Conditions: Advanced Head and Neck Squamous Cell Carcinoma
Keywords: Erbitux Cetuximab Oral Cancer Oropharyngeal cancer Laryngeal cancer Head and Neck Squamous Cell Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
This is a study to determine the clinical benefit (how well the drug works), safety and tolerability of combining CDX-3379 and cetuximab. The study will enroll patients with advanced head and neck squamous cell carcinoma who have previously received cetuximab and progressed.

Detailed description:
CDX-3379 is a fully human monoclonal antibody that binds to a molecule called human epidermal growth factor receptor 3 (HER3 or ErbB3) found on certain cells and may act to promote anti-tumor effects.

Cetuximab is a human monoclonal antibody that blocks EGFR, a protein receptor that regulates cell growth.

This study will evaluate the safety, tolerability and efficacy of CDX-3379 in combination with cetuximab in patients with advanced head and neck squamous cell carcinoma who have previously received cetuximab and progressed.

Eligible patients that enroll in the study will be given the dose of 12 mg/kg CDX-3379 once every 3 weeks in combination with 400 mg/m2 cetuximab on the first day followed by weekly doses of 250 mg/m2 cetuximab.

Up to 45 patients will be enrolled. All patients enrolled in the study will be closely monitored to determine if there is a response to the treatment as well as for any side effects that may occur.

Arms:
arm 1: During the treatment phase of the study, eligible patients will receive assigned treatments in 3 week cycles until progression.

Interventions: intervention 1: CDX-3379 and cetuximab
Intervention descriptions: intervention 1: Dose: 12 mg/kg CDX-3379 once every 3 weeks in combination with 400 mg/m2 cetuximab on the first day followed by weekly doses of 250 mg/m2 cetuximab.

Protocol document:
Prot_000.pdf: 






Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 4 of 73 
 
Table 7: 
Schedule of CDX-3379 PK Sampling Times ..............................................................42 
Table 8: 
Schedule of CDX-3379 ADA Sampling Times ...........................................................42 
Table 9: 
Schedule of CDX-3379 Blood Biomarker Sampling Times........................................43 
Table 10: Clinical Laboratory Tests to be Performed During Study ...........................................48 
Table 11: Observed ORR and Associated Precision and Power Calculations under Varying 
Cohort Sample Sizes and Underlying Response Rates ................................................49 
Table 12: Overall response: patients with target +/–non-target disease ......................................67 
Table 13. Overall response: patients with non-target disease only ..............................................67 
LIST OF FIGURES 
Figure 1: Study Schema...............................................................................................................14 


Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
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1 STUDY PERSONNEL AND STUDY ADMINISTRATION 
Information regarding key personnel involved in the conduct of the study, including names and 
contact details for the Celldex Medical Monitor, protocol signatory, monitors, and other staff, 
participating investigators, clinical laboratories and other medical and/or technical departments 
and/or institutions, and members of additional study committees, will be found in the study files 
of Celldex. Names and contact details of relevant study staff (including the responsible Medical 
Monitor) will be provided to all participating investigators. 
For multinational studies, Celldex will assign the coordinating investigator responsible for signing 
the Clinical Study Report. 
Note: As used throughout this document, “Celldex” refers to Celldex Therapeutics, Inc. or any 
designee to whom study-related responsibilities have been appropriately delegated. 
 
 
 


Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
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2 GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibodies/immunogenicity 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AKT 
Protein kinase B 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration time curve 
CBR 
Clinical benefit response  
CI 
Confidence interval 
Cmax 
Maximum concentration 
CPS 
Combined Positive Score 
CRF 
Case report form 
CR 
Complete response 
CT 
Computed tomography 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response  
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ErbB /EGFR 
Epidermal growth factor receptor  
ErbB1 
Human epidermal growth factor receptor 1; HER1 
ErbB2 
Human epidermal growth factor receptor 2; HER2 
ErbB3 
Human epidermal growth factor receptor 3; HER3 
ErbB4 
Human epidermal growth factor receptor 4; HER4 
EU 
European Union 
FAT1 
FAT Atypical Cadherin 1 
FcRn  
Fragment crystallizable receptor – neonatal 
FDA 
Food and Drug Administration 
FNA 
Fine needle aspirate 
5-FU 
5-Fluorouracil 
GCP 
Good Clinical Practice 


Clinical Protocol CDX3379-04 
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Amendment 1 (28-Jun-2019) 
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Abbreviation 
Definition 
GMP 
Good Manufacturing Practice 
HER 
Human epidermal growth factor 
HIPAA 
Health Insurance Portability and Accountability Act 
HNSCC 
Head and neck squamous cell carcinoma 
HPV 
Human papillomavirus 
ICF 
Informed consent form 
IgG1λ 
Immunoglobulin G1 lambda  
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry  
IND 
Investigational new drug application 
INR 
International normalized ratio  
IRB 
Institutional review board 
IV 
Intravenous 
kg 
Kilogram 
m2 
Meter squared 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
Milligram 
mL 
Milliliters 
MRI 
Magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events  
NOTCH 
NOTCH family of cell-signaling receptors 
NRG 
Neuregulin/heregulin  
OS 
Overall survival 
PCR 
Polymerase chain reaction 
PD-1 
Programmed death receptor-1 
PD-L1 
Programmed death-ligand 1 
pErbB3 
Phosphorylated ErbB3 
PFS 
Progression-free survival 
PI3K 
Phosphoinositide 3-kinase  
PK 
Pharmacokinetics 


Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
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Page 8 of 73 
 
Abbreviation 
Definition 
PR 
Partial response 
PTEN 
Phosphatase and tensin homolog 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RTK 
Receptor tyrosine kinases  
SAE 
Serious adverse event 
SD 
Stable disease 
T1/2 
Half-life 
ULN 
Upper limit of normal 
YAP1 
Yes-associated protein 1 
YTE 
M253Y/S255T/T257E; M252Y/S254T/T256E, according to the EU numbering 
system 
 






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Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
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Page 13 of 73 
 
Response-evaluable population: All patients who have measurable disease at baseline and 
receive one full dose of both CDX-3379 and cetuximab and have post baseline tumor 
response assessment or discontinue study prematurely for disease progression, symptomatic 
deterioration, or death. Patients who discontinue treatment prior to the first tumor 
assessment for other reasons will be excluded from this population. Sensitivity analyses for 
efficacy endpoints will be performed in this population. 
Analysis Methods 
Best overall response (as defined by RECIST 1.1) will be summarized for the all treated 
population.  The ORR calculated as defined above, and the corresponding 95% exact CI 
will be calculated using the Clopper-Pearson method.  
CBR will be analyzed using the same approach as ORR. 
DOR will be estimated using the Kaplan-Meier (KM) product limit method. The KM 
estimate of the median DOR will be reported along with the two-sided 95% CI using 
Brookmeyer and Crowley’s method (log-log transformation).   
Progression-Free Survival and Overall Survival will be analyzed using the same approach 
as DOR. 
Additional analyses may be conducted including estimating objective response rate and 
other efficacy parameters for the response-evaluable population and within biomarker 
defined subgroups. 
Safety analyses will consist of data summaries for clinical and laboratory parameters, and 
for adverse events (AEs). The number and percentage of patients experiencing one or more 
AEs will be summarized by the relationship to study drug and severity based on NCI 
CTCAE v 5.0. Adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Laboratory parameters will be summarized using descriptive 
statistics, by post-treatment shifts relative to baseline, and data listings of clinically 
significant abnormalities. Vital signs and ECG data will be summarized using descriptive 
statistics. 
Serum CDX-3379 concentration data will be tabulated by overall study population together 
with descriptive statistics. Individual and mean serum concentration-time profiles of 
CDX-3379 will be generated. Noncompartmental PK data analysis will be performed and 
descriptive statistics provided. If data allows, descriptive statistics of noncompartmental PK 
parameters (AUC, Cmax, CL, t½) will be provided. A population PK analysis may also be 
performed and various PK compartmental models may be explored to characterize the PK 
of CDX-3379 in patients with HNSCC. Exposure response modeling will be performed to 
examine the relationship between CDX-3379 serum exposure and clinical endpoints. The 
impact of physiologically relevant patient characteristics (covariates) and disease on 
PK/pharmacodynamic parameters (and possibly clinical endpoints) may be tested.  
The number and percentage of patients who develop detectable CDX-3379 ADA will be 
summarized. ADA titers will be reported for confirmed ADA-positive patients, and the 
impact of ADA on PK will be assessed if data allow. 
Biomarker data will be summarized descriptively and any correlation with outcome 
(efficacy) will be investigated. Analyses may include estimating objective response rate and 
other efficacy parameters within biomarker defined subgroups (i.e., defined by degree of 
expression or presence of genetic variation).  
 




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Table 1: Schedule of Assessments 
 
Screening 
  
Treatment Period  
End of 
Treatment3 
Follow-up Period4 
Cycle 1 
Cycle 2 and 
subsequent cycles 
Day 1  
Day 8 
 
Day 15 
 
Day 1 
30-day 
 
Survival  
follow-up 
Visit Window1 
Day –28 to –1 
 
(+/- 1 
day) 
(+/- 1 
day) 
 
 
(+/- 3 days) 
Every 12 (±2) weeks 
until study closure 
Informed consent2 
X 
 
 
 
 
 
 
 
Demographics and Medical 
history5 
X 
X 
 
 
 
 
 
 
Tumor tissue 
X6 
 
 
Pregnancy test7 
X 
X 
 
 
 
 
 
 
Vital signs8 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination9 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
(Appendix 3) 
X 
X 
 
 
X 
X 
 
 
12-Lead Electrocardiogram10 
 
X 
X 
 
 
X 
 
 
Serum chemistry11  
X 
X12 
X 
X 
X 
X 
X 
 
Hematology11 
X 
X12 
X 
X 
X 
X 
X 
 
Urinalysis11  
X 
X12 
 
 
X 
X 
 
 
CDX-3379 PK sample13  
 
X14,15 
X14  
X14  
X14,15 
 
X16 
 
Biomarker blood sample13 
X 
X15 
X 
X 
X15,17 
 
X16 
 
Immunogenicity blood sample13 
 
X15 
 
 
X15 
 
X 
 
Diagnostic Imaging / Response 
Assessment18 
X 
 
 
 
X18 
X18 
 
X18 
Administer CDX-337919 
 
X 
 
 
X 
 
 
 
Administer Cetuximab20 
 
 
 
 
 
Concomitant medication review21 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event monitoring22 
 
X 
X 
X 
X 
X 
X 
X 
Survival follow-up 
 
 
 
 
 
 
 
X 
Footnotes on next page 


Clinical Protocol CDX3379-04 
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Amendment 1 (28-Jun-2019) 
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Footnotes for Table 1:   
1. A delay in study treatment or performance of study visits due to holidays, weekends, inclement weather, or other 
unforeseen circumstances will be permitted and not considered a protocol deviation. However, significant delays 
(i.e., greater than one week) due to these reasons should be discussed with the Celldex Medical Monitor to reach 
consensus on subsequent scheduling. See Section 8.2 and Section 8.3 for management of dosing delays due to 
toxicity. 
2. No study-specific procedures will be performed prior to receipt of signed Informed Consent (and, if applicable, 
Health Insurance Portability and Accountability Act [HIPAA] authorization). However, assessments performed 
according to standard of care prior to receipt of Informed Consent may be utilized to fulfill the screening 
requirement, if completed within the required window for screening.  
3. The End-of-Treatment (EOT) visit should be performed as soon as feasible following the decision to discontinue 
study drug dosing and prior to initiation of alternate therapies. This visit may be combined with the 30-day post-
treatment follow-up visit, if the windows overlap, with required assessments completed once for the combined 
visit.   
4. Follow-up visit should occur 30 (±3) days after the last dose of CDX-3379. Thereafter, patients should be 
contacted (may be via telephone) every 12 (±2) weeks until study closure for survival status and subsequent 
therapies. For patients who have discontinued study therapy for reasons other than progression, imaging studies 
to assess response should be obtained every 12 (±2) weeks (relative to last disease assessment) until disease 
progression or until patients are started on subsequent therapy, whichever occurs sooner. For these patients, the 
first survival status may be scheduled to coincide with the first post-treatment disease assessment, rather than 
relative to the 30-day follow-up.   
5. Medical history includes prior/concurrent conditions and cancer history including cancer mutation status and 
HPV status, prior treatments and surgical history. At Day 1, medical history is updated prior to administration of 
study drug. 
6. Unless prior agreement is reached with the Medical Monitor for submission of archival tumor, biopsy is to be 
performed of an accessible site (primary or metastatic) that can be biopsied with acceptable clinical risk (as judged 
by the investigator), obtaining a minimum of 3-5 core biopsies for biomarker analysis. FNAs are not acceptable. 
The biopsy site chosen should not have been previously irradiated and must be distinct from RECIST 1.1 target 
lesions, unless the biopsy is obtained prior to the screening disease assessment. 
7. Pregnancy tests are required only for women of childbearing potential (excluding patients who are post-
menopausal with absence of menses for at least 1 year and/or surgically sterilized). A serum pregnancy test must 
be performed during Screening. If the serum pregnancy test is performed more than 7 days prior to Day 1, then a 
urine or serum pregnancy test must also be performed on Day 1 with results reviewed prior to dosing.  
8. Vital signs should include heart rate, respiratory rate, blood pressure, temperature, and weight. Height should be 
recorded at Screen only, while weight is recorded only once per visit. Patients will be monitored during and after 
infusion of CDX-3379 and cetuximab with assessment of vital signs pre-infusion (within 30 minutes of the start 
of infusion), at 30 (± 5) minutes during the infusion, at the end of the infusion (within 5 minutes), and as clinically 
indicated during the 1-hour post-treatment observation period. When cetuximab is administered over two hours, 
vital signs should additionally be assessed at 60 (± 5) minutes and 90 (± 5) minutes.  
9. Complete physical examination should be performed at screening; thereafter, symptom-directed physical 
examinations are acceptable. 
10. Twelve-lead ECGs will be obtained prior to dosing and at 30-60 minutes following the CDX-3379 infusion on 
day 1 and 8 of cycle 1. A second original copy of the ECG tracing should be retained for possible submission to 
Celldex. 
11. Laboratory assessments to be performed locally, as well as requirements for review prior to CDX-3379 and 
cetuximab dosing, are specified in Section 10.2.5.5. See Section 8 for guidance regarding dosing 
modifications/delays due to laboratory toxicity.  
12. Assessments do not need to be repeated if performed within 24 hours of Cycle 1 dosing as part of the screening 
assessment.  


