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TITLE: A pilot study of Dabrafenib and Trametinib for patients with BRAF-mutated ameloblastoma
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nct02367859

Coordinating Center  
Stanford Cancer Institute  
875 Blake Wilbur Drive, Stanford, CA 94305  
| 875 Blake Wilbur Drive, Stanford, CA 94305 Protocol Director                                                                                                        |                                     |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|
| A Dimitrios Colevas, MD, Professor in Medicine Stanford University Medical Center Blake Wilbur Drive, Stanford, CA 94305-5826 colevas@stanford.edu Co-Investigators |                                     |
| Robert West                                                                                                                                                         |                                     |
| Professor in Pathology Pathology  Stanford, California 94305-5324                                                                                                   | Jonathan Pollack                    |
| Professor in Pathology                                                                                                                                              |                                     |
| 269 Campus Drive, Stanford, California  94305-5176                                                                                                                  |                                     |
| Davud Sirjani                                                                                                                                                       |                                     |
| Clinical Assistant Professor Biostatistician Alex McMillan Sr Res Scientist-Basic Ls HRP (Redwood) Building  Stanford, California 94305                             | Study Coordinator Elizabeth Winters |  
Protocol Amendment 8: 21 August 2018  
| TABLE OF CONTENTS                             |                                                                                                                   |
|-----------------------------------------------|-------------------------------------------------------------------------------------------------------------------|
| PROTOCOL SYNOPSIS                             |                                                                                                                   |
| SCHEMA .                                      |                                                                                                                   |
| LIST OF ABBREVIATIONS AND DEFINITION OF TERMS |                                                                                                                   |
| 1.0                                           | OBJECTIVES                                                                                                        |
| 1.1                                           | Primary Objectives                                                                                                |
| 1.2                                           | Secondary Objectives .                                                                                            |
| 2.0 BACKGROUND .                              |                                                                                                                   |
| STUDY Disease                                 |                                                                                                                   |
| 2.1                                           |                                                                                                                   |
| 2.2                                           | Study Agents/Device/Procedure                                                                                     |
| 2.3                                           | RATIONALE                                                                                                         |
| 2.4                                           | Study Design .                                                                                                    |
| 2.5                                           | Correlative Studies Background .                                                                                  |
| 3.0                                           | PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES                                                                   |
| 3.1                                           | Participant Eligibility Checklist.                                                                                |
| 3.2                                           | Informed Consent Process                                                                                          |
| 3.3                                           | Study Timeline                                                                                                    |
| 4.0                                           | TREATMENT PLAN                                                                                                    |
| 4.1                                           | General Concomitant Medication and Supportive Care Guidelines .................................................19 |
| 4.1.1                                         | Permitted Medications and Non-Drug Therapies .                                                                    |
| 4.1.2                                         | Prohibited Medications and Non-Drug Therapies                                                                     |
| Medications to be used with Caution           |                                                                                                                   |
| 4.1.3                                         |                                                                                                                   |
| 4.2                                           | Criteria for Removal from Study                                                                                   |
| 5.0                                           | STUDY AGENT INFORMATION .                                                                                         |
| 5.1                                           | Study Agents:                                                                                                     |
| 5.2                                           | Availability                                                                                                      |
| 5.3                                           | Agent Ordering .                                                                                                  |
| Agent Accountability .                        |                                                                                                                   |
| 5.4                                           |                                                                                                                   |
| 6.0                                           | DOSE MODIFICATIONS                                                                                                |
| Dose Modification for General Toxicities .    |                                                                                                                   |
| 6.1                                           |                                                                                                                   |
| 6.2                                           | Dose Reductions for AEs of interest in patients taking dabrafenib and  trametinib ......24                        |
| 6.2.1                                         | Plantar-Palmar Erythrodysesthesia                                                                                 |
| 6.2.2                                         | Pancreatitis                                                                                                      |
| 6.2.3                                         | Uveitis and ocular events.                                                                                        |
| 6.2.4                                         | Hyperglycemia                                                                                                     |
| 6.2.5                                         | Pyrexia                                                                                                           |
| 6.2.6                                         | Malignancies .                                                                                                    |
| 6.2.7                                         | New Primary Melanoma .                                                                                            |
| Non-Cutaneous Malignancies .                  |                                                                                                                   |
| 6.2.8                                         |                                                                                                                   |
| 6.2.9                                         | Renal Insufficiency                                                                                               |
| 6.2.10                                        | Gudielines for Prolonges QTc                                                                                      |
| 6.2.11                                        | Guidelines for Pneumonitis .                                                                                      |
| 6.2.12                                        | Guidelines for Cardiomyopathy                                                                                     |
| 6.2.13                                        | Treatment of Study Treatment Overdose                                                                             |
| 7                                             | ADVERSE EVENTS AND REPORTING PROCEDURES ..........................................................34              |
| 7.1                                           | Potential Adverse Events .                                                                                        |
| 7.1.1                                         | Dabrafenib potential adverse effects                                                                              |
| 7.1.2                                         | Trametinib potential adverse effects                                                                              |
| 7.2                                           | Adverse Event Reporting                                                                                           |  
| 8                                                                                                                                      | CORRELATIVE/ SPECIAL STUDIES .                                                                                                                             |
|----------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 8.1                                                                                                                                    | Laboratory Correlative Studies ......................................................................................................................45    |
| 8.1.1                                                                                                                                  | Collection of Specimen(s)                                                                                                                                  |
| 8.1.2                                                                                                                                  | Handling of Specimens(s)                                                                                                                                   |
| 8.1.3                                                                                                                                  | Shipping of Specimen(s)                                                                                                                                    |
| 8.1.4                                                                                                                                  | Site(s) Performing Correlative Study ...................................................................................................................46 |
| 8.1.5                                                                                                                                  | Coding of specimens for privacy protection .........................................................................................................46     |
| 9                                                                                                                                      | STUDY CALENDAR                                                                                                                                             |
| 10                                                                                                                                     | ME A SUREMENTS                                                                                                                                             |
| 10.1                                                                                                                                   | Primary and Secondary Outcome measures                                                                                                                     |
| 10.1.1                                                                                                                                 | Measurement Definition .                                                                                                                                   |
| 10.1.2                                                                                                                                 | Measurement Methods                                                                                                                                        |
| Measurement Time Points                                                                                                                |                                                                                                                                                            |
| 10.1.3                                                                                                                                 |                                                                                                                                                            |
| 10.2                                                                                                                                   | Secondary Outcome                                                                                                                                          |
| 10.2.1                                                                                                                                 | Tumor necrosis .                                                                                                                                           |
| 10.2.2                                                                                                                                 | Measurement Definition .                                                                                                                                   |
| 10.2.3                                                                                                                                 | Measurement Methods                                                                                                                                        |
| Measurement Time Points                                                                                                                |                                                                                                                                                            |
| 10.2.4                                                                                                                                 |                                                                                                                                                            |
| 10.2.5                                                                                                                                 | Response Review                                                                                                                                            |
| 10.3                                                                                                                                   | Secondary Outcome - Proliferation index                                                                                                                    |
| 10.3.1                                                                                                                                 | Measurement Definition .                                                                                                                                   |
| 10.3.2                                                                                                                                 | Measurement Methods                                                                                                                                        |
| 10.3.3                                                                                                                                 | Measurement Time Points                                                                                                                                    |
| 10.3.4                                                                                                                                 | Response Review                                                                                                                                            |
| Secondary Outcome - Phosphorylation of MEK/ERK......................................................................................51 |                                                                                                                                                            |
| 10.4                                                                                                                                   |                                                                                                                                                            |
| 10.4.1                                                                                                                                 | Measurement Definition .                                                                                                                                   |
| Measurement Methods                                                                                                                    |                                                                                                                                                            |
| 10.4.2                                                                                                                                 |                                                                                                                                                            |
| 10.4.3                                                                                                                                 | Measurement Time Points                                                                                                                                    |
| Response Review                                                                                                                        |                                                                                                                                                            |
| 10.4.4                                                                                                                                 |                                                                                                                                                            |
| 11                                                                                                                                     | REGULATORY CONSIDERATIONS                                                                                                                                  |
| Institutional Review of Protocol .                                                                                                     |                                                                                                                                                            |
| 11.1                                                                                                                                   |                                                                                                                                                            |
| 11.2                                                                                                                                   | DATA AND SAFETY Monitoring Plan: .                                                                                                                         |
| 1.3                                                                                                                                    | DATA Management Plan                                                                                                                                       |
| 11.3.1                                                                                                                                 | DATA COLLECTION                                                                                                                                            |
| 11.3.2                                                                                                                                 | Data Submission responsibility .                                                                                                                           |
| 1.3.3                                                                                                                                  | Multicenter Guidelines .                                                                                                                                   |
| 12                                                                                                                                     | STATISTICAL CONSIDERATIONS .                                                                                                                               |
| 12.1                                                                                                                                   | Statistical Design and primary analysis                                                                                                                    |
| 12.2                                                                                                                                   | Secondary Analysis .                                                                                                                                       |
| Sample Size                                                                                                                            |                                                                                                                                                            |
| 12.3                                                                                                                                   |                                                                                                                                                            |
| 12.4                                                                                                                                   | Accrual estimates                                                                                                                                          |
| Feasibility and safety assessment.                                                                                                     |                                                                                                                                                            |
| 12.5                                                                                                                                   |                                                                                                                                                            |
| 13                                                                                                                                     | REFERENCES .                                                                                                                                               |
| Appendix A:  Medication guide for patients .                                                                                           |                                                                                                                                                            |
| Appendix B:  Stanford Cancer Institute Serious Adverse Event Reporting...............................58                                |                                                                                                                                                            |
| Appendix C:  ECOG Performance Status .                                                                                                 |                                                                                                                                                            |
| Appendix D:  Cockcroft-Gault Formula                                                                                                   |                                                                                                                                                            |
| Appendix E:  Ophthalmic exam source sheet                                                                                              |                                                                                                                                                            |
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protocol synopsis

In the table below summarize the basic aspects of this research. This is to be used as a quick reference guide.  
| TITLE                          | A pilot study of Dabrafenib and Trametinib for  patients with BRAF-mutated ameloblastoma   |
|--------------------------------|--------------------------------------------------------------------------------------------|
| STUDY PHASE                    | Pilot                                                                                      |
| INDICATION                     | Ameloblastoma                                                                              |
| INVESTIGATIONAL PRODUCT OR     | Dabrafenib and trametinib                                                                  |
| PROCEDURE PRIMARY OBJECTIVE(S) | Tumor response rate                                                                        |
| SECONDARY OBJECTIVE(S)         | Feasibility, safety, pathological response,  evidence of molecular pathway inhibition      |
| TREATMENT SUMMARY              | Dabrafenib 150 mg po q 12 hours plus  trametinib 2 mg once daily.                          |
| SAMPLE SIZE                    | 17 evaluable patients                                                                      |
| STATISTICAL CONSIDERATIONS     | Simon Optimal 2 stage design                                                               |  
IRB application number: IRB-32275 By determination of the Principal Investigator and the IRB, this study is considered IND-Exempt.
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schema

