Clinical trial NCT02587650
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
Start date: 2015-03-26; Completion date: 2018-07-12
Enrollment: 1 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well capmatinib, ceritinib, regorafenib, or entrectinib work in treating patients with BRAF/NRAS wild-type stage III-IV melanoma. Capmatinib, ceritinib, regorafenib, or entrectinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the clinical activity of tyrosine kinase inhibitors matched to the tumor-specific fusion kinase in patients with metastatic melanoma.

SECONDARY OBJECTIVES:

I. To estimate tumor stability in melanoma patients treated with kinase inhibitors matched to the tumor-specific fusion kinase.

II. To estimate survival in melanoma patients treated with kinase inhibitors matched to the tumor-specific fusion kinase.

III. To examine the safety and tolerability of kinase inhibitors in patients with melanoma with a fusion kinase.

TERTIARY OBJECTIVES:

I. To explore molecular mechanisms of resistance for patients who progress on therapy.

OUTLINE: Patients are assigned to 1 of 4 arms.

ARM A: Patients with MET fusion receive capmatinib orally (PO) twice daily (BID) on day 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.

ARM B: Patients with ALK fusion receive ceritinib PO once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.

ARM C: Patients with RET or BRAF fusion receive regorafenib PO QD on day 1-21. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.

ARM D: Patients with NTRK1, NTRK2, NTRK3, or ROS1 fusion receive entrectinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.

After completion of study treatment, patients are followed up within 30 days and then periodically.

Arms: arm 1: Patients with MET fusion receive capmatinib PO BID on day 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity. arm 2: Patients with ALK fusion receive ceritinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity. arm 3: Patients with RET or BRAF fusion receive regorafenib PO QD on day 1-21. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity. arm 4: Patients with NTRK1, NTRK2, NTRK3, OR ROS1 fusion receive entrectinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.
Interventions: intervention 1: Capmatinib intervention 2: Ceritinib intervention 3: Entrectinib intervention 4: Laboratory Biomarker Analysis intervention 5: Regorafenib
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given PO intervention 4: Correlative studies intervention 5: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
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 


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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 
 
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4. Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. 
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5. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 
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6. Daud, A. & Bastian, B. C. Beyond BRAF in melanoma. Curr. Top. Microbiol. 
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melanoma: response to chemotherapy. Arch. Dermatol. 147, 626–627 (2011). 
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13. Wiesner, T. et al. Kinase fusions are frequent in Spitz tumours and spitzoid 
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14. Botton, T. et al. Recurrent BRAF kinase fusions in melanocytic tumors offer an 
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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 
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23. Kim, Dong-Wan. Ceritinib in advanced anaplastic lymphoma kinase (ALK)- 
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colorectal cancer (CORRECT): an international, multicentre, randomised, placebo- 
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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, 
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(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: 
 
 
 
 
 

ICF_001.pdf: 
IRB NUMBER: 15-15712
IRB APPROVAL DATE: 02/22/2018
IRB EXPIRATION DATE: 02/21/2019
Consent Form (main) 09-20-2017 
Page 1 of 25
UCSF CC#14859
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
Study Title: CC# 14859: A Phase II Trial of Targeted Kinase Fusion Inhibition in 
BRAF/NRAS Wild-Type Melanoma
This is a clinical trial, a type of research study. Your study doctors Adil Daud, MD and Iwei 
Yeh, MD, PhD or one of their associates from the UCSF Helen Diller Family Comprehensive 
Cancer Center will explain the clinical trial to you.
Clinical trials include only people who choose to take part. Please take your time to make your 
decision about participating. You may discuss your decision with your family and friends and 
with your health care team. If you have any questions, you may ask your study doctor.
You are being asked to take part in this study because you have locally advanced or metastatic 
melanoma that has spread or that cannot be cured by surgery.
Why is this study being done?
The purpose of this study is to test the effectiveness (how well the drug works), of an 
investigational drug based on your biomarker status. You are being asked to participate in this 
clinical trial because you have undergone screening for specific biomarkers prior to being 
enrolled in the main part of this study. The screening involves genomic testing. If you have 
already tested positive for the biomarkers relevant in this study in an approved lab, you may be 
eligible to participate in this clinical trial. If you have not been tested, you will be invited to 
participate in an affiliated UCSF study (Study #14-14351), where you are screened for the 
relevant biomarkers. You will not be charged for biomarker testing if you participate in the 
screening study. If you have already been screened at a separate approved lab, covered by your 
insurance, you may also be potentially eligible for enrollment in this clinical trial. The 
biomarker test is investigational, this means it has not been approved by U.S. Food and Drug 
Administration (FDA) for use in melanoma patients.
The biomarkers being tested for are ALK, BRAF, MET, NTRK1, NTRK2, NTRK3, RET and 
ROS1. Biomarkers are substances in your tissues that may provide information on any changes
to your genes or DNA, how your cancer cells are responding to study treatment and whether
your cells are becoming resistant (no longer responding) to the study treatment. You will be
assigned one of four study drugs depending on which biomarker is identified in your tumor.
Two of these study drugs, ceritinib and regorafenib, have been FDA approved for use in patients
with lung cancer and colorectal cancer, respectively however, their use in advanced melanoma 
patients is not FDA approved and is therefore an investigational use of the drugs in this study.
Additionally, the other two study drugs, capmatinib (otherwise known as INC280) and 
entrectinib (otherwise known as RXDX-101) have not been approved by the FDA for use in 
cancer patients, including melanoma patients and is therefore an investigational use of the drugs
NCT# 02587650


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IRB EXPIRATION DATE: 02/21/2019
Consent Form (main) 09-20-2017 
Page 2 of 25
UCSF CC#14859
in this study. In animal studies, lab experiments, and in some early human studies, the study 
drugs, have been shown to prevent or slow the growth of cancer cells.
If you decide to participate, you will be enrolled into one of these 4 groups:

Arm A: Treatment with ceritinib if you have been identified with the ALK biomarker

Arm B: Treatment with capmatinib (INC280) if you have been identified with the MET
biomarker

Arm C: Treatment with regorafenib if you have been identified with the BRAF or RET
biomarker

