A Phase II Trial of Targeted Kinase Fusion Inhibition in Unresectable Stage III/IV BRAF/NRAS Wild-Type Melanoma
Phase: PHASE2
Conditions: ALK Fusion Protein Expression, BRAF wt Allele, Invasive Skin Melanoma, MET Fusion Gene Positive, NRAS wt Allele, NTRK1 Fusion Positive, NTRK2 Fusion Positive, NTRK3 Fusion Positive, RET Fusion Positive, ROS1 Fusion Positive, Stage III Cutaneous Melanoma, Stage IIIA Cutaneous Melanoma, Stage IIIB Cutaneous Melanoma, Stage IIIC Cutaneous Melanoma, Stage IV Cutaneous Melanoma
Sponsor: University of California, San Francisco

s 
PHASE II TRIAL OF TARGETED KINASE FUSION INHIBITION IN UNRESECTABLE
STAGE III/IV BRAF/NRAS WILD-TYPE MELANOMA
Protocol Number: CC #14859 
Study Drug: Capmatinib, Ceritinib, Regorafenib, Entrectinib 
Version Number: 2.0 
Version Date: September 20, 2017 
IND Number: 129452 
Principal Investigator (Sponsor-Investigator) 
Adil Daud, MD 
University of California San Francisco 
 
 
 
 
E-mail: adil.daud@ucsf.edu
Co-Principal Investigator (Sponsor-Investigator) 
Iwei Yeh MD, PhD 
University of California San Francisco 
 
 
 
 
Co-Investigators
Katy Tsai, MD 
Statistician 
Jimmy Hwang, PhD 
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# 02587650

Version date: 09/20/17 
Protocol CC#:14859 
Participating Institutions and Investigators 
California Pacific Medical Center, David Minor, MD 
Stanford, Kim Margolin, MD 
Angeles Clinic, Omid Hamid, MD  
Comprehensive Cancer Centers of Nevada, Wolf Samlowski, MD 
Cincinnati Oncology, Peter Leming, MD 
Mount Sinai Comprehensive Cancer Center, Jose Lutzky, MD 
MD Anderson, Mike Davies, MD 
Dana Farber, Steve Hodi, MD 
University of Pennsylvania, Lynn Schucter, MD 
H Lee Moffitt Cancer Center, Jeffrey Weber, MD and Zeynep Eroglu, MD 
Revision History 
Version 1.0 
7/22/14 
Version 1.1 
7/25/14 
Version 1.2 
9/5/14 
Version 1.3 
Version 1.4 
Version 1.5 
Version 1.6 
Version 1.7 
Version 1.8 
Version 1.9 
Version 2.0 
12/12/14 
2/11/15 
6/12/15 
9/3/15 
2/4/16 
2/20/16 
2/29/16 
9/20/17 
Phase II –Capmatinib, Entrectinib, Ceritinib, Regorafenib 
Page 1 of 46 

Version date: 09-20-2017 
Protocol CC#:14859 
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Protocol Signature Page 
Protocol No.: CC#14859 
Version Date: September 20, 2017 
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.
UCSF Principal Investigator / Study Chair 
Printed Name 
Signature 
Date 
Principal Investigator 
Site 
Printed Name 
Signature 
Date 

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Participating Site(s) 
Mount Sinai Comprehensive 
Cancer Center 
Jose Lutzky, MD 
 
Angeles Clinic 
Omid Hamid, MD 
 
California Pacific Medical Center, 
David Minor, MD 
 
Stanford University Cancer 
Institute 
Kim Margolin, MD 
 
 
Comprehensive Cancer Centers 
of Nevada 
Wolf Samlowski, MD 
 
 
Cincinnati Oncology, 
Peter Leming, MD 
 
 
MD Anderson, 
Mike Davies, MD 
 
 
Dana Farber 
Steve Hodi, MD 
 
 
University of Pennsylvania, 
Lynn Schucter, MD 
 
 
H Lee Moffitt Cancer Center 
Jeffrey Weber, MD and 
Zeynep Eroglu, MD 
 
 
 

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Abstract 
Title 
Phase II trial of targeted kinase fusion inhibition in unresectable stage 
III/IV BRAF/NRAS wild-type melanoma 
Patient 
population 
Patients with metastatic melanoma who are wild-type (WT) status for 
BRAF, NRAS, and who also have an oncogenic kinase fusion. 
Rationale for 
Study 
BRAF WT melanoma patients currently have no options for molecularly 
targeted therapy. Given the low response rate to currently approved 
immunotherapies, there is a need for more therapeutic options in 
patients with BRAF/NRAS WT metastatic melanoma. 
Primary 
Objective 

To estimate the clinical activity of tyrosine kinase inhibitors
matched to the activated kinase fusion partner in patients with
metastatic melanoma.
Secondary 
Objectives 

To estimate tumor stability in kinase fusion melanoma patients
treated with kinase inhibitors matched to the activated fusion
partner.

To estimate survival in kinase fusion melanoma patients treated
with kinase inhibitors matched to the activated fusion partner.

To examine the safety and tolerability of kinase inhibitors in
patients with the kinase fusion targets.
Exploratory 
Objectives 

To explore molecular mechanisms of resistance for patients who
progress on therapy.
Primary 
Endpoint 

Confirmed ORR by RECIST v1.1 at 24 weeks.
Secondary 
Endpoints 

Confirmed CBR (defined as CR or PR or SD for >24 weeks).

Determination of PFS and OS.

Evaluation of the adverse effect profile, using CTCAE v4.03, of
each kinase inhibitor.
Exploratory 
Endpoints 

Exploratory endpoints to include assessment of expression levels of
the fusion kinase protein, reported as percentage by IHC staining.
Measures taken at baseline and after 4 weeks of therapy will be
summarized. Changes in expression level will be assessed
between baskets using a paired t-test if data permit. For patients
who progress on therapy, an additional biopsy may be obtained
and will be compared with baseline expression levels if data permit.
Study Design 
This is a phase II multi-center prospective basket trial designed to test 
the hypothesis that targeting specific kinase fusions in metastatic 
melanoma with pre-specified kinase inhibitors will result in objective 
tumor shrinkage and durable response. The study design is a 2 stage 
optimal design with a sample size of N=35, with n1=11 during stage I 
and n2=24 during stage II. If 1 or fewer responses are observed during 
stage I, the trial will be stopped. If 6 or fewer responses are observed 
by the end of stage II, the trial will be stopped. 

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Number of 
patients 
Estimating a drop-out rate of 20%, we anticipate enrolling 44 patients to 
accrue 35 evaluable patients. 
Study Drugs 
Capmatinib, Entrectinib, Ceritinib, Regorafenib 
Safety 
Assessments 
Physical exam with evaluation of vital signs, performance status, and 
toxicity grading as per CTCAE v4.03. Clinical laboratory evaluations 
including CBC, CMP. 
Efficacy 
Assessments 
ORR and CBR to be assessed as per RECIST v1.1 criteria. 

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List of Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
CBC 
complete blood cell (count) 
CBR 
clinical benefit rate 
CR 
complete response 
CRC 
Clinical Research Coordinator 
CRC 
Colorectal Cancer 
CRF 
case report form 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
DLT 
dose limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
FIH 
First in Humans 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HBcAb 
Hepatitis B core antibody 
HBeAg 
Hepatitis B “e” antigen 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HDFCCC 
Helen Diller Family Comprehensive Cancer Center 
HFSR 
hand foot skin reaction 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IC50 
concentration resulting in 50% inhibition 
IHC 
immunohistochemistry 
IND 
investigational new drug application 
INR 
international normalized ratio 
IP 
investigational product 

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List of Abbreviations 
IRB 
Institutional Review Board 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NSCLC 
non-small cell lung cancer 
ONJ 
osteonecrosis of the jaw 
ORR 
overall response rate 
OS 
overall survival 
PD 
disease progression 
PFS 
progression free survival 
PK 
pharmacokinetics 
PO 
Per os (by mouth, orally) 
PR 
partial response 
PRC 
Protocol Review Committee (UCSF) 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RBC 
red blood cell (count) 
SD 
stable disease 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
UPCR 
urine protein-to-creatinine ratio 

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Table of Contents 
Protocol Signature Page ........................................................................................................................ 2 
UCSF Principal Investigator / Study Chair........................................................................................... 2 
Principal Investigator Site ................................................................................................................... 2 
Participating Site(s)................................................................................................................................. 3 
List of Abbreviations ............................................................................................................................... 6 
List of Abbreviations ............................................................................................................................... 7 
1.1 
Fusion Kinases in Melanoma .................................................................................................. 11 
1.2 
Kinase Inhibitors ........................................................................................................................ 11 
1.3 
Rationale for the Proposed Study ........................................................................................... 12 
1.4 
Correlative Studies ................................................................................................................... 13 
2 
Objectives of the Study ................................................................................................................ 13 
2.2 
Secondary Objectives .............................................................................................................. 13 
2.3 
Exploratory Objectives, Other Assessments ......................................................................... 13 
3 
Endpoints of the Study ................................................................................................................. 13 
3.2 
Secondary Endpoints ............................................................................................................... 14 
3.3 
Exploratory Endpoints .............................................................................................................. 14 
4 
Study Design ................................................................................................................................. 14 
Table 1. Kinase Fusion and Assigned Drug ..................................................................................... 14 
4.2 
Number of Subjects .................................................................................................................. 15 
4.3 
Eligibility Criteria ........................................................................................................................ 15 
4.3.1 
Inclusion Criteria ................................................................................................................... 15 
4.3.2 
Exclusion Criteria .................................................................................................................. 17 
4.4 
Duration of Therapy .................................................................................................................. 17 
4.5 
Duration of Follow Up ............................................................................................................... 18 
5 
Study Drugs ................................................................................................................................... 18 
5.1 
Drug Accountability ................................................................................................................... 18 
5.2 
Drug Ordering ............................................................................................................................ 18 
5.3 
Packaging and Labeling of Study Drugs ................................................................................ 18 
6 
Treatment Plan .............................................................................................................................. 19 
6.1 
Dosage and Administration ..................................................................................................... 19 
Table 2. Drug Regimens ...................................................................................................................... 19 
7.1.1 
Pretreatment and Treatment Period....................................................................................... 20 
7.1.2 
Long Term/Survival Follow-up Procedures ....................................................................... 20 
7.1.3 
Discontinuation of Therapy .................................................................................................. 20 

