nct# 03232892 ii trial to
untitled h2

Protocol Number: CC \# **166521**
Study **Drug:** Trametinib Version **Number:** 7.0 Version **Date:** 06-20-18 IND Number: Exempt PrincipalInvestigator(Sponsor-Investigator)  
  
  
Collin Blakely, MD, PhD  
  
  
  
| RevisionHistory   |          |
|-------------------|----------|
| Version 1.0       | 02-15-16 |
| Version 2.0       | 05-12-16 |
| Version 2.1       | 05-19-16 |
| Version 2.2       | 06-17-16 |
| Version 3.0       | 09-21-16 |
| Version 3.1       | 11-22-16 |
| Version 4.0       | 01-20-17 |
| Version 5.0       | 05-25-17 |
| Version 6.0       | 02-15-18 |
| Version 7.0       | 06-20-18 |  
Proprietary and **Confidential**
The information in this document is considered privileged and confidential, and may not be disclosed to others except to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by Federal and State laws. Persons to whom this information is disclosed should be informed that this information is privileged and confidential and that it should not be further disclosed.
nct# 03232892 ii trial to
protocol signature page

Protocol No.: 166521 Version **Date:** 06-20-2018  
1. I agree to follow this protocol version as approved by the UCSF Protocol Review Committee
(PRC), Institutional Review Board (IRB), and Data Safety Monitoring Committee (DSMC).  
2. I will conduct the study in accordance with applicable IRB requirements, Federal regulations, and state and local laws to maintain the protection of the rights and welfare of study participants.  
3. I certify that I, and the study staff, have received the requisite training to conduct this research protocol.  
4. I have read and understand the information in the Investigators' Brochure (or Manufacturer's Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In accordance with the FDA Modernization Act, I will ensure the registration of the trial on the www.clinicaltrials.gov website.  
5. I agree to maintain adequate and accurate records in accordance with IRB policies, Federal, state and local laws and regulations.  
6.
nct# 03232892 ii trial to
participating site(s)

| Site Name: University of California, Davis Principal Investigator: Jonathan Riess, MD   | Site Name: University of California, San Diego Principal Investigator: Hatim Husain, MD   |
|-----------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------|
| Signature:                                                                              | Signature:                                                                                |  
| Abstract Title                         | Phase II trial to evaluate trametinib in patients with advanced NF1-mutant nonsmall cell lung cancer Patients with metastatic or unresectable locally advanced non-squamous, nonsmall cell lung cancer (NSCLC) whose tumors harbor a non-synonymous NF1 mutation, with progressive disease on at least one prior line of therapy.                                                                                                                        |                                                                                                                                        |              |            |
|----------------------------------------|------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|--------------|------------|
| Patient population Rationale for Study | NF1 is a tumor suppressor gene,                                                                                        | which encodes                                                                                                                          | a RAS GTPase | activating |
| protein (GAP), which facilitates the hydrolysis of RAS-GTP to the inactive RASGDP.7-9 Germline NF1 inactivating mutations are associated with both pediatric and adult malignancies.10 Somatic mutations in NF1 have been associated with adenocarcinoma of lung,11 malignant melanoma,12 glioblastoma,13 as well as myelodysplastic syndrome.10 NF1 loss in melanoma cell lines that were wildtype for BRAF/RAS resulted in elevated RAS-GTP levels and MAPK signaling activation. Treatment of these cells with the MEK inhibitor trametinib resulted in sustained ERK inhibition and suppression of tumor cell proliferation.12 Likewise, leukemias have been shown to arise from either germline or somatic loss of NF114 and treatment of autochthonous myeloid malignancies driven by engineered NF1 loss in the mouse have been shown to be sensitive to MEK inhibition in preclinical models.15 We hypothesize that patients with advanced NSCLC whose tumors harbor nonsynonymous somatic mutations in NF1 will exhibit tumor dependence upon the MAPK signaling pathway and will be sensitive to treatment with the potent and selective MEK inhibitor trametinib.16 To evaluate the efficacy of trametinib in patients with advanced, non-squamous NSCLC who have progressed on at least one prior line of systemic cancer therapy (i.e. platinum doublet, anti-PD1/PDL1 or appropriate EGFR, ALK, or ROS-1 targeted therapy), and whose tumors harbor a non-synonymous mutation in NF1 and is negative for an activating mutation in KRAS.                                        |                                                                                                                        |                                                                                                                                        |              |            |
| Primary Objective                      | -                                                                                                                      | To evaluate secondary measures of clinical efficacy in advanced NSCLC                                                                  |              |            |
| Secondary                              | patients treated with trametinib.                                                                                      |                                                                                                                                        |              |            |
| Objectives                             | -                                                                                                                      | To evaluate the safety and tolerability of trametinib using National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.03. |              |            |
| -                                      | To describe the pharmacokinetics associated with trametinib.                                                           |                                                                                                                                        |              |            |
| -                                      | To assess tissue and blood-based biomarkers that may be predictive of response or primary resistance to trametinib.    |                                                                                                                                        |              |            |
| -                                      | To determine subsets of advanced NSCLC in whom MEK inhibition is especially effective. (e.g., specific NF1 mutations). |                                                                                                                                        |              |            |  
| Version date: 06-20-2018   | Protocol CC#: 166521   |
|----------------------------|------------------------|
| Study Design               | This is a phase II, single-arm, open-label, multicenter clinical trial evaluating the efficacy and safety of trametinib monotherapy in patients with advanced nonsquamous NSCLC whose tumors non-synonymous NF1 mutations and are KRAS wildtype. Eligible patients must have documented disease progression either during or after treatment with platinum doublet chemotherapy or most recent therapy and may not have received prior treatment with a MEK inhibitor. Patients with activating alterations in EGFR, ALK, and ROS-1 must also have received appropriate TKI treatment. Patients who meet eligibility criteria will receive trametinib monotherapy and followed for the primary endpoint of objective response rate and additional secondary endpoints.                        |  
| A total of 27 patients will be enrolled into the study, with the goals of obtaining 24 evaluable patients. Using a Simon 2-stage design, if we do not observe at least 2 responses within the first 15 patients, enrollment will be stopped due to lack of efficacy.   |                                                                                              |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------|
| Number of patients                                                                                                                                                                                                                                                     | Patients may continue treatment until disease progression or up to 24 months                 |
| Duration of                                                                                                                                                                                                                                                            | from the time of study entry or until the study is closed.                                   |
| Therapy                                                                                                                                                                                                                                                                | All patients will be followed for 12 months.                                                 |
| Duration of Follow up                                                                                                                                                                                                                                                  | The study is estimated to reach completion 4 years from the time the study opens to accrual. |
| Duration of study                                                                                                                                                                                                                                                      |                                                                                              |  
  
| Study Drugs                                                                                                                                  | Trametinib is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity. Trametinib will be administered as 2 mg orally once daily. Safety assessments will be based on events occurring during the on-study period, defined as from the first dose of trametinib to 30 days after the last dose of trametinib or until resolution for serious adverse events. Safety will be assessed by reviewing adverse events (AEs), laboratory evaluations, physical examination, and imaging or procedures when clinically indicated. Toxicity will be graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4.03).   |             |                           |    |                     |          |
|----------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|---------------------------|----|---------------------|----------|
| Safety Assessments                                                                                                                           | Efficacy measures will include tumor assessments by CT scans of the chest, abdomen, and pelvis with appropriate slice thickness per RECIST Version 1.1. Brain imaging (CT/MRI) is required at baseline and follow-up scans should include the brain in patients with baseline brain lesions. All sites of disease should be followed and the same imaging methodology should be used throughout the study. Tumor assessments will be carried out at screening and every 8 weeks ± 1 week from the time of trametinib initiation and thereafter until tumor progression. Patients are required to have an end-of-treatment tumor scan using the same methodology used at screening unless:                       |             |                           |    |                     |          |
| Efficacy Assessments                                                                                                                         | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | The patient | has radiographic evidence | of | disease progression | while on |
| study, or                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |             |                           |    |                     |          |
| -                                                                                                                                            | It has been < 2 weeks since their last on-study scan                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |             |                           |    |                     |          |
| Patients who discontinue trametinib without progression should continue to be scanned per standard of care until disease progression occurs. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |             |                           |    |                     |          |
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list of abbreviations

| AE     | adverse event                                   |
|--------|-------------------------------------------------|
| ALP    | alkaline phosphatase                            |
| ALT    | alanine aminotransferase                        |
| ANC    | absolute neutrophil count                       |
| AST    | aspartate aminotransferase                      |
| AUC    | area under the curve                            |
| BUN    | blood urea nitrogen                             |
| CBC    | complete blood cell (count)                     |
| CR     | complete response                               |
| CRC    | Clinical Research Coordinator                   |
| CRF    | case report form                                |
| CSF    | cerebral spinal fluid                           |
| CT     | computerized tomography                         |
| CTCEA  | Common Terminology Criteria for Adverse Events  |
| CTMS   | Clinical Trial Management System                |
| DCR    | Disease control rate                            |
| DFS    | disease-free survival                           |
| DLT    | dose limiting toxicity                          |
| DR     | Duration of Response                            |
| DSMC   | Data and Safety Monitoring Committee            |
| DSMP   | Data and Safety Monitoring Plan                 |
| ECOG   | Eastern Cooperative Oncology Group              |
| FDA    | Food and Drug Administration                    |
| GCP    | Good Clinical Practice                          |
| HBV    | hepatitis B virus                               |
| HCT    | Hematocrit                                      |
| HCV    | hepatitis C virus                               |
| HDFCCC | Helen Diller Family Comprehensive Cancer Center |
| HGB    | Hemoglobin                                      |
| HIV    | human immunodeficiency virus                    |
| ICH    | International Conference on Harmonization       |
| IND    | investigational new drug application            |
| IP     | investigational product                         |
| IRB    | Institutional Review Board                      |  
| IV     | Intravenous                                  |
|--------|----------------------------------------------|
| LDH    | lactate dehydrogenase                        |
| LFT    | liver function test                          |
| MedDRA | Medical Dictionary for Regulatory Activities |
| MRI    | magnetic resonance imaging                   |
| NCI    | National Cancer Institute                    |
| NF1    | Neurofibromatosis type 1                     |
| NSCLC  | non-small cell lung cancer                   |
| ORR    | overall response rate                        |
| OS     | overall survival                             |
| PD     | disease progression                          |
| PK     | Pharmacokinetics                             |
| PO     | Per os (by mouth, orally)                    |
| PFS    | progression Free Survival                    |
| PR     | partial response                             |
| PRC    | Protocol Review Committee (UCSF)             |
| RBC    | red blood cell (count)                       |
| SD     | stable disease                               |
| SD     | standard deviation                           |
| SGOT   | serum glutamic oxaloacetic transaminase      |
| SGPT   | serum glutamic pyruvic transaminase          |
| ULN    | upper limit of normal                        |
| WBC    | white blood cell (count)                     |
nct# 03232892 ii trial to
table of contents