Arm D: Treatment with entrectinib (RXDX-101) if you have been identified with the
NTRK1, NTRK2, NTRK3 or ROS1 biomarker
Funding for this study is being provided by Bayer, Ignyta and Novartis.
How many people will take part in this study?
Approximately 35 patients will be participating in this study in sites across the US. About 15 
people will take part in this study at UCSF.
What will happen if I take part in this research study?
If you give your consent to be in this study by signing this form, you will have tests and 
procedures (called “screening”) done. These are done to reduce the risks of taking part in this 
study and to make sure it is okay for you to be in the study.
It is possible that after these tests are reviewed, you will not be able to be in the study. There may 
be other reasons why you cannot be in this study. Your study doctor or the clinic staff will 
discuss these reasons with you.
Your study doctor will also discuss with you the possibility of receiving or continuing treatment 
with ipilimumab or the anti-PD-1 antibodies, nivolumab or pembrolizumab. Ipilimumab is FDA 
approved for treatment of melanoma and your doctor will discuss with you if this is the best 
treatment option for you. FDA approval of ipilimumab was based on a clinical trial that showed 
that patients treated with ipilimumab had an overall survival of 10 months, whereas patients 
treated with an investigational tumor vaccine had an overall survival of 6 months. The response 
rate for patients treated with ipilimumab was 10.9% in one study. Both pembrolizumab and 
nivolumab are also approved for the treatment of melanoma, both are associated with prolonged 
responses in patients with melanoma such as yours and may improve survival. You may 
participate in this trial if either of these treatments fail or if you wish prior to using these 
treatments.


IRB NUMBER: 15-15712
IRB APPROVAL DATE: 02/22/2018
IRB EXPIRATION DATE: 02/21/2019
Consent Form (main) 09-20-2017 
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UCSF CC#14859
Screening period
After you have signed this consent, the screening tests listed below will be done within 30 days 
of your first dose of study drugs. You will need to have the following exams, tests or procedures 
to find out if you can be in the main part of the study. Most of these exams, tests or procedures 
are part of your regular cancer care (unless notes otherwise as Research Purposes). If you have 
had some of them recently, they may not need to be repeated. This will be up to your study 
doctor.
The total time to complete the screening tests and procedures is about 8-12 hours. The screening 
procedures do not have to be completed in one day and you are allowed to take breaks if you 
have multiple tests in one day.

You will have a complete physical exam and your current symptoms will be reviewed.

You will be asked about your medical history including any past treatments or surgeries
for your disease. Your performance status (your ability to carry out your daily activities) 
will be assessed.

Your vital signs (height, weight, temperature, breathing rate, blood pressure, pulse, and
oxygen saturation) will also be recorded.

You will have an ECG (electrocardiogram).
o
Electrocardiogram (ECG): records the electrical activity of your heart. Wires or
“leads” will be attached to your chest with an adhesive and you will be asked to lie 
still while the machine prints out an electrical “record” of your heart activity. The 
procedure is done in the Cardiology Department takes about 15-30 minutes.

Blood will be drawn to check your health, conduct routine safety tests and blood sugar
levels. When your blood sugar is checked you will be asked to fast (no food or drink 
other than water) at least 12-14 hours before having blood drawn for this test. About 6 
teaspoons of blood will be drawn for these tests.

Urine tests

You will have a CT scan. Your doctor may decide to do a MRI scan instead of a CT scan.
o
A CT scan uses special x-ray equipment to make detailed pictures of body tissues
and organs. For the CT scan, you may be given a "contrast material" (a special dye 
that makes it easier for doctors to see different tissues in your body). The contrast 
material may be given orally, intravenously, or rectally (less likely). Oral contrast 
material is given to you to drink and is used to help outline the stomach  and intestines. 
Intravenous (IV) contrast material is given to you by injecting the contrast material into 
a line which is attached to a needle in your arm, and is used to get clearer pictures 
of your body cavity. A rectal contrast fills up the loops of your lower bowel so the 
doctors can see your tumor better. After you have been given the contrast material 
(either by mouth, by vein, or rectum), you will lie flat on a table that will move you 
into the CT scan machine.  You will be asked to lie still and may be


IRB NUMBER: 15-15712
IRB APPROVAL DATE: 02/22/2018
IRB EXPIRATION DATE: 02/21/2019
Consent Form (main) 09-20-2017 
Page 4 of 25
UCSF CC#14859
asked to hold your breath for a few seconds.  The CT scan is done in the Radiology 
Department and takes about half an hour.
o
An MRI scan takes an image of your head or body to observe the location and size of
your tumor. For the MRI scan, you may be given a "contrast material" (a special dye
that makes it easier for doctors to see different tissues in your body). Gadolinium is 
contrast material that causes some tumors to appear much brighter than normal tissue 
on MRI scans (these tumors may not be visible without gadolinium). The contrast 
material may be given to you in your arm through an intravenous catheter (a tiny tube 
inserted into a vein).  You will then lie down on a narrow bed which will be placed in 
a tunnel that is 6 feet long by 22 inches wide and open at each end.  You will lie there 
quietly for about one hour, during which time you will hear a loud machine-like 
noise. The MRI scan is done in the Radiology Department and takes approximately 
an hour and a half to complete.
The following procedures will be done for research purposes:

Questions about how your disease is affecting your daily life

You will be asked to provide a piece of stored tumor sample from previous
biopsies or surgeries you may have had in the past before you joined this study. 
This sample can be used to study your cancer. This will help researchers better 
understand the reasons for cancer development, growth, spread, and its response 
to treatment. Your consent to provide a sample of your stored tumor tissue if 
available is required to take part in this study.

Blood will be drawn (approximately 2 tablespoons) for:
o
Blood safety and chemistry tests

Pregnancy test (only required in women of child-bearing potential)
Treatment period
Based on the results of the screening visit tests and procedures, if you are eligible to participate 
in the study, you will return to the study doctor's office/clinic and will be assigned to either Arm 
A, Arm B, Arm C, or Arm D depending on which biomarker is identified in your tumor. The 
study doctor will let you know which treatment you have been assigned to.
Description of Study Treatment:
Upon entry into the study, you will be assigned by your biomarker status, to receive the 
following study drug:

Arm A - ALK biomarker: You will be given study drug ceritinib, or;

Arm B - MET biomarker: You will be given study drug capmatinib or;

Arm C – BRAF or RET biomarker: You will be given study drug regorafenib, or;


IRB NUMBER: 15-15712
IRB APPROVAL DATE: 02/22/2018
IRB EXPIRATION DATE: 02/21/2019
Consent Form (main) 09-20-2017 
Page 5 of 25
UCSF CC#14859

Arm D – NTRK1, NTRK2, NTRK3 or ROS1 biomarker: You will be given study drug
entrectinib.
Each period of treatment is called a “cycle” and one cycle is 28 days long or 4 weeks. If you are 
assigned to Arm A, Arm B or Arm D you will take the study drug orally daily for all 28 days. If 
you are assigned to Arm C you will take the study drug orally for the first 21 days (3 weeks) of 
the 28 day cycle.
Day 1 of every cycle, ALL patients will come in for the following tests (each of these visits 
will take about 2 hours):

Physical examination

Vital signs

Urine tests

Blood will be drawn (approximately 3 tablespoons) for safety tests

CT/MRI - odd cycles only (Cycle 3, 5, 7, etc.)
The following procedures will be done for research purposes:

You will be given your study drug

Evaluation of any side effects

Questions about how your disease is affecting your daily life

You will be asked about any medicines you are taking including over-the-counter
medicines, vitamins, or herbal treatments.

