Clinical trial NCT03580382
Conditions: Melanoma
Sponsor: NYU Langone Health
Start date: 2018-07-06; Completion date: 2018-09-26
Enrollment: 3 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main goal of this study is to test if it is safe and effective to give CDX-3379 together to treat advanced melanoma in patients with the NRAS mutation and BRAF/NRAS wildtype.

Detailed description:
Primary Objectives:

Phase 1b: To determine the RP2D and assess the toxicity and tolerability of the combination of CDX-3379 (ERBB3 antibody) and trametinib (MEK inhibitor) in NRAS and BRAF/NRAS WT melanoma patients

Phase 2: To estimate the response rates and duration of response of the combination of CDX-3379 (ERBB3 antibody) and trametinib in NRAS positive and BRAF/NRAS WT melanoma patients

Secondary/Exploratory Objectives:

Phase 1b: To assess clinical activity and steady-state pharmacokinetics of CDX-3379 and trametinib Phase 2: To compare the efficacy of the combination of CDX-3379 (ERBB3 antibody) and trametinib is more effective than a MEK inhibitor alone in NRAS positive and BRAF/NRAS WT melanoma patients alone using locally assessed progression free survival (PFS) and overall survival (OS).

Arms: arm 1: C1D1-C1D21, CDX-3379 D1Trametinib daily Biopsy (days 14-16) arm 2: C1D1-C1D21, CDX-3379 D1Trametinib daily Biopsy (days 14-16)
Interventions: intervention 1: Trametinib daily Until PD intervention 2: CDX-3379 (ERBB3 antibody)
Intervention descriptions: intervention 1: 1.0 mg daily intervention 2: 15mg/kg IV Q3W

Protocol documents:
Prot_SAP_000.pdf: 
  
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
 
 
 
 
A phase Ib/II open label study of CDX-3379, a human monoclonal antibody targeting ERBB3, in 
combination with the MEK inhibitor, trametinib, in patients with advanced stage NRAS mutant 
and BRAF/NRAS wildtype (WT) melanoma 
 
 
 
Regulatory Sponsor: 
Perlmutter Cancer Center at NYU Langone Health 
160 E. 34th Street, 13th Floor 
New York, NY 10016 
212-263-9333 
 
 
With support from: 
Celldex Therapeutics 
53 Frontage Road, Suite 220 
Hampton, NJ 08827 
 
Novartis 
1 Health Plaza 
East Hanover, NJ 07932 
 
Study Product: 
CDX3379 (Human Monoclonal Antibody Targeting ERBB3) 
Trametinib (Mekinist®) 
 
 
Protocol Number: 
S17-00363 
IND Number: 
138637 
NCT Number: 
NCT03580382  
 
Investigators:  
 
         PI - Jeffrey S. Weber MD, Ph.D  
 
 
 
 
 
        Co-Investigators 
 
 
 
 
        Anna Pavlick, DO 
 
 
 
       
 
 
 
 
   
 
 
 
 
        Kathleen Madden, RN, FNP-BC, AOCNP 
 
 
 
 
        Hua (Judy) Zhong, PhD (Statistician) 
 
Sites:  
 
                NYU Langone Health  
 
 
 
 
       University of Pennsylvania 
 
 
 
 
       Thomas Jefferson University  
 
Initial version: September 19, 2017 
Amended: 
March 20, 2018 
Amended:          March 22, 2018 
Amended:          March 23, 2018 
Amended: 
April 12, 2018 
Amended: 
November 12, 2018  
 
Clinical Research Protocol 


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Table of Contents 
 
STUDY SUMMARY ....................................................................................................................................... 1 
1 
INTRODUCTION ................................................................................................................................... 3 
1.1 
BACKGROUND................................................................................................................................. 3 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 7 
1.3 
PRECLINICAL DATA ......................................................................................................................... 7 
1.4 
CLINICAL DATA TO DATE ................................................................................................................. 8 
1.5 
DOSE RATIONALE ......................................................................................................................... 10 
1.6 
RESEARCH RISKS & BENEFITS ...................................................................................................... 10 
1.6.1 
Risk of Study Drug ................................................................................................................. 10 
1.6.2 
Overlapping Toxicities ............................................................................................................ 15 
1.6.3  Dose-Limiting Toxicities ............................................................................................................ 15 
1.6.4  Other Risks of Study Participation ............................................................................................ 15 
1.6.5  Potential Benefit ...................................................................................................................... 155 
2 
STUDY OBJECTIVES ........................................................................................................................ 16 
3 
STUDY DESIGN ................................................................................................................................. 17 
3.1 
GENERAL DESIGN ......................................................................................................................... 17 
3.2 
PRIMARY STUDY ENDPOINTS ......................................................................................................... 20 
3.3 
SECONDARY STUDY ENDPOINTS.................................................................................................... 20 
3.4 
EXPLORATORY ENDPOINTS ........................................................................................................... 20 
3.5        Primary Safety Endpoints ........................................................................................................... 20 
4 
SUBJECT ENROLLMENT AND WITHDRAWAL .............................................................................. 21 
4.1 
INCLUSION CRITERIA ..................................................................................................................... 21 
4.2 
EXCLUSION CRITERIA .................................................................................................................... 22 
4.3 
INCLUSION OF WOMEN AND MINORITIES ......................................................................................... 24 
4.4 
SUBJECT RECRUITMENT AND SCREENING ...................................................................................... 24 
4.4.1 
Method of Subject Identification and Recruitment ................................................................. 36 
    4.5 
EARLY WITHDRAWAL OF SUBJECTS ............................................................................................... 25 
4.5.1 
When and How to Withdraw Subjects.................................................................................... 25 
4.5.2 
Data Collection and Follow-up for Withdrawn Subjects ......................................................... 25 
4.5.3 
Premature Termination or Suspension of Study .................................................................... 25 
5 
STUDY DRUG ..................................................................................................................................... 26 
5.1 
DESCRIPTION................................................................................................................................ 26 
5.1.1 
CDX-3379 -Description, Packaging, and Labeling ................................................................ 26 
        5.1.2       Trametinib (Mekinist®)…………………………………………………………………………….26 
5.2 
TREATMENT REGIMEN ................................................................................................................... 26 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ........................................................ 27 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG.................................................................... 27 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 27 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 28 
5.7 
BLINDING OF STUDY DRUG ............................................................................................................ 28 
5.8 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 28 
5.8.1 
Receipt of Drug Supplies ....................................................................................................... 28 
5.8.2 
Storage and Handling ............................................................................................................ 29 
5.8.3 
Dispensing of Study Drug ...................................................................................................... 29 
5.8.4 
Return or Destruction of Study Drug ...................................................................................... 30 
5.9 
PHARMACOKINETIC VARIABLES AND ASSESSMENTS ........................................................................ 45 
5.10 
BIOMARKER SAMPLES ................................................................................................................... 45 


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6 
STUDY PROCEDURES ...................................................................................................................... 32 
6.1 
VISIT 1 – SCREENING .................................................................................................................... 32 
6.2 
VISIT 2, 4 ..................................................................................................................................... 32 
6.3 
VISIT 3, 5 ..................................................................................................................................... 33 
6.4 
VISIT 6 ......................................................................................................................................... 33 
6.5 
END OF TREATMENT VISIT ............................................................................................................. 33 
6.6 
SURVIVAL FOLLOW-UP .................................................................................................................. 33 
6.7 
SCHEDULE OF ASSESSMENTS SUMMARY ....................................................................................... 33 
7 
STATISTICAL PLAN .......................................................................................................................... 35 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 35 
7.2 
STATISTICAL METHODS ................................................................................................................. 35 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 36 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 36 
8.1 
DEFINITIONS ................................................................................................................................. 36 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................. 38 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS.................................. 38 
8.3.1 
Investigator reporting: notifying the study sponsor ................................................................ 39 
8.3.2 
Investigator reporting: notifying the IRB ................................................................................. 42 
8.3.3 
Sponsor reporting: Notifying the FDA .................................................................................... 42 
Additional Reporting Requirements for the Sponsor .......................................................................... 43 
8.3.4 
Sponsor reporting: Notifying participating investigators ........................................................ 44 
8.4 
REPORTING OF PREGNANCY.......................................................................................................... 44 
8.5 
MEDICAL MONITORING .................................................................................................................. 44 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 45 
9.3  FUTURE USE OF STORED SPECIMENS .................................................................................................. 46 
9.4 SOURCE DOCUMENTS .......................................................................................................................... 46 
9.5  DATA AND SOURCE DOCUMENTATION .................................................................................................. 46 
9.6  RECORDS RETENTION ......................................................................................................................... 47 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 47 
10.2 
AUDITING AND INSPECTING ............................................................................................................ 48 
11 
ETHICAL CONSIDERATIONS ........................................................................................................... 48 
11.1  INFORMED CONSENT ......................................................................................................................... 49 
11.2 REGISTRATION PROCEDURES ............................................................................................................. 49 
11.3 MULTI-SITE SURVEILLANCE ................................................................................................................ 50 
11.4 PATIENT REGISTRATIONS AT ADDITIONAL SITES .................................................................................. 50 
12 STUDY FINANCES ................................................................................................................................ 51 
12.1 
FUNDING SOURCE ........................................................................................................................ 51 
12.2 
SUBJECT STIPENDS OR PAYMENTS ................................................................................................ 51 
13 
PUBLICATION PLAN ......................................................................................................................... 51 
14 
REFERENCES .................................................................................................................................... 52 
15 
ATTACHMENTS ................................................................................................................................. 53 
 
 
 


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List of Abbreviations 
 
ADA 
Anti-drug antibodies/immunogenicity 
AE 
Adverse event 
AKT 
Protein kinase B 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCO 
American Society for Clinical Oncology 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration time curve 
BRAF 
v-Raf murine sarcoma viral oncogene homolog B 
BCNU 
Bis-chloroethylnitrosourea 
CBC 
Complete blood count 
CBR 
Clinical benefit response 
CBRD 
Center for Biospecimen Research & Development 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum serum concentration 
Cmin 
Minimum serum concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CRO 
Contract research organization 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CTO 
Clinical Trials Office 
DLT 
Dose limiting toxicty 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
DSMC 
Data Safety and Monitoring Committee 
DTIC 
Dacarbazine 
EC 
Ethics Committee 
ECOG (PS) 
Eastern Cooperative Oncology Group (performance status) 
eCRF 
Electronic case report form 
EGFR 
Epidermal growth factor receptor 
EKG 
Electrocardiogram 
ErbB 
Epidermal growth factor family of receptor tyrosine kinases 
ERK 
Extracellular signal-related kinase 
FDA 
Food and Drug Administration 
 
 


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 FDG 
 Fluorodeoxyglucose 
 FNA 
Fine needle aspiration 
FOXD3 
Forkhead box D3 transcription factor 
g 
Gram 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GR 
Grade 
HER3 
Human epidermal growth factor receptor 3 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Hazard ratio 
HRG 
Heregulin 
IB 
Investigator’s Brochure 
ICH 
International conference on harmonization 
Ig 
Immunoglobulin 
IHC 
Immunohistochemistry 
IND 
Investigational new drug application 
IRB 
Institutional Review Board 
IRR 
Infusion-Related Reaction 
IV 
Intravenous 
kg 
Kilogram 
m2 
Meter squared 
mAb 
Monocloncal antibody 
MAP kinase 
Mitogen activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
Mitogen-activated kinase/Extracellular signal-related kinas 
mg 
Milligram 
mL 
Milliliter 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NCI CTCAE 
NCI Common Terminology Criteria for Adverse Events 
NRG 
Neuregulin 
NSCLC 
Non Small cell lung cancer 
 
 


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ORR 
Objective Response Rate 
OS 
Overall survival 
pErbB3 
Phosphprylated ErbB3 
PO 
Per os (oral administration) 
PET-CT 
Positron emission tomography - computed tomography 
PFS 
Progression free survival 
PI3K 
Phosphatidylinositol-3-kinase 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PTEN 
Phosphate and tensin homolog 
Q3W 
Every 3 weeks 
RECIST 
Response evaluation criteria in solid tumors 
RP2D 
Recommended Phase 2 dose 
RNA 
Ribonucleic acid 
RNAi 
Ribonucleic acid interface 
RTK 
Receptor tyrosine kinase 
SAE 
Serious adverse event 
SAF 
Safety Population 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
T1/2 
Half-life 
ULN 
Upper limit of normal 
US 
United States 
 
 
 
 


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Study Summary 
Title 
A phase Ib/II open label study of CDX-3379, a human monoclonal antibody 
targeting ERBB3, in combination with the MEK inhibitor, trametinib in patients 
with advanced stage NRAS mutant and BRAF/NRAS wildtype (WT) melanoma 
Short Title 
ERBB3 and MEK Inhibition in NRAS Mutant and WT Advanced Melanoma 
Protocol Number 
S17-00363 
Phase 
Phase Ib/II 
Methodology 
Open label 
Study Duration 
2 years 
Study Center(s) 
Initially NYU, with plans to open at possibly one additional site, University of 
Pennsylvania (PI: Lynn Schuchter, MD) 
Objectives 
Primary Objectives: 
Phase 1b: To determine the RP2D and assess the toxicity and tolerability 
of the combination of CDX-3379 (ERBB3 antibody) and trametinib (MEK 
inhibitor) in NRAS and BRAF/NRAS WT melanoma patients 
 
Phase 2: To estimate the response rates and duration of response of the 
combination of CDX-3379 (ERBB3 antibody) and trametinib in NRAS 
positive and BRAF/NRAS WT melanoma patients  
 
 
Secondary/Exploratory Objectives: 
Phase 1b:  To assess clinical activity and steady-state pharmacokinetics 
of CDX-3379 and trametinib 
 
Phase 2:  To compare the efficacy of the combination of CDX-3379 (ERBB3 
antibody) and trametinib is more effective than a MEK inhibitor alone in 
NRAS positive and BRAF/NRAS WT melanoma patients alone using locally 
assessed progression free survival (PFS) and overall survival (OS) 
 
Exploratory Objectives: 
To evaluate ERBB3 signaling pathway and MAPK signaling pathway 
components, in addition to pathway ligands (including NRG1/HRG1 (neuregulin 
1/heregulin 1, ERBB3 ligand), expression and correlate this with treatment 
response.   
 
 
Number of Subjects 
6 participants in phase Ib (up to 18 if needed due to toxicity); 38 in phase II (19 
on each arm) 
Diagnosis and Main 
Inclusion Criteria 
Unresectable Stage III and Stage IV melanoma who are positive for NRAS 
mutation or who are BRAF/NRAS WT and failed or are ineligible for standard 
treatment options 
Study Product, Dose, 
Route, Regimen 
CDX-3379 – ERBB3 human monoclonal antibody: 15mg/kg IV every three 
weeks 
Trametinib (Mekinist®) – MEK inhibitor: 2 mg PO daily 
 


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Duration of 
administration 
CDX-3379 infusion every three weeks and trametinib orally daily until disease 
progression, intolerable side effects, patient choice, or study closure 
Reference therapy 
Phase 2 results of response rates will be compared to results from the NEMO 
trial for NRAS mutant melanoma – single agent MEK inhibitor (binimetinib) 
compared to DTIC – and WT melanoma to results from a phase I trial of 
trametinib in WT melanoma.   
 
For Phase 2 exploratory objectives, PFS can be compared where PFS was 2.8 
months for trametinib compared to 1.5 months for DTIC in NRAS mutant 
melanoma and PFS was 2 months for trametinib in WT melanoma.    
Statistical 
Methodology 
Phase 1b: Safety run in of the combination of CDX-3379 and trametinib and 
monitored for DLTs.  If DLT occurs in 2 or more participants, then de-escalated 
cohorts will be evaluated.  Six to 18 evaluable participants will be treated to 
identify the MTD/RP2D prior to advancing to phase 2. 
 
Phase 2: There are two Arms of the study – Arm A:  NRAS mutant melanoma 
patients, and Arm B: WT melanoma patients.  This is the first part of a Simon 
Minimax design.  Each Arm will initially enroll 19 patients. If, after the 19 
patients in each cohort, there are two or fewer responses, the cohort will be 
stopped.  Otherwise, the study will be amended to accrue a total of 36 to each 
arm (an additional 17 participants per arm).  If a true response rate is 0.20, we 
will have a probability of 0.46 of stopping early and a probability of 0.90 of 
deciding that the treatment is useful.   
 
 
 


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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted in accordance with US 
government research regulations, and applicable international standards of Good Clinical Practice, and 
institutional research policies and procedures. 
1.1 Background 
Melanoma is the most aggressive form of skin cancer. Its incidence continues to increase yearly, with a 
prediction for approximately 87,110 new invasive melanoma cases and 9,730 deaths related to melanoma in 
2017.1 New advances in recent years in melanoma have resulted in improved treatment options for patients 
with advanced stage melanoma (defined as unresectable Stage III or metastatic melanoma). These treatments 
include ipilimumab, the CTLA-4 antagonist 2; PD1 antagonists pembrolizumab 3 and nivolumab 4; vemurafenib 
5 and dabrafenib 6, targeted BRAF inhibitors; and trametinib and cobimetinib, targeted MEK inhibitors 7-9. Newer 
drugs like MEK inhibitor, binimetinib and BRAF inhibitor encorafenib are undergoing phase III trials 10. These 
treatment advances have led to an increase in overall survival benefit in patients with advanced melanoma, 
which had been lacking with previous melanoma therapies that included traditional chemotherapy, as well as 
immunotherapy approaches 2,11-13. 
 
A number of these treatment advances are due to the identification of genetic events integral to 
melanoma pathogenesis and the pairing of therapies directed towards these molecular events and genetic 
aberrations. In addition to identification of specific somatic mutations in melanoma tumors, the techniques 
available to detect these mutations have also rapidly evolved. In combination, these powerful tools have 
advanced the field, changing the landscape and offering promising treatment options for patients. 
 
There is a lack of targeted therapies for melanomas that are NRAS mutant and BRAF and NRAS 
wildtype (WT). Approximately 20% of melanomas have a NRAS mutation14-16 and 30% of melanomas are WT17-
20.  Despite recent FDA approval of the CTLA-4 antagonist antibody ipilimumab, and PD-1 antagonist antibodies 
pembrolizumab and nivolumab, outcomes in advanced melanoma remain poor. In addition, patients can 
experience significant immune related adverse events that produce considerable morbidity. There is an 
emerging body of literature, in addition to our preliminary data, that support the involvement of ERBB3 (HER3) 
in melanoma cell growth and proliferation in this patient subset, and a strong dependency on the MAP kinase 
pathway21 which support targeting both ERBB3 and MEK in WT melanoma.   
 