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Table of Contents 
8 
Reporting and Documentation of Results .................................................................................. 21 
Definitions .................................................................................................................................................. 21 
Evaluable for toxicity ............................................................................................................................ 21 
Evaluable for objective response ........................................................................................................ 21 
Disease Parameters ................................................................................................................................. 21 
Measurable disease ............................................................................................................................. 21 
Target lesions ........................................................................................................................................ 21 
Non-target lesions ................................................................................................................................. 21 
Non-measurable disease ..................................................................................................................... 21 
Methods for Evaluation of Measurable Disease ................................................................................... 21 
Conventional CT and MRI ................................................................................................................... 21 
Cytology, Histology ............................................................................................................................... 21 
8.1.1.1 Response Criteria ....................................................................................................................... 21 
Evaluation of Target Lesions ............................................................................................................... 21 
Evaluation of Non-Target Lesions ...................................................................................................... 22 
Evaluation of Best Overall Response ................................................................................................ 22 
Table 3. Response Criteria .................................................................................................................. 22 
Duration of Response .......................................................................................................................... 23 
Evaluation of Safety .............................................................................................................................. 23 
8.3 
Definitions of Adverse Events ................................................................................................. 24 
8.3.2 
Adverse Reaction ................................................................................................................. 24 
8.3.2.1 
Suspected .......................................................................................................................... 24 
8.3.2.2 
Unexpected ....................................................................................................................... 24 
8.3.2.3 
Serious ............................................................................................................................... 25 
8.3.2.4 
Life-threatening ................................................................................................................. 25 
8.4 
Recording of an Adverse Event .............................................................................................. 25 
8.5 
Follow-up of Adverse Events .................................................................................................. 26 
8.6 
Adverse Events Monitoring ..................................................................................................... 26 
8.7 
Expedited Reporting ................................................................................................................. 27 
Reporting to UCSF Institutional Review Board (IRB) ...................................................................... 27 
Expedited Reporting to the Food and Drug Administration ............................................................. 27 
Reporting to Pharmaceutical Companies providing Study Drug .................................................... 27 
9 
Statistical Considerations and Evaluation of Results ............................................................... 29 
9.1 
Evaluation of Safety .................................................................................................................. 30 

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Table of Contents 
10 
Study Management .................................................................................................................. 30 
10.2 
Institutional Review Board Approval....................................................................................... 30 
10.3 
Informed Consent ..................................................................................................................... 31 
10.4 
Changes in the Protocol........................................................................................................... 31 
10.5 
Handling and Documentation of Clinical Supplies ................................................................ 31 
10.6 
Case Report Forms (CRFs) .................................................................................................... 31 
10.7 
Oversight and Monitoring Plan ................................................................................................ 32 
10.8 
Record Keeping and Record Retention ................................................................................. 32 
10.9 
Coordinating Center Documentation of Distribution ............................................................. 33 
10.10 
Multicenter communication ...................................................................................................... 33 
11 
Protection of Human Subjects ................................................................................................. 34 
11.2 
Protection of Privacy................................................................................................................. 34 
12.0 References ................................................................................................................................... 35 
13.1 
Appendices ................................................................................................................................ 37 
Monitoring and Reporting Guidelines ................................................................................................. 38 
Multicenter communication .................................................................................................................. 38 
Data and Safety Monitoring Committee Contacts ............................................................................ 39 
Policy/Procedure for Required Regulatory Documents for Single Site and Multicenter 
Investigator-Initiated Oncology Clinical Trials ....................................................................................... 40 
Table 4. Drug-specific restrictions on anticoagulation ..................................................................... 44 
Sample shipment instructions ............................................................................................................. 45 
Instructions for shipment of biological samples to UCSF : .............................................................. 45 
Appendix 6     Capmatinib (see attached document) 
Appendix 7     Ceritinib (see attached document)  
Appendix 8     Regorafinib (see attached document) 
Appendix 9     Entrectinib (see attached document) 
Table 1.  Kinase Fusion and Assigned Drug 
Table 2. Drug Regimens 
Table 3. Response Criteria 

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1 
Introduction 
Melanoma 
Melanoma is the deadliest of all skin cancers, with an incidence rate that is rising 
worldwide. It is estimated that in 2013, in the US alone, over 80,000 cases of melanoma 
were diagnosed and over 8,000 patients died of this disease1. Fortunately, recent 
advances in immunotherapy have led to the development of several new agents for 
metastatic melanoma: the FDA-approved ipilimumab and pembrolizumab, as well as 
promising PD-L1 antibodies. Another major advancement in melanoma therapy has 
been in the field of molecularly targeted therapy: BRAF inhibitors with/without MEK 
inhibitors were recently shown to have benefit in patients whose tumors harbor BRAF 
mutations2–4. 
While 40-50% of cutaneous melanomas have activating BRAF mutations5, there 
remains a sizable BRAF wild type (WT) subset of melanoma that still lacks effective 
molecularly-targeted therapy options6. While 30-40% of patients respond to currently 
approved immunotherapies, many patients with BRAF WT metastatic melanoma are in 
need of more treatment options7,8. The major subsets among BRAF WT are currently 
recognized as those with a mutation of NRAS 9,10 as a molecular driver (15-20% across 
all primary sites except ocular) and those which test WT for both BRAF and NRAS6. 
1.1 
Fusion Kinases in Melanoma 
Targeting fusion Kinases 
There is emerging data that a subset of cutaneous melanomas without mutations in 
BRAF, NRAS, KIT, GNAQ11 or GNA11 12 feature activating kinase fusions. We recently 
discovered in melanocytic neoplasms including melanomas without these mutations the 
presence of fusions involving the kinases ROS1 (17%), NTRK1 (16%), ALK (10%), 
BRAF (5%), RET (3%) and MET 13,14. The kinase fusions occurred in a mutually 
exclusive pattern and invariably fused the kinase domains of the respective genes to a 
variety of N-terminal fusion partners. We showed that the chimeric fusion kinases are 
enzymatically active and act as constitutively activated drivers of multiple oncogenic 
signaling pathways. Importantly, cognate kinase inhibitors can inhibit these pathways. 
Determination of Specific Kinase Fusions 
Identification of kinase fusions can be performed by various methods and is offered by 
different CLIA laboratories. A separate study protocol aimed at determining the 
frequency of kinase fusions in BRAF WT melanoma will provide testing through a UCSF 
CLIA laboratory and report potentially actionable results to the patient’s clinician. In this 
study protocol, fusion kinase detection will be performed using a validated targeted next- 

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generation sequencing platform. Additional methods that may be employed include 
fluorescence in situ hybridization and immunohistochemistry. We expect most eligible 
patients for this study to be tested by the UCSF CLIA laboratory, however, we will accept 
confirmation of a kinase fusion after review of the test results from other CLIA approved 
laboratories (i.e. Foundation Medicine).. 
1.2 
Kinase Inhibitors 
Capmatinib (INC280) 
INC280 is an ATP-competitive, reversible inhibitor of the c-MET receptor tyrosine kinase. 
INC280 is highly selective for c-MET (IC50 value of 0.13 nM) as compared to a panel of 
56 other human kinases tested. In pre-clinical models, INC280 was shown to have 
activity against a c-MET amplified gastric cancer cell line (GTL-16) and a c-MET 
amplified HCC cell line (HCCLM3). Over three phase I trials, 161 patients have been 
treated with various doses of INC280 with 2.2-8.1% of patients experiencing dose- 
limiting toxicities. The most common adverse effects were diarrhea, nausea, and 
vomiting. INC280 is still being evaluated in multiple Phase I and II studies. 
Ceritinib 
Ceritinib is an ATP-competitive, piperidine tyrosine kinase inhibitor with 20 times the 
potency against ALK compared to crizotinib (IC50 value of 0.15 nM compared to 3 nM). 
Ceritinib also has inhibitory activity against INSR and IGF1R, though 50-fold less potency 
than for ALK (IC50 values of 7 nM and 8 nM, respectively21. In pre-clinical     
models, ceritinib was shown to have activity against crizotinib-resistant ALK-positive 
NSCLC. In a phase I clinical trial, 59 patients with ALK-rearranged malignancies were 
enrolled22. The maximum tolerated dose was 750 mg once daily. Dose limiting toxicities 
included diarrhea, vomiting, elevated AST/ALT, and hypophosphatemia. Among 140 
patients, the overall response rate was 58%. In eighty patients who had progressed on 
crizotinib, ORR was 56%. Amongst patients who received at least 400 mg of ceritinib 
per day, the median progression free survival was 7 months and the median duration of 
response was 8.2 months. Additionally, ceritinib was shown to have activity against CNS 
lesions in patients who had progressed on prior therapy with crizotinib. 
Ceritinib was granted accelerated approval by the FDA in April 2014 for the 
treatment of ALK-positive, metastatic NSCLC with disease progression on or who are 
intolerant of crizotinib. The phase I study (CLDK378X2101) is ongoing; enrollment has 
been completed in the expansion phase with interim data presented at ASCO 2014. 
Based on a clinical trial of 163 patients with metastatic ALK-positive NSCLC, treatment 
with ceritinib resulted in an ORR of 54.6% with a median duration of response of 7.4 
months. The complete response (CR) rate was 1.2% and the partial response (PR) rate 
was 53.4%23. 
Regorafenib 
Regorafenib is a carboxamide BRAF and CRAF kinase inhibitor initially developed to 
target VEGF driven xenografts. This compound also inhibits multiple transmembrane 
and intracellular kinases RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, 
PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Eph2A, CRAF, BRAF, BRAFV600E, SAPK2, 
PTK5, and Abl24. Regorafenib was recently approved for use in metastatic CRC based 

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on a placebo controlled Phase III clinical trial25. The median overall survival was 
prolonged from 5 months in the placebo group to 6.4 months in the regorafenib group. 
The median PFS was similar and response rates were similar. The safety profile of 
regorafenib is typical of the VEGF inhibitors and includes asthenia/fatigue, decreased 
appetite and food intake, hand-foot skin reaction, diarrhea, mucositis, weight loss, 
infection, hypertension and dysphonia. Regorafenib has also been shown to provide 
significant improvement in PFS compared with placebo in patients with metastatic 
gastrointestinal stromal tumor (GIST), and is now an approved treatment for GIST26,27. 
We have additional data that BRAF fusion melanoma cell lines are more sensitive to 
regorafenib and sorafenib, both class II BRAF inhibitors, than to vemurafenib, a class I 
BRAF inhibitor (14 and unpublished data, Bastian BC). 
 
