Adagrasib + Cetuximab + Irinotecan for Colorectal Cancer

Overseen By David S. Hong, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A inhibitors, Proton pump inhibitors

Disqualifiers: Brain metastases, Carcinomatous meningitis, Cardiac abnormalities, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the best dose of a new drug combination for patients with colorectal cancer that has a specific genetic mutation called KRAS G12C. The treatment involves three drugs: adagrasib (also known as MRTX849), cetuximab, and irinotecan, with researchers testing different dosing schedules. Patients diagnosed with colorectal cancer that has this KRAS mutation and who have already tried at least two unsuccessful chemotherapy treatments might be a good fit for this trial. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug combination.

Do I have to stop taking my current medications to join the trial?

The trial protocol does not specify if you must stop all current medications, but you cannot take medications with certain characteristics, like those with a known risk of Torsades de Pointes or QT prolongation, or those that are strong inducers or inhibitors of CYP3A and/or P-gp. You should discuss your current medications with the trial team to see if they need to be adjusted.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting, especially those that affect heart rhythm or interact with specific liver enzymes. You should discuss your current medications with the study team to see if any need to be changed or stopped.

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

Research is investigating the safety of combining the drugs adagrasib and irinotecan, with or without cetuximab, for treating colorectal cancer. Earlier studies showed that 19% of patients who took adagrasib alone experienced a response, with many managing to control the disease for some time. This suggests adagrasib has some efficacy on its own, but researchers are still assessing its safety when combined with other drugs like irinotecan and cetuximab.

This trial is in its early stages, focusing primarily on safety, but some information is available. Adagrasib has been tested in other contexts and is generally well-tolerated. However, combining it with irinotecan and cetuximab might produce different effects, highlighting the importance of this study.

Participants in previous studies experienced side effects, but their severity varied. Understanding how these drugs interact is crucial for finding the right treatment balance for patients. As the trial progresses, more detailed safety information will be provided. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for colorectal cancer involve chemotherapy or targeted therapies like cetuximab. But MRTX849, the study drug in this trial, works differently by specifically targeting a mutation in the KRAS gene, which is often involved in cancer cell growth. Researchers are excited about this combination with irinotecan because it could offer a more precise attack on cancer cells with potentially fewer side effects. Additionally, testing different dosing schedules might optimize how these drugs work together, offering more flexibility and possibly better results for patients.

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

Research shows that combining the drugs adagrasib (MRTX849) and irinotecan, which participants in this trial will receive, may help treat colorectal cancer with the KRAS G12C mutation. In earlier studies, adagrasib alone shrank cancer in 19% of patients and halted cancer growth in 73.8% of patients. Adding irinotecan might enhance these outcomes, as the two drugs work together to kill more cancer cells. Early evidence suggests this combination could be more effective for patients with this specific genetic change in their cancer. ^{1 2 4 6 7}

Who Is on the Research Team?

David Hong, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with colorectal cancer that has spread and have a specific genetic change called KRAS G12C. They must have tried at least two chemotherapy treatments, be in good physical condition (ECOG 0 or 1), and have normal organ function tests. Women who can get pregnant and men with partners who can get pregnant must agree to use birth control during the study.

Inclusion Criteria

I have recovered from previous cancer treatments with minimal side effects.

I agree to use birth control during the study.

Completed informed consent process, including signing of IRB-approved informed consent form

Exclusion Criteria

Pregnancy or planning to breast feed during the study or within 6 months after end of treatment

I have been treated with a KRASG12C and EGFR inhibitor combination.

I have had major stomach surgery or intestinal disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment - Stage 1

Participants receive MRTX849 and irinotecan with dose levels depending on when they joined the study, testing concurrent or staggered dosing schedules

8-12 weeks

Treatment - Stage 2

Participants receive MRTX849 and irinotecan at the recommended dose level from Stage 1, testing concurrent or staggered dosing schedules

8-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cetuximab
• Irinotecan
• MRTX849

Trial Overview The trial is testing the safety of combining a new drug, Adagrasib (MRTX849), with Cetuximab and Irinotecan in patients whose colorectal cancer has this KRAS G12C mutation. The goal is to find the best dose for this combination treatment.

How Is the Trial Designed?

