Adagrasib + Cetuximab + Cemiplimab for Colorectal Cancer

Recruiting at 1 trial location

Overseen By Christine Parseghian, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Corticosteroids, Proton pump inhibitors, others

Disqualifiers: Immunodeficiency, Autoimmune disease, Brain metastases, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

31 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a combination of three drugs—adagrasib (a new potential drug), cetuximab, and cemiplimab—can control a specific type of colorectal cancer that has spread and features a KRAS G12C mutation. Participants will receive varying doses of adagrasib to identify the most effective and tolerable amount. This trial may suit individuals with this specific colorectal cancer who have already undergone at least one unsuccessful treatment or experienced issues. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new potential drug.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications at least 7 days before starting the study drugs. If you are on medications that affect heart rhythm, are processed by specific liver enzymes, or are proton pump inhibitors, you may need to switch to alternatives 10 days before the study.

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

Research shows that adagrasib, whether used alone or with cetuximab, is generally well-tolerated. Studies have found this combination effective for patients with KRAS G12C mutations in colorectal cancer. Participants who have received these treatments have tolerated them well, even after multiple prior treatments.

Cemiplimab, another drug in this trial, has already received FDA approval for other uses, such as treating certain skin cancers. This approval indicates its general safety when used correctly, although its use in this combination is still under investigation.

In summary, existing research supports the safety of using adagrasib and cetuximab together. Cemiplimab is known to be safe from its use in other conditions. This trial is exploring how these drugs work together for colorectal cancer, so their combined safety is still being evaluated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining Adagrasib with Cetuximab and Cemiplimab for colorectal cancer because these treatments offer a novel approach to tackling the disease. Unlike the standard treatments that often rely on general chemotherapy, Adagrasib specifically targets a genetic mutation known as KRAS G12C, which is found in some colorectal cancers. By pairing it with Cetuximab, which inhibits cancer cell growth, and Cemiplimab, which boosts the immune system's ability to fight cancer, this combination could provide a more targeted and potentially more effective treatment option. This innovative approach could lead to improved outcomes for patients with this challenging type of cancer.

What evidence suggests that this trial's treatments could be effective for metastatic colorectal cancer with KRAS G12C mutations?

Research has shown that the drug adagrasib, which participants in this trial may receive, may help treat colorectal cancer in patients with a specific genetic change known as KRAS G12C mutations, especially when combined with cetuximab. Studies have found that about 19% of patients respond to adagrasib, with effects lasting around 4.3 months on average. When combined with cetuximab, it might work even better. On average, patients taking adagrasib live about 14.74 months, and the cancer does not worsen for about 6.8 months. This suggests that using these drugs together could help manage colorectal cancer in patients with these specific genetic changes. ^{1 2 5 6 7}

Who Is on the Research Team?

Christine Parseghian

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced colorectal cancer that has spread, specifically those with a KRAS G12C mutation. Participants must have had at least one prior chemotherapy treatment and be able to take oral medication. They should not have serious illnesses or conditions that could affect the study's results or their ability to participate, including certain infections or autoimmune diseases.

Inclusion Criteria

My cancer cannot be removed by surgery or has spread.

Presence of measurable disease per RECIST 1.1

I have recovered from previous cancer treatment side effects, except for hair loss and nerve issues caused by oxaliplatin.

Exclusion Criteria

Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or uncontrolled infection, or other medical history, including laboratory results, which, in the investigator's opinion, would be likely to interfere with the participant's participation in the study, or with the interpretation of results

Breast-feeding or planning to breast feed during the study or within 6 months after end of treatment

Pregnancy. Women of child-bearing potential must have a negative serum or urine pregnancy test during screening

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead-In

Participants receive adagrasib at varying doses to determine the recommended dose

4-8 weeks

Expansion

Participants receive adagrasib at the recommended dose along with cetuximab and cemiplimab

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Adagrasib
• Cemiplimab
• Cetuximab

Trial Overview The trial is testing a combination of three drugs: Adagrasib, Cetuximab, and Cemiplimab in patients with metastatic colorectal cancer harboring KRAS G12C mutations. The goal is to see if this drug combo can control the disease better than current treatments.

How Is the Trial Designed?

Group I: Lead-In Experimental Treatment 3 Interventions

Participants enrolled in the Lead-In phase, the dose of adagrasib participants receive will depend on when the participant join this study. The first group of participants will receive the starting dose level of adagrasib. If intolerable side effects are seen, a second group of participants will be enrolled to receive a lower dose. One (1) of these 2 doses will be chosen as the recommended dose of adagrasib.

Group II: Expansion Experimental Treatment 3 Interventions

Participants enrolled in the Expansion phase, participants will receive adagrasib at the recommended dose that was found in the Lead-In phase.

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

Approved in United States as Krazati for:

• KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC)
• KRAS G12C-mutated locally advanced or metastatic colorectal cancer

Approved in European Union as Krazati for:

• KRAS G12C mutation non-small cell lung cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In a multicentric study of metastatic colorectal cancer patients treated with cetuximab, a high density of FcγRIIIA+ (CD16) immune cells, primarily tumor-associated neutrophils, was linked to better treatment responses, suggesting their role in enhancing antibody-dependent cellular cytotoxicity (ADCC).

