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nci protocol # n/a df/hcc

TITLE: A phase II trial of abbreviated MAPK targeted therapy plus pembrolizumab in patients with unresectable or metastatic melanoma Coordinating Center: Massachusetts General Hospital Cancer Center  
| *Principal Investigator (PI):   | Ryan J. Sullivan, MD Massachusetts General Hospital Cancer Center Rsullivan7@partners.org                                                                                                                                                                                         |
|---------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Other Investigators:            | Massachusetts General Hospital Keith Flaherty, MD kflaherty@mgh.harvard.edu Meghan Mooradian, MD mmooradian@mgh.harvard.edu Donald Lawrence, MD dplawrence@mgh.harvard.edu Howard Kaufman, MD hlkaufman@mgh.harvard.edu Krista Rubin, NP kmrubin@mgh.harvard.edu Riley Fadden, NP |  
Beth Israel Deaconess Medical Center (Biologics)
David F. McDermott, MD
dmcdermo@bidmc.harvard.edu James W. Mier, MD
jmier@caregroup.Harvard.edu Dana Farber Cancer Center Elizabeth Buchbinder, MD
elizabeth_Buchbinder@dfci.harvard.edu  
| Statistician:                                | Study Coordinator:                                                                       |
|----------------------------------------------|------------------------------------------------------------------------------------------|
| Anita Giobbie-Hurder, MS                     | Natalie Ciano                                                                            |
| Dana Farber Cancer Institute                 | Massachusetts General Hospital Cancer                                                    |
| Center Anita_Giobbie-Hurder@dfci.harvard.edu | 101 Merrimac Street, Suite 505D Boston, MA 02114 Phone (617) 643-1540 Fax (617) 724-0599 |  
1  
2  
nciano@mgh.harvard.edu  
| Responsible Research Nurse:              | Responsible Data Manager:             |
|------------------------------------------|---------------------------------------|
| Alexandra Mossali, RN                    | Natalie Ciano                         |
| Cancer Center Protocol Office            | Massachusetts General Hospital Cancer |
| 55 Fruit Street- Yawkey Center, Suite 7E | Center                                |
| Boston, MA 20114                         | 101 Merrimac Street, 505D Boston,     |
| Phone (617) 643-1922                     | MA 02114                              |
| Fax (617) 643-7602                       | Phone (617) 643-1540                  |
| Amossali@partnerts.org                   | nciano@mgh.harvard.edu                |  
NCI-Supplied Agent(s): N/A
Other Agent(s): Pembrolizumab - Merck Dabrafenib plus trametinib - Commercial Trametinib - Commercial IND \#: 132821 IND Sponsor: Ryan J. Sullivan, MD Version Date: 4-Sep-2020
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synopsis rationale for study

Over the past decade, amazing progress has been made culminating in the development of effective molecularly targeted and immune targeted therapies for the treatment of solid tumors. The two diseases that have been at the forefront of this progress are melanoma and non-small cell lung cancer (NSCLC). In each disease, molecular subsets have been identified (BRAF and NRAS mutant in melanoma, EGFR and ALK mutant in NSCLC) that define a patient population associated with high response rates to targeted agents. Additionally, monoclonal antibody targeting of the program death 1 (PD1) receptor and its ligand (PDL1) has shown impressive activity in both diseases with response ranging from 15-30% in NSCLC and 30-50% in melanoma.  
As the field looks to improve upon this activity, one strategy has been to consider combining molecular-targeted and immune therapies. The preponderance of data supporting this approach is from the melanoma field. In particular, a number of groups have shown that MAPK inhibition leads to increased melanoma antigen expression, decreased immunosuppressive cytokines, and increased trafficking of CD8+ T-lymphocytes. Additionally, it appears that BRAF inhibitors with or without MEK inhibitors are capable of triggering this phenomenon, though these findings dissipate in the setting of acquired, BRAF-inhibitor resistance. It has been well described that a common tissue and tumor response to lymphocytic infiltration is the upregulation of PDL1 that then inhibit these invading T-cells through interaction with their PD1 receptor. In melanoma, the BRAF-inhibitor associated infiltration is associated with increased tumor/stromal PDL1 expression. Dual inhibition of BRAF and PD1 has been shown to be associated with more profound and durable responses in animal models of melanoma. We propose to test the hypothesis that induction molecularly targeted therapy triggers a favorable tumor microenvironment to augment the effects of maintenance PD1 targeting with pembrolizumab in two cohorts: BRAF mutant and BRAF-wild-type melanoma. This proposal represents a unique opportunity to test the effectiveness of combined immune and molecularly targeted therapy in two distinct subsets based on preclinical and clinical data. The successful completion of this study will:
1. Determine the immunologic effects of oncogene targeted therapy on tumor microenvironment 2. Prove the concept that abbreviated molecularly targeted therapy will augment the effectiveness of pembrolizumab maintenance therapy
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study objectives

Primary Objective: Document the rate of clinical benefit (SD/PR/CR per RECIST) of abbreviated molecularly targeted therapy in combination with pembrolizumab in patients with unresectable and/or metastatic melanoma. A subject will have achieved clinical benefit if there is evidence of CR, PR, or SD at the time of the 24-week scan and the subject has not resumed targeted therapy.
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secondary objectives

1. To describe progression free survival (PFS) and 1 year overall survival (OS) of abbreviated molecularly targeted therapy in combination with pembrolizumab in patients with metastatic melanoma.  
2. To define the effects of targeted and the combination of immune and molecularly targeted therapy on tumor microenvironment
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study design

A Simon 2-stage design will be implemented for each disease cohort. Patients will be treated with two-week lead-in of molecularly targeted therapy (MTT), followed by two 3 week cycles of combined targeted therapy (MTT) and pembrolizumab (at dose of 200 mg IV every three weeks), followed by maintenance single-agent pembrolizumab in all patients with RECIST defined stable disease (SD), partial response (PR), and complete response (CR). MTT *only will be resumed* if patients develop symptomatic or radiographic evidence of progression. If patients do not develop evidence of progressive disease (PD), then they will continue maintenance single-agent pembrolizumab for up to two years. In each cohort, patients will be accrued to first stage of the Simon design. If a prespecified number of patients maintain SD/PR/CR off MTT
but on pembrolizumab at the 24-week time point, then the second stage of the twostage design will be opened. (Please see details in statistical section) Biopsies will be performed on all patients enrolled to the first stage of the Simon two-stage for each cohort. These will be obtained at baseline and after the two-week lead-in. A third biopsy obtained after the completion of induction therapy will be obtained if feasible. An optional biopsy at time of disease progression will also be performed.
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schema

Key Eligibility:  
Participants must have histologically confirmed metastatic or unresectable melanoma.  
Participants must have BRAFV600-mutation status known.  
Participants must have measurable disease. Age greater than or equal to 18 years. Participants must have disease amenable to and be willing to undergo serial core or excisional biopsies of a tumor lesion(s).  
ECOG performance status <1 (see Appendix A). Participants must have normal organ and marrow function as defined below:
Participants not previously treated with BRAF inhibitors (vemurafenib, dabrafenib, encorafenib), MEK inhibitors (selumetinib, trametinib, binimetinib, cobimetinib), and/or anti-PD1/PDL1 monoclonal antibodies for metastatic or unresectable disease. Any other prior therapy *will be* allowed (including ipilimumab, adjuvant anti-PD1 therapy, high-dose IL-2).  
Has a 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 trial treatment.  
CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.  
Participants with symptomatic brain metastases will be excluded from this clinical trial. Subjects with asymptomatic, stable brain metastases and/or who have been previously treated for these conditions that are asymptomatic in the absence of corticosteroid therapy are allowed to enroll. Brain metastasis must be stable with verification by imaging (brain MRI completed at screening demonstrating no current evidence of progressive brain metastases).  
No symptomatic or untreated leptomeningeal disease.
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sample size justification

This trial will provide preliminary estimates of toxicity and efficacy and will be based on parallel Simon two-stage designs according to disease cohort. The rate of clinical benefit (CBR), defined as the rate of patients who have CR/PR/SD at week 24 while remaining off targeted therapy after induction, will be the primary efficacy endpoint. For each disease cohort, the Simon two-stage design is based on a type-I error rate of 0.1, at least 85% power, and a total sample size of 25 subjects. A complete safety assessment is planned to coincide with the review of clinical benefit at the end of the first stage.  
For both cohorts, the null hypothesis of a true CBR of 0.50 will be tested against a onesided alternative CBR of 0.75. The benchmark CBR rate of 0.50 is based on the results of the Keynote 001 trial in patients with refractory or first-line malignant melanoma treated with pembrolizumab (Robert, ASCO 2016) that reported a CBR of 0.51 regardless of BRAF mutation status. A short course of MAPK-targeted therapy in addition to pembrolizumab would be considered worthy of further investigation if there is evidence of an improvement in CBR to 0.75. Fourteen (14) subjects that are evaluable for the primary endpoint (defined as receiving at least 1 dose of dabrafenib/trametinib/pembrolizumab combination therapy prior to treatment discontinuation for any reason.) will be enrolled in the first stage, and if 8 or fewer subjects with clinical benefit are observed, then enrollment will stop. If there are 9 or more subjects with clinical benefit, then an additional 11 subjects will be enrolled, for a total of 25. The null hypothesis will be rejected if a total of 16 or more subjects with clinical benefit are observed in 25 subjects. This design yields power of 86% (target type II error of 0.15) when the CBR rate is 0.75. If the null hypothesis is true, the probability is 0.79 that enrollment to a cohort will stop at the end of the first stage. This high probability of stopping under the null was chosen to require strong evidence of benefit before opening the second stage. Clinical benefit rates will be presented with 90% confidence intervals based on the method of Atkinson and Brown, which allows for the two-stage design. All reported adverse events will be summarized as part of the early safety review at the end of the first stage. With 14-15 subjects per disease cohort, there is high probability of observing at least one event if a toxicity has an incidence of at least 10%. If the true incidence of an unexpected or severe toxicity is 10% or greater, the probability is at least 0.75 that one or more subjects will experience the toxicity during the early safety monitoring period. The distribution of secondary endpoints of PFS and OS will be based on the method of Kaplan-Meier. ORR within each disease cohort will be estimated by the number of subjects with a best response of CR or PR (per RECIST) and presented with exact 90% confidence intervals. For sample sizes of 25 per disease cohort, the confidence intervals will be no wider than 0.35. Correlative studies will be based on tumor biopsies and will assess changes in biomarkers due to OTT. PD-L1 expression will be classified as positive or negative according to IHC. Pre- versus post-OTT PD-L1 expression will be compared using McNemar's test. Changes in T cell subtypes and in co-stimulatory molecules will be summarized using descriptive methods
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sample size justification

| SCHEMA 5 1. OBJECTIVES 10 1.1 Study Design 10 1.2 Primary Objectives 10 1.3 Secondary Objectives 10 2. BACKGROUND 10 2.1 Study Disease(s) 10 2.2 IND Agents 12 2.3 Rationale 33 2.4 Correlative Studies Background 34 3. PARTICIPANT SELECTION 36 3.1 Inclusion Criteria 36 3.2 Exclusion Criteria 38 - Note: Subjects with ≤ Grade 2 thyroiditis and/or hypophysitis are an exception to  this criterion and may qualify for the study 39 3.3 Inclusion of Women and Minorities 41 4. REGISTRATION PROCEDURES 41 4.1 General Guidelines for DF/HCC Institutions 41 4.2 Registration Process for DF/HCC Institutions 42 5. TREATMENT PLAN 42 5.1 Treatment Regimen 42 5.2 Pre-Treatment Criteria 43 5.3 Agent Administration 44 5.4 General Concomitant Medication and Supportive Care Guidelines 45 5.5 Criteria for Taking a Participant off Protocol Therapy 51 5.6 Duration of Follow Up 53 5.7 Criteria for Taking a Participant Off Study 54 5.8 Contraception 54 6. DOSING DELAYS/DOSE MODIFICATION criteria 56 6.1 Pembrolizumab Dose Modifications 56 6.2 Dabrafenib + Trametinib Dose Modifications 58 7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 74 7.1 Expedited Adverse Event Reporting to the Overall PI and Merck 74 7.2 Expedited Reporting to the Food and Drug Administration (FDA) 75 7.3 Expedited Reporting to Hospital Risk Management 75 7.4 Routine Adverse Event Reporting 76CONFIDENTIAL This document is confidential. Do not disclose or use except as authorized.   |
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| Protocol Version Date: 4-Sep-2020                                                                                              |                                                                                                                                                                                                                                                                                                                                |
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| 7.5                                                                                                                            | Monitoring of Adverse Events and Period of Observation 76                                                                                                                                                                                                                                                                      |
| 8.                                                                                                                             | PHARMACEUTICAL INFORMATION 76 8.1 Pembrolizumab 76 8.2 Dabrafenib mesylate (GSK2118436B) (NSC 763760) 80 8.3 Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093) 81                                                                                                                                                       |
| 9.                                                                                                                             | BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 83 9.1 Collection of Specimen(s) 83 9.2 PD-L1 Immunohistochemistry 84 9.3 Adaptive Biotechnologies immunoSEQ 85 9.4 Tumor Microenvironment Assessment 85 9.5 Pharmacodynamic Studies 85                                                                                            |
| 10.                                                                                                                            | STUDY CALENDAR 86                                                                                                                                                                                                                                                                                                              |
| 11.                                                                                                                            | MEASUREMENT OF EFFECT 90 11.1 Antitumor Effect - Solid Tumors 90                                                                                                                                                                                                                                                               |
| 12.                                                                                                                            | DATA REPORTING / REGULATORY REQUIREMENTS 98 12.1 Data Reporting 98 12.2 Data Safety Monitoring 98 12.3 Regulatory Considerations 99 12.4 Study Documentation 100 12.5 Records Retention 101                                                                                                                                    |
| 13.                                                                                                                            | STATISTICAL CONSIDERATIONS 101 13.1 Study Design/Endpoints 101 13.2 Sample Size, Accrual Rate and Study Duration 102 13.3 Analysis of Primary Endpoints 102 13.4 Analysis of Secondary Endpoints 102 13.5 Analysis of Correlative Measures 103 13.6 Analysis of Safety and Toxicity Data 104 13.7 Reporting and Exclusions 105 |
| 14.                                                                                                                            | PUBLICATION PLAN 106                                                                                                                                                                                                                                                                                                           |
| APPENDIX A: PERFORMANCE STATUS CRITERIA 108 APPENDIX B: INFORMATION ON POSSIBLE DRUG INTERACTIONS 109 APPENDIX C: BIOASSAY 112 |                                                                                                                                                                                                                                                                                                                                |
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1. objectives 1.1 study design

