Advanced Colorectal CancerPhase 2NCT06369259
Open-label Phase 2 Study of Avutometinib (RAF/MEK Clamp) in Combination With Defactinib (FAK Inhibitor) and Cetuximab in Patients With Unresectable, Anti-EGFR-Refractory Advanced Colorectal Cancer
A Phase 2 study testing Defactinib, Cetuximab and Avutometinib in people with Advanced Colorectal Cancer, run by M.D. Anderson Cancer Center at 1 site in United States.
Trial summary
To learn if avutometinib in combination with defactinib and cetuximab can help to control unresectable, anti-EGFR-refractory, advanced colorectal cancer. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Colorectal Cancer
- What is being tested?
- Defactinib, Cetuximab and Avutometinib
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 33 participants
- Where
- 1 siteUnited States
- Study dates
- 24 Feb 2025to 1 Feb 2029
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Provision of signed Informed Consent prior to any screening procedures being performed.
- Non-English speaking participants will be eligible for participation with involvement of the MD Anderson Language Assistance department in the informed consent process (per MD Anderson SOP 04_Informed Consent Process).
- Individuals lacking the ability, based on reasonable medical judgment, to understand and appreciate the nature and consequences of participation in this study will not be eligible for participation.
- Age ≥ 18 years at the time of informed consent.
- Histologically (or cytologically) confirmed diagnosis of adenocarcinoma of the colon or rectum, with clinical confirmation of unresectable and/or metastatic disease that is measurable according to RECIST1.1 criteria.
- Mutation status at the time of colorectal cancer diagnosis performed on tumor tissue or circulating tumor
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- DNA (prior to any anti-EGFR directed therapy):
- KRAS, NRAS, EGFR ectodomain, BRAF V600E wild-type status
- Prior treatment with at least one systemic chemotherapy regimen for mCRC, or recurrence/progression with development of unresectable or metastatic disease within 6 months of adjuvant chemotherapy for resected colorectal cancer.
- Prior treatment with:
- o anti-EGFR therapy (cetuximab or panitumumab) setting for a minimum of 16 weeks with at least SD as best response, prior to progression
- ECOG performance status ≤ 1.
- Participants who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to day 1 of study. A washout period of at least 21 days is required between last chemotherapy dose and day 1 of study (provided the patient did not receive radiotherapy).
- Participants who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 7 days is required between end of radiotherapy and day 1 of study.
- Adequate hematologic status: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; Hemoglobin (Hgb) ≥ 9 g/dL with or without transfusions; Platelets (PLT) ≥ 100 x 109/L without transfusions
- Adequate liver function:
- ALT and AST ≤3 × ULN, or ≤5 × ULN in the presence of liver metastases
- Total bilirubin ≤ 1.5 × ULN and < 1.5 mg/dL
- Note: Participants with hyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled following discussion and agreement with the principal investigator. • Adequate renal function: Serum Creatinine ≤ 1.5 x ULN, or calculated creatinine clearance (measured via 24-hour urine collection) ≥ 40 mL/min at screening • QTc interval ≤ 480 ms (preferably the mean from triplicate ECGs) • Able to take oral medications.
- Because the teratogenicity of cetuximab is not known, the participant, if sexually active, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods). Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrollment
- Willing and able to participate in the trial and comply with all trial requirements.
- Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational agent may be included after consultation with the medical monitor.
Who cannot join
- History of grade 3 or 4 allergic reaction or intolerability attributed to cetuximab or panitumumab.
- History of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab, or if the patient had red meat allergy/tick bite history.
- Previously exposed to ERK1/2, MEK or BRAF inhibitor
- Any known symptomatic brain metastasis
- Note: Participants previously treated or untreated for this condition who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Known brain metastases must be stable for ≥ 4 weeks, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT]) demonstrating no current evidence of progressive brain metastases at screening.
- Known leptomeningeal disease
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- A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
- Previous or concurrent malignancy within 3 years of study entry, with the following exceptions: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy; other solid tumors treated curatively without evidence of recurrence for at least 3 years prior to study entry.
- Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
- 1. History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) <12 months prior to screening, 2. Symptomatic chronic heart failure (i.e., Grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality <6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia, 3. The participant has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
- 4. Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 170 mmHg or diastolic blood pressure ≥ 100 mm Hg, despite current therapy.
- 10. The participant has active systemic bacterial or fungal infection (requiring intravenous (IV) antibiotics and/or antifungals at time of initiating study treatment).