The study also found that HLA-E/β2m was overexpressed in metastatic tumors and associated with poor overall survival, indicating that targeting this immune checkpoint with therapies like monalizumab could improve outcomes when combined with bispecific antibodies in RAS wild-type mCRC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Density of FcγRIIIA+ (CD16+) Tumor-Associated Neutrophils in Metastases Improves the Therapeutic Response of Cetuximab in Metastatic Colorectal Cancer Patients, Independently of the HLA-E/CD94-NKG2A Axis. Denis Musquer, M., Jouand, N., Pere, M., et al.[2021]

In patients with metastatic colorectal cancer (mCRC), Cetuximab showed a significantly higher disease control rate (DCR) in those with KRAS wild-type tumors (61%) compared to those with KRAS mutations (39%), highlighting the importance of KRAS status for treatment efficacy.

Among patients with EGFR downstream mutations, those with the FcγRIIa H/H genotype experienced a notably higher DCR (67%) when treated with Cetuximab compared to other genotypes, suggesting that FcγR polymorphisms may influence the effectiveness of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fc gamma receptor polymorphisms as predictive markers of Cetuximab efficacy in epidermal growth factor receptor downstream-mutated metastatic colorectal cancer. Rodríguez, J., Zarate, R., Bandres, E., et al.[2022]

Cetuximab, a monoclonal antibody targeting EGFR, showed a tumor growth control rate of 38% and a mean overall survival of 49.4 weeks in 24 patients with chemotherapy-refractory metastatic colorectal cancer, indicating its efficacy as a salvage therapy.

The treatment was associated with manageable side effects, the most common being skin reactions (67% reported acne), and other adverse effects included hypocalcemia (50%) and stomatitis (20%), suggesting that while cetuximab is effective, monitoring for these side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab as salvage monotherapy in chemotherapy-refractory metastatic colorectal cancer: A single-center report. Mekata, E., Endo, Y., Sonoda, H., et al.[2021]

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]

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]

A genome-wide association study (GWAS) involving 282 colorectal cancer patients treated with cetuximab found several single nucleotide polymorphisms (SNPs) that may be associated with severe skin toxicity, although none reached the strict significance threshold.

Identifying these SNPs could help predict the risk of severe skin toxicity in patients receiving EGFR inhibitors like cetuximab, potentially allowing for better management and preventive strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genome wide association study to identify predictors for severe skin toxicity in colorectal cancer patients treated with cetuximab. Baas, J., Krens, L., Bohringer, S., et al.[2020]

Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth-factor receptor (EGFR) and has been clinically approved in Europe for treating metastatic colorectal cancer and locally advanced head and neck cancer since 2004 and 2006, respectively.

The review discusses cetuximab's established role in colorectal cancer treatment, ongoing studies, and future challenges, highlighting its significance as the leading anti-EGFR monoclonal antibody in clinical evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: appraisal of a novel drug against colorectal cancer. Hildebrandt, B., le Coutre, P., Nicolaou, A., et al.[2019]

Cetuximab has demonstrated significant efficacy in treating metastatic colorectal cancer, achieving a partial response in 10.8% of patients receiving it alone and 22.9% when combined with irinotecan, based on a Phase III trial involving 329 patients.

The drug is generally well tolerated, with common side effects like acnelike rash and hypersensitivity reactions, but the lack of reliable predictive markers for patient selection remains a challenge for its clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Wong, SF.[2022]

In a study of 57 patients with KRAS wild-type metastatic colorectal cancer, those with the EGFR CA repeat genotype of 36 or more showed a trend towards longer overall survival when treated with cetuximab and FOLFIRI, suggesting a potential genetic influence on treatment outcomes.

The presence of specific FcγR haplotypes (131H and 158V alleles) was linked to a lower response rate to cetuximab, indicating that genetic variations may affect the efficacy of this treatment in mCRC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FcγR and EGFR polymorphisms as predictive markers of cetuximab efficacy in metastatic colorectal cancer. Inoue, Y., Hazama, S., Iwamoto, S., 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 924 patients with metastatic colorectal cancer, those with the CD24 rs52812045 A/A genotype experienced significantly shorter progression-free survival (PFS) and overall survival (OS) when treated with cetuximab-based regimens, indicating that this genetic variant may predict poorer outcomes.

The findings suggest that CD24 genetic variants could be used to identify patients who are more likely to benefit from cetuximab therapy, potentially guiding personalized treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polymorphisms within Immune Regulatory Pathways Predict Cetuximab Efficacy and Survival in Metastatic Colorectal Cancer Patients. Volz, NB., Hanna, DL., Stintzing, S., 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

1. 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 ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38587856/

Efficacy and Safety of Adagrasib plus Cetuximab in ... - PubMed Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e20648

Clinical outcomes and safety profile of adagrasib in KRAS ... Adagrasib showed a median overall survival (OS) of 14.74 months (95% CI: 12.06–17.42, I² = 40.4%) and progression-free survival (PFS) of 6.80 ...

4. annalsofoncology.org annalsofoncology.org/article/S0923-7534(21)04397-0/fulltext

LBA6 KRYSTAL-1: Adagrasib (MRTX849) as monotherapy ... Median DOR was 4.2 months; median PFS was 5.6 months. As of 9 July 2021, 32 pts with CRC (53% female; median age 60 years; 3 median prior lines of therapy) were ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04793958

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. annalsofoncology.org annalsofoncology.org/article/S0923-7534(22)03898-4/fulltext

LBA24 KRYSTAL-1: Updated efficacy and safety of ... Adagrasib is well tolerated as monotherapy and with cetuximab. Both showed clinical activity in heavily pretreated pts with KRASG12C-mutated CRC, with more ...

7. asco.org asco.org/abstracts-presentations/ABSTRACT425082

KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in ... Results: As of October 1, 2022, 64 pts with KRASG12C-mutated solid tumors were enrolled and 63 were treated with adagrasib (median follow-up, 16.8 months); of ...