A Simon 2-stage design will be implemented for each disease cohort. Patients will be treated with two-week lead-in, followed by a 6-week combined targeted therapy (TT) and pembrolizumab, followed by maintenance single-agent pembrolizumab in all patients with RECIST defined stable disease (SD), partial response (PR), and complete response (CR). TT will be resumed if patients develop symptomatic or radiographic evidence of progression. If patients do not develop evidence of progressive disease (PD), then they will continue maintenance single-agent pembrolizumab for up to two years. In each cohort, patients will be accrued to first stage of the Simon design. If a prespecified number of patients maintain SD/PR/CR off TT but on pembrolizumab, then the second stage of the two-stage design will be opened. (Please see details in statistical section) Biopsies will be performed on all patients enrolled to the first stage of the Simon two-stage for each cohort. These will be obtained at baseline and after the two-week lead-in. A third biopsy obtained after the completion of induction therapy will be obtained if feasible. An optional biopsy at time of disease progression will also be performed.
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1.2 primary objectives

Document the rate of clinical benefit (SD/PR/CR per RECIST) of abbreviated molecularly targeted therapy in combination with pembrolizumab in patients with unresectable and/or metastatic melanoma. A subject will have achieved clinical benefit if there is evidence of CR, PR, or SD at the time of the 24-week scan and the subject has not resumed targeted therapy.
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1.3 secondary objectives

1.3.1. To describe progression free survival (PFS) and 1 year overall survival
(OS) of abbreviated molecularly targeted therapy in combination with pembrolizumab in patients with metastatic melanoma.  
1.3.2. To define the effects of targeted and the combination of immune and molecularly targeted therapy on tumor microenvironment
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2. background 2.1 study disease(s)

The incidence of melanoma has dramatically risen over the past several decades and in 2012, an estimated 74,0000 new cases and nearly 10,000 deaths are expected in the United States. (Seigel CA J 2015) In fact, CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.  
melanoma is the 5th and 7th most common malignancy in the US among men and women respectively. The prognosis for patients with metastatic melanoma has been traditionally poor, though is dramatically different if the disease is limited to subcutaneous and/or lymph nodes (M1a), if the lungs are the only site of visceral metastasis (M1b), or if other sites of visceral metastasis are identified and/or if the lactate dehydrogenase (LDH) level is elevated (M1c). In particular, per the AJCC database the 1-year survival rates of M1a, M1b, and M1c are approximately 70%, 60%, and 40% respectively. Still, melanoma typically disseminates widely, and frequently involves sites that are uncommon in other cancers, such as the GI tract and the skin. (Balch J Clin Oncol 2009) Over the past decade, amazing progress has been made culminating in the development of effective molecularly targeted and immune targeted therapies for the treatment of melanoma. In particular, molecular subsets have been identified (BRAF, NRAS, and CKIT mutant) that define a patient population associated with response to targeted agents. Additionally, monoclonal antibody targeting of the program death 1 (PD1) receptor and its ligand (PDL1) is associated with responses in 25-45% of patients, and more importantly, has demonstrated a survival advantage compared to ipilimumab (in the front-line setting) and chemotherapy (in front-line and post-ipilimumab settings). As the field looks to improve upon this level of activity, combination regimens have emerged that are associated with improved efficacy compared with singleagent therapy.  
The first therapeutic regimen to demonstrate superiority over single-agent therapy is the combination of a BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi). In fact, there are now three "positive" randomized trials of combination BRAF/MEK inhibitors showing improved response, progression free survival, and overall survival compared to single-agent BRAF inhibitors. As a result of this data, the FDA approved the dabrafenib (BRAFi) plus trametinib (MEKi) combination in early 2014 and is evaluating the combination of vemurafenib (BRAFi) plus cobimetinib (MEKi) for regulatory approval. Further, there is no longer any dispute that combined targeted therapy is the preferred BRAFtargeted therapy approach. Unfortunately, only a small subset of patients have durable benefit and remain on therapy for more than two or three years. Immunotherapy combination therapy is another approach. The most advanced data with this approach is with the combination of ipilimumab and nivolumab. In particular, Phase I-III trials show that this regimen is associated with high response rates (exceeding 60%) and improved PFS (median ~12 months) at the cost of high toxicity (grade 3 or 4 treatment-related adverse events ~55+%). Given high rate of severe and life-threatening toxicity, this regimen is unlikely to serve the backbone upon which to rationally build three and four drug combinations. A second approach to improve upon the effectiveness of anti-PD1 therapy is to develop patient selection strategies to prospectively differentiate patients most likely to experience long-term benefit from single-agent therapy from those who require combinations. Recently, a number of predictive biomarkers of response to anti-PD1 antibodies in melanoma and other malignancies have been reported. These include tumor factors (such as mutational burden and tumor neoantigen expression) immunologic factors (including cytotoxic T-lymphocyte infiltration with functional capacity to recognize tumor antigens, so-called T-cell diversity), and tumor-immune microenvironmental factors like PD-L1 expression. With each new report, a clear picture is emerging that tumors with high mutational burden and neoantigen expression, increased T-cell diversity, and elevated PD-L1 expression are primed for immune destruction in the setting of single-agent anti-PD1 antibodies. Conversely, tumors with low mutational load and neoantigen expression, low T-cell diversity, and low PD-L1 expression are less susceptible to immune-mediated tumor cell destruction.  
One of the next great challenges in the field is to develop strategies that convert an immunologically non-responsive tumor microenvironment into one primed to respond to anti-PD1 therapy.
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2.2.1.1 mechanism of action

The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has been known for decades. Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in many solid tumors. The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. The normal function of PD1, expressed on the cell surface of activated T-cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2). The structure of murine PD-1 has been resolved. PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade. The mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells. Expression has also been shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, including non-hematopoietic tissues as well as in various tumors. Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits Tcell activation triggered through the T-cell receptor. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PDL1 serves to dampen unwarranted T-cell function in peripheral tissues. Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumorspecific T-cell expansion in subjects with melanoma (MEL). This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an attractive target for therapeutic intervention. Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. A phase 1/2, multipart study is being conducted to evaluate the combination of the approved doses of pembrolizumab and dabrafenib and trametinib for *BRAF*V600E/K-mutant advanced melanoma. Results presented at the American Society of Clinical Oncology (ASCO) Annual Meeting June 3-7, 2016 on the nonrandomized phase 1, dose-finding part of KEYNOTE-022 showed Median days on therapy: 115 (range, 4-524). DLTs were reported in 3 out of 14 DLT-evaluable patients. Overall, 4 (26.7%) patients discontinued because of treatment-related AEs; there were no treatment-related deaths. Potentially immune-mediated AEs were reported in 6 (40.0%) patients, and included 2 cases of hyperthyroidism (1 grade 1, 1 grade 2), 2 cases of hypothyroidism
(grade 1), 2 cases of uveitis (1 grade 1, 1 grade 2), and 1 case each of autoimmune hepatitis (grade 3), severe skin reactions (grade 3), and pneumonitis (grade 2). Based on observed DLTs and the AE profile, no additional dose levels were opened; pembrolizumab 2 mg/kg Q3W + dabrafenib 150 mg BID + trametinib 2 mg QD was the MTD.
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2.2.1.3 nonclinical and clinical pharmacokinetics

An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical activity of single agent MK-3475. The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid tumors. All three dose levels were well tolerated and no dose-limiting toxicities were observed. This first in human study of MK-3475 showed evidence of target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD has been identified to date. 10.0 mg/kg Q2W, the highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol to test for initial tumor activity. Recent data from other clinical studies within the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent schedule may be sufficient for target engagement and clinical activity. PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days). This early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing schedule. A population pharmacokinetic analysis has been performed using serum concentration time data from 476 patients. Within the resulting population PK model, clearance and volume parameters of MK-3475 were found to be dependent on body weight. The relationship between clearance and body weight, with an allometric exponent of 0.59, is within the range observed for other antibodies and would support both body weight normalized dosing or a fixed dose across all body weights. MK-3475 has been found to have a wide therapeutic range based on the melanoma indication. The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to remain well within the established exposure margins of 0.5 - 5.0 for MK-3475 in the melanoma indication. The exposure margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation revealed that there was no significant impact of tumor burden on exposure. In addition, exposure was similar between the NSCLC and melanoma indications. Therefore, there are no anticipated changes in exposure between different indication settings. The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposureresponse relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of pembrolizumab (as assessed by the population PK model) and 4) the assumption that the dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type.  
2.2.1.4 Potential for drug-drug interaction Given the absence of interaction with the Cytochrome P450 enzyme system, the potential for drug-drug interaction is quite low with pembrolizumab.
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2.2.1.5 safety profile

The most common adverse reactions (reported in > 20% of patients) of pembrolizumab include fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.  
Pembrolizumab leads to the development of severe or lifethreatening immune related adverse events in 10-15% of patients treated. The following toxicities are of particular interest: Immunemediated pneumonitis (occurring in approximately 3% of the 411 melanoma patients treated on the phase I trial of pembrolizumab), immune-mediated colitis (1%), immune-mediated hepatitis (0.5%), immune-mediated hypophysitis (0.5%), immune-mediated nephritis (0.7%), immune-mediated hyper- (1.2%) and hypothyroidism (8.3%).
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2.2.1.6 rationale for proposed initial

The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on simulations performed using the population PK model of pembrolizumab showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the exposure range established in melanoma as associated with maximal efficacy response and 3) will maintain individual patients exposure in the exposure range established in melanoma that are well tolerated and safe. A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity in the logistical chain at treatment facilities and reduce wastage. There are extensive data that have been generated in the pembrolizumab development program supporting that a fixed dose of 200 mg is suitable for use in subjects with advanced melanoma as a replacement for weight-based dosing of 2 mg/kg. Details of these supporting data were were published recently (Freshwater T, Kondic A, Ahamadi M, Li CH, de Greef R, de Alwis D, Stone JA. Evaluation of dosing strategy for pembrolizumab for oncology indications. J Immunother Cancer. 2017 May 16;5:43. doi: 10.1186/s40425-017-0242-5. eCollection 2017. PubMed PMID: 28515943; PubMed Central PMCID: PMC5433037). The results presented in this paper demonstrate that fixed dosing of pembrolizumab 200 mg Q3W maintains exposures comparable with or slightly increased relative to those from 2 mg/kg Q3W. Fixed dosing eliminates the waste generated by weight-based dosing, improves compliance, and might also reduce the risk of dosing errors by reducing dosing complexity. Based on these data, trials using pembrolizumab monotherapy or in combination with other therapies have utilized a fixed dosing regimen for pembrolizumab and have resulted in FDA approvals for NSCLC, HNSCC, cHL, urothelial carcinoma, and MSI-H cancer using 200 mg Q3W. With respect to melanoma, on May 17, 2017, the FDA approved to replace the 2 mg/kg Q3W dose for melanoma patients with 200 mg Q3W.
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2.2.2 dabrafenib mesylate (gsk2118436b)

The RAS/RAF/MEK/ERK pathway is a critical proliferation pathway in many human cancers. This pathway can be constitutively activated by molecular alterations including BRAF activating mutations. Approximately 90% of all identified BRAF mutations in human cancer consist of a T1799 transversion mutation in exon 15, which results in a V600 E/D/K(T1799A) amino acid substitution. This mutation appears to mimic regulatory phosphorylation and increases BRAF activity approximately 10-fold compared to wild type (wt). RAF is a validated target in BRAF V600E-containing melanoma. In August 2011, the FDA approved vemurafenib
(PLX4032, Zelboraf®), an ATP-competitive selective RAF inhibitor for the treatment of late-stage BRAFV600E melanoma. In the pivotal phase III trial of vemurafenib vs. dacarbazine (Chapman *et al.,* 2011), vemurafenib demonstrated significant improvement in overall survival (OS) (6-month OS of 84% vs. 64%, hazard ratio [HR]=0.37; P<0.001), progression-free survival (PFS) (estimated median PFS of 5.3 months vs. 1.6 months (HR=0.26; P<0.001]), and overall response rate (ORR) (48% vs. 5%). However, in patients with colorectal cancer (CRC) bearing the BRAF V600E mutation, there was only one partial response (PR) among 20 patients treated (ORR 5%) and four minor responses (Kopetz *et al.,* 2010).
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2.2.2.1 mechanism of action

Dabrafenib mesylate (GSK2118436B), a 4-(3aminosulfonylphenyl)-5-(pyrimidin-3-yl) thiazole, is an ATPcompetitive, selective inhibitor of RAF kinase. Dabrafenib potently inhibits all RAF isoforms, with the strongest potency against the V600 mutant, as compared to its activity against wt BRAF and CRAF (see below). In a panel of 270 kinases tested outside RAF isoforms, only seven kinases (LIMK1, ALK5, NEK11, SIK, SIK2, PKD2, and BRK) were inhibited at a 50% inhibitory concentration (IC50) <100 nM (Investigator's Brochure, 2012a).
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inhibitory activity of dabrafenib on