Pregnancy test (women of child-bearing potential)
You must have a negative pregnancy test to receive or continue receiving study 
drug. Following your first dose, you will have a pregnancy test (urine or blood) 
every 4 weeks.

Tumor biopsy (skin or tissue) will be done at Cycle 2, Day 1 (± 7 days), at time of
progression and/or at the discretion of your doctor. Punch or core biopsy is 
mandatory, and the procedure will be slightly different depending on whether the 
tumor is located on the skin or elsewhere.
o
Tumor biopsy (skin): In this procedure, your doctor will remove a small
piece of skin (the size of a pencil eraser). The area of the biopsy will be 
numbed with local anesthesia before this biopsy is taken. You may get 
stitches in the area where the biopsy is taken from. The biopsy will take 
about 20 minutes to complete.
o
Tumor biopsy (non-skin): As part of this study, we will obtain a small
piece of tumor tissue using a special needle. This procedure will be done 
at the site where we can most easily get a piece of the tumor and the 
biopsy can involve the lungs, liver, bone, lymph node, or other. The 
biopsy needle will be inserted into tumor tissue and a small piece of the 
tumor will be removed. 1-3 passes with this needle will be made. The 
tissue is being used to help us determine if certain types of tumors might 
respond better to certain treatments. This procedure takes about 30 
minutes. You will sign a separate consent form for this procedure.


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Schedule for Each Arm
Outlined below is the schedule you will follow depending on your treatment arm. Your study 
doctor will help you understand this process. Additional ECGs and/or blood tests may be 
collected at the discretion of your doctor if deemed medically necessary.
Arm A patients – study drug Ceritinib

ECG before and after drug dose on Cycle 1, Day 1; before drug dose on Cycle 2, Day 1;
and before drug dose on Day 1 of all subsequent even-numbered cycles.every 4 weeks 
starting Cycle 1, Day 1
The following procedures will be done for research purposes:

Coagulation tests – weekly the first 4 weeks starting Cycle 1, Day 1, every two
weeks starting Cycle 2, Day 1; then every 4 weeks starting Cycle 3, Day 1
Arm B patients – study drug Capmatinib (INC280)

Coagulation Blood tests – every two weeks starting Cycle 1, Day 1; then every 24 weeks
starting Cycle 23, Day 1; then every 4 weeks starting Cycle 5, Day 1.

Thyroid tests every 4 weeks starting Cycle 2, Day 1

Urine tests – every two weeks starting Cycle 1, Day 1; then every 4 weeks starting Cycle
2, Day 1.

ECG – every 8 weeks starting Cycle 3 Day 1.
Arm C patients – study drug Regorafenib

Blood tests – weekly the first 4 weeks starting Cycle 1, Day 1, every two weeks starting
Cycle 2, Day 1; then every 4 weeks starting Cycle 3, Day 1

ECG on Cycle 3, Day 1, and on Day 1 of all subsequent odd cycles (every 8 weeks).
Arm D patients – study drug Entrectinib (RXDX-101)

Blood tests – every two weeks starting Cycle 1, Day 1; then every 4 weeks starting Cycle
4, Day 1.

Urine tests – every two weeks starting Cycle 1, Day 1; then every 4 weeks starting Cycle
4, Day 1.

ECG on Cycle 1, Day 1, and on Day 1 of all subsequent cycles (every 4 weeks).
End of Treatment Visit End of Treatment Visit (this visit will take between 3-6 hours 
depending on your procedures)

Physical examination

Vital signs

Blood will be drawn (approximately 3 tablespoons) for safety tests

Urine tests

ECG

CT scan or MRI


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The following procedures will be done for research purposes:

Evaluation of any side effects

Questions about how your disease is affecting your daily life

You will be asked about any medicines you are taking including over-the-counter
medicines, vitamins, or herbal treatments.

Tumor biopsy

Skin biopsy

Blood will be drawn (approximately 1 tablespoon) for:
Blood chemistry tests

Pregnancy test
Post treatment follow-up
Once you have discontinued all study treatments, your provider or study coordinator will give 
you a call within 30 days following the last dose of study treatment to see how you are doing 
(you will be asked about your health, any side effects, and any medications or treatments you 
might be taking); this is for research purposes). You will be followed for survival information 
and to see how you are doing via a telephone call every few months. You don’t have to come 
back to the clinic.
Study location: All study procedures (clinic visits, biopsies, imaging studies, blood draws, urine 
studies) will be done at UCSF Helen Diller Family Comprehensive Cancer Center.
How long will I be in the study?
After you complete all of the planned study visits, you will be contacted approximately every 3 
months (by office visit or telephone) to determine your health status. This will occur 
indefinitely.
Your total participation in this study from the time you have signed the informed consent form 
through to your last visit may be over one year (depending on how your cancer responds to 
treatment and how well you tolerate the treatment). If treatment is stopped or you withdraw 
from treatment, you will be followed until any side effects from treatment have resolved.
Can I stop being in the study?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping 
or decide to stop. He or she will tell you how to stop your participation safely.
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
study drugs can be evaluated by your doctor. Another reason to tell your doctor that you are


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thinking about stopping is to discuss what follow-up care and testing could be most helpful for 
you.
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped.
What are my Responsibilities?
If you participate in this study, you will be expected to:

Keep all study appointments and follow all instructions given to you by your study doctor
and study staff.

Describe how you feel and discuss possible side effects.

Tell the study doctor about all medications you are taking including prescription, herbal
supplements and over-the-counter medications.

Discuss any medication (prescription or over the counter) that you wish to start taking
with your study doctor before you start taking it.

Tell the study doctor about any changes in your health.

Tell the study doctor about all of the medications (prescription, over-the-counter, herbal)
that you are currently taking. Even if it is not on the list of prohibited drugs, you may 
need to be monitored more frequently.