- 11. Know Human Immunodeficiency Virus (HIV) that is active and or/requires therapy 12. Active hepatitis B or hepatitis C infection
- Active HBV is defined as any of the following:
- HBsAg(+), HBV DNA >200 IU/mL (36 copies/mL) ii) HBsAg(+), HBV DNA ≤200 IU/mL and persistent or intermittent elevation of ALT/AST and/or liver biopsy showing chronic hepatitis with moderate or severe necroinflammation. iii) Note: Participants who are HBsAg(-), HBcAb(+) are eligible and should be monitored/treated as per local standard of care.
- Active HCV is defined as:
- HCV antibody positive; AND ii) Presence of HCV RNA.
- 13. Impaired gastrointestinal function or disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption).
- 14. Any other condition that would, in the Investigator's judgment, contraindicate the participant's participation in the clinical study due to safety concerns or compliance with clinical study procedures.
- 15. Major surgery ≤ 6 weeks prior to starting study drug or failure to recover from side effects of such procedure at the discretion of the treating investigator.
- 16. Systemic anti-cancer therapy within 4 weeks of the first dose of study intervention or within 5 half-lives of the previous drug, whichever is longer.
- 17. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
- 18. History of Rhabdomyolysis 19. Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the participant information, give informed consent, comply with the study protocol or complete the study.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
MD Anderson Cancer Center
Houston, Texas, 77807
Christine Parseghian, MD, giclinicaltrials@mdanderson.org
Christine Parseghian, MD
About this study
To learn if avutometinib in combination with defactinib and cetuximab can help to control unresectable, anti-EGFR-refractory, advanced colorectal cancer.
Read the detailed description
The primary objective is to assess the antitumor activity of the treatment combinations based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Secondary Objectives:
- Assess impact of treatment combinations on survival
- Characterize the safety profile of the treatment combinations (DLTs)
- Evaluate the pharmacodynamics of the avutometinib combination with defactinib plus cetuximab.
- Evaluate for pERK and Ki67 inhibition
Exploratory Objectives
- Assess blood- and tissue-based predictive biomarkers of activity upon treatment with cetuximab plus avutometinib plus defactinib
- Demonstrate feasibility of establishing patient-derived xenograft (PDX) models in matched patients with cetuximab-refractory mCRC to evaluate for biomarkers of response and mechanisms of resistance.
- Explore mechanisms of resistance to cetuximab plus avutometinib and defactinib
- Conditions
- Advanced Colorectal Cancer
- Being tested
- Defactinib, Cetuximab, Avutometinib
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DefactinibDrug
Given by PO
CetuximabDrug
Also called ERBITUX
Given by IV
AvutometinibDrug
Given by PO
| Study group | Role | What they receive |
|---|---|---|
| Safety Run In | Experimental | If you are enrolled in the Safety Run In group, the dose of avutometinib you receive will depend on when you join this study. Up to 3 dose levels of avutometinib will be tested, and between 3-6 participants will be enrolled at each dose level.
The first group of participants will receive the planned starting dose level of avutometinib. Then, if no intolerable side effects are seen, a second group of participants will be enrolled to receive a higher dose. If intolerable side effects are seen, the second group will receive a lower dose. One of these 3 doses will be selected as the recommended dose of avutometinib in combination with cetuximab and defactinib. Receives: Drug: Defactinib; Drug: Cetuximab; Drug: Avutometinib |
| Expansion | Experimental | If you are enrolled in the Expansion, you will receive avutometinib at the recommended dose that was found in Safety Run In. Receives: Drug: Defactinib; Drug: Cetuximab; Drug: Avutometinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety and adverse events (AEs)
Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0
Measured: Through study completion; an average of 1 year.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Apr 2024
- Study start24 Feb 2025
- Primary completion1 Feb 2029 (estimated)
- Study completion1 Feb 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Advanced Colorectal CancerStudies of the same condition, open and under way.
