A Combination Clinical Study of PLX3397 and Pembrolizumab To Treat Advanced Melanoma and Other Solid Tumors

Inclusion Criteria: A subject must satisfy all of the following criteria to be considered for inclusion in the study: * Subjects with histologically or cytologically-confirmed diagnosis of cancer that is recurrent, metastatic, or persistent, who have relapsed from or are refractory to treatment and who also meet the following corresponding requirements for the cohort or phase of the study into which they will enroll: * Dose-escalation Phase: Subjects with advanced solid tumors (any tumor type) considered to have no standard-of care treatment for their malignancy with a curative intent, either as initial therapy or after progressing to prior therapies; subjects who have been treated previously with a CSF1R inhibitor or an anti PD1/PDL1 inhibitor may enroll. * Expansion Phase: Subjects with 1 of the tumor types who have relapsed from or are refractory to standard treatment. Subjects with non-small-cell lung cancer (non-squamous; EGFR, ALK wild type), advanced melanoma, ovarian cancer, unresectable RCC with component of clear-cell histology and/or component of sarcomatoid histology, glioblastoma or gliosarcoma, gastrointestinal stromal tumor. * Subjects with melanoma must have a histologically confirmed diagnosis of stage III disease not amenable to local therapy. Melanoma subjects may have received any number of prior lines of therapy for metastatic disease and must have measurable disease per RECISTv1.1. Subjects with melanoma who have received prior treatment with a BRAF/MEK inhibitor are acceptable candidates. * Expansion cohorts: Subjects must have relapsed or been refractory to standard treatment. NSCLC, SCCHN, and Melanoma must show primary progression with antiPD1/anti-PDL1 therapy. They must have tumor accessible for sequential biopsy (core needle biopsy or excision required) and be willing to provide on study tumor tissue biopsy. Subjects for whom newly obtained samples cannot be obtained (e.g. inaccessible or patient safety concern) may submit an archived specimen onlyupon agreement from the Sponsor. * ECOG performance status 0 or 1. * Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to initiation of dosing. * Women of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Women of non-child bearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year. * Fertile men must agree to use an effective method of birth control starting with the first dose of study treatment through 120 days after the last dose of study treatment. * Adequate organ function as demonstrated by laboratory values. Exclusion Criteria: A subject who meets any of the following criteria will be disqualified from entering the study: * Disease that is suitable for local therapy administered with curative intent. * Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. * Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 28 days prior to the first dose of study treatment. * Has had monoclonal antibody within 28 days of first dose of study treatment or has not recovered from AEs due to agents administered more than 28 days earlier. * Has had chemotherapy, targeted small molecule therapy, or radiation therapy within 14 days prior to first dose of study treatment or who has not recovered from AEs due to a previously administered agent. * Note: Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study. * Note: If a subject received major surgery, he or she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment. * Has received transfusion of blood products (including platelets or red blood cells \[RBC\]) or administration of colony stimulating factors (including granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) within 28 days prior to Day 1. * Evidence of interstitial lung disease or active, noninfectious pneumonitis. * Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, in situ cervical cancer and isolated elevation of prostate-specific antigen. Subjects with a completely treated prior malignancy with no evidence of disease for ≥ 2 years are eligible. * For Dose escalation cohort: patients with liver metastases, inclusion of patients with liver metastases in subsequent cohorts will be based upon clinical data. * For Expansion cohort subjects who have previously received an anti-PD-1, anti-PD-L1, or anti#PD-L2 agent or has previously participated in pembrolizumab clinical trials are excluded, except the following tumor types Melanoma, NSCLC and SCCHN (who must show primary progression to anti-PD1/anti-PDL1 therapy). * Radiation therapy within 14 days of first dose of study treatment.- remove since it's repetitive * Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy is not considered a form of systemic treatment. * Has an active infection requiring systemic therapy. * Has known central nervous system metastases and/or carcinomatous meningitis. o Note: Subjects with previously treated brain metastases may participate if they meet the following criteria: 1) are stable for at least 28 days prior to the first dose of study treatment and if all neurologic symptoms returned to baseline); 2) have no evidence of new or enlarging brain metastases; and 3) have not been using steroids for at least 7 days prior to first dose of study treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. * Uncontrolled intercurrent illness. * Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant small bowel resection that would preclude adequate absorption. * QT interval corrected using Fridericia's formula (QTc) ≥ 450 msec (males) or ≥ 470 msec (females) at Screening. * Congenital long QT syndrome or patients taking concomitant medications known to prolong the QT interval. * Major surgery within 28 days prior to first dose of study treatment. * Has received a live vaccine administered within 30 days prior to first dose of study treatment. * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. * Active and clinically significant bacterial, fungal or viral infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome related illness (HIV testing is not required), including subjects who have an active infection requiring systemic therapy. * Any of the following within 48 weeks (\~1 year) prior to first dose of study treatment: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack. * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study treatment. * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. * Has had prior exposure to PLX3397. * Has had hypersensitivity (≥Grade 3) reaction to pembrolizumab and/or any of its excipients.