Certain medications are prohibited while you are participating in this trial. Your study
doctor will explain what these medications are. If you need treatment with any 
medications that are not allowed during your participation in this trial, you must inform 
the study doctor or the study staff. You will not be denied medications required to treat an 
illness you may have, but you may be required to stop taking the study medication. This 
is for your safety, since some medications may not work well with the study treatment, 
and you might have physical problems. Please keep in mind that you cannot take  
other investigational drugs on other clinical trials while you are being treated on this 
study. Please see the end of the consent form for a detailed list of prohibited medications 
while on any of the study drugs.

Tell your study doctor about any medical treatments that you plan to receive during the
study (such as elective surgery or radiation).

Tell your study doctor or study staff if you change your address, telephone number, or
other contact information.

Use birth control for the duration of the study. If you are taking capmatinib, ceritinib or
entrectinib, you will need to continue birth control for at least 7 days after your last dose 
of study drug. If you are taking regorafenib, you will need to continue birth control for at 
least 3 months after your last dose.
o
If you are woman of child-bearing potential, you should maintain total abstinence,
have had your ovaries removed or a tubal ligation done at least 6 weeks before


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starting study treatment, or practice two of the three following methods of 
contraception: (1) intrauterine device (IUD) placement, (2) barrier contraception 
(condom or occlusive cap, such as diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/vaginal suppository, (3) use of oral, injected or 
implanted hormonal contraception.
o
If you are a man, you should use a condom with spermicidal foam/gel/film/cream.
If you have had a vasectomy, condom use is still required to prevent delivery of 
the drug via semimal fluid. You should also make sure your female partner is 
using highly effective contraceptive methods as described above.

Tell your study doctor or study staff as soon as possible if you discover you become
pregnant, or have fathered a child during the study or within the 7 days after your last 
dose of capmatinib, ceritinib or entrectinib; or within the 3 months after your last dose of 
regorafenib.
What side effects or risks can I expect from being in the study?
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors don't know all the side effects that may happen. 
Side effects may be mild or very serious. Your health care team may give you medicines to help 
lessen side effects. Many side effects go away soon after you stop taking the study drug. In  
some cases, side effects can be serious, long lasting, or may never go away.
You should talk to your study doctor about any side effects you experience while taking part in 
the study.
Ceritinib risks

A first-in-human study of ceritinib is currently being conducted and has enrolled over
300 patients who have been followed for an average of approximately 6 months. For 
patients in this study, the most common side effects include nausea, vomiting, diarrhea, 
abdominal pain, and fatigue.

Elevation of liver laboratory tests in the blood has occurred in patients receiving ceritinib.
In most cases, the elevation of liver laboratory tests in the blood has been mild to 
moderate. The elevation of liver laboratory tests in the blood of greater severity has also 
been reported which may lead to hospitalization and can be life-threatening. The elevation 
of liver laboratory tests in the blood has typically reversed with the interruption 
of ceritinib and often does not recur when a lowered dose of ceritinib is given. You will 
be closely monitored for any signs and symptoms related to the elevation of liver 
laboratory tests in the blood for your safety during the study.

Some patients experience an inflammation of the lungs (pneumonitis) with symptoms of
shortness of breath, cough and fever. Death from inflammation of the lungs


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(pneumonitis) has been reported. In most cases, this condition can improve or resolve 
with interruption of ceritinib and medical treatment. If you develop shortness of breath, 
cough or fever, contact your study doctor immediately to report any of these symptoms.

Sudden loss or decrease of kidney function (“acute renal failure”) has been reported. The
relationship between ceritinib and this condition is unclear. For your safety, your kidney 
function will be closely monitored during the study.

Results from the first-in human study suggest that ceritinib can have an effect on the QT
interval. QT is one of the measurements taken during an ECG (heart tracings). An effect 
on QT could lead to an irregular heartbeat which in rare instances can develop into a 
sudden, life-threatening condition. Slow heart rate, which is usually not serious, has also 
been noted in patients treated with ceritinib. For your safety, repeated ECG tracings will 
be performed throughout the study to closely monitor your heart activity. If you 
experience chest discomfort or changes in your heartbeat (fast or slow), contact your 
study doctor immediately to report any of these symptoms.

Elevation of glucose in the blood has been reported in patients receiving ceritinib. You
will be closely monitored for any signs and symptoms related to the elevation of glucose 
in the blood for your safety during the study.

The elevation of pancreas enzymes in the blood has occurred in patients receiving
ceritinib. In most cases, the elevation of pancreas enzymes in the blood has been mild to 
moderate. The elevation of pancreas enzymes in the blood has typically reversed with 
interruption of ceritinib, and in some cases, may not recur when a lowered dose of 
ceritinib is given. You will be monitored closely for any signs and symptoms related to 
the elevation of pancreas enzymes in the blood for your safety during the study. Few 
patients experience an inflammation of the pancreas (pancreatitis) with severe upper 
abdominal pain which may lead to hospitalization and can be life-threatening.

Other side effects observed with ceritinib include the following: constipation, decreased
appetite, rash, problems with the liver, pancreatitis, and changes in laboratory values (i.e. 
blood cell counts, electrolytes, amylase and lipase). Dehydration may occur as a result of 
diarrhea and vomiting. Some people have also developed problems in their esophagus.

This may not be a complete list of possible side effects. You may experience a side effect
that has not been experienced before.

We do not know the full range of side effects of ceritinib when given either alone or in
combination with other drugs. Some over-the-counter and prescription medications can 
reduce the effectiveness or increase the side effects of ceritinib. Likewise, ceritinib can 
increase the side effects or lessen the effectiveness of some other medications. You 
should always discuss the use of any drugs (over-the-counter drugs, prescription, or 
illegal drugs or health food supplements) with your doctor before taking ceritinib and 
while you are participating in this study.


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At each visit, your doctor will ask you about any unusual symptoms. You will be closely 
monitored for any side effects and should report any changes in the way you feel to your doctor.
Capmatinib (INC280) risks
Patients treated with capmatinib have experienced:

Swelling of the legs and arms

Nausea – the feeling that you will vomit

Fatigue – feeling tired

Tremor

Stomach pain (abdominal pain and upper abdominal pain)

Pain in the joints, (arthralgia)

Loose stool (diarrhea)

Dizziness

Cough

Headache

Pain in the arms and legs

Pain in the bones and muscles

Infection in the urinary tract

Decreased lymphocytes in blood (lymphopenia)

Lung Infection

Increased liver enzymes (increased ALT, AST, Bilirubin, GGT)

Increased pancreatic enzymes (Amylase and Lipase)

Decreased appetite or loss of appetite

Unexplained weight loss

Itching (pruritis), skin rash, and/or dry skin

Shortness of breath

Increased potassium in blood (hyperkalemia)

Increased creatinine in blood

Decreased levels of phosphate in blood (hypophosphatemia)

In animal experiments, capmatinib absorbs light in the UVA-range (sunlight), and caused
skin to be sensitive to sunlight. It may be advisable not to sunbathe or use a solarium for  
a long period of time while taking capmatinib.