| Protocol Signature Page                                                                                                                                          |                                                                                                                                                                 |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Participating Site(s)                                                                                                                                            |                                                                                                                                                                 |
| Abstract .                                                                                                                                                       |                                                                                                                                                                 |
| List of Abbreviations .......................................................................................................................................6   |                                                                                                                                                                 |
| Table of Contents                                                                                                                                                |                                                                                                                                                                 |
| 1.1                                                                                                                                                              | Background on Indication                                                                                                                                        |
| 1.2                                                                                                                                                              | Background on the Compounds................................................................................................................9                    |
| 1.3                                                                                                                                                              | Rationale for the Proposed Study .                                                                                                                              |
| 1.4                                                                                                                                                              | Correlative Studies                                                                                                                                             |
| 1.4.2  Cell-Free DNA .                                                                                                                                           |                                                                                                                                                                 |
| 2                                                                                                                                                                | Objectives of the Study .....................................................................................................................................16 |
| 2.1                                                                                                                                                              | Primary                                                                                                                                                         |
| 2.2                                                                                                                                                              | Secondary                                                                                                                                                       |
| 2.3                                                                                                                                                              | Exploratory Objectives, Other Assessments ......................................................................................16                              |
| 2.4                                                                                                                                                              | Endpoints                                                                                                                                                       |
| w                                                                                                                                                                | Study Design                                                                                                                                                    |
| 3.1                                                                                                                                                              | Characteristics                                                                                                                                                 |
| 3.2                                                                                                                                                              | Number of Subjects                                                                                                                                              |
| 3.3                                                                                                                                                              | EIigibility Criteria .                                                                                                                                          |
| Table 3.1 Definitions for adequate baseline organ function ........................................................................21                            |                                                                                                                                                                 |
| 3.4                                                                                                                                                              | D Duration of Therapy                                                                                                                                           |
| 3.5                                                                                                                                                              | D Duration of Follow Up                                                                                                                                         |
| 3.6                                                                                                                                                              | Study Timeline .                                                                                                                                                |
| 4                                                                                                                                                                | Study Drugs                                                                                                                                                     |
| 4.1                                                                                                                                                              | Description, Supply and Storage of Investigational Drugs ................................................................24                                     |
| 4.2                                                                                                                                                              | D Drug Accountability                                                                                                                                           |
| 4.3                                                                                                                                                              | D Drug Ordering                                                                                                                                                 |
| 4.4                                                                                                                                                              | Packaging and Labeling of Study Drugs....................................................................................................28                     |
| 5                                                                                                                                                                | T Treatment Plan                                                                                                                                                |
| 5.1                                                                                                                                                              | Dosage and Administration                                                                                                                                       |
| 5.2                                                                                                                                                              | Dose Modifications and Dosing Delays....................................................................................................28                      |
| Table 5.2                                                                                                                                                        | Dose Modifications and Dosing Delays ..................................................................................28                                       |
| Table 5.3  Dose Delay and Modification for Events Considered Related to Trametinib...................29                                                          |                                                                                                                                                                 |
| Table 5.4                                                                                                                                                        | Guidelines for Supportive Care of Rash .............................................................................31                                          |
| Table 5.5                                                                                                                                                        | Management and Dose Modification Guidelines for Rash .............................................32                                                            |
| Table 5.6                                                                                                                                                        | Management and Dose Modification Guidelines for Diarrhea .....................................34                                                                |
| Table 5.9                                                                                                                                                        | Withholding and Stopping Criteria for QTc-Prolongation .............................................38                                                          |
| Table 5.10                                                                                                                                                       | Management and Dose Modification Guidelines for Pneumonitis .............................39                                                                     |
| Table 5.15 ...................................................................................................................................................43 |                                                                                                                                                                 |  
Protocol CC\#: 166521  
| 6                                                                                                                                                                | Study Procedures and Observations ...............................................................................................45                              |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 6.1                                                                                                                                                              | Schedule of Procedures and Observations .........................................................................................45                              |
| Table 6.1                                                                                                                                                        | Schedule of Study Procedures and Assessments ...........................................................49                                                       |
| 6.2                                                                                                                                                              |                                                                                                                                                                  |
| 6.3                                                                                                                                                              | Dietary Restrictions .                                                                                                                                           |
| 6.4                                                                                                                                                              | Prohibited Medications                                                                                                                                           |
| 7                                                                                                                                                                | Reporting and Documentation of Results ..................................................................................................53                      |
| 7.1                                                                                                                                                              | Evaluation of Efficacy (or Activity).................................................................................................................53          |
| Table 7.1                                                                                                                                                        | Response Criteria                                                                                                                                                |
| 7.2                                                                                                                                                              | Evaluation of Safety                                                                                                                                             |
| 7.3                                                                                                                                                              | Definitions of Adverse Events                                                                                                                                    |
| 7.4                                                                                                                                                              | Recording of an Adverse Event                                                                                                                                    |
| 7.5                                                                                                                                                              | Follow-up of Adverse Events                                                                                                                                      |
| Adverse Events Monitoring                                                                                                                                        |                                                                                                                                                                  |
| 7.6                                                                                                                                                              |                                                                                                                                                                  |
| 7.7                                                                                                                                                              | Expedited Reporting                                                                                                                                              |
| Statistical Considerations and Evaluation of Results .......................................................................62                                   |                                                                                                                                                                  |
| 8                                                                                                                                                                |                                                                                                                                                                  |
| 8.1                                                                                                                                                              | Study Endpoints ..............................................................................................................................................62 |
| 8.2                                                                                                                                                              | Determination of Sample Size and Accrual Rate .................................................................................62                                |
| 8.3                                                                                                                                                              | Analyses Plans.....................................................................................................................................63            |
| 8.4                                                                                                                                                              | Evaluation of Safety                                                                                                                                             |
| 9                                                                                                                                                                | Study Management .                                                                                                                                               |
| 9.1                                                                                                                                                              | Pre-study Documentation ......................................................................................................................66                 |
| 9.2                                                                                                                                                              | Institutional Review Board Approval                                                                                                                              |
| 9.3                                                                                                                                                              | Informed Consent .                                                                                                                                               |
| 9.4                                                                                                                                                              | Changes in the Protocol...........................................................................................................................67             |
| 9.5                                                                                                                                                              | Handling and Documentation of Clinical Supplies .........................................................................67                                      |
| Case Report Forms (CRFs) ........................................................................................................................68              |                                                                                                                                                                  |
| 9.6                                                                                                                                                              |                                                                                                                                                                  |
| 9.7                                                                                                                                                              | Oversight and Monitoring Plan ................................................................................................................68                 |
| 9.8                                                                                                                                                              | MMULTICENTER COMMUNICATION ................................................................................................................68                    |
| 9.9                                                                                                                                                              | Coordinating Center Documentation of Distribution ........................................................................69                                     |
| 9.10  Regulatory Documentation ...............................................................................................................69                 |                                                                                                                                                                  |
| Protection of Human Subjects                                                                                                                                     |                                                                                                                                                                  |
| 10                                                                                                                                                               |                                                                                                                                                                  |
| 10.1 Protection from Unnecessary Harm ......................................................................................................70                   |                                                                                                                                                                  |
| 10.2  Protection of Privacy ..................................................................................................................................70 |                                                                                                                                                                  |
| References .                                                                                                                                                     |                                                                                                                                                                  |
| Appendices                                                                                                                                                       |                                                                                                                                                                  |
| Appendix 2 Performance Status Criteria ...............................................................................................................74         |                                                                                                                                                                  |
| Appendix 3 UCSF Policy/Procedure for Required Regulatory Documents for a UCSF Investigator-                                                                      |                                                                                                                                                                  |
| Initiated Oncology Clinical Trials with an Investigator held Investigational New Drug (IND) .73                                                                  |                                                                                                                                                                  |
| Appendix 4  Data Safety Monitoring Plan for a Multicenter Study (Phase II or III study)                                                                          |                                                                                                                                                                  |
| ..............................................................................................................................................................79 |                                                                                                                                                                  |
| Appendix 5  Prohibited Medications ..............................................................................................................82              |                                                                                                                                                                  |
| Appendix 6  Specimen Collection ........................................................................................................................84       |                                                                                                                                                                  |
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1 introduction 1.1 background on

The RTK-RAS-MAPK pathway is central in the initiation and maintenance of non-small cell lung cancer (NSCLC). Canonical mutations in KRAS, *EGFR* or fusions in ALK, ROS1, or *NRTK1* are present in about 50% of NSCLC of the adenocarcinoma subtype.24 In two studies of approximately 400 NSCLC patients by The Cancer Genome Atlas (TCGA) Research Network, the frequency of mutations in *NF1* became apparent.  
1,25 These mutations are typically mutually exclusive from KRAS, *EGFR,* or BRAF mutations (Figure **1.1).**
We hypothesize that patients with advanced non-squamous NSCLC whose tumors harbor recurrent non-synonymous somatic mutations in NF1 will exhibit tumor dependence upon the MAPK signaling pathway and will be sensitive to treatment with the potent and selective MEK
inhibitor trametinib.16 Figure 1: Mutations in *BRAF* and NF1 are mutually exclusive from EGFR or *KRAS* mutations in lung  
  
adenocarcinoma (Source: Cancer Genome Atlas Research Network1)
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1.2 background on the compounds

Trametinib (GSK1120212) is a selective MEK1 and MEK2 inhibitor with selective activity towards BRAF and RAS mutant cancer cell lines and hematopoietic cancer cells from acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) origins. Trametinib inhibited the proliferation of most of the BRAF mutant melanoma cell lines tested (22 of 25) and it effectively inhibited the growth of BRAF mutant melanoma xenografts in vivo alone or in combination with dabrafenib. It causes inhibition of ERK phosphorylation leading to Gap-1 (G1) cell cycle arrest and tumor xenograft growth. There were no clinically relevant findings in single dose safety pharmacology studies in rats and dogs evaluating the cardiovascular, respiratory and central nervous systems conducted with trametinib. Left ventricular ejection fraction decrease is a common adverse event in patients taking trametinib. Mice given trametinib at ≥ 0.25 mg/kg/day for 3 weeks (3-times the clinical area under the plasma concentration-time curve [AUC] at steady state) had decreased ventricular function, lower heart rates and lower heart weight in the absence of cardiac histopathology. Importantly, there was no diminution of dobutamine-induced contractility. An in vitro investigative study demonstrated that the echocardiography effects were not likely to be due to acute myocardial toxicity or inhibition of mitochondrial function.
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1.2.2 pharmacokinetics and product metabolism

The nonclinical pharmacokinetics (PK) of trametinib were similar across the species (mouse, rat, dog and monkey). Low plasma clearance relative to liver blood flow and generally long halflives (t1/2) likely contribute to the accumulation upon repeat dosing which is consistent with observations in humans. Upon achieving steady-state, by 7 days for mice and by 3 weeks for rats and dogs (based on sparse sampling study design), the exposure of trametinib generally increased dose proportionally, which is consistent with observations in humans (steady state appeared to be achieved by Day 15). The volume of distribution of trametinib was generally greater than total body water for all species, consistent with the observed wide distribution to tissues in the rat. There was no selective association of drug-related material with melanin containing tissues. Plasma protein binding was high in nonclinical species and humans (>95%). In vitro blood cell association in humans was concentration dependent with a high blood to plasma ratio (ranged from 3 to 8) at the clinically relevant trametinib concentrations of 1 and 10 ng/mL. Nonclinical species, including rats and dogs, showed protracted elimination of DRM (Drug Related Material) consistent with a high volume of distribution, long half-life, and the PK data of trametinib in subjects with solid tumors.  
Absorption and systemic availability in nonclinical species and humans was moderate to high
(>40% to approximately 100%). The fecal route of elimination was the major excretory pathway in humans, rats, dogs, and mice. Trametinib has a high passive permeability and is not an in vitro substrate for human P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1).  
Therefore, the risk for an effect of other drugs on trametinib via these mechanisms is low.  
Trametinib is a weak in vitro substrate of the efflux transporter bile salt export pump (BSEP).  
The current literature suggests that BSEP mostly transports endogenous bile salts26 and is unlikely to play a major role in drug disposition and hence poses a low risk in drug-drug interactions.27 In humans, trametinib is eliminated predominantly by hydrolytic deacetylation, either deacetylation alone (M5) or in combination with mono-oxygenation M7). The enzymes involved are likely hydrolytic enzymes, such as esterases or amidases that are not generally associated with drug interaction risks.  
For the nonclinical species (rat and dog), trametinib was the major circulating component (> 60% of DRM) in plasma at all sampling time points. In humans, trametinib partitions in red blood cells and the majority of the circulating radioactivity is present as trametinib in blood (78-95% of DRM). Three minor metabolites M5, M6 and M7 were identified with the deacetylated metabolite
(M5), which was shown to have similar in vitro pharmacological activity as parent, accounting for
≤11% of plasma (rat and dog) or blood DRM (human). In an earlier investigation of plasma metabolites in humans following repeat dosing, the metabolites do not appear to accumulate to the same degree as parent. Qualitatively, all of the major metabolites of trametinib observed in humans have been detected in the nonclinical species.  
Based on in vitro studies, trametinib is not an inhibitor of cytochrome P450 enzymes including CYP1A2, CYP2A6, CYP2B6, CYP2D6 and CYP3A4. Although trametinib was found to be an in vitro inhibitor of CYP2C8, CYP2C9 and 2C19, inducer of CYP3A4 and inhibitor of the organic anion transporting polypeptide (OATP) transporters (OATP1B1, OATP1B3), Pgp, BCRP,
organic anion transporter (OAT)1, OAT3, organic cation transporter 2 (OCT2), and MATE1), its low efficacious dose, and low clinical systemic concentration (22.2 ng/mL or 0.04 M at 2 mg)
relative to the in vitro inhibition/induction potency suggests an overall low potential for drug-drug interactions.
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1.2.3 pharmacokinetics in humans