Entrectinib (RXDX-101) 
Entrectinib is a potent inhibitor of the tyrosine kinases encoded by genes NTRK1, 
NTRK2, NTRK3, ROS1 and ALK, with IC50 values for kinase inhibition <=12 nM. In pre- 
clinical models, entrectinib has demonstrated concentration-dependent inhibition of Trk, 
ROS1, and ALK phosphorylation in cell-based assays using tumor cell lines. It has also 
demonstrated dose-related antitumor effects in a variety of human tumor xenograft and 
allograft models dependent on Trk, ROS1, or ALK oncoproteins: namely, anaplastic 
large cell lymphoma, and intracranial non-small cell lung cancer (NSCLC). Importantly, 
entrectinib has also exhibited potent antitumor activity both in vitro and in vivo against 
ALK mutants known to be resistant to the ALK inhibitor crizotinib, thus suggesting that 
entrectinib has the potential to treat patients with brain metastases and those who have 
crizotinib-refractory disease. Entrectinib was evaluated in two Phase 1 clinical studies 
(Study ALKA-372-001 and Study RXDX-101-01 [STARTRK-1]) designed to determine 
the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of 
entrectinib in patients with advanced or metastatic solid tumors harboring NTRK1/2/3, 
ROS1, or ALK molecular alterations. Doses tested ranged from 100 to 1200 mg/m2, 
under fasted and fed conditions in both intermittent and continuous daily dosing 
regimens. Two DLTs were observed: one event of Grade 3 cognitive impairment and 
one event of Grade 3 fatigue. Both events were reversible upon study drug interruption. 
Based upon these two DLTs, 400 mg/m2 administered once-daily on a fed regimen was 
selected as the BSA-based RP2D. Subsequently, additional expansion cohorts of 
patients were enrolled to further explore a fixed daily dosing regimen, and 600 mg/day 
was selected as the RP2D. 
 
1.3 
Rationale for the Proposed Study 
 
Current effective treatments for melanoma include immunotherapy and targeted 
molecular therapies. However, not all patients respond to immunotherapy, and currently 
approved targeted molecular therapy is indicated only for patients with activating BRAF 
mutations. Recently, fusion kinases have been identified in melanoma that are mutually 
exclusive with activating mutations in BRAF. In other cancers, inhibition of similar fusion 
kinases with kinase inhibitors have demonstrated clinical efficacy. We propose a study of 
a specific kinase inhibitor for patients with metastatic kinase fusion melanoma. Given  
that patients with kinase fusion melanomas are a rare cohort without extensive FDA- 
approved treatment options, they stand to derive great benefit from promising novel 
agents in melanoma. Patients eligible for this study will be those with melanomas that  
are BRAF/NRAS wild-type and that have an oncogenic kinase fusion, and who have 
received at least one FDA-approved line of therapy for unresectable/metastatic 

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melanoma. Patients who are treatment-naïve but who refuse available standard options 
and prefer to enroll on study as their first line of treatment after a thorough informed 
consent process will be eligible for this study at the discretion of the treating physician. 
 
1.4 
Correlative Studies 
 
The presence of one of the following integral biomarkers will need to be established by 
tumor biopsy to establish trial eligibility: oncogenic kinase fusion involving ALK, BRAF, 
MET, NTRK, RET, or ROS1. Patients will be consented for two biopsies: one biopsy 
after cycle 1, and one biopsy at the time of progression (if applicable). 
Punch or core biopsy is mandatory for easily accessible sites (i.e., palpable, 
cutaneous, or subcutaneous lymph nodes or lesions). All other lesion biopsies (i.e., lung, 
liver) that pose more than minimal risk are optional and will be determined by the treating 
Investigator. Correlative studies to be performed on tumor biopsy specimens will include 
immunohistochemical assessment of fusion kinase expression levels and activation 
status. 
 
2 
Objectives of the Study 
2.1 
Primary Objective 
 
 
To estimate the clinical activity of tyrosine kinase inhibitors matched to the tumor- 
specific fusion kinase in patients with metastatic melanoma. 
 
2.2 
Secondary Objectives 
 
 
To estimate tumor stability in melanoma patients treated with kinase inhibitors 
matched to the tumor-specific fusion kinase. 
 
To estimate survival in melanoma patients treated with kinase inhibitors matched 
to the tumor-specific fusion kinase. 
 
To examine the safety and tolerability of kinase inhibitors in patients with 
melanoma with a fusion kinase. 
 
 
2.3 
Exploratory Objectives, Other Assessments 
 
 
To explore molecular mechanisms of resistance for patients who progress on 
therapy. 
 
 
3 Endpoints of the Study 
3.1 
Primary Endpoint 
 
 
Overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 at 24 weeks. 

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3.2 
Secondary Endpoints 
 
 
Clinical benefit rate (CBR) (with clinical benefit defined as complete response 
(CR) or partial response (PR) or stable disease (SD) for >24 weeks). 
 
Determination of progression-free survival (PFS) and overall survival (OS). 
 
Evaluation of the adverse effect profile of each kinase inhibitor, using National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
v4.03. 
 
3.3 
Exploratory Endpoints 
 
 
Exploratory endpoints to include assessment of expression levels of the fusion 
kinase protein, before and during treatment, reported as percentage by 
immunohistochemistry (IHC) staining. 
 
 
4 
Study Design 
4.1 
Characteristics 
 
This is a phase II prospective multi-center basket trial designed to test the hypothesis 
that targeting specific kinase fusions in metastatic melanoma with kinase inhibitors 
matched to the activated kinase fusion will result in tumor response. The study design is 
a 2-stage optimal design. Patients with a eligible kinase fusion in their melanoma, as 
identified by a CLIA-approved laboratory (targeted next-generation sequencing of tumor 
tissue, fluorescence in situ hybridization and immunohistochemistry) will be offered 
enrollment in this protocol and will be treated in one of five baskets. As testing for fusion 
kinases is not currently part of the standard of care for melanoma, a separate protocol 
will provide screening for kinase fusions for patients with BRAF wild-type melanoma in a 
CLIA-approved laboratory at UCSF. Based on the kinase fusions identified, patients will 
be stratified as follows: 
 
 
 
 
Table 1. Kinase Fusion and Assigned Drug 
 
MET fusion 
Capmatinib 400 mg PO BID 
ALK fusion 
Ceritinib 450 mg PO q day (with low-fat meal) 
RET fusion 
Regorafenib 160 mg PO q day (first 21 days of each 28 day cycle) 
BRAF fusion 
Regorafenib 160 mg PO q day (first 21 days of each 28 day cycle) 
NTRK1 fusion 
NTRK2 fusion 
NTRK 3 fusion 
Entrectinib 600 mg PO q day 
ROS1 fusion 
Entrectinib 600 mg PO q day 

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The dose of capmatinib at 400 mg PO BID is based on the recommended phase II dose 
(RP2D) by Novartis. Ceritinib at 450 mg PO daily with a low-fat meal (approximately 
100-500 calories, 1.5-15 grams of fat) demonstrated comparable AUC0–24h and Cmax at 
Cycle 2 Day 1 to patients treated with ceritinib 750 mg under fasting conditions (the 
FDA-approved dose for ALK-rearranged NSCLC resistant to intolerant to crizotinib). 
Both ceritinib dosing regimens showed similar rates of AEs but GI related AEs and dose 
interruptions were fewer with dosing at 450mg PO daily with a low-fat meal, and for this 
reason is the chosen dosing. For regorafenib we will dose at 160 mg PO daily (first 21 
days of each 28 day cycle) which is the FDA-approved dose for both colon cancer and 
GIST. The dose of entrectinib at 600 mg PO QD is the RP2D based on two Phase 1 
studies conducted by Ignyta. Please refer to Table 1 for drug assignments and Table 2 
for drug dose regimens. 
 
4.2 
Number of Subjects 
 
We anticipate enrollment of 35 evaluable patients to this study. Identification of a fusion 
kinase is required for eligibility and testing for fusion kinases is not standard of care. A 
separate UCSF research protocol will screen melanoma patients in need of treatment 
who are wild-type for BRAF mutation for fusion kinases (PI: Boris Bastian). 
The sample size is based on a 2-stage Simon’s optimal design using ORR at 24 
weeks as primary efficacy endpoint. We assume that a response rate of 10% would be 
unacceptable and a response rate of 30% would be considered clinically meaningful. 
Under type I error of 0.05 and type II error of 0.15, in the first stage of this design, 11 
patients will be accrued. If 1 or fewer patients achieve a response among the initial 11 
patients, the trial will be terminated. If at least 2 patients achieve a response among 
these 11 patients, then an additional 24 patients will be accrued to the second stage. If 6 
or fewer patients achieve a response, then the trial will be terminated. Under these 
conditions, if the response rate is 0.1, the probability of ending the trial during stage 1 is 
0.70. If the true response rate is 0.3, the probability that the trial will be stopped in stage 
I is 0.11. 
If 35 evaluable patients with follow-up of at least 12 months are enrolled, but 
fewer than 5 patients are assigned to a given drug, the study will continue to enroll 
patients until we have enrolled at least 5 patients for each of the 4 study drugs with a 
max of 50 patients enrolled. 
We anticipate enrollment of 35 evaluable patients to this study. Evaluable patients 
would be those with baseline staging, treatment for at least 8 weeks, and at least one 
post-baseline staging scan while on treatment. We estimate a drop-out rate of 20%, and 
therefore 44 patients will be enrolled and started on treatment. Kinase fusion melanoma 
prevalence is currently estimated at 10% of BRAF/NRAS WT melanomas, thus we 
anticipate screening 440 patients to enroll 44 patients. 
 
4.3 
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 from the patient prior to enrollment. The following 
criteria apply to all patients enrolled onto the study unless otherwise specified. 
 
4.3.1 Inclusion Criteria 

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Patients eligible for this study will be those with melanomas that are BRAF/NRAS wild- 
type and that have an oncogenic kinase fusion. Patients who have received at least one 

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FDA-approved line of therapy for unresectable/metastatic melanoma are eligible. 
Patients who are treatment-naïve but who refuse available standard options and prefer 
to enroll on study as their first line of treatment after a thorough informed consent 
process will be eligible for this study at the discretion of the treating physician. 
 
 
Further inclusion criteria vary depending on the basket to which the patient will be 
assigned. Please refer to the drug-specific appendices for further details on inclusion 
criteria. 
 
 
For patients with MET fusion to be treated with capmatinib, see Appendix 6, 
Section 6.1. 
 
For patients with ALK fusion to be treated with ceritinib, see Appendix 7, Section 
7.1. 
 
For patients with RET or BRAF fusion to be treated with regorafenib, see 
Appendix 8, Section 8.1. 
 
