untitled h1
7.1.2 trametinib potential adverse effects

Please see the FDA package insert for trametinib.  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 insert summarizing anticipated AEs Table 16:  Selected Adverse Reactions Occurring in ≥10% of Patients Receiving trametinib (Mekinist) and at a Higher Incidence (≥ 5%) than in the Chemotherapy  
| Arm or ≥ 2% (Grades 3 or 4) Adverse Reactions                                                                 |              |           |          |           |
|---------------------------------------------------------------------------------------------------------------|--------------|-----------|----------|-----------|
| MEKINIST                                                                                                      | Chemotherapy |           |          |           |
| N = 211                                                                                                       | N = 99       |           |          |           |
| All                                                                                                           | Grades       | All       | Grades   |           |
| Adverse Reactions                                                                                             | Grades"      | 3 and 4 b | Grades a | 3 and 4 b |
| Skin and subcutaneous tissue                                                                                  |              |           |          |           |
| disorders                                                                                                     |              |           |          |           |
| Rash                                                                                                          | 57           | 8         | 10       | 0         |
| Acneiform dermatitis                                                                                          | 19           | <1        | 1        | o         |
| Dry skin                                                                                                      | 11           | 0         | 0        | 0         |
| Pruritus                                                                                                      | 10           | 2         | l        | 0         |
| Paronychia                                                                                                    | 10           | 0         | 0        |           |
| l                                                                                                             |              |           |          |           |
| Gastrointestinal disorders                                                                                    |              |           |          |           |
| Diarrhea                                                                                                      | 43           | 0         | 16       | 2         |
| Stomatitis                                                                                                    | 15           | 2         | 2        | 0         |
| Abdominal pain                                                                                                | 13           | s         |          |           |
| l                                                                                                             | l            |           |          |           |
| Vascular disorders                                                                                            |              |           |          |           |
| Lymphedema                                                                                                    | 32           | 1         | 4        | 0         |
| Hypertension                                                                                                  | 15           | 12        | 7        | 3         |
| Hemorrhage 1                                                                                                  | 13           | <1        | 0        | 0         |
| National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.                        |              |           |          |           |
| Grade 4 adverse reactions limited to rash (n = 1) in trametinib arm and diarrhea (n = 1) in chemotherapy arm. |              |           |          |           |
| Includes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation                          |              |           |          |           |  
Arm or ≥ 2% (Grades 3 or 4) Adverse Reactions e
.  
f Includes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation Includes abdominal pain, lower abdominal pain, upper abdominal pain, and abdominal tenderness.  
Includes lymphedema, edema, and peripheral edema.  
Includes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage, hematuria, and conjunctival hemorrhage.  
Other clinically important adverse reactions observed in less than or equal to 10% of patients
(N = 329) treated with Mekinist (trametinib) were:
Cardiac Disorders: Bradycardia Gastrointestinal Disorders: Dry mouth Infections and Infestations: Folliculitis, rash pustular, cellulitis Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis Nervous System Disorders: Dizziness, dysgeusia Ocular Disorders: Blurred vision, dry eye  
| MEKINIST                                   | Chemotherapy                                             |         |        |         |
|--------------------------------------------|----------------------------------------------------------|---------|--------|---------|
| N = 211                                    | N = 99                                                   |         |        |         |
| All                                        | Grades                                                   | All     | Grades |         |
| Test                                       | Grades                                                   | 3 and 4 | Grades | 3 and 4 |
| Increased aspartate aminotransferase (AST) | 60                                                       | 2       | 16     | 1       |
| Hypoalbuminemia                            | 42                                                       | 2       | 23     | l       |
| Increased alanine aminotransferase (ALT)   | 39                                                       | 3       | 20     | 3       |
| Anemia                                     | 38                                                       | 2       | 26     | 3       |
| Increased alkaline phosphatase             | 24                                                       | 2       | 18     | 3       |
| a                                          | No Grade 4 events were reported in either treatment arm. |         |        |         |  
Table 17:  Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in Patients Treated With trametinib (Mekinist) in Trial 1
[Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or 4) ª]
Table 18: Incidence of Adverse Reactions Occurring in ≥10% (All Grades) of Patients  
| Pooled MEKINIST plus                                                                                                       | Trial 2           |            |         |        |        |     |
|----------------------------------------------------------------------------------------------------------------------------|-------------------|------------|---------|--------|--------|-----|
| Dabrafenib                                                                                                                 | MEKINIST plus     | Dabrafenib |         |        |        |     |
| N = 559                                                                                                                    | Dabrafenib N =209 | N = 211    |         |        |        |     |
| All                                                                                                                        | Grades            | All        | Grades  | All    | Grades |     |
| 3 and 4                                                                                                                    |                   |            |         |        |        |     |
| Grades                                                                                                                     | 3 and 4           | Grades     | 3 and 4 | Grades |        |     |
| Adverse Reactions                                                                                                          | (%)               | (%)        | (%)     | (%)    | (%)    | (%) |
| General disorders and administrative site conditions                                                                       | 57                | 3          | 1.9     |        |        |     |
| Pyrexia                                                                                                                    | 54                | S          | 7       |        |        |     |
| Chills                                                                                                                     | 31                | 0.5        | 31      | 0      | 17     | 0.5 |
| Edema peripheral 6                                                                                                         | 0.7               | 25         | 0.5     |        |        |     |
| 21                                                                                                                         | 1.4               | 11         |         |        |        |     |
| Gastrointestinal disorders                                                                                                 |                   |            |         |        |        |     |
| Nausea                                                                                                                     | 35                | 0.4        | 34      | 0.5    | 27     | 1.4 |
| Diarrhea                                                                                                                   | 31                | 1.3        | 30      | 1.4    | 0.9    |     |
| 16                                                                                                                         |                   |            |         |        |        |     |
| Vomiting                                                                                                                   | 27                | 1.1        | 25      | 1.0    | 14     | 0.5 |
| Abdominal pain                                                                                                             | 18                | 0.9        | 26      | 1.0    | 14     | 2.4 |
| Nervous system disorders                                                                                                   | 7                 |            |         |        |        |     |
| Dizziness                                                                                                                  | 11                | 0.2        | 14      | 0      | 0      |     |
| Vascular disorders                                                                                                         |                   |            |         |        |        |     |
| Hypertension                                                                                                               | 26                | 11         | 25      | 6      | 16     | 6   |
| Hemorrhaged                                                                                                                | 18                | 2.0        | 19      | 1.9    | 15     | 1.9 |
| Skin and subcutaneous tissue disorders                                                                                     |                   |            |         |        |        |     |
| Rash                                                                                                                       | 32                | 1.1        | 42      | 0      | 27     | 1.4 |
| * >5% for All Grades or >2% for Grades 3-4 incidence in patients receiving MEKINIST with dabrafenib compared with patients |                   |            |         |        |        |     |
| receiving dabrafenib as a single agent                                                                                     |                   |            |         |        |        |     |
| National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.                                       |                   |            |         |        |        |     |  
Receiving trametinib (MEKINIST_ with Dabrafenib and at a Higher Incidence* than in Patients Receiving Single-Agent Dabrafenib Includes peripheral edema, edema, lymphedema, localized edema , and generalized edema Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal discomfort.  
Most common events ( ≥ 1%) include epistaxis, hematochezia, decreased hemoglobin, purpura, and rectal hemorrhage. Grade 4 events were limited to hepatic hematoma and duodenal ulcer hemorrhage (each n = 1 in the pooled combination arm)
Includes rash, generalized rash, pruritic rash, erythematous rash, papular rash, vesicular rash, macular rash, maculo-papular, and folliculitis rash.  
e Other clinically important adverse reactions for trametinib observed in less than 10% of patients receiving trametinib in combination with dabrafenib (N = 559) were:
Cardiac Disorders: Bradycardia Musculoskeletal Disorders: Rhabdomyolysis  
| Patients Receiving Single-Agent Dabrafenib                                                                                   |               |            |          |        |          |     |
|------------------------------------------------------------------------------------------------------------------------------|---------------|------------|----------|--------|----------|-----|
| Pooled MEKINIST                                                                                                              | MEKINIST plus |            |          |        |          |     |
| plus Dabrafenib                                                                                                              | Dabrafenib    | Dabrafenib |          |        |          |     |
| N = 559 a                                                                                                                    | N = 209 b     | N = 211 b  |          |        |          |     |
| All                                                                                                                          | All           | Al         |          |        |          |     |
| Grades                                                                                                                       | Grades        | Grades     |          |        |          |     |
| Grades                                                                                                                       | 3 and 4°      | Grades     | 3 and 4° | Grades | 3 and 4° |     |
| Test                                                                                                                         | (%)           | (%)        | (%)      | (%)    | (%)      | (%) |
| Hematology                                                                                                                   |               |            |          |        |          |     |
| Neutropenia                                                                                                                  | 46            | 7          | 50       | 6      | 16       | 1.9 |
| 2.3                                                                                                                          | 2.4           |            |          |        |          |     |
| Anemia                                                                                                                       | 43            | 43         | 38       | 4.3    |          |     |
| Lymphopenia                                                                                                                  | 32            | 8          | 38       | 9      | 28       | 7   |
| Thrombocytopenia                                                                                                             | 21            | 0.7        | 19       | 0.5    | 10       | 0.5 |
| Liver Function Tests                                                                                                         |               |            |          |        |          |     |
| Increased AST                                                                                                                | 59            | 4.1        | 60       | 4.3    | 21       | 1.0 |
| Increased blood alkaline                                                                                                     | 49            | 2.7        | 50       | 1.0    | 25       | 0.5 |
| phosphatase                                                                                                                  |               |            |          |        |          |     |
| Increased ALT                                                                                                                | 48            | 4.5        | 44       | 3.8    | 28       | 1.0 |
| Chemistry                                                                                                                    |               |            |          |        |          |     |
| Hyperglycemia                                                                                                                | 60            | 4.7        | 65       | 6      | 57       | 4.3 |
| Hypoalbuminemia                                                                                                              | 48            | 1.1        | 53       | 1.4    | 27       | 0   |
| Hyponatremia                                                                                                                 | 25            | 8          | 6        | 14     | 2.9      |     |
| 24                                                                                                                           |               |            |          |        |          |     |
| * > 5% for All Grades or > 2% for Grades 3–4 incidence in patients receiving MEKINIST with dabrafenib compared with patients |               |            |          |        |          |     |
| receiving dabrafenib as a single agent                                                                                       |               |            |          |        |          |     |
| AST = Aspartate aminotransferase; ALT = Alanine aminotransferase.                                                            |               |            |          |        |          |     |  
Table 19:  Treatment-Emergent Laboratory Abnormalities Occurring at ≥ 10% (All Grades) of Patients Receiving trametinib (Mekinsit) with Dabrafenib and at a Higher Incidence* than in AST = Aspartate aminotransferase; ALT = Alanine aminotransferase.  
For these laboratory tests the denominator is 556.  
b For these laboratory tests the denominator is 208 for the combination arm, 207-209 for the dabrafenib arm.  
Grade 4 adverse reactions limited to lymphopenia and hyperglycemia (each n = 4), increased ALT and increased AST (each n = 3),
neutropenia (n = 2), and hyponatremia (n = 1), in the pooled combination arm; neutropenia, lymphopenia, increased ALT,
increased AST, hyperglycemia (each n = 1) in the Trial 2 combination arm; neutropenia, thrombocytopenia, increased ALT, and increased AST (each n = 1) in the dabrafenib arm.
untitled h1
7.2 adverse event reporting for