Trametinib pharmacokinetics were determined after single- and repeat-dose oral administration of trametinib tablets in subjects with solid tumors. Trametinib is absorbed rapidly with median time to maximum plasma concentration (tmax) generally occurring 1.50 hours after single oral administration of trametinib under fasting conditions. The absolute oral bioavailability of a single trametinib 2.0 mg tablet is moderate to high (72%) relative to a co-administered intravenous (IV)
microdose. Single-dose administration of trametinib with a high-fat, high-calorie meal resulted in a 70% decrease in Cmax, a 24% decrease in area under the concentration-time curve from time zero (predose) to last time point (AUC[0-t]) and a 10% decrease in AUC extrapolated to infinity
(AUC [0- ]) compared to fasted conditions. Following repeat-dosing the mean area under the curve from 0 hours to the time of next dosing
(AUC[0- ]) and Cmax increased in an approximately dose proportional manner. Trametinib accumulates with repeat dosing with a mean accumulation ratio at the recommended dose of 2 mg once daily of 5.97 and a terminal half-life of 5.3 days determined after single dose administration. Steady state appears to be achieved by Day 15, with little difference in pre-dose
(trough) concentration at the end of the dosing interval (C ), Cmax and area under the concentration-time curve from time zero (pre-dose) to 24 hrs (AUC[0-24]) between Days 15 and 21. Trametinib is a low extraction ratio drug based on plasma IV clearance of 3.21 L/hr, which represents approximately 1% of liver blood flow. Trametinib has a high volume of distribution (Vd) of 1060 L determined following an IV microdose. Fecal excretion is the major route of elimination after [14C] trametinib oral dose, accounting for
>80% of excreted radioactivity recovered (or 39.2% and 35.0% of the radioactive dose in 2 subjects) while urinary excretion accounted for <19% of excreted radioactivity recovered (<10% of the radioactive dose). Following a single dose of [14C]-trametinib, approximately 50% of circulating radioactivity is represented as the parent compound. However, based on metabolite profiling after repeat dosing of trametinib, ≥75% of drug-related material in plasma is the parent compound. In vitro and in vivo data suggest that trametinib is unlikely to affect the PK of other drugs and that the PK of trametinib is unlikely to be affected by other drugs. Trametinib is metabolized predominantly via deacetylation which is likely mediated by hydrolytic esterases which are not generally associated with drug interaction risk, nor is it a substrate of Pgp or BCRP.
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1.2.4 trametinib efficacy

Efficacy results from the MEK114267 (melanoma) study and the supporting studies MEK113583 (melanoma), MEK111054 (solid tumors or lymphoma), and MEK114653
(non-small cell lung carcinoma; NSCLC) indicated:
- Substantial evidence of effectiveness in unresectable *BRAF* V600 mutation positive melanoma as evidenced by prolongation of progression-free survival (PFS) and overall survival (OS). Updated long term results from MEK114267 study also consolidated the OS benefit of trametinib treatment over chemotherapy in this patient population.  
- The clinical activity of trametinib observed in melanoma subjects whose tumors harbor BRAF V600K mutations is comparable to the activity seen in *BRAF* V600E mutations
- Comprehensive efficacy data to support the recommended dose of trametinib of 2 mg once daily for all subjects
- The efficacy of trametinib in melanoma across all demographic (e.g., age, gender) and prognostic factors (e.g., tumor stage, Eastern Cooperative Oncology Group Performance Status [ECOG PS], lactate dehydrogenase (LDH) levels, history of brain metastases).
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1.2.5 safety

Based on the adverse events (AEs) observed in the dose escalation phase of the first-time-inhuman (FTIH) study MEK111054, the maximum tolerated dose was established at 3.0 mg once daily, and the RP2D of trametinib was identified as 2.0 mg once daily. In the 11 monotherapy studies of trametinib for which data are available (MEK111054, MEK111759, MEK113583, MEK113708, MEK113709, MEK114267, MEK114375, MEK115064, MEK114653, MEK114655, and MEK115892), all studies except MEK113708 had AEs.  
In the studies with AEs, 50% to 100% of all subjects in any dose group had at least 1 AE, and 0% to 70% of all subjects in any dose group had at least 1 serious adverse event (SAE). Of the studies with discontinuations or withdrawals, 3% to 26% of subjects receiving trametinib permanently discontinued study treatment or withdrew due to AEs.  
Of the > 700 subjects (including crossover subjects) in the 2.0 mg dose group, in 8 monotherapy studies with AEs (MEK111054, MEK111759, MEK113583, MEK113709, MEK114267, MEK115064, MEK114655, and MEK114653), 50% to 100% of subjects had at least 1 AE, and 0% to 70% of all subjects had SAEs. Of the studies with discontinuations or withdrawals (MEK111054, MEK113583, MEK114267, MEK114653, and MEK111759), 3% to 24% in the 2.0 mg does group permanently discontinued study treatment or withdrew from the study due to AEs. Data from studies with the combination of trametinib and dabrafenib
(GSK2118436) are included in another IB [GlaxoSmithKline Document Number 2011N126811_02]. In the 2.0 mg dose group across all completed monotherapy studies with AEs, the most common AEs had were rash, diarrhea, fatigue, edema peripheral, nausea, dermatitis acneiform, vomiting, constipation, anemia, pruritus, alopecia, hypertension, decreased appetite, dyspnea and dry skin.
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1.3 rationale for the proposed

Recent genomic studies, including the Cancer Genome Atlas (TCGA), have identified >140 different recurrent somatic mutations in *neurofibromin-1* (NF1) in human NSCLC17,18. These NF1-mutants are present in ~10% of NSCLC patients and often occur in the absence of another known genetic driver event, suggesting a potential driver role for mutant NF117,18; thus, NF1mutant NSCLC comprises an emerging distinct genetic subtype of NSCLC and the largest population of NF1-mutant patients across all tumor types. NF1 is a tumor suppressor that is genetically inactivated in several tumor types including melanoma, glioblastoma, certain leukemias, and the hereditary syndrome neurofibromatosis12,19-23. NF1 is a GTPase activating protein (GAP) for RAS GTPases, which require GTP binding to signal to downstream effector pathways such as the RAF-MEK-ERK cascade20. NF1 enhances the intrinsic rate of GTP
hydrolysis of RAS, thereby switching RAS off. Loss of NF1 activity enhances RAS-GTP levels to promote RAF-MEK-ERK signaling, cellular proliferation and growth, and oncogenesis12,20,23.  
There are currently no FDA-approved targeted therapy options for patients with advanced nonsquamous NSCLC whose tumors harbor NF1 mutations and have failed treatment with first-line  
  
platinum-containing cytotoxic chemotherapy or appropriate EGFR, ALK, or ROS-1 targeted therapies. After progression on first-line platinum doublet chemotherapy or second-line immunotherapy, single-agent cytotoxic chemotherapy in the second or third-line setting has limited efficacy28. . This highlights the ongoing unmet need for patients with advanced NSCLC
with NF1 mutations.  
Figure 1.4. Relative sensitivity of NF1-mutant patient-derived lung adenocarcinoma cell line to the MEK inhibitor trametinib. (A) Detection of cell-free DNA by Guardant 360 assay in a patient with known, metastatic NF1-mutant lung **adenocarcinoma** (A)Western blot showing a decrease in ERK phosphorylation upon trametinib treatment of cell lines derived from the patient's tumor. (B) Cell viability assay showing a ~ 50 % reduction in cell viability upon trametinib treatment of NF1 mutant lung adenocarcinoma cells.  
NF1 is a tumor suppressor gene, which encodes a RAS GTPase activating protein (GAP),
which facilitates the hydrolysis of RAS-GTP to the inactive RAS-GDP.7-9 Germline NF1 inactivating mutations are associated with both pediatric and adult malignancies.10 Somatic mutations in *NF1* have been associated with adenocarcinoma of lung,11 malignant melanoma,12 glioblastoma,13 as well as myelodysplastic syndrome.10 NF1 loss in melanoma cell lines that were wild-type for BRAF/RAS resulted in elevated RAS-GTP levels and MAPK signaling activation. Treatment of these cells with the MEK inhibitor trametinib resulted in sustained ERK
inhibition and suppression of tumor cell proliferation.12 Likewise, leukemias have been shown to arise from either germline or somatic loss of NF114 and treatment of autochthonous myeloid malignancies driven by engineered NF1 loss in the mouse have been shown to be sensitive to MEK inhibition in preclinical models.15 We have generating a non-small cell lung cancer cell line from a patient whose only know somatic mutations were in *TP53* E349* and NF1 S1759C. Notably, the frequency of these mutations detectable by cell-free DNA from the patients' blood have increased as the lung cancer progressed radiographically (Figure 1.4A). MEK activity, as determined by ERK phosphorylation is rapidly decreased upon treatment of these cells with trametinib (Figure 1.4B). Meanwhile, cell viability decreases by ~50 % upon trametinib treatment (Figure 1.4C).  
With demonstrated activity against and NF1 mutant melanoma12 and myeloid malignancy31 and lung adenocarcinoma preclinical models (Figure 1.4), we hypothesize that trametinib will provide an effective and tolerable therapy for patients with NF1-mutant NSCLC. The goals of the current study are to determine the anti-tumor efficacy and safety of oral single-agent trametinib in patients with NF1 mutated advanced non-squamous NSCLC after failure of at least one prior line of chemotherapy including a platinum doublet, and appropriate treatment with an EGFR, ALK, or ROS-1 inhibitor in patients whose tumors harbor activating alterations in those genes.
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1.4 correlative studies 1.4.1 whole

We will use whole exome and transcriptome deep sequencing (WES; RNAseq) in the pretreatment, on treatment, and post-resistance samples to uncover somatic genetic alterations
(mutations and copy number alterations) and transcriptional events associated with clinical resistance (either de novo or acquired), using our methods and with a minimum depth of WES coverage of 100X to capture events occurring down to ~1% frequency. This approach will enable identification and/or validation of RNA signatures of potential resistance events, such as ERK1/2 transcriptional output. The analysis of samples from patients with de novo resistance and of matched paired tumor samples acquired from individual patients before treatment and at acquired resistance (based on standard radiographic assessment in the trial, such as RECIST criteria) will be prioritized for study to facilitate the clinical correlation of the genetic findings with bona fide clinical resistance. Orthogonal validation of specific findings will be done using individualized assays in the clinical specimens (e.g. direct sequencing, SNP arrays, fluorescence in situ hybridization for DNA alterations; q-RT-PCR, IHC for RNA and protein abundance changes) and associated circulating free DNA, where feasible.
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1.4.2 ihc for phospho-erk and

