The goal of this clinical research study is to learn if durvalumab and trametinib can help to control microsatellite stable (MSS) colorectal cancer. The safety of these drugs will also be studied.

This is an investigational study. Durvalumab is FDA approved and commercially available for the treatment of previously treated advanced bladder cancer. Trametinib is FDA approved in combination with another drug called dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or BRAF V600K.

It is investigational to use durvalumab and trametinib to treat MSS colorectal cancer.

Up to 56 participants will be enrolled in this study. All will take part at MD Anderson.

Study Drug Administration:

Each cycle is 28 days.

Participant will take trametinib tablets by mouth every day with at least 8 ounces of water. Each dose should be taken at about the same time each day, 1 hour before or 2 hours after a meal. Participant should not crush, cut, or chew the tablets. If participant misses a dose of trametinib, participant may take the tablets as soon as participant remembers but only if participant's next scheduled dose is at least 12 hours later. If participant's next scheduled dose is less than 12 hours, participant should wait and take participant's next dose as scheduled.

Participant will take trametinib alone for the first 7 days of the study and then participant will begin receiving it in combination with durvalumab.

Every 4 weeks, participant will receive durvalumab by vein over about 60 minutes.

Length of Treatment:

Participant will be able to receive the study drugs for as long as the doctor thinks it is in participant's best interest. Participant no longer will take the study drugs if intolerable side effects occur or if the study doctor decides that the drugs are no longer working.

It is expected that participation in this study may last about 12 months.

Participation in this study will be over after follow-up.

Study Visits:

On Day 1 of Weeks 0, 2, 4, 6, 12, and then every 4 weeks after that (Weeks 16, 20, 24, and so on):

• Participant will have a physical exam.
• Blood (about 6 tablespoons) will be drawn for routine tests, immune system testing, and biomarker testing.
• If participant had a biopsy at screening, participant will have another biopsy during Week 4 to check the status of the disease and for biomarker testing. Depending on when participant joins the study, this biopsy may be optional.

On Day 1 of Week 8:

• Participant will have a physical exam.
• Blood (about 6 tablespoons) will be drawn for routine tests, immune system testing, and biomarker testing.
• Participant will have a CT scan.

On Day 1 of Week 16 and then every 8 weeks after that (Weeks 24, 32, 40, and so on), participant will have a CT scan.

End-of-Treatment:

About 28 days after participant's last dose of study drugs, participant will have a physical exam.

Follow-Up:

After participant's end-of-treatment visit, participant will be called by the study staff every 3 months for up to 18 months to ask how participant is doing. Each call should last about 5-10 minutes.

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed metastatic colorectal cancer.
2. Patients must have measurable disease per RECIST v1.1 criteria.
3. Patients must have had at least prior treatment with a fluoropyrimidine and either oxaliplatin or irinotecan.
4. Age >/=18 years. Because no dosing or adverse event data are currently available on the use of this combination in patients <18 years of age, children are excluded from this study.
5. Body weight > 30kg.
6. Life expectancy of greater than 6 months.
7. ECOG performance status 0-1 (Karnofsky >/=70%).
8. Patients must have normal organ and marrow function as defined below: - Leukocytes >/=3,000/mcL, Absolute neutrophil count >/=1,500/mcL, Hemoglobin >/=9.0g/dL, Platelets >/=75,000/mcL, Total bilirubin < 1.5 X institutional normal limits (subjects with known Gilbert syndrome are eligible with total bilirubin < 3.0 mg/dL), AST(SGOT)/ALT(SGPT) </=2.5 X institutional ULN (</= 5 if liver metastases present), Creatinine within normal institutional limits OR, Creatinine clearance > 40mL/min by Cockcroft-Gault or 24h urine collection.
9. Known MSS status by either IHC or PCR. Known or evaluable BRAF and KRAS status.
10. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal subjects. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: -- Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
11. Inclusion #10 cont'd -- Women >/=50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
12. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately and will be removed from the study.
13. Ability to understand and the willingness to sign a written informed consent document.
14. Willingness to have 2 tumor biopsies; the first before and the second while on therapy (optional for all patients and may become mandatory in order to ensure 15 patients at MTD have paired biopsies).

Exclusion Criteria:

1. Patients who have had chemotherapy within 2 weeks prior to first dose of study drug.
2. Any unresolved toxicity NCI CTCAE Grade >/=2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria: -- Subjects with Grade >/=2 neuropathy will be evaluated on a case-by-case basis after consultation with the Principal investigator.-- Subjects with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Principal investigator.
3. Patients may not be receiving any other investigational agents.
4. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of study medication. Note: Local surgery of isolated lesions for palliative intent is acceptable.
5. Patients with known brain metastases or leptomeningeal carcinomatosis will be excluded from this clinical trial. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry.
6. Mean QT interval corrected for heart rate (QTc) >/= 470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's Correction.
7. History of pneumonitis or interstitial lung disease (ILD).
8. History of allogenic organ transplantation.
9. Subjects with active, known, or suspected autoimmune disease including patients with a history of inflammatory bowel disease (ulcerative colitis or Crohn's disease); patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis (e.g., Wegener's granulomatosis), and central nervous system or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome, myasthenia gravis, multiple sclerosis). Subjects with vitiligo, type I diabetes mellitus, Grave's disease, Hashimoto thyroiditis, psoriasis, and other mild autoimmune disease not requiring systemic treatment are permitted to enroll at the discretion of the investigator.
10. Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
11. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Subjects, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
12. Prior exposure to T cell checkpoint inhibitor therapies.
13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
14. History of active primary immunodeficiency.
15. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice for patients suspected of having active infection), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
16. Female subjects who are pregnant or breastfeeding or male or female subjects of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of study medications.
17. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

from Baseline to 2 years