To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient has provided the main informed consent and until at least 30 days after the patient has stopped study treatment must be reported to Novartis within 24 hours of learning of its occurrence.  
Any SAEs experienced after this 30 days period should only be reported to Novartis if the investigator suspects a causal relationship to the study treatment. Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up to the original episode within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a different time interval or otherwise considered completely unrelated to a previously reported one should be reported separately as a new event. Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form; all applicable sections of the form must be completed in order to provide a clinically thorough report. The investigator must assess and record the relationship of each SAE to each specific study treatment (if there is more than one study treatment), complete the SAE Report Form in English, and send the completed, signed form by fax within 24 hours to the oncology Novartis Drug Safety and Epidemiology (DS&E) department - Fax:
(877-778-9739). The original copy of the SAE Report Form and the fax confirmation sheet must be kept with the case report form documentation at the study site. Follow-up information is sent to the same contact(s) to whom the original SAE Report Form was sent, using a new SAE Report Form stating that this is a follow-up to the previously reported SAE and giving the date of the original report. Each re-occurrence, complication, or progression of the original event should be reported as a follow-up to that event regardless of when it occurs. The follow-up information should describe whether the event has resolved or continues, if and how it was treated, whether the blind was broken or not, an whether the patient continued or withdrew from study participation. If the SAE is not previously documented in the Investigator's Brochure or Package Insert (new occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require further information from the investigator for Health Authority reporting. Novartis may need to issue an Investigator Notification (IN), to inform all investigators involved in any study with the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC or as per national regulatory requirements in participating countries.
untitled h1
pregnancies