Decreased levels of sodium in the blood (hyponatremia)
Rare but serious risk:  There is a rare but serious risk of severe or fatal Interstitial Lung Disease or 
ILD. ILD means that your lungs are being damaged. Some of the events reported in studies with 
capmatinib have resulted in death. If you experience increasing shortness of breath or a persistent dry 
cough you should inform your study doctor as soon as possible.


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Entrectinib risks
Based on testing of entrectinib in animals and preliminary data from other studies in patients  
with advanced cancer who have been treated with entrectinib, certain side effects are possible, as 
described below:
Likely (Side Effects That Occurred in > 10% patients)

Fatigue

Tingling, tickling, prickling, or burning sensation of skin


Loss of taste or a bad taste in your mouth

Pain in muscles and joints

Vomiting

Confusion

Diarrhea (if severe, could also result in low sodium and low potassium levels)

Dizziness
Less Likely (Side Effects That Occurred in 2 to 10% patients)

Constipation

Neuropathy (nerve injury which could result in feeling of numbness or pain, or cause
weakness)

Pain in mouth or throat

Rash

Dry mouth

Edema (swelling)

Decreased appetite

Ear pain

Eye swelling

Headache

Indigestion

Low levels of red blood cells (which carry oxygen)

Low levels of white blood cells (which fight infection)

Pain in arms or legs

Trouble with balance

Dry skin

Flatulence

High blood pressure

Increased salivation

Low blood pressure

Low levels of platelets (which help with blood clotting)

Nail infection

Shortness of breath


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
Stomach pain

Tremors

Voice spasms
Rare but serious (occurred in < 1% of patients)

Allergic reaction involving the heart muscle
Regorafenib risks
Risks for regorafenib can also be obtained from the package insert available for the drug. 
Side effects you may experience from regorafenib listed are:
Likely (Side Effects That Occurred in > 20% patients)

Anemia

Increased AST

Asthenia

Proteinuria

Hypocalcemia

Hypophosphatemia

Lymphopenia

Decreased appetite and food intake

Increased lipase

Hand-foot skin reaction (HFSR)

Hyperbilirubinemia

Increased ALT

Diarrhea

Thrombocytopenia

Mucositis

Weight loss

Infection

Hypertension

Dysphonia

Hyponatremia

Pain

Fever

Rash

Hypokalemia

Increased amylase

Increased INR

Hemorrhage
Less Likely (Side Effects That Occurred in 1 to 10% patients)


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
Headache

Alopecia

Taste disorder

Musculoskeletal stiffness

Xerostomia

Hypothyroidism

Neutropenia

Tremor

GERD

Myocardial ischemia and infarction
Rare but serious (occurred in < 1% of patients)

Gastrointestinal fistula

Keratoacanthoma/squamous cell carcinoma of the skin

Pancreatitis
Other Risks
Risks of screening for kinase fusions: You are eligible for this study based on genetic analysis 
that identifies a kinase fusion rearrangement in your melanoma. This genetic testing is new and 
is not currently part of the standard of care of melanoma. If there is an error in this test, it is 
possible that you could receive a study drug that is ineffective because it targets a genetic 
mutation that your melanoma may not have.
Blood drawing (venipuncture) risks: Drawing blood may cause temporary discomfort from the 
needle stick, bruising, lightheadedness, and infection.
Electrocardiogram (EKG/ECG) risks: The ECG involves placing electrodes on the skin. You 
may experience an allergic reaction to the adhesive used to attach the electrodes to the skin.
These symptoms are generally mild and clear up on their own. Please let your doctor know if 
you are aware of any allergies.
No radiation risk beyond routine clinical care: This study involves radiation exposure as part 
of routine clinical care. You will not receive additional radiation as a result of participating in 
this study. If you have any questions regarding the use of radiation or the risks involved, please 
consult the physician conducting the study.
CT scan risks: CT scans involve the risks of radiation. In addition, if contrast material (iodine 
dye) is used, there is a slight risk of developing an allergic reaction, from mild (itching, rash) to 
severe (difficulty breathing, shock, or rarely, death). The contrast material may also cause 
kidney problems, especially if a patient is dehydrated or has poor kidney function. The study 
doctors will ask about any allergies or related conditions before the procedure. If you have any 
of these problems, you may not be allowed to have a CT scan.


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Having a CT scan may mean some added discomfort. In particular, patients may be bothered by 
feelings of claustrophobia when placed inside the CT scanner, or by lying in one position for a 
long time. If contrast material is used, patients may feel discomfort when it is injected. Patients 
may feel warm and flushed and get a metallic taste in their mouth. Rarely, the contrast material 
may cause nausea, vomiting or a headache.
MRI scan risks: Because the MRI machine acts like a large magnet, it could move iron- 
containing objects in the MRI room during the examination, which in the process could possibly 
harm you. Precautions have been taken to prevent such an event from happening; loose metal 
objects, like pocket knives or key chains, are not allowed in the MRI room. If you have a piece 
of metal in your body, such as a fragment in their eye, aneurysm clips, ear implants, spinal nerve 
stimulators, or a pacemaker, you will not be allowed into the MRI room and cannot have an 
MRI.
Having an MRI may mean some added discomfort. In particular, patients may be bothered by 
feelings of claustrophobia and by the loud banging noise during the study. Temporary hearing 
loss has been reported from this loud noise. This is why you will be asked to wear ear plugs. At 
times during the test, you may be asked to not swallow for a while, which can be uncomfortable.
Contrast agent (gadolinium) for MRI:
A few side effects of gadolinium injection such as mild headache, nausea, and local pain may 
occur. Rarely (less than 1% of the time) low blood pressure and lightheadedness occurs. This 
can be treated immediately with intravenous fluids. Very rarely (less than one in one 
thousand), patients are allergic to gadolinium. These effects are most commonly hives and 
itchy eyes, but more severe reactions have been seen which result in shortness of breath.
Patients with severe kidney disease sometimes have a bad reaction to gadolinium contrast. 
The condition is called nephrogenic systemic fibrosis (NSF). It can cause skin to tighten or 
scar and can damage internal organs. Sometimes it can be life-threatening. There are no 
reports of NSF in patients with normal kidney function. Before you have an MRI scan 
requiring an injection of gadolinium contrast, you will have a blood test in order to check the 
function of your kidneys. Based on your medical history and the results of the test, a doctor 
will decide whether it is safe to undergo the MRI scans.
Tumor Biopsy (non-skin): The biopsy has small but serious risks. While we make every effort 
to minimize the pain related to the procedure, the procedure is usually uncomfortable and 
sometimes painful. Wherever the biopsy is done in your body, it can lead to bleeding in that area, 
damage of organs near where the biopsy is done, or infection. While it is uncommon, sometimes 
bleeding or pain from the biopsy will require you to stay overnight in the h to go to the operating 
room to control any bleeding. We check your laboratory values before the biopsy to make sure 
that the procedure is as safe as possible and to minimize your chance of having a complication. 
Additionally, if the biopsy involves the lungs, it can cause the lungs to deflate and if this occurs, 
you might require treatment to correct this. We try to take as little tissue as possible when we do 
the biopsy, and this means that sometimes the biopsy procedure