We will evaluate whether trametinib effectively shuts down the MEK signaling axis by performing IHC analysis on pre-treatment and on-treatment biopsy specimens. YAP-TAZ
signaling will also be evaluated, given that its upregulation is associated with resistance to MAPK pathway inhibitors32.
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1.4.3 patient-derived xenografts and organoids

When possible, patient derived xenografts or organoids will be generated from patient biopsy specimens. Alterations discovered in the clinical specimen analysis will be functionally studied using our standard cell-based assays. We will test if activation or suppression of the candidate resistance gene (as indicated by whether the gene is increased or decreased in resistance) promotes MEK inhibitor resistance, in vitro and in vivo in tumor xenograft and organoid studies.  
Version date: 02-15-2018 Protocol CC\#: 166521
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1.4.2 cell-free dna

Blood samples for circulating tumor DNA (ctDNA) will be collected pre-treatment and postresistance tissue biopsy to identify mechanisms of resistance. Concordance of ctDNA with preand post- tissue biopsy will be assessed. 20ml of whole blood for ctDNA analysis will be collected at the time of pre-treatment biopsy, monthly until tumor progression, and at the time of post-resistance biopsy to monitor dynamic changes in the quantity of ctDNA for the specific NF1 mutations. The rate of ctDNA clearance of the specific NF1 mutations will be serially tracked and will be compared to radiologic change on CT scans. Acquired somatic mutations in, NF1 or off-target genes qualitatively evaluated to identify second site mutations that may confer resistance to therapy.
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2 objectives of the study

To evaluate the efficacy of trametinib in patients with advanced, non-squamous NSCLC who have progressed on at least one prior systemic anti-cancer therapy (i.e. platinum doublet chemotherapy, anti-PD1 or anti-PDL1 immunotherapy, or appropriate EGFR, ALK, and ROS-1 targeted therapy) and whose tumors harbor a non- synonymous mutation in NF1 and is negative for activating mutations in *KRAS.*
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2.2 secondary

- To evaluate secondary measures of clinical efficacy in advanced NSCLC patients treated with trametinib.  
- To evaluate the safety and tolerability of trametinib using National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.03.
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2.3 exploratory objectives other assessments

- Determine whether specific mutations in NF1 identified in pretreatment tumor samples correlate with response and/or resistance to trametinib.  
- To identify biomarkers of clinical benefit and mechanisms of resistance (de novo resistance, incomplete response, and acquired resistance) to trametinib therapy in NF1 mutant NSCLC.  
- Assess circulating tumor DNA (ctDNA) for biomarkers of response and/or resistance to trametinib.
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2.4 endpoints 2.4.1 primary endpoints

- Objective Response Rate (ORR) according to RECIST Version 1.1 criteria as determined by investigator assessment. The ORR is defined as the best overall response recorded from the start of the treatment until disease progression or recurrence from the start of treatment.
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2.4.2 secondary endpoints

- Efficacy: DR, DCR, PFS, and OS according to RECIST Version 1.1 criteria as determined by investigator assessment. - The DR for CR and PR will be measured from the date that the best response if first recorded until the date that PD is documented. For patients who continue treatment post progression, the date of PD documentation will be used for analysis.  
- DCR will be defined as the percentage of patients who have achieved CR, PR, or SD
for at least 12 weeks.  
- PFS will be calculated as 1+ the number of days from the first dose of study drugs to documented radiographic progression or death due to any cause over a period of 1 year. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis.  
- OS will be calculated as 1+ the number of days from the first dose of study drugs to death due to any cause over a period of 1 year.  
- Safety and tolerability:
- All treatment-emergent AEs - Treatment-emergent AEs by CTCAE grade
- Grade 3 or greater treatment-emergent AEs
- Treatment-related, treatment-emergent AEs - Dose-limiting toxicity AEs
- Serious treatment-emergent AEs
- Treatment-emergent AEs with an outcome of death - Treatment-emergent AEs leading to discontinuation of trametinib.  
- Treatment-emergent AEs resulting in interruption or reduction or delay of trametinib.
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2.4.3 exploratory endpoints

- Specific mutations in NF1 identified in pretreatment tumor samples correlated with response and/or resistance to trametinib.  
- Circulating cell free DNA (cfDNA) biomarkers associated with response and/or resistance to trametinib.  
- RNA and DNA changes in samples during therapy and at progression.
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3 study design 3.1 characteristics

This is a Phase II, open-label, multicenter clinical trial evaluating the efficacy and safety of
*II –*  Page 17 of 86 trametinib monotherapy in patients with advanced non-squamous NSCLC whose tumors harbor Version date: 02-15-2018 Protocol CC\#: 166521 a non-synonymous NF1 mutation and are wildtype for activating mutations in KRAS. Eligible patients must have documented disease progression either during or after treatment with appropriate EGFR, ALK, or ROS-1 inhibitors (in patients with EGFR activating mutations, or ALK or ROS-1 fusions) and platinum doublet chemotherapy (or inability to tolerate) or most recent therapy and must not have received prior treatment with a MEK inhibitor.  
  
Patients will receive trametinib monotherapy in 28-day cycles. The primary outcome is objective response rate.
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3.2 number of subjects

A total of 27 patients will be enrolled in the study, with the goal of obtaining 24 evaluable patients. This will provide 80% power to detect a 30% ORR with trametinib compared to the null hypothesis of a 10% ORR. Using a Simon 2-stage design, if we do not observe at least 2 responses within the first 15 patients, enrollment will be stopped due to lack of efficacy.
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3.3 eligibility criteria

Patients must have baseline evaluations performed prior to the first dose of study drug and must meet all inclusion and exclusion criteria.  In addition, the patient must be thoroughly informed about all aspects of the study, including the study visit schedule and required evaluations and all regulatory requirements for informed consent.  The written informed consent must be obtained Phase II - Trametinib Page 19 of 86  
from the patient prior to enrollment. The following criteria apply to all patients enrolled onto the study unless otherwise specified.
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3.3.1 inclusion criteria

1. Histologically or cytologically confirmed metastatic or unresectable locally advanced, non-squamous, NSCLC.  
2. Documented non-synonymous somatic mutation in NF1 in any tumor specimen or cellfree DNA assay by CLIA-approved laboratory.  
3. Received at least one prior line of cancer therapy for the treatment of NSCLC. This should include at least one of the following: platinum (carboplatin or cisplatin) doublet chemotherapy (acceptable combinations include: paclitaxel, docetaxel, abraxane, pemetrexed, gemcitabine, vinorelbine, or etoposide), anti-PD1/PDL1 therapy (pembrolizumab, nivolumab, or atezolizumab), or appropriate targeted therapy in patients with activating EGFR (osimertinib, erlotinib, gefitinib, or afatinib), ALK (alectinib, crizotinib, ceritinib, brigatinib, or loralatinib), or ROS-1 (crizotininb or entrectinib)
alterations. Therapy may be given as monotherapy or in combination with other cancer therapy (e.g. bevacizumab, ipilumimab)
4. Patients with a known activating mutation in EGFR (Exon 19 deletion, G719A, S768I,
V769L, T790M, L833F, L858R, L861Q), must have progressed or been intolerant to treatment with a first-line EGFR TKI (erlotinib, afatinib, gefitinib or osimertinib). Patients whose tumors were found to have an EGFR T790M mutation must also have progressed or been intolerable to treatment with osimertinib.  
5. Patients with a known ALK-rearrangement must have progressed or been intolerant to treatment with at least one ALK TKI: crizotinib, ceritinib, alectinib, brigatinib, or loralatinib.  
6. Patients with a known ROS-1- rearrangement must have progressed or been intolerant to treatment with crizotinib or entrectinib.  
7. Patients with PDL1 level of ≥ 50%, who do not have an ALK-rearrangement or EGFR-mutation, must have progressed or been intolerant to treatment with antiPD1/PDL1 therapy (pembrolizumab, nivolumab, or atezolizumab).  
8. Documented disease progression or intolerance to treatment either during or after treatment with most recent therapy.  
9. Willingness to undergo research biopsy. 10. Measurable disease defined by RECIST 1.1 criteria. 11. Life expectancy of at least 3 months. 12. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.  
13. Age ≥ 18 years.  
14. Resolution of all acute toxic effects of prior chemotherapy, immunotherapy, radiotherapy or surgical procedures to NCI CTCAE Version 4.03 grade 1.  
15. Adequate baseline organ function defined in Table 3.1.  
| Table 3.1                                                                                                                                                                                                          | Definitions for adequate baseline organ function   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------|
| System                                                                                                                                                                                                             | Laboratory Values                                  |
| Hematologic Absolute neutrophil count                                                                                                                                                                              | 1.2 × 109 /L                                       |
| Hemoglobin                                                                                                                                                                                                         | 9 g/dL                                             |
| Platelets                                                                                                                                                                                                          | 100 × 109 /L                                       |
| PT/INR and PTT                                                                                                                                                                                                     | ≤ 1.5 x ULN                                        |
| Hepatic Albumin                                                                                                                                                                                                    | 2.5 g/dL                                           |
| Total bilirubin                                                                                                                                                                                                    | 1.5xULN                                            |
| AST and ALT                                                                                                                                                                                                        | 2.5× ULN                                           |
| Renal Creatinine or                                                                                                                                                                                                | 1.5 ULN                                            |
| Calculated creatinine                                                                                                                                                                                              | 50 mL/min                                          |
| clearancea                                                                                                                                                                                                         |                                                    |
| Cardiac                                                                                                                                                                                                            | ≥ LLN by ECHO or MUGAb                             |
| Left Ventricular Ejection fraction (LVEF)                                                                                                                                                                          |                                                    |
| ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio; PT = prothrombin time; PTT= partial thromboplastin time; ULN = upper limit of normal; LLN = lower limit of |                                                    |  
ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio; PT = prothrombin time; PTT= partial thromboplastin time; ULN = upper limit of normal; LLN = lower limit of normal a. Calculated by the Cockcroft-Gault formula. b. Same method as used at baseline must be use throughout the study
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table 3.1 definitions for adequate

16. Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to study enrollment. The effects of trametinib on the developing human fetus are unknown. For this reason and because animal studies with trametinib have shown reproductive toxicity, women of child-bearing potential and men must agree to use effective methods of contraception (hormonal or barrier method of birth control) prior to study entry, for the duration of study participation, and for 4 months following discontinuation of trametinib. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study drug administration.  
17. Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.  
18. All prior treatment- related toxicities must be CTCAE (Version 4.03) ≤ Grade 1 (except alopecia) at the time of randomization
19. Ability to understand a written informed consent document, and the willingness to sign it.
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3.3.2 exclusion criteria

Patients eligible must not meet any of the following criteria:
1. Known mutation in KRAS at position G12, G13, or Q61.  
2. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. Treated brain metastases are allowed as long as they are stable for at least 28 days post-treatment.  
3. Pregnant women are excluded from this study because trametinib is a MEK inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with trametinib, breastfeeding should be discontinued if the mother is treated with trametinib.  
4. History of another malignancy.
Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer and/or subjects with indolent second malignancies are eligible.  
5. Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.  
6. The subject has received cytotoxic chemotherapy, molecular targeted therapy, or immunotherapy within 21 days before the first dose of study drug (trametinib).  
7. Prior treatment with MEK inhibitor.  
8. History of interstitial lung disease or pneumonitis.  
9. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).  
10. Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to study enrollment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to study enrollment.  
11. History of retinal vein occlusion (RVO). 12. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C
Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV infection will be permitted).  
13. History or evidence of cardiovascular risk including any of the following:
- LVEF< LLN  
- A QT interval corrected for heart rate using the Bazett's formula (QTcB) 480 msec;
- History or evidence of current clinically significant uncontrolled arrhythmias.  
- **Clarification:** Subjects with atrial fibrillation controlled (defined as not requiring change in cardiac drug dosing, emergency room visit, or hospital admission) for
>30 days prior to dosing are eligible.  
- History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to study enrollment.  
- History or evidence of current ≥ Class II congestive heart failure as defined by New York Heart Association (NYHA).  
- Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by antihypertensive therapy;
- Patients with intra-cardiac defibrillators.
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3.4 duration of therapy