ERBB3 functions as a critical signaling node in tumor pathogenesis and disease progression in a 
number of solid tumors including melanoma22-26. Moreover, high levels of ERBB3 have been associated with 
poor survival in melanoma patients 27,28, in both BRAF mutant and BRAF WT samples, as demonstrated by 
immunohistochemistry, and was also noted to be higher in metastatic lesions compared to paired primary 
melanoma samples with unknown BRAF status24. Furthermore, ERBB3 knockdown by RNA interference 
resulted in decreased melanoma cell proliferation, migration, and invasion in vitro24. ERBB3 inhibition in 
combination with RAF and/or MEK inhibition in BRAF V600 mutant melanoma demonstrating durable tumor 
responses, supporting a role for ERBB3 in BRAF resistance 29-32.  A recent study demonstrated that treatment 
of WT melanoma cell lines with a pan-erbB tyrosine kinase inhibitor decreased ligand-dependent erbB signaling 
and effective growth inhibition31.  Targeting ERBB3 with specific neutralizing antibodies decreased cell growth 
and ERBB3 signaling25, supporting its importance in BRAF WT melanoma.   
 
Numerous studies have established the importance of MAP kinase (MAPK) activation and signaling in 
melanoma5,15,16, even in the absence of activating somatic mutations in pathway components24,31. Loss of 
pathway negative regulators and reliance on autocrine signaling contributes to enhanced signaling through the 
MAPK pathway33,34. Treatment of WT melanomas with the RAF inhibitor, RAF265, resulted in reduction of tumor 
growth35. Patient-derived melanoma xenografts were transplanted into nude mice and evaluated for response 
to treatment with RAF26535. Of the seven tumor samples that responded, three (43%) were WT melanoma, 
and these samples demonstrated decreased tumor growth and activated MEK, the signaling molecule 
downstream of RAF in the MAPK pathway35. These results suggest that the MAPK pathway is a critical signaling 
node in WT melanoma, independent of acquired somatic mutations.      
 
The combination of MEK inhibition with ERBB3 inhibition results in decreased cell growth and 
proliferation in WT melanoma cell lines25. ERBB3 is a member of the epidermal growth factor receptor family of 
receptor tyrosine kinases and regulates cell growth and proliferation by heterodimerizing with receptor family 
members, as well as other receptor tyrosine kinases.  CDX-3379 is an ERBB3 antibody which inhibits ligand 
binding, receptor heterodimerization, and activation of ERBB3 signaling cascade.   


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MEK inhibitors have been used in the treatment of mutant BRAF melanoma 7,36,37and most recently in 
clinical trials to target NRAS mutant melanoma 38,39. However, there is promising evidence that MEK inhibition 
targets the MAPK pathway and decreasing cell growth in WT melanoma cell lines25. Indeed, early studies have 
observed partial response in 10% (4/39) of BRAF WT melanoma patients treated with the MEK inhibitor, 
trametinib7. Although there has been significant progress in molecularly targeted therapy in BRAF, NRAS, and 
KIT mutant melanomas, there remains a substantial number of patients who are not current candidates for 
targeted therapy. Therefore, targeting these parallel pathways represents a feasible and rational combination 
strategy which could result in improvement in survival in patients with WT melanomas.   
 
There are limited treatment options beyond immunotherapy for patients with advanced stage NRAS 
mutant melanoma and WT melanoma (BRAF/NRAS wildtype).  Recent studies have demonstrated the 
importance of the MAPK pathway in these two cohorts of melanoma patients. In addition, ERBB3 
overexpression and activation have been identified as a critical signaling pathway in overcoming MAPK 
inhibition and integral to cell growth and survival.  This proposed clinical trial fulfills an unmet need in the 
treatment of NRAS mutant and WT melanoma and provides a unique targeted therapy approach in these two 
melanoma patient populations.     
 
1.1.1 CDX-3379 
A brief description of CDX-3379 and summary of available data is provided below.  The CDX-3379 
Investigator’s Brochure should be consulted for detailed technical information, a complete discussion of 
nonclinical evaluations and relevant information regarding the known and theoretical safety profile of CDX-
3379. The Investigator’s Brochure is the Single Reference Safety Document that provides complete and 
relevant information about the known safety profile of CDX-3379. Updates to these data will be provided as 
revisions to the Investigator’s Brochure and through Investigational New Drug (IND) Safety Reports submitted 
to the investigator by Celldex, rather than by amendment to this section of the protocol.  
 
CDX-3379 is a human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody (mAb) that 
specifically binds ErbB3 at a unique epitope and locks ErbB3 in an auto-inhibited configuration making the 
ErbB3 incapable of binding ligand or dimerizing with known tumor growth drivers such as HER2 and possibly 
EGFR. The heavy chain CH2 domain of CDX-3379 contains 3 amino acid substitutions that are referred to as 
YTE (M253Y/S255T/T257E; M252Y/S254T/T256E, according to the EU numbering system). The YTE 
mutations increase IgG affinity for human fragment crystallizable receptor – neonatal (FcRn) resulting in 
significantly increased half-life (T1/2) and serum exposure in cynomolgus monkeys; similar effects are 
predicted in humans 40. 
 
It is hypothesized that CDX-3379 will inhibit ErbB3 via two distinct primary mechanisms of action, 
ligand-dependent and ligand-independent. The crystal structure of CDX-3379 binding to ErbB3 has been 
solved and identified a unique binding epitope that gives the structural basis for CDX-3379’s potency and dual 
mechanism of action.  CDX-3379 binds ErbB3 outside of the ligand domain and locks ErbB3 in an auto-
inhibited configuration making the ErbB3 incapable of binding either ligand or dimerizing with HER2.  Locking 
the receptor in the auto-inhibited state with potent binding affinity should result in comprehensive blockage of 
ErbB3 signaling that is either neuregulin-driven or directly by interaction with other ErbB receptors (ligand-
independent). The antitumor activity of CDX-3379 utilizing both ligand-dependent and ligand-independent 
inhibition of ErbB3 has been demonstrated nonclinically in multiple xenograft tumor mouse models. An 
attractive feature of CDX-3379 based on the nonclinical pharmacodynamics studies is the capacity for CDX-
3379 to add to the antitumor activity of currently approved therapeutic agents targeting other ErbB family 
members (dual ErbB blockage), for example, cetuximab targeting EGFR in ligand-dependent models, and 
trastuzumab targeting HER2 in ligand-independent models.  
 
1.1.2  Trametinib (Mekinist®) 
MAPK pathways are evolutionarily conserved kinase modules that link extracellular signals to the machinery 
that controls fundamental cellular processes such as growth, proliferation, differentiation, migration and 
apoptosis41. This signaling pathway is an attractive therapeutic target because it is aberrantly activated in 
many human cancers.  
 
Trametinib (Mekinist®) is a reversible and highly selective allosteric inhibitor of MEK1 and 
MEK2. MEK proteins are critical components of the MAPK pathway which is commonly hyperactivated in 
tumor cells. Oncogenic mutations in both BRAF and RAS signal through MEK1 or MEK2. Trametinib was first 
approved by the FDA in 2013 as a single -agent oral treatment for unresectable or metastatic melanoma in 
adult patients with BRAF V600 mutations.  Trametinib is currently also approved in the EU, Canada, and 


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Australia and multiple other countries for the treatment of adult patients with unresectable or metastatic 
melanoma. The recommended dose of trametinib is 2 mg once daily (QD). 
 
Trametinib in combination with dabrafenib was first approved by the FDA in 2014 to treat 
unresectable or metastatic melanoma in adult patients with BRAF V600 mutations. The combination therapy 
is currently also approved in the EU, Australia, Chile, Canada, and multiple other countries. 
 
NRAS mutations signal through multiple intracellular signaling pathways of which MAPK pathway is 
one.  MEK inhibitors have been used most recently in clinical trials to target NRAS mutant melanoma15,38,39.  
In a recent study, indirect inhibition of NRAS signaling using a MEK inhibitor was evaluated.  Advanced stage 
melanoma patients with a NRAS mutation were randomized to treatment with single agent MEK inhibitor, 
binimetinib, versus DTIC15.   Results demonstrated that median PFS for patients treated with binimetinib was 
2.8 months compared to 1.5 months in patients treated with DTIC, with an objective response rate of 15% 
compared to 7%, respectively15.   These results suggest the possibility for future use of targeted therapy in 
NRAS mutant melanoma treatment.   
 
1.1.3 Combination of CDX-3379 and Trametinib 
Together, the observations of enhanced ERBB3 and MAPK signaling in advanced melanoma suggest that 
these signaling pathways may serve as integral mechanisms of tumor growth in a subset of NRAS mutant 
and WT melanomas and the combination of ERBB3 and MEK inhibition would be synergistic in inhibiting 
tumor growth, as both MAPK and PI3K signaling pathways would be inhibited.      
 
MEK inhibitors have been used in the treatment of 
mutant BRAF melanoma7,36,37 and most recently in clinical 
trials to target NRAS mutant melanoma15,38,39. However, 
there is promising evidence that MEK inhibition targets the 
MAPK pathway and decreasing cell growth in WT melanoma 
cell lines.  Indeed, early studies have observed partial 
response in 10% (4/39) of BRAF WT melanoma patients 
treated with the MEK inhibitor, trametinib7.  Although there 
has been significant progress in molecularly targeted therapy 
in BRAF, NRAS, and KIT mutant melanomas, there remains 
a substantial number of patients who are not current 
candidates for targeted therapy. Therefore, targeting these 
parallel pathways – ERBB3 and MAPK pathways - 
represents a feasible and rational combination strategy which 
could result in improvement in survival in patients with WT 
melanomas.   
 
 
We have preliminary data which support the combination of ERBB3 and MEK inhibition in vitro from 
experiments performed with my collaborators, as well as studies performed here at NYU. 
 
ERBB3 and its ligand, neuregulin, are upregulated in WT melanoma tumor samples 
Since enhanced ERRB3 signaling may be integral to WT melanomas, we next analyzed the nine WT melanoma 
tumor samples by Western blot analysis for activation of ERBB3. In the nine WT melanoma tumor samples, we 
detected increased phospho-ERBB3 (pERBB3) in eight out of nine samples as compared to control 
melanocytes, normalized to β-actin (Figure 1A). We also observed expression of activated pERBB3 in BRAF 
mutant and NRAS mutant melanoma tumor samples (Figure 1B). Recent data from early phase clinical trials, 
as well as a recent study with another ERBB3 antibody42, demonstrated that expression of ERBB3 ligand, 
neuregulin (NRG1), is a crucial determinant for response to ERBB3 inhibition. We evaluated this relationship in 
our WT tumor samples.  Western blot analysis demonstrated variable levels of neuregulin in the WT samples, 
levels which were higher than in control melanocytes (Figure 1A), consistent with NRG1 mediated signaling.  
   
Combination ERBB3 and MEK inhibition results in decreased cell growth in WT melanoma cell lines  
Capparelli et al.25 demonstrated decreased cell growth and proliferation in WT melanoma cell lines when treated 
with the combination of ERBB3 antibody and MEK inhibitor (Figure 2), similar to their recently published data25. 
CHL-1 is a WT melanoma cell line that depends upon the NRG1 autocrine pathway.  A Western blot 
demonstrates that treatment with ERBB3 antibody (MM-121) decreases signaling through ERBB3 and the PI3K 


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pathway, 
confirmed 
by 
decreased 
phospho-AKT 
(pAKTS473) 
and 
pERBB3 
(pErbB3Y1197) (Figure 2A). 
The MAPK pathway molecule, 
ERK, is phosphorylated after 
48 hr of treatment (pERK1/2). 
Using an inhibitor of the MAPK 
pathway, the MEK inhibitor 
GSK212, 
EKR 
phosphorylation is inhibited, 
but after 48hr of treatment, 
AKT 
phosphorylation 
is 
increased. 
However, 
combination 
of 
both 
the 
ERBB3 antibody and MEK 
inhibitor results in decreased 
phosphorylation of AKT and 
ERK, indicative of pathway 
inhibition. 
Pertuzumab, 
a 
HER2(ERBB2) 
inhibiting 
antibody confirms that ERBB2 
is the signaling partner for 
ERBB3, as previously demonstrated25,43, as ERBB3 has no intracellular signaling moiety and signals through 
heterodimerization with a receptor in the EGFR family. These data are supported by growth assays with CHL-
1 cells and crystal violet staining (Figure 2B) where the combination of ERBB3 and MEK inhibitors produced 
more growth inhibition than either treatment alone. FEMX is a WT melanoma cell line that expresses ERBB3, 
but does not express NRG1. In these cells, treatment with the MEK inhibitor, GSK212, inhibits ERK 
phosphorylation (pERK), but does not affect pERBB3 levels (Figure 2C). Treatment with exogenous NRG1 
results in activation of ERBB3 signaling with increased pERBB3 and pAKT, but pERK remains decreased.  In 
the presence of exogenous NRG1, treatment with the combination of an ERBB3 antibody (LJM716) and 
GSK212 results in inhibition of ERBB3 and MAPK pathway activation, again with decreased pAKT and pERK.   
Results are recapitulated with pertuzumab, confirming that the ERBB3 signaling partner is ERBB2. Again, these 
data are supported by in vitro growth assays, demonstrating decreased cell growth in the setting of pathway 
inhibition with the combination of compounds, especially in the presence of NRG1 (Figure 2D). In sum, these 
in vitro data strongly support a role for ERBB3 inhibition, either alone or in combination with MEK inhibition, in 
WT melanoma. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2 Investigational Agent 
 
This clinical trial uses the investigational agent CDX-3379, an ERBB3 monoclonal antibody which inhibits 
ligand binding, receptor heterodimerization, and activation of ERBB3 signaling cascade.  This clinical trial will 
also use the MEK inhibitor, trametinib, in melanoma populations for which it is not currently approved, NRAS 
mutant and BRAF/NRAS wildtype (WT) melanomas.   
 
1.2.1 CDX-3379  
Detailed technical information regarding CDX-3379 is provided in the Investigator’s Brochure. 
 
CDX-3379 isa human IgG1λ mAb that specifically binds ErbB3 at a unique epitope and locks ErbB3 in an auto-
inhibited configuration making the ErbB3 incapable of binding ligand or dimerizing with known tumor growth 
drivers such as HER2 and possibly EGFR. 
 
 
1.2.2 Trametinib (Mekinist®) 
 
Trametinib is absorbed orally with median time to achieve peak concentrations (tmax) of 1.5 hours post-dose. 
The mean absolute bioavailability of a single 2 mg tablet dose is 72%. The increase in exposure (Cmax and 
AUC) was dose proportional following repeat dosing.  Trametinib accumulates with repeat daily dosing with a 
mean accumulation ratio of 6.0 following a 2 mg once daily dose. Mean terminal half-life is 127 hours (5.3 
days) after single oral dose administration. Steady-state was achieved by Day 15. In vitro and in vivo studies 
demonstrated that trametinib is metabolized predominantly via deacetylation alone or in combination with 
mono-oxygenation. The deacetylated metabolite was further metabolized by glucuronidation. The 
deacetylation is mediated by the carboxyl -esterases 1b, 1c and 2, with possible contributions by other 
hydrolytic enzymes. Drug-related material was excreted predominantly in the feces (≥ 81% of recovered 
radioactivity) and to a small extent in urine (≤19%). Less than 0.1% of the excreted dose was recovered in 
urine. 
 
 
 
1.3 Preclinical Data 
 
1.3.1  CDX-3379 - Summary of Nonclinical Experience 
CDX-3379 has shown the following activity in nonclinical studies as summarized in greater detail in the CDX-
3379 investigator brochure: 
• 
In vivo antitumor activity in ligand-independent xenograft models in which the tumor is driven by HER2. 
High levels of heterodimerization partners of ErbB3 through amplification or mutation (such as EGFR or 
HER2) may drive tumor growth without involvement of NRG 
• 
Significant in vivo antitumor activity in ligand-dependent xenograft models in which an autocrine loop drives 
growth (tumor provides NRG and ErbB3) including models of HNSCC, squamous NSCLC and BRAF 
mutated tumors.  Evaluation of human tumors indicates that the highest prevalence of NRG is observed in 
squamous tumors such as HNSCC, NSCLC and esophageal as well as BRAF mutated thyroid samples. 
Analysis of human HNSCC tumors indicates NRG is expressed broadly and independent of anatomical site 
and expressed in both HPV positive and negative tumors, although NRG levels are higher in HPV negative 
tumors. 
• 
Significant in vivo antitumor activity including tumor regression when given in combination with agents that 
target other ErbB family members (in combination with cetuximab, which inhibits EGFR, in combination with 
afatinib, which inhibits EGFR, and in combination with trastuzumab, which inhibits HER2). 


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• 
Increased expression of ErbB3 and sensitivity to NRG stimulation in response to BRAF mutated cells after 
treatment with BRAF inhibitors or MEK inhibitors. Combination treatment of tumor bearing mice with CDX-
3379 with either a MEK inhibitor, a BRAF inhibitor, or their combination did not enhance antitumor activity 
in BRAF mutated tumor models that lack NRG expression, but resulted in enhanced antitumor activity in 
tumor models which express NRG.  
To obtain sufficient nonclinical data on the safety and efficacy of CDX-3379 to support use in clinical trials and 
approval to market, the nonclinical testing program was designed to address efficacy and safety. The mouse 
and cynomolgus monkey were selected as pharmacologically relevant species for evaluation of safety of CDX-
3379 based on sequence homology of ErbB3, affinity for binding of CDX-3379 to ErbB3, and comparable in 
vitro functional activity (ability to block NRG-induced ErbB3 phosphorylation).  
CDX-3379 overall exhibited non-linear PK. Following the intravenous (IV) bolus administration of CDX-3379, 
exposure (area under the concentration time curve; AUC) increased in a greater than dose-proportional manner 
and clearance of CDX-3379 decreased from 96.0 to 49.9 milliliters (mL)/day/kilogram (kg) as the dose increased 
from 10 to 150 mg/kg twice weekly in mice, 41.0 to 5.74 mL/day/kg as the dose increased from 0.3 (single dose) 
to 150 mg/kg (weekly dose) in cynomolgus monkeys. There was moderate accumulation of CDX-3379 in mice 
and cynomolgus monkeys after repeat IV administrations. The accumulation ratio (AR) ranged from 1.2 to 2.3 
for mice (twice weekly dosing), and 1.1 to 3.5 for cynomolgus monkeys (weekly dosing). No differences in the 
pharmacokinetics (PK) were observed between male and female animals. The presence of antibodies against 
CDX-3379 (anti-drug antibodies, ADA) within the dosing phase appeared to reduce CDX-3379 exposure in 
some animals. 
There were no observed adverse effects in cluster of differentiation 1 (CD-1) mice or cynomolgus monkeys that 
were attributed to repeated IV administration of up to 150 mg/kg/dose of CDX-3379, the highest dose tested. 
In the Good Laboratory Practice (GLP) CD-1 mouse study, 8 toxicity animals and 14 toxicokinetic (TK) animals 
administered CDX-3379 died or were euthanized in moribund condition; however, the effects were not 
considered directly related to CDX-3379, but were attributed to anaphylactoid reactions from repeated exposure 
to a foreign antigen (because CDX-3379 is a human IgG1). In cynomolgus monkeys, there were also no CDX-
3379-related effects on safety pharmacology parameters including behavior (as assessed by standard clinical 
observations), heart rate, body temperature, blood pressure, or electrocardiogram (ECG) measurements in 
cynomolgus monkeys. There were no adverse effects on local tolerance following IV bolus or infusion 
administration of CDX-3379 to CD-1 mice or cynomolgus monkeys. 
 