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can be unsuccessful and require a repeat biopsy to get enough tissue. Other potential risks will be 
described to you and discussed with you by doctors who conduct these biopsies.
Tumor Biopsy (skin): There will be some discomfort with this procedure, and there may be 
bleeding as well. One or two stitches at the biopsy site may be required, which would need to be 
removed one week later. This procedure may result in temporary pain and bruising. In addition, 
scarring may occur at the biopsy site. Infection at the skin biopsy site occurs rarely.
Drug Interaction Risks: You must also review with your study doctor all of your medications 
(including supplements and herbal or natural substances) at every visit, as well as notify your 
study doctor before starting any new medications, supplements, or herbal treatments while 
participating in the study because there is a risk of serious interaction with the study drug.
Reproductive Risks: You should not become pregnant or while on this study because the drugs 
in this study can affect an unborn baby. You must notify the investigator immediately if you 
become pregnant while you are taking part in this study. Women should not breastfeed a baby 
while on this study. It is important to understand that you need to use birth control while on this 
study. Check with your study doctor about what kind of birth control methods to use and how 
long to use them. Some methods might not be approved for use in this study.
Unknown Risks: The experimental treatments may have side effects that no one knows about 
yet. The researchers will let you know if they learn anything that might make you change your 
mind about participating in the study.
Safe Handling of Medications: Handling the study drug assigned to you and having contact 
with any urine, feces or vomit from patients receiving the study drug may pose some risk to you 
and your caregivers. To avoid exposure to the study drug and any associated risks, you and your 
family members/caregivers will be educated by a member of the study team on how to safely 
handle, properly dispose of, and clean products that may be contaminated with your study drug.
For more information about risks and side effects, ask your study doctor.
Are there benefits to taking part in the study?
The study drugs may or may not lead to improvement of your melanoma. The knowledge gained 
from this study may be of help to other subjects with cancer in the future. Benefit may be 
expected from these study drugs, though this cannot be guaranteed.
What other choices do I have if I do not take part in this study?
Your other choices may include:

Getting treatment or care for your cancer without being in a study. Current FDA- 
approved, standard of care therapies for advanced melanoma that you may be eligible for 
include:


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UCSF CC#14859
o
Immunotherapy:

Nivolumab (Opdivo) or pembrolizumab (Keytruda): These are antibodies
against a cell receptor called PD-1. Nivolumab is given intravenously
every 2 weeks, and pembrolizumab is given intravenously every 3 weeks
in a clinic setting. Both PD-1 antibodies have been shown in phase III
trials to result in objective response rates of 30-40%, and to significantly
prolong progression-free and overall survival compared to chemotherapy.
Ipilimumab (Yervoy): This is an antibody against a cell receptor called
CTLA-4. It is given intravenously every 3 weeks for 4 doses in a clinic
setting. It has been shown in phase III trials to result in objective response
rate of about 11% and to prolong overall survival compared to
chemotherapy, but its role as a single agent has decreased with
development of the PD-1 agents. The combination of ipilimumab plus
nivolumab has been approved for advanced melanoma treatment as well.
Combining these drugs has been shown in a phase III trial to increase 
objective response rate to about 60%, but with increased toxicity.

High-dose interleukin 2 (IL-2): This is a growth factor of T cells that is
given intravenously in a hospital setting. It is associated with severe 
multiorgan toxicity and an objective response rate of about 15%, though a 
minority of patients have achieved durable response.
o
Chemotherapy: Cytotoxic chemotherapy does not play a role in the initial
management of advanced melanoma, but it can be an option for patients whose 
o

Taking part in another study.

Getting no treatment.

Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat 
the cancer directly, but instead tries to improve how you feel. Comfort care tries to keep 
you as active and comfortable as possible.
Please talk to your study doctor about your choices before deciding if you will take part in this 
study.
disease can no longer be controlled with immunotherapy or targeted therapy 
approaches. Dacarbazine, temozolamide, cisplatin, carboplatin and paclitaxel are 
examples of agents that can be used alone or in combination. These approaches 
have not been shown to increase overall survival, but can be associated with 
objective disease response in a minotiry of patients.
eived at least one FDA- approved therapy for melanoma before enrolling in this 
study. If you have not yet received any drug for treatment of your melanoma, you 
may still participate in this study as long as you understand that you are taking 
the risk that your disease may spread without having received a standard of care, 
approved drug. If this is the case, please discuss your decision with your doctor.


IRB NUMBER: 15-15712
IRB APPROVAL DATE: 02/22/2018
IRB EXPIRATION DATE: 02/21/2019
Consent Form (main) 09-20-2017 
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UCSF CC#14859
Will my medical information be kept private?
We will do our best to make sure that the personal information in your medical record is kept 
private. However, we cannot guarantee total privacy. Your personal information may be given 
out if required by law. If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include:

The study sponsors Bayer Inc, Ignyta and or their representatives, including companies it
hires to provide study-related services

Novartis (the drug supplier) and its authorized agents

Researchers who are conducting this study at other research sites

Food and Drug Administration (FDA), National Cancer Institute (NCI), or other
government agencies involved in keeping research safe for people

The University of California

Governmental agencies in other countries where the study drug may be considered for
approval
To ensure the scientific integrity of the study, you may not be able to review some of your 
records related to the study until after the study has been completed. When the study is over, you 
may write to the study doctor to ask to see health data about you that was collected during the 
study and to correct any errors.
Participation in research may involve a loss of privacy, but information about you will be 
handled as confidentially as possible. A medical record will be created because of your 
participation in this study. Your consent form and some of your research test results will be 
included in this record. Therefore, your other doctors may become aware of your participation. 
Hospital regulations require that all health care providers treat information in medical records 
confidentially.
What are the costs of taking part in this study?
You and/or your health plan/insurance company will need to pay for some or all of the costs of 
treating your cancer in this study. Some health plans will not pay these costs for taking part in 
studies. Check with your health plan/insurance company to find out what they will pay for.
Taking part in this study may or may not cost you or your insurance company more than the cost 
of getting routine cancer treatment. Ceritinib, regorafenib or entrectinib will be provided free of 
charge while you are participating in this study.