In the absence of treatment delays due to adverse events, treatment may continue for 24 months or until:  
- Disease progression
- Inter-current illness that prevents further administration of treatment
- Unacceptable adverse event(s) - Patient decides to withdraw from the study
- Significant patient non-compliance with protocol
- General or specific changes in the patients' condition render the patient unacceptable for further treatment in the judgment of the investigator.  
- The study is closed by the sponsor or investigator.
Patients who are continuing to respond to the study drug after 24 months of therapy will be provided with continued access to the drug by Novartis.
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3.5 duration of follow up

Patients will be followed for 30 days after completion of treatment or removal from study, or until death, whichever occurs first. Patients removed from study for unacceptable treatment related adverse event(s) will be followed until resolution or stabilization of all treatment related adverse events to Grade 2 or lower.
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3.6 study timeline 3.6.1 primary

It is expected that the study will reach primary completion 36 months from the time the study opens to accrual.
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3.6.2 study completion

It is expected that the study will reach full completion 48 months from the time the study opens to accrual.
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4 study drugs 4.1 description

Trametinib tablets are provided as immediate release tablets for oral administration containing trametinib dimethyl sulfoxide (GSK1120212B) equivalent to 0.5 mg or 2 mg of trametinib. All formulation excipients are compendial and are commonly used in oral formulations. Refer to the trametinib Investigator's Brochure for a list of excipients.  
The trametinib tablets are packaged in high-density polyethylene bottles with labels bearing the appropriate label text as required by governing regulatory agencies. All study drug will be dispensed in child-resistant packaging.  
Refer to the Pharmacy Manual/site investigational product manual for additional guidance on study drug storage, preparation and handling. Study drug labels will contain information to meet the applicable regulatory requirements.
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mechanism of action

Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 256 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are 257 upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes 258 cellular proliferation.
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metabolism

Trametinib is metabolized predominantly via deacetylation alone or with mono282 oxygenation or in combination with glucuronidation biotransformation pathways in vitro. 283 Deacetylation is likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases. 284 Following a single dose of [14C]-trametinib, approximately 50% of circulating radioactivity is 285 represented as the parent compound. However, based on metabolite profiling after repeat dosing 286 of trametinib, > 75% of drug-related material in plasma is the parent compound.
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storage and handling

Trametinib tablets should be stored refrigerated at 2° to 8°C (36° to 46°F). Do not freeze.  
Dispense in original bottle. Do not remove desiccant. Protect from moisture and light. Do not place medication in pill boxes.
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side effects

The following undesirable effects have been observed in subjects with metastatic melanoma receiving trametinib 2 mg once daily in the integrated safety population as of 25 June 2012 cutoff date (n=329). Of these 329 subjects, 211 were from MEK114267 (Phase III randomized open label study), 97 were from MEK113583 (Phase II study), and 21 were from MEK111054
(FTIH study). The most common adverse reactions (> 20%) for trametinib include rash, diarrhea, fatigue, edema peripheral, nausea, and dermatitis acneiform. In clinical trials with trametinib, adverse reactions of diarrhea and rash were managed with appropriate supportive care.  
Adverse reactions are listed below by MedDRA body system organ class. The following convention has been utilized for the classification of frequency:
Very common >1 in 10 (> 10%) Common > 1 in 100 and < 1 in 10 (> 1% and <10%)
Uncommon > 1 in 1,000 and < 1 in 100 (> 0.1% and <1%)
Rare > 1/10,000 and <1/1,000 (> 0.01% and <0.1%)
Categories have been assigned based on frequencies of AEs (considered related to trametinib) observed in the integrated safety summary (ISS) data (n=329).  
Infections and **Infestations** Very Common: Urinary tract infection  
Nasopharyngitis  
Common: Folliculitis  
Paronychia  
Cellulitis Rash pustular  
Neoplasms benign, malignant and unspecified (incl cysts and **polyps)**
Common: Cutaneous squamous cell carcinoma (SCC) including SCC of the skin, SCC in situ (Bowen's disease), and keratoacanthoma Papilloma including skin papilloma Seborrhoeic keratosis Acrochordon (skin tags)
Uncommon: New primary melanoma  
Blood and lymphatic system **disorders**  
Very Common: Neutropenia  
Common: Anemia  
Thrombocytopenia Leukopenia  
Immune system **disorders**
Uncommon: Hypersensitivity May present with symptoms such as fever, rash, increased liver function tests, and visual disturbances  
| Metabolism and Nutrition Disorders Very Common: Decreased appetite Common: Dehydration Hyponatraemia Hypophosphataemia Hyperglycemia Nervous system disorders Very Common: Headache Dizziness Eye disorders Common: Vision blurred Periorbital edema Visual impairment Uncommon: Chorioretinopathy (also known as Retinal Pigment Epithelial Detachment (RPED)) Uveitis Retinal vein occlusion Papilledema Retinal detachment Peiorbital oedema Cardiac disorders Common: Left ventricular dysfunction Ejection fraction decreased Uncommon: Cardiac failure Vascular disorders Very common: Hypertension Hemorrhage. The majority of bleeding events were mild. Major events, defined as symptomatic bleeding in a critical area or organ, and fatal intracranial hemorrhages have been reported. Common: Lymphedema Hypotension Respiratory, thoracic and mediastinal disorders Very common: Cough Dyspnea Common: Epistaxis Pneumonitis Uncommon: Interstitial lung disease Gastrointestinal disorders Very common: Diarrhea Nausea Vomiting Constipation Abdominal pain   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Dry mouth                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |              |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|
| Common:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Stomatitis   |
| Uncommon:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Pancreatitis |
| Hepatobiliary disorders Very Common: Aspartate aminotransferase increased Alanine aminotransferase increased Common: Blood alkaline phosphatase increased Gamma-glutamyltransferase increased Skin and subcutaneous tissue disorders Very common: Rash Dermatitis acneiform Dry skin Pruritus Alopecia Common: Skin chapped Erythema Palmar-plantar erythrodysaesthesia syndrome Skin fissures Actinic keratosis Night sweats Hyperkeratosis Hyperhidrosis Skin lesion Panniculitis Musculoskeletal and connective tissue disorder Very Common: Arthralgia Myalgia Pain in extremity Common: Blood creatine phosphokinase increased Muscle spasms Renal Disorders Uncommon: Renal Failure Nephritis General disorders Very Common: Fatigue Edema peripheral Pyrexia Chills Asthenia Common: Face edema Mucosal inflammation Influenza-like illness |              |  
Complete and updated adverse event information is available in the Investigational Drug Brochure and product package insert.
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4.3 drug ordering

UCSF will obtain trametinib directly from pharmaceutical company as study supply.
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4.4 packaging and labeling of

Drugs will be packaged and labeled per UCSF institutional standards, adhering to applicable local and federal laws.
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5 treatment plan 5.1 dosage

| StudyDrug Trametinib   |
|------------------------|  
Treatment will be administered on an outpatient basis.
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table 5.1 regimen description

If a dose of trametinib is missed, the dose can be taken if it is more than 12 hours until the next scheduled dose.  
| Premedication;                                                                                 | Cycle            |       |           |                   |
|------------------------------------------------------------------------------------------------|------------------|-------|-----------|-------------------|
| precautions                                                                                    | Dose             | Route | Schedule  | Length            |
| Take with a full glass of water, without food, at least 1 hour before or 2 hours after a meal. | 2 mg, once daily | Oral  | Days 1-28 | 4 weeks (28 days) |  
The patient will be requested to maintain a medication diary of each dose of medication. The medication diary will be returned to clinic staff at the end of each 28 day cycle.
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5.2 dose modifications and dosing

The management of adverse reactions may require treatment interruption, dose reduction, or treatment discontinuation.  
Table 5.2 Dose Modifications and **Dosing Delays**  
| Dose Level                                                       | Dose of Study Drug   |
|------------------------------------------------------------------|----------------------|
| -2                                                               | 1 mg daily           |
| -1                                                               | 1.5 mg daily         |
| 1                                                                | 2 mg daily           |
| Dose adjustment for trametinib below 1 mg QD is not recommended. |                      |  
A maximum of two trametinib dose level reductions are allowed. If a third dose level reduction is required, treatment will be permanently discontinued.  
If a dose reduction of trametinib is required, but the toxicity resolves and no additional toxicities are seen after two cycles of treatment, the dose of trametinib may be re-escalated but should not exceed 2 mg once daily.  
The following dose modification rules will be used with respect to potential toxicity. Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE v4.03. Table 5.3 Dose Delay and Modification for Events Considered Related to Trametinib  
| CTCAE Grade   | Action and Dose Modification - Continue trametinib at current dose level                                                                                                                                       |                                                              |
|---------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|
| Grade 1       | -                                                                                                                                                                                                              | Monitor closely                                              |
| -             | Provide supportive care according to institutional standards                                                                                                                                                   |                                                              |
| -             | Interrupt trametinib if clinically indicated                                                                                                                                                                   |                                                              |
| -             | Monitor closely                                                                                                                                                                                                |                                                              |
| Grade 2       | -                                                                                                                                                                                                              | Provide supportive care according to institutional standards |
| -             | When toxicity resolves to Grade 1 or baseline, restart trametinib at current dose level                                                                                                                        |                                                              |
| -             | Interrupt trametinib if clinically indicated                                                                                                                                                                   |                                                              |
| -             | Monitor closely                                                                                                                                                                                                |                                                              |
| -             | Provide supportive care according to institutional standards                                                                                                                                                   |                                                              |
| -             | When toxicity resolves to Grade 1 or baseline, restart trametinib reduced by one dose level                                                                                                                    |                                                              |
| -             | If the Grade 3 toxicity recurs, interrupt trametinib                                                                                                                                                           |                                                              |
| -             | When toxicity resolves to Grade 1 or baseline, restart trametinib reduced by another dose level                                                                                                                |                                                              |
| Grade 3       | -                                                                                                                                                                                                              | Interrupt trametinib                                         |
| -             | Monitor closely                                                                                                                                                                                                |                                                              |
| -             | Provide supportive care according to institutional standards                                                                                                                                                   |                                                              |
| -             | If event resolves to Grade 1 or baseline discuss potential continuation of trametinib with investigator-sponsor; if continuation of treatment agreed then restart trametinib at dose reduced by one dose level |                                                              |
| -             | If event does not resolve permanently discontinue trametinib                                                                                                                                                   |                                                              |
| Grade 4       |                                                                                                                                                                                                                |                                                              |  
Note: Approval from the investigator-sponsor is required to restart study treatment after ≥ 28 days of interruption.  
Trametinib dose modification guidelines are outlined in Table 5.2 and Table 5.3 for clinically significant toxicities that are deemed related to trametinib (i.e. peripheral and periorbital edema)
with the exception of the following events of special **interest:**  
- rash (Section 5.2.1)
- diarrhea (Section 5.2.2), - ejection fraction changes (Section 5.2.3),
- hypertension (Section 5.2.4)
- prolonged QTc (Section 5.2.5)
- pneumonitis (Section 5.2.6),
- visual changes (Section 5.2.7), - liver chemistry elevation (Section 5.2.8)
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for these refer to the