For patients with NTRK1, NTRK2, NTRK3, or ROS1 fusion to be treated with 
entrectinib, see Appendix 9, Section 9.1. 
 
 
 
4.3.2 Exclusion Criteria 
 
Exclusion criteria vary depending on the basket to which the patient will be assigned. 
Please refer to the drug-specific appendices for further details on exclusion criteria. 
 
 
For patients with MET fusion to be treated with capmatinib, see Appendix 6, 
Section 6.2. 
 
For patients with ALK fusion to be treated with ceritinib, see Appendix 7, Section 
7.2. 
 
For patients with RET or BRAF fusion to be treated with regorafenib, 
see Appendix 8, Section 8.2. 
 For patients with NTRK1, NTRK2, NTRK3, or ROS1 fusion to be treated with 
entrectinib, see Appendix 9, Section 9.2. 
 
 
 
4.4 
Duration of Therapy 
 
Subjects may discontinue study treatment or withdraw their consent to participate in the 
study at any time without prejudice. The Investigator may withdraw a subject from study 
treatment or from the study if, in his or her clinical judgment, it is in the best interest of 
the subject of if the subject cannot comply with the protocol. In addition, any of the 
following conditions require discontinuation of the subject from study treatment: 
 
Disease progression. 
 
An AE or inter-current illness that in the opinion of the Investigator warrants the 
subject’s withdrawal from study. 

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 
If the subject does not recover from his or her toxicities to tolerable Grade ≤2 
within 6 weeks, the subject will have study treatment discontinued unless there is 
unequivocal evidence that the subject is benefitting. In this situation, a subject 
may be able to restart therapy with a dose reduction upon resolution of the 
toxicity. 
 
Inability to tolerate the lowest dose of study drug as detailed in Table 2. 
 
Women who become pregnant or are breastfeeding. 
 
Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (e.g., male or female condom) during the course of the study and 
for 4 months after discontinuation of study treatment. 
 
Necessity for treatment with other anti-cancer treatment prohibited by protocol. 
 
Request by regulatory agencies for termination of treatment of an individual 
subject or all subjects under the protocol. 
 
Significant patient non-compliance with protocol. 
 
4.5 
Duration of Follow Up 
Patients will be followed until death or removal from study, whichever occurs first. 
 
5 
Study Drugs 
 
 
Capmatinib – See Appendix 6 
 
Ceritinib – See Appendix 7 
 
Regorafenib - See Appendix 8 
 
Entrectinib – See Appendix 9 
 
 
5.1 
Drug Accountability 
 
The Investigational Pharmacist will manage drug accountability records. Accurate 
records of receipt of all study drugs will be kept, including dates of receipt. In addition, 
accurate records will be kept regarding when and how much study treatment is being 
dispensed and used by each subject in the study. Reasons for deviation from the 
expected dispensing regimen must also be recorded. At completion of the study, to 
satisfy regulatory requirements regarding drug accountability, all unused study drug will 
be reconciled and destroyed in accordance with applicable state and federal regulations. 
 
5.2 
Drug Ordering 
 
UCSF will obtain capmatinib, ceritinib, regorafenib and entrectinib directly from their 
respective pharmaceutical companies as study supply. 
 
5.3 
Packaging and Labeling of Study Drugs 
 
Drugs will be packaged and labeled per UCSF institutional standards, adhering to 
applicable local and federal laws. 

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6 
Treatment Plan 
 
Patients will be treated with an appropriate kinase inhibitor as outlined in Table 1. Cycle 
length is defined for this study as 4 weeks. Patients will be restaged every 2 cycles (8 
weeks), and best objective response will be confirmed using RECIST v1.1 with 
measurements at a minimum of 4 weeks after the response-defining determination. 
Dose reductions and dose interruptions for management of toxicity will be specified in 
the sections below. 
6.1 
Dosage and Administration 
 
Treatment will be administered on an outpatient basis. See Table 2 for dosage and 
administration information. 
 
Table 2. Drug Regimens 
 
Study Drug 
Precautions 
Start 
Dose 
Dose 
Level 
–1 
Dose 
Level 
–2 
Dose 
Level 
–3 
Route 
Schedule 
Cycle 
Length 
Capmatinib 
Do not take 
with food (do 
not eat at 
least 1 hour 
before or 2 
hours after 
drug 
ingestion) 
400 
mg 
300 
mg 
200 
mg 
N/A 
PO 
BID 
28 
days 
Ceritinib 
 
Take with 
low-fat meal 
450 
mg 
300 
mg 
150 
mg 
N/A 
PO 
Once 
daily 
28 
days 
Regorafenib 
Take each 
morning with 
a low-fat 
breakfast 
160 
mg 
120 
mg 
80 mg 
N/A 
PO 
Once 
daily 
(21 days 
on, 7 
days off) 
28 
days 
Entrectinib 
Take within 1 
hour 
following a 
meal 
600 
mg 
400 
mg 
200 
mg 
N/A 
PO 
daily 
28 
days 

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7 
Study Procedures and Observations 
7.1 
Schedule of Procedures and Observations 
 
The study-specific assessments are detailed in this section. Screening assessments 
must be performed within 30 days prior to the first dose of investigational product except 
for the staging which can be done 90 days prior. Any laboratory 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 ± 7 days unless otherwise noted. Treatment 
or visit delays for public holidays or weather conditions do not constitute a protocol 
violation. Additional follow-up visits may be added and additional tests ordered per 
discretion of treating Investigator. 
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 (HDFCCC) Clinical Trial Management System 
(CTMS). The system is password protected and meets HIPAA requirements. 
7.1.1 Pretreatment and Treatment Period 
In addition to the assessments outlined in the study calendars, the following will be 
performed within 30 days before the Day 1 visit. 
 
 
Documentation of measureable disease 
 
History of prior treatments and any residual toxicity relating to prior treatment 
 
Determination of baseline medications taken within 30 days of Day 1 
 
Serum Hepatitis assessment, including Hepatitis B surface antigen (HBsAg), 
Hepatitis B surface antibody (HBsAb), Hepatitis B core antibody (HBcAb), 
Hepatitis C antibody 
 
Serum HIV test 
 
7.1.2 Long Term/Survival Follow-up Procedures 
 
Follow-up history to be conducted by phone call, otherwise per standard of care for 
metastatic melanoma and PI discretion. 
 
7.1.3 Discontinuation of Therapy 
 
The Investigator will withdraw a patient whenever continued participation is no longer in 
the patient’s best interests. Reasons for withdrawing a patient include, but are not 
limited to, disease progression, the occurrence of an adverse event or a concurrent 
illness, a patient’s request to end participation, a patient’s non-compliance or simply 
significant uncertainty on the part of the Investigator that continued participation is 
prudent. There may also be administrative reasons to terminate participation, such as 
concern about a patient’s compliance with the prescribed treatment regimen. 

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8 
Reporting and Documentation of Results 
8.1 
Evaluation of Efficacy (or Activity) 
 
Evaluation of efficacy to be assessed by ORR and CBR, using RECIST v1.1 criteria. 
 
Response and progression in this study will be evaluated using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee28. Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST v1.1 criteria. Local review of response or 
progression will be performed at each site. Data for each patient with a response will be 
reviewed at UCSF. 
 
 
Definitions 
Evaluable for toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with the 
study drug. 
Evaluable for objective response 
Only those patients who have measurable disease present at baseline, have received at 
least one cycle of therapy (with at least 90% of intended dosing administered during 
cycle 1), and have had their disease re-evaluated will be considered evaluable for 
response. These patients will have their response classified according to the definitions 
stated below. (Note: Patients who exhibit objective disease progression prior to the end 
of Cycle 1 will also be considered evaluable.) 
Disease Parameters 
Measurable disease 
Measurable disease is defined as the presence of at least one measurable lesion by 
radiographic assessment or by clinical examination (e.g., skin lesion). If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. Positive bone scans and radiographic studies of bone involved with 
tumor are not considered to be measurable disease. 
 
All tumor measurements will be recorded in millimeters or decimal fractions of 
centimeters. Previously irradiated lesions are considered non-measurable except in 
cases of documented progression of the lesion since the completion of radiation therapy. 
Target lesions 
All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total 
representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline. Target lesions will be selected on the basis of their size 
(lesions with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically). A sum of the longest 
diameter (LD) for all target lesions will be calculated and reported as the baseline sum 
LD. The baseline sum LD will be used as reference by which to characterize the 
objective tumor response. 

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Non-target lesions 
All other lesions (or sites of disease) including any measurable lesions over and above 
the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. It is possible to record multiple non-target lesions involving the 
same organ as a single item on the case record form (e.g. “multiple enlarged pelvic 
lymph nodes” or “multiple liver metastases”). Bone lesions may be measureable if ≥ 1 
cm on MRI. 
Measurements of these lesions are not required, but the presence or 
absence of each will be noted throughout follow-up. 
Non-measurable disease 
Non-measurable disease is all other lesions (or sites of disease), including small lesions 
(longest diameter < 20mm with conventional techniques or < 10mm using spiral CT 
scan). Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques are all non-measurable. 
Methods for Evaluation of Measurable Disease 
All measurements will be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations will be performed as closely as possible to the beginning of 
treatment and never more than 28 days before the beginning of the treatment. 
The same method of assessment and the same technique will be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
Conventional CT and MRI 
These techniques should be performed with cuts of 10 mm or less in slice thickness 
contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction 
algorithm. This applies to tumors of the chest, abdomen, and pelvis. 
Cytology, Histology 
These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
8.1.1.1 Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions, determined by two separate observations conducted 
not less than 4 weeks apart. Any pathological lymph nodes (whether target or non- 
target) must have reduction in short axis to <10 mm (the sum may not be “0” if there are 
target nodes). There can be no appearance of new lesions. 
Partial Response (PR) 

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At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking 
as reference the baseline sum LD. There can be no appearance of new lesions. 
Progressive Disease (PD) 
At least a 20% increase in the sum of the SLD of target lesions, taking as reference the 
smallest sum SLD recorded since the treatment started and minimum 5 mm increase 
over the nadir, or the appearance of one or more new lesions. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD 
taking as reference the smallest sum LD since the treatment started. Patients having a 
documented response with no reconfirmation of the response will be listed with stable 
disease. 
 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker level. If 
tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Incomplete Response/Stable Disease (SD) 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of existing non- 
target lesions. Although a clear progression of “non-target” lesions only is exceptional, in 
such circumstances, the opinion of the treating physician should prevail 
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
Table 3. Response Criteria 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
Category Also Requires 
CR 
CR 
No 
CR 
> 4 weeks confirmation 
CR 
PR 
Non-CR/ 
Non-PD 
Non-PD 
No 
No 
PR 
PR 
> 4 weeks confirmation 
SD 
Non-PD 
No 
SD 
documented at least once > 4 
weeks from baseline 
PD 
Any 
Any 
Any 
PD* 
Any 
Yes or No 
Yes or No 
Yes 
PD 
PD 
PD 
no prior SD, PR or CR 

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* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression 
 
 
 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
The best overall response for an early death, i.e., a patient who dies without 
documentation of disease progression and before it was time to conduct the first tumor 
reassessment, will be considered inevaluable or not assessed adequately. Response 
will also be considered inevaluable for any patient receiving treatment (regardless of 
how much was received) who did not have any follow-up assessment completed before 
initiation of alternative treatment. 
In some circumstances it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends upon this 
determination, it is recommended that the residual lesion be imaged by PET scan or be 
investigated by fine needle aspirate/biopsy before confirming the complete response 
status. 
 