1.3.2  Trametinib (Mekinist®) – Summary of Nonclinical Experience 
See IB for detailed information 
 
 
1.4 Clinical Data to Date 
1.4.1 CDX-3379 - Summary of Clinical Experience  
 
The clinical experience with CDX-3379 has included three clinical studies.  
Study KTN3379-CL-001 was a first-in-human Phase 1/1b study of adult patients with advanced solid tumors 
refractory to standard therapy (or for which no standard therapy existed). Patients received a 60-minute IV 
infusion of CDX-3379 once every three weeks as monotherapy (Phase 1) or in combination with other targeted 
anticancer agents (Phase 1b). In the Phase 1 study portion, a total of 21 patients were treated across three 
dose-escalation cohorts (5, 10, and 20 mg/kg), an intermediate-dose level cohort (15 mg/kg), and a flat-dose 
cohort (1200 mg). As no dose limiting toxicities were reported, a maximum tolerated dose for CDX-3379 
monotherapy was not determined. Pharmacokinetic (PK) analysis showed trough CDX-3379 plasma levels 
exceeding target concentrations at doses ≥10 mg/kg. During this portion of the study, plasma ErbB3 levels 
increased in all patients at all doses consistent with target engagement; however, no objective tumor responses 
were reported.   


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In the Phase 1b study portion, a total of 43 patients were treated with CDX-3379 in combination with cetuximab 
(head and neck cancer or K Ras wild type colon cancer), erlotinib (non-small cell lung cancer), vemurafenib 
(BRAF mutated melanoma), or trastuzumab (HER2 positive breast or gastric cancer). Patients with other cancer 
types and no other standard therapeutic options were also treated in Part II if thought to have the potential to 
benefit from therapy. The starting dose of CDX-3379 in all cohorts was 20 mg/kg. However, due to the 
occurrence of two dose-limiting toxicities in the cetuximab combination cohort (Grade 3 diarrhea and Grade 3 
mucositis), the starting dose of CDX-3379 was reduced to 15 mg/kg for new patients receiving treatment of 
cetuximab and CDX-3379. The starting dose of CDX-3379 was also reduced to 15 mg/kg in the trastuzumab 
combination cohort after a patient with gastroesophageal cancer experienced grade 4 pulmonary hypertension 
and pulseless electrical activity arrest resulting in death.  However, this event was ultimately assessed as 
associated with progression of disease and right-sided cardiomyopathy and unrelated to study therapy. 
Additional dose-limiting toxicity (DLT) were a second case of Grade 3 diarrhea in the cetuximab cohort (after 
reduction of the CDX-3379 dose to 15 mg/kg); Grade 3 diarrhea in the erlotinib combination cohort (per final 
data as per communication with Celldex 12 Oct 2017). Per a preliminary PK analysis conducted in May 2016, 
half-life of CDX-3379 was 17 days and the clearance for CDX-3379 was 2.6 mL/kg/day. All patients achieved 
serum concentrations required for maximal antitumor activity in animal tumor models.  RECIST tumor 
responses were observed in this portion of the study. One patient with advanced HNSCC who had previously 
progressed on single-agent cetuximab experienced a complete response with CDX-3379 20 mg/kg and 
cetuximab. The patient remained on study therapy without progression for over 10 months compared with a 5 
month progression free interval during his prior therapy with single agent cetuximab. The patient’s cancer history 
was notable for having undergone multiple surgeries and prior treatment with chemoradiation (cisplatin), 
cisplatin/5-fluorouracil in addition to single agent cetuximab. The patient’s cancer tissue tested positive for NRG 
mRNA. Two patients with BRAF-mutated non-small cell lung cancer achieved partial responses with CDX-3379 
and vemurafenib. One of these patients had progressive disease as best response after 2 months of an 
alternative BRAF inhibitor (dabrafenib), but received CDX-3379 and vemurafenib for 13 months before 
experiencing disease progression. Finally, one patient with multifocal papillary thyroid cancer experienced a 
partial response at a single timepoint before discontinuing study due to adverse events of diarrhea, hypokalemia 
and hypophosphatemia.  
Study KTN3379-CL-002 was conducted to evaluate ErbB3 phosphorylation (pErbB3) and other molecular 
endpoints in tumor tissue before and after treatment with CDX-3379.  In this study, twelve patients with 
surgically resectable, untreated HNSCC were treated with CDX-3379 every 14 days at a dose of 1000 mg IV 
over 60 minutes, for a maximum of 3 doses prior to surgical resection. Interim data analysis from the first five 
patients showed that CDX-3379 treatment resulted in a decrease in pErbB3 in post-treatment tumor tissue in 3 
of 5 patients. One marked clinical response was noted. A patient with recently diagnosed HPV-negative 
squamous cell carcinoma of the floor of the mouth experienced a 26% decrease in target lesions 
radiographically, reported to represent 92% reduction in tumor volume by physical exam. The patient also 
experienced marked improvement in pain and ability to eat.   
 
Study KTN3379-CL-003 was a pilot study to determine whether the combination of vemurafenib and CDX-3379 
can increase tumoral iodine incorporation sufficient to warrant 131I treatment as determined by PET/CT lesional 
dosimetry, for patients with BRAF mutant, radioiodine-refractory (RAIR) thyroid cancer. This study was closed 
to accrual after enrollment of 7 patients due to slow enrollment and project prioritization. 
 
1.4.2   Trametinib (Mekinist) - Summary of Clinical Experience  
 
Phase II dosing of trametinib was determined to be 2 mg once a day based on the phase I dose-
escalation trial 7,44 of 206 advanced solid tumor patients which included 97 patients with both BRAF mutant and 
wild type melanoma.  The loading dose of trameitnib at 10mg daily for two days followed by 3 mg daily thereafter 
exceeded the maximum tolerated dose, with dose-limiting toxicities including rash, diarrhea, and retinopathy.  
Trametinib 3 mg daily was deemed to be the maximum tolerated dose and after the first cycle, 1 patient 
discontinued therapy due to fatigue, 5 patients required dose interruptions, and 2 patients required dose-
reduction.  Pharmacodynamic testing of trametinib 2 mg once daily in BRAF mutant patients showed a 62% 
inhibition of pERK, 83% inhibition of Ki67, and 171% increase of p27, which were improved from the pre-clinical 
target threshholds 44.  Trametinib produced a response rate of 33% in the 30 BRAF mutant patients including 2 
complete responses and 5 partial responses among the 16 patients on a dose of 2 mg once daily.  Treatment-
related adverse events included acneiform dermatitis or rash, (82%), diarrhea (45%), peripheral edema (35%), 


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fatigue (35%), nausea (12%), ocular events (10%) (which occurred mostly at doses greater than 2 mg daily), 
and a decrease in ejection fraction (7%) 7.   
 
See IB for further detailed information 
1.5 Dose Rationale 
 
Participants on this clinical trial will receive CDX-3379 at 15mg/kg IV every three weeks and trametinib 2mg 
PO daily. 
 
A single agent study evaluated CDX-3379 at a range of concentrations, with upper limit of 20mg/kg without 
observed dose limiting toxicity.  Pharmacokinetic (PK) analysis showed trough CDX-3379 plasma levels 
exceeding target concentrations at doses ≥10 mg/kg.  In combination studies of CDX-3379 with other 
monoclonal antibodies, a few patients experienced side effects at the 20mg/kg dosing, requiring decrease to 
15mg/kg. CDX-3379 in combination with another oral TKI that disrupts the BRAF/MEK/ERK pathway 
(vemurafinib) was well tolerated with no reported DLTs with doses up to 20mg/kg.      At 15mg/kg, objective 
tumor responses were observed. 
 
The  recommended dose of trametinib is 2mg daily.  This dose was chosen based on a number of clinical 
trials as the recommended dosing, even though the maximum tolerated dose being 3 mg daily.     
 
Given the cumulative information regarding dosing and observed response, the recommended starting doses 
for the combination of ERBB3 and trametinib were chosen to be CDX-3379 at 15mg/kg IV every three weeks 
and trametinib 2mg PO daily. 
  
 
1.6 Research Risks & Benefits 
1.6.1 Risk of Study Drug 
 
1.6.1.1  CDX-3379 
CDX-3379 has been given to approximately 80 patients with different types of advanced cancers in three clinical 
studies. More than half of these patients have received CDX-3379 in combination with another anticancer 
treatment. The patients who received CDX-3379 in combination with other anticancer medications, including 
cetuximab, tended to experience more frequent and more severe side effects.   
Overall, side effects thought to be related to study treatment have included the following: 
• 
Frequent side effects (occurring in >20% of the patients):   
- 
Diarrhea (54%; diarrhea)   
- 
Nausea (27%; nausea) 
- 
Fatigue (28%; fatigue) 
- 
Rash (21%; Rash, Rash erythematous, Rash macular, Rash maculo-papular, Rash popular, Rash 
pruritic) 
• 
Somewhat frequent side effects (occurring in 11-20% of the patients):  
- 
Mucositis/Stomatitis (painful inflammation and ulceration of the mucous membranes lining the mouth 
or digestive tract) (16%; Mucosal inflammation, Stomatitis) 
- 
Vomiting (15%; vomiting) 
- 
Low blood potassium (15%, Hypokalaemia, Blood potassium decreased) 


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- 
Decreased appetite (12%; Decreased appetite) 
• 
Less frequent side effects (occurring in 6-10% of the patients): 
- 
Bad taste in the mouth (10%; Dysgeusia) 
- 
“Pimply” (or acne-like) rash (10%; Dermititis acneiform) 
- 
Weight loss (9%; Weight decreased) 
- 
Low blood magnesium (9%; Hypomagnesaemia, Blood magnesium decreased) 
- 
Dehydration (7%; Dehydration) 
- 
Itching (7%; Pruritus) 
 
- 
Weakness (6%; Asthenia) 
- 
Dizziness (6%; Dizziness) 
- 
Dry skin (6%; Dry skin) 
Some of the above events required hospitalization or were otherwise considered serious.  
 
The adverse drug reactions (ADRs; expected adverse events) listed were identified by the Sponsor based on 
reasonable evidence of casual association with CDX- 3379, based on clinical experience as of May 24, 2017. 
The Sponsor consults this section as reference for expectedness of SAEs with regard to expedited reporting 
requirements for regulatory purposes. A SAE will be considered “unexpected” if not consistent in nature or 
severity with the listed ADRs, with consideration to the noted serious adverse drug reactions (SARs; treatment 
related SAEs recorded per CTCAE v4.03 criteria). The table of ADRs is not a complete list of adverse events 
reported in clinical trials. A cumulative tabulation of all adverse events assessed as treatment-related by the 
investigators across all Celldex-sponsored studies of CDX-3379 are provided in the IB.   
 
1.6.1.1.1   Management of Toxicity Related to CDX-3379 
 
Potential toxicity and guidance for the management of toxicity is summarized below.  However, the CDX-3379 
Investigator’s Brochure is the Single Reference Safety Document that provides complete and relevant 
information about the known safety profile of CDX-3379. Updates to these data will be provided as revisions to 
the Investigator’s Brochures and through Investigational New Drug (IND) Safety Reports submitted to the 
investigator by Celldex, rather than by amendment to this section of the protocol. 
 
CDX-3379 alone has been well tolerated with mild to moderate adverse events including diarrhea, rash, 
mucositis, fatigue and dry mouth and severe toxicity (diarrhea, hypokalemia) reported in only two of 21 patients. 
Most common adverse events reported in the Phase 1b study for the combination of CDX-3379 and targeted 
agents (including other EGFR or BRAF inhibitors) have included diarrhea, mucositis and rash with diarrhea and 
mucositis meeting criteria for DLTs.  
 
As a routine precaution, the investigative site's medical staff is to closely observe patients for the duration of 
the CDX-3379 infusion and for at least 1 hour after the end of the infusion, in an area with resuscitation 
equipment and agents used for management of infusion related reactions (e.g., antihistamines, epinephrine, 
corticosteroids). A nurse must be present in the immediate treatment area throughout the infusion and 
observation period. A physician must be in close proximity to the patient treatment area.    
 
In order to mitigate the risk and severity of adverse events resulting from study therapy, patients will undergo 
extensive monitoring throughout the study and guidelines will be implemented per this protocol to ensure that 
study therapy is discontinued and/or modified as necessary and medical therapy is instituted when appropriate 
to manage adverse events. 
 
Dermatologic Toxicity 
Dermatologic toxicities have been reported with CDX-3379 as single agent in the Phase 1 trial in advanced 
cancer patients, and have also been reported in study KTN3379-CL-001 amongst patients treated with the 


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combinations containing CDX-3379.  Supportive management with topical, oral antibiotic therapy or other 
measures should be taken according to institutional standards.   
Recommended dose modification for grade 3 or 4 acneiform rash is provided in Table 5.  
 
Table 5.  Dose Modification Guidance for Rash 
 
 
CDX-3379 
1st Occurrence 
 
Delay infusion by 1-2 weeks 
·         Improvement: Resume at 
same dose 
·         No Improvement: Discontinue  
2nd  Occurrence Delay infusion by 1-2 weeks 
·         Improvement: Resume at 
same dose 
·         No Improvement: Discontinue 
3rd Occurrence 
Delay infusion by 1-2 weeks  
·         Improvement: Reduce dose by 
one level  
·         No Improvement: Discontinue  
4th Occurrence 
Delay infusion by 1-2 weeks  
·         Improvement: Reduce dose by 
one level  
·         No Improvement: Discontinue  
 
Diarrhea 
 
Diarrhea is a common toxicity associated with cancer treatments in general and occurs frequently with mAb 
and tyrosine kinase inhibitors that target the ErbB family of receptors (Stein et al, 2010).  Specifically, diarrhea 
was reported in the Phase 1 study of CDX-3379 conducted in patients with advanced solid tumors and was 
also a frequent adverse event among patients treated with the combination of CDX-3379 and targeted agents.   
 
Treatment guidelines exist for the management of cancer treatment-induced diarrhea that include, but are not 
limited to, the following key elements independent of dose modifications: 
· 
Patient education 
· 
Maintaining oral hydration 
· 
Early intervention with and frequent use of anti-diarrheals until sustained resolution (eg., 
loperamide initial dose of 4 mg followed by 2 mg every 2 hours) 
· 
Frequent monitoring and replacement of electrolyes (eg., potassium, magnesium) 
 
Patients should be managed according to institutional standards and patients should be carefully instructed to 
monitor for diarrhea as well as be instructed on proper management of these symptoms as they occur or change 
during the course of study therapy.  
 
Patients with grade 4 diarrhea should discontinue study therapies unless the toxicity resolves quickly and the 
patient is benefitting from therapy, in which case the therapy may be continued at a reduced dose after 
discussion with the Medical Monitor. 
 
Recommended dose modification grade 2 or 3 diarrhea is provided in Table 6. 
 
Table 6.  Dose Modification Guidance for Diarrhea 
 
Grade 3 or Persistent 
Grade 2 Diarrhea* 
CDX-3379 


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1st Occurrence 
·         Delay infusion by 1-2 
weeks till diarrhea ≤ Grade 1 
·         Resume at same dose 
2nd Occurrence 
·         Delay infusion by 1-2 
weeks till diarrhea ≤ Grade 1 
·         Reduce dose by one level 
3rd Occurrence 
·         Delay infusion by 1-2 
weeks till diarrhea ≤ Grade 1 
·         Reduce dose by one level 
Additional occurance(s) 
·         Delay infusion by 1-2 
weeks till diarrhea ≤ Grade 1 
·         Reduce dose by one level 
or discontinue 
* Despite maximum medical therapy with anti-diarrheals. Persistent is defined as diarrhea that lasts ≥ 3 days. 
 
Infusion Reactions 
Infusion reactions, including those that are severe, are possible with CDX-3379. Infusion reactions may occur 
during the infusion of CDX-3379 or may be delayed until any time after the infusion. 
  
For infusion-related reactions that occur during the administration of CDX-3379 consider temporarily or 
permanently discontinuing CDX-3379depending on the severity of the infusion reaction and the required 
interventions. For NCI CTC Grade 1 or Grade 2 infusion reactions, the infusion may be resumed at a 50% 
reduction in rate after symptoms have resolved and may be considered for subsequent cycles. For Grade 1 or 
Grade 2 infusion reactions, patients will be treated with Benadryl and/or Solucortef for their first infusion related 
reaction. If patients experience an infusion related reaction, patients will be pre-medicated with Benadryl and/or 
Solucortef prior to their next infusion. The following infusion will resume at the full dose. If a second infusion 
related reaction occurs, subsequent infusions will be given at a 50% reduction. Immediately and permanently 
discontinue CDX-3370 for serious infusion reactions, requiring medical intervention and / or hospitalization.  
 
Patients who develop a grade 3 or 4 infusion reaction during CDX-3379 should not receive further treatment 
with CDX-3379. Grade 3 or Grade 4 reactions will be treated with Benadryl, Solucortef and/or an H2 blocker. 
 
 
1.6.1.2  Trametinib (Mekinist®) 
 
The safety profile of trametinib has been well established and detailed in the product’s package insert and IB.  
The most common adverse reactions (occurring in greater than 20% of patients) include rash, diarrhea, and 
lymphedema (package insert).  Additional common side effects (occurring in greater than 10% of patients) 
dermatitis acneiform, dry skin, pruritis, paronychia, stomatitis, abdominal pain, hypertension, and hemorrhage 
(package insert). Additional side effects (occurring in less than 10% of patients) include blurred vision, dry eye, 
dizziness, dysgeusia, folliculitis, pustular rash, cellulits, bradycardia, cardiomyopathy, xerostomia, and 
rhabdomyolysis (package insert).  Rare adverse events (occurring in less than 5% of patients) include retinal 
pigment epithelial detachment (RPED), retinal vein occlusion (EVO), and interstitial lung disease (package 
insert).  Laboratory abnormalities (occurring in greater than 5% of patients) include increased AST, increased 
ALT, hypoalbuminemia, anemia, and increased alkaline phosphatase (package insert).   
 
Trametinib is an inducer of CYP3A4 in vitro. However, trametinib’s efficacious dose of 2 mg once 
daily results in a low systemic maximal concentration (22.2 ng/mL or 0.036 μM), relative to its in vitro inhibition 
potency of CYP enzymes and transporters, rendering the risk of an inhibitory effect of trametinib on the PK of 
co-administered CYP or transporter substrates low. Trametinib is eliminated primarily via deacetylation and 
possibly other hydrolases. There is little evidence from clinical studies for drug interactions mediated by 
carbox ylesterases. Trametinib is also a substrate of P-gp and BSEP. However, due to its high passive 
permeability, these active transport processes are likely of limited relevance. Therefore, a clinically relevant 
effect of a co-administered P-gp or BSEP inhibitor on the PK of trametinib is unlikely. 
 