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Amendment 1 (28-Jun-2019) 
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13. Analyses will be performed centrally. Sample collection, processing and shipping instructions will be provided 
separately.   
14. Blood samples for CDX-3379 PK analysis will be drawn predose, immediately after the end of infusion (within 
5 minutes), and 60 minutes (± 5 minutes) post-infusion on Day 1 of each cycle prior to cetuximab administration. 
PK samples will also be collected prior to cetuximab dosing on Day 8 and 15 of Cycle 1.  
15. Predose blood sample may be collected within 24 hours prior to CDX-3379 administration. 
16. To be collected at 30-day follow-up visit, only if additional anticancer therapy has not been started. 
17. Biomarker blood samples to be collected predose at cycle 2, 3, 5, 7, and 9. 
18. See Section 10.2.1 and Appendix 2. Disease evaluation done at screening, near the end of every 2nd cycle (i.e., 
after day 15 of cycles 2, 4, 6, 8, etc. and prior to dosing for the next cycle), and, for patients who have not 
experienced progression at end of treatment, every 12 (±2) weeks until progression or initiation of alternate cancer 
therapies. Disease evaluation is required at end of treatment only if disease progression is not previously 
document. If a partial or complete response is noted, a follow-up radiographic assessment must be done no sooner 
than 28 days later to confirm response. Prior to any intervention (such as surgical resection, palliative radiation 
or alternate anticancer therapy), every effort should be made to perform a tumor response assessment in order to 
document progression and/or confirm an objective response. 
19. Unless otherwise specified, all study assessments should be performed prior to administration of study treatment 
and may be performed up to 24 hours prior to treatment administration if assessments remain within the specified 
visit window. CDX-3379 should be administered first, with a 1-hour observation period before administration of 
cetuximab. Diarrhea prophylaxis is required in accordance with Section 8.4.1.4 
20. Cetuximab will be administered weekly on Days 1, 8, and 15 of each cycle. On Day 1 of each Cycle, cetuximab 
should be administered approximately 1 hour after the completion of CDX-3379 administration and after 
collection of the 60 minute post-infusion PK blood sample. As a routine precaution, patients should be observed 
for at least 1 hour after the end of the cetuximab infusion. See Section 8.4.2 for guidance on cetuximab 
premedication and diarrhea prophylaxis. See Section 8 for additional details regarding study treatment dosing, 
precautions, monitoring, and management of toxicity.   
21. All concomitant medications will be documented if taken within 28 days prior to Day 1, and either (whichever 
occurs sooner): a) through the 30-day post-treatment follow-up, or b) initiation of alternate anticancer therapy. In 
addition, all anticancer surgeries or medications and response to those medications, as well as any concomitant 
medications required to treat study drug-related serious adverse events (SAEs), should also be recorded 
throughout the duration of study follow-up. See Section 9 for further guidance.   
22. Documentation of AEs will continue until the 30-day post-treatment follow-up, or until the initiation of 
subsequent anticancer treatment, whichever occurs first. For AEs or SAEs with a causal relationship to the 
investigational product, follow-up by the investigator is required until the event or its sequelae resolve to 
≤ grade 1, or stabilize for at least three months after the last administration of study treatment (whichever is 
sooner). In addition, any SAE occurring any time after the reporting period must be promptly reported if a causal 
relationship to study treatment is suspected. See Section 10.2.5.1, Section 10.2.5.2, Section 10.2.5.3 and 
Section 10.2.5.4 for further guidance.  
 


















Clinical Protocol CDX3379-04 
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Amendment 1 (28-Jun-2019) 
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Page 26 of 73 
 
7 INVESTIGATIONAL PLAN 
7.1 
Overall Design and Plan of the Study 
This is an open-label, multicenter Phase 2 study of CDX-3379 in combination with cetuximab in 
patients with cetuximab-resistant HNSCC. Patients will be treated with CDX-3379 plus cetuximab 
until progressive disease, unacceptable toxicity, or other criteria for discontinuation of study 
treatment (Section 7.4.1) are met.  
The study was initially designed according to a Simon’s 2-stage design in which one tumor 
response (CR or PR) would need to be observed in the first 13 evaluable patients before completion 
of accrual to a total of 27 evaluable patients. Patients who discontinue treatment in the absence of 
progression/symptomatic deterioration/death before the first tumor assessment will be considered 
unevaluable for primary analysis and will be replaced. Following completion of stage 1 of the 
study, where 1 complete response was observed, emerging biomarker data were reviewed to assess 
correlation with efficacy.  In the overall CDX-3379 development program, in a small patient 
dataset, FAT1 and NOTCH1, NOTCH2 and NOTCH3 mutations appeared to be associated with 
clinical activity including objective response and durable stable disease.  Given these findings, the 
study design has been amended to enroll up to approximately 45 total patients, including at least 
15 patients whose tumor harbor a FAT1 mutation based on retrospective gene sequencing.  
Screening tissue samples will be required to be submitted as directed by the Sponsor at the time of 
enrollment to allow for gene sequencing and tracking the number of patients whose tumor harbor 
a FAT1 mutation. 
Tumor assessments will be performed approximately every 6 weeks during treatment. Patients 
who discontinue treatment in the absence of progression will continue to have assessments 
approximately every 12 weeks until documented progression or initiation of alternate anticancer 
therapies. Tumor response will be assessed by the investigator in accordance with RECIST 1.1 
guidelines (Eisenhauer, et al. 2009) (Section 10.2.1 and Appendix 2).  
Continuous evaluation of toxicity will be performed by the investigators and Celldex throughout 
the entire course of patient treatment and through 30 days following the last dose of CDX-3379. 
Subsequently, patients will be followed for survival, with contact every 12 weeks until study 
closure. 
7.2 
Selection of Study Population 
7.2.1 
Number of Patients 
It is anticipated that approximately 45 patients will be accrued. Enrollment will be competitive 
with no maximum per site. 
7.2.2 
Patient Eligibility 
7.2.2.1 
Inclusion Criteria 
Patients may be included in the study only if they meet all of the following inclusion criteria prior 
to receiving study treatment: 


Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 27 of 73 
 
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. Histologically or cytologically confirmed HNSCC that is recurrent or metastatic, not curable 
with local treatment modalities (e.g., surgery, radiation), and progressive (based on 
radiographic, clinical or pathologic assessment) during or subsequent to last therapy.  
4. Human papilloma virus (HPV) negative tumor, as established by the local site. Acceptable 
standards include p16 immunohistochemistry (where a tumor is classified as p16-positive 
when showing diffuse nuclear and cytoplasmic staining in at least 70% of tumor cells) and/or 
assessment of HPV deoxyribonucleic acid (DNA).  
5. Prior treatment must include (in any combination or sequence):  
a. check-point inhibitor targeting programmed death receptor-1 axis (PD-1/PDL-1), unless 
not a candidate  
b. cetuximab, with tumor progression during or within 6 months after completing treatment 
(regardless of any intervening therapies) 
6. Measurable (target) disease by RECIST 1.1 criteria (Eisenhauer, et al. 2009) (Appendix 2). 
Target lesions selected for tumor measurements should be those where additional (e.g., 
palliative) treatments are not indicated or anticipated.   
7. Willingness to consent for tumor biopsy from an accessible site (primary or metastatic) prior 
to initiating study therapy. In cases where a fresh biopsy is not feasible (i.e., if an accessible 
site cannot be biopsied with acceptable clinical risk or upon patient refusal), archival tissue 
may be submitted instead, after discussion with and approval by the medical monitor. 
8. 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.  
9. 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)  


Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 28 of 73 
 
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 ≤ 1.5 × ULN 
h.  Serum calcium and potassium within normal limits 
10. Life expectancy ≥ 12 weeks 
11. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (Appendix 3) 
12. 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 or cetuximab, whichever is later. Patients and/or partners who are surgically sterile 
or postmenopausal are exempt from this requirement. 
7.2.2.2 
Exclusion Criteria 
Patients will be excluded from the study for any of the following reasons: 
1. Nasal, paranasal sinus, or nasopharyngeal carcinoma, aside from WHO Type I and II 
(keratinizing, non-EBV positive) nasopharyngeal carcinoma which will be allowed.  
2. Received CDX-3379 or other anti-ErbB3 targeted 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 3 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. 
5. Known brain metastases, unless previously treated and asymptomatic for 2 months and not 
progressive in size or number for 2 months prior to enrollment. Continued use of 
anticonvulsants (in the absence of any suspicion of progressive brain metastases) is acceptable.   
6. Known HIV, hepatitis B or hepatitis C infection, or active infection requiring systemic 
intravenous therapy   
7. 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.   
8. Chemotherapy within 21 days or at least 5 half-lives (whichever is shorter) prior to the planned 
start of study treatment 
9. 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. 


Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 29 of 73 
 
10. Use of other investigational drugs within 2 weeks or 5 half-lives (whichever is longer) prior to 
study treatment administration 
11. 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,); the use of concomitant 
medications that prolong the QT/QTc interval; 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. 
12. Requirement for chronic immunosuppressive medication including systemic corticosteroids 
above the physiologic dose (defined as 30 mg/day hydrocortisone or the equivalent).  
13. 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.  
14. Known alcohol or drug abuse. 
15. Women who are pregnant or nursing. All female patients with reproductive potential must have 
a negative pregnancy test prior to starting treatment 
16. Known allergy or past administration reaction including infusion reactions, anaphylactic, or 
anaphylactoid reactions to any component of the CDX-3379 formulation.  
17. Prior history of clinically significant hypersensitivity reaction or significant intolerance to 
cetuximab; history of allergic reactions attributed to compounds of chemical or biologic 
composition similar to those of cetuximab. 
7.3 
Measures to Minimize Bias  
This is non-randomized open-label study. The analysis of tumor response and progression-free 
survival will be based on tumor response assessments performed by the investigator according to 
standardized, objective response criteria (RECIST 1.1). In addition, in the event of a positive study 
outcome, an additional assessment of tumor response and progression may be performed by an 
independent review committee blinded to investigator assessments.  
7.4 
Withdrawal and Replacement of Patients 
Every effort should be made within the bounds of safety and patient choice to have each patient 
complete the study.  
Patients who discontinue the study for reasons other than disease progression, symptomatic 
deterioration or death prior to the first radiographic assessment will be considered unevaluable for 
primary analysis and will be replaced. 


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Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 42 of 73 
 
eighteen weeks, or more frequently if clinically indicated. The same method of assessment and the 
same technique should be used to characterize each identified and reported lesion at baseline and 
during follow-up.  
Target lesions selected for tumor measurements should be those where surgical resection or 
radiation are not indicated or anticipated. 
10.2.2 
Pharmacokinetic Evaluation  
Table 7 details the PK sample collection schedule. Details will be provided separately in a 
laboratory manual to include procedures for collection, processing, storage, and shipment of 
samples, as well as laboratory contact information.   
 
Table 7: Schedule of CDX-3379 PK Sampling Times 
Day 
Time 
Day 1 for all Cycles 
Predose (within 24 hours of CDX-3379 infusion) 
Immediately after the end of CDX-3379 infusion (within 5 minutes) 
Post CDX-3379 dose at 60 minutes after end of CDX-3379 infusion (+ 5 minutes) and 
prior to cetuximab administration 
Cycle 1, Day 8 
During visit prior to cetuximab administration 
Cycle 1, Day 15  
During visit prior to cetuximab administration 
30-Day Follow-up 
During visit, in cases where new anticancer therapy hasn’t yet been started 
10.2.3 
Immunogenicity of CDX-3379 
Table 8 details the immunogenicity sample collection schedule. Details will be provided separately 
in a laboratory manual to include procedures for collection, processing, storage, and shipment of 
samples, as well as laboratory contact information.   
The ADA titer will be reported for samples confirmed positive for the presence of anti-CDX-3379 
antibodies. Tiered analysis will be performed to include screening, confirmatory and titer assay 
components and Positive-Negative cut points will be employed that were statistically determined 
from CDX-3379-naïve validation samples.  
Samples will be collected for assessing the neutralization capacity in the future.  
 
Table 8: Schedule of CDX-3379 ADA Sampling Times  
Cycle and Day 
Time 
Day 1 of each Cycle 
Predose (within 24 hours prior to CDX-3379 infusion) 
30-Day Follow-up 
During visit 
10.2.4 
Biomarker Evaluation and Methods 
Pre-treatment biopsy tumor samples (fresh preferred, archival upon approval by the Medical 
Monitor) are planned to be evaluated for biomarkers that may enrich for patient benefit to 
CDX-3379. Details on performing the core or excisional biopsies (a minimum 3-5 core or 
excisional biopsies preferred, FNAs are not acceptable), preparing the samples and shipping 
instructions can be found in the laboratory manual.  






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Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 49 of 73 
 
11 SAFETY MONITORING 
As this study is a single-arm, Phase 2 design, an IDMC will not be utilized. To ensure both study 
integrity and patient safety, processes are in place within Celldex for regular review and 
monitoring of emerging safety data. Celldex will regularly communicate study conduct and safety 
information to participating investigators. 
12 STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this trial will 
be documented in a Statistical Analysis Plan (SAP), which will be developed and maintained by 
Celldex. 
The SAP may modify the plans outlined in the protocol; however, any major modifications of the 
primary endpoint definition and/or its analysis will also be reflected in a protocol amendment. 
12.1 
Sample Size and Power Calculation 
The original sample size for the study was based on Simon’s 2-stage MinMax design. The first 
stage was completed, and the futility stopping rule was not met. The current amendment will 
increase the total sample size from 30 to approximately 45 treated patients, including at least 15 
patients whose tumors harbor a FAT1 mutation based on retrospective gene sequencing.  
Table 11 shows confidence intervals associated with a range of observed ORRs in all treated 
patients (n=45) and in those who are FAT1 mutation-positive (n=15) that would provide sufficient 
precision to rule out < 10%, < 15%, and< 20% ORR based on the lower 95% confidence bound 
for different underlying true response rates (true p). The table also shows the likelihood of 
observing at least the number of responses associated with each of these thresholds (power).  
If the true response rate is ≥ 30%, a sample size of 45 treated patients provides sufficient power to 
rule out < 10% ORR; if the true response rate is ≥ 40%, then the study is adequately powered to 
rule out < 20% ORR. 
A cohort size of 15 treated patients in the FAT1 mutation-positive cohort provides ≥ 70% power 
to rule out < 10% ORR if the true response is ≥ 30%; ≥ 78% power to rule out < 15% ORR if the 
true ORR is ≥ 40%; and ≥ 70% power to rule out < 20% ORR if the true ORR is ≥ 50%. 
Table 11: Observed ORR and Associated Precision and Power Calculations under Varying 
Cohort Sample Sizes and Underlying Response Rates 
Cohort  
Observed 
No. Responses 
r (ORR) 
95% CI a  
of ORR 
(%) 
Power: P (No. observed responses ≥ r | true p)*100 
true p = 50% 
true p = 40% 
true p = 30% 
true p = 20% 
All 
Treated 
Patients 
n=45 
9/45 (20.0%) 
(9.6, 34.6) 
> 99% 
> 99% 
95% 
56% 
12/45 (26.7%) 
(14.6, 41.9) 
> 99% 
98% 
74% 
17% 
15/45 (33.3%) 
(20.0, 49.0) 
> 99% 
86% 
37% 
2% 
FAT1 
mutation 
positive 
n=15 
4/15 (26.7%) 
(7.8, 55.1) 
98% 
91% 
70% 
35% 
5/15 (33.3%) 
(11.8, 61.6) 
94% 
78% 
48% 
16% 
7/15 (46.7%) 
(21.3, 73.4) 
70% 
39% 
13% 
2% 
a Clopper-Pearson 


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Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 52 of 73 
 
Progression-Free Survival and Overall Survival will be analyzed using the same approach as DOR.  
Additional analyses may be conducted including estimating objective response rate and other 
efficacy parameters for the response-evaluable population and within biomarker defined 
subgroups. 
12.5.2 
Safety Analyses 
Safety analyses will consist of data summaries for clinical and laboratory parameters, and for AEs. 
The number and percentage of patients experiencing one or more AEs will be summarized by the 
relationship to study drug and severity based on NCI CTCAE v 5.0. Adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Laboratory parameters will be 
summarized using descriptive statistics, by post-treatment shifts relative to baseline, and data 
listings of clinically significant abnormalities. Vital signs and ECG data will be summarized using 
descriptive statistics. 
12.5.3 
Pharmacokinetic Analyses 
Serum CDX-3379 concentration data will be tabulated by overall study population together with 
descriptive statistics. Individual and mean serum concentration-time profiles of CDX-3379 will be 
generated. Noncompartmental PK data analysis will be performed and descriptive statistics 
provided. If data allows, descriptive statistics of noncompartmental PK parameters (AUC, Cmax, 
CL, t½) will be provided. A population PK analysis may also be performed and various PK 
compartmental models may be explored to characterize the PK of CDX-3379 in patients with 
HNSCC. Exposure-response modeling will be performed to examine the relationship between 
CDX-3379 serum exposure and clinical endpoints. The impact of physiologically relevant patient 
characteristics (covariates) and disease on PK/pharmacodynamic parameters (and possibly clinical 
endpoints) may be tested.  
12.5.4 
Immunogenicity Analyses 
The number and percentage of patients who develop detectable CDX-3379 ADA will be 
summarized.  ADA will be reported for confirmed ADA-positive patients, and the impact of ADA 
on PK will be assessed if data allow. 
12.5.5 
Biomarker Analyses 
Biomarker data will be summarized descriptively and any correlation with outcome (efficacy) will 
be investigated.  Analyses may include estimating objective response rate and other efficacy 
parameters within biomarker defined subgroups (i.e., defined by degree of expression or presence 
of genetic variation).  
12.5.6 
Study Treatment and Medications 
The duration of treatment, total number of doses and total dose administered will be tabulated for 
study treatments. The primary reason for treatment modifications will be tabulated. 
All medications will be coded using WHO Drug Dictionary, and they will be listed and 
summarized by anatomical therapeutic class and preferred name. 


Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 53 of 73 
 
13 DATA HANDLING AND RECORD KEEPING 
13.1 
Data Quality Assurance 
Monitoring and auditing procedures defined by Celldex will be followed in order to comply with 
Good Clinical Practice (GCP) guidelines. Each center will be visited at regular intervals by a 
monitor to ensure compliance with the study protocol, GCP and legal aspects.  
To ensure the safety of participants in the study and to ensure accurate, complete, and reliable data, 
the investigator will keep records of laboratory tests, clinical notes, and patient medical records in 
the patient files as original source documents for the study. All the information required by the 
protocol should be provided; any omissions require explanation. 
Celldex will provide CRFs for the recording and collection of data. The CRF will either be in paper 
or via an electronic data capture (EDC) system. Entries made in the CRF must be either verifiable 
against source documents, or have been directly entered into the CRF, in which case the entry in 
the CRF will be considered as the source data. The source data parameter to be verified and the 
identification of the source document must be documented. Corrections to CRFs and source data 
will be made only by authorized members of the study staff, clearly entered, initialed and dated. 
The investigator will sign the CRFs to indicate that, to his/her knowledge, they are complete and 
accurate. If further changes are made after this, the investigator will be made aware of the 
corrections and his/her approval will be documented by re-signing. In cases where an EDC system 
is utilized, an electronic audit trail is maintained. 
The investigator will permit Celldex direct access to source data/documents for trial-related 
monitoring, audits, review, and inspection(s). Through ongoing monitoring visits at the 
investigational sites, Celldex will periodically check the patient data recorded in the CRF’s against 
source documents, to ensure accuracy, completeness, and adherence to the protocol, regulatory 
compliance, and the maintenance of comprehensive clinical records.  
The study may be audited by Celldex and/or regulatory agencies at any time. If requested, the 
investigator will provide Celldex, applicable regulatory agencies, and/or applicable ethical review 
boards with direct access to original source documents, which may include applicable electronic 
medical record system(s). 
13.2 
Archiving of Study Documentation 
To enable evaluations and/or audits by regulatory authorities or Celldex, the investigator agrees to 
keep records, including the identity of all participating patients (sufficient information to link 
records, e.g., CRFs and hospital records), all original signed informed consent forms (ICFs), copies 
of all CRFs, SAE forms, source documents, and detailed records of treatment disposition, and 
adequate documentation of relevant correspondence (e.g., letters, meeting minutes, telephone calls 
reports). The duration of record retention by the investigator should be according to International 
Conference on Harmonisation (ICH), local regulations, or as specified in the Clinical Trial 
Agreement, whichever is longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), Celldex should be prospectively notified. The study 
records must be transferred to a designee acceptable to Celldex, such as another investigator, 


Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 54 of 73 
 
another institution, or to an independent third party arranged by Celldex. The investigator must 
obtain written permission from Celldex before disposing of any records, even if retention 
requirements have been met. 
14 ETHICAL CONSIDERATIONS 
14.1 
Institutional Review Board or Ethics Committee 
International Conference on Harmonisation GCP guidelines require that all investigational drug 
studies be conducted under the auspices of an Institutional Review Board/Ethics Committee 
(IRB/EC). This committee, the makeup of which must conform to national, state, and local 
guidelines regarding such, will approve all aspects of the study, including the protocol and 
informed consent to be used and any modifications made to the protocol or informed consent. The 
investigator will provide Celldex with a copy of the communication from the IRB/EC to the 
investigator indicating approval/favorable opinion of the protocol and consent form. All changes 
to the protocol or consent form must be reviewed and approved prior to implementation, except 
where necessary to eliminate apparent immediate hazards to human patients. 
The investigator will provide Celldex with documentation of ethical review board approval of the 
protocol and the informed consent document before the study may begin at the investigative site(s). 
The investigator will also be responsible for obtaining periodic IRB/EC re-approval throughout 
the duration of the study. Copies of the investigator’s periodic report to the IRB/EC and copies of 
the IRB/EC’s continuance of approval must be retained in the site study files and furnished to 
Celldex. 
The IRB/ECs must supply to Celldex, upon request, a list of the IRB/EC members involved in the 
vote and a statement to confirm that the IRB/EC is organized and operates according to GCP and 
applicable laws and regulations. 
14.2 
Ethical Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that Celldex and investigator abide by GCP Guidelines and 
under the guiding principles detailed in the Declaration of Helsinki. The study will also be carried 
out in keeping with applicable local law(s) and regulation(s). The investigator is responsible for 
complying with the protocol and all appropriate regulations and guidelines governing global 
clinical research. Additionally, he/she is responsible for ensuring that all participating staff 
members are adequately trained and competent to perform his/her assigned tasks. 
14.3 
Patients Information and Informed Consent  
Sample ICFs will be provided. Prior to the beginning of the study, the investigator must have the 
IRB/EC’s written approval/favorable opinion of the written ICF and any other written information 
to be provided to patients. The written approval of the IRB/EC together with the approved patient 
information/ICFs must be filed in the study files. The ICF must contain all elements required ICH 
GCP Guidelines (E6) in addition to any other elements required by national, state, local or 
institutional policy.  


Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 55 of 73 
 
The investigator will be responsible for obtaining an ICF signed by each patient or his/her legally 
authorized representative, prior to his/her participation in the study, in accordance with ICH GCP 
guidelines. Informed Consent will be obtained from a patient or his/her legally authorized 
representative after a full explanation of the purpose of the study, the risks and discomforts 
involved, potential benefits, etc., have been provided by the investigator or designee, both verbally 
and in writing. The investigator is responsible to see that informed consent is obtained from each 
patient or legal representative and to obtain the appropriate signatures and dates on the ICF 
document prior to the performance of any protocol-specific procedures and prior to the 
administration of study drug. Participation in the study and date of informed consent given by the 
patient should be documented appropriately in the patient’s files. The investigator will be 
responsible for communicating in a timely fashion any new findings, including amendments to the 
protocol, that could affect a patient’s willingness to continue in the study. 
The original or copy of the signed copy of the ICF must be maintained in the institution’s records 
and is subject to inspection by Celldex or regulatory agencies. The patient or his/her legally 
authorized representative will also be given a copy of the signed consent form. 
As used in this protocol, the term "informed consent" includes all consent and/or assent given by 
patients or their legal representatives. 
14.4 
Protocol Amendments 
Modifications to the study protocol will not be implemented by either Celldex or the investigator 
without agreement by each party and IRB/EC approval/favorable opinion. However, the 
investigator may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to the trial patients without prior IRB/EC/Celldex approval/favorable 
opinion. In these cases, the implemented deviation or change, the reasons for it, and if appropriate, 
the proposed protocol amendment, should be submitted to the IRB/EC and Celldex as soon as 
practical. Any deviations from the protocol must be fully explained and documented by the 
investigator with notification to the Sponsor and IRB/EC as appropriate.  
14.5 
Confidentiality 
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.  
Patient names will not be supplied to Celldex. Only the patient number and patient initials (as 
permissible) will be recorded in the CRF, and if the patient name appears on any other document 
(e.g., pathologist’s report), it must be obliterated before a copy of the document is supplied to 
Celldex. Study findings stored on a computer will be stored in accordance with local data 
protection laws. The patients will be informed in writing that representatives of Celldex, IRB/EC, 
or Regulatory Authorities may inspect their medical records to verify the information collected, 
and that all personal information made available for inspection will be handled in strictest 
confidence and in accordance with local data protection laws. 
If the results of the study are published, the patient’s identity will remain confidential.  
The investigator will maintain a list to enable patients’ records to be identified. 


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Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 57 of 73 
 
16 REFERENCES 
 
1. 
Alvarado D, Ligon GF, Lillquist JS, et al. ErbB activation signatures as potential 
biomarkers for anti-ErbB3 treatment in HNSCC. PLoS One. 2017;12(7):e0181356. 
2. 
American Cancer Society. Cancer Facts & Figures 2017. Atlanta: American Cancer 
Society. 2017. 
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Amin DN, Campbell MR, Moasser MM. The role of HER3, the unpretentious member of 
the HER family, in cancer biology and cancer therapeutics. Seminars in Cell & 
Developmental Biology. 2010;21(9):944-950. 
4. 
Bauman JE, Saba NF, Wise-Draper TM, et al. CDX3379-04:  Phase II evaluation of CDX-
3379 in combination with cetuximab in patients with advanced head and neck squamous 
cell carcinoma (HNSCC). J Clin Oncol. 2019;37. 
5. 
Burtness B, Anadkat M, Basti S, et al. NCCN Task Force Report: Management of 
dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. 
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Cancer Genome Atlas Network. Comprehensive genomic characterization of head and 
neck squamous cell carcinomas. Nature. 2015;517(7536):576-582. 
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Chiu CG, Masoudi H, Leung S, et al. HER-3 Overexpression Is Prognostic of Reduced 
Breast Cancer Survival. Annals of Surgery. 2010;251(6):1107-1116. 
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Cohen EEW, Licitra LF, Fayette J, et al. Biomarker analysis in recurrent and/or metastatic 
head and neck squamous cell carcinoma (R/M HNSCC) patients (pts) treated with second-
line afatinib versus methotrexate (MTX): LUX-Head & Neck 1 (LUX-H&N1). Journal of 
Clinical Oncology. 2015;33(15_suppl):6023-6023. 
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Dall'Acqua WF, Kiener PA, Wu H. Properties of Human IgG1s Engineered for Enhanced 
Binding to the Neonatal Fc Receptor (FcRn). Journal of Biological Chemistry. 
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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
11. 
Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET Amplification Leads to Gefitinib 
Resistance 
in 
Lung 
Cancer 
by 
Activating 
ERBB3 
Signaling. 
Science. 
2007;316(5827):1039-1043. 
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Ferlay J, Shin H-R, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide 
burden of cancer in 2008: GLOBOCAN 2008. International Journal of Cancer. 
2010;127(12):2893-2917. 
13. 
Ferris RL, Blumenschein G, Jr., Fayette J, et al. Nivolumab for Recurrent Squamous-Cell 
Carcinoma of the Head and Neck. N Engl J Med. 2016;375(19):1856-1867. 
14. 
Hayes DN, Van Waes C, Seiwert TY. Genetic Landscape of Human Papillomavirus–
Associated Head and Neck Cancer and Comparison to Tobacco-Related Tumors. Journal 
of Clinical Oncology. 2015;33(29):3227-3234. 


Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 58 of 73 
 
15. 
He C, Lv X, Hua G, et al. YAP forms autocrine loops with the ERBB pathway to regulate 
ovarian cancer initiation and progression. Oncogene. 2015;34(50):6040-6054. 
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Koyama T, Chen H. Proper inference from Simon's two-stage designs. Stat Med. 
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Martin D, Degese MS, Vitale-Cross L, et al. Assembly and activation of the Hippo 
signalome by FAT1 tumor suppressor. Nat Commun. 2018;9(1):2372. 
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Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 
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Sacco AG, Cohen EE. Current Treatment Options for Recurrent or Metastatic Head and 
Neck Squamous Cell Carcinoma. Journal of Clinical Oncology. 2015;33(29):3305-3313. 
20. 
Shames DS, Carbon J, Walter K, et al. High Heregulin Expression Is Associated with 
Activated HER3 and May Define an Actionable Biomarker in Patients with Squamous Cell 
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21. 
Stein A, Voigt W, Jordan K. Chemotherapy-induced diarrhea: pathophysiology, frequency 
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22. 
Vermorken JB, Stohlmacher-Williams J, Davidenko I, et al. Cisplatin and fluorouracil with 
or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma 
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2013;14(8):697-710. 
23. 
Wang C, Gu C, Jeong KJ, et al. YAP/TAZ-Mediated Upregulation of GAB2 Leads to 
Increased Sensitivity to Growth Factor-Induced Activation of the PI3K Pathway. Cancer 
Res. 2017;77(7):1637-1648. 
24. 
Wheeler DL, Huang S, Kruser TJ, et al. Mechanisms of acquired resistance to cetuximab: 
role of HER (ErbB) family members. Oncogene. 2008;27(28):3944-3956. 
25. 
Zhang J, Ji JY, Yu M, et al. YAP-dependent induction of amphiregulin identifies a non-
cell-autonomous component of the Hippo pathway. Nat Cell Biol. 2009;11(12):1444-1450. 
 
 
 


Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 59 of 73 
 
Appendix 1. 
Investigator Signature 
 
Investigator Signature 
Protocol CDX3379-04 
I confirm that I have read this protocol; I understand it; and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
ICH guidelines for good clinical practices, and the applicable laws and regulations of the country 
of the study site for which I am responsible. I will accept the monitor's overseeing of the study. I 
will abide by the publication plan set forth in the protocol and my agreement with Celldex 
Therapeutics, Inc. I will promptly submit the protocol to applicable ethical review board(s) and 
will not begin the study until regulatory approval has been obtained and all required essential 
documents have been completed. 
 
Instructions to the investigator: Please SIGN and DATE this signature page and PRINT your name.  
Return a completed and signed version to Celldex Therapeutics, Inc., and retain a copy with this 
protocol. 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
 
 
 
Investigator Name (Please Print) 
 
Investigator Title 
 
 
 
 
 
 
 
Name of Facility 
 
Location of Facility 
 
 
(City, State (if applicable), Country) 
 
 


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Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 67 of 73 
 
Table 12: Overall response: patients with target +/–non-target disease 
Target lesions   
Non-target lesions  
New lesions  
Overall response 
CR  
CR  
No  
CR 
CR  
Non-CR/non-PD  
No  
PR 
CR  
Not evaluated  
No  
PR 
PR  
Non-PD or not all evaluated 
No  
PR 
SD  
Non-PD or not all evaluated 
No  
SD 
Not all evaluated 
Non-PD  
No  
NE 
PD  
Any  
Yes or No  
PD 
Any  
PD  
Yes or No  
PD 
Any  
Any  
Yes  
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable. 
 
Table 13. Overall response: patients with non-target disease only 
Non-target lesions 
New lesions  
Overall response 
CR  
No  
CR 
Non-CR/non-PD  
No  
Non-CR/non-PD a 
Not all evaluated  
No  
NE 
Unequivocal PD  
Yes or No  
PD 
Any  
Yes  
PD 
CR = complete response, PD = progressive disease, and NE = inevaluable. 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured 
is not advised. 


Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 68 of 73 
 
FREQUENTLY ASKED QUESTIONS 
What should be done if several unique lesions at baseline become confluent at a follow-up 
evaluation? 
Measure the longest diameter of the confluent mass and record to add into the sum of the longest 
diameters. 
How large does a new lesion have to be to count as progression? Does any small sub-
centimeter lesion qualify, or should the lesion be at least measurable? 
New lesions do not need to meet ‘measurability criteria’ to be considered valid. If it is clear on 
previous images (with the same technique) that a lesion was absent then its definitive appearance 
implies progression. If there is any doubt (because of the techniques or conditions) then it is 
suggested that treatment continue until next scheduled assessment when, generally, all should be 
clear. Either it gets bigger and the date of progression is the date of the first suspicion, or it 
disappears and one may then consider it an artefact with the support of the radiologists. 
How should one lesion be measured if on subsequent exams it is split into two? 
Measure the longest diameter of each lesion and add this into the sum.  
Does the definition of progression depend on the status of all target lesions or only one? 
As per the RECIST 1.1 guideline, progression requires a 20% increase in the sum of diameters of 
all target lesions AND a minimum absolute increase of 5 mm in the sum.  
What is the criterion for a measurable lesion if the CT slice thickness is >5 mm? 
RECIST 1.1 recommends that CT scans have a maximum slice thickness of 5 mm and the 
minimum size for a measurable lesion is twice that: 10 mm (even if slice thickness is <5 mm). If 
scanners with slice thickness >5 mm are used, the minimum lesion size must have a longest 
diameter twice the actual slice thickness. 
What should we record when target lesions become so small they are below the 10 mm 
‘measurable’ size? 
Target lesion measurability is defined at baseline. Thereafter, actual measurements, even if <10 
mm, should be recorded. If lesions become very small, some radiologists indicate they are ‘too 
small to measure’. This guideline advises that when this occurs, if the lesion is actually still present, 
a default measurement of 5 mm should be applied. If in fact the radiologist believes the lesion has 
gone, a default measurement of 0 mm should be recorded 
If a patient has several lesions which have decreased in size to meet PR criteria and one has 
actually disappeared, does that patient have PD if the ‘disappeared’ lesion reappears? 
Unless the sum meets the PD criteria, the reappearance of a lesion in the setting of PR (or SD) is 
not PD. The lesion should simply be added into the sum. If the patients had had a CR, clearly 
reappearance of an absent lesion would qualify for PD. 
When measuring the longest diameter of target lesions in response to treatment, is the same 
axis that was used initially used subsequently, even if there is a shape change to the lesion 
that may have produced a new longest diameter? 
The longest diameter of the lesion should always be measured even if the actual axis is different 
from the one used to measure the lesion initially (or at different time point during follow-up). The 


Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 69 of 73 
 
only exception to this is lymph nodes: as per RECIST 1.1 the short axis should always be followed 
and as in the case of target lesions, the vector of the short axis may change on follow-up. 
Target lesions have been selected at baseline and followed but then one of these target lesions 
then becomes non-evaluable (i.e. different technique used). What is the effect this has on the 
other target lesions and the overall response? 
What may be done in such cases is one of the following:  
(a) If the patient is still being treated, call the center to be sure that future evaluations are done 
with the baseline technique so at least SOME courses are fully evaluable 
(b) If that is not possible, check if there IS a baseline exam by the same technique which was used 
to follow patients...in which case if you retrieve the baseline measures from that technique you 
retrieve the lesion evaluability 
(c) If neither (a) nor (b) is possible then it is a judgement call about whether you delete the lesion 
from all forms or consider the impact of the lesion overall is so important that its being non-
evaluable makes the overall response interpretation inevaluable without it. Such a decision should 
be discussed in a review panel.  
It is NOT recommended that the lesion be included in baseline sums and then excluded from 
follow-up sums since this biases in favor of a response. 
What if a single non-target lesion cannot be reviewed, for whatever reason; does this negate 
the overall assessment? 
Sometimes the major contribution of a single non-target lesion may be in the setting of CR having 
otherwise been achieved: failure to examine one non-target in that setting will leave you unable to 
claim CR. It is also possible that the non-target lesion has undergone such substantial progression 
that it would override the target disease and render patient PD. However, this is very unlikely, 
especially if the rest of the measurable disease is stable or responding. 
A patient has a 32% decrease in sum cycle 2, a 28% decrease cycle 4 and a 33% decrease 
cycle 6. Does confirmation of PR have to take place in sequential scans or is a case like this 
confirmed PR? 
It is not infrequent that tumor shrinkage hovers around the 30% mark. In this case, most would 
consider PR to have been confirmed looking at this overall case. Had there been two or three non-
PR observations between the two time point PR responses, the most conservative approach would 
be to consider this case SD. 
A patient has a lesion measurable by clinical exam and by CT scan. Which should be 
followed? 
CT scan. Always follow by imaging if that option exists since it can be reviewed and verified. 
A lesion which was solid at baseline has become necrotic in the center. How should this be 
measured? 
The longest diameter of the entire lesion should be followed. Eventually, necrotic lesions which 
are responding to treatment decrease in size. In reporting the results of trials, you may wish to 
report on this phenomenon if it is seen frequently since some agents (e.g. angiogenesis inhibitors) 
may produce this effect.  


Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 70 of 73 
 
If I am going to use MRI to follow disease, what is minimum size for measurability? 
MRI may be substituted for contrast enhanced CT for some sites, but not lung. The minimum size 
for measurability is the same as for CT (10 mm) as long as the scans are performed with slice 
thickness of 5mm and no gap. In the event the MRI is performed with thicker slices, the size of a 
measurable lesion at baseline should be two times the slice thickness. In the event there are inter-
slice gaps, this also needs to be considered in determining the size of measurable lesions at 
baseline. 
Can PET–CT be used with RECIST?  
At present, the low dose or attenuation correction CT portion of a combined PET–CT is not always 
of optimal diagnostic CT quality for use with RECIST measurements. However, if your site has 
documented that the CT performed as part of a PET–CT is of the same diagnostic quality as a 
diagnostic CT (with IV and oral contrast) then the PET–CT can be used for RECIST 
measurements. Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed. 
 
Adapted from Eisenhower 2009 (Eisenhauer, et al. 2009) 
 
 


Clinical Protocol CDX3379-04 
Celldex Therapeutics, Inc. 
Amendment 1 (28-Jun-2019) 
CDX-3379 
 
 
Confidential 
Page 71 of 73 
 
Appendix 3. 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
* As published in Am. J. Clin. Oncol (Oken, et al. 1982)  
 
 





SAP_001.pdf: 
CONFIDENTIAL
 
Celldex Therapeutics, Inc.
CDX3379-04
A Phase 2, Multicenter, Open-label Study to Evaluate the 
Efficacy and Safety of CDX-3379 in Combination with 
Cetuximab in Patients with Advanced Head and Neck 
Squamous Cell Carcinoma
Version 1
Statistical Analysis Plan
June 24, 2020 
Prepared by:
 
Statistics Collaborative, Inc. 
© 2020 Statistics Collaborative, Inc.
 




CELLDEX CDX3379-04: STATISTICAL ANALYSIS PLAN
June 24, 2020
Page i
CONFIDENTIAL
Contents
1.
Introduction.......................................................................................................................................1
2.
Study description..............................................................................................................................1
2.1. 
Study design ............................................................................................................................ 1
2.2. 
Study objectives ...................................................................................................................... 2
2.3. 
Study treatments..................................................................................................................... 3
2.4.
Study visits and assessments................................................................................................7
2.5. 
Eligibility ............................................................................................................................... 11
2.6. 
Blinding and measures to minimize bias .......................................................................... 12
3. Analysis populations ...................................................................................................................... 12
3.1.1.
All treated population ............................................................................................ 12
3.1.2.
Response-evaluable population ............................................................................ 12
3.1.3.
Biomarker-evaluable population .......................................................................... 12
4. General conventions and statistical considerations ................................................................... 13
4.1. 
Study centers ......................................................................................................................... 13
4.2. 
Presentation of results.......................................................................................................... 13
4.3. 
Software ................................................................................................................................. 13
4.4. 
Units of time .......................................................................................................................... 14
4.5. 
Study days and duration ..................................................................................................... 14
4.6. 
Visit windows ....................................................................................................................... 14
4.7. 
Baseline .................................................................................................................................. 14
4.8. 
Missing data .......................................................................................................................... 14
4.8.1.
Partial or missing dates .......................................................................................... 14
4.9. 
Sample size determination and power calculation.......................................................... 16
4.10. Censoring............................................................................................................................... 16
4.11. Changes to planned analyses .............................................................................................. 16
5. Study population characteristics .................................................................................................. 17 


CELLDEX CDX3379-04: STATISTICAL ANALYSIS PLAN
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Contents, continued
5.1.
Patient accrual.......................................................................................................................17
5.2.
Patient disposition................................................................................................................17
5.3. 
Protocol violations................................................................................................................ 17
5.4. 
Demographics and baseline characteristics ...................................................................... 18
5.5. 
Prior and concomitant medications ................................................................................... 19
5.6. 
Prior anti-cancer therapies .................................................................................................. 19
6.
Efficacy analyses.............................................................................................................................20
6.1. 
Primary efficacy endpoint ................................................................................................... 21
6.2. 
Secondary efficacy endpoints ............................................................................................. 22
6.2.1.
Duration of response .............................................................................................. 22
6.2.2.
Clinical benefit response ........................................................................................ 23
6.2.3.
Disease control rate ................................................................................................. 23
6.2.4.
Progression-free survival ....................................................................................... 23
6.2.5.
Overall survival ....................................................................................................... 25
6.3. 
Subgroup analyses ............................................................................................................... 26
6.4. 
Handling of dropouts or missing data for the primary and secondary analyses ....... 26
6.5. 
Interim analyses and data monitoring .............................................................................. 26
6.6. 
Multiplicity ............................................................................................................................ 26
7. Safety summaries ............................................................................................................................ 26
7.1. 
Extent of exposure ................................................................................................................ 27
7.2. 
Adverse events...................................................................................................................... 27
7.3. 
Deaths .................................................................................................................................... 28
7.4. 
Vital signs .............................................................................................................................. 28
7.5. 
Electrocardiogram ................................................................................................................ 29
7.6. 
Eastern Cooperative Oncology Group (ECOG) performance status ............................ 29
7.7. 
Clinical laboratory parameters ........................................................................................... 29
8. Biomarker analyses ......................................................................................................................... 32 


CELLDEX CDX3379-04: STATISTICAL ANALYSIS PLAN
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Contents, continued
9.
References........................................................................................................................................32
10. Appendices......................................................................................................................................33
10.1. Estimand framework ........................................................................................................... 33
10.2. ECOG Performance Status .................................................................................................. 35
10.3. RECIST 1.1 criteria................................................................................................................ 35
10.3.1. Measurability of tumor at baseline ....................................................................... 36
10.3.2. Methods of lesion measurement...........................................................................38
10.3.3. Tumor response evaluation ................................................................................... 40


CELLDEX CDX3379-04: STATISTICAL ANALYSIS PLAN
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Exhibits
Exhibit 1.
Study schema.......................................................................................................................4
Exhibit 2.
CDX-3379 dose levels .........................................................................................................5
Exhibit 4. Schedule of assessments .....................................................................................................8
Exhibit 5. Inclusion and exclusion criteria.......................................................................................11
Exhibit 6. Censoring rules ..................................................................................................................24
Exhibit 7.
Study drug parameter definitions ..................................................................................27
Exhibit 8. Clinical laboratory parameters ........................................................................................ 31
Exhibit 9. ECOG Performance Status ...............................................................................................35
Exhibit 10. Overall response: patients with target +/- non-target disease .....................................46
Exhibit 11. Overall response: patients with non-target disease only ............................................. 46
Exhibit 12. Best overall response when confirmation of CR and PR is required .........................47
Tables
Table 1.
Estimand attributes for the primary efficacy analysis .................................................33
Table 2.
Estimand attributes for the important secondary efficacy analysis ........................... 34


CELLDEX CDX3379-04: STATISTICAL ANALYSIS PLAN
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Abbreviations
ADA
anti-drug antibodies
AE
adverse event
ALP
alkaline phosphatase 
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
area under the concentration-time curve
BMI
body mass index
BOR
best overall response
BSA 
body surface area
CBR 
clinical benefit response
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CR
complete response
CT 
computed tomography 
DCR 
disease control rate 
DNA 
deoxyribose nucleic acid 
DOR
duration of response
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
eDISH 
evaluation of drug-induced serious hepatotoxicity
EOT 
End of Treatment
ErbB3
human epidermal growth factor receptor 3
FAT1 
FAT Atypical Cadherin 1 
FNA 
fine needle aspirate 
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HLT 
high level term 
HNSCC
head and neck squamous cell carcinoma
HPV 
human papilloma virus 
ICH
International Conference on Harmonization
INR 
international normalized ratio
IV 
intravenous
 


CELLDEX CDX3379-04: STATISTICAL ANALYSIS PLAN
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Abbreviations, continued
kg
kilogram(s)
KM
Kaplan-Meier
m2
meter squared
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram(s)
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NE
not evaluable
NOTCH
NOTCH family of cell-signaling receptors
ORR 
objective response rate 
OS 
overall survival
PD
progressive disease 
PFS 
progression-free survival 
PI
Principal Investigator
PK 
pharmacokinetic(s) 
PR
partial response 
PR interval 
period from the beginning of the P wave until the beginning of the QRS complex
PT 
preferred term
PTEN
phosphatase and tensin homolog 
QRS interval
combination of the Q wave, R wave, and S wave
QT interval 
period from the beginning of the QRS complex to the end of the T wave 
QTc 
corrected QT interval 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR interval 
time elapsed between two successive R waves 
SAE 
serious adverse event 
SAP
statistical analysis plan
SCI 
Statistics Collaborative, Inc. 
SD
stable disease
SOC 
system organ class 
t½
apparent elimination half-life 
TEAE 
treatment emergent adverse event 
TdP 
torsades de pointes 
WHO 
World Health Organization
 


CELLDEX CDX3379-04: STATISTICAL ANALYSIS PLAN
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Page vii
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Definitions
Adverse event 
An adverse event (AE) is any reaction, side effect, or other untoward 
event, regardless of relationship to study drug, which occurs 
anytime during the study in a patient administered study treatment. 
All treated population
All patients treated with CDX-3379 
Response-evaluable population 
All patients who have measurable disease at baseline and receive 
one full dose of both CDX-3379 and cetuximab and have post-
baseline tumor response assessment or discontinue study 
prematurely for disease progression, symptomatic deterioration, or 
death. 
Serious AE 
An AE occurring at any dose that: results in death; is a 
life-threatening experience; requires inpatient hospitalization or 
prolongation of an existing hospitalization; results in a persistent or 
significant disability/incapacity; or is a congenital anomaly/birth 
defect in the offspring of a patient who received study drug.
Treatment-emergent AE 
AEs with an onset time after the initial dose of study drug.
 
 


CELLDEX CDX3379-04: STATISTICAL ANALYSIS PLAN
June 24, 2020
Page 1
CONFIDENTIAL
1.
Introduction
This statistical analysis plan (SAP) is based on Celldex’s Protocol CDX3379-04 Amendment 1 
[A Phase 2, Multicenter, Open-label Study to Evaluate the Efficacy and Safety of CDX-3379 in 
Combination with Cetuximab in Patients with Advanced Head and Neck Squamous Cell 
Carcinoma], dated June 28, 2019. The SAP summarizes key aspects of the study to provide 
context for statistical methods and presents details of the planned statistical methods 
addressing the study aims. To the extent that analyses described in this SAP differ from those 
described in the protocol, the methods of the SAP prevail. Any deviations to the SAP will be 
documented in the final clinical study report. Pharmacokinetic (PK) data analyses will be 
addressed in a separate analysis plan. 
The statistical principles applied in the design and planned analyses of this study are 
consistent with the International Conference on Harmonization (ICH) guidelines E9 (Statistical 
Principles for Clinical Trials) [1]. 
2.
Study description
2.1.
Study design 
This is an open-label, multicenter Phase 2 study of CDX-3379 in combination with cetuximab 
in patients with cetuximab-resistant head and neck squamous cell carcinoma (HNSCC). In this 
single-arm study, patients will be treated with CDX-3379 plus cetuximab until progressive 
disease, unacceptable toxicity, or other criteria for discontinuation of study treatment are met. 
Prior to Amendment 1 of the protocol, the study was initially designed according to a Simon’s 
2-stage design in which one tumor response (complete response [CR] or partial response [PR]) 
would need to be observed in the first 13 evaluable patients before completion of accrual to a 
total of 27 evaluable patients. Patients who discontinue treatment in the absence of 
progression/symptomatic deterioration/death before the first tumor assessment will be 
considered unevaluable for primary analysis and will be replaced. Following completion of 
stage 1 of the study, where one CR was observed, emerging biomarker data were reviewed to 


CELLDEX CDX3379-04: STATISTICAL ANALYSIS PLAN
June 24, 2020
Page 2
CONFIDENTIAL
assess correlation with efficacy. In the overall CDX-3379 development program, in a small 
patient dataset, FAT Atypical Cadherin 1 (FAT1) and NOTCH1, NOTCH2 and NOTCH3 
mutations appeared to be associated with clinical activity including objective response and 
durable stable disease. 
Given these findings, the study design was amended to enroll up to approximately 45 total 
patients, including at least 15 patients whose tumors harbor a FAT1 mutation based on 
retrospective gene sequencing. Screening tissue samples will be required to be submitted as 
directed by Celldex at the time of enrollment to allow for gene sequencing and tracking the 
number of patients whose tumors harbor a FAT1 mutation. 
Tumor assessments will be performed approximately every six weeks during treatment. 
Patients who discontinue treatment in the absence of progression will continue to have 
assessments approximately every 12 weeks until documented progression or initiation of 
alternate anticancer therapies. The investigator will assess tumor response in accordance with 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines [2] (see Section 10.3). 
Study investigators and Celldex will continuously evaluate adverse events (AEs) throughout 
the entire course of patient treatment and through 30 days following the last dose of 
CDX-3379. For AEs or serious adverse events (SAEs) with a causal relationship to the 
investigational product, follow-up is required until the event or its sequelae resolve to 
 grade 1 or stabilize for at least three months after the last administration of study treatment 
(whichever is sooner). Subsequently, patients will be followed for survival, with contact every 
12 weeks until study closure. 
2.2.
Study objectives 
The primary objective of this study is to estimate the objective response rate (ORR) for the 
combination of CDX-3379 and cetuximab in patients with cetuximab-resistant advanced 
HNSCC. 
 


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The secondary objectives of this study are as follows:  
To estimate the clinical benefit response (CBR), duration of response (DOR), 
progression-free survival (PFS), and overall survival (OS) for patients with 
cetuximab-resistant advanced HNSCC treated with CDX-3379 in combination with 
cetuximab. 
To evaluate the safety of CDX-3379 in combination with cetuximab. 
To evaluate the pharmacokinetics (PK) of CDX-3379 in combination with cetuximab. 
To evaluate the anti-drug antibodies (ADA)/immunogenicity of CDX-3379 in 
combination with cetuximab. 
To evaluate tumor deoxyribose nucleic acid (DNA) biomarkers for CDX-3379 in 
combination with cetuximab and assess correlation with efficacy. 
 
 
 
2.3.
Study treatments 
Patients will be treated with CDX-3379 plus cetuximab until progressive disease, unacceptable 
toxicity, or other criteria for discontinuation of study treatment.  
A cycle is defined as 21 days. The dose of CDX-3379 is 12 mg/kg, with the option to increase 
the dose to 15 mg/kg if tolerated, delivered via intravenous (IV) infusion over 60 minutes. 
CDX-3379 will be administered every 3 weeks (on Day 1 of each 21-day cycle). 
Cetuximab will be dosed with an initial loading dose of 400 mg/m2 on Day 1 over 2 hours, 
followed by weekly doses of 250 mg/m2 over 60 minutes. Patients who were previously treated 
with cetuximab within three months of study enrollment and required dose reduction due to 
adverse events attributed solely to cetuximab (e.g., rash) may initiate cetuximab at the same 
dose as was last received in the prior regimen, with or without an initial loading dose, as 
clinically appropriate. Cetuximab will be administered on Days 1, 8, and 15 of each 21-day 
 
 
 
 
 
 


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cycle. On Day 1 of each cycle, cetuximab should be administered approximately one hour after 
the completion of CDX-3379 infusions (and after completion of PK sampling). 
As a routine precaution, the investigative site's medical staff is to closely observe patients for 
the duration of the cetuximab and CDX-3379 infusions and for at least one hour after the end 
of the infusions. 
Exhibit 1. Study schema
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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2.4.
Study visits and assessments
The study is divided into three periods: Screening, Treatment, and Post-Treatment Follow-up. 
Exhibit 4 summarizes the specific procedures that must be performed at specific time points 
during each period. 
The three periods are defined as follows: 
Screening: Day -28 to Day -1. Patients who are screened but do not meet all entry 
criteria (i.e., screen failures) will not be entered in the clinical database. 
Treatment: Cycle 1 Day 1 to End of Treatment (EOT). The EOT Visit should be 
performed as soon as feasible following the decision to discontinue study drug 
dosing and prior to initiation of alternate therapies.
Post-Treatment Follow-up: 30 days post-EOT to study closure. 
 
 
 
 








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2.5.
Eligibility
Patients must meet all of the inclusion criteria in Exhibit 5 prior to receiving study treatment to be included in the study. 
Exhibit 5. Inclusion and exclusion criteria
Inclusion criteria 
Exclusion criteria
Read, understood, and provided informed 
consent 
Eighteen years of age or older 
Histologically or cytologically confirmed 
HNSCC that is recurrent or metastatic, not 
curable with local treatment modalities, and 
progressive during or subsequent to last therapy 
Human papilloma virus (HPV) negative tumor 
Prior treatment must include: a check-point 
inhibitor targeting programmed death receptor-1 
axis, unless not a candidate, and cetuximab with 
tumor progression during or within six months 
after completing treatment 
Measurable disease by RECIST 1.1 criteria 
Willingness to consent for tumor biopsy from an 
accessible site prior to initiating study therapy 
All residual toxicity related to prior radiotherapy 
or anticancer therapies must resolve to Grade 1 
severity or less prior to receipt of study treatment
Adequate electrolytes, liver, renal, and 
hematology function (see protocol for precise 
definition) 
 
Eastern Cooperative Oncology Group (ECOG) 
Performance Status of 0 or 1 
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 or cetuximab 
Nasal, paranasal sinus, or nasopharyngeal carcinoma, aside from World Health Organization (WHO) Type I and 
II nasopharyngeal carcinoma 
Received CDX-3379 or other anti-human epidermal growth factor receptor 3 (ErbB3) targeted agents previously 
Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment 
Other prior malignancy active within three years (see protocol for exceptions) 
Known brain metastases, unless previously treated and asymptomatic for two months and not progressive in size 
or number for two months prior to enrollment  
Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection, or active infection requiring 
systemic IV therapy  
Use of any monoclonal based therapies within four weeks, excluding cetuximab, and all other immunotherapy 
within two weeks, prior to the first dose of study treatment 
Chemotherapy within 21 days or at least 5 half-lives prior to the planned start of study treatment  
Major surgery within four weeks prior to the first dose of study treatment 
Use of other investigational drugs within two weeks or five half-lives prior to study treatment administration 
A marked baseline prolongation of QT/corrected QT (QTc) interval; additional risk factors for torsades de pointes 
(TdP); the use of concomitant medications that prolong the QT/QTc interval; significant cardiovascular disease; or 
any of the following within six 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 
Requirement for chronic immunosuppressive medication
Any other acute or chronic medical or psychiatric condition or laboratory abnormality that could increase the risk 
associated with trial participation 
Known alcohol or drug abuse 
Women who are pregnant or nursing
Known allergy or past administration reaction including infusion reactions, anaphylactic, or anaphylactoid 
reactions to any component of the CDX-3379 formulation 
Prior history of clinically significant hypersensitivity reaction or significant intolerance to cetuximab; history of 
allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.6.
Blinding and measures to minimize bias
This is non-randomized open-label study. The analysis of tumor response and 
progression-free survival (PFS) will be based on tumor response assessments performed by the 
investigator according to standardized, objective response criteria (RECIST 1.1). In addition, in 
the event of a positive study outcome, an additional assessment of tumor response and 
progression may be performed by an independent review committee blinded to investigator 
assessments. 
3.
Analysis populations
3.1.1.
All treated population 
All patients treated with CDX-3379. The primary and secondary efficacy analyses as well as all 
safety and biomarker analyses will be performed in this population. 
3.1.2.
Response-evaluable population 
All patients who have (a) measurable disease at baseline, (b) receive one full dose of both 
CDX-3379 and cetuximab, and (c) have post-baseline tumor response assessment or 
discontinue study prematurely for disease progression, symptomatic deterioration, or death. 
Patients who discontinue treatment prior to the first tumor assessment for other reasons will 
be excluded from this population. Sensitivity analyses for efficacy endpoints will be performed 
in this population. 
3.1.3.
Biomarker-evaluable population 
All patients who have a biomarker result for the biomarker analysis of interest, e.g., FAT1 or 
NOTCH or both. 


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4.
General conventions and statistical considerations
4.1.
Study centers
A study center is defined as a treatment administration site or group of such sites under the 
control and supervision of the same Principal Investigator (PI). This study is being conducted 
at approximately 10-15 study centers. Given that the study has many investigative sites 
relative to the number of randomized patients, analyses will not be stratified by site. All sites 
use the same protocol, entry criteria, data collection methods, and endpoints; sites are 
monitored to verify compliance with the protocol. According to Meinert [3] these criteria 
justify pooling results across centers. 
4.2.
Presentation of results 
Descriptive statistics will summarize results. Unless otherwise stated, confidence intervals 
(CIs) will be computed using a two-
5 level of significance.  
Standard descriptive statistics, such as mean, standard deviation, median, quartiles, minimum, 
and maximum, will be calculated for continuous variables. For discrete variables, descriptive 
analyses will be based on numbers of patients and related percentages of patients with 
non-missing data. Unless otherwise specified, tables and figures will present such descriptive 
statistics for both the observed values and change at each scheduled visit. 
Medical history and AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA®). Prior and concomitant medications will be coded using World Health 
Organization Drug (WHO) Global dictionary. 
In addition to tabular summaries, by-patient listings will present all relevant electronic case 
report form (eCRF) data. 
4.3.
Software 
All data listings, summaries, figures, and statistical analyses will be generated using SAS 
Version 9.4 or higher [4] or other validated software. 
 
 


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4.4.
Units of time
The following conversion factors will be used to convert days to months or years: 
1 month  
 
4.5.
Study days and duration 
For the purpose of the analysis, study day will be calculated relative to Cycle 1 Day 1. Cycle 1 
Day 1 is the planned time point for the first dose administration.  
– First 
Dose 
– First Dose 
Date. By this convention, there is no Study Day of zero. 
For duration calculations requiring 
– Start Date + 1. 
DOR, PFS, and OS will be presented in months. 
4.6.
Visit windows 
The planned analyses do not require visit window calculations. 
4.7.
Baseline 
Unless otherwise noted, baseline is defined as the last non-missing measurement recorded 
prior to the date and time of the first dose of study treatment. Measurements taken once per 
visit will be assumed to occur prior to dosing unless otherwise specified. Unscheduled visits 
will be used in the determination of baseline values, when applicable. 
4.8.
Missing data 
4.8.1.
Partial or missing dates 
Missing and partial date or time data will be handled using endpoint-specific procedures 
detailed as follows. The imputed dates must be logical, e.g., ensuring that no end date is after 
database lock, after death, or before the start date. 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 


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If date of response is completely missing or the day and month are missing, date of response 
will not be imputed. If response year and month are present and day is missing, the response 
day is the first day of the month. 
If date of progression is completely missing or the day and month are missing, date of 
progression will not be imputed. If progression year and month are present and day is 
missing, the progression day is the first day of the month. If death date is present, the 
minimum of the imputed progression date and date of death will be considered as the date of 
progression. 
Timing of observations relative to dosing will rely on time point labels in the case of vital 
signs, electrocardiograms (ECGs), and PK/biomarker blood samples, and will otherwise be 
assumed to be prior to infusion of study drug. Hence, missing first dose times will not be 
imputed. 
If date of prior diagnosis or prior treatment start is complete missing, the date will not be 
imputed. If year is present and month and day are missing, the month and day are July 1. If 
month and year are present and day is missing, the day is the 15th of the month. If imputed 
date is on or after the first dose date, the date will be set to the day before the date of first dose. 
If AE onset date is completely missing, the date is set to the date of first dose. If year is present 
and month and day are missing: 
If 
 
If year > year of first dose, then month and day is January 1. 
If month and year of AE onset date are present and day is missing: 
 
o
th of first dose, then day is the day of first dose date. 
o
month > month of first dose, then day is the first day of month. 
If year > year of first dose, then day is the first day of month. 
For all other cases, the date is the date of first dose. 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
  
 
 
 
 
 


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If year of AE end date is present and month and day are missing, the month and day is 
December 31. If month and year of AE end date are present and day is missing, the day is the 
last day of the month. If the event is fatal, the date is the minimum of the imputed end date 
and the death date. For all other cases, the date is missing and the event is considered ongoing. 
If concomitant medication start date is completely missing, the start date will not be imputed. 
If start year is present and month and day are missing, the start month and day is January 1. If 
start year and month are present and day is missing, the start day is the first day of the month. 
If end date is completely missing, the end date will not be imputed. If end year is present and 
month and day are missing, the end month and day is December 31. If end year and month are 
present and day is missing, the end day is the last day of the month. 
4.9.
Sample size determination and power calculation 
The original sample size for the study was based on Simon’s 2-stage MinMax design. The first 
stage was completed, and the futility stopping rule was not met. Protocol Amendment 1 
increased the total sample size from 30 to approximately 45 treated patients, including at least 
15 patients whose tumors harbor a FAT1 mutation based on retrospective gene sequencing. 
According to the protocol, the planned sample size of 45 treated patients provides >80% power 
to rule out <20% ORR based on the lower 95% confidence bound for the for different 
underlying true response rates 
 
The cohort size of 15 treated patients in the FAT1 mutation-positive cohort provides nearly 
 
4.10.
Censoring 
Censoring methods for the primary and secondary efficacy endpoints are outlined in Section 6. 
4.11.
Changes to planned analyses 
Changes to the analyses described in this plan will be fully documented in a revised version of 
the plan prior to locking the study database and conducting the primary efficacy analysis. 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
  
 


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5.
Study population characteristics
5.1.
Patient accrual 
Patient accrual will be presented as the number and percentage of patients enrolled at each 
study center. 
5.2.
Patient disposition 
The number and percentage of patients will be presented for each of the following:  
Treated 
Response-evaluable 
Reason for not being response-evaluable 
Biomarker evaluable 
Discontinued study treatment  
Reason for treatment discontinuation 
Discontinued the study 
Reason for study discontinuation (including study completion) 
Survival status 
Cause of death 
5.3.
Protocol violations 
Deviations from the eligibility criteria and on-study requirements that affect the interpretation 
of primary and secondary efficacy and safety outcomes will be considered important protocol 
deviations. (Note: ICH E3 defines “important protocol deviations” as a subset of protocol 
deviations that might significantly affect the completeness, accuracy, and/or reliability of the 
study data or that might significantly affect a patient’s rights, safety, or well-being). These 
protocol deviations will be identified through manual clinical reviews and recorded separately 
for inclusion in the clinical study report. 
 
 
 
 
 
 
 
 
 
 


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Important protocol deviations will be determined by medical review prior to database lock. 
5.4.
Demographics and baseline characteristics 
Patient demographics and baseline characteristics will be summarized for the all treated 
population. Information to be summarized includes age in years, categorical age (<
-<75, 
 years), gender, race, ethnicity, height (in meters), and weight (in kilograms). Age will be 
calculated in years relative to the informed consent date. 
Other baseline characteristics include medical and surgical history, cancer history, and disease 
characteristics. Descriptive statistics will be presented for age, height, weight, body mass index 
(BMI; in kg/m2), categorical BMI (<25, 25 -
2) and the following intervals relative 
to first dose date: 
Time since initial diagnosis 
Time since initial advanced disease 
Time since initial metastatic disease 
Time since last progression 
Frequency counts and percentages will be presented for sex, ethnicity, race, and other baseline 
characteristics to include: 
Stage at initial diagnosis 
Number of prior relapses 
Stage at study entry 
Prior treatment with PD-1 
Prior treatment with cetuximab 
Metastasis staging at study entry 
Mutations or other relevant tumor aberrations 
Baseline human papillomavirus (HPV) status 
The number and percentage of patients in each of the following subgroups will be presented: 
FAT1 mutation-positive treated patients, FAT1 or NOTCH mutation-positive treated patients, 
and all treated patients with a primary tumor site of oral cavity.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.5.
Prior and concomitant medications
Prior and concomitant medication verbatim terms on eCRFs will be coded to Anatomical
Therapeutic Chemical (ATC) class and Preferred Names using the WHODrug Global 
dictionary. The dictionary will be up-versioned to the most current version available, as 
feasible, prior to database lock. 
Prior medications are those medications taken within 28 days prior to the initial dose of study 
drug, with the exception of prior anti-cancer therapies. Prior anti-cancer therapies will be 
included regardless of their timing relative to first dose. Concomitant medications are those 
medications taken after the initial dose of study drug. A medication can be classified as both 
prior and concomitant. If it cannot be determined whether the medication was a prior (or 
concomitant) medication due to a partial start or stop date then it will be counted as both. 
Prior and concomitant medications will be summarized by WHO ATC class and Preferred 
Name. These summaries will present the number and percentage of patients using each 
medication. Patients may have more than one medication per ATC class and Preferred Name. 
At each level of patient summarization, a patient is counted once if he/she reported one or 
more medications at that level. Each summary will be ordered by descending order of 
incidence of ATC class and Preferred Name within each ATC class. 
5.6.
Prior anti-cancer therapies 
The number and percentage of patients who underwent prior cancer-related surgery, 
radiation, and systemic therapies will be summarized. Prior systemic therapy regimens will be 
categorized and presented by WHODrug Preferred Name and summarized as: 
The number and percentage of prior systemic cancer therapy regimens (1, 2, 3, 4, 5 or 
more), 
The number and percentage of prior systemic cancer therapy regimens in the 
advanced/metastatic setting, and 
Types of prior systemic cancer therapies of interest, as categorized by medical 
review. 
 
 
 


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The best response (CR, PR, stable disease [SD], progressive disease [PD], or unknown) to the 
most recent prior regimen will be presented in addition to the reason for discontinuing. 
6.
Efficacy analyses
To support calculation of ORR, CBR, DOR, and PFS, tumor assessments will be performed 
approximately every six weeks during treatment. Patients who discontinue treatment in the 
absence of progression will continue to have assessments approximately every 12 weeks until 
documented progression or initiation of alternate anti-cancer therapies. The investigator will 
assess tumor response in accordance with RECIST 1.1 guidelines [2] (see Section 10.3). The 
investigator will record the overall response at each timepoint (CR, PR, SD, PD, or NE) as well 
as the date of first response (CR or PR) and date of PD. Best overall response (BOR) will be 
derived from timepoint responses per RECIST 1.1 guidelines. 
The efficacy analyses will be conducted within the estimand framework. The details are 
provided in Appendix 10.1. 
The primary analysis is planned upon achievement of complete data for ORR, i.e., after all 
treated patients have been followed for at least six months after receiving their first dose of 
study treatment or after all patients have discontinued study treatment, whichever occurs 
sooner. 
Following the primary analysis, study follow-up will continue until adequate data are 
available to support secondary analyses. 
The primary efficacy analysis will be based on the all treated population. Additional 
supportive efficacy analyses will be performed using the FAT1 mutation-positive treated 
patients, FAT1 or NOTCH mutation-positive treated patients, and all treated patients with a 
primary tumor site of oral cavity. A patient is considered NOTCH mutation-positive if they 
express a mutation in any one of the NOTCH family genes (NOTCH1, NOTCH2, or 
NOTCH3). 


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If more than five patients have a dose delay that impacts the timing of tumor assessments, 
additional analyses may be performed to assess the impact of delayed treatment and tumor 
assessment schedule on duration of response and PFS. 
6.1.
Primary efficacy endpoint 
The primary efficacy endpoint of this study is ORR, defined as the percentage of patients who 
achieve a best response of CR or PR, confirmed according to RECIST 1.1. That is, the criteria 
for response (CR or PR) must be met again at the next scheduled tumor assessment no sooner 
than 28 days after the initial documentation. Best response is recorded between the date of first 
dose and the date of documented progression per RECIST 1.1 or the date of subsequent anti-
cancer treatment, whichever occurs first. Anti-cancer treatment includes (a) systemic anti-
cancer therapy or (b) radiation or surgical resection of a target or non-target lesion. All anti-
cancer treatments will be reviewed and confirmed by the Celldex medical team. For patients 
without documented progression or subsequent anti-cancer treatment, all available tumor 
assessments will contribute to the best response assessment. 
The number and percentage of patients in each category of BOR (CR, PR, SD, PD, or not 
evaluable [NE]) will be summarized for the all treated population. ORR will be calculated as 
defined above, and the corresponding two-sided 95% exact CI will be calculated using the 
Clopper-Pearson method. 
A waterfall plot showing the maximum change from the baseline sum of the diameters of 
target lesions will be produced for the response-evaluable population. Subgroup waterfall 
plots may be produced. 
A swimmer plot will be produced to present individual patient’s tumor response and duration 
of response over time. 
A spider plot will be produced to present change in an individual patient’s tumor size with 
tumor size relative to baseline plotted against month from baseline scan; new lesion and end 
of treatment dates will be annotated in the plot. Subgroup spider plots may be produced. 


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Change from baseline in tumor size will be calculated as: Sum of diameters at Week X (mm) – 
Sum of diameters at Baseline (mm). Percent change from baseline in tumor size will be 
calculated as: (Sum of diameters at Week X (mm) – Sum of diameters at Baseline (mm)) / Sum 
of diameters at Baseline (mm) * 100%. 
All primary and secondary efficacy outcomes (BOR, DOR if applicable, date of PD if 
applicable, PFS status, and OS status) will be presented in a single by-patient listing. 
Individual timepoint assessment data for each lesion will be presented in a separate listing. 
6.2.
Secondary efficacy endpoints 
6.2.1.
Duration of response 
DOR is defined as the interval from which measurement criteria are first met for CR or PR 
until the first date that progressive disease is objectively documented or death, whichever 
occurs first. Patients who have not progressed or died will be censored on the date of last 
evaluable tumor assessment; patients who did not have any on-study assessments and have 
not died will be censored on the date of first dose. If a patient receives subsequent anti-cancer 
treatment before documented progression, then DOR will be censored on the last evaluable 
tumor assessment on or before initiation of subsequent anti-cancer treatment. The censoring 
rules are outlined in Exhibit 6. 
DOR will be estimated in the all treated population using the Kaplan-Meier (KM) product 
limit method and displayed graphically. The KM estimate of the median DOR and the 
corresponding two-sided 95% CI, calculated using the Brookmeyer and Crowley’s method 
(log-log transformation), will be presented. 
Time to response, defined as the time from first dose date to the date of first confirmed 
response (CR or PR), will also be estimated in the all treated population using the 
Kaplan-Meier (KM) product limit method. The KM estimate of the median time to response 
and the corresponding two-sided 95% CI, calculated using the Brookmeyer and Crowley’s 
method (log-log transformation), will be presented alongside DOR. 


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6.2.2.
Clinical benefit response 
CBR, defined as the percentage of patients who achieve a best response of confirmed CR or 
PR, or SD for at least 12 weeks. Best response is assessed as described for ORR. 
CBR will be calculated in the all treated population as defined above, and the corresponding 
two-sided 95% exact CI will be calculated using the Clopper-Pearson method. 
6.2.3.
Disease control rate 
Disease control rate (DCR), defined as the percentage of patients who achieve a best response 
of confirmed CR or PR, or SD. Best response is assessed as described for ORR. 
DCR will be calculated in the all treated population as defined above, and the corresponding 
two-sided 95% exact CI will be calculated using the Clopper-Pearson method. 
6.2.4.
Progression-free survival 
PFS is defined as the time from the start of study treatment to the time of progression or death, 
whichever occurs first. Patients who have not progressed or died will be censored on the date 
of last evaluable tumor assessment; patients who did not have any on-study assessments and 
did not die will be censored on the date of first dose. If a patient receives subsequent anti-
cancer treatment before documented progression, then PFS will be censored on the last 
evaluable tumor assessment on or before initiation of subsequent anti-cancer treatment. The 
censoring rules are outlined in Exhibit 6. 


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Exhibit 6. Censoring rules
Situation 
Date of Event or Censoring 
Outcome 
Progression 
Date of progression 
Event 
Death without progression
Date of death
Event
No baseline disease assessment 
Date of first dose 
Censored 
No on-study disease assessments and no death 
Date of first dose 
Censored 
No progression and no death 
Date of last evaluable tumor 
assessment 
Censored 
Subsequent anti-cancer therapy before 
documented progression 
Date of last evaluable tumor 
assessment on or before initiation of 
subsequent anti-cancer therapy 
Censored 
PFS will be estimated in the all treated population using the KM product limit method and 
displayed graphically. The KM estimate of the median PFS and the corresponding two-sided 
95% CI, calculated using the Brookmeyer and Crowley’s method (log-log transformation), will 
be presented. 
The number and percentage of patients with an event and the type of event (progression or 
death) will be summarized. The status of patients who are censored in the PFS KM analysis 
will be presented using the following categories: 
No baseline or inadequate baseline assessment 
No post-baseline or death before first scheduled assessment 
Received additional anti-cancer therapy 
 
Alive and without disease progression 
The KM estimates of the median PFS rate at 3 months and 6 months will be presented with the 
corresponding 95% CIs. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2.4.1. Subsequent therapy
The number and percentage of patients receiving subsequent cancer therapies will be 
summarized by the type of therapy as reported on the eCRF (radiotherapy, cancer medication, 
other anti-cancer treatment, biopsy, resection, or other surgery). Biopsies will not be 
considered for censoring purposes. 
A by-patient listing of subsequent therapy will be produced for patients who had any 
subsequent therapy. 
6.2.5.
Overall survival 
OS is defined as the time from the start of study treatment to the time of death. Patients who 
have not died will be censored on the last known alive date. 
OS will be estimated in the all treated population using the KM product limit method and 
displayed graphically. The KM estimate of the median OS and the corresponding two-sided 
95% CI, calculated using the Brookmeyer and Crowley’s method (log-log transformation), will 
be presented. 
The number and percentage of patients with an event will be summarized. The status of 
patients who are censored in the OS KM analysis will be presented using the following 
categories: 
Alive 
Lost to follow-up 
Withdrawal of consent 
Study closure 
The KM estimates of the median OS rate 6 months, 9 months, 12 months, and 18 months will 
be presented with the corresponding 95% CIs. 
 
 
 
 


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6.3.
Subgroup analyses 
The primary and secondary efficacy analyses will be repeated for each of the following 
subgroups using the methods described in Sections 6.1 and 6.2:  
FAT1 mutation status (positive vs. negative) among treated subjects who have 
evaluable FAT1 results 
FAT1/NOTCH mutation status (positive for either FAT1 or NOTCH vs. negative for 
both) among treated subjects who have evaluable FAT1 and NOTCH results 
Primary tumor site (oral cavity vs. other) in all treated subjects 
Specifically, the number and percentage of patients in each category of BOR will be 
summarized for each subgroup. The estimates of ORR, CBR, and DCR and the corresponding 
two-sided 95% exact CIs for each subgroup will be presented in forest plots for each endpoint.  
DOR, PFS, and OS will be estimated in each subgroup using the KM product limit method and 
displayed graphically with the estimated median and two-sided 95% CI. The median estimates 
for each subgroup will also be presented in forest plots. 
6.4.
Handling of dropouts or missing data for the primary and secondary analyses 
No imputations will be made for missing values. Summaries will be based on observed data 
only. 
6.5.
Interim analyses and data monitoring 
There are no planned interim analyses for this study. 
6.6.
Multiplicity 
No adjustments for multiplicity will be made in this study. 
7.
Safety summaries
All safety analyses will be based on the all treated population. 
 
 
 


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7.1.
Extent of exposure
Study drug exposure will be summarized for the all treated population. Summaries will be 
separated for CDX-3379 and cetuximab. Summaries will include the number of infusions per 
patient as well as cumulative dose received, relative dose intensity, and duration of treatment. 
These parameters are defined in Exhibit 7. 
Exhibit 7. Study drug parameter definitions
CDX-3379 
Cetuximab 
Dosing schedule per protocol 
12 mg/kg every 3 weeks, with 
option to increase to 15 mg/kg 
400 mg/m2 IV (loading dose) once, 
then 250 mg/m2 weekly
Dose 
Dose (mg/kg) is defined as total 
dose administered (mg)/most 
recent weight (kg). 
Dose (mg/m2) is defined as total 
dose administered (mg)/most 
recent body surface area (BSA) 
(m2). 
Cumulative dose 
Cumulative dose (mg/kg) is the 
sum of the doses administered to a 
patient. 
Cumulative dose (mg/m2) is the 
sum of the doses administered to a 
patient. 
Dose intensitya 
Cumulative dose / [(Last dose date 
- first dose date + 21)/7] 
Cumulative dose - first dose / 
[(Last dose date - second dose date 
+ 7)/7] 
Relative dose intensity (%)b 
(Dose intensity/4 mg/kg/wk)*100
(Dose intensity/250 mg/m2/wk)*100
Duration of treatment (weeks)
(Last dose date - First dose date)/7
(Last dose date - First dose date)/7
a. Dose intensity reported in mg/kg/wk for CDX-3379 and mg/m2/week for cetuximab. Dose intensity for 
cetuximab starts at the second dose. 
b. Relative dose intensity for cetuximab starts at the second dose.
Dose delays will be summarized as the number of patients with at least one delay, the number 
of doses delayed per patient, and the reason for the delay. 
 
 
 
7.2.
Adverse events 
Adverse events will be coded by MedDRA and summarized by system organ class (SOC), high 
level term (HLT), and preferred term (PT), and worst National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE version 5.0) grade per patient. If a 


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patient reports more than one AE that was coded to the same SOC, HLT, or PT, the patient 
will be counted only once for that specific SOC, HLT, or PT. 
Investigators will assess the relationship of each adverse event to each study drug. The 
relationship of each adverse event to study drug will be categorized as unrelated or related. If 
attribution is missing, the event will be assumed to be related to study drug. 
All AE tables and listings will summarize treatment-emergent adverse events (TEAEs) defined 
as adverse events with onset on or after the date or the first dose of study drug or onset prior 
to the first dose of study drug but with worsened severity post-treatment. AEs without a 
severity rating that are reported post-treatment will be considered treatment-emergent. 
Presentations will include all adverse events through the 30 days following the last dose date. 
The following TEAEs will be presented by severity: 
Serious adverse events 
All adverse events 
Adverse events related to CDX-3379 
Adverse events related to cetuximab, and 
Adverse events leading to study discontinuation. 
All adverse events will be listed with MedDRA coding, onset and resolution dates, duration, 
seriousness, severity, relationship, actions, and outcome. 
7.3.
Deaths 
The number of patients who died will be summarized in a by-patient listing of deaths 
including death date, cause of death, and relationship to study treatment. 
7.4.
Vital signs 
Vital signs (weight, blood pressure, pulse rate, temperature, and respiratory rate) are collected 
according to the schedule in Exhibit 4 and categorized according to time point label. Patients 
will be monitored during and after infusion of CDX-3379 and cetuximab with assessment of 
 
 
 
 
 


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vital signs within 30 minutes pre-infusion, at 30 minutes during the infusion, within 5 minutes 
post-infusion, and as clinically indicated during the 1-hour post-treatment observation period. 
When cetuximab is administered over two hours, vital signs should additionally be assessed at 
60 minutes and 90 minutes during the infusion.  
For each vital sign parameter, summary statistics on the analysis value and change from 
baseline will be calculated by time point within each scheduled assessment. Pre-infusion 
values will be presented for by-visit reporting in tables and figures.  
7.5.
Electrocardiogram 
Electrocardiogram (ECG) is administered according to the schedule in Exhibit 4 to collect heart 
rate, PR interval, RR interval, QRS interval, QT interval, and QTcF both pre- and post-infusion. 
For each ECG parameter, summary statistics on the analysis value and change from baseline 
will be calculated by time point within each scheduled assessment. Pre-infusion values will be 
presented for by-visit reporting in tables and figures. In addition, a by-visit shift table of pre- 
vs. post-infusion values will be presented. 
7.6.
Eastern Cooperative Oncology Group (ECOG) performance status 
ECOG performance status will be assessed at Screening, on Day 1 of each cycle, and at EOT. 
Shift from baseline to worst post-baseline value will be presented. Further details on the 
ECOG assessment can be found in Appendix 10.2. 
7.7.
Clinical laboratory parameters 
Laboratory tests are conducted according to the schedule in Exhibit 4. For each quantitative, 
laboratory parameter (Exhibit 8) and scheduled visit, summary statistics on the analysis value 
and the change from baseline will be calculated and presented in SI units. If multiple records 
are available for a parameter on the same date, the results will be averaged to calculate the 
analysis value for reporting. Select laboratory parameters will be graded based on NCI 
CTCAE v5.0, and the shift from baseline to worst post-baseline grade will be presented. 


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Liver function test (ALT, AST, total bilirubin, and alkaline phosphatase [ALP]) elevations will 
be presented in categories relative to the upper limit of normal to identify potential cases of 
drug-induced liver injury. An evaluation of drug-induced serious hepatotoxicity (eDISH) plot 
that includes all pairs of ALT and total bilirubin values at scheduled and unscheduled 
assessments will also be presented. 
All clinically significant abnormalities in laboratory values will be presented in a data listing. 
Urinalysis results will not be summarized but will be provided in a data listing. 


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Exhibit 8. Clinical laboratory parameters
Clinical chemistry 
Hematology & 
differential panel
Coagulation panel 
Urinalysis 
Thyroid function
Sodium 
Hemoglobin 
Prothrombin time (PT) 
Protein 
Thyroid stimulating 
hormone (TSH)
Potassium 
Hematocrit 
Activated partial 
thromboplastin time 
(aPTT) 
Glucose 
Free T4 
Chloride 
Mean corpuscular
volume (MCV)
International 
normalized ratio (INR)
Specific 
gravity
Free T3
Bicarbonate 
Erythrocyte count 
(RBC)
Blood
Glucose
Platelets
 
 
Blood urea nitrogen
Leukocytes (WBC)
 
 
Creatinine 
Neutrophil bands 
 
 
Calcium 
Absolute 
neutrophils
 
 
Magnesium 
Absolute 
lymphocytes 
 
 
Phosphate 
Absolute 
monocytes 
 
 
Alkaline 
phosphatase (ALP) 
Absolute 
eosinophils 
 
 
 
Alanine 
transaminase (ALT) 
 
 
 
Aspartate 
transaminase (AST) 
 
 
 
Total protein
 
 
Albumin 
 
 
Lactate 
dehydrogenase 
 
 
 
Total bilirubin
 
 
 
Uric acid
 
 
 
Amylase
 
 
Lipase 
 
 
Table created manually.


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8.
Biomarker analyses
DNA sequencing will be conducted on pre-treatment tumor samples to assess for mutations in 
cancer-related genes such as FAT1, NOTCH1, NOTCH2, NOTCH3, AKT/PI3K, phosphatase 
and tensin homolog (PTEN) and/or ErbB family members. 
Blood samples for biomarker analyses will be collected pre-infusion of CDX-3379, immediately 
after infusion, 60 minutes post-infusion on Day 1 of each cycle, and prior to cetuximab dosing 
on Days 8 and 15 of Cycle 1.  
Baseline biomarker data for the subgroups of interest (FAT1 or NOTCH or both) will be 
summarized descriptively and any correlation with efficacy endpoints will be investigated as 
described in Section 6.3. 
 
 
9.
References
1.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. Statistical principles for clinical trials (E9). 
International Conference on Harmonization; 1998. 
2.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.  
3.
Meinert, C. Clinical Trials: Design, Conduct, and Analysis. New York: Oxford University 
Press, 1986. 
4.
SAS, Version 9.4, Cary NC: SAS Institute; 2013. 
5.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 


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10.
Appendices
10.1.
Estimand framework
A summary of the attributes of the primary estimand is provided in Table 1.
Table 1.
Estimand attributes for the primary efficacy analysis
Estimand attribute
Description of attribute
Target population
All treated population: All patients treated with CDX-3379.
Primary patient-level variable 
Best overall response (BOR) according to RECIST 1.1. 
Patients can have a BOR of complete response (CR), partial 
response (PR), stable disease (SD), progressive disease 
(PD), or unknown. 
Handling of intercurrent events 
Alternative anti-cancer therapies will be intercurrent events 
in the determination of BOR. Assessments that occur after 
the date of documented progression per RECIST 1.1. or the 
date of anti-cancer treatment, whichever occurs first, will 
not contribute to the determination of BOR.  
Population-level summary 
ORR, defined as the percentage of patients who achieve a 
best response of CR or PR, confirmed according to RECIST 
1.1., for all patients treated with CDX-3379 in combination 
with cetuximab. 
The trial product estimand is defined as ORR based on assessments on or prior to the date of 
PD or data of anti-cancer therapy, whichever occurs first. Patients who discontinue study 
therapy for reasons other than progression will continue to have tumor assessments until 
disease progression or initiation of subsequent anti-cancer therapy, whichever occurs first. 
Therefore, treatment discontinuation is not considered an intercurrent event. The primary 
efficacy analysis will be an estimation analysis for this estimand (point estimate of ORR and 
associated 95% confidence interval). 
Duration of response is an important secondary analysis because it characterizes ORR. A 
summary of the attributes of the estimand associated with this important secondary endpoint 
is provided in Table 2. 


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Table 2.
Estimand attributes for the important secondary efficacy analysis
Estimand attribute
Description of attribute
Target population 
All patients treated with CDX-3379 who have a BOR of 
confirmed CR or PR (objective response).
Primary patient-level variable 
Duration of response is calculated as the date of first CR or 
PR that is subsequently confirmed to date of documented 
disease progression or death due to any cause, whichever 
occurs first. In patients who have objective response and 
are progression-free and alive at the time of the analysis, 
duration of response is calculated as the date of first CR or 
PR that is subsequently confirmed to the date of last 
evaluable tumor assessment.
Handling of intercurrent events 
Alternative anti-cancer therapies may be intercurrent 
events in the calculation of duration of response. In 
patients with objective response who receive an anti-cancer 
therapy prior to documented disease progression, duration 
of response will be censored on the start date of the anti-
cancer therapy. 
Population-level summary 
A Kaplan-Meier plot will show duration of response in 
patients who have objective response. The median duration 
of response will be shown as a population-level summary 
statistic. 


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10.2.
ECOG Performance Status
Exhibit 9. ECOG Performance Status
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.
5 
Dead 
As published in Am. J. Clin. Oncol [5]
10.3.
RECIST 1.1 criteria 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. All baseline 
evaluations should be performed as close as possible to the treatment start and never more 
than four weeks before the beginning of the treatment. The same method of assessment and 
the same technique should be used to characterize each identified and reported lesion at 
baseline and during follow-up. Imaging based evaluation should always be done rather than 
clinical examination, unless the lesion(s) being followed cannot be imaged but are assessable 
by clinical exam. (See “Methods of Lesion Measurement” for further guidance.) 
At baseline, lesions should be identified as either “Target” or “Non-Target” as follows: 
Target Lesions: 
Up to a maximum of five measurable target lesions total (with a maximum of two 
target lesions per organ) should be identified as target lesions and will be recorded 
and measured at baseline. (This means in instances where patients have only one or 
two organ sites involved a maximum of two and four lesions respectively will be 
recorded.) 
 


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Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, and should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected. 
All target lesion measurements should be recorded in metric notation, using calipers 
if clinically assessed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum diameters. 
The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. (See “Tumor 
response evaluation”.) 
Non-Target Lesions: 
All other measurable/non-measurable lesions (or sites of disease) including 
pathological lymph nodes should be identified as non-target lesions and should also 
be recorded at baseline. It is acceptable to record multiple non-target lesions 
involving the same organ as a single item on the case report form (e.g. ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Non-target lesions should be followed as ‘present’, ‘absent’, or in rare cases 
‘unequivocal progression’. (See “Tumor response evaluation”.) While some non-
target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively. 
10.3.1. Measurability of tumor at baseline 
Measurable: Tumor lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
o 10mm by computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm). 
 
 
 
 
 


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o 10mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable). 
o 20mm by chest X-ray. 
Note: To be considered pathologically enlarged and measurable, a lymph node must be 
lymph nodes, only the short axis is 
measured and followed). 
Non-measurable: All other lesions, including small lesions (longest diameter <10mm or 
-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin 
or lung, and abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 
Special considerations regarding lesion measurability: 
Malignant lymph nodes: Lymph nodes merit special mention since they are normal anatomical 
structures which may be visible by imaging even if not involved by tumor. Nodal size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT scan 
this is almost always the axial plane; for magnetic resonance imaging (MRI) the plane of 
acquisition may be axial, saggital or coronal). The smaller of these measures is the short axis. 
At baseline and in follow-up, only the short axis will be measured and followed. To be 
axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 
considered non-target lesions. Nodes that have a short axis <10mm are considered non-
pathological and should not be recorded or followed. 
Bone lesions: Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions. However, these techniques can be used to confirm the 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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presence or disappearance of bone lesions. Lytic bone lesions or mixed lytic-blastic lesions, 
with identifiable soft tissue components, that can be evaluated by cross sectional imaging 
techniques such as CT or MRI can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above. Blastic bone lesions are non-
measurable. 
Cystic lesions: Lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for selection 
as target lesions. 
Lesions with prior local treatment: Tumor lesions situated in a previously irradiated area, or in 
an area subjected to other loco-regional therapy, are usually not considered measurable unless 
there has been demonstrated progression in the lesion. 
10.3.2. Methods of lesion measurement 
Clinical exam: Clinical lesions will only be considered measurable when they are superficial 
and 10mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the 
lesion is suggested. As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 


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CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5mm or less. When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). If there is 
concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression. (See “Tumor Response Evaluation”.) 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient 
to be considered in complete response. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (e.g., residual lesions in tumor types such as germ cell tumors, 
where known residual benign tumors can remain). When effusions are known to be a potential 
adverse effect of treatment (e.g., with certain taxane compounds or angiogenesis inhibitors), 


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the cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumor has met criteria for response or 
stable disease in order to differentiate between response (or stable disease) and progressive 
disease. 
10.3.3. Tumor response evaluation 
Evaluation of target lesions: 
Target lesions will be assigned an overall response assessment at each evaluation time point 
according to the following definitions: 
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance 
of one or more new lesions is also considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
Special notes on the assessment of target lesions: 
Lymph nodes: Lymph nodes identified as target lesions should always have the 
actual short axis measurement recorded (measured in the same anatomical plane as 
the baseline examination), even if the nodes regress to below 10mm on study. This 
means that when lymph nodes are included as target lesions, the ‘sum’ of lesions 
may not be zero even if complete response criteria are met, since a normal lymph 
 
 
 
 
 


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node is defined as having a short axis of <10mm. For PR, SD and PD, the actual short 
axis measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become ‘too small to measure’: While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at 
baseline become so faint on CT scan that the radiologist may not feel comfortable 
assigning an exact measure and may report them as being ‘too small to measure’. 
When this occurs, it is important that a value be recorded on the case report form. If 
it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0mm. If the lesion is believed to be present and 
is faintly seen but too small to measure, a default value of 5mm should be assigned. 
(Note: It is less likely that this rule will be used for lymph nodes since they usually 
have a definable size when normal and are frequently surrounded by fat such as in 
the retroperitoneum; however, if a lymph node is believed to be present and is 
faintly seen but too small to measure, a default value of 5mm should be assigned in 
this circumstance as well). This default value is derived from the 5mm CT slice 
thickness (but should not be changed with varying CT slice thickness). The 
measurement of these lesions is potentially non-reproducible, therefore providing 
this default value will prevent false responses or progressions based upon 
measurement error. To reiterate, however, if the radiologist is able to provide an 
actual measure, that should be recorded, even if it is below 5mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate 
the target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’. 
 
 


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Evaluation of non-target lesions: 
Non-target lesions will be assigned an overall response assessment at each evaluation time 
point according to the following definitions: 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10mm 
short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing 
non-target lesions. (Note: the appearance of one or more new lesions is also 
considered progression). 
Special notes on assessment of progression of non-target disease: 
When the patient also has measurable disease: In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR 
in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy (see further details below). A modest ‘increase’ in the size 
of one or more non-target lesions is usually not sufficient to quality for unequivocal 
progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be 
extremely rare. 
When the patient has only non-measurable disease: The same general concepts apply 
here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease 
burden. Because worsening in non-target disease cannot be easily quantified (by 
definition: if all lesions are truly non-measurable) a useful test that can be applied 
when assessing patients for unequivocal progression is to consider if the increase in 
overall disease burden based on the change in non-measurable disease is comparable 
 
 
 
 
 


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in magnitude to the increase that would be required to declare PD for measurable 
disease: i.e., an increase in tumor burden representing an additional 73% increase in 
‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase 
in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is 
seen, the patient should be considered to have had overall PD at that point. While it 
would be ideal to have objective criteria to apply to non-measurable disease, the very 
nature of that disease makes it impossible to do so, therefore the increase must be 
substantial. 
New lesions: 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. 
There are no specific criteria for the identification of new radiographic lesions; 
however, the finding of a new lesion should be unequivocal: i.e. not attributable to 
differences in scanning technique, change in imaging modality or findings thought to 
represent something other than tumor (for example, some ‘new’ bone lesions may be 
simply healing or flare of pre-existing lesions). This is particularly important when 
the patient’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, 
which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease progression. 
An example of this is the patient who has visceral disease at baseline and while on 
study has a CT or MRI brain ordered which reveals metastases. The patient’s brain 
metastases are considered to be evidence of PD even if he/she did not have brain 
imaging at baseline. 
 
 


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If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using 
the date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 
in assessment of progression (particularly possible ‘new’ disease). New lesions on 
the basis of FDG-PET imaging can be identified according to the following 
algorithm: 
o
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. (A ‘positive’ FDG-PET scan lesion means one which is FDG 
avid with an uptake greater than twice that of the surrounding tissue on the 
attenuation corrected image.) 
o
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
Evaluation of overall response: 
It is assumed that at each protocol specified time point, an overall response assessment occurs. 
The patient’s overall response assignment will depend on the findings of both target and non-
target disease and will also take into consideration the appearance of new lesions. 
 
 


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Exhibit 10 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. When patients have non-measurable 
(therefore non-target) disease only, Exhibit 11 is to be used. 
Special notes on evaluation of overall response: 
Missing assessments and inevaluable designation:
o
When no imaging/measurement is done at all at a particular time point, the 
patient is not evaluable (NE) at that time point. 
o
If only a subset of lesion measurements are made at an assessment, usually the 
case is also considered NE at that time point, unless a convincing argument can 
be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to happen in 
the case of PD. For example, if a patient had a baseline sum of 50mm with three 
measured lesions and at follow-up only two lesions were assessed, but those 
gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 
‘Symptomatic deterioration’: Patients with a global deterioration of health status 
requiring discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as ‘symptomatic deterioration’. Every 
effort should be made to document objective progression even after discontinuation 
of treatment. Symptomatic deterioration is not a descriptor of an objective response: 
it is a reason for stopping study therapy. The objective response status of such 
patients is to be determined by evaluation of target and non-target disease as shown 
in Exhibit 10 and Exhibit 11. 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends upon this determination, 
it is recommended that the residual lesion be investigated (fine needle 
aspirate/biopsy) before assigning a status of complete response. FDG-PET may be 
used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring. 
 
 
 


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For equivocal findings of progression (e.g. very small and uncertain new lesions; 
cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment. If at the next scheduled assessment, progression is confirmed, 
the date of progression should be the earlier date when progression was suspected. 
Confirmation of response: In the event of complete or partial responses, efforts 
should be made to obtain a confirmatory scan (no sooner than 28 days later). 
Exhibit 10.
Overall response: patients with target +/- non-target disease
Target lesions 
Non-target lesions
New lesions 
Overall response 
CR 
CR 
No
CR
CR 
Non-CR/non-PD
No
PR 
CR 
Not evaluated
No
PR 
PR 
Non-PD or not all evaluated
No
PR 
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD 
No
NE 
PD 
Any
Yes or No
PD
Any 
PD 
Yes or No
PD
Any 
Any
Yes
PD
inevaluable. 
Exhibit 11.
Overall response: patients with non-target disease only
Non-target lesions
New lesions
Overall response 
CR 
No
CR
Non-CR/non-PD
No
Non-CR/non-PD 
Not all evaluated
No
NE 
Unequivocal PD
Yes or No
PD
Any 
Yes 
PD
inevaluable. 
a. ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised. 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  


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Exhibit 12.
Best overall response when confirmation of CR and PR is required
Overall response 
First time point
Overall response 
Subsequent time 
point
Best overall response
CR 
CR 
CR
CR 
PR
SD, PD or PRa
CR 
SD 
SD provided minimum criteriab for SD duration met, otherwise, PD 
CR
PD
SD provided minimum criteria for SD duration met, otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise, NE
PR
CR
PR
PR
PR
PR
PR 
SD 
SD
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
PR 
NE
SD provided minimum criteria for SD duration met, otherwise, NE
NE 
NE
NE 
inevaluable. 
a. If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the original 
CR should be changed to PR and the best response is PR. 
b. Minimum criteria for SD duration is 12 weeks for this study. 
Adapted from Eisenhower 2009 [2]
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