- More trials run by M.D. Anderson Cancer CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 33 participants (estimated)
Sponsor and investigators
- Lead sponsor
- M.D. Anderson Cancer Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Christine Parseghian, MD, Principal investigator, M.D. Anderson Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06369259
- Sponsor's protocol ID
- 2023-0997
- Other IDs
- NCI-2024-03302
- Status last verified
- Sep 2026
- First submitted
- 12 Apr 2024
- Last updated
- 25 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 25 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Open-label Phase 2 Study of Avutometinib (RAF/MEK Clamp) in Combination With Defactinib (FAK Inhibitor) and Cetuximab in Patients With Unresectable, Anti-EGFR-Refractory Advanced Colorectal Cancer
- ClinicalTrials.gov ID
- NCT06369259
- Acronym / sponsor ID
- 2023-0997
- Conditions
- Advanced Colorectal Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 33 participants (estimated)
- Lead sponsor
- M.D. Anderson Cancer CenterUniversity, hospital or other
- Study start
- 24 Feb 2025 (actual)
- Primary completion
- 1 Feb 2029 (estimated)
- Study completion
- 1 Feb 2029 (estimated)
- First posted
- 16 Apr 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
To learn if avutometinib in combination with defactinib and cetuximab can help to control unresectable, anti-EGFR-refractory, advanced colorectal cancer.
Detailed description
The primary objective is to assess the antitumor activity of the treatment combinations based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Secondary Objectives:
- Assess impact of treatment combinations on survival
- Characterize the safety profile of the treatment combinations (DLTs)
- Evaluate the pharmacodynamics of the avutometinib combination with defactinib plus cetuximab.
- Evaluate for pERK and Ki67 inhibition
Exploratory Objectives
- Assess blood- and tissue-based predictive biomarkers of activity upon treatment with cetuximab plus avutometinib plus defactinib
- Demonstrate feasibility of establishing patient-derived xenograft (PDX) models in matched patients with cetuximab-refractory mCRC to evaluate for biomarkers of response and mechanisms of resistance.
- Explore mechanisms of resistance to cetuximab plus avutometinib and defactinib
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Safety Run In | Experimental | Drug: Defactinib, Drug: Cetuximab, Drug: AvutometinibIf you are enrolled in the Safety Run In group, the dose of avutometinib you receive will depend on when you join this study. Up to 3 dose levels of avutometinib will be tested, and between 3-6 participants will be enrolled at each dose level. The first group of participants will receive the planned starting dose level of avutometinib. Then, if no intolerable side effects are seen, a second group of participants will be enrolled to receive a higher dose. If intolerable side effects are seen, the second group will receive a lower dose. One of these 3 doses will be selected as the recommended dose of avutometinib in combination with cetuximab and defactinib. |
| Expansion | Experimental | Drug: Defactinib, Drug: Cetuximab, Drug: AvutometinibIf you are enrolled in the Expansion, you will receive avutometinib at the recommended dose that was found in Safety Run In. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (22 listed)
- Provision of signed Informed Consent prior to any screening procedures being performed.
- Age ≥ 18 years at the time of informed consent.
- Histologically (or cytologically) confirmed diagnosis of adenocarcinoma of the colon or rectum, with clinical confirmation of unresectable and/or metastatic disease that is measurable according to RECIST1.1 criteria.
- Mutation status at the time of colorectal cancer diagnosis performed on tumor tissue or circulating tumor
- KRAS, NRAS, EGFR ectodomain, BRAF V600E wild-type status
Key exclusion criteria (23 listed)
- History of grade 3 or 4 allergic reaction or intolerability attributed to cetuximab or panitumumab.
- History of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab, or if the patient had red meat allergy/tick bite history.
- Previously exposed to ERK1/2, MEK or BRAF inhibitor
- Any known symptomatic brain metastasis
- Note: Participants previously treated or untreated for this condition who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Known brain metastases must be stable for ≥ 4 weeks, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT]) demonstrating no current evidence of progressive brain metastases at screening.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DefactinibGiven by PO | Drug | Expansion, Safety Run In |
| CetuximabAlso: ERBITUXGiven by IV | Drug | Expansion, Safety Run In |
| AvutometinibGiven by PO | Drug | Expansion, Safety Run In |
Primary outcome
Safety and adverse events (AEs)
Time frame: Through study completion; an average of 1 year.
Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Sep 2026.
- MD Anderson Cancer CenterLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Christine Parseghian, MD principal investigator
M.D. Anderson Cancer Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Defactinib, Cetuximab and Avutometinib in people with Advanced Colorectal Cancer, run by M.D. Anderson Cancer Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 25 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Christine Parseghian, MD ((713) 795-9280, giclinicaltrials@mdanderson.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety and adverse events (AEs) (time frame: Through study completion; an average of 1 year.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Sep 2026.