1.6.1.2.1   Management of Toxicity Related to Trametinib 


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Table 1. Recommended Dose Modifications for Trametinib 
 
Target Organ Adverse Reactiona 
Dose Modification 
Cutaneous 
Grade 2 rash (tolerable) 
Continue treatment and monitor 
Intolerable Grade 2 rash or Grade 3 or 4 rash 
Withhold Trametinib for up to 3 weeks 
If improved within 3 weeks, resume 
Trametinib at a lower dose (reduced by 
0.5 mg) or discontinue Trametinib in patients 
taking Trametinib 1 mg daily 
Intolerable Grade 2 or Grade 3 or 4 rash that 
does not improve within 3 weeks despite 
interruption of Trametinib dosing 
Permanently discontinue Trametinib 
Cardiac 
Asymptomatic, absolute decrease in LVEF of 
10% or greater from baseline and is below 
institutional lower limits of normal (LLN) from 
pretreatment value 
 
Withhold Trametinib for up to 4 weeks. 
 
If improved within 4 weeks, resume 
Trametinib at a lower dose (reduced by 
0.5 mg) or discontinue Trametinib in patients 
taking Trametinib 1 mg daily 
- 
Symptomatic congestive heart failure 
- 
Absolute decrease in LVEF of greater 
than 
20% from baseline that is below LLN 
- 
Absolute decrease in LVEF of 10% or 
greater from baseline and is below 
LLN that does not improve to normal 
LVEF value within 4 weeks following 
interruption of Trametinib
Permanently discontinue Trametinib 
Ocular 
Grade 2-3 retinal pigment epithelial 
detachments (RPED) 
 
Withhold Trametinib for up to 3 weeks.  
If improved to ≤ Grade 1  within 3 weeks, resume 
Trametinib at a lower dose (reduced by 
0.5 mg) or discontinue Trametinib in patients 
taking Trametinib 1 mg daily. If it does not 
improve to ≤ Grade 1 within 3 weeks, discontinue 
Trametinib.  


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Ocular 
Retinal Vein Occlusion 
Permanently discontinue Trametinib 
Pulmonary 
Interstitial lung disease/pneumonitis 
Permanently discontinue Trametinib 
Other 
Intolerable Grade 2 adverse reaction 
Grade 3 adverse reaction 
Withhold Trametinib for up to 3 weeks. If  
Grade 3 adverse reaction improves to ≤ Grade 1 
following interruption of Trametinib within 3  
weeks then reduce dose of Trametinib by 
 0.5mg or discontinue Trametinib in patients 
 taking Trametinib 1 mg daily.  
 
 
Grade 4 adverse reaction or  
Grade 3 adverse reaction that does not improve to 
Grade 0-1 within 3 weeks 
Permanently discontinue Trametinib 
       
 
 
 
1.6.2 Overlapping Toxicities  
 
Unless a side effect is specific to only trametinib (cardiac (red LVEF), ocular (RPED, RVO), and/or pneumonitis), 
both drugs should be held together. With the exception of the trametinib specific side effects, all other side 
effects can be considered from either medication.  
1.6.3  Dose-Limiting Toxicities 
 
For this study, DLT is defined as all toxicities regardless of attribution to study drug, with the exception of 
toxicities clearly due to disease progression or identified extraneous cause.  
 
The following AEs will be considered to be DLTs: 
 
• 
Any toxicity that requires permanent discontinuation of either drug. Note: this would include 
retinal vein occlusion, interstitial lung disease, and any toxicity identified in the dose 
modification guidelines for CDX-3379. 
• 
Any toxicity regardless of grade that requires an interruption of more than 4 weeks.  
• 
Any fatal adverse event.  
 
 
Hematologic Toxicity: 
 
-Grade 4 neutropenia (absolute neutrophil count (ANC) < 500/ul) lasting > 7 days. 


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-Febrile neutropenia (ANC<1,000/ul). 
 
 
-Grade 4 thrombocytopenia (platelet count < 25,000/ul). 
 
 
-Grade 3 thrombocytopenia (platelet count 25,000/ul to 50,000/ul) with clinically important bleeding.  
 
Nonhematologic Toxicity: 
 
All other Grade 3 or higher nonhematologic toxicities with the following  exceptions: 
 
 
-Alopecia 
 
 
-Grade 3 nausea, vomiting, and/or diarrhea that lasts <72 hours with adequate antiemetic and 
supportive care. 
 
 
- Grade 3 electrolyte abnormalities that are asymptomatic and last  ≤ 24 hours with medical intervention.  
 
1.6.4 Other Risks of Study Participation 
 
Risks of study participation may be that the drugs under study will not be effective for some participants.  In this 
case, the study drugs will be discontinued and participants will continue regular care by their provider to 
determine the next appropriate step in therapy.  The study may also require additional outpatient visits, blood 
tests, and tissue biopsies that may otherwise not be required off study.  The risks associated with blood draw 
include weakness, redness, pain, bruising, bleeding, or infection at the needle site.  The effects of FNA and 
core biopsies are generally mild; slight discomfort and light bleeding are to be expected.  Participants have the 
option of discontinuing study treatment at any time.  Trial investigators will determine the appropriate drug dose 
and will administer this in the phase 2 portion of the trial.  There has been clinical experience previously with all 
of the study drugs and investigators will continually monitor for adverse events. 
 
1.6.5   Potential Benefit  
 
Participants participating in the research study will have access to combination therapy with trametinib and  
CDX-3379, an ERBB3 inhibitor.  The information obtained from this research may help others with this  
disease in the future.  Subjects’ health may improve while on the trial, but it may not.  It is hoped that  
results from this trial may help others with this disease. 
 
 
2 Study Objectives 
Primary Objectives: 
 
Phase 1b: To determine the MTD/RP2D and asses the toxicity and tolerability of the combination of CDX-
3379 (ERBB3 antibody) and trametinib (MEK inhibitor) in NRAS and BRAF/NRAS WT melanoma patients 
 
Phase 2: To estimate the response rate and duration of response of the combination CDX-3379 and 
trametinib in NRAS mutant and BRAF/NRAS  WT melanoma patients  
 
 
Secondary/Exploratory Objectives: 
 
Phase 2:  To compare the efficacy of the combination of CDX-3379 (ERBB3 antibody) and trametinib is more 
effective than a MEK inhibitor alone in NRAS positive and BRAF/NRAS WT melanoma patients alone using 
locally assessed progression free survival (PFS) and overall survival (OS)  


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Exploratory Objectives: 
To evaluate ERBB3 signaling pathway and MAPK signaling pathway components, in addition to pathway 
ligands, including NRG1/HRG1 (neuregulin 1/heregulin 1, ERBB3 ligand) expression and correlate this with 
treatment response.   
- archival tissue and pre-treatment, on treatment, and progression tumor samples will also be obtained for all 
patients in Phase Ib and the first 5 patients with NRAS mutant melanoma and the first 5 patients with WT 
melanoma in Phase II.  
 
 
 
3 Study Design 
3.1 General Design 
 
This study is an open-label, non-randomized phase Ib/II study in patients with unresectable stage III or stage 
IV NRAS mutant or BRAF/NRAS WT melanoma.    
 
Following signing informed consent and evaluation of initial eligibility criteria, all participants will provide an 
archived tissue sample (which meets the requirements for collection and processing as outlined in the study 
lab manual).  In addition, all patients enrolled on Phase Ib and the first five NRAS mutant melanoma participants 
and first five WT melanoma participants on Phase II will undergo a mandatory core biopsy for pretreatment 
tumor tissue.  For these procedures, investigators are asked to choose an easily accessible tumor lesion to 
minimize any possible risk associated with the collection of the tissue. As a general guideline, if the selected 
procedural location of the core needle biopsy or FNA has an established serious complication rate of >2% at 
the institution completing the procedure, this is considered a high risk procedure and should be avoided.   
 
The purpose of this phase Ib study is to determine the MTD/RP2D and assess the toxicity and tolerability of 
combination of CDX-3379 (ERBB3 inhibitor) and trametinib (MEK inhibitor) in NRAS mutant and WT advanced 
stage melanoma.  The purpose of phase II study is to estimate the response rate and duration of response of 
the combination in each cohort of participants that are NRAS mutant and WT advanced stage melanoma  
 
 
 
 
Abbreviations: C = cycle; D = day; PD = progressive disease. 
Figure 1: Phase Ib study design 
 
    
Phase 1b:  6-18 evaluable subjects will be treated to identify the MTD/RP2D prior to advancing to phase II. 
Enrollment & 
Screeningll 
(archival tissue)  
C1D1-C1D21 
CDX-3379 D1 
trametinib daily 
Biopsy (days 14-
16) 
C2D1-C2D21 
(and continues) 
CDX-3379 D1 
trametinib daily 
Until PD or toxicities 
Biopsy at trial 
discontinuation 
Core biopsy prior to D1 


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Definition of MTD/RP2D - 
Once the subject has completed the screening procedures and is deemed eligible for the study, the subjects 
will be assigned to the following therapy: 
 
Trametinib:   2 mg PO daily  
ERBB3 antibody (CDX-3379) 15mg/kg IV on day 1 of each 21-day cycle 
 
MTD/RPRD will be determined by combining ERBB3 antibody (CDX-3379) 15mg/kg IV Q3W with 2mg 
trametinib.  Dose de-escalation of ERBB3 antibody (CDX-3379) and/or trametinib, if needed, will be allowed if 
significant toxicity is experienced with the two drugs at their recommended doses (which were previously 
determined). 
 
Cohort levels for MTD/RP2D:  
No of pts 
Cohort Level 
CDX-3379 
Trametinib 
6 
1 
15mg/kg IV Q 
3wks 
2mg daily 
 
6 
-1A 
15mg/kg IV Q 
3wks 
1.5mg daily 
 
6 
-1B 
10 mg/kg IV Q 
3wks 
1.5mg daily 
 
6 
-2A 
10mg/kg IV Q 
3wks 
1.0 mg daily 
6 
-2B 
5 mg/kg IV Q 
3wks 
1.0mg daily 
 
 
Safety has been established for the combination of CDX-3379 (ERBB3 antibody) and chemotherapeutic agents 
and targeted therapy at the standard doses with maximum dose of 20mg/kg.  In addition, the  recommended 
treatment dose of trametinib is 2mg.  However, no data is available for the combination of CDX-3379 (ERBB3 
antibody) and trametinib.  In Phase Ib, all patients will start treatment at the cohort 1 doses.  Six patients will be 
enrolled at this dose level and monitored for DLTs for 6 weeks (which is two treatment cycles (42 days)).   
 
In these six participants, if none or one subject experiences a DLT, then dose cohort 1 will be considered the 
RP2D, and phase II of the clinical trial will proceed.  After the first 20 patients are enrolled in the initial cohort, 
enrollment will be placed on hold to monitor for toxicity. At this point, a stopping rule for the cohort expansion 
portion of the trial for excessive toxicity such that if ≥ 30% of patients enrolled across groups discontinue 
treatment due to toxicity, enrollment will pause and an assessment of the toxicity of the treatment regimen(s) 
will be performed. This assessment, along with justification for resumption of enrollment, should be submitted 
to FDA. This stopping rule for the cohort expansion portion of the trial for excessive toxicity applies regardless 
of which dose is selected as the RP2D. Toxicities will be reviewed by study sponsor (NYU Langone Health) 
and DSMC.  If ≤33 % of patients experience DLT based on review, then the study will continue enrollment.  If 
> 33% of patients experience a DLT, then the study sponsor (NYU Langone Health), DSMC will convene to 
determine the best course of action (i.e. enrollment at decreased dosing cohort, etc). 
 
If two or more of the six subjects experience DLT, we will consider the initial dose cohort beyond the MTD and 
we will enroll six more patients in cohort 1A or 1B, based on the toxicity pattern observed that is felt to be 
attributed to a particular drug.  Dose reduction to -1A or -2A is specifically for toxicity related to trametinib, LVEF 
reduction, RPED, pneumonitis and LFT abnormalities. -1A is the first reduction, followed by –2A as the second 
reduction. For all other observed toxicities the default dose-reduced cohort is -1B followed by -2B. In the  new 
dose cohort, if none or one patient experiences a DLT, then the study will open to full enrollment on the Phase 
II portion of the trial.  If two or more of these additional six patients experience DLT, we will then enroll six 


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additional patients at additional dose de-escalation cohorts, to be determined by sponsor (NYULMC) and NYU 
DSMC), again based on toxicity pattern observed and drug attribution.  If two or more patients experience DLT 
at this new dose cohort, then the trial will be terminated. 
 
 
 
Phase 2:  There are two Arms - Arm A (NRAS mutant melanoma patients) and Arm B (WT melanoma patients).  
This is the first part of a Simon Minimax design.  Each arm will initially enroll 19 subjects.  If there are three or 
fewer responses, then accrual to that cohort will be stopped.  Otherwise, the study will be amended to enroll a 
total of 36 subjects to each approved arm/cohort.    
 
 
 
Abbreviations: C = cycle; D = day; PD = progressive disease. 
Figure 2: Phase II study design 
 
 
 
 
Translational Research - 
We will perform biopsies on all phase Ib patients (expected 6 patients, but could be up to 18) and five patients 
on each Arm of the study for Phase II.  Biopsies will be obtained pre-treatment, on-treatment between day 14-
16, and at the time of disease progression.  Archival tissue will also be collected.  We will investigate pathway 
inhibition of ERBB3 signaling and MAPK signaling pathways by analyzing components of the signaling 
pathways in addition to key components integral in these signaling pathways.  We will also evaluate 
NRG1/HRG1 (neuregulin 1/heregulin 1, ERBB3 ligand) expression and correlate this with treatment response.  
Enrollment & 
Screening 
(archival tissue) 
C2D1-C2D21 
(and continues) 
CDX-3379 D1 
Trametinib daily 
Until PD or 
toxicities 
Biopsy at trial 
discontinuation 
C1D1-C1D21 
CDX-3379 D1 
Trametinib daily 
Biopsy (days 
14-16) 
C1D1-C1D21 
CDX-3379 D1 
Trametinib daily 
Biopsy (days 
14-16) 
C2D1-C2D21 
(and continues) 
CDX-3379 D1 
Trametinib daily 
Until PD or 
toxicities 
Biopsy at trial 
discontinuation
Core biopsy prior to D1 
Arm A 
NRAS mutant 
melanoma 
Arm B 
WT melanoma 


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Analysis will be performed using immunohistochemistry, Western Blot analysis (if there is enough tissue), and 
in situ hybridization.   
 
3.2 Primary Study Endpoints 
 
For Phase Ib, the primary endpoint is identification of toxicities, tolerability and definition of a recommended 
phase II dose (RP2D) of Q3WK infusions of CDX-3379 in combination with once daily oral administration of 
trametinib. 
 
 
For Phase II, the primary endpoint is an estimation of the overall response rate and duration of response in 
patients treated with CDX-3379 in combination with trametinib in NRAS mutant and WT melanoma.  
 
 
3.3 Secondary Study Endpoints 
 
 
For Phase 1b, the secondary endpoints are to assess clinical activity and steady-state pharmacokinetics 
of CDX-3379 and trametinib 
 
 
For Phase II, the secondary endpoints are description of antitumor activity of the combination CDX-3379 and 
trametinib and include progression free survival (PFS) and overall survival (OS).   
 
3.4 Exploratory Endpoints 
 
Exploratory endpoints for both phase Ib and II include evaluation of pharmacodynamic markers of CDX-3379 
and trametinib activity in serial tumor biopsies and potential predictive biomarkers of response and resistance 
to CDX-3379 and trametinib. Evaluations may include, but are not limited to, ERBB3, pERBB3, FOXD3, 
ERBB2, pERBB2, EGFR, pAKT, PTEN, ERK1/1, pERK1/2, DUSP4, NRG1 (neuregulin), NRG2, transforming 
growth factor alpha (TGFα) and amphiregulin (AREG), as well as other markers identified to be integral to 
ERBB3 and MEK inhibition.  
3.5 Primary Safety Endpoints 
Safety assessments will consist of monitoring and recording all adverse events, including serious adverse 
events as well as blood monitoring of hematologic and chemistry values with each cycle of therapy.   
Patients will also be clinically assessed with regular monitoring of vital signs and physical exam.  The 
secondary endpoints of the phase Ib portion of the study includes adverse event rates.  Refer to Section 
8 for further information on safety monitoring.   
 
Determination of final MTD/RP2D will be guided by the incidence of drug-related side effects and dose de-
escalations occurring within 6 weeks (two cycles) which allows for substantial amount of time for unexpected 
toxicities with combination of CDX-3379 with trametinib.   This is detailed in section 3.1. 
 


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4 Subject Enrollment and Withdrawal 
4.1 Inclusion Criteria 
 
1. Read, understood, and provided written informed consent and, if applicable, Health Insurance 
Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully 
explained and must be willing to comply with all study requirements and procedures. 
2. Male or female patients who are 18 years of age or older. 
3. Patients with a diagnosis of histologically confirmed advanced (defined as unresectable stage III or 
IV) melanoma with the NRAS Q61 mutation or BRAF/NRAS WT who are refractory to or intolerant of 
existing therap(ies) known to provide clinical benefit for their condition, including anti PD-1 and/or 
CTLA-4 agent.    
• 
Any CLIA certified mutation testing is acceptable to document mutation status.  
4. Patients must have adequate cardiac function as demonstrated by a left ventricular ejection fraction 
(LVEF) ≥ 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram.  
5. Patients must have archival tissue and at least one disease site amenable to biopsy: 
• 
For phase Ib, all patients will undergo fresh tumor biopsy 
• 
For phase II, five patients with NRAS mutation and five patients with BRAF/NRAS WT 
melanoma will undergo fresh tumor biopsy  
6. Measurable (target) disease by Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria.  
Target lesions selected for tumor measurements should be those where additional (eg palliative) 
treatments are not indicated or anticipated.   
• 
Measurable disease per RECIST 1.1 requirements:  defined as longest diameter to be 
recorded for non-nodal lesions > 10mm and short axis for nodal lesions >15 mm using 
conventional techniques  
7. All residual toxicity related to prior radiotherapy or anticancer therapies (excluding alopecia, grade 2 
fatigue, vitiligo or endocrinopathies on stable replacement therapy) must resolve to grade 1 severity 
or less (or returned to baseline) prior to receipt of study treatment.  
8. Adequate electrolytes, liver, renal, and hematology function as defined below: 
a. Hemoglobin ≥ 9 g/dL 
b. Absolute neutrophil count ≥ 1500/mm3 
c. Platelet count ≥ 100,000/mm3 
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal 
(ULN) (≤ 5 × ULN for cases involving liver metastasis) 
e. Bilirubin ≤ 1.5 × ULN (≤ 5 × ULN for cases of documented or suspected Gilbert's disease)  
f. 
Serum creatinine ≤ 1.5 g/dL or calculated creatinine clearance (CrCl) ≥60 mL/min for patients with 
serum creatinine > 1.5 x ULN 
g. Serum magnesium, calcium and potassium within normal limits  
9. Life expectancy ≥ 12 weeks 
10. ECOG performance status (PS) < 1 
11. Willing and able to comply with scheduled visits, treatment plan, and laboratory tests. 
12. Screening EKG without clinically significant abnormalities. 
13. Corrected (Fridericia’s) QTcF must be < 480 milliseconds. 