Group I: Stage 2 ( MRTX849 and Irinotecan) Experimental Treatment 3 Interventions

Participants assigned to Stage 2 will receive MRTX849 and irinotecan at the dose level that was recommended during Stage 1. This study will also test 2 different dosing schedules: concurrent dosing or staggered dosing

Group II: Stage 1 ( MRTX849 and Irinotecan) Experimental Treatment 3 Interventions

Participants assigned to Stage 1, participants dose levels of MRTX849 and irinotecan will depend on when the participants joined the study. This study will also test 2 different dosing schedules: concurrent dosing or staggered dosing

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

Approved in United States as Erbitux for:

• Locally or regionally advanced squamous cell carcinoma of the head and neck
• Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer
• BRAF V600E mutation-positive metastatic colorectal cancer

Approved in European Union as Erbitux for:

• Squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Mirati Therapeutics

Collaborator

Trials

1

Recruited

20+

Published Research Related to This Trial

Cetuximab, a monoclonal antibody targeting the EGFR, has been approved for first-line treatment of KRAS mutation-negative metastatic colorectal cancer (mCRC) in combination with FOLFIRI, showing significant improvements in progression-free survival and overall survival.

The combination of cetuximab with FOLFIRI also resulted in higher objective response rates compared to FOLFIRI alone, making it a valuable treatment option for patients with EGFR-expressing, KRAS wild-type mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: a guide to its use in combination with FOLFIRI in the first-line treatment of metastatic colorectal cancer in the USA. Lyseng-Williamson, KA.[2021]

In a study involving 1,147 patients with metastatic colorectal cancer (mCRC), the combination of cetuximab and irinotecan achieved a 12-week progression-free survival (PFS) rate of 61% and a median overall survival of 9.2 months, confirming its efficacy in a community practice setting.

The treatment was generally well tolerated, with the most common severe side effects being diarrhea (19%) and neutropenia (10%), while the incidence of severe infusion-related reactions was notably low at 1% when patients received premedication with antihistamines and corticosteroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab plus irinotecan in heavily pretreated metastatic colorectal cancer progressing on irinotecan: MABEL Study. Wilke, H., Glynne-Jones, R., Thaler, J., et al.[2022]

In a study involving 65 patients with advanced colorectal cancer who had previously been treated with multiple therapies, the combination of cetuximab and irinotecan showed a response rate of 20% and a median overall survival of 10.4 months, confirming the efficacy of this treatment regimen.

The treatment was associated with low rates of severe toxicity, with only 8% experiencing grade 3 skin toxicity, indicating that cetuximab and irinotecan can be a safe option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab and irinotecan as third line therapy in patients with advanced colorectal cancer after failure of irinotecan, oxaliplatin and 5-fluorouracil. Pfeiffer, P., Nielsen, D., Yilmaz, M., et al.[2018]

In a multicenter phase II study involving 79 Latin American patients with metastatic colorectal cancer (mCRC) who had previously failed irinotecan treatment, the combination of cetuximab and irinotecan showed an overall response rate of 27% and a disease control rate of 56%.

The treatment was found to be tolerable, with a median overall survival of 9.2 months and a safety profile consistent with previous studies, although 57% of patients experienced grade 3/4 adverse events, primarily skin-related issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab Plus irinotecan in pretreated metastatic colorectal cancer progressing on irinotecan: the LABEL study. Buzaid, AC., Mathias, Cde C., Perazzo, F., et al.[2018]

Cetuximab, when combined with irinotecan, can provide patients with metastatic colorectal cancer an additional 1.7 to 2.0 years of life, indicating its efficacy as a treatment option.

However, the cost-effectiveness analysis revealed that the treatment is quite expensive, with costs per life year gained ranging from 205,536 to 323,040 Euros, highlighting the financial considerations of using cetuximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab in the treatment of metastatic colorectal cancer: a model-based cost-effectiveness analysis. Norum, J.[2019]

Cetuximab monotherapy is a feasible treatment option for patients with metastatic colorectal cancer (MCRC) who are intolerant to irinotecan, with no severe adverse events reported in the study of 22 patients.

The efficacy of cetuximab was modest, with a response rate of only 9.1% and median overall survival of 3.5 months, indicating a need for more effective therapies for this patient group, especially since most had wild-type KRAS tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective analysis of cetuximab monotherapy for patients with irinotecan-intolerant metastatic colorectal cancer. Mizota, A., Shitara, K., Kondo, C., et al.[2021]

In a study of 8 patients with recurrent/advanced colorectal cancer, 6 patients showed a positive response to cetuximab, a targeted therapy that binds to epidermal growth factor receptors (EGFR), indicating its efficacy even in later lines of treatment.

Patients receiving cetuximab in combination with CPT-11 had significantly better progression-free survival (7.3 months) and time to treatment failure (9.3 months) compared to those on cetuximab monotherapy (3.0 months and 4.5 months, respectively), highlighting the potential benefits of combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy of cetuximab for metastatic colorectal cancer]. Katsumoto, Y., Aritake, N., Endoh, A.[2018]

In a study of 1147 patients with metastatic colorectal cancer, using a combination of antihistamines and corticosteroids as premedication significantly reduced the incidence of infusion-related reactions (IRRs) from 25.6% to 9.6%.

