Cetuximab in Third Line for Mutant APC, TP53 and RAS Patients With Refractory Metastatic Colorectal Cancer

Inclusion Criteria:

• Male or female subject aged ≥ 18 years.

• Histologically confirmed metastatic colorectal adenocarcinoma with mutant APC, TP53and KRAS genes as determined by the local Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory are eligible. All RAS mutations are allowed (KRAS,Neuroblastoma RAS (NRAS), HRAS). Patients with wild type KRAS, APC or TP53 areineligible.

• Progression or unwanted toxicities on at least 2 prior lines of treatment including 5-Fluorouracil, oxaliplatin and irinotecan-based regimen

• Study participants must have measurable disease by RECIST 1.1 criteria by CT or MRI.

• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.

• Study participants with treated and/or stable brain metastases are allowed

• Study participants must have anticipated life expectancy > 3 months

• Adequate organ function as defined as:

• Hematologic:

• Absolute neutrophil count (ANC) ≥ ≥1000/µL

• Platelet count ≥ 100,000/mm3

• Hemoglobin ≥ 9 g/dL

• Hepatic:

• Serum Bilirubin ≤ 2 x ULN or ≤ 3 x ULN for subjects with Gilbert'ssyndrome

• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 timesthe upper limit of normal (ULN; or 5.0 times the ULN in the setting ofliver metastases)

• Renal:

• Serum creatinine ≤1.5 times the ULN, or creatinine clearance (measured via 24-hour urine collection) ≥40 mL/minute (that is, if serum creatinine is >1.5 times the ULN, a 24-hour urine collection to calculate creatinineclearance must be performed)

• For female subjects: Negative pregnancy test or evidence of post-menopausal status.The post-menopausal status will be defined as having been amenorrheic for 12 monthswithout an alternative medical cause. The following age-specific requirements apply:

• Women < 50 years of age:

• Amenorrheic for ≥ 12 months following cessation of exogenous hormonaltreatments; and

• Luteinizing hormone and follicle-stimulating hormone levels in thepost-menopausal range for the institution; or

• Underwent surgical sterilization (bilateral oophorectomy or hysterectomy).

• Women ≥ 50 years of age:

• Amenorrheic for 12 months or more following cessation of all exogenoushormonal treatments; or

• Had radiation-induced menopause with last menses >1 year ago; or

• Had chemotherapy-induced menopause with last menses >1 year ago; or

• Underwent surgical sterilization (bilateral oophorectomy, bilateralsalpingectomy, or hysterectomy).

• Female subjects of childbearing potential and male subjects with a sexual partner ofchildbearing potential must agree to use a highly effective method of contraceptionthroughout the study and for at least 12 months after last study treatmentadministration.

• Male subjects must agree to use a condom during intercourse for the duration ofstudy therapy and for at least 12 months after last study treatment administration.

• Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any priorcancer therapy, unless considered clinically not significant by the treatinginvestigator.

• Able to provide informed consent and willing to sign an approved consent form thatconforms to federal and institutional guidelines.

Exclusion Criteria:

• Prior use of systemic anti-EGFR therapy including cetuximab or panitumumab is notallowed but prior use irinotecan, oxaliplatin, regorafenib or Trifluridine/Tipiracil (TAS-102) is allowed

• Study participants with prior or concurrent malignancy whose natural history ortreatment have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen, as determined by the investigator

• Study participants with new or progressive brain metastases (active brainmetastases) or leptomeningeal disease who need immediate central nervous system (CNS)-specific treatment during first cycle of treatment as determined by thetreating physician.

--Note: Brain metastases or cranial epidural disease adequately treated withradiotherapy and/or surgery and stable for at least 4 weeks before the first dose ofstudy treatment will be allowed on trial. Subjects must be neurologicallyasymptomatic and without corticosteroid treatment at the time of the first dose ofstudy treatment.

• Current evidence of uncontrolled, significant intercurrent illness including, butnot limited to, the following conditions:

• The patient has clinically relevant coronary artery disease or history ofmyocardial infarction in the last 12 months or high risk of uncontrolledarrhythmia or uncontrolled cardiac insufficiency.

• The patient has uncontrolled or poorly-controlled hypertension (>180 mmHgsystolic or > 130 mmHg diastolic.

• Any other condition that would, in the Investigator's judgment, contraindicatethe subject's participation in the clinical study due to safety concerns orcompliance with clinical study procedures (e.g., infection/inflammation,intestinal obstruction, unable to swallow medication, [subjects may not receivethe drug through a feeding tube], social/ psychological issues, etc.)

• Known HIV infection with a detectable viral load within 6 months of the anticipatedstart of treatment.

--Note: Subjects on effective antiretroviral therapy with an undetectable viral loadwithin 6 months of the anticipated start of treatment are eligible for this trial.

• Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination, radiographic findings, and tuberculosis (TB) testingin line with local practice), hepatitis B (known positive hepatitis B virus (HBV)surface antigen (HBsAg) result), or hepatitis C.

--Note: Subjects with a past or resolved HBV infection (defined as the presence ofhepatitis B core antibody (anti-HBc) and absence of HBsAg) are eligible. Subjectspositive for hepatitis C (HCV) antibody are eligible only if polymerase chainreaction is negative for HCV RNA.

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

• Known prior severe hypersensitivity attributed to compounds of chemical or biologiccomposition similar to those of cetuximab, or if the patient had red meatallergy/tick bite history (NCI CTCAE v5.0 Grade ≥ 3).

• Live attenuated and inactive vaccinations within 4 weeks of the first dose of studytreatment and while on trial is prohibited. Coronavirus Disease 19 (COVID-19)vaccines are allowed

• The patient is pregnant or breast-feeding.