Study of Durvalumab (MEDI4736) (Anti-PD-L1) and Trametinib (MEKi) in MSS Metastatic Colon Cancer
Condition: Malignant Neoplasms of Digestive Organs; Colorectal Cancer; Colon Cancer
MeSH terms: Neoplasms; Colorectal Neoplasms; Colonic Neoplasms
Intervention: Durvalumab; Trametinib
Intervention description: Dose Escalation and Dose Expansion Dose: 1500 mg by vein every 4 weeks in a 28 day cycle.; Dose Escalation Starting Dose: 2mg by mouth daily in a 28 day cycle.
Dose Expansion Dose: MTD from Dose Escalation.
Intervention MeSH terms: Durvalumab; Trametinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 29.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Malignant neoplasms of digestive organs; Colorectal Cancer; Colon Cancer; Durvalumab; MEDI4736; Trametinib; GSK1120212

Summary:

      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.
    

Eligibility criteria:

        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.