Dabrafenib + Trametinib + PDR001 In Colorectal Cancer

Inclusion Criteria:

* Participants must have histologically or cytologically confirmed metastatic colorectal cancer and a documented BRAF V600E mutation by a CLIA-certified laboratory test and must be wild-type for KRAS and NRAS.
* Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease.
* Patients may have received prior chemotherapy, prior anti-EGFR therapy, prior BRAF or MEK inhibitor, or prior immunotherapy (e.g. anti-PD1/PD-L1). Patients will also be allowed without prior treatments. If patient has been treated in the past, they must be at least 4 weeks since prior chemotherapy or radiation therapy.
* Age ≥ 18 years
* ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
* Life expectancy of greater than 3 months
* Participants must have normal organ and marrow function as defined below:

  * leukocytes ≥3,000/mcL
  * absolute neutrophil count ≥1,500/mcL
  * platelets ≥100,000/mcL
  * total bilirubin within normal institutional limits
  * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
  * creatinine within normal institutional limits --- OR
* creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.

  * PT/INR \<1.5 x ULN and PTT \<1.5 ULN
  * Albumin \> 2.5 g/dl
  * Patients must meet eligibility criteria on C1D1.
* LVEF \> LLN by ECHO or MUGA
* The effects of trametinib, dabrafenib and PDR001 on the developing human fetus are unknown. For this reason and because these agents may be teratogenic, 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 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 4 months after completion of treatment.
* Ability to understand and the willingness to sign a written informed consent document.
* Subjects must avoid consumption of grapefruit, Seville oranges or products containing the juice of each during the entire study and preferably 7 days before the first dose of study medications, due to potential CYP3A4 interaction with the study medications. Orange juice is allowed.
* Exclusion Criteria
* Participants who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
* Participants who are receiving any other investigational agents.
* Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to of trametinib, dabrafenib or PDR001.
* Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible but once on treatment must be used with caution. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant women are excluded from this study because trametinib, dabrafenib or PDR001 have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with trametinib, dabrafenib or PDR001 breastfeeding should be discontinued if the mother is treated with trametinib, dabrafenib or PDR001.
* HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with trametinib, dabrafenib or PDR001. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
* Active known or suspected autoimmune disease or a documented history of autoimmune disease, including ulcerative colitis and Crohn's disease (Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll).
* Systemic chronic steroid therapy (≥ 10mg/day prednisone or equivalent) or any immunosuppressive therapy 7 days prior to planned date for first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids are allowed.
* Current pneumonitis or interstitial lung disease.
* History of organ transplant requiring use of immunosuppressive medication.
* Taken an investigational drug ≤ 28 days or ≤ 5 half-lives (minimum 14 days) prior to start of study treatment, whichever is shorter.
* Current use of a prohibited medication.
* Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers and any completely resected carcinoma in situ.
* Active infection requiring systemic antibiotic therapy within 2 weeks prior to start of study treatment.
* Subjects with active Hepatitis B infection (HbsAg positive) will be excluded. Note: Subjects with antecedent of Hepatitis B (anti-HBc positive, HbsAg and HBV-DNA negative) are eligible.
* Subjects with positive test for hepatitis C ribonucleic acid (HCV RNA) Note: Subjects in whom HCV infection resolved spontaneously (positive HCV antibodies without detectable HCV-RNA) or those that achieved a sustained virological response after antiviral treatment and show absence of detectable HCV RNA ≥ 6 months (with the use of IFN-free regimes) or ≥ 12 months (with the use of IFN-based regimes) after cessation of antiviral treatment are eligible.
* Any medical condition that would, in the investigator's judgment, prevent the subject's participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results.
* Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment
* Uncorrectable electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), long QT syndrome or taking medicinal products known to prolong the QT interval
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
* A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy including:

  * Presence of predisposing factors to RVO or central serous retinopathy (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or
  * Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or central serous retinopathy such as:
  * Evidence of new optic disc cupping;
  * Evidence of new visual field defects on automated perimetry;
  * Intraocular pressure \>21 mmHg as measured by tonometry.
* Cardiac or cardiac repolarization abnormality, including any of the following:

  * History or current diagnosis of cardiac disease indicating significant risk of safety for subjects participating in the study such as uncontrolled or significant cardiac disease, including any of the following:

    * Recent (within last 6 months) myocardial infarction (MI)
    * Unstable angina (within last 6 months),
    * Uncontrolled congestive heart failure (CHF)
    * Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree atrioventricular \[AV\] block without a pacemaker).