Despite the reduction in IRRs with combined premedication, there was no significant difference in progression-free survival (PFS) or overall survival (OS) between patients receiving antihistamines with or without corticosteroids, indicating that while safety may improve, efficacy remains similar.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced incidence of infusion-related reactions in metastatic colorectal cancer during treatment with cetuximab plus irinotecan with combined corticosteroid and antihistamine premedication. Siena, S., Glynne-Jones, R., Adenis, A., et al.[2018]

In a post-marketing surveillance study involving 2126 patients with metastatic colorectal cancer, cetuximab was found to be well tolerated, with a median treatment duration of 15.3 weeks and a high incidence of adverse reactions at 89.6%.

The most common adverse reactions included skin disorders (83.7%) and infusion reactions (5.7%), primarily occurring during the first administration, indicating that while side effects are common, they align with previous reports and suggest that cetuximab is clinically useful in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. Ishiguro, M., Watanabe, T., Yamaguchi, K., et al.[2022]

In a study of 56 colorectal cancer patients treated with cetuximab, smokers experienced fewer skin reactions compared to non-smokers, suggesting that smoking may alter the drug's effectiveness.

However, smokers also reported higher rates of anorexia, indicating that while smoking might reduce certain side effects, it could negatively impact overall treatment outcomes, highlighting the importance of quitting smoking during cetuximab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab-induced skin reactions are suppressed by cigarette smoking in patients with advanced colorectal cancer. Kajizono, M., Saito, M., Maeda, M., et al.[2021]

The CIFRA study is investigating the effectiveness of cetuximab combined with irinotecan and fluorouracil in patients with metastatic colorectal cancer who have a specific genetic profile (FcγRIIIa V/V), which may enhance the drug's action through a mechanism called Antibody-Dependent Cell-mediated Cytotoxicity (ADCC).

This phase II trial aims to determine if patients with the FcγRIIIa V/V genotype have a higher response rate to cetuximab, potentially improving treatment outcomes, while also assessing safety and survival metrics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: the CIFRA study protocol. Ottaiano, A., Scala, S., Normanno, N., et al.[2020]

In a study of 139 patients with KRAS wild-type metastatic colorectal cancer, panitumumab combined with irinotecan showed a higher response rate (34%) compared to cetuximab with irinotecan (20%).

Both treatments were well-tolerated, with panitumumab demonstrating similar overall survival (13.6 months) compared to cetuximab (11.2 months), indicating that panitumumab is an effective option for patients previously treated with other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Panitumumab Plus Irinotecan and Cetuximab Plus Irinotecan for KRAS Wild-type Metastatic Colorectal Cancer. Yamaguchi, T., Iwasa, S., Nagashima, K., et al.[2018]

Citations

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Study Details | NCT05722327 | Phase I Trial of Adagrasib ... Phase I Trial of Adagrasib (MRTX849) in Combination With Cetuximab and Irinotecan in Patients With Colorectal Cancer ... MRTX849 exposure and patient outcomes ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-01157

Adagrasib (MRTX849) Plus Cetuximab and Irinotecan for ... Giving adagrasib with cetuximab and irinotecan may kill more tumor cells in patients with unresectable or metastatic, KRAS positive colorectal cancer.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12323406/

Adagrasib in the treatment of colorectal cancer - PMC At a median follow-up of 16.1 months, 42 patients received adagrasib monotherapy, and results showed an ORR of 19% with a disease control rate of 73.8%, PFS of ...

4. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05722327/phase-i-trial-of-adagrasib-mrtx849-in-combination-with-cetuximab-and-irinotecan-in-patients-with-colorectal-cancer

Phase I Trial of Adagrasib (MRTX849) in Combination With ... To find the recommended dose of MRTX849 that can be given in combination with cetuximab and irinotecan to patients with colorectal cancer.

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NCT04793958 | Phase 3 Study of MRTX849 With ... An open-label, randomized Phase 3 clinical trial comparing the efficacy of MRTX849 administered in combination with cetuximab versus chemotherapy in the second ...

6. nejm.org nejm.org/doi/full/10.1056/NEJMoa2212419

Adagrasib with or without Cetuximab in Colorectal Cancer ... In our trial, adagrasib monotherapy resulted in a response of 19% and a median response duration of 4.3 months. In addition, adagrasib ...

7. annalsofoncology.org annalsofoncology.org/article/S0923-7534(21)01315-6/fulltext

P-71 KRYSTAL-10: A randomized phase 3 study ... A randomized phase 3 study of adagrasib (MRTX849) in combination with cetuximab vs chemotherapy in patients with previously treated advanced colorectal cancer ...