IRB NUMBER: 15-15712
IRB APPROVAL DATE: 02/22/2018
IRB EXPIRATION DATE: 02/21/2019
Consent Form (main) 09-20-2017 
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UCSF CC#14859
You will not be billed for any of the tests (such as optional biopsy, blood samples for biomarker 
testing) required specifically by the study. These are procedures noted above as “research 
purposes” in this consent form. Other procedures, which are also done in this study but are part 
of your routine care will be paid for by you or your insurance.
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy.
Will I be paid for taking part in this study?
You will not be paid for taking part in this study.
What happens if I am injured because I took part in this study?
It is important that you tell your study doctors, Adil Daud, M.D. or Iwei Yeh, MD, PhD if you 
feel that you have been injured because of taking part in this study. You can tell the doctor in 
person or call her at 
3-9900.
Treatment and Compensation for Injury: If you are injured as a result of being in this 
study, the University of California will provide necessary medical treatment. The costs of 
the treatment may be billed to you or your insurer just like any other medical costs, or 
covered by the University of California or the study sponsor (BMS), depending on a number 
of factors. The University and the study sponsor do not normally provide any other form of 
compensation for injury. For further information about this, you may call the office of the 
Committee on Human Research at 415-476-1814.
What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits. Leaving the study will not affect your medical care. You can still get your medical care 
from our institution.
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.


IRB NUMBER: 15-15712
IRB APPROVAL DATE: 02/22/2018
IRB EXPIRATION DATE: 02/21/2019
Consent Form (main) 09-20-2017 
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UCSF CC#14859
Who can answer my questions about the study?
You can talk to your study doctor about any questions, concerns, or complaints you have about 
this study. Contact your study doctors Adil Daud, M.D or Iwei Yeh, MD, PhD. at 
If you wish to ask questions about the study or your rights as a research participant to someone 
other than the researchers or if you wish to voice any problems or concerns you may have about 
the study, please call the Office of the Committee on Human Research at 415-476-1814.
ClinicalTrials.gov is a website that provides information about clinical trials. A description of 
this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.
Please note: This section of the informed consent form is about additional research studies 
that are being done with people who are taking part in the study. You may take part in 
these additional studies only if you want to. Everyone who is taking part in the study is 
being asked to take part in this optional study.
You can say "yes" or "no" to each of the following studies. Please mark your choice for 
each study.
About Using Tissue Samples and Blood for Research
Your study doctor wants to use your blood and tissue samples to help better understand how the 
study drug works in your body, in addition to helping develop new ways to monitor and treat 
diseases. We would like to use your previous biopsies of your tumor tissue (called archival 
tissue) and any remaining tissue from biopsies on this study, for biomarker testing and to use 
some of your blood collected during your biomarker to be stored for future tests. If you decide to 
participate, your archived tissue will be collected at any time while you are on study and your 
additional blood samples will be collected during your already scheduled study blood draws.
What will happen if I agree to donate my specimens?
If you agree to let researchers collect and store your blood and tissue samples for future research, 
the following will happen:


IRB NUMBER: 15-15712
IRB APPROVAL DATE: 02/22/2018
IRB EXPIRATION DATE: 02/21/2019
Consent Form (main) 09-20-2017 
Page 21 of 25
UCSF CC#14859

After all routine tests required for your care are finished, instead of discarding your leftover
specimens we will save them in what is called a “tissue bank” for possible future research.
We also will collect and save information from your medical record, including things like
results of physical examinations, diagnostic tests, medical questionnaires and histories, and
cancer diagnoses and treatments. We do not know for sure if your specimens or medical
record will be used, but they might be used in research about breast cancer.

We may give your specimens and certain medical information about you (for example,
diagnosis, blood pressure, age) to other scientists or companies not at UCSF, including to a 
government health research database, but we will not give them your name, address, phone 
number, or any other information that would identify you. Reports about any research will 
not be given to you or your doctor.

Your specimens will be kept for indefinitely. If you decide later that you do not want your
specimens and information to be used for future research, you can notify the investigator in 
writing and we will destroy any remaining identifiable specimens and information if they 
are no longer needed for your care. However, if any research has already been done using 
portions of your specimens, the data will be kept and analyzed as part of those research 
studies.
What are the benefits?
The benefits of research using tissue and blood include learning more about what causes cancer 
and other disease, how to prevent them, and how to treat them.
What risks are involved with donating specimens for research?
Any extra blood we take will come through already scheduled blood draws done during this 
study, and should not cause you any added risk, discomfort, or pain beyond what we normally 
expect from blood draws.
Things to Think About
The choice to let us keep the left over tissue samples and blood for future research is up to you. 
No matter what you decide to do, it will not affect your care.
If you decide now that your tissue can be kept for research, you can change your mind at any 
time. Just contact the study doctors Adil Daud, M.D and Iwei Yeh, MD, PhD in writing at the 
address below, and let us know that you do not want us to keep your specimens.
Adil Daud, M.D. and Iwei Yeh, MD, PhD 
University of California, San Francisco 
Any identifiable specimen that remains will no longer be used for research and destroyed. 
However, if any research has already been done using portions of your specimens, the data will 
be kept and analyzed as part of those research studies.


IRB NUMBER: 15-15712
IRB APPROVAL DATE: 02/22/2018
IRB EXPIRATION DATE: 02/21/2019
Consent Form (main) 09-20-2017 
Page 22 of 25
UCSF CC#14859
In the future, people who do research may need to know more about your health. While the study 
doctor may give them reports about your health, it will not give them your name, address, phone 
number, or any other information that will let the researchers know who you are.
Your specimen will be used only for research and will not be sold. The research done with your 
tissue may help to develop new products in the future. You will not be paid for allowing your 
tumor samples to be used in research even though the research done with your samples may help 
to develop new products in the future. You will not receive any payment or financial benefit 
from any products, tests, or discoveries derived from these samples.
Making Your Choice
Please read each sentence below and think about your choice. After reading each sentence put 
your initials in the "Yes", or "No" box. If you have any questions, please talk to your doctor or 
nurse, or call our research review board at 415-476-1814.
No matter what you decide to do, it will not affect your care.
Previous tumor tissue - If you provide your consent, your tumor tissue previously removed 
during surgery or from old biopsies will be requested. The tumor tissue will be sent to a 
laboratory where tests will be performed. Researchers will be performing tests that may provide 
additional information that may be helpful in understanding your response to the study drug.
1. I agree to donate previously collected tissue to be used for research purposes as described
above.
YES
NO
Additional blood - If you provide your consent, additional blood taken during your study blood 
draws will be collected. The blood will be sent to a laboratory where it will be stored and tests 
will be performed. Researchers will be performing tests that may provide additional information 
that may be helpful in understanding your response to the study drug, and for future research 
about melanoma. The results from these tests will not have any effect on your treatment.
2. I agree to the collection of additional blood samples to be used for research purposes as
described above.
YES
NO