Pathologically-documented ameloblastoma with BRAF-V600E or other known Dabrafenib-sensitive BRAF mutation in tumor by any CLIA-certified lab Confirmation of eligibility and documentation of informed consent Baseline biopsy, imaging, staging and clinical assessment by
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list of abbreviations and definition

| ADL    | Activities of daily living                     |
|--------|------------------------------------------------|
| AE     | Adverse event                                  |
| BID    | Twice daily                                    |
| BSA    | Body surface area                              |
| CBC    | Complete blood count                           |
| CI     | Confidence interval                            |
| CRF    | Case report/Record form                        |
| CR     | Complete response                              |
| CTCAE  | Common Terminology Criteria for Adverse Events |
| DLT    | Dose-limiting toxicity                         |
| DSMB   | Data Safety Monitoring Board                   |
| ECG    | Electrocardiogram                              |
| GI     | Gastrointestinal                               |
| Hgb    | Hemoglobin                                     |
| HTN    | Hypertension                                   |
| IRB    | Institutional Review Board                     |
| IV     | Intravenous                                    |
| LLN    | Lower limit of normal                          |
| OS     | Overall survival                               |
| PLT    | Platelet                                       |
| PD     | Progressive diseased                           |
| PFS    | Progression free survival                      |
| PR     | Partial response                               |
| QD     | Once daily                                     |
| RECIST | Response evaluation criteria in solid tumors   |
| RR     | Response rate                                  |
| SAE    | Serious adverse event                          |
| SD     | Stable disease                                 |
| TTP    | Time to progression                            |
| ULN    | Upper limit of normal                          |
| UNK    | Unknown                                        |
| WBC    | White blood cell                               |
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1.0 objectives 1.1 primary objectives

To observe the response rate of ameloblastoma to dabrafenib plus trametinib at 6 weeks.
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1.2 secondary objectives

Secondary endpoints will include feasibility and safety in this patient population. Additionally, response will be assessed pathologically. Two main histologic assays for treatment response will be used: tumor necrosis and phosphorylated-MEK; phosphorylated-ERK; and Ki-67 levels as measured by immunohistochemistry.
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2.0 background 2.1 study disease

Ameloblastoma is a rare, benign, slow-growing but locally-invasive neoplasm of odontogenic origin involving the mandible (80%) and maxilla with a high recurrence rate attributed to conservative treatment. The neoplasm was first described by Cusack in 1827. {Cusack, 1827} Etymologically, the name derives from the old French word "amel" which means enamel and the Greek word "blastos" meaning germ or bud. Over time, this tumor has been referred to by many different names including "cystosarcoma," "adamantine epithelioma," "adamantinoma," and finally "ameloblastoma." {Ivy, 1930; Malassez, 1885; Wedl, 1870; Brazis, 1995] Ameloblastoma shows variable geographic prevalence, being the most common benign odontogenic tumor in China {Lu, 1998; Wu, 1985} and Africa {Anand, 1967; Mosadomi, 1975; Barnes, 2005}, while it is the second most common in the United States and Canada {Daley, 1994; Regezi, 1978} (odontoma being most common). Racial bias has also been observed, with African Americans at an overall five-fold increased risk of disease versus Caucasians. {Regezi, 1978} Global incidence has been estimated at 0.5 cases per million person years, with most cases diagnosed in the age range of 30 to 60 years. {Larsson, 1978} Up to 80% of ameloblastoma cases occur in the mandible, with a particular predilection for the posterior mandibular region. {Reichart, 1995} Rare cases have been reported as primary to the sinonasal cavities. {Schafer, 1998} Often ameloblastoma can be associated with unerupted third molar teeth {Stanley, 1965; Gerzenshtein, 2006; Becelli, 2002} particularly in the unicystic type. Desmoplastic ameloblastomas often occur in the anterior or premolar regions of the mandible or maxilla. Ameloblastic carcinomas also favor the mandible (~2/3) over the maxilla. {Slootweg, 1984} Maxillary ameloblastomas also mostly occur in the posterior molar region. Histopathologically, ameloblastoma resembles normal odontogenic/enamel epithelium and ectomesenchyme. Odontogenesis consists of chronographic and reciprocal interactions between the ectomesenchymal cells, which are derived from the neural crest, and the oral cavity lining epithelium. {Chai, 2000} The exact origin of ameloblastic epithelium has been hypothesized to arise from: (1) cells from the rests of enamel organ, (2) cells of the sheet of Hertwig's or epithelial cell rest of Malassez, (3) epithelial boundary of an odontogenic cyst, particularly a dentigerous cyst, (4) basal cells of the oral mucosa, and (5) heterotrophic epithelial from other parts of the body, perhaps pituitary. {Ritchie, 1990; Bhasker, 1981} Until recently, little was known about the molecular aberrations driving ameloblastoma, due to the tumor's rarity and the fact that technologies to query the tumor genome do not work as efficiently in formalin-fixed paraffin-embedded tissue. However, in 2014, three separate reports, including one form our group at Stanford, profiling ameloblastoma via DNA sequencing were published, all showing the vast majority of tumors to contain somatic mutations impacting the mitogen-activated protein kinase (MAPK) signaling pathway (FGFR2-> RAS -> BRAF) that controls cell proliferation. {Kurppa, 2014; Sweeney, 2014; Brown, 2014} In particular, all three studies reported a high frequency of BRAF-V600E (valine to glutamic acid substitution at amino acid 600) activating mutations at high allele frequencies in ameloblastomas. In each of these reports, the BRAF-mutated neoplasms were almost exclusively located in the mandible. Two of the three reports went on to characterize the sensitivity of BRAF-mutated ameloblastoma cells to vemurafenib, a V600E targeted small molecule inhibitor FDA-approved for metastatic melanoma. Both studies showed that AM-1, a mandibular-derived ameloblastoma cell line harboring the BRAF-V600E mutation, was exquisitely sensitive to vemurafenib at concentrations similar to BRAF-V600E mutated melanoma and colorectal cancer cell lines. Surgery is the standard treatment for ameloblastomas. Historically, the extent of resection has been controversial, comprising of two surgical options: "conservative" vs. "radical". The former involves enucleation/curettage of the bony cavity, while the latter involves a radical operation with proper margins. Advantages of enucleation include the fact that it is an outpatient procedure able to be performed by many different service providers (Oral Surgeons and ENT), since it requires no reconstruction. Despite these facts, historical data on simple enucleation demonstrate recurrence rates 60 to 90% and this treatment modality is currently believed to play no role in the management of multicystic ameloblastomas. The "radical" surgical option is the current standard of care for ameloblastoma, which includes enbloc resection with 1 to 2cm bone margins {Sham, 2009; Carlson, 2006; Gardner, 1980; Williams, 1993; Gortzak, 2006; Becelli, 2011; Pandya, 1972} and immediate bone reconstruction to help with speech and swallowing. {Sham, 2009; Vayvada, 2006; Tsai, 2006; Urken, 1991; Urken, 1998} The bony margin is defined as the distance away from the radiographic margin predicted to be disease free and oncologically safe to perform osteotomies. Data from 82 ameloblastoma specimens showed microscopic tumor extension 2 to 8mm (mean of 4.5mm) beyond the radiographic boundaries of the tumor. {Carlson, 2006} Hence, the recommended bone margins are1 to 1.5cm for unicystic and 1.5 to 2cm for solid/multicystic histological types providing increased cure rates. {Wenig, 2007; Becelli, 2002; Carlson, 2006; Zwahlen, 2002; Ueno, 1989; Vayvada, 2006} Ameloblastic carcinoma requires 2 to 3cm bone margins with an elective neck dissection. {Ndukwe, 2010} Therefore surgery for ameloblastoma, when possible, tends to be radical and disfiguring. Systemic chemotherapy has been attempted a number of times, with numerous agents and combinations being employed (see Table 1) {Gall, 1975; Eliasson, 1989; Ramadas, 1990; Grunwald, 2001; Campbell, 2003; Amzerin, 2011; Van Dam, 2010}. Anecdotal reports have suggested that ameloblastoma may be sensitive to platinum based agents {Amzerin, 2011} although occasional reports highlight lengthy survival without chemotherapy. {Ciment, 2002; Hasim, 2007} Chemotherapy may also have a role in improvement of clinical symptoms in non-surgical patients. {Ciment, 2002} Much like radiotherapy though, only with continuous reporting of empirical case-based data will the role of systemic chemotherapy be evaluable in this rare entity.  
| Case   | Regimen                                                                   | Response   | Reference             |
|--------|---------------------------------------------------------------------------|------------|-----------------------|
| 1      | Cyclophosphamide, Methotrexate,  5-Fluorouracil                           | None       | Gall, et al, 1975     |
| 2      | Vinblastine, Cisplatin, Bleomycin                                         | PR         | Eliasson, et al, 1989 |
| 3      | Adriamycin, Cisplatin,  Cyclophosphamide                                  | PR         | Ramadas, et al, 1990  |
| 4      | 1st line: 5-Fluorouracil and Cisplatin;  2nd line: Paclitaxel-Carboplatin | PR         | Grünwald, et al, 2001 |
| 5      | Cyclophosphamide                                                          | None       | Campbell, et al, 2003 |
| 6      | Doxorubicin and Cisplatin                                                 | PR         | Amzerin, et al, 2011  |
| 7      | Gemcitabine and Carboplatin                                               | PR         | Van Dam, et al, 2010  |
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2.2 study agents

Dabrafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF-V600E mutation as detected by an FDA-approved test. Dabrafenib is an inhibitor of some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF-V600E, BRAF-V600K, and BRAF-V600D enzymes, respectively. It is manufactured in 50 and 75 mg capsules. According to the FDA approved package insert, the safety of dabrafenib has been evaluated in 586 patients with BRAF-mutant melanoma, including 181 patients treated for at least 6 months and 86 additional patients for 12 months. The most commonly occurring adverse reactions in these patients treated with dabrafenib were, in order of decreasing frequency hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES). The most frequent adverse reactions leading to dose reduction of dabrafenib were pyrexia (9%); PPES (3%); chills (3%); fatigue (2%); and headache (2%). Dabrafenib has been demonstrated to induce response rates of 52% with a duration median of 5.6 months, in patients with BRAF-mutant melanoma. There are presently no safety or efficacy data for dabrafenib in patients with BRAF-mutant ameloblastoma. Dabrafenib is not FDA approved for treatment of patients with ameloblastoma, therefore conduct of this study will be under either an IND or FDA authorized IND exemption. Trametinib is a kinase inhibitor of MEK1 and MEK2 FDA-approved for use in patients with metastatic V600E mutated melanoma based upon a randomized control trial (RCT) of trametinib vs chemotherapy in which PFS (4.8 vs 1.5 mo) and RR (22% vs 8%) were higher in patients treated with trametinib. {Flaherty, 2012} In January 2014, the combination of dabrafenib and trametinib was approved for the treatment of patients with BRAF-V600E mutant melanoma. This approval was based upon a RCT which demonstrated an improvement in survival in the combination (25.1 mo median OS ) vs dabrafenib alone (18.7 mo median OS) with corresponding response rates of 69 vs 53% respectively. {Long, 2015} Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was fever (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group. Another RCT compared the combination of dabrafenib and trametinib vs vemurafenib, another TKI active against V600E mutant melanoma. {Robert, 2015} In that trial, the combination demonstrated improved PFS (11.4 vs 7.3 months), with similar AE and drug discontinuance rates. Therefore, it appears that in melanoma with BRAF-V600E mutations, the combination is active and provides clinical benefit. More recently, this combination has also been shown to be active in other cancers with this BRAF mutation. {Williams, 2015; Brastianos, 2016; Escandell, 2015} Most relevant is a report of a dramatic response in a patient with BRAF-mutant ameloblastoma. {Kaye, 2015} Earlier this year we treated an ameloblastoma patient who declined major surgical resection off-label with single agent dabrafenib. After 2 months of treatment the patient decided to have the resection. We observed massive amounts of tumor necrosis in the specimen, a finding very atypical for untreated ameloblastoma (report accepted for publication, Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, 14 December 2015).
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2.3 rationale

Present accepted standard of care treatment for patients with ameloblastoma is limited to surgical resection and reconstruction. These operations for patients with advanced disease are morbid and disfiguring. There is no defined role for radiation or chemotherapy treatment for ameloblastoma patients at any stage.  
Based on the recent discovery of potentially relevant BRAF mutations in ameloblastoma and preclinical data which suggest that BRAF-mutant ameloblastoma may respond to relevant mutant BRAF tyrosine kinase inhibition, we propose to ask in a pilot trial whether there is any evidence of anti- tumor activity against ameloblastoma in patients with advanced disease. Because of robust data with combined BRAF and MEK inhibition in BRAF-mutant melanoma, we plan to use dabrafenib and trametinib in combination. Novartis has agreed to supply both agents for this investigator-initiated study. Because most patients with advanced disease have significant mandibular bone involvement but do not have metastatic disease, we are proposing a trial which will focus on this group of patients. This allows us to ask in a preliminary way whether there is clinical, pathological, or microbiological evidence of anti-cancer activity of a relevant TKI, dabrafenib in combination with a MEK inhibitor, trametinib, in this situation. The design of the trial will facilitate collection of tissue at baseline and after 6 weeks of treatment to allow for assessment of the pathological and microbiological endpoints, but will also not unduly delay attempts at definitive surgical treatment for appropriate patients.
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2.4 study design

This will be a single-group, single-arm, 2-stage, open non-randomized treatment study whose primary endpoint is tumor response rate with feasibility, safety, pathological and molecular biological secondary endpoints.
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2.5 correlative studies background

Activation of the Ras/Raf/MAPK signaling pathway begins with the binding of ligands to receptor-linked tyrosine kinases, such as epidermal growth factor receptor or fibroblast growth factor receptor. This leads to phosphorylation of tyrosine residues on the receptor that then recruits adaptor proteins (eg, GRB2 and SOS). This protein complex allows SOS to switch to an activated state that in turn leads to activation of Ras proteins by binding GTP. This turns on the activity of Raf serine/threonine kinases, including B-Raf (BRAF). The signaling transduction cascade then continues with the phosphorylation and activation of MEK1 and MEK2 tyrosine/threonine kinases. Through phosphorylation, the MEKs activate the Erk MAPKs which regulate transcriptional factors that influence differentiation, senescence, survival, and proliferation. Mutations in the Ras/Raf/MAPK pathway are essential in a number of cancers including the majority of melanomas with ~50% exhibiting BRAF mutations and ~ 20% exhibiting NRAS mutations. In melanoma, these mutations appear at an early stage in tumorigenesis, including precursor lesions like benign nevi, and are preserved through progression. These are activating mutations which result in the Ras/Raf/MAPK pathway constitutively signaling for proliferation and survival. Inhibition of this pathway in tumors with BRAF mutations turns off this pathway and shuts down essential survival pathways resulting in cell death. BRAF inhibitor (dabrafenib; formerly GSK2118436) showed promising results with an approximately 2-fold increase in progression-free survival in a phase III trial, which is in a similar range as that of vemurafenib. {Hauschild, 2012} Recent studies on ameloblastoma have found BRAF-V600E mutations to be present in the majority of cases arising in the mandible. Two studies have demonstrated that cell lines of ameloblastoma are responsive to V600E targeted small molecule inhibitors in cell proliferation assays. Two main histologic assays for treatment response will be used: tumor necrosis and phosphorylated-MEK, phosphorylated-ERK, and Ki-67 levels as measured by immunohistochemistry. As mentioned above, since the activation of the Ras/Raf/MAPK pathway promotes cell proliferation and survival, blockade of this pathway will result in cell decrease in proliferation, death and necrosis. Furthermore, activation of the Ras/Raf/MAPK pathway leads to phosphorylation of several of the pathway components, including MEK and ERK. These assays for treatment response thus examine both early and late effects of Ras/Raf/MAPK pathway inhibition. Routine Hemotoxylin-Eosin stained slides from both the pre-treatment biopsy as well as definitive resection specimens will be scored for the presence of tumor necrosis, which will be quantified. Additionally, unstained slides from both pre- and post- specimens from participating institutions will be sent to Stanford University for analysis of phospho-MEK/ERK and Ki-67 staining. Tumors will be scored, by at least two pathologists using percentage positive cells as the primary metric. The results of the immunohistochemical analysis will be expressed as both raw data in addition to a ratio between pre- and post- treatment We will also be consenting patients for permission to sequence the genome of their tumor, to publish in public databases anonymized sequence data and to attempt to establich cell cultures of tumor specimens if there is sufficient material to do so. These studies are exploratory and will only be done should there be sufficient specimen from the planned biopsies remaining after the tumor material for tumor necrosis and phosphorylation assays has been obtained.
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3.0 participant selection and enrollment

In order to reduce redundancy, we have incorporated the actual eligibility checklist into the body of the protocol.
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3.1 participant eligibility checklist

A Participant Eligibility Checklist must be completed in its entirety for each subject prior to registration. The completed, signed, and dated checklist must be retained in the patient's study file and the study's Regulatory Binder. The study coordinator, treating physician and an independent reviewer must verify that the participant's eligibility is accurate, complete, and legible in source records. A description of the eligibility verification process should be included in the EPIC or other Electronic Medical Record progress note or a signed version of the eligibility checklist must be available in EPIC or other Electronic Medical Record for review.
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eligibility criteria in checklist form

| Protocol Title:          | A pilot study of dabrafenib and trametinib for patients with  BRAF-mutated ameloblastoma.   |
|--------------------------|---------------------------------------------------------------------------------------------|
| Protocol Number:         | IRB-32275 / ENT0043                                                                         |
| Principal Investigator:  | A Dimitrios Colevas                                                                         |
| II. Subject Information: |                                                                                             |  
Subject Name/ID: Gender: Male Female
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iv. inclusion/exclusion criteria