To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine outcome, including spontaneous or voluntary termination, details of the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications. Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). Pregnancy follow-up should be recorded on the same form and should include an assessment of the possible relationship to the study treatment any pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form. Adverse events will be graded according to CTCAE v4.03. Both Serious and Non-Serious Adverse Events will be clearly noted in source documentation and listed on study specific Case Report Forms (CRFs). The Protocol Director (PD) or designee will assess each Adverse Event (AE) to determine whether it is unexpected according to Section 7.1 of the protocol and related to dabrafenib and trametinib. SAEs and all subsequent follow-up reports will be reported to the CCTO Safety Office regardless of the event's relatedness to the investigation. Following review by the CCTO
Safety Officers, any events meeting the IRB definition of "Unanticipated Problem" will be reported to the IRB using eProtocol within 10 working days of the review, or within 5 working days for deaths or life-threatening experiences. **SAEs will be relayed back to** Novartis.
untitled h1
7.2.1 sae definitions

Serious adverse event (SAE) is defined as one of the following:
Is fatal or life-threatening Results in persistent or significant disability/incapacity  
Constitutes a congenital anomaly/birth defect Is medically significant, ie, defined as an event that jeopardizes the patient or may require medical or surgical intervention to prevent one of the outcomes listed above Requires inpatient hospitalization or prolongation of existing hospitalization,
Note that hospitalizations for the following reasons should not be reported as serious adverse events:
Routine treatment or monitoring of the studied indication, not associated with any deterioration in condition  
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under study and has not worsened since signing the informed consent Social reasons and respite care in the absence of any deterioration in the patient's general condition
Note that treatment on an emergency outpatient basis that does not result in hospital admission and involves an event not fulfilling any of the definitions of a SAE given above is not a serious adverse event
untitled h1
7.3 pregnancy

Pregnancy Testing and Prevention The need for a screening pregnancy test depends on whether a female subject is of childbearing potential or non-childbearing potential. A female of non-childbearing potential (ie, physiologically incapable of becoming pregnant) is defined as any female who has had a hysterectomy, bilateral oophorectomy (ovariectomy), bilateral tubal ligation or tubal occlusion, or is post-menopausal. A practical definition accepts menopause after 1 year without menses with an appropriate clinical profile, eg, age appropriate, > 45 years in the absence of hormone-replacement therapy (HRT). In questionable cases, the subject must have a follicle-stimulating hormone (FSH) value > 40 mIU/mL and an estradiol value < 40 pg/mL (< 140 pmol/L). A female of child-bearing potential is defined as any female who does not meet the criteria of non-childbearing potential as described in the previous paragraph. If a female subject is of childbearing potential, she must have a serum β-human chorionic gonadotropin (HCG) pregnancy test performed within 14 days prior to randomization.  
Subjects with a positive pregnancy test result must be excluded from the study. Subjects with a negative pregnancy test result must agree to use an effective contraception method as described below throughout study treatment and until 4 months after the last dose of study treatment. Novartis acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows:
An intrauterine device with a documented failure rate of less than 1% per year.  
Male partner sterilization prior to the female subject's entry, and this male is the sole sexual partner for that female.  
Complete abstinence from sexual intercourse for 14 days prior to enrollment, throughout study treatment, and for at least 4 months after the last dose of study treatment. Abstinence is only acceptable when in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods, etc) and withdrawal are not acceptable methods of contraception.  
Double-barrier contraception: condom and occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/cream/suppository).
Note: Hormonal-based methods (eg, oral contraceptives) are not permitted as contraception due to potential drug-drug interactions with dabrafenib. Female subjects who are lactating must discontinue nursing prior to the first dose of study treatment and must refrain from nursing throughout the treatment period and for 4 months following the last dose of study treatment. If a subject becomes pregnant during the treatment period of the study, the study treatments should be stopped immediately.
untitled h1
8 correlative/ special studies 8.1

Biopsy specimens will be collected per normal institutional methods for biopsy and surgical resection procedures.
untitled h1
8.1.2 handling of specimens(s)

At the time of the baseline biopsy, endpoint biopsy, and/or resection specimen, the tissue will be handled and processed by routine tissue protocol at the pathology laboratory of the institution performing the procedure. Standard morphologic assessment of the tissue (including H&E stain) will be performed by the pathology laboratory of the institution performing the procedure with an emphasis to avoid decalcification of the tumor material, if possible.
untitled h1
8.1.3 shipping of specimen(s)

The archived biopsy or representative portions of the resection specimen, including formalin fixed paraffin embedded block and matching H&E slide, will be sent to the laboratory of Dr Robert West at the Site Performing Correlative Study
(Stanford Cancer Institute) by overnight courier at room temperature. Once archived, the tissue is stable at room temperature.
untitled h1
8.1.4 site(s) performing correlative study

The Site Performing Correlative Study is the laboratory of Dr Robert West at the Stanford Cancer Institute at the Stanford University Medical Center. Dr West's laboratory will be responsible for all the correlative study tests.
untitled h1
8.1.5 coding of specimens for

