicating a favorable safety profile for this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of treatment with irinotecan and oxaliplatin combination in FU-resistant metastatic colorectal cancer patients. Bajetta, E., Beretta, E., Di Bartolomeo, M., et al.[2018]

References

1. 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]

2. China pubmed.ncbi.nlm.nih.gov

Irinotecan or oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer: a meta-analysis. [2018]

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

A randomized phase II trial evaluating safety and efficacy of an experimental chemotherapy regimen (irinotecan + oxaliplatin, IRINOX) and two standard arms (LV5 FU2 + irinotecan or LV5 FU2 + oxaliplatin) in first-line metastatic colorectal cancer: a study of the Digestive Group of the Fédération Nationale des Centres de Lutte Contre le Cancer. [2020]

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

Randomized multicenter phase II trial of oxaliplatin plus irinotecan versus raltitrexed as first-line treatment in advanced colorectal cancer. [2018]

5. Japan pubmed.ncbi.nlm.nih.gov

[The validity of full administration of 5-fluorouracil, irinotecan, and oxaliplatin to unresectable or recurrent colorectal cancer]. [2018]

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

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

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

Updated efficacy and toxicity analysis of irinotecan and oxaliplatin (IROX) : intergroup trial N9741 in first-line treatment of metastatic colorectal cancer. [2013]

8. Germany pubmed.ncbi.nlm.nih.gov

Differential toxicity biomarkers for irinotecan- and oxaliplatin-containing chemotherapy in colorectal cancer. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Oxaliplatin plus irinotecan and leucovorin-modulated 5-fluorouracil triplet regimen every other week: a dose-finding study in patients with advanced gastrointestinal malignancies. [2020]

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

A systematic review of FOLFOXIRI chemotherapy for the first-line treatment of metastatic colorectal cancer: improved efficacy at the cost of increased toxicity. [2018]

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

Oxaliplatin plus irinotecan and FU-FOL combination and pharmacokinetic analysis in advanced colorectal cancer patients. [2019]

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

Phase II trial of oxaliplatin/irinotecan/5-fluorouracil/leucovorin for metastatic colorectal cancer. [2018]

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

FOLFOXIRI plus biologics in advanced colorectal cancer. [2020]

14. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy of treatment with irinotecan and oxaliplatin combination in FU-resistant metastatic colorectal cancer patients. [2018]