| Inclusion Criteria   | Yes                                                                                                                                                                                                                   | No   | Supporting documents   |
|----------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------|------------------------|
| 1.                   | Histological diagnosis of ameloblastoma. All  stages are eligible. Patients must have evaluable  disease by RECIST criteria                                                                                           |      |                        |
| 2.                   | BRAF-V600E or other known dabrafenib  sensitive BRAF mutation in tumor by any  CLIA-certified lab. May include, for example,  Sanger sequencing, SNaPshot platform,  immunohistochemistry, Foundation One tests, etc) |      |                        |
| 3.                   | At least 18 years old                                                                                                                                                                                                 |      |                        |
| 4.                   | Life expectancy > 3 months                                                                                                                                                                                            |      |                        |
| 5.                   | ECOG performance status ≤ 2 (see Appendix C)                                                                                                                                                                          |      |                        |  
| 6.                                                                                                                                                                                                                                                                                                 | Lab values:  ANC > 1.5 x 109 /L  PLT > 99 x 109 /L  Hemoglobin > 8 g/dL  Tbili < 1.6 x ULN o Except subjects with known Gilbert's  syndrome  AST, ALT and alk phos < 2.6 x upper limit of  normal (ULN)  Serum creatinine ≤ 1.5 mg/dL, or if serum  creatinine is > 1.5 mg/dL, creatinine  clearance must be  50 mL/min (calculate  creatinine clearance using the Cockcroft-Gault  formula (see Appendix D).   PR / INR and PTT ≤ 1.3 X ULN. Subjects  receiving anticoagulation treatment may be  allowed to participate with INR established  within the therapeutic range prior to  randomization   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 7.                                                                                                                                                                                                                                                                                                 | Ability to understand and the willingness to sign a  written informed consent document                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| 8.                                                                                                                                                                                                                                                                                                 | Patients of childbearing potential must agree to  use effective contraception until at least 6 months  after treatment with dabrafenib and trametinib.  See exclusion criteria re pregnancy testing                                                                                                                                                                                                                                                                                                                                                                                                             |
| 9.                                                                                                                                                                                                                                                                                                 | Able to swallow and retain oral medication and  must not have any clinically significant  gastrointestinal abnormalities that may alter  absorption such as malabsorption syndrome or  major resection of the stomach or bowels                                                                                                                                                                                                                                                                                                                                                                                 |
| 10. Left ventricular ejection fraction equal to or  greater than normal within 1 month of enrollment.  ECHO scans must be used throughout the study. Exclusion Criteria 1. No prior treatment with agents targeting  BRAF-mutant tyrosine kinases or MEK inhibitors or radiation of target lesions |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |  
| 2.                                                                                           | Invasive malignancy other than ameloblastoma  within 3 years, excluding curatively treated basal  cell carcinoma, and other highly curable cancers  such as early stage cutaneous squamous cell  carcinoma (T1 NO) cervical CIS, early stage  prostate cancer, thyroid cancer, breast cancer or  history of malignancy with confirmed activating  RAS mutation at any time   |
|----------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 3.                                                                                           | Uncontrolled hypertension (systolic blood  pressure > 140 mm Hg and diastolic blood  pressure of > 90 mm Hg which cannot be  controlled by anti-hypertensive therapy), CHF, or  other major medical illness.                                                                                                                                                                 |
| 4.                                                                                           | Prior allergic reactions attributed to compounds of  similar chemical or biologic composition to  dabrafenib or trametinib.                                                                                                                                                                                                                                                  |
| 5.                                                                                           | Concomitant use of strong inhibitors  (eg, ketoconazole, nefazodone, clarithromycin,  gemfibrozil) or strong inducers (eg, rifampin,  phenytoin, carbamazepine, phenobarbital, St  John's wort) of CYP3A4 or CYP2C8 . For a full  list of excluded drugs see Section 4.1.2 of the  protocol                                                                                  |
| 6.                                                                                           | Concomitant use of proton pump inhibitors,  H2-receptor antagonists, antacids                                                                                                                                                                                                                                                                                                |
| 7.                                                                                           | Known G6PD deficiency                                                                                                                                                                                                                                                                                                                                                        |
| 8.                                                                                           | Pregnant or nursing patients. Women of  childbearing potential must have a negative  SERUM pregnancy test within 14 days of  enrollment. Women of child-bearing potential  must agree to use effective contraception for  14 days prior to enrollment, throughout the  treatment period and for 4 to 6 months after the  last dose of study treatment.                       |
| 9.                                                                                           | EKG with QTcB (Bazett's formula) > 480 ms  done within 14 days of enrollment                                                                                                                                                                                                                                                                                                 |
| 10. Interstitial lung disease or pneumonitis. 11. A history of retinal vein occlusion (RVO). |                                                                                                                                                                                                                                                                                                                                                                              |  
| 12. Congestive heart fauilure NYHA Class III or  worse (Marked limitation of physical activity.  Comfortable at rest. Less than ordinary activity  causes fatigue, palpitation, or dyspnea.) 13. A history of acute coronary syndromes (including  myocardial infarction or unstable angina),  coronary angioplasty, or stenting within 6 months or a history or evidence of current clinically  significant uncontrolled arrhythmias or  intra-cardiac defibrillators or abnormal cardiac  valve morphology (≥ Grade 2) documented by  echocardiogram. Subjects with Grade 1  abnormalities (ie, mild regurgitations/stenosis)  may be entered. Subjects with moderate valvular  thickening are not eligible. Subjects with atrial  fibrillation controlled for > 30 days prior to  dosing are eligible. 14. Prior systemic anti-cancer treatment  (chemotherapy, immunotherapy, biologic therapy,  vaccine therapy or investigational treatment  within 3 weeks preceding first dose of study  treatment, or chemotherapy without delayed  toxicity within 2 weeks preceding first dose of  study treatment. 15. Any serious or unstable pre-existing medical  conditions, psychiatric disorders or other  conditions which could interfere with the  subject's safety, obtaining informed consent, or  compliance with study procedures. 16. A history of Hepatitis B virus (HBV) or  Hepatitis C virus (HCV) infection. Subjects with  laboratory evidence of cleared HBV and/or HCV  will be allowed.   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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v. statement of eligibility

By signing this form of this trial I verify that this subject is [ eligible / **ineligible**] for participation in the study. This study is approved by the Stanford Cancer Institute Scientific Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as required by Stanford School of Medicine's Research Management Group.  
Treating Physician Signature: Date: Printed Name:  
Secondary Reviewer Signature: Date:  
Printed Name:  
Study Coordinator Signature: Date:  
| Printed Name:   |
|-----------------|
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3.2 informed consent process

All participants must be provided a consent form describing the study with sufficient information for participants to make an informed decision regarding their participation.  
Participants must sign the IRB approved informed consent prior to participation in any study specific procedure. The participant must receive a copy of the signed and dated consent document. The original signed copy of the consent document must be retained in the medical record or research file.
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3.3 study timeline primary completion

We estimate the study will reach primary completion 27 months from the time the study opens to accrual.
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study completion

The study will reach study completion 36 months from the time the study opens to accrual.
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4.0 treatment plan

All patients will have a diagnosis of ameloblastoma pathologically confirmed by the participating institution's department of pathology. The mutational status of BRAF in the tumor must be determined by any CLIA-certified lab using standard techniques . These may include, for example, Sanger sequencing, SNaPshot platform, immunohistochemistry, Foundation One tests, etc.). While we are primarily expecting to identify V600 E mutations, other BRAF mutations known to confer sensitivity to dabrafenib are acceptable if approved by the study principal investigator. Every patient must have baseline blood chemistries and counts and other eligibility criteria as defined in Section 3 done according to the schedule defined in the study calendar in Section 9. Baseline imaging used to define RECIST v1.1 {Eisenhauer, 2009} measurements are at the discretion of the local investigator. These will typically be either a contrast enhanced CT or MRI of the relevant anatomy, but PET-CT is also appropriate if the lesion is evaluable by PET-CT per RECIST v1.1 criteria. To maintain consistency of data and quality of science, whatever imaging modality is used at baseline for each patient should be used throughout the trial. Photographic documentation is encouraged but cannot substitute for imaging. The starting dose for all patients will be: Dabrafenib, 150 mg orally twice daily taken at least 1 hour before or at least 2 **hours** after a meal. Dabrafenib comes as 75 mg and 50 mg capsules. Therefore the initial dose will be two 75 mg capsules as specified above. The second dose of dabrafenib (150 mg) should be administered approximately 12 hours after the morning dose.
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trametinib 2 mg once daily.

Take the once-daily dose of trametinib at approximately the same time each day with either the morning dose or the evening dose of dabrafenib. Study medications should be taken orally with approximately 200 mL of water under fasting conditions, either 1 hour before or 2 hours after a meal. If a subject vomits after taking study medication, the subject should be instructed not to retake the dose and should take the next dose as originally scheduled. If administration of trametinib is interrupted or permanently discontinued, administration of dabrafenib may be continued. If administration of dabrafenib is interrupted or permanently discontinued, administration of trametinib may continue. If a subject misses a dose of dabrafenib, the subject may take the dose immediately if the next dose is scheduled for at least 6 hours later. If the next scheduled dose of dabrafenib is due in less than 6 hours, the subject should skip the dose and resume dabrafenib dosing at the next scheduled dose. If a subject misses a dose of trametinib, the subject may take the dose immediately if the next dose is scheduled for at least 12 hours later. Patients whose tumors are amenable to surgical resection will continue dosing continuously for at least 6 weeks and proceed to surgery between weeks 6 and 7, without dose interruption. Patients undergoing surgical resection will continue dabrafenib and trametinib until it is necessary to take nothing by mouth in the hours preceding surgery, but ideally the patients will be dosed with dabrafenib and trametinib within 12 hours of the surgical resection. Patients whose tumors are grossly completely resected will not resume dabrafenib and trametinib. Patients whose tumors are not resected completely have the option to resume the dabrafenib and trametinib at the dose they were receiving immediately prior to surgery if ALL of the following criteria are met:  
1. Prior to surgery the patient did not have AEs or progression which necessitated dabrafenib or trametinib cessation.  
2. The patient has recovered from surgery without unexpected complication. 3. At least 1 week has passed since surgery. 4. The patient has evaluable residual tumor. 5. No more than 6 weeks has elapsed since surgery.
Patients whose disease is judged to be not amenable to resection will continue dabrafenib and trametinib indefinitely as long as there has not been tumor progression either by RECIST v1.1 or clinical progression criteria, there have not been unacceptable adverse events and the patient has not decided to discontinue for other reasons. Clinical evaluations for protocol purposes will take place according to the schedule defined in Section 9. Dose modifications will be according to the guidelines in Section 6.
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4.1 general concomitant medication and

The investigator must be informed as soon as possible about any medication taken from the time of screening until the end of investigational drug administration. Documentation of concomitant medication(s), including dietary supplements, taken during the study will be recorded in the patient medical record according to the schedule specified in Section 9. The minimum requirement is that drug name, dose, and the dates of administration are to be recorded. Subjects should receive full supportive care during the study, including transfusions of blood and blood products, and treatment with antibiotics, anti-emetics, anti-diarrheals, and analgesics, and other care as deemed appropriate, and in accordance with their institutional guidelines. Use of anticoagulants such as **warfarin is permitted however, caution should** be exercised and additional International Normalized Ratio (INR) monitoring is recommended when dabrafenib is used concomitantly with warfarin. See Section 4.1.3 for guidelines concerning concomitant warfarin and dabrafenib administration. Radiation skin injury has been reported with concurrent use of dabrafenib and radiation. It is recommended that dabrafenib and trametinib be held for 7 days before and 2 days after XRT.
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medicinal products that increase gastric

The use of certain medications (see Table 2 below) and illicit drugs within 28 days or 5 half-lives, whichever is shorter, prior to and during dabrafenib study treatment. will not be allowed. The following medications or non-drug therapies are prohibited while on treatment in this study:
Other anti-cancer therapies;  
Other investigational drugs; Herbal remedies (eg, St John's wort);
Dabrafenib is metabolized primarily by Cytochrome P450 (CYP) 2C8 and CYP3A4.  
Co-administration of dabrafenib with ketoconazole, a CYP3A4 inhibitor, or with gemfibrozil, a CYP2C8 inhibitor, resulted in increases in dabrafenib AUC of 71% and 47%, respectively. Drugs that are strong inhibitors or inducers of CYP3A and CYP2C8 (see list in the table below) may only be used under special circumstances (e.g. as a single use for a procedure) while treatment with study drug is interrupted as they may alter dabrafenib concentrations; consider therapeutic substitutions for these medications. Approval of the protocol principal **investigator is required and must** be documented in these situations.  
| PROHIBITED - Strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib  may be decreased Class/Therapeutic Area Drugs/Agents Antibiotics Rifamycin class agents (eg, rifampin, rifabutin, rifapentine),  Anticonvulsant Carbamazepine, oxcarbazepine phenobarbital, phenytoin,  s-mephenytoin  Miscellaneous bosentan, St-John's wort PROHIBITED - Strong inhibitors of CYP3A, or CYP2C8 since concentrations of dabrafenib  may be increased Class/Therapeutic Area Drugs/Agents Antibiotics Clarithromycin, telithromycin, troleandomycin Antidepressant Nefazodone Antifungals Itraconazole, ketoconazole, posaconazole, voriconazole Hyperlipidemia Gemfibrozil Antiretroviral ritonavir, saquinavir, atazanavir Miscellaneous Conivaptan   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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4.1.3 medications to be used