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14. Allowance of prior therapy regimens: 
• 
No limit on prior number of regimens 
• 
Must have completed prior cytotoxic chemotherapy a minimum of 4 weeks prior to starting 
study treatment (except for bis-chlorethynitrosurea (BCNU)), which must have been 
completed a minimum of 6 weeks prior to starting therapy. 
• 
Prior localized radiation therapy must have been completed a minimum of 2 weeks prior to 
starting therapy and the patient must have baseline imaging with a full body PET-CT or CT 
scans of the chest, abdomen, and pelvis and within 4 weeks prior to study enrollment.   
• 
For CNS metastases, disease must be treated and demonstrate stability with Brain MRI a 
minimum of 4 weeks prior to starting therapy.  
15. Both male and female patients enrolled in this trial must agree to use highly effective contraception 
during the course of the trial and for at least for 6 months after the final dose of CDX-3379 (an effective 
form of contraception is an oral contraceptive or a double barrier method), or greater, as in 
accordance with the label requirements for trametinib.  Patients and/or partners who are surgically 
sterile or postmenopausal are exempt from this requirement. 
• 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, unless they are using highly effective methods of contraception during dosing and 
for 3 months after stopping study drug. Highly effective contraception methods include: 
• 
Total abstinence or 
• 
Male or female sterilization or 
• 
Combination of any two of the following (a+b or a+c or b+c): 
• 
(a) Use of oral, injected or implanted hormonal methods of contraception; hormonal 
contraceptives are not acceptable as a sole method of contraception. 
•  (b) Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
•   (c) Barrier methods of contraception: condom or occlusive cap (diaphragm or   cervical/vault 
caps) with spermicidal foam/gel/film/cream/vaginal suppository 
16.  Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or 
without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential. 
 
 
4.2 Exclusion Criteria 
Patients will be excluded from the study for any of the following reasons: 
1. Received CDX-3379 or other anti-ErbB3 targeted agents previously. 
2. Received trametinib or other MEK inhibitor agents previously. 
3. Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy for cancer 
treatment. Concurrent use of hormones for non-cancer related conditions (e.g., insulin for diabetes and 
hormone replacement therapy) is acceptable.  
4. Other prior malignancy active within 2 years, except for localized prostate cancer, cervical carcinoma in 
situ, non-melanomatous carcinoma of the skin, stage 1 differentiated thyroid cancer or ductal carcinoma in 
situ of the breast that has/have undergone curative surgery or radiation. 


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5. Active central nervous system (CNS) metastases are excluded.  Known brain metastases must have been 
previously treated and asymptomatic for 2 weeks and not progressive in size or number for 4 weeks prior 
to enrollment, documented via scans. Continued use of anticonvulsants (in the absence of any suspicion 
of progressive brain metastases) is acceptable.  Patients must currently be on a stable, lowest possible 
dose of steroids.         
6. Radiation therapy within 14 days prior to the first scheduled dose in this study, including, in addition (if 
necessary), the timeframe for resolution of any actual or anticipated toxicities from such radiation. 
7. Known HIV, hepatitis B or hepatitis C infection, or active infection requiring systemic intravenous therapy. 
8. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled 
glaucoma or ocular hypertension, history of hyper viscosity or hypercoagulability syndromes).     
9. Use of any monoclonal based therapies within 4 weeks (excluding cetuximab which does not require a 
wash-out), and all other immunotherapy (tumor vaccine, cytokine, or growth factor given to control the 
cancer) within 2 weeks, prior to the first dose of study treatment.   
10. Chemotherapy within 4 weeks (except for bis-chlorethynitrosurea (BCNU), which must have been 
completed a minimum of 6 weeks) prior to starting therapy. 
11. Major surgery within 4 weeks prior to the first dose of study treatment. Surgery requiring local/epidural 
anesthesia must be completed at least 72 hours before study drug administration and patients should be 
recovered. 
12. Use of other investigational drugs within 2 weeks or 5 half-lives (whichever is longer) prior to study treatment 
administration. 
13. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 
ms); additional risk factors for torsades de pointes (TdP) (e.g., a history of heart failure, family history of 
Long QT Syndrome, or active hypokalemia or uncorrectable electrolyte abnormality); significant 
cardiovascular disease including unstable angina pectoris, uncontrolled hypertension or arrhythmia, 
congestive heart failure (New York Heart Association Class III or IV) related to primary cardiac disease, 
uncontrolled ischemic or severe valvular heart disease; or any of the following within 6 months prior to the 
first dose of study treatment: myocardial infarction, severe/unstable angina, coronary artery bypass graft, 
congestive heart failure, cerebrovascular accident, transient ischemic attack. 
14. Requirement for chronic immunosuppressive medication including systemic corticosteroids above the 
physiologic dose (defined as 20 mg/day prednisone or the equivalent).  
15. Any other acute or chronic medical or psychiatric condition or laboratory abnormality that could increase 
the risk associated with trial participation or trial drug administration or could interfere with the interpretation 
of trial results and, in the judgment of the investigator, would make the patient inappropriate for entry into 
the trial.  
16. Known alcohol or drug abuse. 
17. Sexually active males must use a condom during intercourse while taking the drug and for 3 months after 
stopping study drug and should not father a child in this period. A condom is required to be used also by 
vasectomized men in order to prevent delivery of the drug via seminal fluid. 
18. Inability to swallow pills 
19. Patients unwilling or unable to comply with the protocol. 
 


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4.3 Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4.4 Subject Recruitment and Screening 
 
The inclusion and exclusion criteria in this study should not have a negative effect on the enrollment of the 
desired populations. 
Eligible patients with advanced stage NRAS mutant and WT melanoma age 18 years and older who agree to 
participate in the study will be identified from the Laura and Isaac Perlmutter Cancer Center outpatient 
melanoma practice of the clinical investigators during a routine office visit or consult.  Patients will also be 
recruited through NYU Langone Health and an additional site, the University of Pennsylvania, which will be 
added.   All participants will be required to sign informed consent prior to trial enrollment. After signing informed 
consent, subjects will provide an archived tissue sample. 
 
 
 
  
4.4.1 Method of Subject Identification and Recruitment 
  
Target enrollment for this study is 44 patients. The target accrual goal at NYU is 10 patients per year. 
 
The patients who are eligible for this research study come directly from the study investigators’ clinical patient 
population. Thus, the investigators are very familiar with their patients’ disease status and potential eligibility 
given the protocol’s inclusion and exclusion criteria. The investigator will approach eligible potential subjects 
and explain the study in a private room, including the reasons why subjects will be eligible, risks, benefits, and 
the regimes to be evaluated. They will also receive the informed consent document to read.  Consent will be 
obtained in a private room by the PI, Co-Investigator, or research coordinator/research nurse at the time of 
the subject’s visit prior to any study assessments/procedures. The subjects will be given a chance to ask 
questions to the person consenting him/her and will be able to take the consent home to discuss it with 
family/friends prior to signing. If the subject agrees s/he will sign the consent form either at the first contact (if 
the investigator/delegate is convinced that the subject understands) or at the time of a return visit after having 
had time to study the consent in more depth. Study procedures will not begin until after the consent form has 
been properly obtained. The subject is entitled to decide not to participate in the trial, without affecting their 
right to other medical care, and may discontinue participation in the trial at any time without penalty or loss of 
benefits to which they are entitled. 
 
The Principal Investigator will: 
1.  Obtain signed and dated informed consent from the potential subject before any study specific 
procedures are performed. 
 
2.  Determine patient eligibility; see Section 4.1 and 4.2  
 
3.  Submit registration to NYU Langone Health Perlmutter Cancer Center CTO 
4.  Receive registration confirmation from the NYU Langone Health Perlmutter Cancer Center CTO, 
including a unique study identification number assigned to the patient that will be distributed to the 
study team upon registration of the patient. 


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The informed consent process and documentation follows that established procedures of the NYU Langone 
Health Perlmutter Cancer Center Clinical Trials Office. 
 
   
 
4.5 Early Withdrawal of Subjects 
4.5.1 When and How to Withdraw Subjects 
A subject may withdraw from the study at any time and for any reason.  Discontinuation of therapy will not affect 
the subject’s relationship with the treating physician.  It is intended that subjects will be treated until investigator-
determined progressive disease (radiologic or clinical deterioration) or unacceptable toxicity. Reasons for 
withdrawal from treatment include, but are not limited to:  progressive disease as determined by RECIST v1.1, 
clinical deterioration, adverse events, protocol violation, non-compliance, withdrawal of consent, investigator or 
sponsor decision, or if the subject is lost to follow-up.  Withdrawal from the study can be made in writing to the 
Principal Investigator, Dr. Weber.  Any samples/specimens remaining after formal withdrawal, will be 
destroyed/discarded per Institutional guidelines. 
4.5.2 Data Collection and Follow-up for Withdrawn Subjects 
When a subject is discontinued from treatment for any reason, they are to undergo the assessments in the end 
of treatment visit within 4 weeks of the last dose. All subjects who discontinue treatment as a result of an 
adverse event must be followed until resolution or stabilization of the adverse event. If a subject withdraws 
from study treatment, attempts should be made to contact the subject to determine the reason(s) for 
discontinuation. The subject will continue to be followed for survival information every 3 months after completion 
of the End of Treatment visit. All subjects, including subjects who discontinue treatment for other reasons than 
progressive disease per RECIST 1.1, should undergo a scan to assess disease status prior to termination from 
the study. 
 
If a subject does not return to the clinic for the end of treatment visit or is not reached for overall survival follow-
up, at least 3 documented attempts, including one via certified mail, should be made to contact the subject. If 
the subject does not respond to these requests, the date of death should be captured from public records. 
 
4.5.3 Premature Termination or Suspension of Study 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to the investigator, funding agency, the IND sponsor and regulatory 
authorities. If the study is prematurely terminated or suspended, the PI will promptly inform the IRB and will 
provide the reason(s) for the termination or suspension. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
 
 
Study may resume once concerns about safety, protocol compliance, data quality are addressed and satisfy 
the sponsor, IRB and/or FDA. 
 
 


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5 Study Drug  
5.1 Description 
5.1.1 
CDX-3379 -Description, Packaging, and Labeling 
Detailed technical information regarding CDX-3379 is provided in the Investigator’s Brochure. 
CDX-3379 is a human IgG1λ mAb that specifically binds ErbB3 at a unique epitope and locks ErbB3 in an auto-
inhibited configuration making the ErbB3 incapable of binding ligand or dimerizing with known tumor growth 
drivers such as HER2 and possibly EGFR. 
CDX-3379, manufactured by MedImmune for Celldex, is supplied as a clear to opalescent, colorless to brown-
yellow liquid, free from or practically free from visible particulates.  CDX-3379 will be provided at a 1.0 mL or 
2.0 mL fill volume in a 3 cc glass vial, as a 50 mg/mL solution containing 25 millimolar (mM) histidine/histidine-
hydrochloride, 205 mM sucrose and 0.02% (weight/volume) polysorbate 80, at a pH of 6.0. CDX-3379 is 
manufactured in accordance with Good Manufacturing Practices (GMP) and labeled according. 
 
 
5.1.2  Trametinib (Mekinist®) 
 
Trametinib tablets (also referred to as GSK1120212B Tablets, TMT212-NXA Tablets) are immediate release 
tablets for oral administration containing trametinib dimethyl sulfoxide (GSK1120212B/TMT212-NXA) 
equivalent to 0.125 mg, 0.5 mg or 2 mg of trametinib (GSK1120212/TMT212, non-solvated parent). 
Trametinib Tablets, 0.125 mg are dark pink, round, biconvex, film-coated tablets. Trametinib Tablets, 0.5 mg 
are yellow, modified oval, biconvex, film-coated tablets. Trametinib Tablets, 2 mg are pink, round, biconvex, 
filmcoated tablets. Trametinib Tablets are packaged into a high density polyethylene (HDPE) bottle that 
contains desiccant with a child-resistant closure that includes an induction seal liner. 
 
List of Excipients 
Tablet Core 
- Mannitol 
- Microcrystalline cellulose 
- Hypromellose 
- Croscarmellose sodium 
- Magnesium stearate (non-animal) 
- Colloidal silicon dioxide 
- Sodium lauryl sulfate 
 
Film-coat (aqueous film-coating; water is removed during processing) 
- Opadry Red 03B25344 (0.125 mg) containing hypromellose, titanium dioxide, polyethylene glycol, and iron 
oxide red 
- Opadry Yellow 03B120006 (0.5 mg) containing hypromellose, titanium dioxide, polyethylene glycol, and iron 
oxide yellow 
- Opadry Pink YS-1-14762-A (2 mg) containing hypromellose, titanium dioxide, polyethylene glycol, 
polysorbate 80, and iron oxide red. 
All excipients used in the tablet core are standard and of pharmacopoeial quality. The coating pre-mixes 
(Opadry) are a combination of standard ingredients, which are of pharmacopoeial or international standards’ 
quality. 
 
5.2 Treatment Regimen 
CDX-3379 will be given IV at 15mg/kg every three weeks of a 21-day cycle.  Trametinib will be given at a 
dose of 2 mg PO daily.  Treatment will continue until disease progression, intolerable side effects, subject 
choice, or study closure. 


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5.3 Method for Assigning Subjects to Treatment Groups 
This is an open label, non-randomized study.  All subjects with NRAS mutant or WT melanoma will be 
enrolled on the Phase 1B portion of the study.  During Phase 2, subjects with NRAS mutant or WT melanoma 
will be enrolled and assigned to their respective study arm – based on mutation status – for the purpose of 
analysis.   
5.4 Preparation and Administration of Study Drug 
5.4.1 CDX-3379 Storage and Handling 
CDX-3379 is shipped in insulated shippers and must be stored at 2 - 8°C (36 - 46°F) until use. Do not freeze 
CDX-3379 solutions. A temperature log must be kept to document the refrigerator temperature.  If the 
temperature is not maintained, Celldex should be contacted. 
CDX-3379 is not formulated with a preservative.  Therefore, once the sterile vials are entered (i.e., needle 
puncture of the vial), the drug should be used as soon as possible (typically within 3 hours if kept at room 
temperature or within 6 hours if refrigerated; or in accordance with any applicable institutional guidance). 
Additional guidance regarding storage and handling of CDX-3379 will be provided on the pharmacy sheet 
provided by Celldex.    
 
5.4.2 CDX-3379 Administration 
The dose of CDX-3379 is 15 mg/kg, administered intravenously every 3 weeks (on day 1 of each 21-day cycle).  
Subjects will be treated with CDX-3379 until progressive disease, unacceptable toxicity, or other criteria for 
discontinuation of study treatment.    
Subjects will receive CDX-3379 as an IV infusion over 60 ± 5 minutes. As a routine precaution, the investigative 
site's medical staff is to closely observe patients for the duration of CDX-3379 infusion and for at least 1 hour 
after the end of the infusion.  
The entire contents of the IV bag should be administered through an IV administration set with a low protein 
binding 0.2-μm in-line filter.  Since the compatibility of CDX-3379 with other IV medications and solutions other 
than normal saline (0.9% [w/v] Sodium Chloride for Injection) is not known, the CDX-3379 solution shall not be 
infused through an IV line in which other solutions or medications are being co-administered. The date, start 
time, interruption, and completion time of CDX-3379 administration must be recorded in the source documents.  
 
 
5.4.3 Trametinib Storage and Handling 
The recommended storage conditions, shelf-life and expiry date, where required, are stated on the product 
label.  Trametinib will be provided as 0.5 mg and 2 mg tablets.  Trametinib tablets must be kept refrigerated. 
 
5.4.4 Trametinib Administration 
Trametinib will be administered orally daily at 2 mg (on an empty stomach either one hour prior to or two hours 
after eating).  On days where the subject receives both CDX-7739 and trametinib, the subject will take 
trametinib immediately following infusion of CDX-3379 (on an empty stomach either one hour prior to or two 
hours after eating).  Do not take a missed dose within 12 hours of the next dose.  Subjects are expected to be 
treated until investigator assessed progressive disease is noted, in the event of unacceptable toxicity, subject 
choice, or study closure.   
5.5 Subject Compliance Monitoring 
CDX-3379 will be administered by study staff, and details regarding each administration will be recorded in the 
subject’s medical record and the CRFs.   Trametinib will be self-administered, and a medication diary will be 
provided to subjects.   
 


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5.6 Prior and Concomitant Therapy 
No other investigational agents or concurrent therapy for melanoma will be allowed during treatment on this 
clinical trial.  
 
There are no restrictions on the number of prior therapies, however, subjects may not have been treated 
previously with an ERBB3 or MEK inhibitor. 
 
Drug Interactions:  No formal drug interaction studies have been conducted with trametinib.  Trametinib is not 
a substrate of CYP enzymes or efflux transporters P-gp or BCRP in vitro.  Based on in vitro studies, trametinib 
is not an inhibitor of CYP450 including CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and 
CYP3A4 or of transporters including OATP1B1, OATP1B3, P-gp, and BCRP at a clinically relevant systemic 
concentration of 0.04 µM.  Trametinib is an inhibitor of CYP2C8 in vitro (trametinib package insert).   
 
Trametinib is an inducer of CYP3A4 in vitro.  Based on cross-study comparisons, oral administration of 
trametinib 2mg once daily with everolimus (sensitive CYP3A4 substrate) 5 mg once daily, had no clinically 
important effect on the AUC and Cmax of everolimus (trametinib package insert).  
 
In general, concomitant medications and therapies deemed necessary for the supportive care (e.g., such as 
anti-emetics, anti-diarrhea) and safety of the subject are allowed.   
 
Subjects are permitted to use the following medications during study treatment: 
- Medications to prevent or treat nausea or vomiting. 
- Anti-diarrheal medications (e.g., loperamide) for subjects who develop diarrhea. 
- Pain medication to allow the subject to be as comfortable as possible. 
- Bone targeted therapies (e.g., bisphosphonates, denosumab) to treat bone metastases or to prevent 
skeletal related events. 
- Palliative radiotherapy: any radiotherapy must be listed on the ‘Surgical and Medical Procedures’ eCRF. 
- Immunosuppressive agents to treat suspected AEs. 
- Nutritional support or appetite stimulants (e.g., megestrol). 
- Oxygen therapy and blood products or transfusions. 
- Limited-field palliative radiotherapy to non-target lesion(s) may be allowed as concomitant therapy. Such 
local therapies administered during the study treatment 
- Inactivated vaccines. 
- The subject must be told to notify the investigational site about any new medications he/she takes after the 
start of the study drug. All medications (other than study drug) and significant non-drug therapies (including 
physical therapy, herbal/natural medications and blood transfusions) administered during the study must be 
listed on the Concomitant Medications or the Procedures and Surgical and Medical Procedures eCRF. 
 