The specimens will be coded at the time of receipt in the laboratory of Dr Robert West.  
The specimen will be given a 5-digit number with no relationship to the subjects' HIPPA data. The key for the coded specimens and the patient data will be kept by Dr Robert West in a locked office.  
| 9                                                                                                         | STUDY CALENDAR PreStudy Wk                    | Wk   | Wk   | Wk   | Wk   | Wk   | Wk   | Wk   | Wk   | Wk   | Wk   | Wk 12   | Off-Study d   |
|-----------------------------------------------------------------------------------------------------------|--------------------|------|------|------|------|------|------|------|------|------|------|---------|---------------|
| 1                                                                                                         | 2                  | 3    | 4    | 5    | 6    | 7    | 8    | 9    | 10   | 11   |      |         |               |
| Dabrafenib                                                                                                | Dabrafenib will be |      |      |      |      |      |      |      |      |      |      |         |               |
| administered twice daily as  specified in Section 4 until  surgical resection                             | FOR SUBJECTS       |      |      |      |      |      |      |      |      |      |      |         |               |
| NOT UNDERGOING                                                                                            |                    |      |      |      |      |      |      |      |      |      |      |         |               |
| SURGICAL RESECTION:  dabrafenib will continue  until disease progression or  intolerance                  |                    |      |      |      |      |      |      |      |      |      |      |         |               |
| Trametinib                                                                                                | Trametinib will be |      |      |      |      |      |      |      |      |      |      |         |               |
| administered daily as                                                                                     |                    |      |      |      |      |      |      |      |      |      |      |         |               |
| specified in Section 4 until  surgical resection                                                          | FOR SUBJECTS       |      |      |      |      |      |      |      |      |      |      |         |               |
| NOT UNDERGOING                                                                                            |                    |      |      |      |      |      |      |      |      |      |      |         |               |
| SURGICAL RESECTION:  trametinib will continue  until disease progression or  intolerance                  |                    |      |      |      |      |      |      |      |      |      |      |         |               |
| Informed consent                                                                                          | X                  |      |      |      |      |      |      |      |      |      |      |         |               |
| Demographics                                                                                              | X                  |      |      |      |      |      |      |      |      |      |      |         |               |
| Medical history                                                                                           | X                  |      |      |      |      |      |      |      |      |      |      |         |               |
| Biopsy of tumor for  correlative studies                                                                  | X                  | X g  |      |      |      |      |      |      |      |      |      |         |               |
| Surgical resection for  patients with  resectable tumors, and  tissue collection for  correlative studies | X                  |      |      |      |      |      |      |      |      |      |      |         |               |
| Concurrent meds                                                                                           | X                  | X    | X a  |      |      |      |      |      |      |      |      |         |               |
| Physical exam                                                                                             | X                  | X    | X    | X a  | X a  | X    |      |      |      |      |      |         |               |
| a                                                                                                         | X a                | X    |      |      |      |      |      |      |      |      |      |         |               |
| Vital signs                                                                                               | X                  | X    | X    | X    |      |      |      |      |      |      |      |         |               |
| Height                                                                                                    | X                  |      |      |      |      |      |      |      |      |      |      |         |               |
| Weight                                                                                                    | X                  |      |      |      |      |      |      |      |      |      |      |         |               |
| Performance status                                                                                        | X                  |      |      |      |      |      |      |      |      |      |      |         |               |
| CBC w/diff, plts                                                                                          | X                  | X    | X    | X a  | X a  | X    |      |      |      |      |      |         |               |
| Serum chemistry b                                                                                         | X                  | X    | X    | X a  | X a  | X    |      |      |      |      |      |         |               |
| EKG within 14 days  of enrollment                                                                         | X                  |      |      |      |      |      |      |      |      |      |      |         |               |
| ECHO cardiogram  within 1 month of                                                                        | X                  | X    | X f  |      |      |      |      |      |      |      |      |         |               |
| enrollment                                                                                                |                    |      |      |      |      |      |      |      |      |      |      |         |               |  
| PreStudy                                                                                                                                  | Wk                                                                                                                                                                                                                        | Wk                                                                                                                                                                                                                        | Wk   | Wk   | Wk   | Wk   | Wk   | Wk   | Wk   | Wk   | Wk   | Wk 12   | Off-Study d   |
|----------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------|------|------|------|------|------|------|------|------|---------|---------------|
| 1                                                                                                                                | 2                                                                                                                                                                                                                         | 3                                                                                                                                                                                                                         | 4    | 5    | 6    | 7    | 8    | 9    | 10   | 11   |      |         |               |
| Adverse event  evaluation. See  Section 7 for expected  AEs and Section 6 for  dose modification  rules.                         | a                                                                                                                                                                                                                         | X a                                                                                                                                                                                                                       | X a  |      |      |      |      |      |      |      |      |         |               |
| X                                                                                                                                | X                                                                                                                                                                                                                         | X                                                                                                                                                                                                                         | X    |      |      |      |      |      |      |      |      |         |               |
| Tumor measurements                                                                                                               | Tumor measurements are repeated every 6 weeks. After  Week 7, tumor measurements are repeated every  6 to 9 weeks. Documentation (radiologic) must be  provided for patients removed from study for progressive  disease. | d                                                                                                                                                                                                                         |      |      |      |      |      |      |      |      |      |         |               |
| X                                                                                                                                |                                                                                                                                                                                                                           |                                                                                                                                                                                                                           |      |      |      |      |      |      |      |      |      |         |               |
| X                                                                                                                                |                                                                                                                                                                                                                           |                                                                                                                                                                                                                           |      |      |      |      |      |      |      |      |      |         |               |
| Radiologic evaluation  (CT, MRI, X-ray)                                                                                          | X                                                                                                                                                                                                                         | Tumor measurements are repeated every 6 weeks. After  Week 7, tumor measurements are repeated every  6 to 9 weeks. Documentation (radiologic) must be  provided for patients removed from study for progressive  disease. | X d  |      |      |      |      |      |      |      |      |         |               |
| Serum Pregnancy  testing within 14 days                                                                                          | X                                                                                                                                                                                                                         |                                                                                                                                                                                                                           |      |      |      |      |      |      |      |      |      |         |               |
| of enrollment Ophthalmologic  examination. See  Section 6 on  guidelines for visual  changes and exam  source sheet in  appendix | X                                                                                                                                                                                                                         | X e                                                                                                                                                                                                                       |      |      |      |      |      |      |      |      |      |         |               |
| a:                                                                                                                               | Only for patients continuing on dabrafenib and/ or trametinib who have not undergone surgery.                                                                                                                             |                                                                                                                                                                                                                           |      |      |      |      |      |      |      |      |      |         |               |
| b:                                                                                                                               | Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose,  phosphorus, potassium, total protein, AST, ALT, sodium.                                                        |                                                                                                                                                                                                                           |      |      |      |      |      |      |      |      |      |         |               |
| d:                                                                                                                               | Off-study evaluation.                                                                                                                                                                                                     |                                                                                                                                                                                                                           |      |      |      |      |      |      |      |      |      |         |               |
| e:                                                                                                                               | Ophthalmologic exams to be repeated annually.                                                                                                                                                                             |                                                                                                                                                                                                                           |      |      |      |      |      |      |      |      |      |         |               |
| f:                                                                                                                               | Every 3 months while on trametinib.                                                                                                                                                                                       |                                                                                                                                                                                                                           |      |      |      |      |      |      |      |      |      |         |               |
| g.                                                                                                                               | For subjects not undergoing surgical resection.                                                                                                                                                                           |                                                                                                                                                                                                                           |      |      |      |      |      |      |      |      |      |         |               |
untitled h1
10 measurements