| BRAFV600E   | BRAFV600K   | BRAFV600D   | wt BRAF   | CRAF   |        |
|-------------|-------------|-------------|-----------|--------|--------|
| IC50        | 0.65 nM     | 0.50 nM     | 1.84 nM   | 3.2 nM | 5.0 nM |  
In a panel of 110 human tumor cell lines with known BRAF mutational status, dabrafenib potently inhibited proliferation of a majority (73%) of BRAFV600E mutant cell lines with growth IC50
(gIC50) <100 nM. In contrast, there was poor or no activity in other BRAF mutants or wt BRAF cell lines. Dabrafenib given orally (PO) for 14 days at doses ranging from 0.1300 mg/kg administered once daily (QD), twice daily (BID), or three times daily (TID) inhibited tumor growth in mice bearing BRAFV600E A375P F11s or Colo205 tumor xenografts. The effect was generally dose dependent up to 10 mg/kg/day (A375P F11s) or 30 mg/kg/day (Colo205), yielding 90-120% tumor reduction relative to untreated animals. However, cessation of treatment was associated with regrowth of the tumors. In A375P F11s melanoma xenografts, inhibition of pERK by >50% in the tumor was seen at doses of ≥3 mg/kg. Based on the single-dose studies, ~100 nM (52 ng/mL) dabrafenib in blood at 6 h post-dosing was needed for effective pharmacodynamic biomarker inhibition in the tumor. At repeated dosing of 30 mg/kg/day, the tumor pERK levels were reduced by >50% at 8 h after dosing (69% on Day 1 and 53% on Day 14). Levels of pERK returned to baseline 24 h post-dosing. Similar ↓pERK effects were seen in the ES-2 ovarian xenograft model, but pERK inhibition was weaker in the Colo205 xenograft model. Of note, concentrations of dabrafenib showing pharmacodynamic activity in xenografts did not cause a reduction in pERK/tERK levels in the normal intact brain.  
2.2.2.2 Clinical Pharmacokinetics (PK) and Activity of Dabrafenib GSK has sponsored several dabrafenib monotherapy studies, mostly in patients with BRAF V600 mutant melanoma; and trials for combinations with a MEK inhibitor. FTIH Phase 1 Trial of Dabrafenib Monotherapy (BRF112680) BRF112680 is the FTIH study of dabrafenib (gelatin capsule) monotherapy, administered at escalating doses at different schedules (12-600 mg PO QD, BID, or TID). A total of 184 patients who had BRAF mutations (V600E or V600K) in their tumors were treated (Investigator's Brochure, 2012a). PK and metabolism of dabrafenib: In the single-dose studies, plasma dabrafenib concentrations peaked at a median time of 2 h (Tmax) and bi-exponentially declined thereafter. The median terminal half-life (t1/2) was approximately 8 hours after a single dose. Increases in Cmax and AUC were generally dose proportional up to 300 mg. However, on repeat daily dosing, the drug exposure decreased with time. At the recommended phase 2 dose (RP2D) of 150 mg PO BID, Cmax and AUC were about 40% lower on Day 15 vs. Day 8 (geomean Cmax of 1.35 vs. 0.81 mcg/mL and geomean AUC of 2.62 vs. 4.17 mcg•hr/mL), although the AUC remained stable over subsequent administrations. The decreased exposure with time may be a result of GSK2118436-mediated induction of its own metabolism. Three metabolites of dabrafenib were characterized and may contribute to activity. GSK2285403 (hydroxy-metabolite [M7]) PK paralleled that of dabrafenib, while the carboxy- (GSK2298683 [M4]) and desmethyl- (GSK2167542 [M8]) metabolites exhibited a longer t1/2 and accumulated following repeat dosing. Similar to dabrafenib concentrations, exposure for all metabolites showed a less than dose proportional increase with repeat dosing. Fecal excretion was a major route of dabrafenib elimination in humans, accounting for 71.1% of the dose administered, and renal excretion accounted for about 20% of drug elimination. Administration of dabrafenib with a high-fat, high-calorie meal reduced the oral bioavailability of dabrafenib when compared to the fasted state with a decrease in Cmax and AUC of 51% and 31%,
respectively, and delayed its absorption. Therefore, the current recommendation is to administer dabrafenib under fasting conditions, either 1 h before or 2 h after a meal.  
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Drug-drug interactions: As a CYP3A4 inducer, dabrafenib, when administered 150 mg BID in combination with midazolam (a substrate of CYP3A4), significantly reduced the midazolam exposure by 74% (the ratios of midazolam with or without dabrafenib were 0.39 for Cmax and 0.26 for AUC). Dabrafenib thus induces CYP3A4 metabolism and may induce other enzymes such as CYP2B6, CYP2C8, CYP2C9, and CYP2C19. Co-administration of dabrafenib and medicinal products which are affected by the induction of these enzymes such as hormonal contraceptives, warfarin, or dexamethasone may result in decreased concentrations and loss of efficacy.  
Based on preclinical in vitro studies, dabrafenib was shown to be primarily metabolized by CYP2C8 and CYP3A4. Co-administration of ketoconazole (CYP3A4 inhibitor) increased the AUC of dabrafenib by 57%. Medicinal products that are strong inhibitors or inducers of CYP2C8 or CYP3A are likely to increase or decrease, respectively, dabrafenib concentrations. Alternative agents should be considered during administration with dabrafenib when possible. Use caution if strong inhibitors (*e.g.*, ketoconazole, nefazodone, clarithromycin, ritonavir) or inducers (*e.g.*, rifampin, phenytoin, carbamazepine, phenobarbital) of CYP2C8 or CYP3A4 are coadministered with dabrafenib.
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pharmacodynamic effect of dabrafenib

Median tumor pERK inhibition was 83.9% (range: 38.0 to 93.3%) in BRAF mutant melanoma subjects receiving doses of 70 to 200 mg BID. The relationship between exposure and % pERK inhibition was characterized using a maximum response (Emax) model with 100% maximum inhibition and IC50 of 134 ng/mL (95% CI: 92.7, 155) based on the sum of the potency-adjusted parent and active metabolite concentrations. A dose-related decrease in pERK was predicted with total daily doses <200 mg (100 mg BID) dabrafenib, with a plateau occurring beyond total daily doses of 200 mg thereafter.
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selection of the rp2d

The single-agent MTD for dabrafenib was not reached. A dose of 150 mg BID was selected for further single-agent development, based on the following PK/pharmacodynamics, safety, and activity:
a) dose increases beyond 150 mg BID yielded no increase in Cmax and <50% increase in AUC; b) incidence and severity of AEs was similar at 100-300 mg BID; c) pERK target suppression was >80%; and d) the tumor response rate (RR) was 50% at 150 mg BID.
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antitumor activity of dabrafenib monotherapy

Activity in patients with BRAF V600E or V600K melanoma: The FTIH monotherapy study (BRF112680) enrolled 114 enrolled patients with BRAF V600 mutant melanoma in the dose escalation phase (Part 1), and 70 patients at the RP2D (150 mg BID) in Part 2. Within this study, a cohort of 10 patients with previously untreated asymptomatic brain metastasis was evaluated for intracranial response to dabrafenib (Long *et al.,* 2011). All patients had decreases in the size of the brain metastasis; three patients achieved complete radiographic resolution of brain lesions (bCR) as well as reduction in extracranial disease. The response rates in patients treated at 150 mg BID are shown below.  
| FTIH monotherapy study (BRF112680) response rates in melanoma patients Subgroup Patient # ORR Part 1 V600E 77 50% V600K 14 20% Part 2, Cohort  V600E/K with brain mets 10 40% A V600E/K without brain  20 55% mets   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
When dabrafenib was used at 50 mg BID (Part 2, Cohort C) in patients with BRAF V600E mutant melanoma, the response rate was only 17%. Correlative studies in the phase 1 monotherapy trial: Preliminary genomic analysis was performed on 37 patients with melanoma, using a Sequenom mutation analysis for 11 genes (AKT, BRAF, CDK4, CDKN2A, GNAQ, GNA11, Kit, MEK1, MEK2, and NRAS), and PTEN analysis by sequencing, comparative genomic hybridization (CGH), and multiplex ligation-dependent probe amplification (MPLA) (Nathanson *et al.,* 2011). Nine patients (24%) had PTEN genetic alterations including mutation, hemi- /homozygous deletion. PTEN deficiency was associated with lower responses (ORR of 11% and 54% in patients with and without PTEN alteration, respectively). Phase III trial of dabrafenib versus chemotherapy in patients with advanced BRAFV600 mutant melanoma (BREAK3 Trial): Patients with previously untreated, unresectable stage III or IV
BRAFV600E-mutated melanoma were randomized (3:1) and stratified by stage to dabrafenib (150 mg PO BID) or dacarbazine (DTIC)
(1000 mg/m2, IV, every 3 weeks [Q3W]). Of 250 patients enrolled, 187 were randomized to dabrafenib and 63 to DTIC from February to September 2011. At the time of the primary analysis, there were 118 events (77 dabrafenib and 41 DTIC). The hazard ratio for PFS was 0.30 (95% CI: 0.18-0.53; P<0.0001), with median PFS of 5.1 months for dabrafenib and 2.7 for DTIC. OS data were immature, with 30 deaths reported. Confirmed RR was 53% for dabrafenib and 19% for DTIC. Benefits in PFS and RR were observed in all subgroups evaluated. Activity in BRAF V600E mutant tumors other than melanoma: Efficacy data for dabrafenib in non-melanoma tumors are limited to 18 patients enrolled in the phase 1 trial. Among them, seven had CRC, nine had thyroid cancer, and one each had NSCLC and ovarian cancer, respectively. Confirmed partial responses (PRs)
were seen in one patient with CRC, and in 2 patients with thyroid cancer; the patient with NSCLC had an unconfirmed PR at 6 weeks followed by progressive disease (PD) at 12 weeks. Eleven patients (six with thyroid cancer and five with CRC) had stable disease (SD) as their best response; the ovarian cancer patient had SD before progressing at approximately 36 weeks.
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2.2.2.3 safety profile

A comprehensive list of adverse events is included in Section 7 of the protocol. As of February 20, 2012, among 184 patients treated on the FTIH phase 1 trial, 99% experienced at least one adverse event (AE) (any grade). The most common (>20% of all subjects) AEs of any grade across all dosing cohorts in Part 1 and Part 2 were fatigue (42%), pyrexia (37%), headache (35%), nausea (34%), hyperkeratosis (33%), diarrhea (27%), arthralgia (25%), pain in extremity (25%), decreased appetite (24%), alopecia (23%) and rash (23%).  
Serious AEs (SAEs) were reported in 39% of patients, including SCC (12%), pyrexia (7%), and urinary tract infection (3%). Sixtyfour patients are reported to have had study drug interrupted due to the occurrence of AEs. Pyrexia was the AE that led most frequently to a dose interruption. Fifteen patients reported a dose reduction due to the occurrence of AEs. There were no instances of discontinuation of study treatment due to AEs and no fatal AEs reported in the study among patients who received at least one dose of dabrafenib.
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aes of special interest

The following events observed in dabrafenib monotherapy studies are discussed in detail because they may be a class effect of BRAF inhibitor compounds, have occurred at high frequency, and/or are potentially life-threatening. Dermatologic effects: Rashes and other skin lesions, from hyperkeratosis to SCC, have been observed at the frequencies below in FTIH study BRF112680.  
| AE Term                 | Any Grade   | Grade ≥3   |
|-------------------------|-------------|------------|
| Hyperkeratosis          | 61 (33)     | 0          |
| Skin papilloma          | 46 (25)     | 1 (<1)     |
| Rash                    | 42 (23)     | 1 (<1)     |
| Skin lesion             | 26 (14)     | 0          |
| Actinic keratosis       | 21 (11)     | 0          |
| Squamous cell carcinoma | 22 (12)     | 21 (11)    |
| Pruritis                | 22 (12)     | 0          |
| Seborrheic keratosis    | 25 (14)     | 0          |
| Acrochordon             | 19 (10)     | 0          |
| Melanocytic nevus       | 19 (10)     | 0          |
| Rash pruritic           | 11 (6)      | 0          |  
Pre-malignant and malignant skin lesions: Cutaneous SCC and keratocanthoma were reported in 11% and 2%, respectively, of patients treated with dabrafenib in FTIH study BRF112680. SCC and proliferative skin toxicities are considered a class effect of BRAF inhibitors such as vemurafenib and sorafenib (Long *et al.,* 2011). SCC was treated with local excision, and treatment with dabrafenib was continued. Most SCCs of the skin have been localized and generally treated with curettage, and have been without significant clinical sequelae. Only one patient required a dose reduction in response to the event. The median onset of the first SCC occurred on Day 67 (range: Day 9-217).  
Other treatment-emergent malignancies: Other treatmentemergent cutaneous malignancies such as basal cell carcinoma and new primary melanoma have been reported with BRAF inhibitors (Zelboraf, 2011).  
Pyrexia: Across dabrafenib studies, all SAEs of pyrexia, influenzalike illness, cytokine release syndrome, systemic inflammatory response syndrome underwent clinical review for serious events of pyrexia complicated by hypotension, dehydration, circulatory collapse, severe rigors, or renal failure in the absence of another identifiable etiology (*i.e.*, infection). Abnormal ejection fraction: Left ventricular ejection fraction (LVEF) changes were not observed in the early safety reviews of CONFIDENTIAL
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dabrafenib. However, these events are included in AEs of special interest because they are known side effects of several kinase inhibitors including imatinib, sunitinib, and lapatinib (Force *et al.*, 2007). Cardiac valvular abnormalities: Data from preclinical studies suggested that dabrafenib has the potential to cause cardiac valve abnormalities. In a 28-day dog toxicology study, high doses (50 mg/kg/day; approximately 40-fold over the therapeutic dose) of dabrafenib in 1 dog (n=10) resulted in hypertrophy of the right atrioventricular valve (tricuspid valve). Therefore, this was monitored in clinical trials with echocardiograms.  
Uveitis: Uveitis was reported at a frequency of 3.8% as an AE of vemurafenib in previously treated patients with BRAF V600 mutation-positive metastatic melanoma (Chapman *et al.*, 2011; Sosman *et al.*, 2010), and has been observed in patients receiving dabrafenib (incidence in study BRF112680 was 1%). Renal failure: Cases of renal failure have been identified on clinical trials with a possible causal relationship to dabrafenib.  
2.2.2.4 Clinical Experience with the Combination of **Dabrafenib + Trametinib**
Data on 247 patients with metastatic melanoma and BRAF V600 mutations participating in the phase 1/2 study of dabrafenib and trametinib, BRF113220, have been published (Flaherty *et al.*, 2012 \#2). PK Repeat-dose trametinib (2 mg QD) had no effect on the PK of single-dose dabrafenib (75 mg), but the plasma levels of dabrafenib after repeated dosing were higher in combination with trametinib as compared to that with previously reported PK with monotherapy. Geometric mean Day 15 AUC of dabrafenib in combination ranged from 3539 to 5187 ng•hr/mL, while the AUC observed in the monotherapy study was 2619 ng•hr/mL. The data suggest that trametinib may have a minor inhibitory effect on dabrafenib clearance (Flaherty *et al.*, 2012 \#2). Preliminary results showed that trametinib accumulated with repeat dosing; Day 21 AUC0-24 was 314 ng•hr/mL in combination with dabrafenib at 75 mg BID and 335 ng•hr/mL in combination with dabrafenib at 150 mg BID (Investigator's Brochure, 2012b).
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safety and the rp2d for

dabrafenib In the dose escalation portion (Part B) of study BRF113220, one DLT of a recurrent grade 2 neutrophilic panniculitis occurred, among the 24 patients treated at the highest dose level (150 mg dabrafenib BID + 2 mg trametinib QD) (150/2) (Flaherty *et al.*, 2012). The MTD of the combination was not reached, and the RP2D was therefore 150/2. Pyrexia was common in the 150/2 group, occurring in 88% of patients. In the randomized, open-label, phase 2 portion (Part C) of the study, the incidence of certain AEs were lower with the combination as compared to single agent dabrafenib: cutaneous squamous-cell carcinoma (including keratoacanthoma) (19 vs. 7%), and rash (27 vs. 36%) (Flaherty *et al.*, 2012 \#2). On the other hand, the frequencies of pyrexia appeared increased (39 vs. 14%). The combination was also associated with an increased prevalence of MEK inhibitor-associated acneiform dermatitis (16 vs. 4%, with no grade 3 or 4 events reported). There was one death from sepsis in the 150/1 combination group, and there were three deaths in the combination 150/2 group (two from brain hemorrhage and one from pulmonary embolism); none of these events were considered to be related to a study drug. The incidences of main AEs (all grades) observed in Part C of the trial are presented in the table below as patients (percent).  
| Adverse Event               | Dabrafenib  Monotherapy  (n=53)   | Combination  150/1   | Combination  150/2   |
|-----------------------------|-----------------------------------|----------------------|----------------------|
| (n=54)                      | (n=55)                            |                      |                      |
| Pyrexia                     | 14 (26)                           | 37 (69)              | 39 (71)              |
| Nausea                      | 11 (21)                           | 25 (46)              | 24 (44)              |
| Vomiting                    | 8 (15)                            | 23 (43)              | 22 (40)              |
| Diarrhea                    | 15 (28)                           | 14 (26)              | 20 (36)              |
| Rash                        | 19 (36)                           | 11 (20)              | 15 (27)              |
| Hyperkeratosis              | 16 (30)                           | 3 (6)                | 5 (9)                |
| Cutaneous squamous cell     | 10 (19)                           | 1 (2)                | 4 (7)                |
| carcinoma Alopecia          | 18 (34)                           | 5 (9)                | 3 (5)                |
| Skin papilloma              | 8 (15)                            | 4 (7)                | 2 (4)                |
| Decreased ejection fraction | 0                                 | 2 (4)                | 5 (9)                |
| Cardiac failure             | 0                                 | 1 (2)                | 0                    |
| Hypertension                | 2 (4)                             | 2 (4)                | 5 (9)                |
| Chorioretinopathy           | 0                                 | 0                    | 1 (2)                |
| Neutropenia                 | (11)                              |                      |                      |
| Acneiform dermatitis        | (4)                               | (11)                 | (16)                 |
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activity