5.7 Blinding of Study Drug 
This is an open label, non-randomized study.  There is no blinding of treatments. 
5.8 Receiving, Storage, Dispensing and Return 
5.8.1 Receipt of Drug Supplies 
 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug receipt log 
filled out and signed by the person accepting the shipment.  It is important that the designated study staff 
counts and verifies that the shipment contains all the items noted in the shipment inventory.  Any damaged or 
unusable study drug in a given shipment (active drug or comparator) will be documented in the study files.  
The investigator must notify study sponsor of any damaged or unusable study treatments that were supplied 
to the investigator’s site. 


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5.8.2 Storage and Handling 
5.9.2.1 CDX-3379 
CDX-3379 is shipped in insulated shippers and must be stored at 2 - 8°C (36 - 46°F) until use. Do not freeze 
CDX-3379 solutions. A temperature log must be kept to document the refrigerator temperature.  If the 
temperature is not maintained, Celldex should be contacted. 
CDX-3379 is not formulated with a preservative.  Therefore, once the sterile vials are entered (i.e., needle 
puncture of the vial), the drug should be used as soon as possible (typically within 3 hours if kept at room 
temperature or within 6 hours if refrigerated; or in accordance with any applicable institutional guidance). 
Additional guidance regarding storage and handling of CDX-3379 will be provided on the pharmacy sheet  
provided by Celldex.    
5.9.2.2 Trametinib 
Store refrigerated at 2o to 8oC (36o to 46oF).  Do not freeze.  Dispense in original bottle.  Do not remove 
desiccant.  Protect from moisture and light.  Do not place medication in pill boxes. 
5.8.3 Dispensing of Study Drug 
 
5.9.3.1 CDX-3379 Preparation 
General notes regarding the preparation of CDX-3379: 
• 
Only qualified personnel who are familiar with procedures that minimize undue exposure to them and to the 
environment should undertake the preparation, handling, and safe disposal of biotherapeutic agents. 
• 
Aseptic technique should be employed in the preparation of all study drugs. 
• 
CDX-3379 is expected to be free from, or essentially free from, visible particulates. Parenteral drug products 
should be inspected visually for particulate matter and discoloration prior to administration. If significant 
particulate matter is present or the solution is discolored, the vial should not be used. 
• 
Refrigerated solutions should be equilibrated to room temperature prior to administration. 
• 
Before use, the vial should be gently swirled to ensure uniform mixing of the contents. Solution should be 
gently withdrawn (avoiding foaming and excess shearing). 
A designated member(s) of the investigational site’s pharmacy staff with appropriate training and experience 
(i.e., the pharmacist) will prepare CDX-3379. The pharmacist(s) will be required to complete a Dosage 
Preparation Record to document the preparation process for each dose of CDX-3379.  Additional guidance will 
be provided within a pharmacy sheet provided by Celldex. 
Dose Calculation 
Doses of CDX-3379 will be based on body weight in kilograms.  Patients are to be weighed at the start of each 
cycle and the dose adjusted based on current body weight and rounded to the nearest mg of CDX-3379.  Half 
milligrams (mgs) should be rounded up to the next mg of dose.   If body weight is within +10% of the baseline 
measurement, the baseline weight may be used for dose calculation and preparation.  
Dose Preparation Steps 
CDX-3379 is diluted with 0.9% (w/v) saline to a minimum final volume of 100 mL, in an appropriately sized 
polyolefin, IV infusion bag. The final CDX-3379 concentration in the admixture shall be maintained in the 
qualified range of 1.8 to 13.8 mg/mL. Diluted CDX-3379 is administered to the patient via IV infusion, through 
an IV administration set with a low protein binding, 0.2-μm in-line filter.  
 


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5.9.3.2 Trametinib 
The investigator or responsible site personnel must instruct the subject or caregiver to take trametinib as per 
protocol. This study drug will be dispensed to the subject by authorized site personnel only. All dosages 
prescribed to the subject and all dose changes during the study must be recorded on the Dosage 
Administration Record eCRF.  Trametinib with instructions for administration will be provided to subjects for 
self-administration at home, until their next scheduled study visit. 
 
Study drugs must be received at the study site by a designated person, handled and stored safely 
and properly, and kept in a secure location.   Upon receipt, the study drug should be stored according to the 
instructions specified on the drug labels. Storage conditions must be adequately monitored and appropriate 
temperature logs maintained as source data. Appropriate documentation of the subject specific dispensing 
process must be maintained. Bulk medication labels will be in the local language, will comply with the legal 
requirements of each country, and will include storage conditions for the drug but no information about the 
subject. 
 
All drug supplies are to be used only for this protocol and not for any other purpose. Unless 
specifically instructed by Novartis, the Investigator must not destroy any drug labels, or any partly used or 
unused drug supply. Only after receiving a written authorization by Novartis, the Investigator/designee will 
send all the unused and partly used drug supplies as well as the empty containers to the address provided at 
the time of authorization for destruction. 
 
Trametinib will be either sourced as local commercial supply or provided as global clinical open label 
supply. Global clinical open label supply will be provided in bottles. Study treatment labels will comply with the 
legal requirements of each country and will include storage conditions.   
 
Novartis Drug Supply Management supplied treatments will also contain a unique medication number 
(corresponding to study treatment and strength).   
 
Responsible site personnel will identify the study treatment package(s) to dispense by the medication 
number(s) assigned by IRT to the subject. If the label has 2 parts (base plus tear-off label), immediately 
before dispensing the package to the subject, site personnel will detach the tear-off part of the label from the 
package and affix it to the subject’s source document. 
 
 
5.8.4 Return or Destruction of Study Drug 
5.9.4.1 – CDX-3379 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and drug 
remaining.  This reconciliation will be logged on the drug reconciliation form, signed and dated.  Any 
discrepancies noted will be investigated, resolved, and documented prior to return or destruction of unused 
study drug.  Drug destroyed on site will be documented in the study files. 
 
CDX-3379 will be supplied by Celldex as open-label stock.  The investigational product is to be used 
only for this protocol and not for any other purpose, and must be kept in an appropriate, secure area (e.g., 
locked refrigerator/cabinet) and stored in accordance with the conditions specified in this protocol/on the 
labels.  
 
The investigator will assume responsibility for administration and dispensation of study medication. 
An accurate record of all study drugs received, dispensed, returned, and destroyed must be maintained. Drug 
supplies will be inventoried and accounted for throughout the study, and accountability records must be 
available for inspection at any time and provided to Celldex upon the completion of the study. 
 
Upon receipt of any investigational product, an inventory must be conducted to confirm the quantity 
and condition of material received, and verification of receipt must be completed and returned in accordance 
with instructions provided by Celldex.  
 
Resupply of study medication may be requested in accordance with instructions provided by Celldex. 
 
Used, partly used, and/or remaining unused investigational product will be either returned to Celldex 
or destroyed according to the site’s Standard Operating Procedures (SOPs), as directed by Celldex, and a 
record of this disposition will be maintained. 
 
5.9.4.2 -Trametinib 
The investigator or designee must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Drug accountability will be noted by the CRA during site visits and at 


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the completion of the study. Subjects will be asked to return all unused study treatment and packaging on a 
regular basis, at the end of the study or at the time of study treatment discontinuation. 
 
At study close-out, and, as appropriate during the course of the study, the investigator will return all 
used and unused study treatment, packaging, drug labels, and a copy of the completed drug accountability 
log to the Novartis monitor or to the Novartis address provided in the investigator folder at each site. 
 
Any waste material should be disposed of in accordance with local regulations and according to 
institutional guidelines. If local regulations disallow storage of empty or pierced vials at the site, the site is able 
to destroy the vials as per local requirements and procedures. Documentation regarding the local regulations 
and the destruction of the empty vials will be provided to the Sponsor to ensure full drug accountability. 
 
 
 
5.9 
Pharmacokinetic Variables and Assessments 
 
Blood samples will be collected to determine the levels of CDX-3379 and Trametinib.  Approximately 5 ml of 
blood will be collected.  The time of blood collection must be documented.  A laboratory manual will be provided 
with instructions for collecting, processing, and shipping the samples. 
 
Pharmacokinetic blood samples will be drawn from study patients at the time points indicated in Section 6.6 
during the Phase Ib portion of the study.  For cycles 1 and 2, blood will be drawn prior to treatment with CDX-
3379, following CDX-3379 adminstration, and one hour after trametinib.  On days where both CDX-3379 and 
trametinib are administered, trametinib will be taken immediately following CDX-3379 infusion. On cycle 3 day 
1, blood will be drawn prior to treatment with CDX-3379 for minimum concentration (Cmin) determination. 
Serum concentrations will be determined for CDX-3379 and trametinib.  All samples will be stored at the CBRD, 
until future use, which is detailed in the lab manual.   Trametinib PK samples will be analyzed by Covance. This 
study provides the opportunity to assess PK of CDX-3379 in combination with trametinib.  We believe that CDX-
3379 and trametinib will be well tolerated and safe.     
 
 
 
5.10 Biomarker Samples 
Biomarker data will be explored from archived tissue and pre-treatment, on-treatment, and disease progression 
tumor biopsy samples during Phase Ib and from ten subjects during the Phase II portion of the study (five 
subjects with NRAS mutation and five subjects with BRAF/NRAS WT melanoma), to assess potential 
associations with tumor response.  These samples will be collected prior to treatment on cycle 1 day 1, on day 
14-16 after initial treatment, and at the time of disease progression.  These samples will be used to assess 
additional clinically relevant biomarkers, including but not limited to expression levels of ERBB3, cMET, ERBB2, 
and EGFR and will include assessment of respective receptor ligands.  Efficacy outcomes considered for pre-
specified mechanistic biomarker analysis will include PFS, objective response rate, and OS based on 
investigator assessments. 
 
 
 
5.10.1 Archived Tumor Samples 
If available, formalin-fixed paraffin embedded tumor samples (either a tumor block or freshly cut slides) 
from the patient’s most recent tumor sampling will be collected for biomarker analysis. Tumor samples 
obtained at the time of metastasis are preferred over tumor samples obtained at the time of primary 
diagnosis; however, in the event that both are available for analysis, we ask that samples from both time 
points should be submitted. Directions and requirements for processing and shipping the archived tumor 
samples can be found in the laboratory manual. 
 
 
5.10.2 Tumor Biopsy 
Core biopsies are required for the Phase Ib and Phase II portion of the study, in order to perform 
correlative studies.  Core biopsies will be collected pre-treatment, on-treatment (day 14-16), and at the time 


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of progression during Phase Ib and from ten patients during the Phase II portion of the study (five NRAS 
mutant melanoma and five WT melanoma), to assess potential associations with tumor response.   
 
6 Study Procedures 
 
Screening 
 
The screening phase begins once written informed consent is provided and ends after 28 days or when 
subject receives the first treatment dose.   
 
Subjects must sign an informed consent form (ICF) prior to any study specific screening evaluations, within 28 
days prior to the first dose of study treatment. Following completion of screening procedures and verifying 
subject eligibility based on assessments, the subject will be enrolled via the Interactive Response Technology 
(IRT) system.  
 
6.1 Visit 1 – Screening 
 
An initial screening visit will occur to ensure subjects meet the inclusion criteria.  This visit will include a 
physical exam and medical history, baseline EKG, ophthalmologic exam, baseline laboratory tests including a 
comprehensive metabolic panel and a complete blood count, and a clinical evaluation to ensure the patient 
has no factors that would render them ineligible for the study.  Subjects will be required to give information 
regarding their medical history and melanoma treatment course.   
 
Subjects will undergo screening procedures, including documentation of a medical history, patient 
demographics, vital signs, and ECOG performance status.  Labs drawn will include CBC, chemistry, and 
coagulation profile.  Archival tumor biopsy samples should be obtained from tissue available from any time prior 
to signing consent for this trial, focusing on samples since last treatment regimen until signing consent for this 
trial.  Pre-treatment tumor biopsy will be performed prior to treatment administration during the screening period. 
A Pregnancy test will be performed on all women of childbearing potential.  Baseline EKG and ECHO screening 
will be performed.  Subjects will be asked to identify all concomitant medications they are or will be taking during 
the time of the study.  Baseline imaging with a full body PET-CT or CT scans of the chest, abdomen, pelvis and 
areas of disease, along with brain MRI must be completed within 4 weeks prior to study enrollment. 
 
6.2 Visit 2, 4 
Visit 2 will consist of the start date of the study treatment, representing day 1 of week 1 of cycle 1.  Visit 4 will 
represent day 1 of week 1 of cycle 2.  As with all clinical visits, vital signs and ECOG performance status will 
be recorded, an ophthalmologic exam will be performed and CBC and chemistry will be drawn from the subject 
as well as serum samples for PK during the first two cycles of treatment in the Phase 1b group. All assessments 
must be resulted prior to administration of CDX-3379.  Medication review will be performed as will AE 
assessment and reporting.  CDX-3379 will be administered at visit 2 and will continue once every three weeks 
thereafter until disease progression, unacceptable toxicity, subject decision to withdrawal, study closure, or 
another reason as determined by the study investigators.  Dosing is 15mg/kg IV. Blood will be drawn prior to 
CDX-3379 infusion, immediately following CDX-3379 infusion.  Following infusion and blood draw, trametinib 
will be started at 2mg and should be taken on a continuous basis as prescribed unless otherwise instructed by 
study investigators. Blood will be drawn one hour after trametinib administration.   


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6.3 Visit 3, 5 
Visit 3 and 5 will represent day 1 of week 2 of cycles 1 and 2, respectively.  This visit will include documentation 
of vital signs, ECOG performance status, current medications, and AE assessment and reporting.  Blood will 
be drawn for CBC, chemistry, and PK.    
6.4 Visit 6 
Visit 6 will represent day 1 of week 1 of cycle 3.  Blood will be drawn for CBC and chemistry, and an 
ophthalmologic exam will be performed. Serum samples for PK will be obtained before treatment administration. 
All assessments must be resulted prior to administration of CDX-3379.  For each visit thereafter, subjects will 
be seen and evaluated on the first day of each cycle when they receive CDX-3379.  Disease evaluation should 
be reported every 12 weeks after the first dose of CDX-3379. 
6.5 End of Treatment Visit 
The end of treatment visit should be completed within 4 weeks of the last dose of the study drug.  Vital signs, 
ECOG performance status, AE assessment and reporting, and disease evaluation should be performed.  Blood 
will be drawn for CBC, chemistry, and PK.  Progression tumor biopsy should be obtained within 4 weeks of last 
dose of study drug (last dose of study drug is calculated from the last dose of trametinib). 
 
6.6 Survival Follow-up 
Survival data will be collected via telephone or clinic visits every 3 months (±10 days) from the date of last 
treatment (date of last treatment is calculated from the last dose of trametinib) until death, loss to follow-up, 
withdrawal of consent, study termination by the Sponsor, or up to 5 years.  In addition, any new anti-cancer 
therapies and procedures should be collected and documented. Should subjects refuse or drop out of survival 
follow-up, attempts should be made to obtain any death information via public records whenever possible. 
 
 
6.7 Schedule of Assessments Summary 
 
 
 
 
 
Cycle 14 
 
 
 
Cycle 24 
 
 
 
Additional cycle4 
 
Every 12 
weeks or 
sooner, at the 
discretion of 
the physician 
 
 
 
End of 
Treatme
nt (EoT)8 
 
 
 
Survival 
Follow-
up12 
Procedure 
Screening 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
 
X 
X 
 
X 
 
 
 
X 
 
 
Vital Signs 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
ECOG PS 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
CBC 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Serum Chemistry13 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Tumor Biopsy 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Baseline imaging within 
4 weeks prior to 
enrollment (CT/PET-
CT/MRI)  
 
Pregnancy Test (Urine) 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
EKG 
 
X 
 
X11 
 
 
 
X11 
 
 
 
X11 
 
 
 
 
 
 
Archived tumor 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh Core Biopsy  
 
X2 
 
 
 
X3 
 
X3 
 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacokinetic blood 
samples 
 
 
 
X10 
 
X 
 
 
X10 
 
X 
 
 
X 
 
 
 
 
X 
 
Immunogenicity sample  
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
Concomitant meds 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
CDX-3379 dosing16 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Trametinib dosing 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
AE assessment and 
reporting 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Disease evaluation5,7 
 
X 
 
 
 
 
 
 
 
 
 
 
X9 
 
X1 
 
 
Overall Survival 
Reporting6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Echocardiogram/MUGA
15 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Ophthalmologic Exam14 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Footnotes: 
1 = Unless performed in the prior 6 weeks as part of a previous visit 
2= prior to first treatment with CDX-3379 and trametinib 
3= performed between days 14-16 
4= All procedures should occur ±2 calendar days from scheduled date of visit 
5 = Disease evaluation per RECIST version 1.1.  
6 = Should patients refuse or drop out of survival follow-up, attempts should be made to obtain any death 
information available via public records. 
7 = Upon disease progression determination 
8 = End of treatment visit should be completed within 4 weeks of the last dose of study drug 
9 = end of treatment biopsy/disease progression.  Should occur within 4 weeks of last treatment.  
10 = PK blood samples are collected predose before CDX-3379, immediately following CDX-3379 infusion,  and 1 
hour post dose following trametinib 
11= one reading prior to the start of CDX_3379 infusion 
12= Survival data will be collected via telephone or clinic visits every 3 months (+10 days) from the date of last 
treatment until death, loss to follow-up, withdrawal of consent, or study termination by the Sponsor 
13= Comprehensive metabolic panel (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, 
creatinine, glucose, calcium, protein total, albumin, AST, ATL, alkaline phosphatase and total bilirubin), LDH, 
magnesium, and phosphorus.  


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14 = With hand held Ophthalmoscope. Patients will also be asked about eye symptoms at each visit. A formal 
ophthalmologic examination will be performed as per standard of care if patients develop signs or symptoms of 
ocular toxicity.  
15= ECHO/MUGA should be performed every 12 weeks, or at the discretion of the physician. 
16= Pre and post infusion vitals (HR, Blood pressure, O2 sat, temperature) will be taken prior to infusion +/-15 
minutes, 30 minutes into the infusion +/- 5 mins, at the end of the infusion (which is 60 minutes) +/- 15 minutes, 
and 60 minutes after the infusion has finished +/- 15 minutes 
 
   
 
 
7 Statistical Plan 
 
7.1 Sample Size Determination 
For Phase Ib:   
No data are available for the combination of CDX-3379 (ERBB3 antibody) and trametinib.  Six subjects will be 
enrolled at an initial dose level – a safety run-in - and monitored for DLTs.  In these six subjects, if none or one 
subject experiences a DLT, then dose cohort 1 will be considered the RP2D, and phase II of the clinical trial 
will proceed.  If two or more of the six subjects experience DLT, we will consider the initial dose cohort beyond 
the MTD and we will enroll six more subjects on a de-escalated cohort, based on toxicity pattern observed 
attributed to a particular drug (Cohort -1A or -1B).  In this new dose cohort, if none or one subject experiences 
a DLT, then the study will open to full enrollment on the Phase II portion of the trial.  If two or more of these 
additional six subjects experience DLT, we will then enroll six additional subjects at an additional dose de-
escalation cohort -2, to be determined by sponsor (NYUL Health) and DSMC), again based on toxicity pattern 
observed and drug attribution.  If two or more subjects experience DLT at this new dose cohort, then the trial 
will be terminated. 
 