Primary Outcome Measure: Response rate according to RECIST v1.1 at 6 **weeks**
RECIST v1.1 response rate, specifically, the sum of CR and PR per RECIST v1.1
**Time Frame**: 6 weeks **Safety Issue:** Not a safety issue primary endpoint
untitled h1
10.1 primary and secondary outcome

The primary endpoint will be tumor response rate (CR + PR) at 6 weeks. We intend to use modified RECIST v1.1 criteria {Eisenhauer, 2009}, knowing that since this patient population will include presurgical subjects, we will be unable to obtain response confirmation following the surgical resection of tumors. {Eisenhauer, 2009 \#311}
untitled h1
10.1.1 measurement definition

The definition we will use for the primary endpoint of response will be per the RECIST v1.1 criteria, with the exception that for patients undergoing surgical resection there will be no confirmatory imaging as this would be irrelevant following surgical resection. CR, PR, SD, PR are all defined in the cited RECIST reference and are widely available and therefore will not be repeated here.
untitled h1
10.1.2 measurement methods

Standard CT or MRI scans and physical exam, per RECIST v1.1 criteria, will be used to measure tumors for purposes of response assessment. 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.
untitled h1
10.1.3 measurement time points

Initial response evaluation for the primary endpoint will be at 6 weeks. For patients not undergoing surgical resection, follow-up imaging will be every 6 to 9 weeks, which we consider to be standard of care.
untitled h1
10.2 secondary outcome 10.2.1 tumor

One secondary outcome will be percent of tumor necrosis at the time of endpoint biopsy or surgical resection. We intend to use this outcome with criteria established for treatment response in other tumors.
untitled h1
10.2.2 measurement definition

The definition we will use for the first secondary endpoint of response will be evaluation of extent of tumor necrosis by H&E slide review. This will be performed on either the endpoint biopsy or the resection specimen.
untitled h1
10.2.3 measurement methods

Routine H&E slide review will be used to measure extent of tumor necrosis for purposes of response assessment. Percentage of tumor necrosis by volume will be assessed as routinely done with other solid tumors such as osteosarcoma. The biopsy slide or multiple slides of the resection specimen will be examined and the volume of the necrosis compared to the volume of the total tumor will be determined by the centrally reviewing pathologists and percentage readouts of tumor necrosis, in increments of 10%, will be determined. In addition to measuring tumor necrosis the slide review will also estimate therapy effect on intact cells by estimating the percent cells with therapy-associated nuclear atypia.
untitled h1
10.2.4 measurement time points

Tumor necrosis evaluation for this secondary endpoint will be at the time of the endpoint biopsy or the surgical resection.
untitled h1
10.2.5 response review

Tumor necrosis evaluation will be centralized review by the study co-investigator, Robert West, and at least one designee with substantial experience with tumor necrosis evaluation. Disagreements concerning response assessment between the PI and the second reviewer will be adjudicated by a board certified pathologist with tumor necrosis evaluation experience.
untitled h1
10.3 secondary outcome - proliferation

A second secondary outcome will be proliferation index as measured by Ki67 percent positivity at the time of endpoint biopsy or surgical resection. We intend to use this outcome as measured with immunohistochemistry with criteria established for assessment of proliferation index for other tumors.
untitled h1
10.3.1 measurement definition

The definition we will use for the second secondary endpoint of response will be evaluation of percent proliferation index by Ki67 immunohistochemistry. This will be performed on the initial pre-treatment biopsy and either the endpoint biopsy or the resection specimen.
untitled h1
10.3.2 measurement methods

Proliferation index evaluation will be performed in the laboratory of Dr. Robert West on the initial pre-treatment biopsy and either the endpoint biopsy or the resection specimen. Ki-67 immunohistochemistry 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. All pathological evaluations will be done centrally by the pathology co- investigators, Robert West and Jonathan Pollack or their designees.
untitled h1
10.3.3 measurement time points

Proliferation index evaluation for this secondary endpoint will be at the time of the endpoint biopsy or the surgical resection.
untitled h1
10.3.4 response review

Proliferation index evaluation will be centralized review by the study co-investigator, Robert West and Jonathan Pollack and at least one designee with substantial experience with proliferation index evaluation. Disagreements concerning response assessment between the PI and the second reviewer will be adjudicated by a board certified pathologist with proliferation index evaluation experience.
untitled h1
10.4 secondary outcome - phosphorylation

A second secondary outcome will be expression of phosphorylation of MEK and ERK as measured by phospho-MEK/ERK positivity at the time of endpoint biopsy or surgical resection. We intend to use this outcome as measured with immunohistochemistry using antibodies specific for phospho-MEK/ERK and total MEK/ERK (either phosphorylated or un-phosphorylated) with criteria established for assessment of protein expression by immunohistochemistry for other tumors.
untitled h1
10.4.1 measurement definition

The definition we will use for the second secondary endpoint of response will be evaluation of protein expression by immunohistochemistry. This will be performed on the initial pre-treatment biopsy and either the endpoint biopsy or the resection specimen.
untitled h1
10.4.2 measurement methods

Immunohistochemistry evaluation for MEK/ERK will be performed in the laboratory of Dr. Robert West on the initial pre-treatment biopsy and either the endpoint biopsy or the resection specimen. Immunohistochemistry will be scored by at least two pathologists using percentage positive cells and intensity of staining as the primary metrics. The results of the immunohistochemical analysis will be expressed as both raw data in addition to a ratio between pre- and post- treatment. All pathological evaluations will be done centrally by the pathology co- investigators, Robert West and Jonathan Pollack or their designees.
untitled h1
10.4.3 measurement time points

Immunohistochemistry evaluation for MEK/ERK for this secondary endpoint will be at the time of the endpoint biopsy or the surgical resection.
untitled h1
10.4.4 response review

Immunohistochemistry evaluation for MEK/ERK will be centralized review by the study co-investigator, Robert West and Jonathan Pollack and at least one designee with substantial experience with protein expression evaluation. Disagreements concerning response assessment between the PI and the second reviewer will be adjudicated by a board certified pathologist with protein expression evaluation experience.
untitled h1
11 regulatory considerations 11.1 institutional

The protocol, the proposed informed consent and all forms of participant information related to the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC). Any changes made to the protocol will be submitted as a modification and will be approved by the IRB prior to implementation. The Protocol Director will disseminate the protocol amendment information to all participating investigators. All participating sites will similarly have the informed consent document and protocol reviewed and approved by their local IRB and scientific review committee. There is to be only one version of the protocol to be used across all participating sites and no site can individually modify or amend the protocol at their site alone. That is, all protocol amendments and modifications must be reviewed and approved by all institutions' relevant review boards.
untitled h1
11.2 data and safety monitoring

