Open-label Phase 1b Study of Ulixertinib and Cetuximab or Ulixertinib in Combination With Cetuximab and Encorafenib in Patients With Unresectable or Metastatic Colorectal Cancer Who Have Previously Received EGFR or BRAF-directed Therapy

Patients who fulfill one or more of the following criteria will not be eligible for inclusion in this trial:

1. History of grade 3 or 4 allergic reaction or intolerability attributed to cetuximab or panitumumab.

2. 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.

3. History of a Grade 3 or 4 allergic reaction or intolerability attributed to encorafenib or other BRAF inhibitor (BRAF Expansion Cohort)

1. Previously exposed to ERK1/2 inhibitor

2. Any known symptomatic brain metastasis

• Note: Patients 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.

3. Known leptomeningeal disease

4. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR).

5. 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.

6. 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,

* Symptomatic chronic heart failure (i.e. NYHA class 3 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,

* The patient 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.

7. Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 170 mmHg or diastolic blood pressure ≥ 100 mm Hg, despite current therapy;

8. The patient has active systemic bacterial or fungal infection (requiring intravenous (IV) antibiotics and/or antifungals at time of initiating study treatment).

9. Participants positive for HIV are ineligible unless they meet all of the following:

a. A stable regimen of HAART that is not contraindicated b. No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections c. A CD4 count \>250 cells/mcL, and an undetectable HIV viral load on standard PCR-based tests.

10. Active hepatitis B or hepatitis C infection

a. Active HBV is defined as any of the following:

• HBsAg(+), HBV DNA \>200 IU/mL (36 copies/mL);

* 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.

* Note: Participants who are HBsAg(-), HBcAb(+) are eligible and should be monitored/treated as per local standard of care.

b. Active HCV is defined as:

* HCV antibody positive; AND

* Presence of HCV RNA.

11. 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).

12. Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures.

13. 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.

14. 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.

15. Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study

What this study is about