Panitumumab With or Without Trametinib in Treating Patients With Stage IV Colorectal Cancer

PRIMARY OBJECTIVES: I. To evaluate the anti-tumor efficacy of panitumumab monotherapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently have detectable EGFR ectodomain mutation post-progression in circulating free tumor deoxyribonucleic acid (DNA). II. To evaluate the anti-tumor efficacy of panitumumab and trametinib combination therapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently have detectable levels of KRAS, NRAS, and/or BRAF mutation post-progression in circulating free tumor DNA. III. To evaluate the anti-tumor efficacy of panitumumab monotherapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently do not have detectable KRAS, NRAS, BRAF, or EGFR ectodomain mutation post-progression in circulating free tumor DNA. SECONDARY OBJECTIVES: I. To evaluate the toxicities of panitumumab and trametinib combination therapy. II. To evaluate the anti-tumor efficacy of panitumumab and trametinib combination therapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who progressed on prior anti-EGFR therapy, developed detectable EGFR ectodomain mutations, and progress through retreatment with panitumumab. III. To evaluate the anti-tumor efficacy of panitumumab and trametinib combination therapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who progressed on prior anti-EGFR therapy, did not develop detectable mutations in KRAS, NRAS, BRAF, or EGFR ectodomain, and progress through retreatment with panitumumab. IV. To evaluate clinical outcomes with panitumumab monotherapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently have detectable EGFR ectodomain mutation post-progression in circulating free tumor DNA. V. To evaluate clinical outcomes with panitumumab and trametinib combination therapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently have detectable levels of KRAS, NRAS, and/or BRAF mutation post-progression in circulating free tumor DNA. VI. To evaluate clinical outcomes with panitumumab monotherapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently do not have detectable KRAS, NRAS, BRAF, or EGFR ectodomain mutation post-progression in circulating free tumor DNA. VII. To study the biological basis of development of primary and secondary resistance to anti-EGFR antibodies and MEK inhibitors. OUTLINE: Patients are assigned to 1 of 3 cohorts. COHORT 1: Patients with EGFR ectodomain mutation receive panitumumab intravenously (IV) over 30-90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Cohort 2. COHORT 2: Patients with KRAS, NRAS, or BRAF mutation receive trametinib orally (PO) once daily (QD) on days 1-14 and panitumumab as in Cohort 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. COHORT 3: Patients without EGFR ectodomain, KRAS, NRAS, or BRAF mutation receive panitumumab as in Cohort 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Cohort 2. After completion of study treatment, patients are followed up for 4 weeks and then every 3 months for 24 months.