Amivantamab + FOLFIRI for Colorectal Cancer

(OrigAMI-3 Trial)

Recruiting at 170 trial locations

Overseen By Study Contact

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Janssen Research & Development, LLC

Must not be taking: Irinotecan, EGFR agents, MET agents

Disqualifiers: ILD, Second malignancy, HER2-positive, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years 1 month

700 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to compare how long the participants are disease-free (progression-free survival) and and the length of time until a participant dies (overall survival), when treated with amivantamab and chemotherapy with 5-fluorouracil, leucovorin calcium (folinic acid) or levoleucovorin, and irinotecan hydrochloride (FOLFIRI) versus either cetuximab or bevacizumab and FOLFIRI given to participants with Kirsten rat sarcoma viral oncogene/ neuroblastoma RAS viral oncogene homolog (KRAS/ NRAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) wild-type recurrent, unresectable or metastatic colorectal cancer who have previously received chemotherapy.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug combination Amivantamab and Cetuximab for colorectal cancer?

Research shows that adding cetuximab to the FOLFIRI regimen (a combination of chemotherapy drugs) significantly improves survival and response rates in patients with a specific type of colorectal cancer. This suggests that cetuximab, when combined with other treatments, can be effective in managing colorectal cancer. ^{1 2 3 4 5}

Is the combination of Amivantamab and FOLFIRI safe for humans?

The safety of cetuximab, a drug similar to Amivantamab, has been studied in combination with various chemotherapy regimens like FOLFOX and CAPIRI for colorectal cancer. These studies generally found that the combination was safe, but patients experienced some side effects like skin reactions and diarrhea. ^{2 6 7 8 9}

How is the drug Amivantamab + FOLFIRI unique for treating colorectal cancer?

The combination of Amivantamab with FOLFIRI for colorectal cancer is unique because it includes Amivantamab, a newer drug that targets specific proteins involved in cancer growth, potentially offering a novel mechanism of action compared to traditional chemotherapy regimens. This approach may provide an alternative for patients with specific genetic profiles, such as those with KRAS wild-type tumors, where other treatments like cetuximab have shown effectiveness. ^{3 5 10 11 12}

Research Team

Janssen Research & Development, LLC Clinical Trial

Principal Investigator

Janssen Research & Development, LLC

Eligibility Criteria

This trial is for people with a specific type of colorectal cancer that hasn't changed certain genes called KRAS/NRAS and BRAF. Participants should have already tried chemotherapy but still have cancer that can't be removed by surgery or has spread.

Inclusion Criteria

My colon or rectum cancer has returned, can't be removed, or has spread.

My tumor is KRAS, NRAS, and BRAF wild-type.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

My cancer is MSI-H/dMMR and I haven't had immunotherapy.

I have been treated with drugs targeting EGFR or MET, or have received irinotecan.

I have or might have a lung condition not caused by an infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Amivantamab + FOLFIRI or Cetuximab/Bevacizumab + FOLFIRI in 28-day cycles until disease progression or other discontinuation criteria are met

Up to 2 years 1 month

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 4 years 4 months

Treatment Details

Interventions

• Amivantamab
• Cetuximab

Trial Overview The study tests if Amivantamab combined with FOLFIRI chemotherapy works better than the usual treatment, either Cetuximab or Bevacizumab with FOLFIRI, in extending the time patients live without their disease getting worse and overall survival time.

Participant Groups

Group I: Arm A: Amivantamab + FOLFIRI Experimental Treatment 4 Interventions

Participants will receive amivantamab along with FOLFIRI (consisting of 5-fluorouracil, leucovorin calcium \[folinic acid\] or levoleucovorin, and irinotecan) as a chemotherapy regimen for 28-days treatment cycles and will continue to receive the treatment until radiographic disease progression or other discontinuation criteria are met.

Group II: Arm B: Cetuximab or Bevacizumab + FOLFIRI Active Control 5 Interventions

Participants will receive either cetuximab or bevacizumab along with FOLFIRI as a chemotherapy regimen for 28-days treatment cycles and will continue to receive the treatment until radiographic disease progression or other discontinuation criteria are met.

Who Is Running the Clinical Trial?