The following medications should be used with caution as their concentrations may be altered by dabrafenib or they may alter dabrafenib concentrations:  
Drugs that are moderate inhibitors or inducers of CYP3A and CYP2C8 as they may alter concentrations of dabrafenib.  
Dabrafenib has been shown to induce CYP3A4 and CYP2C9 in vivo using midazolam
(CYP3A4 substrate) and S-warfarin (CYP2C9 substrate). Dabrafenib is an in vitro inducer of CYP2B6 and other enzymes such as CYP2C8, CYP2C19, UDP-glucuronyl transferases. Transporters may also be affected. Co-administration of dabrafenib and medications which are affected by the induction of these enzymes (including warfarin) and transporters may result in loss of efficacy. If co-administration of these medications is necessary, investigators should monitor subjects for loss of efficacy or consider substitutions of these medications. A partial list of these medications is provided in Table 2 above.  
Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site. Warfarin exposure has been shown to decrease (37% decrease) due to dabrafenib-mediated enzyme induction. Conversely, if dabrafenib dosing is reduced, interrupted, or discontinued, warfarin exposure may be increased. Thus, warfarin dosing may need to be adjusted based on PT/INR during and after treatment with dabrafenib. Prophylactic low dose warfarin may be given to maintain central catheter patency.  
InfromDabrafenib solubility is pH-dependent with decreased solubility at higher pH.  
Drugs such as proton pump inhibitors that inhibit gastric acid secretion to elevate gastric pH may decrease the solubility of dabrafenib and reduce its bioavailability. No clinical study has been conducted to evaluate the effect of pH on dabrafenib pharmacokinetics. In an ad-hoc analysis, no differences in Cmax and AUC were noted between subjects who reported taking pH-elevating products relative to other subjects. Due to the theoretical risk that pH-elevating agents may decrease oral bioavailability and exposure to dabrafenib, these **medicinal products that increase gastric pH** should be used with caution when administered with dabrafenib.
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4.2 criteria for removal from

Patients should have dabrafenib discontinued for unacceptable adverse events, clinically unacceptable or RECIST v1.1 defined progression, or patient withdraws of consent. For patients who stop dabrafenib because of unacceptable AEs or progression of disease, providers may proceed to surgical resection as clinically indicated. Patients who have not withdrawn consent to be studied should have all planned restaging and secondary tissues analyses performed per protocol prior to surgery and on the surgical specimens resected at the time of surgery. Patients should be followed for protocol related AEs for 4 weeks after the last dabrafenib dose unless another systemic anti- cancer agent has been initiated.
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5.0 study agent information 5.1

Dabrafenib is a kinase inhibitor FDA approved for the treatment of patients with unresectable or metastatic melanoma with BRAF-V600E mutation as detected by an FDA-approved test. It comes in 50 mg and 75 mg capsules. Active ingredient: dabrafenib. Inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose. Capsule shells contain: hypromellose, red iron oxide (E172), titanium dioxide (E171). Trametinib is a FDA-approved kinase inhibitor for the treatment of patients with unresectable or metastatic melanoma with BRAF-V600E or -V600K mutations as detected by an FDA-approved test. Tablets are supplied as 0.5 mg and 2 mg tablets for oral administration. Each 0.5 mg tablet contains 0.5635 mg trametinib dimethyl sulfoxide equivalent to 0.5 mg of trametinib non-solvated parent. Each 2 mg tablet contains 2.254 mg trametinib dimethyl sulfoxide equivalent to 2 mg of trametinib non-solvated parent. The inactive ingredients are tablet core: mannitol, microcrystalline cellulose, hypromellose, croscarmellose sodium, magnesium stearate (vegetable source), sodium lauryl sulfate, colloidal silicon dioxide; and coating: hypromellose, titanium dioxide, polyethylene glycol, polysorbate 80 (2 mg tablets), iron oxide yellow (0.5 mg tablets), iron oxide red (2 mg tablets). Dabrafenib and trametinib will be dosed as specified in Section 4 of this protocol, with dose modifications in Section 6.
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5.2 availability

Dabrafenib and trametinib will be obtained from Novartis and distributed to all investigational sites according to a pharmacy appendix to be developed prior to protocol activation.
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5.3 agent ordering

Dabrafenib and trametinib will be ordered by site investigational pharmacies according to guidelines to be developed prior to protocol activation and included in the pharmacy appendix section.
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5.4 agent accountability

Access to dabrafenib and trametinib will be restricted according to the standard operating procedures of the investigational pharmacies of each collaborating institution's pharmacy.  
Drug accountability will similarly be according to each institution's standard operating procedures.
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5.5 combination dosage and administration

Dabrafenib and trametinib must be dispensed and administered in accordance with the protocol, and only to subjects enrolled in the study. Dabrafenib and trametinib must be stored in a secure area under the appropriate physical conditions for the product. Study medication is to be stored at the temperature specified on the label. Maintenance of a temperature log (manual or automated) is required. Access to and administration of dabrafenib and trametinib will be limited to the investigator and authorized site staff.
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6.0 dose modifications 6.1 dose

General guidelines regarding management and dose reduction for adverse events that are considered by the investigator to be related to study treatment and for which specific guidelines do not apply are provided in the table below. These guidelines are intended primarily for toxicities not easily managed with routine supportive care. For example, alopecia is not an indication for dose modification, nor is grade 2 nausea and vomiting that can be easily managed with anti-emetics.  
| DABRAFENIB       | TRAMETINIB         |                  |                   |
|------------------|--------------------|------------------|-------------------|
| Dose Level       | Dose/Schedule      | Dose Level       | Dose/Schedule     |
| Full dose        | 150 mg twice daily | Full dose        | 2 mg once daily   |
| First reduction  | 100 mg twice daily | First reduction  | 1.5 mg once daily |
| Second reduction | 75 mg twice daily  | Second reduction | 1 mg once daily   |
| Third reduction  | 50 mg twice daily  | Third reduction  | 0.5 mg once daily |  
| Table 4: Dose Modification Guidelines - General   |                                                                                                                                                                        |                                                                                                                                                                 |
|---------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| CTCAE Grade                                       | Occurance                                                                                                                                                              | Action and Dose Modification a,b                                                                                                                                |
| Grade 1 or  Grade 2  (tolerable)                  | N/A                                                                                                                                                                    | Continue study treatment at same dose level (no dose  modification) and monitor as clinically indicated                                                         |
| Grade 2  (Intolerable) or  Grade 3                | 1 st, 2nd or  rdoccurrence 3                                                                                                                                           | Interrupt study treatment until toxicity resolves to ≤ grade 1  then restart at next lower dose level                                                           |
| th or greater                                     | Discontinue treatment                                                                                                                                                  |                                                                                                                                                                 |
| 4 occurrence                                      |                                                                                                                                                                        |                                                                                                                                                                 |
| Grade 4                                           | 1 st occurrence                                                                                                                                                        | Interrupt study treatment until toxicity resolves to ≤ grade 1  or baseline then restart at next lower dose level or  discontinue at discretion of investigator |
| nd occurrence                                     | Interrupt study treatment until toxicity resolves to ≤ grade 1                                                                                                         |                                                                                                                                                                 |
| 2                                                 | or baseline then restart at two dose levels lower than the  starting dose or discontinue at discretion of investigator and  after discussion with the medical monitor. |                                                                                                                                                                 |
| rd occurrence                                     | Discontinue treatment                                                                                                                                                  |                                                                                                                                                                 |
| 3                                                 |                                                                                                                                                                        |                                                                                                                                                                 |
| a.                                                | Treatment should be discontinued if more than 3 dose reductions are required                                                                                           |                                                                                                                                                                 |
| b.                                                | Approval from the protocol PI is required to restart study treatment after ≥ 21 days                                                                                   |                                                                                                                                                                 |  
When an individual's adverse reactions are under effective management, dose re-escalation following the same dosing steps as de-escalation may be considered. These are general guidelines and investigators should always use clinical judgment in determining dose adjustments for any individual patient. Some toxicities may require hospitalization for stabilization, additional work-up, and consultation with a specialist before treatment can be restarted. Specific adverse events and recommended management include the following:
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6.2 dose reductions for aes

6.2.1 Plantar- **Palmar Erythrodysesthesia** (Hand foot syndrome, PPES) - Measures for PPES should include:
Lifestyle modification: avoidance of hot water; traumatic activity; constrictive footwear; or excessive friction on the skin. Adopt the use of thick cotton socks and gloves, and shoes with padded insoles. Symptomatic treatments: apply moisturizing creams frequently; topical keratolytics (eg, urea 20 to 40% cream; salicylic acid 6%; tazarotene 0.1% cream; fluorouracil 5% cream), clobetasol propionate 0.05% ointment for erythematous areas; topical lidocaine 2%; and/or systemic pain medication such as nonsteroidal anti-inflammatory drugs (NSAIDs); codeine; and pregabalin for pain. Dose modification may also be required.
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6.2.2 pancreatitis

In the event of abdominal pain or suspected pancreatitis, amylase and lipase laboratory samples should be collected for confirmation of the diagnosis. Patients should be closely monitored when re-starting dabrafenib after an episode of pancreatitis.
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6.2.3 uveitis and ocular events