Duration of Response 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are 
met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the 
treatment started. 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment 
to time of progression. 
Evaluation of Safety 
 
Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE v4.03 for reporting of non-hematologic adverse 
events and modified criteria for hematologic adverse events. 
 
For multicenter studies, the Principal Investigator at the UCSF Coordinating Center will 
hold the role of Study Chair. The Study Chair is responsible for the overall conduct of 
the study and for monitoring its safety and progress at all participating sites. 

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8.3 
Definitions of Adverse Events 
8.3.1 Adverse Event 
 
An adverse event (also known as an adverse experience) is defined as any untoward 
medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. More specifically, an adverse event (can be any unfavorable 
and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, without any judgment about causality. An 
adverse event can arise from any use of the drug (e.g., off-label use, use in combination 
with another drug) and from any route of administration, formulation, or dose, including 
an overdose. 
8.3.2 Adverse Reaction 
 
An adverse reaction is defined as any adverse event caused by the use of a drug. 
Adverse reactions are a subset of all suspected adverse reactions for which there is 
reason to conclude that the drug caused the event. 
8.3.2.1 Suspected 
 
A suspected adverse reaction is defined as any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the purposes of IND 
safety reporting, “reasonable possibility” indicates that there is evidence to suggest a 
causal relationship between the drug and the adverse event. A suspected adverse 
reaction implies a lesser degree of certainty about causality than an adverse reaction. 
8.3.2.2 Unexpected 
 
An adverse event or suspected adverse reaction is considered unexpected if it is not 
listed in the investigator brochure or package insert(s), or is not listed at the specificity or 
severity that has been observed, or, if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application. 
“Unexpected,” as used in this definition, also refers to adverse events or 
suspected adverse reactions that are mentioned in the investigator brochure as 
occurring with a class of drugs or as anticipated from the pharmacological properties of 
the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation. 
Adverse events that would be anticipated to occur as part of the disease process 
are considered unexpected for the purposes of reporting because they would not be 
listed in the investigator brochure. For example, a certain number of non-acute deaths 
in a cancer trial would be anticipated as an outcome of the underlying disease, but such 
deaths would generally not be listed as a suspected adverse reaction in the investigator 
brochure. 
Some adverse events are listed in the Investigator Brochure as occurring with 
the same class of drugs, or as anticipated from the pharmacological properties of the 
drug, even though they have not been observed with the drug under investigation. Such 
events would be considered unexpected until they have been observed with the drug 
under investigation. For example, although angioedema is anticipated to occur in some 
patients exposed to drugs in the ACE inhibitor class and angioedema would be 
described in the investigator brochure as a class effect, the first case of angioedema 

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observed with the drug under investigation should be considered unexpected for 
reporting purposes. 
8.3.2.3 Serious 
 
An adverse event or suspected adverse reaction is considered serious if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: 
 
Death 
 
Life-threatening adverse event 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life function 
 
Congenital anomaly/birth defect 
 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
8.3.2.4 Life-threatening 
 
An adverse event or suspected adverse reaction is considered life-threatening if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
8.4 
Recording of an Adverse Event 
 
All grade 3 and above adverse events will be entered into OnCore®, whether or not the 
event is believed to be associated with use of the study drug. Data about these events 
and their severity will be recorded using the NCI CTCAE v4.03. 
The Investigator will assign attribution of the possible association of the event 
with use of the investigational drug, and this information will be entered into OnCore® 
using the classification system listed below: 
 
 
Relationship 
Attribution 
Description 
 
 
Unrelated 
The AE is clearly NOT related to the 
Unrelated to investigational 
drug/intervention 
 
Related to investigational 
drug/intervention 
intervention 
Unlikely 
The AE is doubtfully related to the intervention 
Possible 
The AE may be related to the intervention 
Probable 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention 
 
Signs or symptoms reported as adverse events will be graded and recorded by the 
Investigator according to the CTCAE. When specific adverse events are not listed in the 
CTCAE they will be graded by the Investigator as none, mild, moderate or severe 
according to the following grades and definitions: 

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Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL) 
Grade 3: 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to AE 
8.5 
Follow-up of Adverse Events 
 
All adverse events will be followed with appropriate medical management until resolved. 
Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event. For selected adverse events for which 
administration of the investigational drug was stopped, a re-challenge of the subject with 
the investigational drug may be conducted if considered both safe and ethical by the 
Investigator. 
8.6 
Adverse Events Monitoring 
 
All adverse events, whether or not unexpected, and whether or not considered to be 
associated with the use of the study drug, will be entered into OnCore®, as noted above. 
The Investigator will assess all adverse events beginning at the time of informed 
consent and determine reportability requirements to the UCSF Data and Safety 
Monitoring Committee (DSMC) and UCSF’s Institutional Review Board, the Institutional 
Review Board (IRB); and, when the study is conducted under an Investigational New 
Drug Application (IND), to the Food and Drug Administration (FDA) if it meets the FDA 
reporting criteria. 
All adverse events entered into OnCore® will be reviewed by the Helen Diller 
Family Comprehensive Cancer Center Site Committee on a weekly basis. The Site 
Committee will review and discuss at each weekly meeting the selected toxicity, the 
toxicity grade, and the attribution of relationship of the adverse event to the 
administration of the study drug(s). 
All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a 
monthly basis at the Site Committee meetings. The Site Committee will review and 
discuss the selected toxicity, the toxicity grade, and the attribution of relationship of the 
adverse event to the administration of the study drug(s). 
In addition, all suspected adverse reactions considered “serious” entered into 
OnCore®, will be reviewed and monitored by the Data and Safety Monitoring Committee 
on an ongoing basis and discussed at DSMC meetings, which take place every six 
weeks. 
For a detailed description of the Data and Safety Monitoring Plan for a 
Multicenter Phase 2 or 3 Institutional Study at the Helen Diller Comprehensive Cancer 
Center please refer Appendix 4 Multicenter Institutional Studies. 

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8.7 
Expedited Reporting 
Reporting to the Data and Safety Monitoring Committee 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study 
drug(s) or to a study procedure, the Investigator or his/her designee must notify the 
DSMC Chair (or qualified alternate) within 1 business day of knowledge of the event. 
The contact may be by phone or e-mail. 
Reporting to UCSF Institutional Review Board (IRB) 
The Principal Investigator must report events meeting the UCSF IRB definition of 
“Unanticipated Problem” (UP) within 10 business days of his/her awareness of the event. 
Expedited Reporting to the Food and Drug Administration 
If the study is being conducted under an IND, the Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for 
expedited reporting in accordance with Federal Regulations (21 CFR §312.32). 
The Investigator must report in an IND safety report any suspected adverse 
reaction that is both serious and unexpected. The Investigator needs to ensure that the 
event meets all three definitions: 
 
Suspected adverse reaction 
 
Unexpected 
 
Serious 
 
If the adverse event does not meet all three of the definitions, it should not be submitted 
as an expedited IND safety report. 
The timeline for submitting an IND safety report to FDA is no later than 15 
calendar days after the Investigator determines that the suspected adverse reaction 
qualifies for reporting (21 CFR 312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be 
reported to FDA no later than 7 calendar days after the Investigator’s initial receipt of 
the information (21 CFR 312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND 
safety report will be submitted to FDA as a Follow-up IND Safety Report without delay, 
as soon as the information is available (21 CFR 312.32(d)(2)). 
Reporting to Pharmaceutical Companies providing Study Drug 
Any serious adverse event occurring after the patient has provided informed 
consent and until 4 weeks after the patient has stopped study participation must be 
reported. This includes the period in which the study protocol interferes with the standard 
medical treatment given to a patient (e.g. treatment withdrawal during washout period, 
change in treatment to a fixed dose of concomitant medication). As soon as an 
Investigator becomes aware of an AE that meets the definition of “serious”, this should 
be documented to the extent that information is available. This includes serious, related, 
labeled (expected) and serious, related, unlabeled (unexpected) adverse experiences. 
All deaths during treatment or within 30 days following completion of active protocol 
therapy must be reported within 24 hours. Serious adverse events occurring more than 4 
weeks after study discontinuation need only be reported if a relationship to the study 
drug (or therapy) is suspected. 

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Investigator shall notify the appropriate pharmaceutical company within twenty- 
four (24) hours of making such discovery by submitting the completed SAE report form 
and any other pertinent SAE information as indicated on the SAE reporting form. 
Applicable events will be reported to the IRB and FDA as per current policies. 
This report must be submitted by Institution to the appropriate pharmaceutical 
company even if it is not felt to be drug related: 
 
 
o 
 
o 
 
 
 
 
o 
 
o 
 
 
 
 
o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all 
serious adverse experiences will be forwarded to the product manufacturer by 
the investigator. 
 
Pregnancy (for a subject or for the partner of a subject) that occurs during study 
participation, although not itself an SAE, should be reported. To ensure patient 
safety each pregnancy must also be reported to the appropriate pharmaceutical 
company within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary 
termination, details of birth, and the presence or absence of any birth defects, 
congenital abnormalities or maternal and newborn complications. 
 
 
SAEs that must be recorded on an SAE Reporting form include the following: 

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 
all SAEs that occur after informed consent and through 30 days after the decision 
to discontinue study treatment (or the date the subject is deemed to be a screen 
failure); 
 
any SAEs assessed as related to study treatment or study procedures, even if 
the SAE occurs more than 30 days after the decision to discontinue study 
treatment; 
 
although most hospitalizations necessitate reporting of an SAE, some 
hospitalizations do not require SAE reporting, as follows: 
o elective or previously scheduled surgeries or procedures for pre-existing 
conditions that have not worsened after initiation of treatment (e.g., a 
previously scheduled ventral hernia repair); 
o pre-specified study hospitalizations for observation; or 
o events that result in hospital stays of fewer than 24 hours and that do not 
require admission (e.g., an emergency room visit for hematuria that 
results in a diagnosis of cystitis and discharge to home on oral 
antibiotics). SAEs must, however, be reported for any surgical or 
procedural complication resulting in prolongation of the hospitalization. 
 