Janssen Research & Development, LLC

Lead Sponsor

Trials

1,022

Recruited

6,408,000+

Giacomo Salvadore

Janssen Research & Development, LLC

Chief Medical Officer since 2023

MD from the University of Rome, Tor Vergata

Ricardo Attar

Janssen Research & Development, LLC

Chief Executive Officer since 2008

PhD in Molecular Biology from the University of Buenos Aires

Findings from Research

In the phase III CRYSTAL study, adding cetuximab to the FOLFIRI regimen significantly improved overall survival and progression-free survival in patients with KRAS exon 2 wild-type metastatic colorectal cancer, highlighting its efficacy in this specific patient group.

However, patients with other RAS mutations did not experience any benefit from cetuximab, indicating the importance of comprehensive RAS mutation testing to tailor treatment and maximize effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. Van Cutsem, E., Lenz, HJ., Köhne, CH., et al.[2022]

In a study of 60 metastatic colorectal cancer patients, cetuximab combined with FOLFOX showed a clinical benefit of 75% in terms of partial response and stable disease, indicating its effectiveness as a second- and third-line therapy.

The treatment was well-tolerated, with most adverse events being mild (grade 1 and 2) and primarily related to hematologic and gastrointestinal issues, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of cetuximab plus FOLFOX in second-line and third-line therapy in metastatic colorectal cancer. Ozaslan, E., Topaloglu, US., Inanc, M., et al.[2020]

The combination of cetuximab with the FOLFOXIRI regimen (irinotecan, oxaliplatin, 5-FU, and folinic acid) is feasible and has an acceptable safety profile, with a recommended dose of 125 mg/m2 irinotecan established for further trials.

This treatment showed a promising overall response rate of 75% and a median progression-free survival of 16 months, indicating significant efficacy in patients with metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose escalating study of cetuximab and 5-FU/folinic acid (FA)/oxaliplatin/irinotecan (FOLFOXIRI) in first line therapy of patients with metastatic colorectal cancer. Folprecht, G., Hamann, S., Schütte, K., et al.[2022]

Capecitabine, an oral chemotherapy drug, is at least as effective as traditional 5-FU plus leucovorin regimens for metastatic colorectal cancer (mCRC) and has a favorable safety profile.

Combining cetuximab with chemotherapy (like FOLFIRI) has been shown to improve progression-free survival and response rates in mCRC patients, with a recent phase III trial confirming these benefits over chemotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab plus XELIRI or XELOX for first-line therapy of metastatic colorectal cancer. Moosmann, N., Heinemann, V.[2018]

In patients with metastatic colorectal cancer (mCRC) who have KRAS wild-type tumors, adding cetuximab to the FOLFIRI treatment regimen significantly improves overall survival (23.5 months vs. 20.0 months) and progression-free survival (9.9 months vs. 8.4 months).

The study confirmed that KRAS mutation status is a crucial predictive biomarker for the effectiveness of cetuximab, with 37% of tumors showing mutations, while BRAF mutations indicate a poorer prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. Van Cutsem, E., Köhne, CH., Láng, I., et al.[2022]

In a phase II trial involving 82 patients with advanced colorectal cancer, the combination of cetuximab and FOLFOX6 showed an overall response rate of 44.8%, indicating its efficacy as a first-line treatment.

Patients who developed skin toxicity while on the treatment had significantly longer median survival times (21.7 months) compared to those who did not experience this side effect, suggesting a potential correlation between skin reactions and treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of FOLFOX6 and cetuximab in the first-line treatment of patients with metastatic colorectal cancer. Boccia, RV., Cosgriff, TM., Headley, DL., et al.[2016]

In a randomized phase II study involving 83 patients with irinotecan-refractory metastatic colorectal cancer, the combination of cetuximab and bevacizumab with irinotecan (CBI) showed a longer time to tumor progression (7.3 months) and a higher response rate (37%) compared to cetuximab and bevacizumab alone (CB), which had a time to progression of 4.9 months and a response rate of 20%.

The concurrent administration of cetuximab and bevacizumab was found to be safe, with toxicity profiles similar to those expected from the individual agents, suggesting that this combination therapy is a feasible option for patients who have not previously been treated with these drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. Saltz, LB., Lenz, HJ., Kindler, HL., et al.[2022]

In a pilot study of 30 patients with metastatic colorectal cancer, the combination of FOLFOXIRI and cetuximab achieved a high overall response rate of 70%, with 13.3% of patients showing complete responses and 56.7% showing partial responses.