IRB NUMBER: 15-15712
IRB APPROVAL DATE: 02/22/2018
IRB EXPIRATION DATE: 02/21/2019
Consent Form (main) 09-20-2017 
Page 23 of 25
UCSF CC#14859
CONSENT
You have been given copies of this consent form and the Experimental Subject's Bill of Rights to 
keep.
You will be asked to sign a separate form authorizing access, use, creation, or disclosure of 
health information about you.
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to which 
you are otherwise entitled.
If you wish to participate in this study, you should sign below. 
If you wish to participate in this study, you should sign below.
Date
Participant's Signature for Consent
Printed Name of Participant
Date
Signature of Person Obtaining Consent
Printed Name of Person Obtaining Consent
Date
Witness Signature (Only required if the participant is
a non-English speaker)


IRB NUMBER: 15-15712
IRB APPROVAL DATE: 02/22/2018
IRB EXPIRATION DATE: 02/21/2019
Consent Form (main) 03-23-2016 
Protocol (v.1.9) 02-29-2016
Page 24 of 25
UCSF CC#14859
Medications to Avoid
CC# 14859: A Phase II Trial of Targeted Kinase Fusion Inhibition in 
BRAF/NRAS Wild-Type Melanoma
The following is a list of medications to avoid while you are participating in this study. If you go to any medical visit, please take this list with you 
for the doctor’s reference.
Before you begin treatment, Dr. Daud or one of his associates will review all medications you are taking. Make sure you talk with Dr. Daud before 
you start or stop taking any medications. This list contains only the most common drugs that are known to interact with the drugs used in this study. 
It is very important to discuss all medications that you are taking with your study doctor. This information will be reviewed at each study 
visit.
If you are taking capmatinib, the followi
rohibited:
alfentanil
azithromycin
Cipro- 
floxacin
Dexlan- 
soprazole
Elvite- 
gravir
grapefruit 
juice
Levo- 
methadyl
Ome- 
prazole
Pimo- 
zidefentanyl
saquinavir
terfenadine
tizanidine
amiodarone
bepridil
cisapride
Diergo- 
tamine
Ergo- 
tamine
Halo- 
fantrine
lopinavir
Panto- 
prazole
Posa- 
conazole
Seville (sour) 
oranges
tacrolimus
tofisopam
amprenavir
boceprevir
citalopram
diltiazem
Erythro- 
mycin
Halo- 
peridol
Meso- 
ridazine
pimozide
Proca- 
inamide
Star fruit
terfenadine
Troleando- 
mycin
aprepitant
Carba- 
mazepine
Clarithro- 
mycin
dofetilide
Eso- 
meprazole
ibutilide
methadone
Penta- 
midine
quinidine
St. John’s 
wort
thioridazine
vavdetanib
arsenic 
trioxide
casopitant
cobicistat
Dom- 
peridone
Erythro- 
mycin
indinavir
mibefradil
probucol
Rabe- 
prazole
schisandra 
sphenanthera
tipranavir
verapamil
astemizole
chloroquine
conivaptan
Dron- 
edarone
flecainide
Itra- 
conazole
Moxi- 
floxacin
Pome- 
granate 
mitotane
rifabutin
telaprevir
voriconazole
atazanavir
Chlorpro- 
mazine
Cyclo- 
sporine
droperidol
Fluco- 
nazole
Keto- 
conazole
Nefa- 
zodone
Pheno- 
barbital
rifampin
telithromycin
avasimibe
cimetidine
darunavir
Diso- 
pyramide
Fosam- 
prenavir
Lanso- 
prazole
Nelfinavir
phenytoin
ritonavir
theophylline


IRB NUMBER: 15-15712
IRB APPROVAL DATE: 02/22/2018
IRB EXPIRATION DATE: 02/21/2019
Consent Form (main) 03-23-2016 
Protocol (v.1.9) 02-29-2016
Page 25 of 25
UCSF CC#14859
If you are taking ceritinib, the following drugs are prohibited:
IRB EXPIRATION DATE: 03/25/2017
alfentanil
clarithromycin
disopyramide
erythromycin
ibutilide
moxifloxacin
procainamide
sparfloxacin
troleandomycin
amiodarone
chloroquine
diltiazem
ethotoin
indinavir
nelfinavir
quinidine
St. John’s wort
vavdetanib
arsenic 
trioxide
chlorpromazine
felbamate
itraconazole
pentamidine
rifabutin
tacrolimus
voriconazole
astemizole
fentanyl
ketoconazole
phenobarbital
rifampin
telithromycin
warfarin sodium or any 
other Coumadin- 
derivative anticoagulatns
avasimibe
cisapride
droperidol
flecainide
levomethadyl
pimozide
ritonavir
terfenadine
azithromycin
citalopram
elvitegravir
fosphenytoin
lopinavir
posaconazole
saquinavir
thioridazine
bepridil
cyclosporine
enzyme inducing anti- 
epileptic drugs 
(EIAEDs)
Halofantrine
mesoridazine
primidone
sirolimus
tipranavir
carbamazepi 
ne
diergotamine
ergotamine
haloperidol
mibefradil
probucol
sotalol
topiramate
If you are taking regorafenib, the following drugs are prohibited:
o
Other anticancer therapy (chemotherapy, targeted therapy, biologic therapy, or radiation therapy, hormonal therapy, bone marrow
transplant or stem cell rescue)
o
Erythropoietic stimulating agents (darbepoetin alfa, epoetin alfa)
o
Any herbal remedies (e.g., St. John’s wort).
Please tell your doctor if you are taking other drugs like warfarin, phenytoin, quinidine, carbamazepine, phenoparbital, cyclosporine or 
digoxin – if so, you may need to be monitored more frequently.
If you are taking entrectinib, the following drugs and procedures are prohibited:
o
Other anticancer therapy (chemotherapy, targeted therapy, biologic therapy, or radiation therapy except palliative radiotherapy and
anit-cancer surgery)