Amivantamab + Chemotherapy for Colorectal Cancer

(OrigAMI-1 Trial)

Recruiting at 94 trial locations

Overseen By Study Contact

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Janssen Research & Development, LLC

Disqualifiers: KRAS, NRAS, BRAF, EGFR, others

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

Compensation: Varies

Number of Visits: 1

Duration: Variable, up to 4 years 3 months

225 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new medicine called amivantamab on patients with advanced colorectal cancer. The medicine helps the immune system find and destroy cancer cells. Researchers want to see how well it works alone and with standard chemotherapy.

Will I have to stop taking my current medications?

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

What data supports the effectiveness of the drug combination Amivantamab + Chemotherapy for Colorectal Cancer?

Research shows that combinations of chemotherapy drugs like fluorouracil (5-FU), leucovorin, oxaliplatin, and irinotecan have improved survival rates in colorectal cancer patients. These combinations are standard treatments and have shown to be effective in both early and advanced stages of the disease. ^{1 2 3 4 5}

Is the combination of Amivantamab and chemotherapy safe for treating colorectal cancer?

The safety of chemotherapy combinations like 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin has been studied in colorectal cancer, showing they are generally safe with manageable side effects. However, specific safety data for Amivantamab combined with these chemotherapies in colorectal cancer is not provided in the available research. ^{3 6 7 8 9}

What makes the drug Amivantamab + Chemotherapy unique for colorectal cancer?

This treatment combines Amivantamab, a novel drug targeting specific cancer cell pathways, with established chemotherapy agents like Fluorouracil, Irinotecan, Leucovorin, and Oxaliplatin, which are standard in colorectal cancer treatment. The inclusion of Amivantamab, which is not typically used for colorectal cancer, may offer a new approach by potentially enhancing the effectiveness of the chemotherapy regimen. ^{1 2 10 11 12}

Research Team

Janssen Research & Development, LLC Clinical Trial

Principal Investigator

Janssen Research & Development, LLC

Eligibility Criteria

This trial is for adults with advanced colorectal cancer that can't be removed by surgery or has spread. They must have a specific performance status, agree to a tumor biopsy, and not be pregnant. People with certain genetic mutations or brain metastasis are excluded.

Inclusion Criteria

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

I have been diagnosed with a type of colon or rectal cancer that cannot be removed by surgery.

I am not pregnant, breastfeeding, or planning to become pregnant and agree to regular pregnancy tests.

Exclusion Criteria

Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (for example, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments

My cancer has a specific mutation identified through a blood test.

I have a history of cancer spreading to the lining of my brain and spinal cord.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

Up to 4 weeks

Treatment

Participants receive amivantamab monotherapy or in combination with standard-of-care chemotherapy in 28-day cycles

Variable, up to 4 years 3 months

Multiple visits per cycle, including Days -1, -2, 1, 8, 15, and 22

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 4 years 3 months

Treatment Details

Interventions

• Amivantamab
• Fluorouracil
• Irinotecan
• Leucovorin
• Oxaliplatin

Trial Overview The study tests amivantamab alone and alongside standard chemotherapy (Fluorouracil, Leucovorin, Oxaliplatin, Irinotecan) in patients with metastatic colorectal cancer. It aims to find the safest dose when combined with chemo and measure its effectiveness against tumors.

Participant Groups

Group I: Cohorts A, B, and C: Amivantamab Monotherapy Experimental Treatment 1 Intervention

Participants with left-sided colorectal cancer (CRC) in Cohort A (no prior anti-epidermal growth factor receptor \[EGFR\] therapy) and in Cohort B (post anti-EGFR therapy), and right-sided CRC in Cohort C (with or without anti-EGFR therapy), will be administered intravenous (IV) infusion of amivantamab 1050 milligrams (mg) if body weight (BW) is less than (\<) 80 kilograms (kg) or 1400 mg if BW is greater than or equal to (\>=) 80 kg, as monotherapy on Days 1 and 15 of Cycle 2 (28-days cycle).

Group II: Cohorts Ph1b-E and E: Amivantamab+5-Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) Active Control 4 Interventions

Participants who are anti-EGFR treatment naïve, have not received irinotecan-based chemotherapy in the metastatic setting, will be administered IV infusion of amivantamab along with FOLFIRI SOC chemotherapy on Days -1, -2, and 8 of Cycle 1 and Days 1 and 15 of Cycle 2 in Ph1b-E. For Cohort E, RP2CD determined in Ph1b-E will be administered.

Group III: Cohorts Ph1b-D and D: Amivantamab+5-Fluorouracil, Leucovorin, and Oxaliplatin (mFOLFOX6) Active Control 4 Interventions

Participants who are anti-EGFR treatment naïve, have not received oxaliplatin-based chemotherapy in the metastatic setting, will be administered IV infusion of amivantamab 1050 or 700 mg (dose level 0 \[DL0\]) if BW is \<80 kg, or 1400 or 1050 mg (dose de-escalation \[DL-1\]) if BW is \>= 80 kg, on Days -1, -2, 8 and 22 of Cycle 1 and along with mFOLFOX6 SOC chemotherapy on Days 1 and 15 of Cycle 1 and Days 1 and 15 of Cycle 2 (each cycle of 28 days) in Phase 1b dose confirmation Cohort (Cohort Ph1b-D). Participant in Phase 2 Cohort (Cohort D) will receive recommended Phase 2 combination dose (RP2CD) of amivantamab along with mFOLFOX6 SOC chemotherapy determined in Cohort Ph1b-D.

Amivantamab is already approved in United States, European Union for the following indications:

Approved in United States as Rybrevant for:

• Locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations
• Locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations

Approved in European Union as Rybrevant for:

• Locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations
• Locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations

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

Adjuvant therapy with 5-fluorouracil and levamisole has been established as a standard treatment for patients with resected lymph node-positive colon cancer (stage 3), significantly improving survival rates.

Preliminary results suggest that combining 5-fluorouracil with leucovorin may reduce disease relapse in advanced cases, while ongoing research aims to enhance treatment efficacy and minimize side effects through new therapies and better understanding of cancer biology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of adjuvant therapy in surgically resected colorectal carcinoma. Sinicrope, FA., Sugarman, SM.[2019]

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]

The combination of fluorouracil (5-FU)/leucovorin and irinotecan (CPT-11) has significantly improved response rates and survival times for patients with metastatic colorectal cancer, making it a recommended first-line treatment.

Ongoing randomized phase III trials in Europe are investigating the efficacy of this combination as adjuvant chemotherapy for patients with stage II or III colorectal cancer, aiming to enhance cure rates in those with resected, locally advanced, nonmetastatic disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on European adjuvant trials with irinotecan for colorectal cancer. Douillard, JY., Barbarot, V., Bennouna, J.[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]

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]

In a study involving 101 patients with metastatic colorectal cancer who had previously failed a 5-FU-based treatment, three different chemotherapy combinations showed promising tumor growth control, with overall response rates ranging from 11.4% to 21.2%.

All treatment regimens resulted in similar overall survival rates around 11 to 12 months, and while there was a notable incidence of grade 3-4 neutropenia (33-39% of patients), the safety profile was considered acceptable for these second-line therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumour activity of three second-line treatment combinations in patients with metastatic colorectal cancer after optimal 5-FU regimen failure: a randomised, multicentre phase II study. Rougier, P., Lepille, D., Bennouna, J., et al.[2020]

In a study of 570 patients with stage III colorectal cancer, three different administration types of 5-fluorouracil (5-FU) in FOLFOX treatment showed similar disease-free survival (DFS) and overall survival (OS) rates, indicating comparable efficacy.

While all treatment regimens were manageable in terms of toxicity, the modified FOLFOX-6 group experienced more grade 1-2 adverse events like thrombocytopenia and neuropathy, suggesting that while efficacy is similar, side effects may vary among the different regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The comparison of FOLFOX regimens with different doses of 5-FU for the adjuvant treatment of colorectal cancer: a multicenter study. Akdeniz, N., Kaplan, MA., Uncu, D., et al.[2021]

In a meta-analysis of 6 randomized controlled trials involving 2165 participants, the addition of bevacizumab to chemotherapy regimens (FOLFIRI or IFL) significantly improved the partial and objective response rates in patients with metastatic colorectal cancer (mCRC).

While bevacizumab reduced the risk of mortality and improved progression-free survival (PFS) and overall survival (OS), it also increased the risk of adverse events, indicating a trade-off between efficacy and safety in its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of addition of bevacizumab to FOLFIRI or irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer: A meta-analysis. Chen, K., Gong, Y., Zhang, Q., 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]

Adjuvant therapy, particularly the combination of fluorouracil (5-FU) and folinic acid (FA), is standard for improving survival and reducing recurrence in stage III colorectal cancer, but its role in stage II remains debated.

Combination therapies that include 5-FU/FA with irinotecan or oxaliplatin have shown greater effectiveness than 5-FU/FA alone in treating advanced colorectal cancer, while oral fluoropyrimidines like capecitabine and UFT/FA are similarly effective as traditional intravenous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Systemic treatment of colorectal cancers--factual standards and perspectives]. Miron, L.[2018]

Recent advancements in chemotherapy for metastatic colorectal cancer have introduced new drugs like irinotecan and oxaliplatin, which have improved survival rates compared to the traditional treatment of 5-FU alone or with leucovorin.

Oral fluoropyrimidines have been found to be as effective as the standard bolus 5-FU and leucovorin, offering a more convenient administration method, while ongoing trials are exploring the potential of novel targeting agents to further enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Controversy of treatment for advanced colorectal cancer--intermedisine]. Sato, A., Shimada, K., Taguchi, S.[2018]

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]

References

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

Role of adjuvant therapy in surgically resected colorectal carcinoma. [2019]

2. England pubmed.ncbi.nlm.nih.gov

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

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

Update on European adjuvant trials with irinotecan for colorectal cancer. [2018]

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

FOLFOXIRI plus biologics in advanced colorectal cancer. [2020]

5. 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]

6. England pubmed.ncbi.nlm.nih.gov

Antitumour activity of three second-line treatment combinations in patients with metastatic colorectal cancer after optimal 5-FU regimen failure: a randomised, multicentre phase II study. [2020]

7. Germany pubmed.ncbi.nlm.nih.gov

The comparison of FOLFOX regimens with different doses of 5-FU for the adjuvant treatment of colorectal cancer: a multicenter study. [2021]

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

Efficacy and safety of addition of bevacizumab to FOLFIRI or irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer: A meta-analysis. [2022]

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

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

10. Romania pubmed.ncbi.nlm.nih.gov

[Systemic treatment of colorectal cancers--factual standards and perspectives]. [2018]

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

[Controversy of treatment for advanced colorectal cancer--intermedisine]. [2018]

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

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