The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the monitoring entity for this study. The DSMC will audit study-related activities to determine whether the study has been conducted in accordance with the protocol, local standard operating procedures, FDA regulations, and Good Clinical Practice (GCP). This may include review of the following types of documents participating in the study: regulatory binders, case report forms, eligibility checklists, and source documents. In addition, the DSMC will regularly review serious adverse events and protocol deviations associated with the research to ensure the protection of human subjects. Results of the DSMC audit will be communicated to the IRBs of all participating institutions and the appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as needed.
untitled h1
11.3 data management plan 11.3.1

Data collection for this study will be via REDCap, a password protected HIPAA compliant web- based electronic data capture system. Prior to opening this study at any site, case report forms for the collection of all relevant required data will be developed and relevant site staff trained on the access and use of REDCap. Eligibility for each patient enrolled will be confirmed by the PI or designee centrally before authorization to enroll and patient number assignment is made via REDCap. The Protocol Director, or his/her designee, will prepare and maintain adequate and accurate participant case histories with observations and data pertinent to the study. At each participating site, that site's PI or designee is responsible for collecting and storing in one central location copies of all primary clinical documents and be prepared to transmit these documents via secure electronic means for remote audit and review. All sites should also be able to readily access actual primary documentation, either electronically or in paper form, for on-site audit purposes.
untitled h1
11.3.2 data submission responsibility

It is the responsibility of each site PI to ensure that all investigators and designees at that site understand and are trained in all the relevant procedures for data collection and submission. For the purposes of site data submission compliance, data will be considered delinquent and such delinquency reported to that site's IRB if the data for any required routine evaluation is not submitted within 4 weeks after the relevant visit, test, or assessment has been completed or resulted.
untitled h1
11.3.3 multicenter guidelines

The overall PI is responsible for distribution of all IND action letters and safety reports to all participating institutions.
untitled h1
12 statistical considerations 12.1 statistical

We propose a two stage Optimal design per Simon, et al. (Simon R ,1989. Controlled Clinical Trials. 10:1-10), and using the UNC calculator: http://www.cscc.unc.edu/cscc/aivanova/SimonsTwoStageDesign.aspx The null hypothesis that the true response rate is 0.05 will be tested against a one-sided alternative. In the first stage, 9 evaluable patients will be accrued. If there is less than one response (defined in Section 10.1) in these 9 patients, the study will be stopped. If at the time of the 9th patient's enrollment there has not been at least one centrally documented response, accrual will stop until responses have been centrally determined for the first nine patients. Otherwise, 8 additional evaluable patients will be accrued for a total of 17 evaluable patients. The null hypothesis will be rejected if 3 or more responses are observed in 17 patients. We will allow for up to 11 patients in the first stage and up to 10 patients in the second stage to account for patient drop-out / uneavaluable patients. This design yields a type I error rate of 0.0466 and power of 0.8122 when the true response rate is 0.25. We believe that anything below a response rate of 25% would not be clinically meaningful given the potential risks of dabrafenib and trametinib. The likelihood of stopping early if the null hypothesis is true will be 0.63. A response rate of 25% or higher, in the context of other promising secondary endpoint results such as a high % of tumor necrosis, would warrant further study.
untitled h1
12.2 secondary analysis

We will determine secondary responses for: 1) tumor necrosis; 2) proliferation index; and 3) ERK/MEK phosphorylation. These assays will be exploratory and not subjected to a prospective statistical plan for analysis. Tumor necrosis % will be estimated according the standard surgical pathology techniques. Proliferation index will be measured by percentage of cells in mitosis and Ki 67 staining per standard surgical pathiology assays. The ratio of unphosphorylated to phosphorylated ERK and MEK will be done using standard phosphorylation specific antibodies on tumor tissue specimens in Dr West's lab according to his lab's SOPs. See Section 10 for details.
untitled h1
12.3 sample size

11 to 21 patients (9 to 17 evaluable pateints). See Section 12.1
untitled h1
12.4 accrual estimates

We estimate 3 to 6 patients will be accrued among collaborating institutions annually. This is a very rare disease, incidence 0.5/ million estimated. Stanford sees and evaluates outside pathology on about 5 cases per year and our collaborating centers estimate about the same.
untitled h1
12.5 feasibility and safety assessment

Because this is a very rare disease, our assumptions concerning the ability to accrue in a timely way are considerably uncertain. Therefore, at each annual review, should the accrual in the preceding year be less than 3 patients, we will re-evaluate the feasibility of conducting this protocol and either modify the protocol or close the protocol. Also as part of that annual review, if the cumulative rate of completion of 6 weeks of dabrafenib and trametinib treatment as specified in Section 4 is not achieved in at least 2/3 of all subjects , we will review the feasibility of administering treatment on this study and modify or close the protocol. Safety data, collected as specified in the study calendar in section nine, will be summarized in tabular form using the CTCAE v4.03 for AE description and grading. Cumulative safety data and all SAE reports will be reviewed by investigators both annually and at the end of the first stage of accrual. Should less than 2/3 of patients enrolled at any of these annual reviews or first stage analysis not complete the protocol treatment as stipulated in this protocol, the protocol will either be amended to address these safety issues or the protocol will be closed to further accrual. High-grade AEs alone are not to be construed as an indication to stop accrual or amend the protocol as long as treatment of those AEs per standards of care and modifications per Section 6 allow for completion of treatment as specified in Section 4. Reporting of SAEs is covered in Section 7.2.
untitled h1
13 references