Treatment or visit delays for public holidays or weather conditions do not constitute a protocol violation.
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5.2.1 guidelines for rash

Rash is a frequent AE observed in subjects receiving trametinib (see the Investigator Brochures for more information). Recommendations for supportive care and guidelines for dose modifications for rash are based on experience with other MEK inhibitors33 and EGFR
inhibitors34 and are provided in Table 5.4 and Table 5.5.  
The institutional standards for the management of skin-related AEs can differ from these guidelines. In this case, best clinical judgment should be applied and a consultation with the investigator-sponsor may be required.
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table 5.4 guidelines for supportive

| Type of Care                                                                                                                              | Action - Avoid unnecessary exposure to sunlight                                                                                                                                                                                                                                                                                                  |                                                                                                                                          |
|-------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------|
| Prevention/Prophylaxisa                                                                                                                   | -                                                                                                                                                                                                                                                                                                                                                | Apply broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) with a skin protection factor (SPF) ≥15 at least twice daily. |
| -                                                                                                                                         | Use thick, alcohol-free emollient cream (e.g., glycerine and cetomacrogol cream) on dry areas of the body at least twice daily.                                                                                                                                                                                                                  |                                                                                                                                          |
| -                                                                                                                                         | Topical steroids and antibiotics should be applied at least twice daily starting on Day 1 of study treatment, to body areas such as face, chest, and upper back. Use mild-strength topical steroid (hydrocortisone 1% cream) or topical antibiotic (e.g., clindamycin) or oral antibiotics (e.g.,doxycycline 100 mg BID, minocycline 100 mg BID) |                                                                                                                                          |
| -                                                                                                                                         | Pruritic lesions: cool compresses and oral antihistamine                                                                                                                                                                                                                                                                                         |                                                                                                                                          |
| Symptomatic Careb                                                                                                                         | therapies                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                          |
| -                                                                                                                                         | Fissuring lesions: Monsel's solution, silver nitrate, or zinc oxide cream                                                                                                                                                                                                                                                                        |                                                                                                                                          |
| -                                                                                                                                         | Desquamation: thick emollients and mild soap                                                                                                                                                                                                                                                                                                     |                                                                                                                                          |
| -                                                                                                                                         | Paronychia: antiseptic bath, local potent corticosteroids in addition to oral antibiotics; if no improvement, consult dermatologist or surgeon                                                                                                                                                                                                   |                                                                                                                                          |
| -                                                                                                                                         | Infected lesions: appropriate bacterial/fungal culture-driven systemic or topical antibiotics                                                                                                                                                                                                                                                    |                                                                                                                                          |
| Abbreviations: BID = twice daily; SPF = sun protection factor a. Rash prophylaxis is recommended for the first 6 weeks of study treatment |                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                          |  
Abbreviations: BID = twice daily; SPF = sun protection factor  
a. Rash prophylaxis is recommended for the first 6 weeks of study treatment  
b. Subjects who develop rash/skin toxicities should be seen by a qualified physician and should  
receive evaluation for symptomatic/supportive care management  
Guidelines for management and dose reduction for rash considered to be related to study treatment are provided in Table 5.5.  
| CTCAE Grade                                                                                                                                       | Adverse Event Management                                                                                               | Action and Dose Modification   |                                                                                                                         |
|---------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------|--------------------------------|-------------------------------------------------------------------------------------------------------------------------|
| -                                                                                                                                                 | Initiate prophylactic and                                                                                              |                                |                                                                                                                         |
| Grade 1                                                                                                                                           | symptomatic treatment measuresa                                                                                        | -                              | Continue trametinib                                                                                                     |
| -                                                                                                                                                 | If rash does not recover to baseline within 2 weeks despite best supportive care, reduce trametinib by one dose levelc |                                |                                                                                                                         |
| -                                                                                                                                                 | Use moderate strength topical steroidb                                                                                 |                                |                                                                                                                         |
| -                                                                                                                                                 | Reassess after 2 weeks                                                                                                 |                                |                                                                                                                         |
| -                                                                                                                                                 | Initiate prophylactic and                                                                                              |                                |                                                                                                                         |
| Grade 2                                                                                                                                           | symptomatic treatment measures                                                                                         | -                              | Reduce trametinib by one dose level - If rash recovers to ≤grade 1 within 2 weeks, increase dose to previous dose level |
| -                                                                                                                                                 | Use moderate strength topical steroidb                                                                                 |                                |                                                                                                                         |
| -                                                                                                                                                 | Reassess after 2 weeks                                                                                                 | -                              | If no recovery to ≤grade 1 within 2 weeks, interrupt trametinib until recovery to ≤grade 1                              |
| -                                                                                                                                                 | Restart trametinib at reduced dose levelc                                                                              |                                |                                                                                                                         |
| -                                                                                                                                                 | Use moderate strength                                                                                                  |                                |                                                                                                                         |
| Grade ≥3                                                                                                                                          | topical steroidsb PLUS oral methyl-prednisolone dose pack                                                              | -                              | Interrupt trametinib until rash recovers to grade ≤1, after discussion with study PI.                                   |
| -                                                                                                                                                 | Restartc with trametinib reduced by one dose leveld                                                                    |                                |                                                                                                                         |
| -                                                                                                                                                 | Consult dermatologist                                                                                                  | -                              | If no recovery to grade ≤2 within 4 weeks, permanently discontinue trametinib                                           |
| Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events a. Rash prophylaxis is recommended for the first 6 weeks of study treatment |                                                                                                                        |                                |                                                                                                                         |  
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events a. Rash prophylaxis is recommended for the first 6 weeks of study treatment b. Moderate-strength topical steroids: hydrocortisone 2.5% cream orfluticasone prioprionate 0.5% cream c. Approval of the investigator-sponsor is required to restart study treatment after >4 weeks of interruption.  
d. Escalation of study treatment to previous dose level may be considered if no rash is evident 4 weeks after restarting study treatment
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5.2.2 guidelines for diarrhea

Episodes of diarrhea have occurred in subjects receiving trametinib (see the Investigator Brochures for more information). Other, frequent causes for diarrhea including concomitant medications (e.g., stool softeners, laxatives, antacids, etc.), infections by C. *difficile* or other pathogens, partial bowel obstruction, etc., should be clinically excluded.  
Guidelines regarding management and dose reduction for diarrhea considered to be related to trametinib by the investigator are provided in Table 5.6.  
| Table 5.6                                                                                                                                                                                                                                       | Management and Dose Modification Guidelines for Diarrhea                                                                                                                 |                                                                                                                                                             |                                                          |                                                                                                      |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------|------------------------------------------------------------------------------------------------------|
| CTCAE Grade                                                                                                                                                                                                                                     | Adverse Event Management                                                                                                                                                 | Action and Dose Modification                                                                                                                                |                                                          |                                                                                                      |
| -                                                                                                                                                                                                                                               | Diet: stop all lactose containing products; eat small meals, BRAT-diet (banana, rice, apples, toast) recommended                                                         | -                                                                                                                                                           | Continue trametinib                                      |                                                                                                      |
| Uncomplicated Diarrheaa                                                                                                                                                                                                                         | -                                                                                                                                                                        | If diarrhea is grade 2 for > 48h, interrupt trametinib until diarrhea resolves to grade ≤1                                                                  |                                                          |                                                                                                      |
| Grade 1 or 2                                                                                                                                                                                                                                    | -                                                                                                                                                                        | Hydration: 8-10 large glasses of clear liquids per day (e.g., Gatorade or broth)                                                                            | -                                                        | Restart trametinib at the same dose level                                                            |
| -                                                                                                                                                                                                                                               | Loperamidec : initially 4 mg, followed by 2 mg every four hours or after every unformed stool; maximum 16 mg/day. Continue until diarrhea free for 12 hours              |                                                                                                                                                             |                                                          |                                                                                                      |
| -                                                                                                                                                                                                                                               | Diarrhea > 24h: loperamide 2 mg every two hours; maximum 16 mg/day. Consider adding oral antibiotics                                                                     |                                                                                                                                                             |                                                          |                                                                                                      |
| -                                                                                                                                                                                                                                               | Diarrhea > 48h: loperamide 2 mg every two hours; maximum 16 mg/day. Add budesonide or other second-line therapies (otreotide, or tincture of opium) and oral antibiotics |                                                                                                                                                             |                                                          |                                                                                                      |
| -                                                                                                                                                                                                                                               | Clinical evaluation mandatory                                                                                                                                            | -                                                                                                                                                           | Interrupt trametinib until diarrhea resolves to grade ≤1 |                                                                                                      |
| Uncomplicated Diarrheaa Grade 3 or 4                                                                                                                                                                                                            | -                                                                                                                                                                        | Loperamidec : initially 4 mg, followed by 2 mg every four hours or after every unformed stool; maximum 16 mg/day. Continue until diarrhea free for 12 hours | -                                                        | Restart with trametinib reduced by one dose leveld                                                   |
| Any Complicated Diarrheab                                                                                                                                                                                                                       | -                                                                                                                                                                        | Oral antibiotics and second-line therapies if clinically indicated                                                                                          | -                                                        | If 3 dose reductions of study treatment are clinically indicated, permanently discontinue trametinib |
| -                                                                                                                                                                                                                                               | Hydration: intravenous fluids if clinically indicated                                                                                                                    |                                                                                                                                                             |                                                          |                                                                                                      |
| -                                                                                                                                                                                                                                               | Antibiotics (oral or intravenous) if clinically indicated                                                                                                                |                                                                                                                                                             |                                                          |                                                                                                      |
| -                                                                                                                                                                                                                                               | Intervention should be continued until the subject is diarrhea free for ≥ 24 hours                                                                                       |                                                                                                                                                             |                                                          |                                                                                                      |
| -                                                                                                                                                                                                                                               | Intervention may require hospitalization for subjects at risk of life-threatening complications                                                                          |                                                                                                                                                             |                                                          |                                                                                                      |
| Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events a. Uncomplicated diarrhea defined by the absence of symptoms such as, cramping, nausea/vomiting ≥grade 2, decreased performance status, pyrexia, sepsis, neutropenia grade |                                                                                                                                                                          |                                                                                                                                                             |                                                          |                                                                                                      |  
b. Complicated **diarrhea** defined by the presence of symptoms such as, cramping, nausea/vomiting ≥grade 2, decreased performance status, pyrexia, sepsis, neutropenia grade
≥3, frank bleeding, and/or dehydration requiring intravenous fluid substitution c. Loperamide should be made available prior to start of study treatment so loperamide administration can begin at the first signs of diarrhea d. Escalation of trametinib to previous dose level is allowed after consultation with the medical monitor and in the absence of another episode of complicated or severe diarrhea in the 4 weeks subsequent to dose reduction.
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5.2.3 guidelines for ejection fraction

