ASCEND-CRC: Profiling and Targeting Dynamic Tumor Resistance in Patients With Metastatic Colorectal Cancer

Eligibility Criteria * The participant has a histologically or cytologically confirmed diagnosis of colorectal cancer. * Confirmation of non-MSI-H/pMMR status. * Tumor that is measurable as per RECIST v1.1 and biopsy able, defined as lesion/tumor that can be biopsied without undue risk. * Age ≥ 18 years. * ECOG performance status 0-2. * Due to the potential teratogenic effect of chemotherapy, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for an adequate amount of time following end of treatment based on the SOC indications for the administered regimen (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female participants, between the onset of menses and 55 years unless the participant presents with an applicable exclusionary factor which may be one of the following: * Postmenopausal (no menses in greater than or equal to 12 consecutive months). * History of hysterectomy or bilateral salpingo-oophorectomy. * Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy). * History of bilateral tubal ligation or another surgical sterilization procedure. * Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. * Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for an adequate amount of time following end of treatment based on the SOC indications for the administered regimen. * The participant is willing and able to sign the informed consent in compliance with protocol requirements, including mandatory biopsies. Exclusion Criteria * Pregnancy. * Participants with concurrent or recent (less than 1 year before consent) malignancies that have the potential to interfere with the study safety and/or endpoint assessments will be excluded. * Participants for whom there is an intent to proceed to curative therapy (i.e., resection) will be excluded. * Participants who have undergone treatment with both oxaliplatin and irinotecan in the metastatic setting will be excluded. Treatment with oxaliplatin in the adjuvant setting with relapse within 6 months will be counted as treatment in the metastatic setting for the purpose of this criterium. * For participants who have undergone treatment for metastatic disease, participants who have not progressed (clinically or radiographically) on the most recent therapy will be excluded. * Concurrent participation in any other interventional trial.