For Phase 2:  There are two Arms - Arm A (NRAS mutant melanoma participants) and Arm B (WT melanoma 
participants).  This is the first part of a Simon Minimax design.  Each Arm will initially enroll 19 patients.  If 
there are two or fewer responses, the specific cohort will be stopped.  Otherwise, the study will be amended 
to enroll a total of 36 patients to each approved Arm/cohort (an additional 17 patients per arm).  If a true 
response rate is 0.20, we will have a probability of 0.46 of stopping early and a probability of 0.90 of deciding 
that the treatment is useful.   
 
7.2 Statistical Methods 
Data collection will begin from time of enrollment and subjects will be followed until death (PFS and OS 
endpoints). If subjects are still alive, they will be censored at the time of evaluation. We will first 
investigate the association between biomarker expression and disease characteristics using t-test, 
ANOVA, or Chi-squared tests.  We will then investigate the association between biomarker expression 
and PFS and OS using Kaplan-Meier approach and log rank test where biomarker expression is 
dichotomized. We may also use Cox proportional models to assess the association between biomarkers 
and outcome with adjustment for potential confounders such as disease characteristics.  Biomarkers 
measured pre-, on-and post-treatment will be examined and are mainly exploratory at this time.  Future 
tests will be derived from these results.  For phase 2, the primary efficacy endpoint, response rate, will be 
compared with the historically reported response rate for the single agent trametinib in NRAS mutant and 
BRAF/NRAS WT melanoma.For secondary endpoints, we will estimate median PFS, OS and 95% CI 
using the Kaplan-Meier approach.  In NRAS mutant melanoma patients treated with single agent MEK 
inhibitor, response rate was 15% and median PFS was 2.8 months15, and in BRAF/NRAS WT melanoma 


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patients treated with single agent MEK inhibitor, response rate was 10% and median PFS was 2 months7  
   
Assuming a true response rate of 0.20, Simon’s two-stage Minimax design will test the null hypothesis that RR 
≤0.20; the sample size of 36 patients provides an alpha level of 0.10 and power of 0.80.  Nineteen patients 
will be enrolled to the NRAS mutant arm of the study and 19 patients will be enrolled to the BRAF/NRAS WT 
arm of the study in the phase 2.  If at least 3 patients respond (PR or better) out of 19 evaluable patients, then 
the study will be amended to enroll an additional 17 patients (for a total of 36 evaluable patients).  If the Simon 
two-stage Minimax design is fully completed, a minimum of 10 patients must demonstrate a response (PR or 
better) to reject the null hypothesis.     
 
Detailed methodology for summary and statistical analyses of the data collected in this study will be 
documented in a Statistical Analysis Plan (SAP), which will be dated and completed prior to database lock. 
The SAP may modify the plans outlined in the protocol; however, any major modifications of the primary 
endpoint and/or its analysis will also be reflected in a protocol amendment. 
7.3 Subject Population(s) for Analysis 
All subjects enrolled on the study who are treated will have data collected at the pre-specified time points and 
this data will be subjected to the study analysis.  Data analysis will be intention to treat, based on all subjects 
enrolled onto the study protocol. 
 
 
8 Safety and Adverse Events 
 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such as 
the IRB-approved protocol or consent form, the investigators brochure, etc) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 


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• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result in 
in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would typically 
be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from the 
initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as 30 days following the last administration of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during the 
study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the end 
of the study, any new clinically significant findings/abnormalities that meet the definition of an adverse event 
must also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, the subject 
is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the investigator 
should instruct each subject to report any subsequent event(s) that the subject, or the subject’s personal 
physician, believes might reasonably be related to participation in this study.  The investigator should notify 
the study sponsor of any death or adverse event occurring at any time after a subject has discontinued or 
terminated study participation that may reasonably be related to this study.  The sponsor should also be 
notified if the investigator should become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a subject that has participated in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, discontinuation 
of the drug, more frequent follow-up assessments, further diagnostic investigation, etc. 
 
Abnormal lab values that are not clinically significant are not considered adverse events. 
 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any condition 
responsible for surgery should be documented as an adverse event if the condition meets the criteria for and 
adverse event.  


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Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse event 
in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it is a 
worsening or increase in frequency of hospital admissions as judged by the clinical investigator. 
8.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should recorded 
in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation should be 
recorded and reported immediately. 
8.3 Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, formats and 
requirements of the various entities to which they are responsible, but at a minimum those events that must 
be reported within 5 days of PI notification are those that are: 
• related to study participation, 
• unexpected, and  
• Harmful or have the potential to cause harm (see definitions, section 8.1) 
   
Events should be reported using the NYU CTO Medical Events Form (see section 8.3.1 below). 
 
Adverse events that do not fit the above immediately reportable criteria must still be reported to the IRB at 
each annual review, either in a summary or tabular format. 
 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an UP report 
form. It is the site investigator’s responsibility to report UPs to their IRB and to the study sponsor. The UP 
report will include the following information: 
 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• A detailed description of the event, incident, experience, or outcome; 
• An explanation of the basis for determining that the event, incident, experience, or outcome represents 
an UP; 
• A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 
• UPs that are SAEs will be reported to the IRB and to the DSMC/study sponsor within 24 hours of the 
investigator becoming aware of the event. 
• Any other UP will be reported to the IRB and to the DSMC/study sponsor within 24 hours of the 
investigator becoming aware of the problem. 


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• All UPs should be reported to appropriate institutional officials (as required by an institution’s written 
reporting procedures), the supporting agency head (or designee), and OHRP within 5 days of the IR’s 
receipt of the report of the problem from the investigator. 
 
Serious adverse event reporting will begin in conjunction with the date of informed consent. Any SAEs occurring 
prior to study drug administration that the investigator believes may have been caused by a protocol procedure 
must be reported immediately to the Sponsor or its designee and recorded on the case report form. 
 
All fatal or life-threatening adverse events must be immediately reported to the Principal Investigator, via 
appropriate reporting mechanism and the NYU Langone Health IRB by telephone or e-mail. Within 24 hours of 
the event, the Serious Adverse Event Form must be emailed to NYUPCCsafetyreports@nyumc.org whether 
full information regarding the event is known or not. Additional follow-up by the investigator will be required if 
complete information is not known. De-identified source documentation of all examinations, diagnostic 
procedures, etc. which were completed with respect to the event should be included with the SAE form. Care 
should be taken to ensure that the patient’s identity is protected and the patient’s identifiers (as assigned at the 
time of study enrollment) are properly mentioned on any copy of source document provided to the Sponsor. 
For laboratory results, include the laboratory normal ranges.  
 
In case of accidental or intentional overdose of study drug (CDX-3379 or trametinib), even if asymptomatic or 
not fulfilling a seriousness criterion, the overdose is to be reported to the Sponsor immediately (within 1 working 
day) using the AE and SAE forms supplied by NYU Langone Health PCC. Overdose of study drug will be 
defined as ≥16.5mg/kg of CDX-3379 and 2 mg of trametinib.  
 
All other serious adverse events must be reported to the sponsor and DSMC within 24 hours by phone (212) 
273-2748 or e-mail (NYUPCCsafetyreports@nyumc.org) . Details are outlined in the study procedure manuals. 
The Serious Adverse Event Form must also be faxed to the sponsor and DSMC within 24 hours of the event 
whether full information regarding the event is known or not.  Additional follow-up by the investigator will be 
required if complete information is not known. 
 
Current contact information shall be maintained at the site within the regulatory binder. 
 
All serious adverse events (SAEs) will be evaluated by the DSMC if meeting the requirements for expedited 
reporting, the Sponsor will report the adverse event to all regulatory authorities with jurisdiction over ongoing 
trials with the study drug and to all other investigators involved in clinical trials with the study drug. The 
investigator is responsible for reporting all SAEs to the appropriate IRB, DSMC, and FDA. 
  
For Narrative Reports of Safety Events 
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of the 
initial report includes: 
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study treatment was discontinued 
• 
The reason why the event is classified as serious 
• 
Investigator assessment of the association 
between the event and study treatment 
 
8.3.1 Investigator reporting: notifying the study sponsor 
 
Since multiple sites may be participating, the following describes events that must be reported to the study 
sponsor (NYU Langone Health PCC), Celldex Therapeutics and Novartis in an expedited fashion. 
 
The following describes events that must be reported to the study sponsor in an expedited fashion. 
 
Initial Report: within 24 hours: 


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The following events must be reported to the study sponsor (NYULMC PCC) by email within 24 hours of 
awareness of the event using the NYU CTO Medical Events Form:  
 
• 
Unanticipated problems related to study participation,  
• 
Serious adverse events, regardless of whether they are unexpected.  
 
The investigator shall maintain a copy of the Medical Events Form on file at the study site. All report forms 
must be signed and dated by the Principal Investigator.  If the Principal Investigator is not available at the time 
of the initial report, then the form can be submitted by a Sub-Investigator.  This form should be reviewed by 
the Principal Investigator, whom sign/date initial report upon return. 
   
Report to: 
NYUPCCsafetyreports@nyumc.org 
(212) 273-2748 
 
 
AND 
 
Jeffrey Weber, MD, PhD 
160 E. 34th Street, 13th Floor 
New York, NY 10016 
Phone: 212-263-9333 
Fax: 212-731-6017 
Jeffrey.weber@nyulangone.org  
 
Events of Clinical Interest (any medical event that is deemed significant via Principal Investigator’s expertise, 
but does not apply to SAE categories) will be reported within 2-5 days, or as per study Sponsor specifications. 
 
 
Follow-up report: within 48 hours: 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator 
shall provide further information, as applicable, on the unanticipated device event or the unanticipated 
problem in the form of a written narrative.  This should include a copy of the completed Unanticipated 
Problem form, and any other diagnostic information that will assist the understanding of the event.  Significant 
new information on ongoing unanticipated adverse device effects shall be provided promptly to the study 
sponsor. 
 
Other Reportable events: 
• 
Deviations from the study protocol 
Deviations from the protocol must receive both Sponsor and the investigator’s IRB approval before 
they are initiated. Any protocol deviations initiated without Sponsor and the investigator’s IRB 
approval that may affect the scientific soundness of the study, or affect the rights, safety, or welfare of 
study subjects, must be reported to the Sponsor and to the investigator’s IRB as soon as a possible, 
but no later than 5 working days of the protocol deviation. 
 
• 
Withdrawal of IRB approval 
An investigator shall report to the sponsor a withdrawal of approval by the investigator’s reviewing 
IRB as soon as a possible, but no later than 5 working days of the IRB notification of withdrawal of 
approval. 
 
Reporting to Celldex 
Expedited reporting by investigator to Celldex. Note that reporting to Celldex is required in addition to 
reporting to the FDA, as necessary, and does not replace the requirement to notify the FDA, if required. 


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• 
NYU will  inform Celldex in writing using an SAE form or MEDWATCH 3500A form of any 
SAE within 24 hours of being aware of the event (see Section 8.1X for the definition of 
SAE). The written report must be completed and supplied to Celldex by facsimile within 24 
hours/1 business day. The initial report must be as complete as possible, including an 
assessment of the causal relationship between the event and the investigational 
product(s), if available. Information not available at the time of the initial report (e.g., an 
end date for the adverse event or laboratory values received after the report) must be 
documented on a follow-up report.  
 
• 
Completed SAE reports are to be submitted to: 
Celldex Therapeutics, Inc. 
Pharmacovigilance 
Facsimile : 781-644-6434  
Email: SAE@celldex.com (note-check for removal of HIPAA identifiers prior to sending 
information) 
 
Reporting to Novartis 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient has provided 
the main informed consent and until at least 30 days after the patient has stopped study treatment must be 
reported to Novartis within 24 hours of learning of its occurrence. 
 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the investigator suspects 
a causal relationship to the study treatment. Recurrent episodes, complications, or progression of the initial 
SAE must be reported as follow-up to the original episode within 24 hours of the investigator receiving the 
follow-up information. An SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new event. 
 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form; all applicable 
sections of the form must be completed in order to provide a clinically thorough report. The investigator must 
assess and record the relationship of each SAE to each specific study treatment (if there is more than one study 
treatment), complete the SAE Report Form in English, and send the completed, signed form by fax within 24 
hours to the oncology Novartis Drug Safety and Epidemiology (DS&E) department - Fax: (877-778-9739). The 
original copy of the SAE Report Form and the fax confirmation sheet must be kept with the case report form 
documentation at the study site. 
 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form was sent, using a 
new SAE Report Form stating that this is a follow-up to the previously reported SAE and giving the date of the 
original report. Each re-occurrence, complication, or progression of the original event should be reported as a 
follow-up to that event regardless of when it occurs. The follow-up information should describe whether the 
event has resolved or continues, if and how it was treated, whether the blind was broken or not, and whether 
the patient continued or withdrew from study participation. 
 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new occurrence) and 
is thought to be related to the Novartis study treatment, an oncology Novartis Drug Safety and Epidemiology 
(DS&E) department associate may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN), to inform all investigators involved in any 
study with the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in participating countries. 
 
Additional safety information collected between IB updates will be communicated in the form of Investigator 
Notifications. This information will be included in the patient informed consent and should be discussed with the 
patient during the study as needed. 
 


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8.3.2 Investigator reporting: notifying the IRB 
 
Federal regulations require timely reporting by investigators to their local IRB of unanticipated problems 
posing risks to subjects or others.  The following describes the NYULMC IRB reporting requirements, though 
Investigators at participating sites are responsible for meeting the specific requirements of their IRB of record.  
 
Report Promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later than 5 working 
days from the time the investigator becomes aware of the event: 
• 
Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not accurately reflected 
in the protocol-related documents, such as the IRB-approved research protocol, any applicable 
investigator brochure, and the current IRB-approved informed consent document and other 
relevant sources of information, such as product labeling and package inserts.  
– Related to the research procedures: An event is related to the research procedures if in the 
opinion of the principal investigator or sponsor, the event was more likely than not to be caused by 
the research procedures.  
– Harmful: either caused harm to subjects or others, or placed them at increased risk 
 
Other Reportable events: 
The following events also require prompt reporting to the IRB, though no later than 5 working days: 
• Complaint of a research subject when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
• Protocol deviations or violations (includes intentional and accidental/unintentional deviations from 
the IRB approved protocol) for any of the following situations:  
– one or more participants were placed at increased risk of harm  
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 
• Incarceration of a participant when the research was not previously approved under Subpart C and 
the investigator believes it is in the best interest of the subject to remain on the study. 
• New Information indicating a change to the risks or potential benefits of the research, in terms of 
severity or frequency. (e.g. analysis indicates lower-than-expected response rate or a more severe or 
frequent side effect; Other research finds arm of study has no therapeutic value; FDA labeling change 
or withdrawal from market) 
 
Reporting Process 
The reportable events noted above will be reported to the IRB using the form: “Reportable Event Form” or as 
a written report of the event (including a description of the event with information regarding its fulfillment of the 
above criteria, follow-up/resolution and need for revision to consent form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
8.3.3 Sponsor reporting: Notifying the FDA 
 


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The study sponsor is required to report certain study events in an expedited fashion to the FDA.  These 
written notifications of adverse events are referred to as IND safety reports. The following describes the safety 
reporting requirements by timeline for reporting and associated type of event: 
 
• Within 7 calendar days (via telephone or facsimile report) 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening 
 
• Within 15 calendar days (via written report) 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit the 
criteria for reporting (reporting within 15 calendar days from when event was deemed reportable). 
Any finding from tests in laboratory animals that:  
– suggest a significant risk for human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
 
Celldex Reporting guidelines: 
Additional Reporting Requirements for the Sponsor  
Reporting to the FDA 
• Serious and unexpected suspected adverse reactions will be reported to the FDA no later 
than 15 calendar days after the sponsor determines that the requirements for an IND 
safety report have been met. The FDA will be notified using an FDA Form 3500a. 
• Unexpected fatal or life-threatening suspected adverse reactions will be reported to the 
FDA no later than 7 calendar days after the Sponsor receives the initial information of the 
event. The FDA will be notified using an FDA Form 3500a. 
• Other adverse event information will be sent to the FDA in the IND annual report. 
 
 
Additional reporting requirements 
Sponsors are also required to identify in IND safety reports all previous reports concerning similar adverse 
events and to analyze the significance of the current event in light of the previous reports. 
 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A (MEDWATCH Form; see Attachment 1), or in a 
narrative format. If supplied as in a narrative format, the minimum information to be supplied is noted above at 
the beginning of section 8.3. The contact information for submitting IND safety reports is noted below: 
NYU Langone Health Contacts: 
  
NYUPCCsafetyreports@nyulangone.org 
 
AND 
 
Jeffrey Weber, MD, PhD 
160 E. 34th Street, 13th Floor 
New York, NY 10016 
Phone: 212-263-9333 
Fax: 212-731-6017 
Jeffrey.Weber@nyulangone.org  


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8.3.4 Sponsor reporting: Notifying participating investigators 
 
It is the responsibility of the study sponsor to notify all participating investigators of any adverse event that 
meets the FDA 15-day reporting requirement criteria as note above in section 8.3.3.  The same materials and 
timeline used to report to the FDA are used for notifying participating investigators. 
 
We will put a Safety Management Plan in place in order to report any adverse events to Celldex Therapeutics 
and Novartis, also allowing the study sponsor to receive any cross-reports from Celldex Therapeutics and 
Novartis studies as well. 
 
8.4 Reporting of Pregnancy 
Should a pregnancy occur, it must be reported immediately to the principal investigator, and 
NYUPCCsafetyreports@nyumc.org in accordance with the procedures described below.  Celldex and Novartis 
will be notified in accordance with procedures detailed below. Pregnancy in itself is not regarded as an adverse 
event unless there is a suspicion that the investigational product may have interfered with the effectiveness of 
a contraceptive medication.  This will be reported to the IRB if necessary. 
 