Left Ventricular Ejection Fraction (LVEF)
Decreases of the left-ventricular-ejection-fraction (LVEF) have been observed in subjects receiving trametinib. Therefore, ECHO/MUGAs must be performed to assess cardiac ejection fraction in regular intervals as outlined in the Time and Events Table (Table X). The same procedure (either ECHO or MUGA, although ECHO is preferred) should be performed at baseline and at follow-up visit(s). Electronic copies of all ECHO/MUGA scans will be collected by Novartis for review. Instructions for submission of ECHO/MUGA scans are provided in the Study Procedures Manual (SPM).  
| Table 5.7             | Dose Modification Guidelines and Stopping Criteria for LVEF Decrease                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
|-----------------------|----------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Clinic                | LVEF-drop (%) or                                                                                         | Action and Dose Modification                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| CTCAE grade           |                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| Asymptomatic          | Absolute decrease of >10% in LVEF compared to baseline and ejection fraction below the institution's LLN | Interrupt trametinib and repeat ECHO/MUGA within 2 weeksa If the LVEF recovers within 4 weeks (defined as LVEF ≥LLN and absolute decrease ≤10% compared to baseline) - Consult with the Novartis medical monitor and request approval for restart - Restart treatment with trametinib reduced dose by one dose levelb - Repeat ECHO/MUGA 2 , 4 , 8 and 12 weeks after re-start; continue in intervals of 12 weeks thereafter If LVEF does not recover within 4 weeks - Consult with cardiologist - Permanently discontinue trametinib - Report as SAE |
| Phase II - Trametinib | Page 35 of 86                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |  
Dose modification guidance and stopping criteria for LVEF decrease are provided in Table 5.7.  
| -                                                                                                                                                                     | Repeat ECHO/MUGA after 2, 4, 8, 12, and 16 weeks or until resolution   |                                                                            |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|----------------------------------------------------------------------------|
| -                                                                                                                                                                     | Consult with Novartis medical monitorc                                 |                                                                            |
| Symptomaticc                                                                                                                                                          | Grade 3: resting LVEF 39- 20% or >20% absolute reduction from baseline | Permanently discontinue trametinib Report as SAE Consult with cardiologist |
| Grade 4: resting LVEF                                                                                                                                                 | Repeat ECHO/MUGA after 2, 4, 8, 12, and                                |                                                                            |
| <20%                                                                                                                                                                  | 16 weeks or until resolution                                           |                                                                            |
| Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; LLN = lower limit of normal; LVEF = left ventricular ejection fraction; |                                                                        |                                                                            |  
Permanently discontinue trametinib Report as SAE  
Consult with cardiologist Repeat ECHO/MUGA after 2, 4, 8, 12, and  
16 weeks or until resolution  
Grade 4: resting LVEF <20%  
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; LLN = lower limit of normal; LVEF = left ventricular ejection fraction; a. If ECHO/MUGA does not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 weeks later.  
b. Escalation of trametinib to previous dose level can be considered if LVEF remains stable for 4 weeks  
after restarting of trametinib. Approval from Novartis Medical Monitor is required.  
c. Symptoms may include: dyspnea, orthopenea, and other signs and symptoms of pulmonary congestion  
and edema.
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5.2.4 guidelines for hypertension

Increases in blood pressure have been observed in subjects receiving trametinib. Recommendations for blood pressure monitoring and management are provided below.
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monitoring of hypertension

All blood pressure assessments should be performed under the following optimal conditions:  
- the subject has been seated with back support, ensuring that legs are uncrossed and flat on the floor
- the subject is relaxed comfortably for at least 5 minutes
- restrictive clothing has been removed from the cuff area and the right cuff size has been selected
- the subjects arm is supported so that the middle of the cuff is at heart level
- the subject remains quiet during the measurement.
In subjects with an initial blood pressure reading within the hypertensive range, a second reading should be taken at least 1 minute later, with the 2 readings averaged to obtain a final blood pressure measurement. The averaged value should be recorded in the eCRF. Persistent hypertension is defined as an increase of systolic blood pressure (SBP) > 140 mm Hg and/or diastolic blood pressure (DBP) > 90 mm Hg in three consecutive visits with blood pressure assessments from two readings collected as described above. Visits to monitor increased blood pressure can be scheduled independently from the per-protocol visits outlined in the Schedule of Study Procedures and Assessments (Table 6.1). Ideally, subsequent blood pressure assessments should be performed within one week.  
Asymptomatic hypertension is defined as an increase of SBP >140 mm Hg and/or DBP >90 mm Hg in the absence of headache, light-headedness, vertigo, tinnitus, episodes of fainting or other symptoms indicative of hypertension.
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management of hypertension

For subjects experiencing an increase in systolic and/or diastolic blood pressure that is persistent and may be associated with the study treatment, recommendations for the clinical management of hypertension are described in Table 5.8:
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table 5.8 management and dose

| Hypertension                                                                                                                                                                                                             | Action and Dose Modification                                                                                                                                                                                                                     |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (Scenario A)                                                                                                                                                                                                             | Continue trametinib at the current dose Adjust current or initiate new antihypertensive medication                                                                                                                                               |
| Asymptomatic and persistenta SBP of ≥140 and <160 mmHg, or DBP ≥90 and <100 mmHg,                                                                                                                                        | Titrate antihypertensive medication(s) during the next 2 weeks as indicated to achieve well-controlledb BP                                                                                                                                       |
| or Clinically significant increase in DBP of 20 mmHg (but DBP still <100 mmHg).                                                                                                                                          | If BP is not well controlled within 2 weeks, consider referral to a specialist and go to scenario (B).                                                                                                                                           |
| (Scenario B)                                                                                                                                                                                                             | Interrupt trametinib if clinically indicated Adjust current or initiate new antihypertensive medication(s)                                                                                                                                       |
| Asymptomatic SBP ≥160 mmHg, or DBP ≥100 mmHg, or                                                                                                                                                                         | Titrate antihypertensive medication(s) during the next 2 weeks to achieve well-controlled BP                                                                                                                                                     |
| Failure to achieve well-controlled BP within 2 weeks in Scenario A                                                                                                                                                       | Once BP is well controlledb , restart trametinib reduced by one dose levelc                                                                                                                                                                      |
| (Scenario C)                                                                                                                                                                                                             | Interrupt trametinib Adjust current or initiate new antihypertensive medication(s)                                                                                                                                                               |
| Symptomaticd hypertension or Persistent SBP ≥160 mmHg, or DBP ≥100 mmHg, despite antihypertensive medication and dose reduction of trametinib                                                                            | Titrate antihypertensive medication during the next 2 weeks to achieve well-controlled BP Referral to a specialist for further evaluation and follow-up is recommended Once BP is well controlled, restart trametinib reduced by one dose levelc |
| (Scenario D)                                                                                                                                                                                                             | Permanently discontinue trametinib Continue follow-up per protocol.                                                                                                                                                                              |
| Refractory hypertension unresponsive to above interventions or having hypertensive crisis. Abbreviations: BP = blood pressure; DBP = diastolic blood pressure; mmHg = millimetresmercury; SBP = systolic blood pressure; |                                                                                                                                                                                                                                                  |  
Abbreviations: BP = blood pressure; DBP = diastolic blood pressure; mmHg = millimetresmercury; SBP = systolic blood pressure; a. Hypertension detected in two separate readings during up to three consecutive visits b. Well-controlled blood pressure defined as SBP ≤140 mm Hg and DBP ≤90 mm Hg in two separate readings during up to three consecutive visits.  
c. Escalation of trametinib to previous dose level can be considered if BPs remains well-controlled for 4 weeks after restarting  
of trametinib. Approval from Novartis MedicalMonitor is required.  
d. Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g., headache, light-headedness, vertigo, tinnitus, episodes of fainting) that resolve after the blood pressure is controlled within the normal range.
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5.2.5 guidelines for prolonged qtc

Guidelines for dose modification and stopping criteria due to QTC-prolongation are provided in
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table 5.9 withholding and stopping

| QTc-Prolongationa                                                                               | Action and Dose Modification Interrupt study treatment until QTcB prolongation resolves to Grade 1 or baseline                                   |                                                                                                                                      |
|-------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|
| QTcB ≥501 msec or                                                                               | -                                                                                                                                                | Test serum potassium, calcium, phosphorus and magnesium. If abnormal, correct per routine clinical practice to within normal limits. |
| uncorrected QT>600 msec or QTcB>530 msec for subjects with bundle branch block                  | Review concomitant medication usage for a prolonged QTc. Restart at current dose levelb If event recurs, permanently discontinue study treatment |                                                                                                                                      |
| Abbreviations: msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using the |                                                                                                                                                  |                                                                                                                                      |  
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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5.2.6 guidelines for pneumonitis

Pneumonitis has been observed in subjects receiving trametinib. 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 in Table 5.10.  
| Table 5.10   | Management and Dose Modification Guidelines for Pneumonitis                                         |                                                         |                                                 |                                    |
|--------------|-----------------------------------------------------------------------------------------------------|---------------------------------------------------------|-------------------------------------------------|------------------------------------|
| CTCAE Grade  | Adverse Event Management                                                                            | Action and Dose Modification                            |                                                 |                                    |
| 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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5.2.7 guidelines for visual changes

Episodes of visual changes have been observed in subjects receiving trametinib, and ocular adverse events are known to be related to trametinib. An ophthalmologist should be consulted if changes in vision develop. However, if the visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), then monitor closely as it may be reasonable to defer ophthalmic examination. Special attention should be given to retinal findings (e.g., retinal pigment epithelial detachment (RPED) or retinovascular abnormalities (i.e., 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 Table 5.11.  
| Table 5.11                                                   | Management and Dose Modification Guidelines for Visual Changes and/or                    |                                                                                                                                           |                                                                 |                                                                           |
|--------------------------------------------------------------|------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|---------------------------------------------------------------------------|
| OphthalmicExaminationFindings CTCAE Adverse Event Management | Action and Dose Modification                                                             |                                                                                                                                           |                                                                 |                                                                           |
| Gradea b                                                     | -                                                                                        | Consult ophthalmologist                                                                                                                   | -                                                               | If dilated fundus examination                                             |
| Grade 1                                                      | within 7 days of onset                                                                   | cannot be performed within 7 days of onset, interrupt trametinib until RPED and RVO can be excluded by retina specialist/ophthalmologist. |                                                                 |                                                                           |
| -                                                            | 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 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 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      |    |                                                                                                                                  |
| -                                                                                       | Report as SAE             | -  | If RVO or RPED diagnosed, permanently discontinue trametinib                                                                     |
| Abbreviations: RPED = retinal pigment epithelial detachment; CTCAE = Common Terminology |                           |    |                                                                                                                                  |  
Abbreviations: RPED = retinal pigment epithelial detachment; CTCAE = Common Terminology Criteria for Adverse Events; RVO= retinal vein occlusion; SAE = serious adverse event a. Refers to CTCAE Version 4.03 'Eye disorders - Other, specify' c. If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis),
monitor closely but ophthalmic examination is not required.  
Table 5.12 Recommended dose modifications fortrametinib forretinal pigment **epithelial**
detachments(RPED)a  
| CTCAE Grade                                                                                                          | Action and Dose Modification                                                                                                           |                                                                                                                |
|----------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------|
| Grade 1 RPED (Asymptomatic; clinical or                                                                              | -                                                                                                                                      | Continue treatment with retinal evaluation monthly until resolution. If RPED worsens follow instructions below |
| diagnostic observations only) Grade 2-3 RPED (Symptomatic with                                                       | -                                                                                                                                      | 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 |                                                                                                                |
| mild to moderate decrease in visual acuity; limiting instrumental ADL) a. Refers to CTCAE Version 4.03 'Retinopathy' |                                                                                                                                        |                                                                                                                |
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5.2.8 guidelines for liver chemistry

| Grade of Event   | Management/Next Dose for Trametinb                                   |
|------------------|----------------------------------------------------------------------|
| ≤ Grade 1        | No change in dose                                                    |
| Grade 2          | Hold until ≤ Grade 1 Resume at same dose level                       |
| Grade 3          | Hold* until ≤ Grade 1 Resume at one dose level lower, if indicated** |
| Grade 4          | Off protocol therapy                                                 |
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5.2.9 guidelines for other toxicity