 
9 Statistical Considerations and Evaluation of Results 
 
This is a phase II, prospective, multicenter, single arm trial to test the hypothesis that 
targeting specific kinase fusions in melanoma with pre-specified kinase inhibitors will 
result in objective tumor response. Patients will be screened for one of the eligible fusion 
proteins under a separate protocol, and if identified will be treated in this study in one of 
six baskets (ALK, NTRK, ROS1, RET, MET, or BRAF kinase fusions). The primary 
endpoint is composite (all fusion types analyzed together) confirmed objective response 
as defined as a complete or partial response as per RECIST v1.1 criteria. Standard 
therapies such as IL-2 and ipilimumab have shown response rates of approximately 
10%. The newly approved immunotherapy pembrolizumab has a response rate of 
approximately 30%. 
A 2-stage optimal design will be employed in which a 10% response rate is 
considered not promising, a 30% response rate is considered promising, and the 
probabilities of a type I error (falsely accepting a non-promising therapy) and type II error 
(falsely rejecting a promising therapy) are set at 0.05 and 0.1, respectively. In this 
scenario, the maximum trial size would be 35 evaluable patients. Evaluable patients 
would be those with baseline staging, treatment for at least one cycle (with at least 90% 
of intended doses administered during cycle 1), and at least one post-baseline staging 
scan while on treatment. We estimate a drop-out rate of 20%, and therefore 44 patients 
will be enrolled and started on treatment. In the first stage of this design, 11 patients will 
be accrued. If 1 or fewer patients achieve a response among the initial 11 patients, the 
trial will be terminated. If at least 2 patients achieve a response among these 11 patients, 
then an additional 24 patients will be accrued to the second stage. If 6 or fewer patients 
achieve a response in the second stage, the trial will be terminated. Under these 
conditions, if the response rate is 0.1, the probability of ending the trial during           
stage 1 is 0.70. If the true response rate is 0.3, the probability that the trial will be 
stopped in stage I is 0.11. 

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Analysis of study results will be carried out by the study statistician and will 
include overall response rate (ORR) estimations of ALK, NTRK, ROS1, RET, MET, and 
BRAF rearrangement-positive patients. 
Clinical benefit rate (CBR) defined as the proportion of patients achieving a 
complete response (CR) or partial response (PR) or stable disease (SD) for > 24 weeks 
will be estimated for each arm along with a 95% confidence interval. 
Progression free survival (PFS) defined as the time from treatment start to the 
progression or death and overall survival defined as the time from treatment start to 
death will be estimated using Kaplan-Meier methodology. 
Frequencies of toxicities will be tabulated according to CTCAE v4.03 to assess 
drug safety and tolerability. 
Exploratory endpoints will include expression levels (reported as percentage by 
IHC) of the fusion kinase protein. Measures taken at baseline as well as after four weeks 
of therapy will be summarized. Changes in expression level will be assessed between 
baskets using a paired t-test if data permit. For patients who progress on therapy, an 
additional biopsy may be obtained and will be compared with baseline expression levels 
if data permit. This will inform on molecular mechanisms of resistance for patients who 
progress while on therapy. 
 
9.1 
Evaluation of Safety 
 
Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the NCI CTCAE v4.03. 
 
 
10 
Study Management 
10.1 
Pre-study Documentation 
 
This study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with 
GCP and all applicable regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject 
recruitment materials, and any other written information to be provided to subjects before 
any protocol related procedures are performed on any subjects. 
The clinical investigation will not begin until either FDA has determined that the 
study under the Investigational Drug Application (IND) is allowed to proceed or the 
Investigator has received a letter from FDA stating that the study is exempt from IND 
requirements. 
The Investigator must comply with the applicable regulations in Title 21 of the 
Code of Federal Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all 
applicable regulatory requirements. The IRB must comply with the regulations in 21 
CFR §56 and applicable regulatory requirements. 
10.2 
Institutional Review Board Approval 
 
The protocol, the proposed informed consent form, and all forms of participant 
information related to the study (e.g., advertisements used to recruit participants) will be 
reviewed and approved by the UCSF Institutional Review Board (IRB). Prior to obtaining 

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IRB approval, the protocol must be approved by the Helen Diller Family Comprehensive 
Cancer Center Site Committee and by the Protocol Review Committee (PRC). The 
initial protocol and all protocol amendments must be approved by the IRB prior to 
implementation. 
10.3 
Informed Consent 
 
All participants must be provided a consent form describing the study with sufficient 
information for each participant to make an informed decision regarding their 
participation. Participants must sign the IRB-approved informed consent form prior to 
participation in any study specific procedure. The participant must receive a copy of the 
signed and dated consent document. The original signed copy of the consent document 
must be retained in the medical record or research file. 
10.4 
Changes in the Protocol 
 
Once the protocol has been approved by the UCSF IRB, any changes to the protocol 
must be documented in the form of an amendment. The amendment must be signed by 
the Investigator and approved by PRC and the IRB prior to implementation. 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to 
patients, an amendment may be implemented prior to IRB approval. In this 
circumstance, however, the Investigator must then notify the IRB in writing within five (5) 
working days after implementation. The Study Chair and the UCSF study team will be 
responsible for updating any participating sites. 
10.5 
Handling and Documentation of Clinical Supplies 
 
The UCSF Principal Investigator and each participating site will maintain complete 
records showing the receipt, dispensation, return, or other disposition of all 
investigational drugs. The date, quantity and batch or code number of the drug, and the 
identification of patients to whom study drug has been dispensed by patient number and 
initials will be included. The sponsor-investigator will maintain written records of any 
disposition of the study drug. 
The Principal Investigator shall not make the investigational drug available to any 
individuals other than to qualified study patients. Furthermore, the Principal Investigator 
will not allow the investigational drug to be used in any manner other than that specified 
in this protocol. 
10.6 
Case Report Forms (CRFs) 
 
The Principal Investigator and/or his/her designee will prepare and maintain adequate 
and accurate participant case histories with observations and data pertinent to the study. 
Study specific Case Report Forms (CRFs) will document safety and treatment outcomes 
for safety monitoring and data analysis. All study data will be entered into OnCore® via 
standardized CRFs in accordance with the CTMS study calendar, using single data entry 
with a secure access account. The Clinical Research Coordinator (CRC) will complete 
the CRFs as soon as possible upon completion of the study visit; the Investigator will 
review and approve the completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original 
source documents. Source documents will be found in the patient’s medical records 
maintained by UCSF personnel. All source documentation should be kept in separate 
research folders for each patient. 

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In accordance with federal regulations, the Investigator is responsible for the 
accuracy and authenticity of all clinical and laboratory data entered onto CRFs. The PI 
will approve all completed CRFs to attest that the information contained on the CRFs is 
true and accurate. 
All source documentation and CTMS data will be available for review/monitoring 
by the UCSF DSMC and regulatory agencies. 
The Principal Investigator will be responsible for ensuring the accurate capture of 
study data. At study completion, when the CRFs have been declared to be complete 
and accurate, the database will be locked. Any changes to the data entered into the 
CRFs after that time can only be made by joint written agreement among the Study 
Chair, the Trial Statistician, and the Protocol Project Manager. 
10.7 
Oversight and Monitoring Plan 
 
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the 
monitoring entity for this study. The UCSF DSMC will monitor the study in accordance 
with the NCI-approved Data and Safety Monitoring Plan (DSMP). The DSMC will 
routinely review all adverse events and suspected adverse reactions considered 
“serious”. The DSMC will audit study-related activities to ensure that the study is 
conducted in accordance with the protocol, local standard operating procedures, FDA 
regulations, and Good Clinical Practice (GCP). Significant results of the DSMC audit will 
be communicated to the IRB and the appropriate regulatory authorities at the time of 
continuing review, or in an expedited fashion, as applicable. See Appendix 2 Data and 
Safety Monitoring Plan for a Phase 2 or 3 Institutional Study, for additional information. 
10.8 
Record Keeping and Record Retention 
 
The Principal Investigator is required to maintain adequate records of the disposition of 
the drug, including dates, quantity, and use by subjects, as well as written records of the 
disposition of the drug when the study ends. 
The Principal Investigator is required to prepare and maintain adequate and 
accurate case histories that record all observations and other data pertinent to the 
investigation on each individual administered the investigational drug or employed as a 
control in the investigation. Case histories include the case report forms and supporting 
data (e.g., signed and dated consent forms and medical records, such as progress notes 
of the physician, the individual's hospital chart(s), and the nurses' notes. The case history 
for each individual shall document that informed consent was obtained prior to 
participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of 
the clinical research study. 
In accordance with FDA regulations, the investigator shall retain records for a 
period of 2 years following the date a marketing application is approved for the drug for 
the indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified. 

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10.9 
Coordinating Center Documentation of Distribution 
 
It is the responsibility of the Study Chair to maintain adequate files documenting the 
distribution of study documents as well as their receipt (when possible). The HDFCCC 
recommends that the Study Chair maintain a correspondence file and log for each 
segment of distribution (e.g., FDA, drug manufacturer, participating sites, etc.). 
Correspondence file: should contain copies (paper or electronic) of all protocol 
versions, cover letters, amendment outlines (summary of changes), etc., along with 
distribution documentation and (when available) documentation of receipt. 
Correspondence log: should be a brief list of all documents distributed including 
the date sent, recipient(s), and (if available) a tracking number and date received. 
At a minimum, the Study Chair must keep documentation of when and to whom 
the protocol, its updates and safety information are distributed. 
 