Acosta D, Affolder T, Akimoto H, et al. (2003). "Search for the supersymmetric partner of the top quark in dilepton events from pp collisions at square root of s=1.8 TeV." *Phys Rev Lett*.  
90(25 Pt 1):251801.  
Amzerin M, Fadoukhair Z, Belbaraka R, et al. (2011). "Metastatic ameloblastoma responding to combination chemotherapy: case report and review of the literature." *J Med Case Rep*. 5:491.  
Anand SV, Davey WW, Cohen B, et al. (1967). "Tumours of the jaw in West Africa. A review of 256 patients." *Br J Surg*. 54(11):901-917.  
Barnes L. (2005). *Pathology and Genetics of Head and Neck Tumours*, IARC:296-300. Becelli R, Carboni A, Cerulli G, et al. (2002). "Mandibular ameloblastoma: analysis of surgical treatment carried out in 60 patients between 1977 and 1998." *J Craniofac Surg*. 13(3):395-400; discussion 400.  
Becelli R, Morello R, Renzi G, et al. (2011). "Treatment of recurrent mandibular ameloblastoma with segmental resection and revascularized fibula free flap." *J Craniofac S*urg. 22(3):1163-1165.  
Brastianos PK, et al. (2016). "Dramatic Response of BRAF-V600E Mutant Papillary Craniopharyngioma to Targeted Therapy." *J Natl Cancer Inst*. 108.  
Bhasker S. (1981). "Synopsis of Oral Pathology." Brazis PW, Miller NR, Lee AG, et al. (1995). "Neuro-ophthalmologic Aspects of Ameloblastoma." *Skull Base Surg*. 5(4):233-244.  
Brown NA, Rolland D, McHugh JB, et al. (2014). "Activating FGFR2-RAS-BRAF mutations in ameloblastoma." *Clin Cancer Res*. 20(21):5517-5526.  
Carlson ER, Marx RE. (2006). "The ameloblastoma: primary, curative surgical management." J
Oral Maxillofac Surg. 64(3):484-494.  
Chai Y, Jiang X, Ito Y, et al. (2000). "Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis." *Development*. 127(8):1671-1679.  
Ciment LM, Ciment AJ. (2002). "Malignant ameloblastoma metastatic to the lungs 29 years after primary resection: a case report." *Chest*. 121(4):1359-1361.  
Cusack JW. (1827). "Report of the amputations of the lower jaw." *Dublin Hosp Rec*. 4:1-38. Daley TD, Wysocki GP, Pringle GA, et al. (1994). "Relative incidence of odontogenic tumors and oral and jaw cysts in a Canadian population." *Oral Surg Oral Med Oral Pathol*. 77(3):276-280.  
Eisenhauer EA, Therasse P, Bogaerts J, et al. (2009). "New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)." *Eur J Cancer*. 45(2):228-247.  
Eliasson AH, Moser RJ, 3rd, Tenholder MF. (1989). "Diagnosis and treatment of metastatic ameloblastoma." *South Med J*. 82(9):1165-1168.  
Escandell I, et al. (2015). "Effective treatment with Dabrafenib and Trametinib for a BRAF-mutated metastatic dedifferentiated malignant spindle cell neoplasm." *J Eur Acad* Dermatol Venereol.  
Flaherty KT, et al. (2012). "Improved survival with MEK inhibition in BRAF-mutated melanoma." *N Engl J Med*. 367:107-114.  
Gall JA, Sartiano GP, Shreiner DP, et al. (1975). "Ameloblastoma of the mandible with pulmonary metastasis." Oncology 32(3-4):118-126-126.  
Gardner DG, Pecak AM. (1980). "The treatment of ameloblastoma based on pathologic and anatomic principles." *Cancer*. 46(11):2514-2519.  
Gerzenshtein J, Zhang F, Caplan J, et al. (2006). "Immediate mandibular reconstruction with microsurgical fibula flap transfer following wide resection for ameloblastoma." *J Craniofac* Surg. 17(1):178-182.  
Gortzak RA, Latief BS, Lekkas C, et al. (2006). "Growth characteristics of large mandibular ameloblastomas: report of 5 cases with implications for the approach to surgery." Int J Oral Maxillofac Surg. 35(8):691-695.  
Grunwald V, Le Blanc S, Karstens JH, et al. (2001). "Metastatic malignant ameloblastoma responding to chemotherapy with paclitaxel and carboplatin." *Ann Oncol*. 12(10):1489-1491.  
Hasim FW, Poon CC, Smith AC. (2007). "Prolonged survival with confirmed metastatic pulmonary ameloblastoma." *Int J Oral Maxillofac Surg*. 36(10):953-955.  
Hauschild A, et al. (2012). "Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial." *Lancet*. 380(9839):358-365.  
Hertog D, Bloemena E, Aartman IH, et al. (2012). "Histopathology of ameloblastoma of the jaws; some critical observations based on a 40 years single institution experience." *Med Oral* Patol Oral Cir Bucal. 17(1):e76-82.  
Ivy RH, Churchill HR. (1930). "The need of a standardized surgical and pathological classification of tumors and anomalies of dental origin." *Am Assoc Dent Sch Trans*. 7:240-245.  
Kaye FJ, et al. (2015). "Clinical and radiographic response with combined BRAF-targeted therapy in stage 4 ameloblastoma." *J Natl Cancer Inst*. 107(1):378.  
Kurppa KJ, CatonJ, Morgan PR, et al. (2014). "High frequency of BRAF-V600E mutations in ameloblastoma." *J Pathol*. 232(5):492-498.  
Larsson A, Almeren H. (1978). "Ameloblastoma of the jaws. An analysis of a consecutive series of all cases reported to the Swedish Cancer Registry during 1958-1971." *Acta Pathol Microbiol* Scand A. 86a(5):337-349.  
Long GV, et al. (2015). "Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial." Lancet. 386(9992):444-451.  
Lu Y, Xuan M, Takata T. (1998). "Odontogenic tumors. A demographic study of 759 cases in a Chinese population." *Oral Surg Oral Med Oral Pathol Oral Radiol Endod*. 86(6):707-714.  
Malassez L. (1885). "Sur les role des débris épithéliaux paradentaires." Arch Physiol Norm Pathol. 5,6:309-340, 379-449.  
Mosadomi, A. (1975). "Odontogenic tumors in an African population. Analysis of twenty-nine cases seen over a 5-year period." *Oral Surg Oral Med Oral Pathol*. 40(4):502-521.  
Ndukwe KC, Adebiyi EK, Ugboko VI, et al. (2010). "Ameloblastic carcinoma: a multicenter Nigerian study." *J Oral Maxillofac Surg*. 68(9):2111-2114.  
Pandya NJ, Stuteville OH. (1972). "Treatment of ameloblastoma." *Plast Reconstr Surg*."
50(3):242-248.  
Ramadas K, Jose CC, Subhashini J, et al. (1990). "Pulmonary metastases from ameloblastoma of the mandible treated with cisplatin, adriamycin, and cyclophosphamide." *Cancer*. 66(7):1475-1479.  
Regezi JA, Kerr DA, Courtney RM(1978). "Odontogenic tumors: analysis of 706 cases." J Oral Surg. 36(10):771-778.  
Reichart PA, Philipsen HP, Sonner S. (1995). "Ameloblastoma: biological profile of 3677 cases." *Eur J Cancer B Oral Oncol*. 31b(2):86-99.  
Robert C, et al. (2015). "Improved overall survival in melanoma with combined dabrafenib and trametinib." *N Engl J Med*. 372(1):30-39.  
Schafer DR, Thompson LD, Smith BC, et al. (1998). "Primary ameloblastoma of the sinonasal tract: a clinicopathologic study of 24 cases." *Cancer*. 82(4):667-674.  
Sham E, Leong J, Maher R, et al. (2009). "Mandibular ameloblastoma: clinical experience and literature review." *ANZ J Surg*. 79(10):739-744.  
Slootweg PJ, Muller H. (1984). "Malignant ameloblastoma or ameloblastic carcinoma." *Oral* Surg Oral Med Oral Pathol. 57(2):168-176.  
Stanley HR, Diehl DL. (1965). "Ameloblastoma Potential of Follicular Cysts." Oral Surg Oral Med Oral Pathol. 20:260-268.  
Sweeney RT, McClary AC, Myers BR, et al. (2014). "Identification of recurrent SMO and BRAF
mutations in ameloblastomas." *Nat Genet*. 46(7):722-725.  
Tsai CY, Wei FC, Chang YL, et al. (2006). "Vastus lateralis muscle flap used for reconstruction of the maxilla after radical resection of recurrent ameloblastoma." Chang Gung Med J 29(3):331-335.  
Ueno S, Mushimoto K, Shirasu Ral. (1989). "Prognostic evaluation of ameloblastoma based on histologic and radiographic typing." J Oral Maxillofac Surg 47(1):11-15.  
Urken ML, et al. (1991). "Functional evaluation following microvascular oromandibular reconstruction of the oral cancer patient: a comparative study of reconstructed and nonreconstructed patients." *Laryngoscope*. 101(9):935-950.  
Urken ML, Buchbinder D, Costantino PD, et al. (1998). "Oromandibular reconstruction using microvascular composite flaps: report of 210 cases." *Arch Otolaryngol Head Neck Surg*. 124:46-55.  
Vayvada H, Mola F, Menderes A, et al. (2006). "Surgical management of ameloblastoma in the mandible: Segmental mandibulectomy and immediate reconstruction with free fibula or deep circumflex iliac artery flap (evaluation of the long-term esthetic and functional results)." *J Oral* Maxillofac Surg. 64(10):1532-1539.  
Wedl C. (1870). *Pathologie der Zähne: mit besonderer Rücksicht auf Anatomie und Physiologie*.  
Felix.  
Wenig BM. (2008). *Atlas of head and neck pathology*. Elsevier Health Sciences. Williams, CB, et al. (2015). "A metastatic colon adenocarcinoma harboring BRAF-V600E has a durable major response to dabrafenib/trametinib and chemotherapy." *Onco Targets*. Ther 8:3561-3564.  
Williams TP. (1993). "Management of ameloblastoma: a changing perspective." *J Oral* Maxillofac Surg. 51(10):1064-1070.  
Wu PC, Chan KW. (1985). "A survey of tumours of the jawbones in Hong Kong Chinese:
1963-1982." *Br J Oral Maxillofac Surg*. 23(2):92-102.  
Zwahlen RA, Gratz KW. (2002). "Maxillary ameloblastomas: a review of the literature and of a 15-year database." *J Craniomaxillofac Surg*. 30(5):273-279.
appendix a medication guide /
dabrafenib capsules

