Irinotecan + FOLFOX Chemotherapy for Rectal Cancer

(JANUS Trial)

Not currently recruiting at 774 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding irinotecan (also known as Camptosar or CPT-11) to the usual chemotherapy regimen after chemoradiation can improve outcomes for people with stage II-III rectal cancer. Researchers compare two different treatment combinations to determine which one more effectively stops the cancer from growing or spreading. This trial may suit individuals with stage II-III rectal cancer requiring surgery who have not received chemotherapy or radiation for colorectal cancer in the past five years. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the FOLFIRINOX treatment, which includes irinotecan and oxaliplatin, presents some safety concerns. Studies have found it can lead to higher rates of severe neutropenia (a low white blood cell count) and nausea or vomiting compared to treatments like CAPOX. Adjusting the order of drug administration in FOLFIRINOX can help reduce these side effects.

Oxaliplatin, used in both treatment groups, is generally safe but can cause side effects like neuropathy, leading to tingling or numbness. In standard treatments, oxaliplatin has a well-known safety record. While side effects exist, these treatments have been used in other situations and are well-researched. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine traditional chemoradiation with innovative chemotherapy regimens to treat rectal cancer. Unlike the standard FOLFOX regimen, which includes leucovorin, fluorouracil, and oxaliplatin, the FOLFIRINOX regimen adds irinotecan, potentially enhancing the treatment's effectiveness. This addition could offer a more aggressive approach against cancer cells. Moreover, the inclusion of CAPOX, which swaps out intravenous fluorouracil for oral capecitabine, might provide more convenience and flexibility for patients. These new combinations aim to improve outcomes by either intensifying the attack on cancer cells or offering more practical treatment options.

What evidence suggests that this trial's treatments could be effective for rectal cancer?

Research shows that FOLFIRINOX, which includes irinotecan, is promising for treating colorectal cancer. In this trial, participants in Group II will receive the FOLFIRINOX regimen. Studies have found that this combination can lead to better outcomes, such as more patients experiencing tumor reduction or remission, longer periods without cancer progression, and increased overall survival compared to treatments like FOLFIRI. Specifically, patients receiving FOLFOXIRI had better results than those receiving FOLFIRI, with manageable side effects.

Participants in Group I will receive either the FOLFOX or CAPOX regimen. For FOLFOX, research has shown a better 5-year survival rate than treatments without oxaliplatin. These findings suggest confidence in the effectiveness of FOLFIRINOX and FOLFOX for rectal cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

J. Joshua Smith, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

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

Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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 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]

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]

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 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]

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 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 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]

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]

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]

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