The treatment demonstrated significant efficacy, with a median survival time of 30.3 months and secondary R0 resection performed in 37% of patients, although it was associated with notable side effects, including grade 3 or 4 diarrhea in 53% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A triplet combination with irinotecan (CPT-11), oxaliplatin (LOHP), continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in KRAS wt, metastatic colorectal cancer: a pilot phase II trial. Saridaki, Z., Androulakis, N., Vardakis, N., et al.[2022]

The AIO KRK-0104 trial showed that adding cetuximab to either CAPIRI or CAPOX is effective for first-line treatment of metastatic colorectal cancer, with objective response rates (ORR) of 46% and 48%, respectively, in 177 patients.

Both treatment regimens were found to be safe with manageable toxicity, and the effectiveness did not significantly differ based on KRAS gene mutation status, although patients with KRAS wild-type showed a trend toward longer overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab plus capecitabine and irinotecan compared with cetuximab plus capecitabine and oxaliplatin as first-line treatment for patients with metastatic colorectal cancer: AIO KRK-0104--a randomized trial of the German AIO CRC study group. Moosmann, N., von Weikersthal, LF., Vehling-Kaiser, U., et al.[2020]

The combination of FOLFOXIRI and bevacizumab demonstrated a promising progression-free survival (PFS) rate of 74% at 10 months in patients with unresectable metastatic colorectal cancer, based on a phase 2 study involving 57 patients.

The treatment was found to be safe, with no unexpected adverse events reported, although common serious side effects included neutropenia and hypertension, indicating that while effective, careful monitoring for these side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Masi, G., Loupakis, F., Salvatore, L., et al.[2022]

Infusional 5-fluorouracil (5-FU) is more effective and safer than bolus 5-FU in treating metastatic colorectal cancer (mCRC), while capecitabine offers similar efficacy with improved safety compared to 5-FU when combined with oxaliplatin.

The combination of chemotherapy with biologic agents like bevacizumab and cetuximab enhances treatment efficacy, and the approach to mCRC is shifting towards individualized therapy based on factors like KRAS mutational status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Seeing the forest through the trees: a systematic review of the safety and efficacy of combination chemotherapies used in the treatment of metastatic colorectal cancer. Bekaii-Saab, T., Wu, C.[2018]

The combination of cetuximab with oxaliplatin-based chemotherapy (FOLFOX) is established as a standard first-line treatment for metastatic colorectal cancer in patients with RAS wild type, showing both safety and efficacy.

Clinical trials, including the updated Calgb/Swog 80405 study, indicate that FOLFOX combined with cetuximab is more effective than chemotherapy with bevacizumab, particularly in left-sided tumors, which represent 70-80% of patients in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cetuximab in association with an oxaliplatin-based chemotherapy as first-line treatment of metastatic colorectal cancer.] Petrelli, F., Ghidini, A., Zaniboni, A.[2018]

References

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

Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. [2022]

2. Cyprus pubmed.ncbi.nlm.nih.gov

Efficacy and safety of cetuximab plus FOLFOX in second-line and third-line therapy in metastatic colorectal cancer. [2020]

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

Dose escalating study of cetuximab and 5-FU/folinic acid (FA)/oxaliplatin/irinotecan (FOLFOXIRI) in first line therapy of patients with metastatic colorectal cancer. [2022]

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

Cetuximab plus XELIRI or XELOX for first-line therapy of metastatic colorectal cancer. [2018]

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

Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. [2022]

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

A phase II trial of FOLFOX6 and cetuximab in the first-line treatment of patients with metastatic colorectal cancer. [2016]

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

Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. [2022]

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

A triplet combination with irinotecan (CPT-11), oxaliplatin (LOHP), continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in KRAS wt, metastatic colorectal cancer: a pilot phase II trial. [2022]

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

Cetuximab plus capecitabine and irinotecan compared with cetuximab plus capecitabine and oxaliplatin as first-line treatment for patients with metastatic colorectal cancer: AIO KRK-0104--a randomized trial of the German AIO CRC study group. [2020]

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

Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. [2022]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Seeing the forest through the trees: a systematic review of the safety and efficacy of combination chemotherapies used in the treatment of metastatic colorectal cancer. [2018]

12. Italy pubmed.ncbi.nlm.nih.gov

[Cetuximab in association with an oxaliplatin-based chemotherapy as first-line treatment of metastatic colorectal cancer.] [2018]