Conditions: Non-small Cell Lung Cancer (NSCLC)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 33
Healthy volunteers: no

Brief summary:
Based on promising data from our laboratory demonstrating synergy between ablative local radiotherapy and FLT3 ligand immunotherapy in murine NSCLC models, investigators are performing a phase II study combining FLT3L immunotherapy and SBRT for patients with advanced NSCLC that has progressed following standard systemic therapy. All patients will receive daily subcutaneous injections of CDX-301 (75 µg/kg) for 5 days, beginning on the first day of SBRT. SBRT will be delivered to a single pulmonary or extrapulmonary lesion. The SBRT regimen will depend on the size and location of the target lesion. The primary endpoint will be progression-free survival at 4 months, defined using immune-related response criteria (irRC).

Detailed description:
Primary Objective

* To explore the efficacy of combining stereotactic body radiotherapy (SBRT) with FLT3 ligand immunotherapy for advanced non-small cell lung cancer (NSCLC).

Secondary Objectives

* To establish the feasibility and safety of combining SBRT with FLT3 ligand immunotherapy for advanced NSCLC.
* To quantify and evaluate potential surrogate outcomes for clinical efficacy of this treatment approach, including radiographic responses, immunologic responses, and circulating tumor cell levels.

Arms:
arm 1: Patients will be treated with stereotactic body radiotherapy (SBRT) to a single pulmonary or extrapulmonary lesion as well as FLT3 immunotherapy.

FLT3 Ligand Therapy (CDX-301)

* Daily subcutaneous injections of CDX-301 (75 ug/kg) will be administered for 5 days, beginning on the first day of SBRT.
* Additional cycles of SBRT (to distinct lesions) and CDX-301 may be administered every 2-4 months to subjects who demonstrate evidence of clinical benefit (lack of treatment-related toxicity and no disease progression).
* Study therapy will be discontinued in cases of treatment-related toxicity or disease progression.

Interventions: intervention 1: FLT3 Ligand Therapy (CDX-301) intervention 2: Stereotactic Body Radiotherapy (SBRT)
Intervention descriptions: intervention 1: See Arm 1 descriptions intervention 2: See Arm 1 descriptions

Protocol document:
Prot_SAP_000.pdf: 
FLT3 Ligand Immunotherapy and Stereotactic Radiotherapy 
for Advanced Non-small Cell Lung Cancer
Protocol ID: 2015-5267
NCT02839265
IRB NUMBER: 2015-5267
IRB APPROVAL DATE: 
10/06/2021


1
FLT3 Ligand Immunotherapy and Stereotactic 
Radiotherapy for Advanced Solid Tumors
CONFIDENTIAL
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
Principal Investigators
Nitin Ohri, MD
Albert Einstein College of Medicine
Department of Radiation Oncology
1300 Morris Park Avenue, Mazer 610
Bronx, NY 10461
Phone: 718-430-3682
Fax: 718-430-8618
Email: nohri@montefiore.org
Chandan Guha, MD, PhD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
Email: cguha@montefiore.org
Co-Investigators (Radiation Oncology)
Madhur Garg, MD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
Email: mgarg@montefiore.org
William Bodner, MD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
Email: wbodner@montefiore.org
Rafi Kabarriti, MD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
Email: rkabarri@montefiore.org
Co-Investigators (Medical Oncology)


2
Roman Perez-Soler, MD 
Montefiore Medical Center
Department of Oncology, Hofheimer 100
111 East 210th Street
Bronx, NY 10467-2490
Phone: 718-920-4826
Fax: 718-798-7474
Email: rperezso@montefiore.org
Haiying Cheng, MD, PhD
Montefiore Medical Center
Department of Oncology
111 East 210th Street
Bronx, NY 10461-2374
Phone: 718-405-8505
Fax: 718-405-8501
Email: hcheng@montefiore.org 
Rasim Gucalp, MD
Montefiore Medical Center
Department of Oncology, Hofheimer 100
111 East 210th Street
Bronx, NY 10467-2490
Phone: 718-920-4826
Fax: 718-798-7474
Email: rgucalp@montefiore.org
Andreas Kaubisch, MD
Montefiore Medical Center
Department of Medical Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4057
Fax: 718-798-7474
Email: akaubisc@montefiore.org
            
Co-Investigators (Medical Physics)
Wolfgang Tomé, PhD
Albert Einstein College of Medicine
Department of Radiation Oncology
1300 Morris Park Avenue, Mazer 106
Bronx, NY 10461
Phone: 718-430-3188
Fax: 718-430-8618
Email: wtome@montefiore.org
     
Co-Investigators (Statistics)
Shankar Viswanathan, DrPH, MSc
Albert Einstein College of Medicine
1300 Morris Park Avenue, Belfer 1312D
Bronx, New York 10461
Phone: 718-430-3762
Fax: 718-430-8780
Email: shankar.viswanathan@einstein.yu.edu
                          


3
Research Nurse
Hilda Haynes-Lewis, NP
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-7750
Fax: 718-231-5064
Email: hhaynes@montefiore.org 


4
Abbreviations
AE
Adverse Event
AJCC
American Joint Committee on Cancer
BED
Biologically effective dose
CRT
Case report form
CT
Computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte antigen 4
DLT
Dose-limiting toxicity
DSMB
Data safety and monitoring board
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
FLT3
Fms-like tyrosine kinase 3
HIPAA
Health Insurance Portability and Accountability Act
irRC
Immune-related response criteria
ICOS
Inducible costimulator
IRB 
Institutional review board
NCCN
National Comprehensive Cancer Network
NSCLC
Non-small cell lung cancer
PET
Positron emission tomography
PFS
Progression-free survival
PHI
Protected health information
PI
Principal investigator
PTV
Planning target volume
RECIST
Response Evaluation Criteria in Solid Tumors
RT
Radiotherapy
RTOG 
Radiation Therapy Oncology Group
SAE
Serious adverse event
SBRT
Stereotactic body radiotherapy
WHO
World Health Organization


5
Contents
1.0  OBJECTIVES ............................................................................................................7
1.1  Primary Objective...................................................................................................7
1.2  Secondary Objectives ............................................................................................7
2.0  BACKGROUND.........................................................................................................7
2.1  Non-Small Cell Lung Cancer..................................................................................7
2.2  FLT3 Ligand ...........................................................................................................8
2.3  Stereotactic Body Radiotherapy.............................................................................9
2.4  FLT3 Ligand and Radiotherapy............................................................................10
2.5  FLT3 Ligand and Stereotactic Radiotherapy – Early Clinical Experience............11
3.0  PATIENT ELIGIBILITY ............................................................................................13
3.1  Inclusion Criteria...................................................................................................13
3.2  Exclusion Criteria .................................................................................................13
4.0  STUDY DESIGN......................................................................................................14
4.1  General Design ....................................................................................................14
4.2  Study Calendar.....................................................................................................15
4.3  Primary Endpoint..................................................................................................15
4.4  Secondary Endpoints ...........................................................................................15
5.0  STUDY THERAPY...................................................................................................16
5.1  Stereotactic Body Radiotherapy...........................................................................16
5.2  FLT3 Ligand Therapy (CDX-301).........................................................................17
5.3  Treatment Modifications.......................................................................................17
5.4  Toxicity Management ...........................................................................................18
5.5  Investigational Drug Description...........................................................................18
6.0  STATISTICAL CONSIDERATIONS.........................................................................19
6.1  Primary Endpoint – Progression-Free Survival ....................................................19
6.2  Secondary Endpoints - Safety and Tolerability ....................................................20
6.3  Other Secondary Endpoints .................................................................................20
7.0  REGULATORY CONSIDERATIONS.......................................................................21
7.1  Protection of Human Subjects..............................................................................21
7.2  Potential Risks......................................................................................................21
7.3  Additional Warnings and Precautions ..................................................................22
7.4  Potential Benefits to Human Subjects and Others ...............................................24
7.5  Compliance with the Protocol and Protocol Revisions.........................................24


6
7.6  Inclusion of Women and Minorities ......................................................................24
7.7  Patients Under the Age of 18 Years.....................................................................25
8.0  DATA HANDLING AND RECORD KEEPING .........................................................25
8.1  Confidentiality.......................................................................................................25
8.2  Source Documents...............................................................................................25
8.3  Case Report Forms..............................................................................................26
9.0  DATA SAFETY AND MONITORING BOARDS.......................................................26
10.0  ADVERSE EVENTS ..............................................................................................28
10.1  Adverse Event Definitions ..................................................................................28
10.2  Adverse Event Reporting ...................................................................................29
11.0  REFERENCES ......................................................................................................31
12.0  APPENDICES........................................................................................................35
12.1 Appendix A – Common Toxicity Criteria..............................................................35
12.2 Appendix B – ECOG/WHO/Zubrod Performance Status ....................................35


7
1.0  OBJECTIVES
1.1  Primary Objective

To explore the efficacy of combining stereotactic body radiotherapy (SBRT) with 
FLT3 ligand immunotherapy for advanced non-small cell lung cancer (NSCLC) 
and for other advanced solid tumors after treatment with immune checkpoint 
inhibitors targeting the PD-1/PD-L1 axis.
1.2  Secondary Objectives

To establish the feasibility and safety of combining SBRT with FLT3 ligand 
immunotherapy for advanced NSCLC and for other advanced solid tumors after 
treatment with immune checkpoint inhibitors targeting the PD-1/PD-L1 axis.

To quantify and evaluate potential surrogate outcomes for clinical efficacy of this 
treatment approach, including radiographic responses, immunologic responses, 
and circulating tumor cell levels.
2.0  BACKGROUND
2.1  Non-Small Cell Lung Cancer
Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality in 
the United States and worldwide, causing nearly one million deaths each year.[1]  For 
the approximately 40% of NSCLC patients who present with stage IV disease and other 
patients who progress after presenting with localized disease, standard first-line therapy 
typically consists of combination chemotherapy, usually with a platinum doublet.  
Median progression-free survival (PFS) for such patients is on the order of 6 months.[2, 
3]  Second-line systemic therapy, when it can be delivered, yields even poorer 
outcomes, with median PFS durations of approximately 3 months.[4, 5]  While targeted 
therapy clearly improves outcomes for the minority of patients with identifiable driver 
mutations, novel strategies to improve outcomes for the remainder of advanced NSCLC 
patients are sorely needed.
Cancer immunotherapy, which refers to treatment strategies that induce the 
patient’s own immune system to attack tumor cells, is an emerging tool in the 
oncologist’s armamentarium.  Sipuleucel-T, a therapeutic vaccine for prostate cancer, 
gained FDA approved for the treatment of metastatic, hormone refractory prostate 
cancer in 2010. Ipilimumab, a monoclonal antibody to CTLA-4 that promotes cancer cell 
killing by cytotoxic T lymphocytes, was approved for the treatment of advanced 
melanoma in 2011.  Pembrolizumab and nivolumab, which both blocks the protein 
programmed cell death 1 (PD-1) from binding its ligands PD-L1 and PD-L2 to permit 
cytotoxic T cell activation, were both approved by the FDA for the treatment of 
advanced melanoma in 2014.  Although several groups are exploring methods to utilize 
the immune system to fight lung cancer, the use of immunotherapy for NSCLC remains 
largely investigational at this point.[6-8]  Of note, nivolumab gained approval for the 
second-line treatment of advanced squamous NSCLC in March 2015 after 
demonstrating an overall survival benefit (median 9 months versus 6 months) when 
compared to docetaxel in a randomized multicenter trial.


8
Our group and others have demonstrated that ionizing radiotherapy (RT) has the 
potential to enhance the effectiveness of cancer immunotherapy.  RT may serve to 
amplify the tumor-specific peptide repertoire and upregulate cell surface expression of 
MHC determinants and costimulatory molecules. [9, 10]  RT may also evoke changes in 
the tumor microenvironment that facilitate the host immune response.[11, 12]  We 
believe that RT is a key to unlocking the potential of immunotherapy as an effective 
approach in the treatment of NSCLC.
2.2  FLT3 Ligand
Fms-like tyrosine kinase 3 (FLT3) ligand is a potent hematopoietic growth factor 
that mobilizes stem cells and greatly increases the number of circulating dendritic cells 
(DCs) in blood and organs.[13]  FLT3 ligand has been shown to evoke immune 
responses and cause tumor regression in animal models of fibrosarcoma, breast 
cancer, prostate cancer, and lung adenocarcinoma.[14-17]  
Amgen’s recombinant human FLT3L, AMG949, has been studied in numerous 
industry and investigator-initiated clinical trials.  Collectively, approximately 150 healthy 
volunteers and 380 cancer patients were enrolled on those trials.  Adverse events 
requiring cessation of treatment were rare (<5%).  However, FLT3L did not demonstrate 
definitive anti-tumor activity in patients with ovarian cancer, breast cancer, or non-
Hodgkin’s lymphoma.  This may have been related to the immobilization of immature 
DCs by FLT3 or limited DC access to tumor antigens.
Celldex Pharmaceuticals has developed a new FLT3L (CDX-301).  CDX-301 is 
produced using a serum-free manufacturing process, and it is identical in amino acid 
sequence to AMG949.  A phase I study using 30 healthy volunteers has been 
completed, and no major toxicities were observed.  (See Section 7.2 for further details)  
DC expansion has been shown to peaks approximately two weeks after initiation of 
FLT3 ligand therapy (Figure 1).  Based on promising data from our laboratory 
demonstrating synergy between ablative local RT and FLT3 ligand immunotherapy in 
murine NSCLC models (summarized below), our first clinical trials in this arena will test 
the combination of CDX-301 and SBRT for advanced NSCLC.  
Figure 1 – Expansion of two dendritic cell populations in healthy volunteers treated with 
CDX-301 peaks at 10-14 days after treatment initiation. (source: Celldex Therapeutics)


9
2.3  Stereotactic Body Radiotherapy
In recent years, hypofractionated stereotactic body radiotherapy (SBRT) has 
emerged as an effective treatment option for numerous malignancies.  SBRT uses the 
principles of intracranial stereotactic radiosurgery (large daily doses delivered precisely 
to a small target volume over a short treatment course) to treat extracranial disease 
sites.  For stage I NSCLC, SBRT has demonstrated excellent local control rates. [18-20] 
Increased utilization of SBRT has been linked to improvements in overall survival. [21]  
Serious adverse events following SBRT for NSCLC are very rare[22], except when 
aggressive SBRT regimens are used to treat central lesions. [23]  Importantly, the 
highly-conformal manner in which SBRT is delivered allows safe treatment of lung 
tumors in patients with poor pulmonary function.[24]  SBRT has also been shown to be 
safe in extrathoracic disease sites such as the liver and spine.[25, 26]
A wide variety of dosing and fractionation schedules has been used to deliver 
lung SBRT for NSCLC.[19, 20] Although there is evidence of a dose-response 
relationship when relatively low-dose regimens (BED < 100 Gy) are used,[19, 20] more 
intense regimens have yielded consistently excellent results and are considered to be 
ablative.  These include 10-12.5 Gy x 4-5 fractions, 18-20 Gy x 3 fractions, and 25-34 
Gy in a single fraction.  A randomized RTOG study demonstrated that 34 Gy x 1 fraction 
is a safe and effective regimen for peripheral tumors.[27]  This single fraction dose will 
be the new standard for the treatment of peripheral lesions in upcoming RTOG SBRT 
trials.  For central lesions, less aggressive regimens such as 10-12 Gy x 5 are 
recommended.  The National Comprehensive Cancer Network (NCCN) now provides 
guidelines for the selection of an SBRT schedule as well as dosimetric constraints that 
should be met for each organ at risk and course length:
SBRT is now often used to treat primary tumors and metastases in sites outside 
the lung, both for NSCLC and for other malignancies. Techniques to safely deliver 


10
SBRT to the skeleton, abdomen, pelvis, and extremities have been established[28]. 
SBRT for patients with limited metastatic disease may become a standard approach 
based on recently completed[29, 30] and ongoing randomized trials. 
2.4  FLT3 Ligand and Radiotherapy
Published laboratory results from our department demonstrate that pretreatment 
of a single lesion with high-dose RT increases the systemic efficacy of FLT3 ligand in a 
murine model of lung adenocarcinoma. [14]  Mice with established, 3-week-old Lewis 
lung tumors were given a single dose of localized primary footpad tumor RT (60 Gy), 
with or without FLT3 ligand (administered daily for 10 days after RT).  The combination 
of RT and FLT3 ligand significantly increased survival compared to either treatment 
alone and compared to controls (Figure 2).  Examination of animal lung tissue revealed 
that the lungs of mice treated with RT and FLT3 ligand showed no carcinoma cells but 
had infiltrates of neutrophils, lymphocytes, and mononuclear leukocytes.  Lungs from 
other cohorts demonstrated massive tumor cell infiltration. (Figure 3)
Figure 2 – Local RT acts synergistically with FLT3 ligand in a murine NSCLC model to 
improve overall survival.
Figure 3 – Murine lungs following treatment with RT plus FLT3 ligand demonstrate 
leukocytic infiltrates without tumor cells (left), compared to tumor-laden lungs of mice 
from other cohorts (right).


11
We recently obtained similar results in a newer, unpublished experiment using 
the Celldex FLT3 ligand CDX-301. (Figures 4 and 5) Again, in a murine 
adenocarcinoma model, combination therapy with RT and FLT3 ligand improved overall 
survival compared to either treatment alone.  In this case, the dose of 60 Gy was 
divided into three fractions to mimic an SBRT schedule commonly employed in NSCLC 
patients.  Poorer outcomes were seen in the combination therapy arm compared to that 
in the prior study, likely because surviving mice were re-challenged with tumor cells 
eight weeks after completion of immunotherapy.  We hypothesize that additional cycles 
of FLT3 ligand, possibly in combination with repeat irradiation of viable lesions, might 
prolong treatment efficacy.
Figure 4 – Design for murine study of FLT3 ligand (CDX-301) and hypofractionated RT.
Figure 5 – Murine survival curves.  Log-rank testing of the combination therapy arm 
against each monotherapy arm yields p-values of 0.04.
The data summarized above indicate that the combination of SBRT to a 
pulmonary or metastatic NSCLC lesion and CDX-301 is likely to be well-tolerated and 
may have significant clinical activity in advanced NSCLC patients.  The study described 
herein will be the first clinical trial to test this approach.
2.5  FLT3 Ligand and Stereotactic Radiotherapy – Early Clinical Experience
From October 2016 to October 2017, we enrolled 10 subjects with advanced 
NSCLC on this clinical trial, which was initially only available to patients with advanced 
NSCLC. One subject suffered clinical deterioration and passed away before initiating 
study therapy. The remaining nine subjects were treated with stereotactic radiotherapy 


12
directed at a thoracic lesion as well as FLT3 ligand. One of these subjects had been 
treated with one prior line of therapy for advanced NSCLC, four received two prior lines 
of therapy, and four received three prior lines of therapy. Seven out of nine subjects 
were previously treated with an immune checkpoint inhibitor targeting the PD-1/PD-L1 
axis (atezolizumab, durvalumab, nivolumab, or pembrolizumab).
No dose-limiting toxicities have been observed. One subject developed 
pneumonitis involving the lung that was not treated with radiotherapy outside the dose-
limiting toxicity window. After multidisciplinary discussion, it was deemed that this was 
likely a delayed side effect of atezolizumab, which the patient received prior to study 
enrollment. The patient was treated with a corticosteroid taper over several weeks and 
supplemental oxygen as needed. His respiratory status returned to baseline after 
approximately one month. No other serious adverse events have been observed.
Early efficacy results have been encouraging, particularly in subjects who were 
previously treated with immune checkpoint inhibitors.  Among all subjects, the actuarial 
rate of progression-free survival at 4 months (based on CT, primary endpoint) is 56%, 
which is consistent with the hypothesized rate of 40.5% or higher. Among subjects who 
were previously treated with immune checkpoint therapy, this rate is 71%. Several 
patients have demonstrated an impressive response to therapy, even when SBRT 
target lesions are excluded from response assessment. Using PERCIST criteria, a 
partial response (reduction in total glycolytic activity of at least 40%) has been observed 
in 5 out of 9 subjects.  All 5 responders were previously treated with immune checkpoint 
therapy. With a median follow-up duration of 10 months for surviving patients, the 
median overall survival time has not been reached (Figure 7).
Figure 6 – Spider plots depicting response to study therapy on PET
for the first 9 study subjects. TGA values do not include SBRT target lesions.


13
0
2
4
6
8
10
12
14
16
18
Time from Study Treatment (months)
0
10
20
30
40
50
60
70
80
90
100
Survival (%)
Overall Survival
Progression-Free Survival
Figure 7 – Kaplan-Meier curves for overall survival 
and progression-free survival for the first 9 study subjects
Based on these exciting results, which were presented at the Clinical Trials 
Plenary Session at the 2018 AACR Annual Meeting, we are adding a second study 
cohort to this protocol. This group will include patients with advanced solid tumors other 
than NSCLC who have previously been treated with immune checkpoint therapy 
targeting the PD-1/PD-L1 axis.
3.0  PATIENT ELIGIBILITY
3.1  Inclusion Criteria

Cohort 1: AJCC stage 3 or 4 histologically proven NSCLC not amenable to 
curative therapy
Cohort 2: Advanced solid (excluding lymphomas and leukemias) malignancy 
other than NSCLC not amenable to curative therapy and previously treated with 
immune checkpoint therapy targeting the PD-1/PD-L1 axis with an agent 
approved by the FDA for that setting.

Age ≥ 18 years

Prior treatment with at least one standard chemotherapy regimen or targeted 
agent prior to enrollment

Radiological assessment within 21 days prior to study entry demonstrating 
measurable disease that includes at least one pulmonary or extrapulmonary 
lesion ≥ 1 cm in greatest dimension that would be amenable to SBRT and at 
least one measurable lesion that would be outside of the SBRT treatment fields

History/physical examination within 30 days prior to registration

ECOG performance status 0-2

Signed, written informed consent
3.2  Exclusion Criteria


14

Less than 21 days between registration and the last receipt of chemotherapy, 
biotherapy, immunotherapy, radiotherapy (excluding palliative radiotherapy), or 
major surgery.  Prior receipt of immunomodulatory therapy (e.g.: nivolumab) is 
permitted, as long as there has been a 21-day washout period following the most 
recent treatment.

Untreated central nervous system metastases.  Patients with a history of brain 
metastases must have had no CNS-directed therapy within the past 60 days and 
radiological assessment within 30 days of study entry demonstrating a lack of 
progressive CNS disease

Ongoing or recent (within 21 days prior to study entry) use of high dose oral 
corticosteroids (≥ 2 mg of dexamethasone daily or equivalent).  Intranasal and/or 
inhaled corticosteroid use is permitted.

Any unresolved CTCAE grade > 2 toxicity from previous anti-cancer therapy.  
Patients with irreversible toxicity that is not reasonably expected to be 
exacerbated by study therapy (e.g., hearing loss) may be enrolled after 
discussion with the principal investigators.

History of allogeneic organ transplant or autoimmune disease

Other active malignancy for which systemic therapy is indicated.  History of 
adequately treated local basal cell or squamous cell carcinoma of the skin, 
cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate 
cancer without known metastatic disease and with no requirement for therapy 
asides from hormonal therapy, adequately treated stage 1or 2 cancer currently in 
complete remission, or any other cancer that has been in complete remission for 
≥ 5 years is permitted.

Uncontrolled intercurrent illness including, but not limited to, symptomatic 
congestive heart failure, unstable angina pectoris, uncontrolled cardiac 
arrhythmia, or psychiatric illness/social situation that would limit compliance with 
study requirements as judged by the treating physicians

The following laboratory results, within 10 days of first study drug administration:
o
Hemoglobin ≤ 9.0 g/dL, Absolute neutrophil count ≤ 1.5 x 109/L, Platelet 
count ≤ 100 x 109/L
o
Serum creatinine ≥ 1.5 x ULN and creatinine clearance (by Cockcroft-
Gault formula) < 60 mL/min

Women of child bearing potential: positive pregnancy test (serum)
4.0  STUDY DESIGN
4.1  General Design
This is a single-arm, phase II study with two cohorts.  A total of 29 patients will be 
enrolled in Cohort 1, and 20 patients will be enrolled in Cohort 2.  All patients will be 
treated with SBRT to a single pulmonary or extrapulmonary lesion as well as FLT3 
ligand immunotherapy.  Patients will be followed closely for the development of any 


15
treatment-related toxicities.  Whole-body PET/CT imaging will be performed prior to 
study entry and every 8 weeks thereafter.  
4.2  Study Calendar
Additional cycles of SBRT and FLT3 ligand may be administered after 8 weeks or more 
in cases where treatment is well-tolerated and seems to provide clinical benefit, at the 
discretion of the treating physicians. In addition to the time points specified above, blood 
samples for immune correlates will also be drawn at the first clinic visit following disease 
progression. Immune correlates will include anti-drug antibody testing for CDX-301, 
which will be performed by sending study samples to Celldex. For diseases where 
PET/CT is not commonly used (e.g., hepatocellular carcinoma), PET/CT may be 
replaced by CT and/or MRI.
4.3  Primary Endpoint

The primary endpoint is progression-free survival rate at four months (PFS4), 
defined as the rate estimate of the percentage of patients who are alive and 
progression-free at 16 weeks (~4 months) after initiation of study therapy.
4.4  Secondary Endpoints

Dose limiting toxicities (DLTs):  For the purposes of this study, a DLT will be 
defined as any treatment-emergent grade 3-5 toxicity, scored using the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0, and occurring 
within 30 days after treatment with SBRT in combination with FLT3 ligand 
therapy.  Asymptomatic laboratory abnormalities (e.g.: leukocytosis) that do not 
require intervention will not be counted as DLTs.  For subjects who receive more 
than one “cycle” of SBRT and FLT3 ligand, only adverse events that occur after 
the first cycle will be scored as potential DLTs.

Clinical/radiographic endpoints:  These will include radiographic response rates, 
disease progression, and death.  Radiographic endpoints will be scored using 
according to immune-related response criteria (irRC).[31]  To allow comparison 
of our data with historical experiences, we will also score radiographic findings 
using RECIST 1.1 criteria.[32]  Pre- and post-treatment assessments will include 
PET/CT imaging, so that we can assess responses using PERCIST criteria[33] 
and with volumetric PET measures, which have been shown to be prognostic in 
metastatic NSCLC patients [34, 35] and predictive of clinical outcomes in 
advanced NSCLC patients treated with targeted therapy.[36]  SBRT target 
lesions will not be considered in the radiographic evaluation of treatment 
responses, as rates of treatment response and disease control in lesions treated 


16
with SBRT have been shown to be excellent and may not be indicative of the 
effectiveness of combined modality therapy. 

Potential surrogate outcomes for clinical endpoints:  We will collect plasma 
samples at regular intervals to facilitate monitoring immune responses such as 
DC expansion.  We will also follow T-cell inducible costimulator (ICOS) 
expression.  ICOS is a member of the immunoglobulin superfamily.  Responses 
to immunotherapy have been associated with increased ICOS expression on 
CD8+ T-cells, particularly following CTLA-4 blockade.[37-40]  We will follow 
serum levels of high-mobility group box 1 (HMGB1), whose release has been 
linked to antitumor immune responses.[41, 42]  Flow cytometry will be performed 
to track measures of DC maturation such as CD83 and CD86 expression.[43]  
Other correlative studies will be performed in collaboration with Dr. Guha’s 
laboratory and the study sponsor.
5.0  STUDY THERAPY
5.1  Stereotactic Body Radiotherapy

SBRT will be administered during the first week of study therapy.

A single pulmonary or extrapulmonary lesion that measures at least 1 cm in 
greatest dimension will be treated.

The target lesion for SBRT will be chosen by the treating radiation oncologist with 
the following considerations:
o
Confidence that the target lesion is cancerous (based on prior biopsy, 
growth on serial imaging, and/or hypermetabolic uptake on FDG-PET)
o
Safety of SBRT to the target lesion and ability to meet the dosimetric 
constraints listed below

Based on lesion size and location, one of three SBRT schedules will be selected 
for each patient receiving SBRT to a pulmonary lesion.  At least 95% of the 
planning target volume (PTV) will receive the full prescription dose.  Based on 
the criteria described below, we expect that approximately equal numbers of 
subjects will receive each of these SBRT schedules:
Schedule
Criteria
Interval between 
treatments
Course duration
34 Gy x 1
Peripheral tumor measuring ≤ 
2 cm in greatest dimension and 
> 1 cm from the chest wall
-
-
18 Gy x 3
Peripheral tumor measuring ≤ 
5 cm and not eligible for 34 Gy 
x 1 fraction
42-54 hours
5 days
10 Gy x 5
Central or peripheral tumor not 
eligible for 34 Gy x 1 fraction or 
18 Gy x 3 fractions
18-30 hours
5 days


17

Based on lesion location, the following SBRT schedules will be employed for 
each patient receiving SBRT to an extrapulmonary lesion.  At least 95% of the 
planning target volume (PTV) will receive the full prescription dose. If this cannot 
be achieved while respecting normal tissue constraints, the prescription dose 
may be lowered by up to 20%.  These treatment schedules are adopted from an 
ongoing cooperative group clinic trial (NRG-BR001):
Schedule
Target Lesion Location
Interval between 
treatments
Course duration
10 Gy x 3
Spinal or Paraspinal
42-54 hours
5 days
10 Gy x 3
Osseous
42-54 hours
5 days
10 Gy x 5
Mediastinal or Cervical Lymph 
Node
18-30 hours
5 days
15 Gy x 3
Liver
42-54 hours
5 days
15 Gy x 3
Abdominal or Pelvic (lymph 
node or adrenal gland)
42-54 hours
5 days
 

The following normal tissue constraints will be used for SBRT planning:
1 Fraction
3 Fractions
5 Fractions
Brachial plexus
max dose < 17.5 Gy
max dose < 21 Gy
max dose < 30 Gy
Esophagus
max dose < 15.4 Gy
max dose < 30 Gy
max dose < 32.5 Gy
Great vessels
max dose < 37 Gy
max dose < 39 Gy
max dose < 55 Gy
Heart/pericardium
max dose < 22 Gy
max dose < 30 Gy
max dose < 35 Gy
Lungs
At least 1500 cc 
receiving < 12.5 Gy
At least 1500 cc 
receiving < 12.5 Gy
At least 1500 cc 
receiving < 12.5 Gy
Ribs
max dose < 30 Gy
max dose < 30 Gy
max dose < 50 Gy
Skin
max dose < 26 Gy
max dose < 30 Gy
max dose < 40 Gy
Spinal cord
max dose < 14 Gy
max dose < 18 Gy
max dose < 30 Gy
Stomach
max dose < 12.4 Gy
max dose < 27` Gy
max dose < 35 Gy
5.2  FLT3 Ligand Therapy (CDX-301)

Daily subcutaneous injections of CDX-301 (75 µg/kg) will be administered for 5 
days, beginning on the first day of SBRT.

Additional “cycles” of SBRT (to distinct lesions) and CDX-301 may be 
administered every 2-4 months to subjects who demonstrate evidence of clinical 
benefit (lack of treatment-related toxicity and no disease progression).

Study therapy will be discontinued in cases of treatment-related toxicity or 
disease progression.
5.3  Treatment Modifications
If SBRT is interrupted due to a non-dose-limiting adverse event or any reason 
other than toxicity, such as a holiday, bad weather, or a transportation problem, the 
SBRT treatment course will be extended accordingly.  In the case of in-field RT 
toxicities requiring treatment interruption, the SBRT course will be terminated.


18
CDX-301 therapy will be terminated in the case of any DLT (defined in Section 
4.4).  CDX-301 will be held if marked leukocytosis (WBCs  > 50,000 cells/mm3) is 
observed.  
5.4  Toxicity Management
Excessive Hematopoietic Stimulation
Leukocytosis, especially monocytosis, is expected during administration of CDX-
301.  Hematological parameters, including WBC and differential, will be monitored as 
detailed in Section 4.2.  CDX-301 will not be administered if marked leukocytosis 
(WBCs > 50,000 cells/mm3) is observed.  
Injection Site Reactions / Dermatological Toxicities
Injection site reactions, generally mild to moderate but occasionally severe, were 
frequently reported in association with FLT3L administration.  Pre-medication with 
diphenhydramine may be effective in the prevention of pruritic and erythemic reactions 
and will be considered for subjects who experience local reactions after treatment with 
CDX-301.  Injection site reactions may also be treated with analgesics.
Patients will be monitored by our nursing staff for at least 15 minutes following 
each CDX-301 injection.  Patients may then receive SBRT (based on the selected 
fractionation schedule, but always on day 1), followed by a physician evaluation that will 
take place approximately one hour after CDX-301 injection.
5.5  Investigational Drug Description
CDX-301
CDX-301 is a recombinant human Flt3 ligand (Flt3L) that is a hematopoietic 
growth factor which is structurally related to stem cell factor (SCF) and macrophage 
colony-stimulating factor (M-CSF).  It is naturally expressed as a membrane bound or 
secreted protein and binds to fms-like tyrosine kinase 3 (Flt3; or FLK-2, STK-1; CD135), 
a receptor tyrosine kinase in the same family as c-kit, c-fms, and PDGFR A and B.
Each 2 mL clear borosilicate glass vial contains 2.5 mg/mL CDX-301 
glycoprotein in a 1.0 mL (with an overfill to 1.2 mL) volume of buffered solution 
composed of 10 mM sodium phosphate, 140 mM NaCl, pH 7.0.  CDX-301 Drug Product 
is formulated as a sterile solution intended for single-use subcutaneous administration.  
Investigational Drug Supply
An initial study drug shipment will be provided following receipt of all required 
documents.  Additional supplies should be ordered with at least one week advance 
notice using a form supplied by Celldex. 
Storage
           All study supplies must be stored in a secured area with limited, approved 


19
access.  CDX-301 temperature must be maintained between 2° to 8°C (36 to 46°F) and 
monitored daily.  Deviations in storage conditions must be reported to IIR@celldex.com 
within 24 hours of awareness.
CDX-301 Dose Calculation
The individual dose is calculated using the actual baseline body weight of the 
subject according to the calculations below.  All subjects will receive 75 µg/kg of CDX-
301 at each administration.
Body Weight (kg) x Dose Level (75µg/kg) = Desired Dose (µg)
Desired Dose (µg) ÷ 2500 µg/mL = Volume of CDX-301 (mL)
For example, for an 80 kg subject, the total dose required to deliver the 75 µg/kg dose 
would be 6000 µg. The calculated volume required from the 2500 µg/ml CDX-301 stock 
solution to obtain 6000 µg of CDX-301 would be 2.4 ml.  See example formula below:
(80 kg x 75 µg/kg) ÷ 2500 µg/mL = 2.4 mL (Three vials will be needed to administer this 
dose)
CDX-301 Preparation 
CDX-301 liquid should be withdrawn from the vial gently, avoiding foaming and 
excess shearing.  As the maximum volume of any individual injection will be 2.0 ml, the 
dose may be split into up to 3 separate syringes/subcutaneous injections as needed to 
administer the required volume.
CDX-301 Administration
CDX-301 will be administered as a daily subcutaneous injection.  The injection 
site may be rotated between the extremities.  CDX-301 injections should not be given to 
areas of skin with conditions such as scarring, tattoos or persistent injection site 
reactions that will not allow easy access for study drug administration or evaluation of 
localized adverse events.  CDX-301 administration will be performed within the clinical 
setting by trained staff personnel.
6.0  STATISTICAL CONSIDERATIONS
6.1  Primary Endpoint – Progression-Free Survival
Cohort 1:
We will present the progression free survival rate at 4 months as a percentage 
along with its 95% confidence interval. In addition, Progression-free survival will be 
examined using the Kaplan-Meier method.


20
A total of 29 patients will be enrolled in Cohort 1 to test the null hypothesis (H0) 
that PFS4 is 20% or less versus the alternative hypothesis (H1) that PFS4 is 40.5% or 
greater.  If at least 10 of 29 patients are alive without progression at 4 months, this 
study regimen will be considered for further development in this setting. Using this 
criterion, the probability of pursuing this regimen for further study if the true PFS4 is ≥ 
40.5% is at least 80%. The chance that this regimen will be considered for further 
development if the true PFS4 is 20% or lower is at most 5%.
Cohort 2:
A total of 20 patients will be enrolled in Cohort 2. We will estimate the PFS4 
probability along with its 95% confidence interval using the Kaplan Meier survival 
procedure. We will also present median progression-free survival duration.  
We assume a type-II censoring mechanism in this study, where the study will 
continue until 16 events occur in this cohort. We also hypothesize that progression-free 
survival durations will follow an exponential distribution with a mean of 5.8 months. 
Under these assumptions, a sample size of 20 subjects would produce a two-sided 95% 
confidence interval width of 4.4 months for the median progression-free survival 
duration (95% CI: 2.6 months to 7.0 months).
6.2  Secondary Endpoints - Safety and Tolerability
An early stopping rule for safety will be implemented for Cohort 1 as follows.  
After the first 6 patients have been enrolled, accrual will be temporarily suspended while 
these patients are monitored for occurrence of DLTs.  The trial will be terminated early if 
more than 1 patient experiences a DLT.  If 1 or fewer grade 3 toxicities and 0 grade 5 
toxicities are observed after the sixth patient has been observed for 30 days following 
completion of treatment, the trial will continue until a total of 29 patients have been 
evaluated. At the end of the trial, the treatment will be considered safe and worthy of 
further study if no more than 4 patients experience a DLT.  For the first six patients 
enrolled, we will not initiate treatment for more than one patient on the same day.
The target Grade 3 toxicity rate is no more than 10% and a toxicity rate greater 
than 30% is considered clinically unacceptable. The design specified above has the 
following operating characteristics:  The probability of accepting the treatment for further 
study if the toxicity rate is unacceptably high (>30%) is at most 4%.  In contrast, there is 
at least am 84% probability of accepting the treatment for further study if the toxicity rate 
is less than 10%.
The proportion of patients who develop a DLT will be computed.  95% confidence 
intervals for the DLT rate will be calculated using Clopper-Pearson exact confidence 
method.
6.3  Other Secondary Endpoints
irRC, RECIST, and PERCIST response rates, based on first post-treatment 
imaging, will be reported using descriptive statistics.  Rates of disease-free and overall 
survival will be reported using actuarial methods.  Exploratory analyses will be 


21
performed to evaluate surrogate endpoints, including radiographic responses and 
immune correlates, as predictors of clinical outcomes.  We will also perform statistical 
tests to explore if response rates, time-to-event outcomes, and immune responses 
correlate with SBRT fraction size.
7.0  REGULATORY CONSIDERATIONS
7.1  Protection of Human Subjects
The Investigator must ensure that patients or their legally acceptable 
representatives are clearly and fully informed about the purpose, potential risks and 
other critical issues regarding clinical trials in which they volunteer to participate.  
Preparation of the consent form is the responsibility of the Investigator and must include 
all elements required by CFR 21 Part 50.25 and the local IRB.
7.2  Potential Risks
Subjects participating in this Phase II study are at risk for the development of 
treatment-related toxicities.  Risks from lung SBRT include damage to the lungs, heart, 
and esophagus that may cause transient symptoms or permanent dysfunction. Risks 
from SBRT to other sites include damage to nearby organs, depending on the target 
location. The risk profile of SBRT to the lung or other sites has been characterized 
clearly over the past decade, and SBRT planning and dosing for patients enrolled on 
this study will be optimized to keep the expected risk of severe complications related to 
SBRT below 5%.
CDX-301 and AMG949 were generally well-tolerated in prior clinical trials.  In the 
Celldex-sponsored phase 1 study in 30 healthy volunteers, treatment-related toxicity 
was infrequent and reported only at the 25 and 75 µg/kg/day dose levels.  One Grade 3 
event, community acquired pneumonia, was considered to be treatment-related.  No 
additional infections, DLT, SAE, or Grade 3 toxicities were reported.  All other 
treatment-related adverse events were Grade 1; these included lymphadenopathy in six 
subjects and single cases of diarrhea, injection site erythema, folliculitis, and dry mouth. 
In studies of AMG949 administered as single agent to healthy volunteers (n=36), 
there were no deaths, SAEs, Grade 3/4 adverse events, or premature withdrawals from 
treatment.  Grade 2 events were limited to injection site reactions and/or pain.  
Laboratory results were generally unremarkable and showed no suggestion of a dose 
response.  The expected pharmacologic effects of rhuFlt3L (increased WBC and 
monocytes) were observed in both studies.  
Across all previous trials of AMG949, the most common treatment-related 
adverse events were injection site reactions. These events were generally mild to 
moderate, consisting of erythema, induration, urticaria, pain, and bruising.  Rarely, more 
severe reactions with blistering have also been reported.  In Immunex-sponsored 


22
studies, additional adverse events occurring for subjects receiving AMG949 with or 
without GM-CSF, regardless of causality, included headache, pain, asthenia, myalgia, 
nausea, diarrhea, arthralgia, fever, rash, paresthesia, pruritus and vomiting.  The 
majority of adverse events were mild to moderate in severity.  Serious adverse events 
deemed to be related to AMG949 occurred in 6 of the 294 subjects treated in Immunex-
sponsored trials.  These events were three cases of hypercoagulability (IV line clotting), 
single cases of left arm thrombosis and deep vein thrombosis in the leg, and a case of 
fever, chills, and hypotension. 
This will be the first study combining SBRT and FLT3L therapy, so the full range 
of potential toxicities remains unknown.
7.3  Additional Warnings and Precautions
Drug-drug Interactions
Interactions between CDX-301 and other drugs have not been fully evaluated. 
Allergic Reaction
CDX-301 is a fully human protein and it is unlikely that it will induce a 
hypersensitivity reaction.  No such reactions have been observed in the AMG949 or CDX-
301 programs to date.  If such reactions were to be observed, possible manifestations 
could include fever, chills, rash, rigors, pruritus, or other symptoms.
 
Immunogenicity
None of the 30 healthy volunteers treated with CDX-301 (5 to 10-day regimen) 
have developed anti-rhuFlt3L antibody. Approximately 16% of subjects treated with 
AMG949 in Immunex sponsored studies and tested for immune response were noted to 
develop anti-rhuFlt3L antibody. Anti-rhuFlt3L antibodies appeared to develop more 
frequently in studies with greater exposure to AMG949.  However, none of the anti-
rhuFlt3L antibodies were neutralizing.  
Coagulation 
No thrombotic events have been reported as potentially related to CDX-301 in the 
prior healthy volunteer study.  However, thrombotic events (hypercoagulability, IV line 
thrombosis, and venous thrombosis) were observed rarely in oncology patients (n=6) 
receiving AMG949 and was more common when combined with GM-CSF or G-CSF. Low 
grade thrombocytopenia has also been observed following AMG949 administration. 


23
Evaluation of coagulation parameters and clotting factors in several of these patients did 
not reveal any abnormalities. 
Autoimmune Disease
Subjects with a known history of autoimmune disorders should not be given 
CDX-301 until further studies have determined the safety profile of CDX-301 in this 
patient population.  Pre-clinical studies have demonstrated that rhuFlt3L may have a 
complicated role in regulating autoimmune diseases and can either exacerbate or 
ameliorate autoimmune disease manifestations. Therefore, CDX-301 may have the 
potential to exacerbate autoimmune disorders by its immunomodulatory effects. 
Subjects administered CDX-301 will be monitored for the development of potential 
autoimmune phenomena, which may include asymptomatic autoantibody 
seroconversion or hyper- or hypothyroidism.
Development of Immune Tolerance 
CDX-301-mediated increases in immature dendritic cells and/or Treg cells could 
potentially be tolerogenic.  Therefore, CDX-301 could potentially have deleterious effects 
in an infectious disease setting or other pre-existing or developing disease. AMG949 
worsened the outcome in a mouse Streptococcus pneumoniae pneumonia challenge 
model[44], indicating that rhuFlt3L treatment could pose a risk for increased lung injury 
associated with S pneumoniae pneumonia.  Study subjects will be monitored closely for 
the development of infections signs and symptoms.  As described in Section Error! 
Reference source not found., any SAE will be reported to the medical monitor within 24 
hours. 
rhuFlt3L may also be associated with a differential response to vaccines. In 
another murine model, intramuscular injection of rhuFlt3L in combination with a hepatitis 
B vaccine suppressed the antibody response to the vaccine in a dose-dependent 
manner, although in situ delivery by plasmid increased the antibody response [45]. In a 
clinical study in which healthy volunteers were administered hepatitis B vaccine and 
either placebo or AMG949, there was no inter-group difference in hepatitis B antibody 
responses, demonstrating that AMG949 neither augmented nor tolerized humoral 
responses to the vaccine. Patients on this study should not receive any vaccinations 
until at least 28 days after the last dose of CDX-301.   
Leukemia
There are data showing that prophylactic treatment with rhuFlt3L can prevent or 
abrogate leukemic activity[46]. There also are data showing the expression of Flt3 and 
the Flt3L receptor on some leukemias and extensive data that support an association 
between an increase in proliferation or suppression of apoptosis in clinical leukemias that 


24
bear constitutively activated Flt3 mutations. These mutations do not appear to be causal 
for AML[47-50]. It is not known whether the addition of rhuFlt3L to patients with leukemia 
expressing Flt3 will promote leukemic proliferation or whether the ligand can promote the 
development of leukemia in people without pre-existing leukemia.  Since the effect of 
administered rhuFlt3L is transient, it would seem unlikely to have any persistent effects, 
and no cases of leukemia were reported after rhuFlt3L administration in previous studies.
Pregnancy, Carcinogenesis, and Teratogenicity
The effects of CDX-301 on fertility, pregnancy, or the unborn fetus have not been 
determined. It is not known if CDX-301 is excreted in milk or can cross the placenta.  For 
this reason, pregnant and nursing women will not be enrolled into this study. Women of 
childbearing potential enrolled into the clinical study must take adequate contraceptive 
measures.
7.4  Potential Benefits to Human Subjects and Others
The benefits to an individual patient are unknown.  This treatment regimen may 
delay the progression of metastatic disease in the lungs and elsewhere.  Delaying 
disease progression may theoretically prolong survival.
7.5  Compliance with the Protocol and Protocol Revisions
The study must be conducted as described in this approved protocol.  All 
revisions to the protocol must be provided to the PI.  The PI should not implement any 
deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the IRB/IEC of an Amendment, except where 
necessary to eliminate an immediate hazard(s) to study patients.
The investigator must ensure that patients or their legally acceptable 
representatives are clearly and fully informed about the purpose, potential risks and 
other critical issues regarding clinical trials in which they volunteer to participate.  
Preparation of the consent form is the responsibility of the PI.
7.6  Inclusion of Women and Minorities
Recruitment will be open to all women and minorities that qualify under the 
study’s eligibility criteria. There will be no effort to exclude women or minority patients 
from the trial if inclusion criteria are met.  Based on our hospital’s patient population, we 
expect the following demographic breakdown for subjects enrolled on this study:
Gender


25
Ethnic Category
Females
Males
Total
Hispanic or Latino
8
8
16
Not Hispanic or Latino
16
17
33
Ethnic Category: Total 
of All Subjects
24
25
49
Racial Category
Females
Males
Total
American Indian/Alaska 
Native
0
0
0
Asian
2
2
4
Native Hawaiian or Other 
Pacific Islander
0
0
0
Black of African American
6
6
12
White
16
17
33
Racial Category: Total 
of All Subjects
24
25
49
Projected distribution of gender and minorities across both study cohorts.
7.7  Patients Under the Age of 18 Years
Children will be excluded from this study.  Since the incidence of NSCLC in 
children is extremely low, it is unlikely that any patients under the age of 18 will meet 
our eligibility criteria.
8.0  DATA HANDLING AND RECORD KEEPING
8.1  Confidentiality
Information about study subjects will be kept confidential and managed according 
to the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:

What protected health information (PHI) will be collected from subjects in this 
study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.

In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior 
to the revocation of subject authorization.  For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission 
to collect at least vital status (i.e. that the subject is alive) at the end of their 
scheduled study period.


26
8.2  Source Documents
Source data is all information, original records of clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial.  Source data are contained in source documents   Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial.
8.3  Case Report Forms
The study case report form (CRF) is the primary data collection instrument for the 
study.  All data requested on the CRF must be recorded.  All missing data must be 
explained.  If a space on the CRF is left blank because the procedure was not done, or 
the question was not asked, write “N/D”.  If the item is not applicable to the individual 
case, write “N/A”.  All entries should be printed legibly in black ink.  If any entry error has 
been made, to correct such an error, draw a single straight line through the incorrect 
entry and enter the correct data above it.  All such changes must be initialed and dated.  
DO NOT ERASE OR WHITE OUT ERRORS.  For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date it.  
9.0  DATA SAFETY AND MONITORING BOARDS
All trials initiated by the Montefiore Medical Center are subject to oversight by the 
Data Safety Monitoring Board (DSMB).  This board meets two times per year with any 
additional meetings scheduled when needed.  The responsibilities are as follows:

Familiarize themselves with the research protocol (s)

Review interim analyses of outcome data and cumulative toxicity data summaries 
to determine whether the trial should continue as originally designed, should be 
changed, or should be terminated based on these data.