Pregnancy reporting to Novartis  
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence or absence of 
any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the investigator to the 
oncology Novartis Drug Safety and Epidemiology Department (DS&E). Pregnancy follow-up should be recorded 
on the same form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
Warnings and precautions 
 
8.5 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, as 
well as the construction and implementation of a site data and safety-monitoring plan detailed below.  
Adverse events are evaluated regularly by the principal investigator in conjugation with the research team, the 
DSMC is notified of adverse events via email initially, and then reviewed at the next DSMC monthly meeting.  
The Data Safety and Monitoring Committee (DSMC) will review the study at least quarterly, with outcome 
data presented upon completion of each cohort.  Medical monitoring will include a regular assessment of the 
number and type of serious adverse events. 
 
8.5.1  Data and Safety Monitoring Committee 
 
This investigator-initiated study will be monitored by the Data Safety Monitoring Committee (DSMC) of the New 
York University Langone Medical Center Perlmutter Cancer Center (NYULMC PCC). The DSMC operates 
based on the  National Cancer Institute approved Charter.  It is an existing and multidisciplinary committee 
(consisting of clinical investigators/oncologists, biostatisticians, nurses, and research administration staff 
knowledgeable of research methodology and design and in proper conduct of clinical trials) that is responsible 
for monitoring safety, conduct and compliance in accordance with protocol data monitoring plans for clinical 
trials conducted in the New York University Perlmutter Cancer Center that are not monitored by another 
institution or agency.  The DSMC reports to the Director of the New York University Langone Medical Center 
Perlmutter Cancer Center. 
 
Per the NYULMC PCC Data Safety and Monitoring Plan, this phase (Ib/II) trial will be monitored by DSMC at 
least quarterly(from the date the first patient is enrolled),  subsequent cohort activation, and at the completion 


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of the study prior to study closure. This review includes accrual data, subject demographics and adverse events. 
Accrual to the next dose within a cohort will be held until real-time review of the toxicity from the prior cohort 
has occurred to assure no defined DLTs have occurred prior to proceeding to the next level or expanding the 
current cohort.  Principal Investigators are required to attend the review of their studies. Additional reviews can 
be scheduled based on SAE reports, investigator identified issues, and external information.  The DSMC will 
review safety data every 3 months. 
 
Other external sites will be monitored and informed of other adverse events by the DSMC within 7 days of 
toxicities and within 3 business days of SAE.  Scheduled conference calls will be conducted after 3 patients are 
enrolled.  Additional conference calls will be scheduled as indicated based on the recommendations from the 
DSMC and the PI of the study. 
 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
 
The study team will maintain clinical and laboratory data in a designed manner to ensure patient 
confidentiality.  All study personnel have passed human subject protection courses.  If applicable, tissue 
samples sent to collaborators outside of NYULMC will only be labeled with an assigned protocol-patient 
identification number without subject identifiers.  Systems used for electronic data capture are compliant with 
HIPAA and applicable local regulatory agency guidelines.  All documents are kept in strictly confidential files 
and are only made accessible for specific study personnel, CTO quality assurance specialists, and authorized 
representatives of regulatory agencies as described in the informed consent document.  Samples sent to 
commercial labs or collaborating labs as per study protocol will be coded.  Samples remaining after 
completion of the study will be destroyed once this study is completed.  None of the samples collected in this 
study will be used to create a repository for future research studies.  
 
9.2  Confidentiality and HIPAA 
Information about study subjects will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at 
least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
 
9.2.1  Research Use of Stored Human Samples, Specimens, or Data 
 
• Intended Use: Samples and data collected under this protocol may be used to to evaluate ERBB3 
signaling pathway and MAPK signaling pathway components in subjects with advanced NRAS mutant 
melanoma. No genetic testing will be performed. 
• Storage: Access to stored samples will be limited  to the study team.  Samples and data will be stored 
using codes assigned by the investigators. Data will be kept in password-protected computers. Only 
investigators will have access to the samples and data. 
• Tracking: Data will be tracked using Trialmaster. 
o 
Disposition at the completion of the study: All stored samples will be sent to CBRD. Study 
participants who request destruction of samples will be notified of compliance with such 
request and all supporting details will be maintained for tracking. 
 
 


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9.3  Future Use of Stored Specimens 
Data collected for this study will be analyzed and stored at NYU Langone Health. After the study is 
completed, the de-identified, archived data will be transmitted to and stored via an electronic database 
system, under the supervision of Dr. Jeffrey Weber, with the potential for use by other researchers including 
those outside of the study. Storage of samples, specimens, and data are required to participate in this study 
and will be included in the informed consent. 
 
With the participant’s approval and as approved by local IRs, de-identified biological samples will be stored at 
the NYU Center for Biospecimen Research & Development., These samples could be used for research into 
identifying mechanisms for pathway activation at the cellular level of advanced melanomas, its complications 
and other conditions for which individuals with advanced melanomas are at increased risk, and to improve 
treatment. The purpose of future research is unknown at this time.  The stored specimen and data will be 
coded, and de-identified; the linking key will be maintained by the Principal Investigator. The CBRD will also 
be provided with a code-link that will allow linking the biological specimens with the phenotypic data from 
each participant, maintaining the masking of the identity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have biological 
specimens stored for future research. However, withdrawal of consent with regard to biosample storage will 
not be possible after the study is completed. 
 
When the study is completed, access to study data and/or samples will be provided through the supervision of 
the principal Investigator, Dr. Jeffrey Weber. 
 
 
 
9.4 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in source 
documents.  Examples of these original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments 
involved in the clinical trial. 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All data requested 
on the CRF must be recorded.  All missing data must be explained.  If a space on the CRF is left blank 
because the procedure was not done or the question was not asked, write “N/D”.  If the item is not applicable 
to the individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any entry error has 
been made, to correct such an error, draw a single straight line through the incorrect entry and enter the 
correct data above it.  All such changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT 
ERRORS.  For clarification of illegible or uncertain entries, print the clarification above the item, then initial 
and date it. 
 
 
9.5  Data and Source Documentation 
TrialMaster, an electronic database capture system will be created to record the data for this trial.  Research 
coordinators will input clinical trial data into the database.  This database is password protected and only the 
PI, assigned study team members, and CTO staff will have access to the database.  DataCore, a core resource 
of the institution, will provide the primary data collection instrument for the study.  All data requested in the 


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system must be reported.  All missing data must be explained.  The quality assurance specialists will monitor 
this trial every 4-6 weeks for data entry accuracy. 
 
Source data is all information, original records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in source 
documents.  Source documentation refers to original records of observations, clinical findings, and evaluations 
that are subsequently recorded as data.  Source documentation should be consistent with data entered into 
any electronic medical record or Trial master.   Relevant source documentation to be reviewed by the DSMC 
throughout the study includes: 
 
1.  Baseline measures to assess pre-protocol disease status 
2.  Concurrent medications  
3.  Treatment records 
4.  Adverse events 
 
9.6  Records Retention 
 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the last 
approval of a marketing application in their country and until there are no pending or contemplated marketing 
applications in their country or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product.  These documents should be retained for a longer period if 
required by an agreement with the sponsor.  In such an instance, it is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained.  
 
 
 
10 Quality Assurance and Quality Control Study Monitoring Plan 
Overall study monitoring will be conducted through a combination of on-site visit and centralized 
monitoring. A risk-based, data-driven monitoring approach will be used to verify data for this trial which will 
also include a centralized review of data for quality, trends, consistency and general safety review. A 
quality assurance specialist, will make regularly scheduled trips to the investigational site to review the 
progress of the trial, study data and site processes.  At each visit, the monitor will review various aspects 
of the trial including, but not limited to:  screening and enrollment logs; compliance with the protocol and 
study manual and with the principles of Good Clinical Practice; completion of case report forms; source 
data verification; study drug accountability and storage; facilities and staff. 
 
During scheduled monitoring visits, the investigator and the investigational site staff must be available to 
meet with the quality assurance specialist in order to discuss the progress of the trial, make necessary 
corrections to case report form entries, respond to data clarification requests and respond to any other 
trial-related inquiries of the monitor. In addition to on-site monitoring visits, the Sponsor and/or 
representatives will also be routinely reviewing data. Any queries identified through this review will be 
managed within the systems established for query resolution and tracking. Inquiries related to study 
conduct , which require further information or action will be discussed within the study team for 
appropriate and documented escalation plans. It is expected that response to data clarification requests 
and other trial-related inquiries will occur throughout the course of the study through regular 
communication with the site monitor, the Sponsor or representatives, and review/entry of data into the 
electronic study database. 
 
At any time during the course of the study, representatives of the FDA and/or local regulatory agencies 


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may review the conduct or results of the study at the investigational site. The investigator must promptly 
inform Celldex Therapeutics and Novartis of any audit requests by health authorities, and will provide 
Celldex Therapeutics and Novartis with the results of any such audits and with copies of any regulatory 
documents related to such audits. 
 
In accordance with HIPAA and associated privacy regulations, a patient’s authorization to use personal 
identifiable health information may be required from each patient before commencement of research 
activities. This authorization document must clearly specify what parties will have access to a patient’s 
personal health information, for what purpose and for what duration. 
 
The investigator will allocate adequate time for such monitoring activities.  The Investigator will also ensure 
that the monitor or other compliance or quality assurance reviewer is given access to all the above noted 
study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has 
adequate space to conduct the monitoring visit. 
 
At the NYULMC Perlmutter Cancer Center, all investigator-initiated protocols are subject to a standardized 
data and safety monitoring, which includes scientific peer review, IRB review and DSMC review as well as 
internal auditing.  
 
The review of AEs and trial conduct for this trial occurs at several levels: 
 
(1) Principal Investigator: Adverse events are evaluated monthly by the principal investigator in conjunction 
with the research nurses, data manager and research team.  
 
 
 
(2) DSMC, quarterly 
 
(3) Institutional Review Board (IRB): An annual report to the IRB is submitted by the trial PI for continuation 
of the protocol. It includes a summary of all AEs, total enrollment with demographics, protocol violations, 
and current status of subjects as well as available research data. 
 
(4) In addition, the quality assurance unit will monitor this trial every 4-6 weeks, this includes real-time 
review of all eCRFs to ensure completeness and to verify adherence to the protocol; the completeness, 
accuracy and consistency of the data; and adherence to ICH Good Clinical Practice guidelines.  
Additionally, a first subject audit is to be conducted within four weeks of enrollment. 
 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB/EC, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.).  The 
investigator will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
11 Ethical Considerations 
This study is to be conducted in accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
 


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This protocol and any amendments will be submitted to a properly constituted Institutional Review Board 
(IRB) or independent Ethics Committee (EC) in agreement with local legal prescriptions, for formal approval of 
the study conduct.  The decision of the IRB/EC concerning the conduct of the study will be made in writing to 
the investigator and a copy of this decision will be provided to the sponsor before commencement of this 
study.  The investigator should provide a list of IRB/EC members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.    This consent 
form will be submitted with the protocol for review and approval by the IRB/EC for the study.  The formal 
consent of a subject, using the IRB/EC-approved consent form, must be obtained before that subject 
undergoes any study procedure.  The consent form must be signed by the subject or legally acceptable 
surrogate, and the investigator-designated research professional obtaining the consent.  
 
 
11.1  Informed Consent 
  
Consent will be obtained only by a participating investigator who has completed requisite training for human 
subject research and has been instructed by the Principal Investigator about the research study and consent 
process. Investigators will review the informed consent form with patients and address any questions or 
concerns prior to obtaining written informed consent for participation and HIPAA authorization. 
  
Patients who are evaluated and/or treated by physicians in the oncology program will be given a consent form 
describing participation in the study. Patients will be given adequate time to read the consent form. They will 
be given time to ask questions about the study in private exam rooms. Questions will be answered by a 
participating physician, nurse practitioner, or research nurse all of whom have completed requisite training for 
human subject research. Investigators will review the informed consent form with patients and address any 
questions or concerns prior to obtaining written informed consent for participation. Investigators will stress that 
participation in the study is completely voluntary and will not affect the care patients receive or result in any 
loss of benefits to which patients are otherwise entitled. 
  
 
For non-English speaking patients, institutional translation services will be utilized.  All procedures for 
consenting non-English speaking patients will be in accordance with NYU Langone Health PCC CTO guidelines 
and policies. 
  
For patients who cannot read; a witness, not related to the research study will be present. The consent will be 
read to the patient. The patient will also be allowed to ask any questions s/he may have. The investigator will 
ask the patient questions to ensure s/he understands the study. If the investigator determines the subject 
understands the study, the patient will mark an X where his/her name would go and the witness will sign the 
consent form. 
 
The informed consent will be signed and personally date by the subject and by the individual who conducted 
the informed consent discussion. 
 
 
11.1.1   Documentation of Consent 
 
The Principal Investigator or IRB approved sub-investigator will be responsible for documentation in the 
medical record that consent has been obtained from all participants. A signed copy of the consent form will be 
given to each participant. Original consent forms will be stored in the subject’s medical chart. 
 
 
11.2 Registration Procedures 
 
Each patient must sign and date an informed consent form before undergoing any study specific procedure 
unless a procedure is being performed as part of the patient’s standard of care. 


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Enrollment in the study requires that all inclusion and exclusion criteria have been met.  Enrollment occurs 
upon confirmation of registration from the NYULMC PCC Clinical Trials Office.  The following materials must 
be submitted to the CTO for subject registration: 
 
1.  Complete signed and dated informed consent form 
2. Complete signed and dated eligibility checklist 
3. All supporting documentation verifying each eligibility criterion has been met 
 
Registration will occur within 48 hours of research coordinator receipt of all of the above documents.  A 
written confirmation of enrollment including a unique study identification number assigned by the research 
coordinator will be disbursed to the study team upon registration. 
 
Once eligibility is verified, a unique patient study number will be issued within 24 hours of receiving all 
required registration material.  The patient will not be identified by name.  This is the point, at which, the 
patient is considered accrued on study.  
 
11.3 Multi-Site Surveillance 
As the lead investigator in a multi-site trial, the Principal Investigator is responsible for organizing and 
conducting monthly teleconferences with all participating sites.  The PI will also be responsible for including 
data from all of the participating sites within the overall trial’s quarterly Data and Safety Monitoring report to 
the DSMC to include minutes from monthly PI teleconferences.  Each participating site will be responsible for 
submitting the results and recommendations from the DSMC’s quarterly reviews to their IRB of record at the 
time of continuing review.  Additionally, the NYU Langone Health PPC Clinical Trial Office, Quality Assurance 
Unit will provide a remote interim monitoring visit, beginning within the first 6-8 weeks of the first subject 
enrollment and every 6-8 weeks thereafter to ensure completeness, accuracy and consistency of the data. 
 
11.4 Patient Registrations at Additional Sites 
  
Enrollment at addition sites can begin once each site’s IRB has approved this protocol, a copy of each site’s 
IRB approval, citi training certificates, Medical Licenses and signed CVs are provided to NYU Langone Health 
Perlmutter Cancer Center (PCC) Clinical Trials Office. Once, all required documents are provided to NYU 
Clinical Trials Office an activation notification will be sent to the PI and research coordinator of that site.  Central 
registration for this study will take place at NYU Langone Health PCC Quality Assurance Unit (PCC-
QAU@nyumc.org). 
  
Each patient must sign and date an informed consent form before undergoing any study specific procedures 
unless a procedure is being performed as part of the patient’s standard of care.  Once a patient has signed 
consent, each site must notify the NYU Langone Health PCC Quality Assurance Unit and forward a copy of the 
signed consent to NYU Langone Health PCC Clinical Trials Office within 24 hours. 
  
Enrollment in the study requires that all inclusion and exclusion criteria have been met.  Enrollment occurs upon 
confirmation of registration from the NYU Langone Health PCC Clinical Trials Office.  The following materials 
must be submitted to the Quality Assurance Unit at NYU Langone Health via email (PCC-QAU@nyumc.org): 
 
 
1.  Complete signed and dated informed consent form 
 
2.  Complete signed and dated informed consent checklist 
 
3.  Complete signed and dated eligibility checklist 
 
4.  All supporting documentation verifying each criterion has been met. 
 
Registration will occur once the Senior Research Nurse for Quality Assurance conducts a central review of the 
submitted materials.  Once eligibility is verified, a unique subject study number will be issued within 48 hours of 
receiving all required registration material.  This number is unique to the participant and must be written on all 


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data and correspondence for the participant.  The NYU Langone Health PCC CTO will return a signed eligibility 
confirmation worksheet email with the subject’s unique study number. 
 
The subject will not be identified by name.  This is the point, at which, the patient is considered accrued on 
study.  Protocol treatment should begin within designated timeframe; issues that would cause treatment delays 
should be discussed with the overall PI, Dr. Weber.  All screen failures/ineligible subjects, as well as subject’s 
who withdraw consent prior to initiation of protocol therapy must be submitted to the CTO in a manner analogous 
to the procedures noted above.  Applicable source documentation will be required within the corresponding 
submissions. 
 
Subjects must not start any protocol procedures prior to registration; each participating institution will order the 
study agent directly from the suppliers, Celldex (CDX-3379) and Novartis (trametinib).  
 
  
Each site is responsible for reporting all unexpected problems involving risks to participants or others to NYU 
Langone  PCC Clinical Trials Office and to their IRB as per site institutional policy. 
 
Please email all SAEs to NYUPCCsafetyreports@nyulangone.org, Dr. Weber, and the NYU Langone Health 
CTO regulatory specialist.  
 
12 Study Finances 
12.1 Funding Source 
The study will be financed with support from Celldex Therapeutics and Novartis.  In addition, application for 
foundation grants will be submitted to in order to fund correlative studies, in addition to philanthropy.   
 
 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that has 
been reviewed and approved by the study sponsor prior to participation in this study.  All NYULMC 
investigators will follow the applicable University conflict of interest policies. 
12.2 Subject Stipends or Payments 
No subjects will receive payments or stipends for participation in this research study.  Celldex Therapeutics 
and Novartis may provide coverage for tests and/or procedures that are part of the research study if they are 
not covered by a subject’s insurance company. 
13 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed on 
to any third party without the consent of the study sponsor.  Any investigator involved with this study is 
obligated to provide the sponsor with complete test results and all data derived from the study.  Any formal 
presentation or publication of data from this trial may be published after review and comment by Celldex 
Therapeutics and Novartis and prior to any outside submission.  Celldex Therapeutics and Novartis must 
receive copies of any intended communication in advance of publication (at least twenty-one working days for 
presentational materials and abstracts and thirty working days for manuscripts).  These requirements 
acknowledge Celldex Therapeutics’ and Novartis’ responsibility to provide peer input regarding the scientific 
content and conclusions of such publications or presentations.  Principal Investigator/Institution shall have the 
final authority to determine the scope and content of its publications, provided such authority shall be 
exercised with reasonable regard for the interests of Celldex Therapeutics and Novartis and, in accord with 
the trial contract and shall not permit disclosure of Celldex Therapeutics and Novartis confidential or 
proprietary information. 


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writing by the study sponsor 
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writing by the study sponsor 
 
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15 Attachments 
1. FDA Form 3500A (MEDWATCH Form) 
2. Informed Consent 
3. CDX-3379 IB 
4. Trametinib IB 
5. Trametinib package insert