| Table 5.14 Worst toxicity (CTCAE 4.03                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Dose Modifications fortrametinib                                                                                                                                      |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade)* GENERALDISORDERS Fatigue(asthenia) Grade 1 or 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Maintain dose level                                                                                                                                                   |
| Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | If grade 3 fatigue resolves to Grade 2 in ≤ 7 days, maintain dose level If grade 3 fatigue lasts > 7 days, omit dose until resolved to ≤ Grade 2 and then ↓dose level |
| PULMONARY Notes: - Withhold trametinib for acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever and during diagnostic workup for pneumonitis/ILD. - During evaluation of potential grade 2, 3, and 4 pneumonitis, if an infectious etiology is confirmed (i.e., pneumonia) and pneumonitis isexcluded, then consider resuming at current dose level after the pneumoniaresolves. PNEUMONITIS Worst toxicity (CTCAE 4.03 Dose Modifications fortrametinib Grade)* AnyGrade treatment-related Permanently discontinue patient from study. ILD/pneumonitis CARDIAC INVESTIGATIONS Electrocardiogram QT corrected (QTc) interval prolonged Grade 1 (QTc 450-480 ms) Maintain dose level Grade 2 (QTc 481-500 ms) Grade 3 (QTc ≥ 501 ms on at least two separate ECGs) Omit dose until QTC is less than 481 ms, then ↓dose level Perform an analysis of serum potassium, and if below lower limit of normal, correct with supplements to within normal limits. -Repeat ECG in 24 hours, or less, as clinically indicated; continue monitoring as clinically indicated until QTc < 481 ms -Repeat ECGs 7 days after dose resumption for all patients who had therapy interrupted due to QTc ≥ 501ms. Grade 4 (QTc ≥ 501 or > 60ms changefrom baseline and Torsades de pointes orpolymorphic ventriculartachycardia or signs/symptoms of serious arrhythmia) Permanentlydiscontinue patient from trametinib. |                                                                                                                                                                       |
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table 5.15

| Table 5.15 Worst toxicity (CTCAE 4.03 Grade)*                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Dose Modifications fortrametinib                                                                                                                                                                          |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| BRADYCARDIA Grade 1 or Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Omit dose until recovery to asymptomatic bradycardia or to a heart rate ≥ 60 bpm Evaluate concomitant medications known to cause bradycardia and adjust the dose of trametinib                            |
| Grade 3 Grade 4 (in patients taking a concomitant medication also known to cause bradycardia or a medication known to causehypotension)                                                                                                                                                                                                                                                                                                                                                                       | Omit dose until recovery to asymptomatic bradycardia or to a heart rate ≥ 60 bpm If the concomitant medication can be adjusted ordiscontinued,resume trametinib at ↓1 dose level with frequent monitoring |
| Grade 4 (in patients who are not taking a concomitant medication also known to cause bradycardia or known to cause hypotension)                                                                                                                                                                                                                                                                                                                                                                               | Permanentlydiscontinuetrametinib                                                                                                                                                                          |
| PANCREATIC Amylase and/or lipase elevations (in the absence of clinical symptoms) Grade 1 (> ULN and ≤1.5 x ULN) Maintain dose level Grade 2 (>1.5 - 2.0 x ULN) Maintain dose level Grade ≥3 (> 2.0 x ULN) Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level Note: Withhold trametinib for acute onset of new or progressive unexplained abdominal symptoms, such as severe pain or vomiting; perform diagnostic procedures (e.g., abdominal CT scan or ultrasound) to exclude pancreatic pathology. |                                                                                                                                                                                                           |
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5.3 monitoring and toxicity management

Each patient receiving trametinib will be evaluable for safety. The safety parameters include all laboratory tests and hematological abnormalities, physical findings, and spontaneous reports of adverse events reported to the investigator by patients.  
Each patient will be assessed periodically for the development of any toxicity as outlined in Section 6 Study Procedures and Observations. Toxicity will be assessed according to the NCI CTCAE v4.03. Dose adjustments will be made according to the system showing the greatest degree of toxicity.  
We will monitor for potential adverse effects including but not limited to fatigue, dehydration, cytopenias, leukocytosis, nausea, vomiting, signs and symptoms of infection. In addition, we will monitor specifically for the following adverse events of special interest (please see corresponding subsections in Section 5.2 for acute toxicity management and dose modifications):  
- Diarrhea (Section 5.2.2),
- Ejection fraction changes (Section 5.2.3), - Hypertension (Section 5.2.4)
- Prolonged QTc (Section 5.2.5) - Pneumonitis (Section 5.2.6),
- Visual changes (Section 5.2.7),
- Liver chemistry elevation (Section 5.2.8)
Acute toxicity will be managed by supportive care and/or delay of dose. Further management will depend upon the judgment of the treating clinician and may include dose reduction. Patients will also be monitored for visual changes and change in cardiac function and QTc as described below.
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ophthalmic examination

Subjects are required to have a standard ophthalmic examination conducted by an ophthalmologist at baseline, week 4/Month 1 (prior to commencement of cycle 2), Month 6 and then annually thereafter unless clinically indicated sooner.  
The exam will include visual acuity (best corrected), tonometry (intraocular pressure measurement), visual field examination, slit lamp biomicroscopy of the anterior segment (with special attention to inflammation) and the posterior segment, and indirect fundoscopic examination with special attention to possible retinal abnormalities. Optical coherence tomography is strongly recommended at scheduled visits, and if retinal abnormalities are suspected or noted. Other types of ancillary testing including color fundus photography and fluorescein angiography are also recommended if clinically indicated.
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cardiac monitoring

LVEF will be assessed by echocardiogram or multigated acquisition (MUGA) scan within 28 days prior to initiation of trametinib. The same cardiac monitoring procedure (either echocardiogram or MUGA scan) will be repeated at one month after initiation of trametinib, and then at every 3 month intervals while on treatment.  
An electrocardiogram will be performed within 28 days prior to initiation of trametinib to assess QTc. An electrocardiogram will be repeated on Cycle 1 Day 1, at one month after initiation of trametinib, and then at every 3 month intervals while on treatment.
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6 study procedures and observations

The study-specific assessments are detailed in this section and outlined in Section 6 Schedule of Study Procedures and Assessments. Screening assessments must be performed within 28 days prior to the first dose of investigational product. Any results falling outside of the reference ranges may be repeated at the discretion of the investigator. All on-study visit procedures are allowed a window of ± 3 **days** unless otherwise noted. Treatment or visit delays for public holidays or weather conditions do not constitute a protocol violation.  
A written, signed, informed consent form (ICF) and a Health Insurance Portability and Accountability Act (HIPAA) authorization must be obtained before any study-specific assessments are initiated. A copy of the signed ICF will be given to the subject and a copy will be filed in the medical record. The original will be kept on file with the study records.  
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family Comprehensive Cancer Center Clinical Trial Management System (CTMS). The system is password protected and meets HIPAA requirements.
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6.1.1 pretreatment period 6.1.1.1 screening

Visit Windows: The Screening procedures and assessments must be completed within 28 days of the Day 1 Visit.  
- Physical examination  
- Vital signs
- Complete medical history including history of prior treatments and any residual toxicity relating to prior treatment
- Baseline conditions assessment - Performance status - Disease assessment including imaging (CT or MRI) of chest/abdomen/pelvis and brain for tumor/lesion assessment
- Baseline medications - Research tumor biopsy for biomarker analysis (to be paid for by study), unless deemed medically unsafe
- Complete blood count (CBC) with differential and platelet count - Blood chemistry assessments, including:
Alkaline phosphatase, aspartate aminotransferase/alanine aminotransferase (ALT/AST),
total bilirubin, calcium, phosphorus, blood urea nitrogen (BUN), creatinine, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate.  
- Coagulation assessment, including prothrombin time, partial thromboplastin time, international normalized ratio (PT/PTT/INR)
- Urinalysis
- Serum or urine pregnancy test within 3 days prior to the start of study drug for patients of child-bearing potential.  
- Electrocardiogram (ECG) in triplicate
- Cardiac assessment (MUGA or TTE)
- Ophthalmic exam
- Specimen collection for biomarkers and banking
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6.1.2 treatment period 6.1.2.1 study

Visit Windows: Screening laboratory tests completed within 3 days of Cycle 1 Day 1 do not need to be repeated
- Physical examination - Vital signs - Performance status
- Evaluation of adverse events - Concomitant medications
- Complete blood count (CBC) with differential and platelet count - Blood chemistry assessment, including:
Alkaline phosphatase, ALT/AST, total bilirubin, BUN, creatinine, fasting glucose, potassium, sodium, chloride, bicarbonate
- Coagulation assessment, including PT/PTT/INR
- Urinalysis
- Serum or urine pregnancy test
- Electrocardiogram (ECG) in triplicate
- Administration of Trametinib in clinic - Blood collection for ctDNA and cfDNA biomarkers
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6.1.2.2 study procedures cycle 1

- Evaluation of adverse events - Concomitant medications - Administration of Trametinib in clinic - Blood collection for ctDNA and cfDNA biomarkers
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6.1.2.3 study procedures cycle 1

- Evaluation of adverse events
- Concomitant medications
- Administration of Trametinib in clinic  
- Blood collection for ctDNA and cfDNA biomarkers
- Ophthalmic exam prior to cycle 2 day 1
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6.1.2.4 study procedures cycle 2

Visit Windows: Lab tests must be completed within 3 days of Day 1 and imaging studies must be completed within 7 days of Day 1.  
- Disease assessment including imaging (CT or MRI) of chest/abdomen/pelvis for tumor/lesion assessment - Cycles 3, 5, 7, and every other cycle thereafter
- If known lesions, brain imaging (CT or MRI) - Cycles 3, 5, 6, and every other cycle thereafter
- Physical examination - Vital signs
- Performance status - Evaluation of adverse events - Concomitant medications  
- Complete blood count (CBC) with differential and platelet count
- Blood chemistry assessments, including:
Alkaline phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate
- Coagulation assessment, including PT/PTT/INR - Urinalysis - Serum or urine pregnancy test
- Brain imaging, if known metastases for tumor/lesion assessment (every other cycle, starting with cycle \#3)
- Electrocardiogram (ECG) in triplicate
- Cardiac Assessments (TTE or MUGA) Cycle 2 day 1, and then every 3 cycles
- Blood collection for ctDNA and cfDNA biomarkers  
- Optional Biopsy (at best response to therapy) for biomarkers and banking
- Ophthalmic exam prior to cycle 2 day 1, again at 6 months, and then annually thereafter unless clinically indicated sooner.
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6.1.3 end-of-treatment study procedures

To be completed within 30 days of the last dose of study drug.  
- Disease assessment including imaging (CT or MRI) of chest/abdomen/pelvis, and brain
(if lesions found in screening), for tumor/lesion assessment
- Physical examination
- Vital signs
- Performance Status - Evaluation of adverse events - Concomitant medications
- Hematology labs (other than CBC with diff)
- Complete blood count (CBC) with differential and platelet count
- Blood chemistry assessment, including:
- Alkaline phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate,
- Coagulation assessment, including PT/PTT/INR - Urinalysis - Electrocardiogram (ECG)
- Blood collection for ctDNA and cfDNA biomarkers - Optional tumor biopsy for biomarker analysis and exploratory studies.
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6.1.4 post-treatment/follow up visits

Patients will be followed every 3 months +/- 14 days for up to 18 months after enrollment or until disease progression.  
The following procedures will be performed at the Follow Up Visit(s):  
- Disease assessment including imaging (CT or MRI) of chest/abdomen/pelvis, and brain
(if lesions found in screening) for tumor/lesion assessment. Scans would only be completed in follow-up for patients whose disease has not yet progressed since entering the study.  
- Physical examination - Vital signs - Performance Status - Evaluation of adverse events - Concomitant medications - Hematology labs (other than CBC w/ Diff) - CBC with differential and platelet count
- Blood chemistry assessment, including:
Alkaline phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate,
- Coagulation assessment, including PT/PTT/INR
- Urinalysis