The DSMB reviews trial performance information such as accrual information.

The DSMB also determines whether and to whom outcome results should be 
released prior to the reporting of study results.

All adverse events are reviewed by the committee with assurances that these 
have been in fact sent for review to all pertinent IRBs.

Review of reports of related studies to determine whether the monitored study 
needs to be changed or terminated.

Review major proposed modifications to the study prior to their implementation 
(e.g., termination, dropping an arm based on toxicity results or other reported trial 
outcomes, increasing target sample size).


27

Following each DSMB meeting, provide the study leadership with written 
information concerning findings for the trial as a whole related to cumulative 
toxicities observed and any relevant recommendations related to continuing, 
changing, or terminating the trial.  The study leadership will provide information 
on cumulative toxicities and relevant recommendations to the local PI to be 
shared with their IRB’s.


28
10.0  ADVERSE EVENTS
An adverse event (AE) is defined as any untoward medical occurrence in a 
patient or clinical investigation subject and does not necessarily have to have a causal 
relationship with study treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of treatment.  During clinical trials, AEs can be 
spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a subject. 
AEs will be recorded in the case report form for the duration of the trial, 
regardless of whether or not the event(s) are considered related to trial intervention or 
medication. All AEs considered related to trial intervention or medication will be followed 
until resolution, even if this occurs post-trial.
10.1  Adverse Event Definitions
Adverse Event (AE):  any new, undesirable medical experience or change of an existing 
condition that occurs during or after treatment, whether or not considered product-
related.
Serious Adverse Event (SAE):  An AE occurring at any dose that results in any of the 
following outcomes (CFR 312.32)

Death

Life-threatening adverse experience

Inpatient hospitalization or prolongation of existing hospitalization excluding  
those for study therapy administration, transfusional support, disease staging/re-
staging procedures, thoracentesis / paracentesis, or placement of an indwelling 
catheter, unless associated with other serious events

Persistent or significant disability or incapacity

Congenital anomaly / birth defect. 
The definition of SAE also includes important medical event.  Medical and scientific 
judgment should be exercised in deciding whether expedited reporting is appropriate in 
other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above.  
These should also usually be considered serious.  Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse.  A new diagnosis of cancer during the course of treatment 
should be considered an important medical event.
The definition of “related” is that there is a reasonable possibility that the drug or the 
study intervention caused the adverse experience.


29
Unexpected Adverse Event:  An AE that is not mentioned in the Investigator's Brochure 
or package insert or the specificity or severity of which is not consistent with the 
investigator's brochure or package insert.
Life-threatening:  Any adverse experience that places the patient or subject, in the view 
of the investigator, at immediate risk of death from the reaction as it occurred.  It does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death.
AEs will use the descriptions and grading scales found in the revised Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Appendix A). A list of 
AEs that have occurred or might occur can be found in sections above.  
10.2  Adverse Event Reporting
Study site personnel must notify the PI and the sponsor (Montefiore/Einstein) within 24 
hours of any SAE experienced by a patient.  In general, SAEs assessed as clearly 
being due to disease progression, and not due to study drug(s), should be excluded 
from AE reporting.  Study-specific clinical outcomes of death because of disease 
progression are exempt from SAE reporting, unless the investigator deems them related 
to use of the study drug.  Hospitalization for study drug administration is not an SAE.
The following steps will be taken to report promptly and document accurately any SAE, 
even if it may not appear to be related to the study treatment:

Report the SAE to the PI and the treating physician by email, telephone or fax 
within 24 hours of becoming aware that a patient has experienced an SAE.

Record the SAE accurately on the AE page of the patient’s CRF.

Using the standard IRB-SAE report form, submit all known patient information 
within 24 hours of SAE occurrence to the clinical trial office to submit to IRB and 
DSMB.  Date and sign each report before submission.  Include the following 
information (or as much as possible to obtain and still report the event within 24 
hours): 
o
Study protocol number and indication
o
Study site and investigator’s identification
o
Patient’s ID (patient number and initials), age or date of birth, and sex
o
Date of enrollment
o
Description of SAE, including date of onset and duration, severity, and 
outcome
o
Date of first and most recent (last) dose administered
o
Action taken regarding study treatment
o
Relationship of SAE to study treatment
o
Concomitant medications, including regimen and indication
o
Intervention, including concomitant medications used to treat SAE
o
Pertinent laboratory data/diagnostic tests conducted and date
o
Pertinent medical history of patient
o
Date of hospital admission/discharge


30
o
Date of death (if applicable)
Fatal or life-threatening, unexpected adverse events will be reported to the 
FDA by telephone, facsimile, or in writing as soon as possible, but no later 
than 7 calendar days after first knowledge by the sponsor followed by as 
complete a report as possible within 8 additional calendar days. Serious, 
unexpected adverse events that are not fatal or life-threatening will be 
reported to the FDA by telephone, facsimile, or in writing as soon as 
possible, but no later than 15 calendar days after first knowledge by the 
sponsor.  The Reference Safety Information for the assessment of 
expectedness of serious adverse reactions for CDX-301 is contained 
within the Investigators Brochure.
Within 10 days of initial IRB notification, the PI is required to submit a completed 
Adverse Event Report to the IRB.  The treating physicians should perform appropriate 
diagnostic tests and therapeutic measures and submit all follow-up substantiating data, 
such as diagnostic test reports and autopsy report to the PI, IRB, and DSMB.
Expedited Reporting of SAEs to Celldex
Note that reporting to Celldex is required in addition to reporting to the FDA, as 
necessary, and does not replace the requirement to notify the FDA, if required.

The investigator will inform Celldex in writing using an SAE form or MEDWATCH 
3500A form of any SAE within 24 hours of being aware of the event (see Section 
10.1 for the definition of SAE).  The written report must be completed and 
supplied to Celldex by email or facsimile within 24 hours/1 business day.  The 
initial report must be as complete as possible, including an assessment of the 
causal relationship between the event and the investigational product(s), if 
available.  Information not available at the time of the initial report (e.g., an end 
date for the adverse event or laboratory values received after the report) must be 
documented on a follow-up report.

Completed SAE reports are to be submitted to:
Celldex Therapeutics, Inc.
Pharmacovigilance
Facsimile: 781-644-6434
Email: SAE@celldex.com
For questions regarding SAE reporting: 908-323-2233 (SAE Hotline)


31
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12.0  APPENDICES
12.1 Appendix A – Common Toxicity Criteria
NCI CTCAE Version 4.0
Toxicity will be scored using NCI  CTC Version 4.0 for toxicity and adverse event 
reporting.  A copy of the NCI CTC Version 4.0 can be downloaded from the CTEP 
homepage: (http://ctep.info.nih.gov).  All appropriate treatment areas have access to a 
copy of the CTC Version 4.0
12.2 Appendix B – ECOG/WHO/Zubrod Performance Status