The current Medication Guide for Tafinlar (dabrafenib) dated November 2015 is attached to the eProtocol IRB-32275 application.
appendix a medication guide /
trametinib tablets

The current Patient Information for Mekinist (trametinib) is provided in the package insert dated November 2015, attached to the eProtocol IRB-32275 application.
appendix a medication guide /
appendix b stanford cancer institute

Standard Operating Procedures (SOPs) for the Stanford Cancer Institute (SCI) pertaining to risks to subjects and safety reporting are available on the SCI Cancer Clinical Trials Office website (http://med.stanford.edu/ccto/services/regulatory.html).
appendix a medication guide /
appendix c ecog performance status

| grade                                                                                  | ECOG PERFORMANCE STATUS                                                             |
|----------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------|
| o                                                                                      | Fully active, able to carry on all pre-disease performance without restriction      |
| Restricted in physically strenuous activity but ambulatory and able to carry out work  |                                                                                     |
| 1                                                                                      | of a light or sedentary nature, e.g., light house work, office work                 |
| Ambulatory and capable of all selfcare but unable to carry out any work activities; up |                                                                                     |
| 2                                                                                      | and about more than 50% of waking hours                                             |
| Capable of only limited selfcare; confined to bed or chair more than 50% of waking     |                                                                                     |
| 3                                                                                      | hours                                                                               |
| 4                                                                                      | Completely disabled; cannot carry on any selfcare; totally confined to bed or chair |
| 5                                                                                      | Dead                                                                                |  
Appendix D: **Cockcroft-Gault formula:**
CCr={((l 40–age) x weight)/(72xSCr)}x 0.85 (if female)
Appendix E: Ophthalmic exam source sheet Note to examiner: Please assess particularly for visible retinal pathology.  
* **Optical coherence tomography is highly recommended** For patients in whom retinal abnormalities are noted,  
color fundus photos, and fluorescein angiography if clinically indicated, are recommended.  
| color fundus photos, and fluorescein angiography if clinically indicated, are recommended.  OPHTHALMIC EXAMINATION Subject name/ MRN: 1. Date of Examination: _ _/_ _ _ /_ _ _ _  dd / mmm / yyyy VISUAL ACUITY Enter corrected visual acuity OD: OS: TONOMETRY Enter IOP (mmHg) OD: OS: INDIRECT FUNDOSCOPY Indirect Exam: Indicate  normal or specify abnormalities OD: OS: CONFRONTATION VISUAL FIELD EXAM OR AUTOMATED PERIMETRY  (eg, Humphrey 24-2 or 30-2 or equivalent if using a non-Humphrey instrument) Indicate normal or specify any  abnormalities OD: OS: OPTICAL COHERENCE TOMOGRAPHY (strongly recommended) Indicate normal or specify any  abnormalities OD: OS: COLOR FUNDUS PHOTOS (recommended if retinal abnormalities are noted)* Indicate normal or specify any  abnormalities OD: OS: FLORESCEIN ANGIOGRAPHY (suggested if retinal abnormalities are noted and  test clinically indicated)* Indicate normal or specify any  abnormalities OD: OS: Were any of the following noted on ocular history or exam? Yes No  History of CSR?  Evidence of new optic disc cupping?  Evidence of new visual field defects? EXCLUSION CRITERIA Yes No  History of RVO? o If yes, patient is not eligible for the study.   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|