Efficacy analyses were performed in the intention-to-treat CONFIDENTIAL
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population of the phase 2 portion (Part C) of study BRF113220, with a median follow-up of 14.1 months (Flaherty *et al.*, 2012). All major efficacy endpoints were improved, including PFS, 12-month PFS, ORR, and duration of response. Endpoint values as assessed by site investigators for this portion of the study are presented in the table below.  
| End Point                                           | Dabrafenib  Monotherapy  (n=54)   | Combination  150/1 (n=54)   | Combination  150/2 (n=54)   |
|-----------------------------------------------------|-----------------------------------|-----------------------------|-----------------------------|
| Progression-free Survival -  months Median (95% CI) | 5.8 (4.6-7.4)                     | 9.2 (6.4-11.0)              | 9.4 (8.6-16.7)              |
| Progression-free Survival at 12                     | 9 (3-20)                          | 26 (15-39)                  | 41 (27-54)                  |
| mo. % (95% CI) CR or PR                             | 29 (54 [40-67])                   | 27 (50 [36-64])             | 41 (76 [62-86])             |
| Patients (% [95% CI]) Duration of response          | 5.6 (4.5-7.4)                     | 9.5 (7.4-NA)                | 10.5 (7.4-14.9)             |
| Median months (95% CI)                              |                                   |                             |                             |
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2.2.2.5 rationale for proposed starting

The safe and efficacious dose of dabrafenib is 150 mg PO twicedaily as reflected by the FDA approval of this dose. Further, this dose is safe and effective in combination with trametinib. Given the known survival advantage with this therapy taken at this dose and schedule, we believe it is a priority to administer this dose of dabrafenib as the backbone of the proposed combination therapy.
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2.2.3 trametinib dimethyl sulfoxide (gsk1120212b)

The RAF-MEK-ERK pathway plays a critical role in multiple cellular functions. Activation of the pathway can result from activation/mutations of the upstream receptor tyrosine kinases (RTKs) and RAS, or upregulation/mutations in RAF and MEK. Upon activation, RAF acts as the MAPK kinase and activates MAPKK (MEK1/2), which in turn catalyze activation of the effectors ERK1/ERK2. Once activated, ERK1/2 translocate into the nucleus and phosphorylate a number of effector proteins and transcriptional factors that regulate cell proliferation, motility, differentiation, and survival. Trametinib is one of the several MEK inhibitors in clinical development. Experience to date indicates that MEK is a valid target. In a phase III trial comparing trametinib with dacarbazine or paclitaxel in patients with BRAF V600E or V600K mutant metastatic melanoma, CONFIDENTIAL
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trametinib demonstrated a significantly better response rate, progression-free survival, and overall survival (Flaherty *et al.*, 2012 \#1). However, single agent activities are limited. Extensive research is underway to identify the patient selection markers and develop rational combination strategies. Preclinical studies have provided strong rationale and proof of principle for combination of MEK inhibitors with RTK inhibitors (EGFR or IGF-1R) (Gopal *et al.,* 2010; Ebi *et al.,* 2011), PI3K/AKT inhibitors (Engelman *et al.,* 2008; Hoeflich *et al.,* 2009), and mTOR inhibitors. On the other hand, the optimal dose/schedule and patient selection criteria for combination regimens have not been defined. Phase 1 results for a number of combinations have been reported, including AZD6244 + MK2206 (Tolcher *et al.,* 2011) and GDC-0973 + GDC-094 (MEK + PI3K
inhibitor) (Bendell *et al.,* 2011).
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2.2.3.1 mechanisms of action and

Trametinib is a dimethyl sulfoxide (DMSO) solvate compound (ratio 1:1) with potent, allosteric and ATP non-competitive inhibition of MEK1/2 (IC50 of 0.7 and 0.9 nM against MEK1 and MEK2, respectively) (Gilmartin *et al.,* 2011). Trametinib inhibited MEK1/2 kinase activity and prevented RAF-dependent MEK phosphorylation (S217 for MEK1), producing prolonged pERK1/2 inhibition. Trametinib showed better potency against unphosphorylated MEK1/2 (u-MEK1/2) when compared with preactivated diphosphorylated MEK (pp-MEK), suggesting that uMEK affords a higher affinity binding site for trametinib than does pp-MEK. The specificity of trametinib was confirmed against a panel of 183 kinases, including MEK5 (the closet kinase homolog to MEK1/2), CRAF, BRAF, ERK1, and ERK2 (Yamaguchi *et al.,* 2011). Trametinib demonstrated equal potency against activated MEK1and MEK2-mediated phosphorylation of ERK (sequence identity of 85% across the whole protein and 100% in the active site for humans). Trametinib demonstrated preferential inhibition of RAFmediated MEK1 activation (IC50 = 0.60 nM) over pMEK1 kinase activity (IC50 = 13 nM) (Investigator's Brochure, 2012a).  
BRAF-mutant Colo205, A375P F11s, and HT-29 human tumor xenograft mouse models showed the most significant mean tumor growth inhibition (TGI) (80% to 87%) at 3.0 mg/kg trametinib, with multiple complete and partial tumor regressions. In the Colo205 model, tumor regression was observed even at a dose of 0.3 mg/kg (Yamaguchi *et al.,* 2011). Two KRAS-mutant xenograft models, HCT-116 and A549, also showed significant TGI (83% and 75%) but without significant tumor regressions (Gilmartin *et al.,* 2011). As predicted by cell proliferation assays, tumor xenograft lines with wild-type (wt) RAF/RAS (PC3, BxPC3, and BT474) were much less sensitive, showing only modest TGI (44-46%) with no tumor regressions. Pharmacodynamic studies were performed in mice treated with trametinib for 14 days (Gilmartin *et al.,* 2011). In the A375P F11s xenograft model, the first dose of trametinib (3 mg/kg) significantly reduced pERK for more than 8 hours on Day 1. pERK inhibition was more sustained (over 24 hours) after the Day 7 dose, probably due to an increase in the steady-state levels of trametinib after repeated doses. The average Cmax in blood was 1,410 nM on Day 7, with an estimated half-life (t1/2) of 33 hours. In addition, immunohistochemistry (IHC) also confirmed inhibition of cell proliferation (reduced Ki67) and G1 cell cycle arrest (elevated p27Kip1/CDKN1B) following 4 days of treatment.  
2.2.3.2 Clinical Pharmacokinetics (PK) and Activity of Trametinib
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ftih phase 1 trial of

There are 3 parts in this ongoing study. Part 1: The doseescalation portion involves administration of trametinib (repeat doses of 0.125 mg to 4.0 mg) to patients with solid tumors or lymphoma in one of three schedules - (1) QD for 21 days followed by 7 days without drug, (2) loading dose on Day 1 or Day 1-2, followed by QD with the designated dose, or (3) QD dosing without a drug holiday. Part 2: cohort expansion at the recommended phase 2 dose (RP2D) for pancreatic cancer, melanoma, NSCLC, CRC, or any BRAF mutation-positive cancer. Part 3: expansion to characterize the biologically active range of trametinib via analysis of pharmacodynamic biomarkers (biopsies or FDG-PET). The dose escalation part and some of the cohort expansion components have been completed. The MTD of trametinib was established as 3 mg QD, but the recommended phase 2 dose (RP2D) was chosen at 2 mg QD based on tolerability of repeated cycles (Infante *et al.,* 2010). PK and metabolism of trametinib: PK measurements were conducted under fasting conditions. After a single dose (Day 1), AUC0-24 and Cmax values were doseproportional up to 6 mg, lower than dose proportional following 8 mg, and greater than dose proportional following the 10 mg dose.  
Median Tmax was 1.5 hours.  
After repeat doses (Day 15), trametinib accumulated with a mean accumulation ratio of 6.6 at the RP2D of 2 mg QD. Betweensubject variability in exposure ranged from 27-50% for Cmax and 2041% for AUC0-24 across all dosing regimens. The effective t1/2 was approximately 4.5 days, and steady state was reached by approximately Day 15. Trametinib had a small peak:trough ratio of
~2 (Infante *et al.,* 2010). At 2 mg QD on Day 15, mean AUC0-24 was 376 ng•h/mL and Cmax 23 ng/mL, and the mean trough concentrations ranged from 10.0 to18.9 ng/mL. The long half-life and small peak:trough ratio of trametinib allowed constant target inhibition within a narrow range of exposure.
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drug-drug interactions

Trametinib is metabolized predominantly via deacetylation (noncytochrome P450 [CYP450]-mediated) with secondary oxidation or in combination with glucuronidation biotransformation pathways (Investigator's Brochure, 2012a). The deacetylation is likely mediated by hydrolytic esterases, such as carboxylesterases, or amidases. Based on *in vitro* studies, trametinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2D6, and CYP3A4. Although trametinib was found to be an *in vitro* inhibitor of CYP2C8, CYP2C9, and 2C19; inducer of CYP3A4; and inhibitor of transporters (OATP1B1, OATP1B3, P-glycoprotein [P-gp], and breast cancer resistance protein [BCRP]), its low efficacious dose, and low clinical systemic concentration (22.2 ng/mL or 0.04 mcM at 2 mg) relative to the *in vitro* inhibition/induction potency suggests an overall low potential for drug-drug interactions.
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pharmacodynamic effect and biomarkers

The relationship between dose and tumor biomarkers such as pERK, Ki67, and p27, were evaluated in patients with BRAF or NRAS mutation-positive metastatic melanoma (Investigator's Brochure, 2012a). In general, increasing exposures and/or doses provided greater pharmacodynamic effects. The median change observed at a dose of 2 mg QD was 62% inhibition of pERK, 83% inhibition of Ki67, and a 175% increase in p27.
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antitumor activity of trametinib monotherapy

In the FTIH phase 1 trial, 14 patients with BRAF-mutant melanoma received trametinib at 2 mg QD (2 mg/day continuously, or 2 mg for 21 days followed by a 1 week break). The overall objective response rate (ORR) was 43% (6/14), including 2 complete responses (CRs) (Investigator's Brochure, 2012a). In 9 patients with BRAF wt melanoma, 2 patients achieved a partial response (PR), and 3 stable disease (SD) (Infante *et al.,* 2010). In 26 evaluable pancreatic cancer patients, there were 2 PRs (1 PR was CONFIDENTIAL
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KRAS mutation-positive) and 11 SD (2 achieved ≥20% tumor reduction) (Messersmith *et al.,* 2011). Among the 27 CRC patients (without selection of RAS or RAF mutations), 8 SD were observed. In a phase 3 trial, patients with unresectable stage IIIC or IV cutaneous melanoma with a BRAF V600E or V600K mutation were randomized (2:1) to trametinib (2 mg, PO, QD) or chemotherapy (dacarbazine or paclitaxel) (Flaherty *et al.*, 2012). There were 322 patients in the intention-to-treat (ITT) population, of whom 273 (85%) were in the primary efficacy population (patients with BRAFV600E-positive cancer who did not have brain metastases at baseline). In the ITT analyses, the ORR was 22% in the trametinib group and 8% in the chemotherapy group; the median duration of PFS was 4.8 months in the trametinib group as compared with 1.5 months in the chemotherapy group; and the 6-month OS rate was 81% in the trametinib group and 67% in the chemotherapy group.
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antitumor activity of trametinib in

In a phase 1/2 monotherapy study, acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) patients were given trametinib at dose levels from 1-2 mg QD. Drug-related AEs in 45 patients were similar to that observed in patients with solid tumors, and 2 mg PO QD was selected for further investigation in this patient population. Twelve patients (23%) withdrew due to an AE, including cardiac failure (2) and infection (2). Efficacy was reported in 39 patients (Borthakur *et al.,* 2010). The best response in 13 patients with KRAS or NRAS mutations included 3 CRs (23%), 7 SD (54%), and 1 PD (progressive disease) (5%). In 26 patients with wild-type RAS or an unknown mutation, there were 2 PRs (8%).
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2.2.3.3 trametinib safety profile

A comprehensive list of adverse events is included in Section 7 of the protocol. Due to limited experience in human subjects, there is currently incomplete information available about the relationship of AEs and administration of trametinib. Based on available AE data from clinical studies involving trametinib to date, the most common toxicities are rash and diarrhea. Rash and diarrhea are common, class-effect toxicities for MEK inhibitors. In addition, visual impairment and left ventricular ejection fraction (LVEF) reduction, although observed at lower frequencies, are also considered classeffect toxicities as they have been observed with trametinib as well as other MEK inhibitors.
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aes of special interest

Rash, diarrhea, visual disorders, hepatic disorders, cardiac-related AEs, and pneumonitis are considered AEs of special interest because they are either known class effects (*i.e.*, have been observed with other MEK inhibitors) or are potentially lifethreatening (Investigator's Brochure, 2012a).  
Rash: Rash was a common AE observed across different dose levels and in different combinations. The majority of rash observed with trametinib was acneiform and appeared to occur most frequently on the face, scalp, chest, and upper back. At the 2 mg dose, rash was seen in 48% to 91% of patients in different trials.  
The majority of rash AEs were grades 1 or 2 (68% to 80%); 1% to 18% of patients experienced grade 3 rash AEs, and one patient had a grade 4 rash AE. Diarrhea: At the 2 mg monotherapy dose, 28% to 58% of patients in three trials had diarrhea. Of 219 patients with diarrhea at this dose, the majority of diarrhea AEs were grade 1 or 2 in severity (28% to 56% of all study patients); 6 patients had grade 3 diarrhea, and none had grade 4 diarrhea. Visual disorders: At the 2 mg monotherapy dose, 6% to 21% of the patients in three trials experienced visual disorders. Of the 62 total patients experiencing visual disorders at this dose level, the majority of visual disorders were grades 1 or 2 (6% to 20% of all study patients); five patients experienced grade 3 visual disorders, and one patient experienced a grade 4 visual disorder. Central serous retinopathy (CSR): CSR is a class side effect of MEK inhibitors. As of 22 May 2012, 13 cases of CSR have been reported amongst approximately 1,600 patients treated with trametinib, either as monotherapy or in combination with other anticancer agents: two cases of grade 1, eight cases of grade 2, and three cases of grade 3. All 13 resolved. Retinal vein occlusion (RVO): As of 22 May 2012, four cases of RVO have been observed with trametinib. All four cases occurred in one eye only, and study drug was stopped at time of diagnosis in all cases. There was a decrease in visual acuity in two patients with central RVO (CRVO), while the other two patients experienced no meaningful decrease in visual acuity. Three of the four cases were considered related to study treatment by the investigators. Hepatic disorders: Abnormalities of liver enzymes and bilirubin have been observed with administration of trametinib. However, assessment of these cases was often confounded by co-morbid conditions (such as biliary obstruction), concomitant use of other CONFIDENTIAL
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potentially hepatotoxic drugs, and liver metastases. At the 2 mg monotherapy dose, 10% to 19% of patients in three trials had hepatic disorders. Of the 56 total patients experiencing hepatic disorders, the majority were grade 1 or 2 in severity (7% to 15% of all study patients); 12 patients had grade 3 hepatic disorders, and 3 patients had grade 4 hepatic disorders. Cardiac-related AEs: At the 2 mg monotherapy dose in three trials, 3% to 21% of patients had cardiac-related AEs. Of the 43 total patients experiencing cardiac-related AEs, the majority were grade 1 or 2 in severity (4% to 16% of all study patients); six patients at this trametinib dose level had grade 3 cardiac-related AEs (three left ventricular dysfunction, two decreased LVEF, and one ventricular dilatation), and one patient experienced a grade 4 cardiac-related AE (cardiogenic shock). One patient died of acute cardiac failure, with evidence of massive tumor invasion of the heart; this AE was considered not drug-related by the investigator. In the phase 3 trial of trametinib vs. chemotherapy in patients with melanoma (MEK114267), patients were monitored by serial echocardiogram or MUGA scans. As of 23 June 2012, among 211 patients on the trametinib arm, 17 cardiac-related AEs were reported and included: decreased LVEF (ten grade 1-2, and two grade 3), left ventricular dysfunction (two grade 2, and two grade 3), and one grade 3 cardiac failure. No cardiac-related AEs have been observed on the chemotherapy arm of the study. Cardiacrelated AEs leading to permanent discontinuation of study drug included decreased LVEF (n=2), left ventricular dysfunction (n=2), cardiac failure (n=1), myocardial infarction (n=1), and tachycardia (n=1). There was also one death due to cardiogenic shock secondary to ischemic heart disease, but it was not considered related to trametinib. Pneumonitis: As of the Investigator Brochure's cut-off date, 20 cases of pneumonitis were reported in subjects treated with trametinib, either as monotherapy or in combination with other anticancer agents, in six studies: five cases of grade 1, five cases of grade 2, nine cases of grade 3, and one case of grade 4.
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2.2.3.4 rationale for proposed starting

The safe and efficacious dose of trametinib is 2 mg PO daily as reflected by the FDA approval of this dose. Further, this dose is safe and effective in combination with dabrafenib. Given the known survival advantage with this therapy taken at this dose and schedule, we believe it is a priority to administer this dose of trametinib as the backbone of the proposed combination therapy.
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2.3 rationale

It has been shown that inhibition of the mitogen-activated protein kinase (MAPK) pathway in patients with melanoma, through inhibition of BRAF and/or MEK, leads to increased melanoma antigen expression, decreased immunosuppressive cytokines, increased trafficking of CD8+ T-lymphocytes, and upregulation of immune exhaustion markers such as PD1 and PDL1. Also, in collaboration with Adaptive Biotechnologies, we have shown that patients with a higher proportion of preexisting tumor infiltrating lymphocyte clones, determined by T-Cell Receptor (TCR) rearrangement sequencing (so-called ImmunoSeq), have better outcomes with BRAF/MEKi therapy, although nearly all patients have an increase in TCR clonality in the setting of BRAF/MEKi therapy. The major conclusion from this data is that MAPK pathway targeting enhances anti-tumor immunity within the tumor microenvironment, which provides a strong rationale for combination MAPK targeted therapy with immune targeted therapy. A number of trials of combination MAPK targeted therapy (MTT) with immune targeted therapy have been opened in recent years with mixed results. One of the major issues has been tolerability, particularly with combinations of MTT and ipilimumab. We believe that the value of combining MTT with immunotherapies, such as pembrolizumab, is that MTT may enhance immune responses in the tumor microenvironment and convert an immunologically nonresponsive tumor microenvironment into an environment that is responsive to anti-PD1 immunotherapy. Thus, we are interested in testing trial designs that incorporate a lead-in phase of MTT and a brief period of concomitant MTT and immune targeted therapy.  
This trial has two planned cohorts, BRAFV600 mutant (cohort 1) and BRAFwild-type melanoma (cohort 2). Treatment commences with 2 weeks of MTT
(dabrafenib plus trametinib in cohort 1, trametinib in cohort 2), then two 3 weeks cycles of concomitant MTT and pembrolizumab, followed by singleagent pembrolizumab thereafter. Serial biopsies will be performed prior to MTT, and (if feasible) following the 2-week lead-in of MTT, and (if feasible) following six weeks of combination immune therapy and MTT. An optional biopsy at time of disease progression will also be performed. This trial represents a unique opportunity to not only test the effectiveness of combined immune and MTT, but also to determine which patients are most likely to benefit from this approach and, more importantly, to begin to understand why patients do or do not benefit. This valuable information that may lead to the next wave of combinatorial therapy in melanoma that involves MTT, anti-PD1 therapy, and other agents that target critical mediators of adaptive or innate resistance to combined MTT and pembrolizumab. Due to a recent shortage of research grade dabrafenib and trametinb, we plan to use commercially availability dabrafenib and trametinib. Since we cannot guarantee supply of "off-label" trametinib for cohort 2, we will open cohort 1 initially and consider CONFIDENTIAL
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opening cohort 2 in mid-2017, after more data is available for MEK inhibitors in patients with BRAF wild-type melanoma.
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2.4 correlative studies background

Recently, a number of predictive biomarkers of response to anti-PD1 antibodies in melanoma and other malignancies have been reported. These include tumor factors (such as mutational burden and tumor neoantigen expression) immunologic factors (including cytotoxic T-lymphocyte infiltration with functional capacity to recognize tumor antigens, so-called T-cell diversity), and tumorimmune microenvironmental factors like PD-L1 expression. With each new report, a clear picture is emerging that tumors with high mutational burden and neoantigen expression, increased T-cell diversity, and elevated PD-L1 expression are primed for immune destruction in the setting of single-agent anti-PD1 antibodies. Conversely, tumors with low mutational load and neoantigen expression, low T-cell diversity, and low PD-L1 expression are less susceptible to immune-mediated tumor cell destruction. One of the next great challenges in the field is to develop strategies that convert an immunologically non-responsive tumor microenvironment into one primed to respond to antiPD1 therapy.  
In this trial, we expect that lead-in MTT will trigger changes in the tumor immune microenvironment that will allow patients to have a more robust response to the anti-PD1 antibody, pembrolizumab. However, it will be critical to document these changes in tumor immune microenvironment. As such, tumor biopsies will be performed in all patients enrolled onto the first Stage of the Simon 2-stage design for both cohorts at four time points:
1. Prior to commencing MTT 2. Following 2-week MTT lead-in 3. Following 6-weeks of combined pembrolizumab with MTT (if feasible) 4. At the time of disease progression (optional)
Multiple cores will be obtained and/or sufficient tumor excised at each biopsy time-point, assuming that it is safe to do so (e.g. patients with rapid responses may have very little tumor to biopsy safely at the latter time points). Core biopsies or portions of the excised tumor will be processed with the following hierarchy in mind:  
| 2. Disaggregation and flow cytometry   | (Sharpe)   |
|----------------------------------------|------------|
| 3. FFPE                                | (Sullivan) |
| 4. Single-cell RNA seq of T cells      | (Hacohen)  |
| 5. Single-cell RNA seq of tumor cells  | (Garraway) |  
Analysis will then be carried out to compare changes seen longitudinally and to determine if those changes are associated with improved outcomes to therapy with study treatment. Most of this work will exploratory in nature, as analysis such as the technology for single-cell sequencing of tumor and T-cells is emerging and no data is presently available to inform how these analyses might be used to help predict which patients are most likely to benefit from singleagent or combination therapy. However, based on previous work, there are two assays that will be incorporated into a predictive model, PD-L1 expression by immunohistochemistry (IHC) and immuno-sequencing (immunoSEQ) using the Adaptive Biotechnologies platform.
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pd-l1 immunohistochemistry

Immunohistochemistry for PD-L1 and CD8 was performed using a monoclonal anti-PD-L1 antibody (Clone E1L3N, Cell Signaling Technologies; Danvers, MA) and a CD8 monoclonal antibody (4B11, RTU, Leica Biosystems, Buffalo Grove, IL), respectively, with an automated stainer (Bond Rx, Leica Microsystems, Buffalo Grove, IL). As there is no recognized standard PD-L1 scoring protocol, we will define PD-L1 positivity as membranous +/- cytoplasmic staining of tumor cells of any intensity using two different cut-offs (≥1% and ≥5 tumor cells) since both have been associated with clinical benefit to PD-1 pathway blockade in melanoma.
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adaptive biotechnologies immunoseq

FFPE specimens (or isolated tumor DNA) and frozen PBMC samples will be shipped to Adaptive. Samples sent to Adaptive will be handled in accordance with Adaptive SOPs. All arriving packages will be opened the same day they arrive and inspected thoroughly for correct labeling and packaging integrity. Adaptive will perform "survey level" sequencing on each tissue sample and "deep level" sequencing on each of the PBMC derived gDNA samples provided. As part of these analyses, Adaptive uses a proprietary assay for the amplification and massive parallel sequencing of millions of CDR3 regions in the T cell receptor beta gene (TCRB) using a multiplex PCR amplification across the VDJ junction of rearranged TCRB.  
Using Adaptive's unique capacity to perform next generation sequencing of Tcell receptors for this study, a large amount of data will be generated using tissue specimens and PBMC samples from all collection time points. In addition to the immunoSEQ Analyzer software, which is available to all of Adaptive clients to aid in data analysis and visualization, Adaptive can directly involve its computational biology and biostatistics personnel in the data analysis.
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tumor microenvironment assessment

To determine how the tumor cells are modulated during MTT alone, anti-PD1 CONFIDENTIAL
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plus MTT and anti-PD1 monotherapy combination, we will use single-cell and bulk RNA-seq, whole exome, etc. to assess the evolution of tumor cells during therapy. Sequential biopsies will provide a means to analyze evolution of tumor cell responsiveness and resistance to therapy To determine how immune cells in the tumor microenvironment are modulated during MTT alone, anti-PD1 plus MTT and anti-PD1 monotherapy combination, we will use single-cell and bulk RNA-seq, and assays to compare immune cell function (e.g., T cell activation vs. exhaustion using cellular immunologic assays, as well as analysis of phosphoproteins and ubiquitination signaling) in temporal biopsies. These studies should reveal how anti-tumor immunity is modulated during the lead-in phase of the clinical trial with MTT, during MTT and anti-PD1 combination therapy and during subsequent anti-PD1 monotherapy.
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3. participant selection 3.1 inclusion

3.1.1 Participants must have histologically confirmed metastatic or unresectable melanoma 3.1.2 Participants must have BRAFV600-mutation status known (molecularly confirmed using validated, commercially available assay performed in a CLIAapproved laboratory).  
If test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided. (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test).  
3.1.3 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) as > 20 mm with conventional techniques or as > 10 mm with spiral CT scan. See section 11 for the evaluation of measureable disease.  
3.1.4 Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of the combination of trametinib with or without dabrafenib, and pembrolizumab in participants less than 18 years of age, children are excluded from this study.  
3.1.5 ECOG performance status ≤ 1 (see Appendix A). 3.1.6 Life expectancy of greater than three months in the opinion of the investigator.
3.1.7 Participants must have normal organ and marrow function as defined below:
Leukocytes (WBC) > 3,000/uL
Absolute neutrophil count > 1,500uL
Platelets > 100,000/uL
total bilirubin < 1.5 X institutional upper limits of normal; total bilirubin > 1.5X above institutional upper limits of normal will be allowed if direct bilirubin is within normal limits or if patients has a documented history of Gilbert's disease AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal Creatinine within normal institutional limits or creatinine clearance
(eGFR) > 60 mL/min/1.73 m2 for subjects with creatinine levels about institutional normal.  
3.1.8 Participants must have disease amenable to and be willing to undergo serial core or excisional biopsies of a tumor lesion(s).
3.1.9 Because both dabrafenib and trametinib are class D agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with either dabrafenib and trametinib, breastfeeding should be discontinued if the mother is treated with either dabrafenib, trametinib, or the combination of dabrafenib and trametinib. Female subjects 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 or 14 days prior to the initiation of study medication for oral contraceptives (Reference Section 5.8. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. 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. Male subjects with partners of childbearing potential should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. If there is any question that a subject of childbearing potential will not reliably comply with the requirements for contraception, that subject should not be entered into the study.  
3.1.10 Ability to understand and the willingness to sign a written informed consent document.  
3.1.11 Ability to swallow and retain oral medication.
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3.2 exclusion criteria

3.2.1 Participants with any clinically significant gastrointestinal abnormalities that may alter absorption.  
3.2.2 Participants treated with prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to the prior chemotherapy, targeted small molecule therapy, and radiation therapy - Note: Subjects with ≤ Grade 2 neuropathy and/or alopecia are an exception to this criterion and may qualify for the study.
- Note: If subject received major surgery, they must have had the surgery > 2 weeks prior to Study Day 1 and recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy  
3.2.3 Participants previously treated with BRAF inhibitors (vemurafenib, dabrafenib, encorafenib), MEK inhibitors (selumetinib, trametinib, binimetinib, cobimetinib), and/or anti-PD1/PDL1 monoclonal antibodies for metastatic or unresectable disease. Any other prior therapy will be allowed (including ipilimumab, adjuvant anti-PD1 therapy, high-dose IL-2).  
3.2.4 Participants with any prior ≥ Grade 3 immune-related adverse event (irAE) which began while receiving immunotherapy.  
3.2.5 Participants with any unresolved immune-related adverse event (irAE) at time of study entry. - Note: Subjects with ≤ Grade 2 thyroiditis and/or hypophysitis are an exception to this criterion and may qualify for the study.  
3.2.6 Participants who have had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
3.2.7 Patients may not be receiving any other anti-neoplastic agents. 3.2.8 Participants with symptomatic brain metastases will 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. Subjects with asymptomatic, stable brain metastases and subjects who, if they have been previously treated for these conditions that are asymptomatic in the absence of corticosteroid therapy are allowed to enroll. Brain metastasis must be stable with verification by imaging (brain MRI completed at screening demonstrating no current evidence of progressive brain metastases). If asymptomatic brain metastasis are first identified on the required pre-study scans, another set of scans must be completed to confirm that they are stable.  
3.2.9 Has a 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 trial treatment. Corticosteroids to prevent contrast reactions is allowable.  
3.2.10 Pregnant women are excluded from this study because both dabrafenib and trametinib are class D agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with either dabrafenib and trametinib, breastfeeding should be discontinued if the mother is treated with either dabrafenib, trametinib, or the combination of dabrafenib and trametinib.  
3.2.11 Participants known to be HIV-positive and on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with either dabrafenib or trametinib. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.  
3.2.12 Has a known history of active TB (Bacillus Tuberculosis) 3.2.13 Known hypersensitivity to pembrolizumab or any of its excipients. 3.2.14 Symptomatic or untreated leptomeningeal disease. 3.2.15 Participants are not permitted to receive enzyme inducing anti-epileptic drugs. 3.2.16 Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.  
3.2.17 Has a history of non-infectious pneumonitis that required steroids or has current/active pneumonitis.  
3.2.18 History of or current evidence of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED):
- History of RVO or RPED
- Current evidence of visible retinal pathology as assessed by pre-study ophthalmic exam that is considered a risk factor for RVO or RPED such as evidence of new optic disc cupping, evidence of visual field defects, and/or intraocular pressure >21 mm Hg.  
3.2.19 Uncontrolled intercurrent illness including, but not limited to:
a. Ongoing or active infection b. LVEF <50% as determined by either MUGA scan or Echo c. Edema > Grade 1 d. Documented myocardial infarction or unstable/uncontrolled cardiac disease (eg, unstable angina, severe arrhythmias, congestive heart failure [New York Heart Association (NYHA) > Class II]) within 6 months of study entry e. Arterial thrombosis or vascular ischemic events, such as transient ischemic attack, cerebral infarction, within 6 months prior to study entry f. Serious or non-healing wound g. History of any medical condition including cardiovascular disease or chronic obstructive pulmonary disease (COPD), that in the opinion of the investigator, may increase the risks associated with study participation or study treatments or may interfere with the conduct of the study or interpretation of study results  
h. Psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements 3.2.20 Individuals with a history of a different malignancy are ineligible except for the following circumstances:
Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy.  
Individuals with the following cancers are eligible if diagnosed and treated within the past 3 years: cervical cancer *in situ* and basal cell or squamous cell carcinoma of the skin.  
3.2.21 Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV
RNA [qualitative] is detected).
3.2.22 Has received a live vaccine within 30 days of planned start of study therapy.
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3.3 inclusion of women and

Men and women and members of all races and ethnic groups are eligible for this trial. There are no inclusion/exclusion criteria that should explicitly lead to reduced enrollment of any specific minority population. Malignant melanoma is similarly prevalent in men and women; however its incidence varies greatly among ethnic groups.
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4. registration procedures 4.1 general

Institutions will register eligible participants in the Clinical Trials Management System (CTMS) OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not registered to the protocol before protocol therapy begins will be considered ineligible and registration will be denied. An investigator will confirm eligibility criteria and a member of the study team will complete the protocol-specific eligibility checklist. Following registration, participants may begin protocol therapy. Lab values do not need to re-meet eligibility criteria on Day 1 Week 1 prior to first. Issues that would cause treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant does not receive protocol therapy following registration, the participant's registration on the study must be canceled. Registration cancellations must be made in OnCore as soon as possible.
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4.2 registration process for df/hcc

DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol Registration (SOP \#: REGIST-101) must be followed.
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5. treatment plan 5.1 treatment

Treatment will be administered on an outpatient basis. Expected toxicities and potential risks as well as dose modifications for dabrafenib, trametinib, and pembrolizumab are described in Section 6 (Expected Toxicities and Dosing Delays/Dose Modification). No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the participant's malignancy. Response and progression will be assessed at the end of the lead-in phase, and at the start of each 3-week visit thereafter by history and physical exam or in the interim if any new symptoms arise. In addition, radiological imaging (either CT or MRI) will be obtained within 4 weeks of lead-in therapy commencement, within 1 week prior to Week 9, and at 6-week intervals (with a window of -1 week), following the commencement of pembrolizumab for 24 weeks and then extended to 12-week intervals (+2 weeks) while patients remain on the study. Response and progression will be determined based on the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). Further, if a patient does not tolerate the combination phase of combination MTT plus pembrolizumab, then MTT will be discontinued and pembrolizumab single-agent phase will begin, presuming that it is safe to treat with pembrolizumab (as outlined in Section 5.3.1). All patients will be evaluated for anti-tumor activity of the combination. Disease control rate (DCR) at the 24-week time point after commencement of pembrolizumab (in combination with MTT) is the primary anti-tumor end-point. DCR is defined as the percentage of patients per cohort who have stable disease (SD), complete or partial response (CR, PR) without requiring restart of MTT for any reasons. Progression free survival (PFS), CR and PR rates, and overall survival (OS) will also be summarized for patients in each cohort.  
A Simon 2-stage design will be implemented for two disease cohorts, BRAFV600 mutant and BRAFV600 wild-type unresectable Stage III or Stage IV melanoma.  
Patients will be treated with a two-week lead-in of MTT, followed by a 6-week course of combined MTT and pembrolizumab (at dose of 200 mg IV every three weeks), followed by maintenance single-agent pembrolizumab in all patients with RECIST defined stable disease (SD), partial response (PR), and complete response (CR). *MTT only will be resumed* if patients develop symptomatic or radiographic evidence of progression. If patients do not develop evidence of progressive disease (PD), then they will continue maintenance single-agent CONFIDENTIAL
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pembrolizumab for up to two years; at which time treatment will be discontinued. In each cohort, patients will be accrued to first stage of the Simon design. If a prespecified number of patients maintain SD/PR/CR off MTT but on pembrolizumab at the 24-week time point, then the second stage of the two-stage design will be opened. (Please see details in statistical section). Biopsies will be performed on all patients enrolled to the first stage of the Simon two-stage for each cohort. These will be obtained at baseline, after the two-week lead-in, and after the completion of induction therapy if feasible. An optional biopsy at the time of disease progression will also be performed.
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5.2 pre-treatment criteria

Please note: TSH results are not required to be available prior to dosing. 5.2.1 Targeted Therapy Lead-in Phase, Day 1 Week 1 Physical examination including vital signs and performance status Labs values do not need to re-meet eligibility criteria on Week 1, Day 1 Comprehensive metabolic panel including liver function tests Complete blood count (CBC w/diff, plts)
ECG (in BRAFV600 mutant cohort only)
5.2.2 Combination Targeted Therapy Plus Phase, Day 1 Week 3 and Day 22 Week 6 Physical exam including vital signs and performance status Comprehensive metabolic panel including liver function tests Complete blood count (CBC w/diff, plts)
ECG (in BRAFV600 mutant cohort)
Serum pregnancy test (Day 1 Week 3 for women of childbearing potential only)
5.2.4 Single-agent pembrolizumab Phase, Week 12 onwards Physical examination including vital signs and performance status Comprehensive metabolic panel including liver function tests Complete blood count (CBC w/ diff, plts) Serum pregnant test (Week 5 and 21 only and for women of childbearing potential only)
5.2.3 Single-agent pembrolizumab Phase, Week 9 Physical examination including vital signs and performance status Dermatology Exam Ophthalmology Exam Echo/MUGA
Comprehensive metabolic panel including liver function tests Complete blood count (CBC w/ diff, plts) Serum pregnant test (for women of childbearing potential only)
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5.3 agent administration 5.3.1 pembrolizumab

o Intravenous o 200 mg IV every three weeks, to commence after 2-week lead-in Phase of MTT
o Missed doses held for toxicity will not be made up. o On days when this treatment is given, it should be done so after trametinib dosing, during the concurrent MTT phase
5.3.2 Dabrafenib (BRAFV600 mutant cohort only)  
o Oral o 150 mg PO BID, to be taken every twelve hours; can be taken together with trametinib o Dabrafenib should be taken on an empty stomach at least one hour before or two hours after a meal; water is permitted during this fasting period.  
o Missed or vomited doses will not be made up. o If a dose is missed, it can be taken up to 6 hours prior to the next dose to maintain the twice daily regimen.  
o The drug cannot be crushed, chewed, or dissolved o In the BRAF mutant cohort, this should be taken before trametinib o The medication diary and pill bottles will be returned to clinic staff at the end of the lead in period and at the end of each three week cycle.  
5.3.3 Trametinib (BRAFV600 mutant or BRAFV600 wild-type cohorts)
o Oral o 2 mg PO daily; can be taken together with dabrafenib o Trametinib should be taken on an empty stomach at least one hour before or two hours after a meal; water is permitted during this fasting period.  
o Missed or vomited doses will not be made up.  
o If a dose is missed, it can be taken up to 12 hours after scheduled dose time.  
o The drug cannot be crushed, chewed, or dissolved o In the BRAFV600 mutant cohort, this should be taken after dabrafenib.  
o On days when pembrolizumab is given to patients in either the BRAFV600 mutant or BRAFV600 wild-type cohorts, this should be taken before pembrolizumab therapy.  
o The medication diary and pill bottles will be returned to clinic staff at the end of the lead in period and at the end of each three week cycle.
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5.3.4 other modality(ies) or procedures

Palliative sterotactic radiation or surgery may be performed during study participation. Dabrafenib and/or trametinib must be held for two days before and two days after surgery or the commencement and completion of stereotactic radiation. Pembrolizumab dosing must be held for two weeks before and after surgery or the commencement and completion of stereotactic radiation. If palliative, standard fractionated, external beam radiation is indicated, then a discussion with the investigator, the principal investigator, and Merck will be held to discuss whether the patient should be allowed to remain on trial, and if so, if and for how long dabrafenib, trametinib, and/or pembrolizumab should be held.
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5.4 general concomitant medication and

5.4.1 Acceptable Concomitant Medications All treatments (outside of the medications or vaccinations specifically prohibited in the exclusion and in Section 5.4.2) that the investigator considers necessary for a subject's welfare may be administered at the discretion of the investigator in keeping with the community standards of medical care. All concomitant medication will be recorded on the case report form (CRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids. If changes occur during the trial period, documentation of drug dosage, frequency, route, and date must also be included on the CRF. All concomitant medications received within 28 days before the first dose of trial treatment and 30 days after the last dose of trial treatment should be recorded. Concomitant medications administered after 30 days after the last dose of trial treatment should only be recorded for SAEs and ECIs as defined in Section 7.
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5.4.2 prohibited concomitant medications

Subjects are prohibited from receiving the following therapies during the Screening and Treatment Phase (including retreatment for post-complete response relapse) of this trial:
Antineoplastic systemic chemotherapy or biological therapy  
Immunotherapy not specified in this protocol Chemotherapy not specified in this protocol Investigational agents other than pembrolizumab not specified in this protocol
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest of suspected immunologic etiology. The use of physiologic doses of corticosteroids may be approved after consultation with the Overall PI.  
Strong inhibitors/inducers of selected CYP450 isoenzymes.  
Dabrafenib mesylate is a substrate for CYP 3A4, 2C8, pglycoprotein (Pgp), and breast carcinoma resistance protein
(Bcrp). These enzymes and transporters are prohibited for eligibility and during the study. 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.  
Concomitant medications should be reviewed for the potential risk of inducing nephrotoxicity and, if so, should be modified if clinically possible (See 6.2.6)
If there is a clinical indication for one of these or other medications or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be required. The investigator should discuss any questions regarding this with the Merck Clinical team. The final decision on any supportive therapy or vaccination rests with the subject's primary investigator.  
Subjects may receive other medications that the investigator deems to be medically necessary. The Exclusion Criteria describes other medications that are prohibited in this trial. There are no prohibited therapies during the Post-Treatment Follow-up Phase.  
5.4.3 Concomitant Medications to be used with caution
The following therapies are to be used with caution during the Screening and Treatment Phase (including retreatment for post-complete response relapse) of this trial:
Mild or moderate inhibitors/inducers of CYP 3A4, 2C8, Pgp, and Bcrp should be used with caution as dabrafenib serum concentrations may be altered. 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.  
Dabrafenib may induce CYP 3A4, 2B6, and possibly 2C8/9 and 2C19.  
Use concomitant medications that are substrates of these isoenzymes with caution as there may be loss of efficacy. Substitute with other medications that are not affected if possible.  
Because there is a low potential for interaction of trametinib with other concomitantly administered drugs through the cytochrome P450 system, the Principal Investigator should be alerted if the patient is taking any agent known to affect or with the potential to affect selected CYP450 isoenzymes.  
5.4.4 Alerting the Principal Investigator about specific agents and capturing the concurrent use of all drugs, over-the-counter medications, or alternative therapies in the case report form Because there is a potential for interaction of dabrafenib with other concomitantly administered drugs through the cytochrome P450 system, the case report form must capture the concurrent use of all other drugs, over-the-counter medications, or alternative therapies. The Principal Investigator must be alerted if the patient is taking any agent known to affect or with the potential to affect selected CYP450 isoenzymes.  
Because there is a low potential for interaction of trametinib with other concomitantly administered drugs through the cytochrome P450 system, the case report form must capture the concurrent use of all other drugs, over-the-counter medications, or alternative therapies. The Principal Investigator should be alerted if the patient is taking any agent known to affect or with the potential to affect selected CYP450 isoenzymes.
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5.4.5.1 supportive care guidelines

Subjects should receive appropriate supportive care measures as deemed necessary by the treating investigator. Suggested supportive care measures for the management of adverse events with potential immunologic etiology are outlined below and in greater detail in the ECI guidance document. Where appropriate, these guidelines include the use of oral or intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve with administration of corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, attempts should be made to rule out other causes such as metastatic disease or bacterial or viral infection, which might require additional supportive care. The treatment guidelines are intended to be applied when the investigator determines the events to be related to pembrolizumab. Note: if after the evaluation the event is determined not to be related, the investigator is instructed to follow the ECI reporting guidance but does not need to follow the treatment guidance (as outlined in the ECI guidance document). Refer to Section 6 for dose modification. It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin photography as part of evaluation of the event. Suggested conditional procedures, as appropriate, can be found in the ECI guidance document.
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suggestions for pneumonitis

o For **Grade 2 events**, treat with systemic corticosteroids.  
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.  
o For **Grade 3-4 events**, immediately treat with intravenous steroids. Administer additional anti-inflammatory measures, as needed.  
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid administration.
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suggestions for diarrhea/colitis

Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus).  
o Advise all subjects who experience diarrhea/colitis to drink liberal quantities of clear fluids. If sufficient oral fluid intake is not feasible, substitute fluid and electrolytes via IV infusion. For Grade 2 or higher diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis.  
o For **Grade 2 diarrhea/colitis** that persists greater than 3 days, administer oral corticosteroids.  
o For **Grade 3 or 4 diarrhea/colitis** that persists > 1 week, treat with intravenous steroids followed by high dose oral steroids.  
o When symptoms improve to Grade 1 or less, start steroid taper and continue over no less than 4 weeks.  
**Suggestions for Type 1 diabetes mellitus (if new onset,**
including diabetic ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA)
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o for t1dm or grade

Insulin replacement therapy is recommended for Type I
diabetes mellitus and for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated hemoglobin, and Cpeptide.
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suggestions for hypophysitis

o For **Grade 2** events, treat with corticosteroids. When symptoms improve to Grade 1 or less, start and continue steroid taper over no less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose is tapered.  
o For **Grade 3-4** events, treat with an initial dose of IV
corticosteroids followed by oral corticosteroids. When symptoms improve to Grade 1 or less, start and continue steroid taper over no less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose is tapered.  
**Suggestions for Hyperthyroidism or Hypothyroidism**:
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of CONFIDENTIAL
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treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.  
o **Grade 2** hyperthyroidism events (and **Grade 2-4**
hypothyroidism): In hyperthyroidism, non-selective beta-blockers (e.g.  
propranolol) are suggested as initial therapy.  
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or liothyroinine, is indicated per standard of care.  
o **Grade 3-4** hyperthyroidism Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose is tapered.
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suggestions for hepatic events

o For **Grade 2** events, monitor liver function tests more frequently until returned to baseline values (consider weekly). Treat with IV or oral corticosteroids o For **Grade 3-4** events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and continued over no less than 4 weeks.
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suggestions for renal failure or

o For **Grade 2** events, treat with corticosteroids.  
o For **Grade 3-4** events, treat with systemic corticosteroids.  
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.
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suggestions for management of infusion

and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion.  
Table 5.4 below shows treatment suggestions for subjects who experience an infusion reaction associated with administration of pembrolizumab (MK-3475). Table 5.4 Infusion Reaction Treatment Suggestions  
| NCI CTCAE Grade                                                                                                                                                                                                                                                                                                                                                           | Treatment                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Premedication at subsequent  dosing   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------|
| Grade 1 Mild reaction; infusion interruption  not indicated; intervention not  indicated                                                                                                                                                                                                                                                                                  | Increase monitoring of vital signs as  medically indicated until the subject is  deemed medically stable in the opinion of the  investigator.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | None                                  |
| Grade 2 Requires infusion interruption but  responds promptly to symptomatic  treatment (e.g., antihistamines,  NSAIDS, narcotics, IV fluids);  prophylactic medications indicated  for < =24 hrs                                                                                                                                                                         | Stop Infusion and monitor symptoms. Additional appropriate medical therapy may  include but is not limited to: IV fluids Antihistamines NSAIDS Acetaminophen Narcotics Increase monitoring of vital signs as  medically indicated until the subject is  deemed medically stable in the opinion of the  investigator. If symptoms resolve within one hour of  stopping drug infusion, the infusion may be  restarted at 50% of the original infusion rate  (e.g., from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until symptoms  resolve and the subject should be  premedicated for the next scheduled dose. Subjects who develop Grade 2 toxicity  despite adequate premedication should  be permanently discontinued from further  trial treatment administration. | Subject may be premedicated  1.5h (± 30 minutes) prior to  infusion of pembrolizumab (MK3475) with: Diphenhydramine 50 mg po (or  equivalent dose of  antihistamine). Acetaminophen 500-1000 mg  po (or equivalent dose of  antipyretic).                                       |
| Grades 3 or 4 Grade 3: Prolonged (i.e., not rapidly  responsive to symptomatic  medication and/or brief interruption  of infusion); recurrence of  symptoms following initial  improvement; hospitalization  indicated for other clinical sequelae  (e.g., renal impairment, pulmonary  infiltrates) Grade 4: Life-threatening; pressor or  ventilatory support indicated | Stop Infusion. Additional appropriate medical therapy may  include but is not limited to: IV fluids Antihistamines NSAIDS Acetaminophen Narcotics Oxygen Pressors Corticosteroids Epinephrine                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | No subsequent dosing                  |
| Increase monitoring of vital signs as  medically indicated until the subject is  deemed medically stable in the opinion of the  investigator. Hospitalization may be indicated. Subject is permanently discontinued from  further trial treatment administration.                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                       |
| Appropriate resuscitation equipment should be available in the room and a physician readily available during the period  of drug administration.                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                       |
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5.5 criteria for taking a

Duration of therapy will depend on individual response, evidence of disease progression and tolerance. In the absence of treatment delays due to adverse events, treatment may continue until one of the following criteria applies:
Completion of two years of pembrolizumab therapy Disease progression, unless patient meets criteria for treatment beyond progression in Section 5.5.1 Intercurrent illness that prevents further administration of treatment,
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5.5.1 treatment beyond progression

Following initial disease progression, if a participant is treated beyond progression per the criteria outlined below, tumor assessments must be repeated > 4 weeks after initial disease progression in order to confirm disease progression. The tumor assessment must not be repeated any sooner than 4 weeks after initial disease progression. Treatment beyond progression will be allowed. In general, patients who develop disease progression (per RECIST1.1) will remain on trial. Since this trial potentially involves four specific treatments "zones", namely 1) MTT induction; 2) concomitant MTT plus pembrolizumab; 3) pembrolizumab single-agent; and 4) follow up after pembrolizumab discontinuation in setting of CR, the specific treatment beyond progression will be dependent on which "zone" the patient is in when progression occurs as described below.
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5.5.1.1 mtt induction (targeted therapy

Patients who develop clinical progression or radiographic progression (e.g. if non-planned imaging is performed) during MTT induction, then patients will be allowed to move onto the concomitant MTT plus pembrolizumab phase of the therapy.  
5.5.1.2 Concomitant MTT plus pembrolizumab (Combined Targeted Therapy Plus)
Patients who develop clinical progression during or radiographic during (e.g. if non-planned imaging is performed) or on routine imaging performed at the end of the concomitant MTT plus pembrolizumab phase will be allowed to be treated with single-agent pembrolizumab beyond progression as long as the following criteria are met:  
A. Absence of signs and symptoms (including worsening of laboratory values) indicating disease progression.  
B. No decline in ECOG performance status.
C. Absence of rapid progression of disease.  
D. Absence of progressive tumor at critical anatomical sites (e.g.,
cord compression) requiring urgent alternative medical intervention.  
Unacceptable adverse event(s), Participant demonstrates an inability or unwillingness to comply with the oral medication regimen and/or documentation requirements Participant decides to withdraw from the study, or General or specific changes in the participant's condition render the participant unacceptable for further treatment in the opinion of the treating investigator.
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5.5.1.3 pembrolizumab single-agent

Patients who develop progression of disease on the pembrolizumab single-agent phase will be allowed to be treated beyond progression as long as the following criteria are met:  
A. Absence of signs and symptoms (including worsening of laboratory values) indicating disease progression.  
B. No decline in ECOG performance status.
C. Absence of rapid progression of disease.  
D. Absence of progressive tumor at critical anatomical sites (e.g.,
cord compression) requiring urgent alternative medical intervention.  
5.5.1.4 Follow up after discontinuation of pembrolizumab in setting of a CR
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR that have been treated for at least 24 weeks with pembrolizumab and had at least two treatments with pembrolizumab beyond the date when the initial CR was declared. Subjects who discontinue treatment and then experience radiographic disease progression may be eligible for up to one year of additional treatment with single-agent pembrolizumab at the discretion of the investigator if no cancer treatment was administered since the last dose of pembrolizumab, the subject meets the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is open. Subjects will resume therapy at the same dose and schedule at the time of initial discontinuation.
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5.6 duration of follow up

If treatment is discontinued for completion of two years of pembrolizumab, or for disease progression, or for withdrawal of consent, participants will be followed for adverse events. All adverse events encountered from time of the first dose of study treatment up until 90 days after the last dose of study treatment will be followed until one of the following occurs:
- The event resolves, - The participating investigator assesses the event as stable, - The participating investigator determines the event to be irreversible, - The participant is lost to follow-up, - The participant dies.  
If the subject is not seen in clinic after the off-study visit, required Adverse Event details must be collected over the phone.  
If treatment is discontinued for a reason other than disease progression, study discontinuation, or withdrawal of consent, participants will be seen every 12 weeks (+/- 2 weeks) for imaging until progressive disease or death, whichever comes first. If there are any adverse events that have not resolved, or been assessed by the participating investigator as stable or irreversible at the time of progressive disease, the participant will be followed until the adverse events resolve, or are assessed by the participating investigator as stable or irreversible.
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5.7 criteria for taking a

Participants will be removed from study when any of the criteria listed in Section 5.6 applies. The reason for study removal and the date the participant was removed must be documented in the study-specific case report form (CRF). Alternative care options will be discussed with the participant. In the event of unusual or life-threatening complications, participating investigators must immediately notify the Principal Investigator, Ryan Sullivan at 617-724-4000.
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5.8 contraception

Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if pembrolizumab has transient adverse effects on the composition of sperm. For this trial, male subjects will be considered to be of non-reproductive potential if they have azoospermia (whether due to having had a vasectomy or due to an underlying medical condition). Female subjects will be considered of non-reproductive potential if they are either: (1) Postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);
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or

(2) Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
(3) Has a congenital or acquired condition that prevents childbearing. Female and male subjects of reproductive potential must agree to avoid becoming pregnant or impregnating a partner, respectively, while receiving study drug and for 120 days after the last dose of study drug by complying with one of the following: Female subjects of childbearing potential and male subjects with partners of childbearing potential must: (1) Practice abstinence† from heterosexual activity;  
(2) Use (or have their partner use) acceptable contraception during heterosexual activity. Acceptable methods of contraception are: Single method (one of the following is acceptable): - Intrauterine device (IUD) - Vasectomy of a female subject's male partner - Contraceptive rod implanted into the skin Combination method (requires use of two of the following): - Diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) - Cervical cap with spermicide (nulliparous women only) - Contraceptive sponge (nulliparous women only) - Male condom or female condom (cannot be used together) - Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection †Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject's preferred and usual lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception. ‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an acceptable method of contraception for subjects participating at sites in this country/region. Subjects should be informed that taking the study medication may involve CONFIDENTIAL
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unknown risks to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the study subjects of childbearing potential must adhere to the contraception requirement (described above) from the day of study medication initiation (or 14 days prior to the initiation of study medication for oral contraception) throughout the study period up to 120 days after the last dose of trial therapy. If there is any question that a subject of childbearing potential will not reliably comply with the requirements for contraception, that subject should not be entered into the study.
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6. dosing delays/dose modification criteria

Dose delays and modifications must be made using the following criteria. Toxicity assessments will be done using the CTEP Active Version of the NCI
Common Terminology Criteria for Adverse Events (CTCAE) which is identified and located on the CTEP website at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, etc.).
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6.1 pembrolizumab dose modifications

Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, non- hematological toxicity ≥ Grade 3 including clinically significant laboratory abnormalities despite appropriate replacement therapies when appropriate, and severe or life-threatening AEs as per Table 6.1.  
Table 6.1 Pembrolizumab dose modification requirements for drug-related adverse events  
| events                                                                      | Hold                                                  |                                                                                                                   |                                                                                                                   |
|-----------------------------------------------------------------------------|-------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|
| Treatmen                                                                    |                                                       |                                                                                                                   |                                                                                                                   |
| Toxicity                                                                    | Timing for Restarting Treatment                       | Discontinue Subject                                                                                               |                                                                                                                   |
| t For  Grade 2-3                                                            | Toxicity resolves to Grade 0-1.                       | Toxicity does not resolve within 12 weeks of last dose or  inability to reduce corticosteroid to 10 mg or less of |                                                                                                                   |
| Diarrhea/Colitis                                                            | prednisone or equivalent per day within 12 weeks.     |                                                                                                                   |                                                                                                                   |
| 4                                                                           | Permanently discontinue                               | Permanently discontinue                                                                                           |                                                                                                                   |
| AST, ALT, or                                                                | 2                                                     | Toxicity resolves to Grade 0-1                                                                                    | Toxicity does not resolve within 12 weeks of last dose.                                                           |
| Increased  Bilirubin                                                        | 3-4                                                   | Permanently discontinue (see exception below)1                                                                    | Permanently discontinue                                                                                           |
| Hold pembrolizumab for new onset  Type 1 diabetes mellitus or Grade 3-4     | Resume pembrolizumab when patients are clinically and |                                                                                                                   |                                                                                                                   |
| hyperglycemia associated with                                               | metabolically stable.                                 |                                                                                                                   |                                                                                                                   |
| evidence of beta cell failure.                                              |                                                       |                                                                                                                   |                                                                                                                   |
| Type 1 Diabetes  Mellitus (if new  onset) or  Hyperglycemia                 | T1DM or  3-4                                          |                                                                                                                   |                                                                                                                   |
| Hypophysitis                                                                | 2-3                                                   | Toxicity resolves to Grade 0-1                                                                                    | Toxicity does not resolve within 12 weeks of last dose or  inability to reduce corticosteroid to 10 mg or less of |
| CONFIDENTIAL                                                                |                                                       |                                                                                                                   |                                                                                                                   |
| This document is confidential. Do not disclose or use except as authorized. |                                                       |                                                                                                                   |                                                                                                                   |  
| Hold                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                   |                                                                                                           |                                                                                                           |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------|-----------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------|
| Treatmen                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                   |                                                                                                           |                                                                                                           |
| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Timing for Restarting Treatment                   | Discontinue Subject                                                                                       |                                                                                                           |
| t For  Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | prednisone or equivalent per day within 12 weeks. |                                                                                                           |                                                                                                           |
| 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Permanently discontinue                           | Permanently discontinue                                                                                   |                                                                                                           |
| Toxicity does not resolve within 12 weeks of last dose or                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                   |                                                                                                           |                                                                                                           |
| 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Toxicity resolves to Grade 0-1                    | inability to reduce corticosteroid to 10 mg or less of  prednisone or equivalent per day within 12 weeks. |                                                                                                           |
| Hyperthyroidism                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | 4                                                 | Permanently discontinue                                                                                   | Permanently discontinue                                                                                   |
| Therapy with pembrolizumab can be                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Therapy with pembrolizumab can be continued while |                                                                                                           |                                                                                                           |
| Hypothyroidism                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | 2-4                                               | continued while treatment for the                                                                         | treatment for the thyroid disorder is instituted.                                                         |
| thyroid disorder is instituted                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                   |                                                                                                           |                                                                                                           |
| Infusion Reaction                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | 3-4                                               | Permanently discontinue                                                                                   | Permanently discontinue                                                                                   |
| Toxicity does not resolve within 12 weeks of last dose or                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                   |                                                                                                           |                                                                                                           |
| 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Toxicity resolves to Grade 0-1                    | inability to reduce corticosteroid to 10 mg or less of                                                    |                                                                                                           |
| Pneumonitis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | prednisone or equivalent per day within 12 weeks. |                                                                                                           |                                                                                                           |
| 3-4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Permanently discontinue                           | Permanently discontinue                                                                                   |                                                                                                           |
| Toxicity does not resolve within 12 weeks of last dose or                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                   |                                                                                                           |                                                                                                           |
| 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Toxicity resolves to Grade 0-1                    | inability to reduce corticosteroid to 10 mg or less of                                                    |                                                                                                           |
| Renal Failure or                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | prednisone or equivalent per day within 12 weeks. |                                                                                                           |                                                                                                           |
| Nephritis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | 3-4                                               | Permanently discontinue                                                                                   | Permanently discontinue                                                                                   |
| Toxicity does not resolve within 12 weeks of last infusion.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                   |                                                                                                           |                                                                                                           |
| Hematologic  Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | 4                                                 | Toxicity resolves to Grade 0-1 or                                                                         | Permanent discontinuation should be considered for any                                                    |
| baseline                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | severe or life-threatening event.                 |                                                                                                           |                                                                                                           |
| Toxicity does not resolve within 12 weeks of last dose or                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                   |                                                                                                           |                                                                                                           |
| All Other DrugRelated                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | 3 or Severe                                       | Toxicity resolves to Grade 0-1                                                                            | inability to reduce corticosteroid to 10 mg or less of  prednisone or equivalent per day within 12 weeks. |
| Toxicity2,3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | 4                                                 | Permanently discontinue                                                                                   | Permanently discontinue                                                                                   |
| Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative  to baseline and lasts for at least 1 week then patients should be discontinued. 2  Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. Permanently discontinue study  drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12  weeks of the last dose.  3  Exception to be treated similar to grade 1 toxicity: Grade 2 alopecia, grade 2 fatigue |                                                   |                                                                                                           |                                                                                                           |  
6.1.1 Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or holidays). In these cases only, subjects must be placed back on study therapy within 2 weeks of the scheduled interruption, unless otherwise discussed with the PI of the study. The reason for interruption must be documented in the patient's study record.
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6.2 dabrafenib + trametinib dose

The table below outlines the dose levels to be used for any necessary dabrafenib and trametinib dose modifications in studies which include the combination:  
| Current Dose         | If Dose Reduction Required   | Reduce To              |
|----------------------|------------------------------|------------------------|
| Dabrafenib 150mg BID |                             | 150 mg QAM, 75 mg  QPM |
| 150 mg QAM, 75 mg    |                             | 75mg BID               |
| QPM 75mg BID         |                             | Discontinue dabrafenib |
| Current Dose         | If Dose Reduction Required   | Reduce To              |
| Trametinib 2mg QD    |                             | 1.5mg QD               |
| 1.5mg QD             |                             | 1.0mg QD               |
| 1.0mg QD             |                             | Discontinue trametinib |  
If an AE resolves to grade 1 or baseline at the reduced dose level, and no additional toxicities are seen after 4 weeks of study treatment at the reduced dose, the dose may be increased to the previous dose level. A dose reduction below 75 mg BID for dabrafenib and 1 mg once daily for trametinib is not allowed. If a dose reduction below 75 mg BID is required, dabrafenib will be permanently discontinued, but the patients will be allowed to continue trametinib. If a dose reduction below 1.0 mg once daily for trametinib is required, then trametinib will be permanently discontinued, but these patients will be allowed to continue pembrolizumab and/or dabrafenib.  
The dose modifications may involve one or both agents, and should be based on the nature, severity and attributions of the AEs. General guidelines are provided below. In the event that trametinib and pembrolizumab need to be discontinued due to toxicity reasons, treatment with dabrafenib may continue at the discretion of the investigator until time of disease progression.  
6.2.1 Dabrafenib +/or Trametinib Dose Modification Requirements for drug-related adverse events **Not Specified** in Subsequent Sections  
| for drug-related adverse events                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                       |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Not Specified in Subsequent Sections                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                       |
| CTCAE Grade                                                                                                                                                                                                                                                                                                                                                                                                                            | Action and Dose Modification                                                                                                                                                                                                                                                                                                                                                                                          |
| Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                |  Continue study treatment at same dose level (no dose  modification).  Monitor closely.  Provide supportive care according to institutional standards.                                                                                                                                                                                                                                                             |
| Grade 2 (Tolerable)                                                                                                                                                                                                                                                                                                                                                                                                                    |  Interrupt study treatment if clinically indicated.  Monitor closely.  Provide supportive care according to institutional standards.  When toxicity resolves to grade 1 or baseline, restart study  treatment at current dose level.                                                                                                                                                                              |
| Grade 2 (Intolerable)                                                                                                                                                                                                                                                                                                                                                                                                                  |  Interrupt study treatment.                                                                                                                                                                                                                                                                                                                                                                                          |
| Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                |  Monitor closely.  Provide supportive care according to institutional standards.  When toxicity resolves to grade 1 or baseline, restart study  treatment reduced by one dose level.  If the grade 3 toxicity recurs, interrupt study treatment.  When toxicity resolves to grade 1 or baseline, restart study  treatment reduced by another dose level.                                                         |
| Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                |  Interrupt study treatment.  Monitor closely.  Provide supportive care according to institutional standards.  Restart with study treatment reduced by one dose level once  toxicity resolves to grade 1 or baseline.  If the grade 4 toxicity recurs, either permanently discontinue  study treatment or, if the patient is clinically benefiting, discuss  continuation of study treatment with the overall PI. |
| *If the AEs are thought to be due to one of the two agents, resumption of the other agents may  be considered if the first agent is discontinued due to toxicities and treatment interruption is <21  days. Overall PI should be consulted for resumption of single agent.  ** In the event of abdominal pain or suspected pancreatitis, amylase and lipase laboratory  samples should be collected for confirmation of the diagnosis. |                                                                                                                                                                                                                                                                                                                                                                                                                       |  
6.2.2 Dabrafenib + Trametinib Dose Modification Requirements for **Pyrexia**
Pyrexia is defined as a body temperature equal to or above 38.5○
Celsius or 101.3○ Fahrenheit  
Pyrexia is an adverse event associated with dabrafenib. In a minority of cases, pyrexia was accompanied by symptoms such as severe chills/rigors, dehydration, hypotension, dizziness or weakness and required hospitalization.  
Subjects should be instructed on the importance of immediately reporting febrile episodes.  
Pyrexia accompanied by hypotension, dehydration, renal insufficiency and/or severe (grade 3) rigors/chills in the absence of an obvious infectious cause should be reported as an SAE.
CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.
table 6-2 dabrafenib + trametinib
event management guideline dose modification

Work up:
Clinical evaluation for infection and hypersensitivity, especially if pyrexia is complicated by rigors, severe chills, dehydration, *etc.*
Laboratory work-up (recommend include full-blood-count, electrolytes, creatinine, BUN, CRP,
liver-function tests, blood and urine culture).  
| Management:   Anti-pyretic treatment should be started immediately at the first occurrence. Anti-pyretic treatment  may include acetaminophen (paracetamol), ibuprofen, or suitable anti-pyretic medication per  institutional standards.  Oral hydration is encouraged in subjects without evidence of dehydration. Intravenous hydration is  recommended if pyrexia is complicated by dehydration/hypotension.  In subject experiencing pyrexia complicated by rigors, severe chills, etc., which cannot be  controlled with anti-pyretic medication, recommend oral corticosteroids be started.  Prophylactic anti-pyretic treatment is recommended after the 2nd event.  1 st Event:  C Clinical evaluation for infection  and hypersensitivity  L Laboratory work-up  Interrupt dabrafenib.  Continue trametinib.  Upon recovery to baseline, restart  dabrafenib at the same dose level. If fever  was associated with dehydration or  hypotension, reduce dabrafenib by one  dose level.  H Hydration as required  A Administer anti-pyretic treatment  if clinically indicated and  continue prophylactic treatment 2 nd Event  Clinical evaluation for infection  and hypersensitivity Laboratory work-up  Hydration as required  Within 3 days of onset of pyrexia:  Optimize anti-pyretic therapy.  Consider oral corticosteroids  (i.e., prednisone 10 mg) for at  least 5 days or as clinically  indicated.  Interrupt dabrafenib.  Continue trametinib.  Upon recovery to baseline, restart  dabrafenib at the same dose level. If fever  was associated with dehydration or  hypotension, reduce dabrafenib by one  dose level.   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Requirements for Pyrexia                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                          |                   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------|
| Event                                                                                                                                                                                                                                                                                                                                                            | Management Guideline                                                                                                                                                                                                     | Dose Modification |
| Subsequent                                                                                                                                                                                                                                                                                                                                                       |  Clinical evaluation for infection                                                                                                                                                                                      |                   |
| Events:                                                                                                                                                                                                                                                                                                                                                          | and hypersensitivity                                                                                                                                                                                                     |                   |
| Laboratory work-up  Hydration as required  Blood sample for cytokine  analysis  Within 3 days of onset of pyrexia:  Optimize oral corticosteroid  dose as clinically indicated for  recalcitrant pyrexia.  If corticosteroids have been  tapered and pyrexia recurs,  restart steroids.  If corticosteroids cannot be  tapered, consult medical  monitor. |  Interrupt dabrafenib.  Continue trametinib.  Once pyrexia resolves to baseline, restart  dabrafenib reduced by one dose level. h  If dabrafenib must be reduced to <75 mg  BID, permanently discontinue dabrafenib. |                   |
| h  Dabrafenib should be reduced by one dose level after three episodes of pyrexia which cannot be  managed by best supportive care and increasing doses of oral steroids. Escalation of dabrafenib is  allowed if no episode of pyrexia is observed in the 4 weeks subsequent to dose reduction.                                                                 |                                                                                                                                                                                                                          |                   |  
6.2.3 Dabrafenib +/or Trametinib Dose Modification for Drug-Related **Rash**
Rash is a frequent AE observed in patients receiving trametinib, dabrafenib, or the combination of both therapies. Recommendations for supportive care and guidelines for dose modifications for rash are based on experience with other MEK inhibitors and EGFR inhibitors (Balagula *et al.*, 2010; Lacouture et al., 2011). The institutional standards for the management of skin-related AEs can differ from these guidelines. In this case, best clinical judgment should be applied and a consultation with the study overall PI may be required.  
| Requirements for Drug-Related Rash   |                          |                              |
|--------------------------------------|--------------------------|------------------------------|
| CTCAE Grade                          | Adverse Event Management | Action and Dose Modification |
| Recommended supportive care:  Prevention: Promote sunscreen use and avoid unnecessary sun exposure, use alcohol-free  emollient creams, topical steroids and antibiotics as needed.  Pruritic lesions: cool compresses and oral antihistamines.  Fissuring lesions: Monsel's solution, silver nitrate or zinc oxide cream.  Desquamation: thick emollients and mild soap.  Paronychia: antiseptic bath, local potent corticosteroids, antibiotics, surgery as needed.  Infected lesions: topical or systemic antibiotics. Grade 1  Initiate prophylactic and   symptomatic treatment measures.1  Use moderate strength topical  steroid.2  Reassess after 2 weeks.  Continue study treatment.  If rash does not recover to baseline within 2  weeks despite best supportive care,  reduce study treatment by one dose  level. 3 Grade 2  Initiate prophylactic and   symptomatic treatment measures.1  Use moderate strength topical  steroid.2  Reassess after 2 weeks.  Reduce study treatment by one dose  level.  If rash recovers to ≤ grade 1 within 2  weeks, increase dose to previous dose  level.  If no recovery to ≤ grade 1 within 2 weeks,  interrupt study treatment until recovery to ≤ grade 1.  Restart study treatment at reduced dose  level.3 Grade ≥3  Use moderate strength topical   steroids PLUS oral methylprednisolone dose pack.2  Consult dermatologist.  Interrupt study treatment until rash  recovers to ≤ grade 1.  Restart with study treatment reduced by  one dose level.3,4 If no recovery to ≤ grade 2 within 21 days,  permanently discontinue study treatment. 1. Rash prophylaxis is recommended for the first 6 weeks of study treatment. 2. Moderate-strength topical steroids: Hydrocortisone 2.5% cream or fluticasone propionate 0.5%  cream. 3. Approval of overall PI is required to restart study treatment after >21 days of interruption. 4. Study treatment may be escalated to previous dose level if no rash is evident 4 weeks after  restarting study treatment.                                      |                          |                              |