Trial Summary
What is the purpose of this trial?
To find the recommended dose of MRTX849 that can be given in combination with cetuximab and irinotecan to patients with colorectal cancer that have a mutation (genetic change) called KRAS G12C.
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.
What data supports the idea that Adagrasib + Cetuximab + Irinotecan for Colorectal Cancer is an effective treatment?
The available research shows that combining Cetuximab with Irinotecan is effective for treating advanced colorectal cancer, especially in patients who have already tried other treatments. For example, one study found that this combination helped 20% of patients, and they lived longer without the cancer getting worse. Another study showed that adding Cetuximab to a treatment plan improved survival and response rates compared to using other drugs alone. While specific data on Adagrasib combined with these drugs isn't provided, the success of Cetuximab and Irinotecan together suggests that adding Adagrasib could be promising.12345
What safety data is available for the treatment of Adagrasib, Cetuximab, and Irinotecan in colorectal cancer?
The combination of Cetuximab and Irinotecan has been studied for safety and efficacy in patients with advanced colorectal cancer. In a study involving 65 patients, grade 3 toxicities were rare, with skin toxicity at 8%, diarrhea at 10%, nausea at 3%, vomiting at 3%, and fatigue at 8%. Another study, the MABEL study, confirmed the safety of this combination in a community practice setting. Post-marketing surveillance in Japan also aimed to verify the safety of Cetuximab in practical use. These studies suggest that the combination is generally well-tolerated, with manageable side effects.16789
Is the drug combination of Cetuximab, Irinotecan, and Adagrasib promising for colorectal cancer?
Yes, the combination of Cetuximab and Irinotecan has shown promise in treating advanced colorectal cancer, especially in patients who have already tried other treatments. Studies have shown that this combination can improve response rates and survival times. Cetuximab works by targeting cancer cells, and when combined with Irinotecan, it can be effective even when previous treatments have failed.13101112
Eligibility Criteria
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
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Exclusion Criteria
Pregnancy or planning to breast feed during the study or within 6 months after end of treatment
My brain metastases are treated and I've been stable for 2 weeks.
I have been treated with a KRASG12C and EGFR inhibitor combination.
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Treatment Details
Interventions
- Cetuximab (Monoclonal Antibodies)
- Irinotecan (Chemotherapy)
- MRTX849 (Small Molecule)
Trial OverviewThe 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.
Participant Groups
2Treatment groups
Experimental Treatment
Group I: Stage 2 ( MRTX849 and Irinotecan)Experimental Treatment3 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 Treatment3 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
M D Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
M.D. Anderson Cancer CenterLead Sponsor
Mirati TherapeuticsCollaborator
References
Cetuximab and irinotecan as third line therapy in patients with advanced colorectal cancer after failure of irinotecan, oxaliplatin and 5-fluorouracil. [2018]Cetuximab (Erbitux) in combination with irinotecan is the most promising combination in heavily pretreated patients with advanced colorectal cancer. Efficacy of this combination was confirmed in the pivotal BOND I study. The aim of the present study was to evaluate efficacy and toxicity of a combination regimen of cetuximab and irinotecan but in contrast to the BOND I study all patients had previously received 5-FU, oxaliplatin and irinotecan and all had progressed during or shortly after completion of treatment. Before January 2005 salvage therapy with cetuximab and irinotecan was not used in Denmark. The Danish government had initiated a national programme for patients with advanced cancer and according to this programme the National Board of Health may approve and finance experimental treatment. From January 2005 to September 2005, 65 consecutive patients were treated with cetuximab (weekly) and irinotecan (each 2 or 3 weeks) at three university hospitals. Median age was 57 years (23-78), and median performance status was 1 (0-3). Response rate was 20%, median TTP was 5.5 months and median OS was 10.4 months. Response and survival was significantly correlated with severity of skin toxicity. Toxicity grade 3 was rare (skin toxicity 8%, diarrhoea 10%, nausea 3%, vomiting 3%, fatigue 8%). Salvage therapy with cetuximab and irinotecan is effective in patients pretreated with irinotecan, and oxaliplatin and in a general population the results from the BOND I study was confirmed.
[The efficacy of cetuximab for metastatic colorectal cancer]. [2018]Cetuximab (Erbitux) is a targeted therapy that used to treat metastatic colorectal cancer. It is classified as a "monoclonal antibody" and "signal transduction inhibitor" by binding to epidermal growth factor receptors (EGFR). We report 6 patients who responded well to cetuximab out of 8 patients with recurrent/advanced colorectal cancer who have received the drug at our hospital since November 2008. Four patients were men and 2 were women, with their ages ranging from 48 to 77 years. The primary cancers were located in the rectum (n=1), sigmoid colon (n=4), and ascending colon (n=1). Performance status (PS) was 0-1. These patients were treated with cetuximab as second-line (n=1), third-line (n=3), fifth-line (n=1), or seventh-line (n=1) therapy. Three patients received cetuximab monotherapy, while the other 3 were given CPT-11 (150 mg/m2, every 2 weeks) as concomitant therapy. Among the 3 patients receiving combination therapy, 2 patients had already received treatment with FOLFIRI. Even in the cetuximab monotherapy group, a partial response (PR) was observed in 2 patients, demonstrating a strong cytoreductive effect. Tumor markers also showed large decreases, with the percent decrease at 1 month being 31.7% and 60.8% in the monotherapy and combination therapy groups, respectively, while it was respectively 14.1% and 29.5% at 2 months. The mean progression-free survival (PFS) time and the time to treatment failure (TTF) were respectively 3.0 months and 4.5 months in the monotherapy group versus 7.3 months and 9.3 months in the combination therapy group. Acneiform rash and paronychia occurred in all 6 patients.
Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: the CIFRA study protocol. [2020]Combination of chemotherapies (fluoropirimidines, oxaliplatin and irinotecan) with biologic drugs (bevacizumab, panitumumab, cetuximab) have improved clinical responses and survival of metastatic colorectal cancer (mCRC). However, patients' selection thorough the identification of predictive factors still represent a challange. Cetuximab (Erbitux®), a chimeric monoclonal antibody binding to the Epidermal Growth Factor Receptor (EGFR), belongs to the Immunoglobulins (Ig) grade 1 subclass able to elicite both in vitro and in vivo the Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). ADCC is the cytotoxic killing of antibody-coated target cells by immunologic effectors. The effector cells express a receptor for the Fc portion of these antibodies (FcγR); genetic polymorphisms of FcγR modify the binding affinity with the Fc of IgG1. Interestingly, the high-affinity FcγRIIIa V/V is associated with increased ADCC in vitro and in vivo. Thus, ADCC could partially account for cetuximab activity.
Cetuximab: a guide to its use in combination with FOLFIRI in the first-line treatment of metastatic colorectal cancer in the USA. [2021]Cetuximab (Erbitux(®)) is a monoclonal antibody that targets the epidermal growth factor receptor (EGFR). In the USA, the approval of cetuximab has been recently expanded to include the first-line treatment of patients with KRAS mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer (mCRC) when used in combination with FOLFIRI (irinotecan, fluorouracil, leucovorin [folinic acid]). The addition of cetuximab to first-line treatment with FOLFIRI improved progression-free survival, overall survival, and objective response rates relative to treatment with FOLFIRI alone in patients with EGFR-expressing mCRC with KRAS wild-type tumors. Therefore, cetuximab plus FOLFIRI is a useful biomarker-directed option in the first-line treatment of this patient population.
Cetuximab plus irinotecan in heavily pretreated metastatic colorectal cancer progressing on irinotecan: MABEL Study. [2022]This large, multinational study aimed to confirm in a community practice setting the efficacy and safety of cetuximab plus irinotecan in patients with epidermal growth factor-expressing metastatic colorectal cancer (mCRC) who had recently failed an irinotecan-containing regimen.
A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. [2022]Cetuximab (Erbitux(®)) was approved for the treatment of metastatic colorectal cancer in Japan in 2008. To verify information on the safety in practical use of cetuximab, we conducted post-marketing surveillance in accordance with the conditions for approval.
Reduced incidence of infusion-related reactions in metastatic colorectal cancer during treatment with cetuximab plus irinotecan with combined corticosteroid and antihistamine premedication. [2018]: The multinational MABEL study of 1147 patients with metastatic colorectal cancer (mCRC) who had recently failed an irinotecan-containing regimen confirmed in a community practice setting the efficacy and safety of cetuximab combined with irinotecan.
Cetuximab-induced skin reactions are suppressed by cigarette smoking in patients with advanced colorectal cancer. [2021]Smoking is widely accepted as the most important risk factor for cancer in the modern world. Several constituents of cigarette smoke are known to interact with drug-metabolizing enzymes, potentially affecting the outcomes of drug treatment. Cetuximab (Erbitux(®); Merck Serono) is indicated for the treatment of colorectal cancer with respect to restoring chemosensitivity to irinotecan in irinotecan-resistant patients. The purpose of this study was to determine whether cigarette smoking adversely affects the actions of cetuximab in the treatment of colorectal cancer.
Retrospective analysis of cetuximab monotherapy for patients with irinotecan-intolerant metastatic colorectal cancer. [2021]The efficacy and safety of cetuximab for irinotecan-intolerant patients has not yet been evaluated in detail.
Cetuximab Plus irinotecan in pretreated metastatic colorectal cancer progressing on irinotecan: the LABEL study. [2018]The aim of this multicenter phase II study was to demonstrate the activity of the epidermal growth factor receptor (EGFR)-targeting monoclonal antibody cetuximab combined with irinotecan in the treatment of Latin American patients with EGFR-expressing metastatic colorectal cancer (mCRC) in whom previous treatment with an irinotecan-containing regimen had failed.
Comparison of Panitumumab Plus Irinotecan and Cetuximab Plus Irinotecan for KRAS Wild-type Metastatic Colorectal Cancer. [2018]Panitumumab and cetuximab are known to be effective treatments for KRAS wild-type metastatic colorectal cancer (mCRC). However, it remains unclear which of these two biologic agents confers the greatest benefit when combined with irinotecan in patients with KRAS wild-type mCRC previously treated with fluoropyrimidine, oxaliplatin and irinotecan.
Cetuximab in the treatment of metastatic colorectal cancer: a model-based cost-effectiveness analysis. [2019]Cetuximab (Erbitux) has shown activity in patients with metastatic colorectal cancer (mCRC). To evaluate the cost-effectiveness of this drug combined with irinotecan in mCRC, a model-based cost-effectiveness analysis (CEA) was performed. Data on cetuximab obtained from Medline in December 2004 and from the 2004 ASCO-meeting were analyzed for life years gained (LYG) with regard to the use of this monoclonal antibody (MAb). Norwegian prices as of January 2005 were employed. The LYG ranged between 1.7 and 2.0 years. The median cost per patient treated was calculated to 34,256 Euro to 45,764 Euro yielding a cost per LYG in the range between 205,536 Euro and 323,040 Euro. Sensitivity analysis documented price of cetuximab and survival gain to be the major factors influencing the cost-effectiveness ratio. In conclusion, the analysis indicates cetuximab to be a promising, but very expensive antibody.