10.10 Multicenter communication 
The UCSF Coordinating Center provides administration, data management, and 
organizational support for the participating sites in the conduct of a multicenter clinical 
trial. The UCSF Coordinating Center for Phase II studies will also coordinate, at 
minimum, monthly conference calls with the participating sites at the completion of each 
cohort or more frequently as needed to discuss risk assessment. The following issues 
will be discussed as appropriate: 
 
Enrollment information 
 
Adverse events (i.e. new adverse events and updates on unresolved adverse 
events and new safety information) 
 
Protocol violations 
 
Other issues affecting the conduct of the study 
 
Record Keeping and Record Retention 
 
The Principal Investigator is required to maintain adequate records of the disposition of 
the drug, including dates, quantity, and use by subjects, as well as written records of the 
disposition of the drug when the study ends. 
The Principal Investigator is required to prepare and maintain adequate and 
accurate case histories that record all observations and other data pertinent to the 
investigation on each individual administered the investigational drug or employed as a 
control in the investigation. Case histories include the case report forms and supporting 
data including, for example, signed and dated consent forms and medical records 
including, for example, progress notes of the physician, the individual's hospital chart(s), 
and the nurses' notes. The case history for each individual shall document that informed 
consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of 
the clinical research study. 
In accordance with FDA regulations, the investigator shall retain records for a 
period of 2 years following the date a marketing application is approved for the drug for 
the indication for which it is being investigated; or, if no application is to be filed or if the 

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application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified. 
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed 
consent form, HIPAA authorization and any other information pertaining to participants 
must be approved by the UCSF Institutional Review Board (IRB). Prior to implementing 
this protocol at the participating sites, approval for the UCSF IRB approved protocol 
must be obtained from the participating site’s IRB. 
The following documents must be provided to UCSF HDFCCC before the 
participating site can be initiated and begin enrolling participants: 
 
Participating Site IRB approval(s) for the protocol, appendices, informed consent 
form and HIPAA authorization 
 
Participating Site IRB approved consent form 
 
Participating Site IRB membership list 
 
Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number 
 
Curriculum vitae and medical license for each investigator and consenting 
professional 
 
Documentation of Human Subject Research Certification training for investigators 
and key staff members at the Participating Site 
 
Participating site laboratory certifications and normals 
 
UCSF will also request that all sub-sites send their Data Safety and Monitoring Plan 
(DSMP) to UCSF for review for approval. If a sub-site does not have its own DSMP in 
place, UCSF will at that time review the resources necessary to include that sub-site and 
determine whether the UCSF study personnel are able to manage the regulatory burden 
for that sub-site. Upon receipt of the required documents, UCSF HDFCCC will formally 
contact the site and grant permission to proceed with enrollment. 
 
11 Protection of Human Subjects 
11.1 
Protection from Unnecessary Harm 
 
Each clinical site is responsible for protecting all subjects involved in human 
experimentation. This is accomplished through the IRB mechanism and the process of 
informed consent. The IRB reviews all proposed studies involving human 
experimentation and ensures that the subject’s rights and welfare are protected and that 
the potential benefits and/or the importance of the knowledge to be gained outweigh the 
risks to the individual. The IRB also reviews the informed consent document associated 
with each study in order to ensure that the consent document accurately and clearly 
communicates the nature of the research to be done and its associated risks and 
benefits. 
11.2 
Protection of Privacy 
 
Patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, 
they will be asked to sign the HIPAA form and informed consent documents. The original 
signed document will become part of the patient’s medical records, and each patient will 
receive a copy of the signed document. The use and disclosure of protected health 
information will be limited to the individuals described in the informed consent document. 

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12.0 References 
 
1. Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2012. CA. Cancer J. Clin. 
62, 10–29 (2012). 
2. Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in 
BRAF-mutant melanoma. Nature 467, 596–599 (2010). 
3. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF 
V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011). 
4. Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. 
N. Engl. J. Med. 363, 809–819 (2010). 
5. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 
(2002). 
6. Daud, A. & Bastian, B. C. Beyond BRAF in melanoma. Curr. Top. Microbiol. 
Immunol. 355, 99–117 (2012). 
7. Hamid, O. et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in 
melanoma. N. Engl. J. Med. 369, 134–144 (2013). 
8. Robert, C. et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in 
ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort  
of a phase 1 trial. Lancet (2014). doi:10.1016/S0140-6736(14)60958-2 
9. Colombino, M. et al. BRAF/NRAS mutation frequencies among primary tumors and 
metastases in patients with melanoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 
30, 2522–2529 (2012). 
10. Soon, C. W. M., Algazi, A. P., Cha, E. N., Webb, E. M. & Daud, A. I. NRAS-mutant 
melanoma: response to chemotherapy. Arch. Dermatol. 147, 626–627 (2011). 
11. Van Raamsdonk, C. D. et al. Frequent somatic mutations of GNAQ in uveal 
melanoma and blue naevi. Nature 457, 599–602 (2009). 
12. Van Raamsdonk, C. D. et al. Mutations in GNA11 in uveal melanoma. N. Engl. J. 
Med. 363, 2191–2199 (2010). 
13. Wiesner, T. et al. Kinase fusions are frequent in Spitz tumours and spitzoid 
melanomas. Nat. Commun. 5, (2014). 
14. Botton, T. et al. Recurrent BRAF kinase fusions in melanocytic tumors offer an 
opportunity for targeted therapy. Pigment Cell Melanoma Res. 26, 845–851 (2013). 
21. Marsilje, T. H. et al. Synthesis, structure-activity relationships, and in vivo efficacy of 
the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro- 
N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2- 
(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (CERITINIB) currently in phase 1 
and phase 2 clinical trials. J. Med. Chem. 56, 5675–5690 (2013). 
22. Shaw, A. T. et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N. Engl. J. 
Med. 370, 1189–1197 (2014). 
23. Kim, Dong-Wan. Ceritinib in advanced anaplastic lymphoma kinase (ALK)- 
rearranged (ALK+) non-small cell lung cancer (NSCLC): Results of the ASCEND-1 
trial. (2014). at <http://meetinglibrary.asco.org/content/92501> 
24. Wilhelm, S. M. et al. Regorafenib (BAY 73-4506): A new oral multikinase inhibitor of 
angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical 
antitumor activity. Int. J. Cancer 129, 245–255 (2011). 
25. Grothey, A. et al. Regorafenib monotherapy for previously treated metastatic 
colorectal cancer (CORRECT): an international, multicentre, randomised, placebo- 
controlled, phase 3 trial. Lancet 381, 303–312 (2013). 

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26. Demetri, G. D. et al. Efficacy and safety of regorafenib for advanced gastrointestinal 
stromal tumours after failure of imatinib and sunitinib (GRID): an international, 
multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381, 295–302 
(2013). 
27. George, S. et al. Efficacy and safety of regorafenib in patients with metastatic and/or 
unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter 
phase II trial. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 30, 2401–2407 (2012). 
28. Therasse, P. et al. New guidelines to evaluate the response to treatment in solid 
tumors. European Organization for Research and Treatment of Cancer, National 
Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl. 
Cancer Inst. 92, 205–216 (2000). 

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13.1 Appendices 
Appendix 1 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on 
all pre-disease performance 
without restriction 
100 
Normal, no complaints, no 
evidence of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease 
1 
Symptoms, but ambulatory 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or 
sedentary nature (e.g., light 
housework, office work) 
80 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work 
2 
In bed < 50% of the time 
Ambulatory and capable of all 
self-care, but unable to carry 
out any work activities 
Up and about more than 50% 
of waking hours 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs 
50 
Requires considerable assistance 
and frequent medical care 
3 
In bed > 50% of the time 
Capable of only limited self- 
care, confined to bed or chair 
more than 50% of waking 
hours 
40 
Disabled, requires special care 
and assistance 
30 
Severely disabled, hospitalization 
indicated 
Death not imminent 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or 
chair 
20 
Very sick, hospitalization 
indicated 
Death not imminent 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 
 
 
 
 

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Appendix 2 Multicenter Institutional Studies 
Data and Safety Monitoring Plan for Multicenter Study (Phase 2 or 3 
Institutional Study) 
 
 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and 
Safety Monitoring Committee (DSMC) is responsible for monitoring data quality and 
subject safety for all HDFCCC institutional clinical studies. A summary of DSMC 
activities for this study include: 
 
Review of subject data 
 
Review of suspected adverse reactions considered “serious” 
 
Monitoring every six months (depending on study accrual) 
 
Minimum of a yearly regulatory audit 
Monitoring and Reporting Guidelines 
 
All institutional Phase 2 or 3 therapeutic studies are designated with a moderate risk 
assessment. The data is monitored every six months, with twenty percent of the subjects 
monitored (or at least three subjects if the calculated value is less than three). 
 
The UCSF Coordinating Center provides administration, data management, and 
organizational support for the participating sites in the conduct of a multicenter clinical 
trial. The UCSF Coordinating Center will also coordinate quarterly conference calls with 
the participating sites to communicate the review of adverse events, safety data, and 
other study matters. 
 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study 
Chair. The Study Chair is responsible for the overall conduct of the study and for 
monitoring its safety and progress at all participating sites. The Study Chair will conduct 
continuous review of data and subject safety and discuss each subject’s treatment at 
monthly UCSF Site Committee meetings. The discussions are documented in the UCSF 
Site Committee meeting minutes. 
Multicenter communication 
 
The UCSF Coordinating Center provides administration, data management, and 
organizational support for the participating sites in the conduct of a multicenter clinical 
trial. The UCSF Coordinating Center will also coordinate, at minimum, quarterly 
conference calls with the participating sites or more frequently as needed to discuss risk 
assessment. The following issues will be discussed as appropriate: 
 
Enrollment information 
 
Adverse Events (i.e., new adverse events and updates on unresolved adverse 
events and new safety information) 
 
Protocol Violations 
 
Other issues affecting the conduct of the study 
Adverse events reporting to the DSMC will include reports from both the UCSF 
Coordinating Center, as well as the participating sites. The DSMC will be responsible for 
monitoring all data entered in OnCore® at the UCSF Coordinating Center and the 
participating sites. The data (i.e. copies of source documents) from the participating sites 

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will be faxed over to the UCSF Coordinating Center prior to the monitoring visits in order 
for the DSMC to monitor the participating site’s compliance with the protocol, patient 
safety, and to verify data entry. 
Adverse Event Review and Monitoring 
All grade(s) 3-5 adverse events, whether or not unexpected, and whether or not 
considered to be associated with the use of the study drug, will be entered into 
OnCore®, UCSF’s Clinical Trial Management System. 
 
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis 
at the UCSF Site Committee meetings. All clinically significant adverse events must be 
reported to the UCSF Coordinating Center by the participating sites within 10 business 
days of becoming aware of the event or during the next scheduled quarterly conference 
call, whichever is sooner. The UCSF Site Committee will review and discuss the 
selected toxicity, the toxicity grade, and the attribution of relationship of the adverse 
event to the administration of the study drug(s) from the UCSF Coordinating Center and 
the participating sites. 
 