Ophthalmological exams will be required at baseline, Week 6 and annually thereafter. Episodes of visual changes have been observed in subjects receiving trametinib, dabrafenib, and combination therapy. An ophthalmologist should be consulted if changes in vision develop. However, if the visual changes are clearly unrelated to study treatment (eg, allergic conjunctivitis), then monitor closely as it may be reasonable to defer ophthalmic examination.  
Treatment with dabrafenib has been associated with the development of uveitis, including iritis. Monitor patients for visual signs and symptoms (such as, change in vision, photophobia and eye pain) during therapy. Special attention should be given to retinal findings (eg, retinal pigment epithelial detachment (RPED) or retinovascular abnormalities (ie, branch or central retinal vein occlusions (RVO). Guidelines regarding management and dose reduction for visual changes and/or ophthalmic examination findings considered to be related to study treatment are provided in the below tables:
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table 5 management and dose

| CTCAE               | Adverse Event Management                                                                                                                               | Action and Dose Modification                                                                                                                                                                                                       |                                                                                                                                    |                                                                           |
|---------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------|
| Grade a             |                                                                                                                                                       | Consult ophthalmologist                                                                                                                                                                                                            |                                                                                                                                   | If dilated fundus examination cannot be                                   |
| Grade 1 b           | within 7 days of onset                                                                                                                                 | performed within 7 days of onset, interrupt  trametinib until RPED and RVO can be  excluded by retina specialist/ophthalmologist. If  subject is receiving trametinib/dabrafenib  combination therapy dabrafenib may be  continued |                                                                                                                                    |                                                                           |
|                    | If RPED and RVO excluded, continue (or  restart) trametinib at same dose level                                                                         |                                                                                                                                                                                                                                    |                                                                                                                                    |                                                                           |
|                    | If RPED suspected or diagnosed: see RPED  dose modification table Y below; report as  SAE if diagnosed                                                 |                                                                                                                                                                                                                                    |                                                                                                                                    |                                                                           |
|                    | If RVO diagnosed: Permanently discontinue  trametinib and report as SAE                                                                                |                                                                                                                                                                                                                                    |                                                                                                                                    |                                                                           |
|                    | Consult ophthalmologist  immediately                                                                                                                   |                                                                                                                                                                                                                                   | If RPED and RVO excluded, restart trametinib at  same dose level                                                                   |                                                                           |
| Grade 2 and Grade 3 |                                                                                                                                                       | Interrupt trametinib. If  subject is receiving  trametinib/dabrafenib  combination therapy  dabrafenib may be continued                                                                                                            |                                                                                                                                   | If RPED diagnosed, see RPED dose  modification table below; report as SAE |
|                    | If RVO diagnosed: Permanently discontinue  trametinib and report as SAE                                                                                |                                                                                                                                                                                                                                    |                                                                                                                                    |                                                                           |
|                    | Consult ophthalmologist                                                                                                                                |                                                                                                                                                                                                                                    |                                                                                                                                    |                                                                           |
| Grade 4             | immediately                                                                                                                                            |                                                                                                                                                                                                                                   | If RPED and RVO excluded, may consider  restarting trametinib at same or reduced dose  after discussion with study medical monitor |                                                                           |
|                    | Interrupt trametinib. If  subject is receiving  trametinib/dabrafenib  combination therapy  dabrafenib may be continued                                |                                                                                                                                                                                                                                   | If RVO or RPED diagnosed, permanently  discontinue trametinib and report as SAE                                                    |                                                                           |
| c.                  | Refers to CTCAE Version 4.0 'Eye disorders - Other, specify'                                                                                           |                                                                                                                                                                                                                                    |                                                                                                                                    |                                                                           |
| d.                  | If visual changes are clearly unrelated to study treatment (eg, allergic conjunctivitis), monitor closely but  ophthalmic examination is not required. |                                                                                                                                                                                                                                    |                                                                                                                                    |                                                                           |  
Table 6: Recommended dose modifications for trametinib for retinal pigment epithelial detachments (RPED)  
| CTCAE Grade a                                                                                            | Action and Dose Modification                                                                                                             |                                                    |
|----------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------|
| Grade 1 RPED (Asymptomatic; clinical                                                                     |                                                                                                                                         | Continue treatment with retinal evaluation monthly |
| or diagnostic observations only)                                                                         | until resolution. If RPED worsens follow instructions  below                                                                             |                                                    |
|                                                                                                         | Interrupt trametinib                                                                                                                     |                                                    |
|                                                                                                         | Retinal evaluation monthly                                                                                                               |                                                    |
|                                                                                                         | If improved to ≤ Grade 1, restart trametinib at lower  dose (reduced by 0.5 mg) or discontinue in patients  taking trametinib 1 mg daily |                                                    |
| e.                                                                                                       | Refers to CTCAE Version 4.0 'Retinopathy'                                                                                                |                                                    |
| Grade 2-3 RPED (Symptomatic with mild to moderate decrease in visual acuity;  limiting instrumental ADL) |                                                                                                                                          |                                                    |
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6.2.4 hyperglycemia

Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral therapy can occur with dabrafenib. Monitor serum glucose levels as clinically appropriate during treatment with dabrafenib in subjects with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination. Investigators should always err on the side of caution in these settings if treatment-related toxicity is a possibility.
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6.2.5 pyrexia

Episodes of pyrexia have been observed in subjects receiving dabrafenib monotherapy, and is increased in incidence and severity in subjects receiving dabrafenib in combination with trametinib. In a minority of cases the pyrexia was accompanied by symptoms such as severe chills; dehydration; hypotension; and dizziness or weakness. Subjects should be instructed on the importance of immediately reporting febrile episodes. In the event of a fever, the subject should be instructed to take anti-pyretics (eg, ibuprofen or acetaminophen) as appropriate to control fever. The use of oral corticosteroids should be considered in those instances in which anti-pyretics are insufficient. Monitor serum creatinine and other evidence of renal function during and following severe events of pyrexia. Guidelines regarding management and dose modifications for pyrexia considered to be related to study treatment provided below.  
| Table 7: Management and Dose Modification Guidelines for Pyrexia                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                     |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Adverse                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Adverse Event Management                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Action and Dose Modification                                                                                                                                                                                                                                        |
| Event                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                     |
| Pyrexia: a                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | All Events:  Clinical evaluation for infection and  hypersensitivity c                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | st Event:  1  Interrupt dabrafenib  Continue trametinib  Once pyrexia resolves to baseline, restart  dabrafenib at the same dose level o If fever was associated with rigors, renal  failure, dehydration or hypotension,  reduce dabrafenib by one dose level g |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Laboratory work-up c                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                     |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Hydration as required d                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                     |
| 1 st Event b :  Administer anti-pyretic treatment as  clinically indicated and initiate prophylactic  treatment if associated with rigors, renal  failure, dehydration or hypotension e                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | nd Event: 2  Interrupt dabrafenib  Continue trametinib  Once pyrexia resolves to baseline, restart  dabrafenib at the same dose level o If fever was associated with rigors, renal  failure, dehydration or hypotension,  reduce dabrafenib by one dose level g Subsequent Events:  Interrupt dabrafenib  Continue trametinib  Once pyrexia resolves to baseline, restart  dabrafenib reduced by one dose level g  If dabrafenib must be reduced to < 50 mg  BID, permanently discontinue  dabrafenib. Trametinib may be  continued |                                                                                                                                                                                                                                                                     |
| nd Event f 2  Within 3 days of onset of pyrexia o Optimize anti-pyretic therapy o Consider oral corticosteroids (ie,  prednisone 10 mg) for at least 5 days or as  clinically indicated f Subsequent Events:   Within 3 days of onset of pyrexia: o Optimize oral corticosteroid dose as  clinically indicated for recalcitrant  pyrexia f o If corticosteroids have been tapered and  pyrexia recurs, restart steroids  o If corticosteroids cannot be tapered consult  medical monitor                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                     |
| a. Pyrexia is defined as a body temperature equal to or above 38.5 Celsius or 101.3ºFahrenheit.  b. For subjects experiencing pyrexia complicated by rigors, severe chills, etc., a clinical evaluation and laboratory work-up is  mandatory for each event; anti-pyretic treatment should be started immediately at the first occurrence and prophylactic  anti-pyretic treatment is recommended c. Thorough clinical examination for signs and symptoms of infection or hypersensitivity is required; laboratory work-up  should include full-blood-count, electrolytes, creatinine, blood urea nitrogen (BUN), C-reactive protein (CRP),  liver-function tests, blood culture, and urine culture. d. Oral hydration should be encouraged in subjects without evidence of dehydration. Intravenous hydration is recommended  in subjects experiencing pyrexia complicated by dehydration/hypotension. e. Anti-pyretic treatment may include acetaminophen, ibuprofen, or suitable anti-pyretic medication according to institutional  standards. Prophylactic anti-pyretic treatment may be discontinued after three days in the absence of pyrexia f. In subject experiencing pyrexia complicated by rigors, severe chills, etc., which cannot be controlled with anti-pyretic  medication, oral corticosteroids should be started at the 2nd event and doses should be gradually increased for subsequent  events. g. Dabrafenib should be reduced by one dose level after three episodes of pyrexia complicated by rigors, severe chills, etc.,  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. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                     |
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6.2.6 malignancies cutaneous squamous cell

Cases of cuSCC (which include those classified as keratoacanthoma or mixed keratoacanthoma subtype) have been observed in subjects treated with dabrafenib.  
Approximately 70 % of events occurred within the first 12 weeks of treatment with a median time to onset of 8 weeks. These should be surgically removed according to institutional practices. Dose modification or interruption of study treatment is not required for cuSCC or KA, however cuSCC should be reported as an SAE. In addition, a biopsy of the lesion should be taken, where possible, and a summary of the results submitted to the PI. Patients should be instructed to immediately inform their physician if new lesions develop. Skin examination should be performed prior to initiation of dabrafenib and during treatment with dabrafenib, every 2 months throughout therapy. Monitoring should continue every 2 months for 6 months following discontinuation of dabrafenib or until initiation of another anti-neoplastic therapy.
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6.2.7 new primary melanoma

New primary melanomas have been reported in patients treated with dabrafenib. These were identified primarily within the first 5 months of therapy and did not require treatment modification other than excision. Monitoring for skin lesions should occur as described for cuSCC.
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6.2.8 non-cutaneous malignancies

In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling in BRAF wild type cells with RAS mutations when exposed to BRAF inhibitors, which may lead to increased risk of non-cutaneous malignancies in patients treated with dabrafenib. Cases of RAS-driven malignancies have been seen with BRAF inhibitors. Patients should be monitored as clinically appropriate. New non-cutaneous malignancies should be reported as a SAE. A biopsy of the new malignancy should be taken, where possible, and submitted for further analyses with the results provided to the PI.
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6.2.9 renal insufficiency

Cases of renal insufficiency have occurred in subjects receiving dabrafenib and the combination of dabrafenib and trametinib. Prior to start of study treatment, concomitant medications should be reviewed for the potential risk of inducing nephrotoxicity and concomitant medications should be modified if clinically possible. Guidelines regarding management and dose reduction for renal insufficiency considered to be related to study treatment by the investigator are provided below.  
| Serum Creatinine                                                                                                   | Adverse Event Management                                                                                                                                                                                                                                                                                                                                                                                                                                   | Action and Dose                                                                                               |
|--------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------|
| Level                                                                                                              | Modification                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                               |
| Serum creatinine  increase > 0.2 mg/dL  (18 umol/L) but   0.5 mg/dL  (44 umol/L) above  baseline                  |  Recheck serum creatinine within 1 week  Serum creatinine increase > 1 week: contact Novartis Medical Monitor. If elevation persists beyond 4 weeks,  recommend evaluation (consider renal biopsy) for etiology;  consider nephrology consultation.  If pyrexia is present, treat pyrexia as per guidelines a  Continue study  treatment at the  same dose level                                                                                       |                                                                                                               |
| Serum creatinine  increase > 0.5 mg/dL  (44 umol/L) above  baseline or  serum creatinine  >2 mg/dL  (> 177 umol/L) |  Monitor serum creatinine ≥ 2 times per week   Hospitalization may be necessary if serum creatinine  cannot be monitored frequently  If pyrexia is present, treat pyrexia per guidelines a  Consult nephrologist if clinically indicated  Perform renal biopsy if clinically indicated, for example: o Renal insufficiency persists despite volume repletion o Subject has new rash or signs of hypersensitivity (such as  elevated eosinophil count) |  Interrupt study  treatment until  serum creatinine  recovers to  baseline  Restart with study  treatment b |
| a.                                                                                                                 | NSAIDs can induce renal insufficiency, especially in subjects with dehydration; encourage oral fluids or  consider intravenous fluids as clinically indicated. See guidelines for pyrexia Section                                                                                                                                                                                                                                                          |                                                                                                               |  
a. NSAIDs can induce renal insufficiency, especially in subjects with dehydration; encourage oral fluids or consider intravenous fluids as clinically indicated. See guidelines for pyrexia Section b. Investigator may restart at either the same or a reduced dose level. Escalation of study treatment to previous dose level is allowed if another episode of renal insufficiency does not occur after 4 weeks of dose reduction.
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6.2.10 guidelines for prolonged qtc

Guidelines for dose modification and stopping criteria due to QTC-prolongation are below.  
| QTc                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                      |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|
| Prolongation a                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Action and Dose Modification                                                                                                         |
|  QTcB ≥ 501 msec or  Uncorrected  QT > 600 msec  or  QTcB > 530  msec for subjects  with bundle  branch block                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Interrupt study treatment until QTcB prolongation resolves to Grade 1 or baseline                                                    |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Test serum potassium, calcium, phosphorus and magnesium. If abnormal, correct  per routine clinical practice to within normal limits |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Review concomitant medication usage for a prolonged QTc                                                                              |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | If event resolves, restart study treatment at current dose level b                                                                   |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | If event does not resolve, permanently discontinue study treatments. Consider  evaluation with cardiologist.                         |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | If event recurs, permanently discontinue study treatment                                                                             |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Consider evaluation with cardiologist                                                                                                |
| Abbreviations: msec = milliseconds; QTc = QT interval on electrocardiogram  a. Based on average QTc value of triplicate ECGs. For example, if an ECG demonstrates a prolonged QT  interval, obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three  ECGs to determine if study treatments should be interrupted or discontinued. b. If the QTc prolongation resolves to grade 1 or baseline, the subject may resume study treatment if the  investigator and Novartis medical monitor agree that the subject will benefit from further treatment |                                                                                                                                      |
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6.2.11 guidelines for pneumonitis

Pneumonitis has been observed in subjects receiving trametinib in combination with dabrafenib. To reduce the risk of pneumonitis, subjects will be monitored closely for symptoms, evaluated with imaging and functional tests. Dose modification and supportive care guidelines for pneumonitis are described below.  
| Table 10: Management and Dose Modification Guidelines for Pneumonitis   |                                                                                                       |                                                          |                                                  |                                    |
|-------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------|----------------------------------------------------------|--------------------------------------------------|------------------------------------|
| CTCAE                                                                   | Adverse Event Management                                                                              | Action and Dose Modification                             |                                                  |                                    |
| Grade Grade 1                                                           |                                                                                                      | CT scan (high-resolution with lung windows)  recommended |                                                  |                                    |
|                                                                        | Clinical evaluation and laboratory work-up for  infection                                             |                                                          |                                                  |                                    |
|                                                                        | Monitoring of oxygenation via pulse-oximetry  recommended                                             |                                                          |                                                  |                                    |
|                                                                        | Consultation of pulmonologist recommended                                                             |                                                         | Continue trametinib at current dose              |                                    |
| Grade 2                                                                 |                                                                                                      | CT scan (high-resolution with lung windows)              |                                                  |                                    |
|                                                                        | Clinical evaluation and laboratory work-up for infection                                              |                                                          |                                                  |                                    |
|                                                                        | Consult pulmonologist                                                                                 |                                                          |                                                  |                                    |
|                                                                        | Pulmonary function tests –if < normal, repeat  every 8 weeks until ≥ normal                           |                                                          |                                                  |                                    |
|                                                                        | Bronchoscopy with biopsy and/or BAL  recommended                                                      |                                                          |                                                  |                                    |
|                                                                        | Symptomatic therapy including corticosteroids  if clinically indicated                                |                                                         | Interrupt trametinib until recovery to  grade ≤1 |                                    |
|                                                                        | Restart with trametinib reduced by one  dose level                                                    |                                                          |                                                  |                                    |
|                                                                        | Escalation to previous dose level after  4 weeks and consultation with medical  monitor possible      |                                                          |                                                  |                                    |
|                                                                        | If no recovery to grade ≤1 within  4 weeks, permanently discontinue study  treatment                  |                                                          |                                                  |                                    |
| Grade 3                                                                 |                                                                                                      | CT scan (high-resolution with lung windows)              |                                                  |                                    |
|                                                                        | Clinical evaluation and laboratory work-up for  infection                                             |                                                          |                                                  |                                    |
|                                                                        | Consult pulmonologist                                                                                 |                                                          |                                                  |                                    |
|                                                                        | Pulmonary function tests-if < normal, repeat  every 8 weeks until ≥ normal                            |                                                          |                                                  |                                    |
|                                                                        | Bronchoscopy with biopsy and/or BAL if  possible                                                      |                                                          |                                                  |                                    |
|                                                                        | Symptomatic therapy including corticosteroids  as clinically indicated                                |                                                         | Interrupt trametinib until recovery to  grade ≤1 |                                    |
|                                                                        | After consultation with medical monitor,  study treatment may be restarted reduced  by one dose level |                                                          |                                                  |                                    |
|                                                                        | If no recovery to grade ≤1 within  4 weeks, permanently discontinue study  treatment                  |                                                          |                                                  |                                    |
| Grade 4                                                                 |                                                                                                      | Same as grade 3                                          |                                                 | Permanently discontinue trametinib |
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6.2.12 guidelines for cardiomyopathy

Across clinical trials of trametinib at the recommended dose 11% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥ 10% below baseline) and 5% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥ 20% below baseline. Assess LVEF before initiation of trametinib, one month after initiation and then at 3-month intervals while on treatment. Withhold treatment if absolute LVEF value decreases by 10% from pre-treatment values and is less than the lower limit of normal. Permanently discontinue for symptomatic cardiomyopathy or persistent, asymptomatic LVEF dysfunction that does not resolve within 4 weeks  
| LVEF Decrease                                                                                                                                                          |                                                                                                                                                                                              |                              |                                                                                                                                                                                                                                                                 |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Clinic                                                                                                                                                                 | LVEF-drop (%) or                                                                                                                                                                             | Action and Dose Modification |                                                                                                                                                                                                                                                                 |
| CTCAE grade                                                                                                                                                            | a,b                                                                                                                                                                                          |                              |                                                                                                                                                                                                                                                                 |
|                                                                                                                                                                       | Interrupt trametinib and repeat ECHO within 2 weeks                                                                                                                                          |                              |                                                                                                                                                                                                                                                                 |
| Asymptomatic                                                                                                                                                           | Absolute decrease of  > 10% in LVEF  compared to baseline  and ejection fraction  below the institution's  LLN                                                                               |                             | If the LVEF recovers within 4 weeks (defined as LVEF  ≥ LLN and absolute decrease ≤ 10% compared to baseline)   Consult with Novartis medical monitor and request  approval for re-start  If approved, re-start treatment with TMT reduced by  one dose level |
|                                                                                                                                                                       | Repeat ECHO at 2, 4, 8, and 12 weeks after re-start,  continue at intervals of 12 weeks                                                                                                      |                              |                                                                                                                                                                                                                                                                 |
|                                                                                                                                                                       | If LVEF does not recover within 4 weeks  Consult with cardiologist  Permanently discontinue trametinib  Report as SAE  Repeat ECHO after 2, 4, 8, 12, and 16 weeks, or  until resolution |                              |                                                                                                                                                                                                                                                                 |
| Symptomatic c                                                                                                                                                          | Grade 3: resting LVEF  39 to 20% or > 20%  absolute reduction from  baseline                                                                                                                 |                             | Permanently discontinue trametinib                                                                                                                                                                                                                              |
|                                                                                                                                                                       | Interrupt dabrafenib d                                                                                                                                                                       |                              |                                                                                                                                                                                                                                                                 |
|                                                                                                                                                                       | Report as SAE                                                                                                                                                                                |                              |                                                                                                                                                                                                                                                                 |
| Grade 4: resting  LVEF < 20%                                                                                                                                           |                                                                                                                                                                                             | Consult with cardiologist    |                                                                                                                                                                                                                                                                 |
|                                                                                                                                                                       | Repeat ECHO after 2, 4, 8, 12, and 16 weeks, or until  resolution b,d                                                                                                                        |                              |                                                                                                                                                                                                                                                                 |
| Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; LLN = lower  limit of normal; LVEF = left ventricular ejection fraction; |                                                                                                                                                                                              |                              |                                                                                                                                                                                                                                                                 |
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6.2.13 treatment of study treatment

In the event of a dabrafenib overdose, defined as administration of more than 300 mg as a single dose or 600 mg per day (the highest dose tested in clinical studies to date), and/or a trametinib overdose, defined as administration of more than 3.0 mg once daily the investigator should closely monitor the subject for AEs/SAEs and laboratory abnormalities. The investigator will use clinical judgment to treat any overdose. Hemodialysis is not expected to enhance the elimination of either dabrafenib or trametinib as both are highly bound to plasma proteins. Decisions regarding dose interruptions or modifications will be made by the investigator in consultation with the PI based on the clinical evaluation of the subject. Information regarding the quantity of the excess dose as well as the duration of the overdosing should be documented in the case report forms.
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7 adverse events and reporting

Please see the FDA package insert for dabrafenib. Additional information can also be found in the Investigator Brochure section titled "Summary of Data and Guidance for the Investigator." Below are tables from the 2015 package summarizing anticipated AEs:
Table 12:  Selected Common Adverse Reactions Occurring in > 10% (All Grades) or ≥ 2%
Grades 3 or 4) of Patients Treated with dabrafenib N = 187  
| TAFINLAR                                                                                                         | Dacarbazine                                                                           |           |        |         |
|------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------|-----------|--------|---------|
| N = 187                                                                                                          | N = 59                                                                                |           |        |         |
| All                                                                                                              | Grades                                                                                | All       | Grades |         |
| Primary System Organ Class                                                                                       | Grades                                                                                | 3 and 4 b | Grades | 3 and 4 |
| Preferred Term                                                                                                   | (%)                                                                                   | (%)       | (%)    | (%)     |
| Skin and subcutaneous tissue disorders                                                                           |                                                                                       |           |        |         |
| Hyperkeratosis                                                                                                   | 37                                                                                    | 0         | 0      |         |
| 1                                                                                                                |                                                                                       |           |        |         |
| Alopecia                                                                                                         | 22                                                                                    | NA        | 2      | NA      |
| Palmar-plantar erythrodysesthesia                                                                                |                                                                                       |           |        |         |
| syndrome                                                                                                         | 20                                                                                    | 2         | 2      | 0       |
| 17                                                                                                               |                                                                                       |           |        |         |
| Rash                                                                                                             | 0                                                                                     | 0         | 0      |         |
| Nervous system disorders                                                                                         |                                                                                       |           |        |         |
| Headache                                                                                                         | 32                                                                                    | 0         | 8      | 0       |
| General disorders and administration                                                                             |                                                                                       |           |        |         |
| site conditions                                                                                                  |                                                                                       |           |        |         |
| Pyrexia                                                                                                          | 28                                                                                    | 10        |        |         |
| 3                                                                                                                | 0                                                                                     |           |        |         |
| Musculoskeletal and connective tissue                                                                            |                                                                                       |           |        |         |
| disorders                                                                                                        |                                                                                       |           |        |         |
| Arthralgia                                                                                                       | 27                                                                                    | 1         | 2      | 0       |
| Back pain                                                                                                        | 12                                                                                    | 3         | 7      | 0       |
| Myalgia                                                                                                          | 11                                                                                    | 0         | 0      | 0       |
| Neoplasms benign, malignant, and                                                                                 |                                                                                       |           |        |         |
| unspecified (including cysts and polyps)                                                                         |                                                                                       |           |        |         |
| Papilloma                                                                                                        | 27                                                                                    | 2         |        |         |
| 0                                                                                                                | 0                                                                                     |           |        |         |
| cuSCCd, e                                                                                                        | 7                                                                                     | 4         | 0      | 0       |
| Respiratory, thoracic, and mediastinal                                                                           |                                                                                       |           |        |         |
| disorders                                                                                                        | 0                                                                                     | s         |        |         |
| Cough                                                                                                            | 12                                                                                    | 0         |        |         |
| Gastrointestinal disorders                                                                                       |                                                                                       |           |        |         |
| Constipation                                                                                                     | 11                                                                                    | 2         | 14     | 0       |
| Infections and infestations                                                                                      |                                                                                       |           |        |         |
| Nasopharyngitis                                                                                                  | 10                                                                                    | 0         | 3      | 0       |
| Adverse drug reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. |                                                                                       |           |        |         |
| b                                                                                                                | Grade 4 adverse reactions limited to hyperkeratosis (n = 1) and constipation (n = 1). |           |        |         |  
c Includes skin papilloma and papilloma.  
a cuSCC = cutaneous squamous cell carcinoma, includes squamous cell carcinoma of the skin and keratoacanthoma.  
Cases of cuSCC were required to be reported as Grade 3 per protocol.  
e 1 NA = not applicable.  
Table 13: Incidence of Laboratory Abnormalities Increased from Baseline Occurring at a Higher Incidence in Patients Treated with dabrafenib (Tafinlar) in a single agent melanoma trial [Between-Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or 4)] a  
| TAFINLAR                                                                                                         | DTIC    |        |         |     |
|------------------------------------------------------------------------------------------------------------------|---------|--------|---------|-----|
| N = 187                                                                                                          | N = 59  |        |         |     |
| All                                                                                                              | Grades  | All    | Grades  |     |
| Grades                                                                                                           | 3 and 4 | Grades | 3 and 4 |     |
| Test                                                                                                             | (%)     | (%)    | (%)     | (%) |
| Hyperglycemia                                                                                                    | 50      | 6      | 43      | 0   |
| 37                                                                                                               | 6b      |        |         |     |
| Hypophosphatemia                                                                                                 | 14      | 2      |         |     |
| Increased alkaline phosphatase                                                                                   | 19      | 0      | 14      | 2   |
| Hyponatremia                                                                                                     | 3       | 0      |         |     |
| S                                                                                                                | 2       |        |         |     |
| Adverse drug reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. |         |        |         |     |
| b                                                                                                                |         |        |         |     |  
b Grade 4 laboratory abnormality limited to hypophosphatemia (n = 1).  
Other clinically important adverse reactions observed in less than 10% of patients (N = 586) treated with TAFINLAR were: Gastrointestinal Disorders: Pancreatitis Immune System Disorders: Hypersensitivity manifesting as bullous rash Renal and Urinary Disorders: Interstitial nephritis Other clinically important adverse reactions observed in < 10% of patients (N = 586)
treated with dabrafenib were:
.  
Gastrointestinal Disorders:  Pancreatitis.  
.  
Immune System Disorders:  Hypersensitivity manifesting as bullous rash
.  
Renal and Urinary Disorders:  Interstitial nephritis.  
| Patients Treated with dabrafenib( tafinlar)  in Combination with Trametinib   |                                                        |          |         |        |         |     |
|-------------------------------------------------------------------------------|--------------------------------------------------------|----------|---------|--------|---------|-----|
| Pooled TAFINLAR plus                                                          | Trial 2                                                |          |         |        |         |     |
| Trametinib                                                                    | TAFINLAR plus                                          | TAFINLAR |         |        |         |     |
| N = 559                                                                       | Trametinib N = 209                                     | N = 211  |         |        |         |     |
| All                                                                           | Grades                                                 | All      | Grades  | All    | Grades  |     |
| Grades                                                                        | 3 and 4b                                               | Grades   | 3 and 4 | Grades | 3 and 4 |     |
| Adverse Reactions                                                             | (%)                                                    | (%)      | (%)     | (%)    |         |     |
| (%)                                                                           | (%)                                                    |          |         |        |         |     |
| General disorders and administrative site conditions                          |                                                        |          |         |        |         |     |
| Pyrexia                                                                       | 54                                                     | 57       | 3       | 1.9    |         |     |
| 5                                                                             | 7                                                      |          |         |        |         |     |
| Chills                                                                        | 31                                                     | 0.5      | 31      | 0      | 17      | 0.5 |
| Gastrointestinal disorders                                                    |                                                        |          |         |        |         |     |
| Constipation                                                                  | 13                                                     | 0.2      | 0.5     | 10     | 0       |     |
| 13                                                                            |                                                        |          |         |        |         |     |
| Nervous system disorders                                                      |                                                        |          |         |        |         |     |
| Headache                                                                      | 30                                                     | 0.9      | 33      | 0.5    | 30      | 1.4 |
| Dizziness                                                                     | 11                                                     | 0.2      | 14      | 0      | 7       | 0   |
| Musculoskeletal, connective tissue, and bone disorders                        |                                                        |          |         |        |         |     |
| Arthralgia                                                                    | 25                                                     | 0.9      | 0.9     | 0      |         |     |
| 26                                                                            | 31                                                     |          |         |        |         |     |
| Myalgia                                                                       | 15                                                     | 0.2      | 13      | 0.5    | 13      | 0   |
| Skin and subcutaneous tissue disorders                                        |                                                        |          |         |        |         |     |
| Rash c                                                                        | 32                                                     | 1.1      | 42      | 0      | 27      | 1.4 |
| Dry skin                                                                      | 10                                                     | 0        | 12      | 0      | 16      | 0   |
| Respiratory, thoracic, and mediastinal disorders                              |                                                        |          |         |        |         |     |
| Cough                                                                         | 20                                                     | 0        | 21      | 0      | 21      | 0   |
| Infections and infestations                                                   |                                                        |          |         |        |         |     |
| Nasopharyngitis                                                               | 12                                                     | 0        | 12      | 0      | 10      | 0   |
| NCI CTCAE version 4                                                           |                                                        |          |         |        |         |     |
| b                                                                             | Grade 4 adverse reactions limited to headache (n = 1). |          |         |        |         |     |
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table 14 select adverse reactions

c Includes rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, rash maculo-papular, and rash folliculitis.  
| Trial 2                                            |               |          |          |        |          |     |
|----------------------------------------------------|---------------|----------|----------|--------|----------|-----|
| Pooled TAFINLAR                                    | TAFINLAR plus |          |          |        |          |     |
| plus Trametinib                                    | Trametinib    | TAFINLAR |          |        |          |     |
| N = 211 b                                          |               |          |          |        |          |     |
| N = 559ª                                           | N = 209b      |          |          |        |          |     |
| Grades                                             | Grades        |          |          |        |          |     |
| All                                                | All           | All      | Grades   |        |          |     |
| Grades                                             | 3 and 4°      | Grades   | 3 and 4° | Grades | 3 and 4° |     |
| Test                                               | (%)           | (%)      | (%)      | (%)    | (%)      | (%) |
| Liver Function Tests                               |               |          |          |        |          |     |
| Increased blood alkaline                           | 49            | 2.7      | 50       | 1.0    | 25       | 0.5 |
| phosphatase                                        |               |          |          |        |          |     |
| Chemistry                                          |               |          |          |        |          |     |
| Hyperglycemia                                      | 60            | 4.7      | 65       | 6      | 57       | 4.3 |
| Hypophosphatemia                                   | 38            | 6        | 38       | 3.8    | 35       | 7   |
| Hyponatremia                                       | 25            | 8        | 24       | 14     | 2.9      |     |
| 6                                                  |               |          |          |        |          |     |
| For these laboratory tests the denominator is 556. |               |          |          |        |          |     |  
b c For these laboratory tests the denominator is 208 for the combination arm, 208-209 for the TAFINLAR arm.  
Grade 4 adverse reactions limited to hyperglycemia (n = 4), hyponatremia and hypophosphatemia (each n = 1), in the pooled combination arm; hyperglycemia (n = 1) in the Trial 2 combination arm; hypophosphatemia (n = 1) in the TAFINLAR arm.