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

NCT06369259 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 2023-0997NCI-2024-03302
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

Brief Summary

To learn if avutometinib in combination with defactinib and cetuximab can help to control unresectable, anti-EGFR-refractory, advanced colorectal cancer.

Conditions

Advanced Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• 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

  Through study completion; an average of 1 year.

Study Arms (2)

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.

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.

Drug: Defactinib; Drug: Cetuximab; Drug: Avutometinib

Interventions

Defactinib DRUG

Given by PO

Expansion; Safety Run In

Cetuximab DRUG

Given by IV

Also known as: ERBITUX

Expansion; Safety Run In

Avutometinib DRUG

Given by PO

Expansion; Safety Run In

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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:
• anti-EGFR therapy (cetuximab or panitumumab) setting for at least 16 weeks with either CR or PR 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:

You may not qualify if:

• 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
• 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:
• \. 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.
• \. Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 170 mmHg or diastolic blood pressure ≥ 100 mm Hg, despite current therapy.
• \. The participant has active systemic bacterial or fungal infection (requiring intravenous (IV) antibiotics and/or antifungals at time of initiating study treatment).
• \. 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: i) 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. 2. Active HCV is defined as: i) 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).
• \. 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.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead

Study Sites (1)

MD Anderson Cancer Center

Houston, Texas, 77807, United States

RECRUITING

Related Links

• MD Anderson Cancer Center

MeSH Terms

Interventions

defactinib; Cetuximab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Christine Parseghian, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Christine Parseghian, MD

CONTACT

(713) 795-9280; giclinicaltrials@mdanderson.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 12, 2024
• First Posted: April 16, 2024
• Study Start: February 24, 2025
• Primary Completion (Estimated): February 1, 2029
• Study Completion (Estimated): February 1, 2029
• Last Updated: April 1, 2026

Record last verified: 2026-02

Locations

US (1)