In addition, all suspected adverse reactions considered “serious” must be entered in 
OnCore® and reported to the UCSF Coordinating Center within 1 business day. The 
suspected adverse reactions considered “serious” will be reviewed and monitored by the 
Data and Safety Monitoring Committee on an ongoing basis and discussed at the DSMC 
meeting, which take place every six (6) weeks. 
 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the 
investigational drug or any research related procedure, the Study Chair at the UCSF 
Coordinating Center or the assigned designee must be notified within 1 business day 
from the participating site(s) and the Study Chair must then notify the DSMC Chair or 
qualified alternate within 1 business day of this notification. The contact may be by 
phone or e-mail. 
Increase in Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported 
in the Investigator Brochure or package insert) is noted in the study, the Study Chair at 
the UCSF Coordinating Center is responsible for notifying the DSMC at the time the 
increased rate is identified. The report will indicate if the incidence of adverse events 
observed in the study is above the range stated in the Investigator Brochure or package 
insert. 
 
If at any time the Study Chair stops enrollment or stops the study due to safety issues, 
the DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail. 
The DSMC must receive a formal letter within 10 business days and the IRB must be 
notified. 
Data and Safety Monitoring Committee Contacts 
 
DSMC 
Chair: 
 
DSMC Monitors 
Phone: 
Email: 
Address: 
 
 
 
Box 0128 
UCSF Helen Diller Family 
Comprehensive Cancer Center 

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San Francisco, CA 94143 
 
* DSMP approved by NCI 09/February2012 
 
 
 
Policy/Procedure for Required Regulatory Documents for Single Site and 
Multicenter Investigator-Initiated Oncology Clinical Trials 
 
Purpose 
 
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator-Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive 
Cancer Center (HDFCCC) for both IND and IND-exempt trials. 
 
Background 
 
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) 
Guidelines define Essential Regulatory Documents as those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of 
data produced. These documents serve to demonstrate compliance with standards of 
GCP and with all applicable regulatory requirements. Filing essential documents in a 
timely manner can greatly assist in the successful management of a clinical trial. 
 
The Regulatory Documents will consist mostly of electronic files in both iRIS and 
OnCore, as well as a few paper files in the Regulatory Binders for both the Coordinating 
Site and the Participating Site(s) in all HDFCCC Investigator Initiated Oncology Clinical 
Trials. 
 
Procedures 
 
1. Single Site (HDFCCC) Therapeutic Essential Regulatory Documents: 
 
Documents Filed in iRIS: 
 
 
Current and prior versions of the Informed Consent Form(s) (ICFs). 
 
IRB approvals for initial submission of application, all modifications, and 
continuing annual renewals. 
 
Current and prior approved protocol versions. 
 
IRB roster 
 
Current and prior versions of the Investigator Brochure (IB). 
 
Serious Adverse Event (SAE) Reports. 
 
Subject diary and handouts (if applicable). 
 
Single Patient Exception (SPE) Report(s) to IRB with Approval Letter(s) from 
IRB. 
 
Protocol Violation (PV) Reports with acknowledgement from the IRB. 

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Documents Filed in OnCore: 
 
 
Package Insert (if the study drug is commercial). 
 
Protocol signature page(s) with PI signature(s) for all protocol versions. 
 
Protocol Review Committee (PRC) approved protocols, protocol amendments 
and Summary of Changes (SOC) document. 
 
Screening/enrollment log. 
 
Data and Safety Monitoring Committee (DSMC) monitoring reports. 
 
DSMC dose escalation approvals with study status summary forms. 
 
Case Report Form (CRF) completion manual. 
 
Drug Destruction Standard Operating Procedure (SOP). 
 
Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator’s signature. 
 
For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will 
need Financial Disclosure Forms, CVs, MD Licenses, and Staff Training 
Documents (i.e., Collaborative Institute Training Initiative (CITI), etc.). 
 
As applicable, approvals for Biosafety Committee, Radiation Committee, and 
Infusion Center. 
 
Serious Adverse Event (SAE) reports to IRB and sponsor. 
 
MedWatch reporting to FDA and sponsor. 
 
Drug Destruction Standard Operating Procedure (SOP). 
 
For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CV(s) and Medical License(s) of Lab Director(s), and 
laboratory reference ranges. 
 
Documents Filed in Regulatory Binder: 
 
 
Delegation of Authority Log with signatures (to be scanned in OnCore once the 
trial is complete). 
 
2. Additional Essential Documents for Therapeutic Multicenter Trials for the  
Coordinating Center (filed in OnCore or Zip Drive): 
 
 
Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent 
Form (ICF), and Health Insurance Portability and Accountability Act (HIPAA) 
Consent Form for the Participating Site(s). 
 
For all Principal Investigators and Sub-Investigators listed on the 1572 at the 
Participating Site(s), will need Financial Disclosure Forms, CVs, MD Licenses, 
and Staff Training documents (i.e. Collaborative Institute Training Initiative (CITI), 
etc.) (for Investigational New Drug Application). 
 
Site Initiation Visit (SIV) minutes and correspondence with the Participating 
Site(s). 
 
As applicable, approvals for Biosafety Committee, Radiation Committee, and 
Infusion Center for the Participating Site(s). 
 
Protocol Violations (PV) Reports to IRB with acknowledgement from IRB for 
Participating Site(s). 
 
Single Patient Exception (SPE) Reports to IRB with IRB Approval Letters for 
Participating Site(s). 

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 
Drug Destruction Standard Operating Procedure (SOP) for the Participating 
Site(s). 
 
Data and Safety Monitoring Committee (DSMC) monitoring reports for the 
Participating Site(s). 
 
For all laboratories listed on FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs and Medical License(s) of Lab Director(s), and 
laboratory reference ranges for the Participating Site(s). 
 
Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all 
participating site(s) in Multicenter studies or Contract Research Organization 
(CRO) Monitoring Plan (if an outside CRO is used for the study). 
 
Serious Adverse Event (SAE) forms submitted to the IRB for the Participating 
Site(s). 
 
Alternate Procedures 
 
There are no alternate procedures to the HDFCCC policy for requirements for Essential 
Regulatory Documents for Multicenter Investigator-Initiated Oncology Clinical Trials. 
 
References 
 
• 
ICH Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance 
(current version). 
• 
International Conference on Harmonization: Good Clinical Practice: Consolidated 
Guideline (current version). 
• 
International Conference on Harmonization: Essential Documents for the Conduct 
of a Clinical Trial (current version). 
• 
21CFR50 
• 
21 CFR56.11 
• 
45CFR46 
21 CFR312 
 
Required Regulatory Documents for Sub-sites Participating in Therapeutic UCSF 
Investigator Initiated Multicenter trial 
Directions: Scan the documents in a zip drive and upload to OnCore. 
1572 
PI and Sub investigators: 
 CV and Medical license 
 Financial disclosure form 
 NIH or CITI human subject protection training certification 
 
 
Laboratories: 

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 CLIA &CAP and Lab Licenses 
 CV and Medical License of Lab Director 
 Laboratory reference ranges 
Local Institutional Review Board 
 
IRB Approval letter 
Reviewed/Approved documents 
 Protocol version date: 
  
 
 Informed consent version date:    
 
 Investigator Brochure version date:    
 
 HIPAA 
 
Current IRB Roster 
 
 
Other 
 
Delegation of Authority Log 
 Include NIH or CITI human subject protection training certificates or GCP 
training certification 
Pharmacy 
 Drug destruction SOP and Policy 
Protocol signature page 
Executed sub contract 

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Appendix 3 Prohibited Medications 
 
The prohibited medications are basket-specific. Please refer to the drug-specific 
appendices for further information on prohibited medications. 
 
 
For patients with MET fusion to be treated with capmatinib, see Appendix 6, 
Section 6.11. 
 
For patients with ALK fusion to be treated with ceritinib, see Appendix 7, Section 
7.11. 
 
For patients with RET or BRAF fusion to be treated with regorafenib, see 
Appendix 8, Section 8.11. 
 
For patients with NTRK1, NTRK2, NTRK3, or ROS1 fusion to treated with 
entrectinib, see Appendix 9, Section 9.11. 
 
 
Each drug also has specific restrictions on the use of therapeutic and prophylactic 
anticoagulation. These are summarized in Table X below: 
 
Table 4. Drug-specific restrictions on anticoagulation 
 
Study drug 
Warfarin 
(T) 
Warfarin 
(P) 
Heparin 
(T) 
Heparin 
(P) 
DTI, FXa 
inhibitor 
Low- 
dose 
ASA 
Clopidogrel 
Capmatinib 
With 
caution 
With 
caution 
Permitted 
Permitted 
Permitted 
Permitted 
Permitted 
Ceritinib 
Not 
permitted 
Not 
permitted 
Permitted 
Permitted 
Permitted 
Permitted 
Permitted 
Regorafenib 
Not 
permitted 
Permitted* 
Not 
permitted 
Permitted* 
Permitted 
Permitted 
Permitted 
Entrectinib 
Permitted 
Permitted 
Permitted 
Permitted 
Permitted 
Permitted 
Permitted 
T: therapeutic 
P: prophylactic 
DTI: Direct thrombin inhibitor 
FXa: Factor Xa 
Low-dose ASA: Low-dose aspirin, <=81 mg daily 
* Prophylactic doses of warfarin or heparin agents resulting in PT/INR and/or PTT <=1.5 X ULN are permitted. 
Infrequent bleeding or elevations in PT/INR have been reported in some subjects taking warfarin while on regorafenib 
therapy. Therefore, subjects taking concomitant prophylactic anticoagulation should be monitored regularly for 
changes in PT/INR and PTT or clinical bleeding episodes. 

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Appendix 4 Specimen Collection 
 
 
Correlative studies assessments 
Tumor biopsy specimens are to be immediately immersed in formalin. 
Sample shipment instructions 
 
For each shipment, an inventory of the samples should accompany the shipment. This 
inventory should include the study ID, subject ID, sample number, visit number 
scheduled time of collection. 
The original inventory will be retained at the site in the Investigator’s file. 
 
All samples will be kept at room temperature up to and during the shipment. Unless 
instructed otherwise, the samples will be packed carefully with suitable packing material 
with absorbent material in case of leakage. 
 
All shipments should be sent by a carrier guaranteeing overnight delivery. The following 
items should be considered: 
 
 
Advise the carrier of the type of service desired, need for personalized door-to- 
door pickup, and delivery guaranteed within 24 hours. 
 
Advise the carrier of the nature of the shipment's contents (human biological 
specimens) and label the package accordingly. 
Instructions for shipment of biological samples to UCSF : 
 
 
 
 
 
 
 
 
Instructions for shipment (and storage) of blood samples: