Testing the Immunologic Effects of CDX-301 and CDX-1140 in Resectable Pancreatic Cancer Patients
Phase: PHASE2
Conditions: Pancreatic Cancer, Cancer of the Pancreas, Pancreas Cancer
Sponsor: Washington University School of Medicine

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Testing the immunologic effects of CDX-301 and CDX-1140 in resectable pancreatic cancer patients 
 
Washington University School of Medicine 
Department of Surgery, 660 S. Euclid Ave., CB 8109, St. Louis, MO  63110 
 
Protocol #: 202011125 
Version Date: 30 November 2023 
 
Principal Investigator: 
Roheena Z. Panni, M.D. 
Phone:  (314) 362-7046 
E-mail:  roheenazpanni@wustl.edu  
 
Sub-Investigators 
 
 
 
 
Modality 
David DeNardo, Ph.D. 
 
 
 
Molecular Oncology 
Ryan Fields, M.D. 
 
 
 
 
Surgical Oncology 
William Chapman, M.D. 
 
 
 
Transplant Surgery 
Maria Bernadette Doyle, M.D. 
 
 
Transplant Surgery 
Adeel Khan, M.D. 
 
 
 
 
Transplant Surgery 
William Hawkins, M.D. 
 
 
 
Hepatobiliary Surgery 
Dominic Sanford, M.D. 
 
 
 
Hepatobiliary Surgery 
Natasha Leigh, M.D.  
 
 
 
Hepatobiliary Surgery 
Kian-Huat Lim, M.D., Ph.D.  
 
 
Medical Oncology 
Olivia Aranha, M.D.   
 
 
 
Medical Oncology 
Nusayba Bagegni, M.D.  
 
 
 
Medical Oncology 
Salman Chaudhry, M.D.  
 
 
 
Medical Oncology 
Patrick Grierson, M.D.  
 
 
 
Medical Oncology 
Tanner Johanns, M.D., Ph.D.  
 
 
Medical Oncology 
Moh’d Khushman, M.D. 
 
 
 
Medical Oncology 
Peter Oppelt, M.D. 
 
 
 
 
Medical Oncology 
Katrina Pedersen, M.D.  
 
 
 
Medical Oncology 
Caron Rigden, M.D.  
 
 
 
Medical Oncology 
Rama Suresh, M.D.   
 
 
 
Medical Oncology 
Benjamin Tan, M.D.   
 
 
 
Medical Oncology 
Nikolaos Trikalinos, M.D.  
 
 
 
Medical Oncology 
Crystal Wolf, M.S. 
 
 
 
 
Medical Oncology 
Samuel Ballentine, M.D. 
 
 
 
Pathology and Immunology 
Liang-I Kang, M.D., Ph.D. 
 
 
 
Pathology and Immunology 
 
Study Drugs:  
 
CDX-301, CDX-1140 
IND#: 
153513 
IND Sponsor: 
Roheena Z. Panni, M.D. 
NCT#: 
NCT04536077 

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Funded by: 
Celldex Therapeutics (drug only) 
 
The Foundation for Barnes-Jewish Hospital 
 
Swim Across America – Siteman Investment Program 
 
National Institutes of Health 
 
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 
 
 
 
 

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Testing the immunologic effects of CDX-301 and CDX-1140 in resectable pancreatic cancer 
patients 
 
Protocol Revision History 
 
Initial Approval 
 
 
 
 
 
 
 
19 November 2020 
Amendment #1 
 
 
 
 
 
 
 
03 February 2021 
Amendment #2 
 
 
 
 
 
 
 
30 September 2021 
Amendment #2.1 
 
 
 
 
 
 
 
08 December 2021 
Amendment #3 
 
 
 
 
 
 
 
06 October 2022 
Amendment #4 
 
 
 
 
 
 
 
13 December 2022 
Amendment #4.1 
 
 
 
 
 
 
 
30 November 2023 
 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 

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PROTOCOL SUMMARY 
 
Synopsis 
 
Title: 
Testing the immunologic effects of CDX-301 and CDX-1140 in 
resectable pancreatic cancer patients 
Study Description: 
Our central hypothesis is that the addition of CDX-301 to CDX-1140 
radically improves anti-tumor immunity in patients with pancreatic 
ductal adenocarcinoma. 
Objectives: 
Primary Objective: To determine the amount of intratumoral 
conventional dendritic cells in patients with resectable pancreatic 
cancer treated with neoadjuvant CDX-1140 vs. CDX-301 plus CDX-
1140. 
 
Exploratory Objectives:  
1. To determine the changes in global immune profile of in patients 
with resectable pancreatic cancer treated with neoadjuvant CDX-
1140 vs. CDX-301 plus CDX-1140. 
2. To assess local control rate in patients with resectable pancreatic 
cancer treated with neoadjuvant CDX-1140 vs. CDX-301 plus 
CDX-1140. 
3. To assess distant metastasis-free survival of surgically resectable 
pancreatic cancer patients treated with neoadjuvant CDX-1140 
vs. CDX-301 plus CDX-1140. 
4. To assess overall survival of surgically resectable pancreatic 
cancer patients treated with neoadjuvant CDX-1140 vs. CDX-
301 plus CDX-1140. 
5. To assess extent of surgical margin negative resection in patients 
treated with neoadjuvant CDX-1140 vs. CDX-301 plus CDX-
1140. 
6. To assess the safety and tolerability profile of CDX-1140 vs. 
CDX-301 plus CDX-1140 in surgically resectable pancreatic 
cancer patients. 
Endpoints: 
Primary Endpoint: Intratumoral conventional dendritic cells (cDCs) 
at surgery.  
 
Exploratory Endpoints: Global immune profiling by CyTOF, single 
cell RNASeq analysis, and histologic assessments, local control rate, 
distant metastasis-free survival, overall survival, margin negative 
resection rate, and adverse events. 
Study Population: 
The study will enroll adults with surgically resectable pancreatic 
ductal adenocarcinoma. Enrollment will continue until 12 patients 
evaluable for the primary objective have been enrolled in each arm. 
Phase: 
II 
Description of Sites / 
Facilities Enrolling: 
Siteman Cancer Center at Washington University School of 
Medicine. 

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Description 
of 
Study 
Intervention: 
Consenting and eligible patients will be randomized on a 1:1 basis 
CDX-1140 followed by surgery or CDX-301 plus CDX-1140 
followed by surgery until 12 patients evaluable for the primary 
objective have been enrolled in each arm. 
 
Patients randomized to the CDX-1140 monotherapy arm will receive 
a single IV infusion at a dose of 1.5 mg/kg, with surgery to follow 7-
12 days after administration of CDX-1140. 
 
Patients randomized to the CDX-301 + CDX-1140 arm will receive 
CDX-301 at 75 mcg/kg/day as a subcutaneous injection every day 
for 5 days (Days 1-5) with CDX-1140 IV at 1.5 mg/kg on Day 8 +/-
1 day.  Surgery will be 7-12 days after administration of CDX-1140. 
 
For both arms, patients will undergo blood collection at the start of 
treatment and at the time of surgery, and all surgically resected 
tissues will be subjected to biomarker analysis. 
Study Duration: 
36 months (recruitment) + 3 weeks (intervention) + 24 months 
(follow-up) + 24 months (analysis) 
Participant Duration: 
30 days 
 
 
 
 
 
 
 
 
 
  
 

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SCHEMA 
 
 
 
 
 

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Table of Contents 
PROTOCOL SUMMARY .............................................................................................................. 5 
Synopsis ...................................................................................................................................... 5 
SCHEMA ........................................................................................................................................ 7 
SCHEDULE OF ACTIVITIES..................................................................................................... 10 
Arm 1 Calendar ......................................................................................................................... 10 
Arm 2 Calendar ......................................................................................................................... 11 
1.0 
INTRODUCTION ............................................................................................................. 12 
1.1 
Study Rationale .............................................................................................................. 12 
1.2 
Background .................................................................................................................... 12 
1.3 
Study Design .................................................................................................................. 16 
1.4 
Risk/Benefit Assessment ................................................................................................ 20 
2 
OBJECTIVES AND ENDPOINTS ....................................................................................... 22 
3 
STUDY POPULATION ........................................................................................................ 23 
3.1 
Inclusion Criteria ............................................................................................................ 23 
3.2 
Exclusion Criteria ........................................................................................................... 24 
3.3 
Inclusion of Women and Minorities............................................................................... 25 
4 
REGISTRATION PROCEDURES ....................................................................................... 25 
4.1 
Confirmation of Patient Eligibility ................................................................................. 25 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 25 
4.3 
Assignment of UPN ....................................................................................................... 26 
4.4 
Screen Failures ............................................................................................................... 26 
4.5 
Strategies for Recruitment and Retention ...................................................................... 26 
4.6 
Measures to Minimize Bias:  Randomization ................................................................ 26 
5 
TREATMENT PLAN............................................................................................................ 26 
5.1 
Premedication Administration........................................................................................ 26 
5.2 
Study Intervention Administration ................................................................................. 27 
5.3 
Definitions of Evaluability ............................................................................................. 27 
5.4 
Concomitant Therapy and Supportive Care Guidelines ................................................. 28 
5.5 
Women of Childbearing Potential .................................................................................. 29 
5.6 
Duration of Therapy ....................................................................................................... 30 
5.7 
Duration of Follow-up .................................................................................................... 30 
5.8 
Lost to Follow-Up .......................................................................................................... 30 
5.9 
Protocol Stopping Criteria .............................................................................................. 31 
6 
DOSE DELAYS/DOSE MODIFICATIONS ........................................................................ 31 
7 
REGULATORY AND REPORTING REQUIREMENTS ................................................... 32 
7.1 
Sponsor-Investigator Reporting Requirements .............................................................. 32 
7.2 
Exceptions to Expedited Reporting ................................................................................ 35 
8 
PHARMACEUTICAL INFORMATION ............................................................................. 36 
8.1 
CDX-301 ........................................................................................................................ 36 
8.2 
CDX-1140 ...................................................................................................................... 38 
9 
CORRELATIVE STUDIES .................................................................................................. 43 
9.1 
Fresh Tumor Tissue ........................................................................................................ 43 
9.2 
Archived Tumor Tissue .................................................................................................. 43 
9.3 
Research Blood .............................................................................................................. 43 
9.4 
Specimen Analysis ......................................................................................................... 44 

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10 
DATA SUBMISSION SCHEDULE ................................................................................. 45 
10.1 Adverse Event Collection in the Case Report Forms ..................................................... 46 
11 
MEASUREMENT OF EFFECT........................................................................................ 46 
12 
DATA AND SAFETY MONITORING ............................................................................ 46 
13 
STATISTICAL CONSIDERATIONS............................................................................... 47 
13.1 Study Design .................................................................................................................. 47 
13.2 Sample Size Calculation................................................................................................. 48 
13.3 Accrual ........................................................................................................................... 48 
13.4 Statistical Analyses ........................................................................................................ 48 
14 
REFERENCES .................................................................................................................. 50 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 53 
APPENDIX B: Definitions for Adverse Event Reporting ............................................................ 54 
APPENDIX C: Reporting Timelines ............................................................................................ 56 
 
 
 
 
 

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SCHEDULE OF ACTIVITIES 
 
Arm 1 Calendar 
 
 
Screening3 
7-12 days prior 
to surgery 
Surgery 
Follow-up4 
Informed consent 
X 
 
 
 
ECOG PS 
X 
 
X7 
 
CBC w/diff 
X 
 
 
 
CMP 
X 
 
 
 
INR, aPTT 
X 
 
 
 
Pregnancy test1 
X 
 
 
 
Randomization 
X2 
 
 
 
CDX-1140 
 
X 
 
 
Research blood 
X 
X5 
X 
 
Research tissue 
 
 
X 
 
AE assessment6 
 
X 
X7,8 
X 
Progression and 
survival 
 
 
 
X 
1. For female patients of childbearing potential only. 
2. After confirmation of eligibility. 
3. Screening should occur no more than 6 weeks prior to surgery, CBC within 3 weeks prior to start of CDX-
1140. 
4. Follow-up will occur at standard of care office visits (approx. Q6M) for 24 months after surgery. 
5. Prior to CDX1140 administration. 
6. AEs will be collected from time of administration of CDX-1140 until surgery, or until 60 days after end of 
treatment if surgery doesn’t take place. A phone call or medical record check may take place at the 60 day 
time point (+/- 2 weeks) for AE collection if surgery doesn’t take place. 
7. Follow-up in person visit or call with physician’s office will occur 24-48 hours after administration of 
CDX-1140 to evaluate any acute changes.  
8. Assessment of AEs may be done at an outpatient visit 7 +/- 2 days after administration of CDX-1140 or 
after admission for surgery. 
 
 

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Arm 2 Calendar 
 
 
Screening5 D1 D2 D3 D4 D5 
D810 
Surgery3 
Follow-
up6 
Informed consent 
X 
 
 
 
 
 
 
 
 
ECOG PS 
X 
 
 
 
 
 
 
X8 
 
CBC w/diff 
X 
 
 
 
 
 
 
 
 
CMP 
X 
 
 
 
 
 
 
 
 
INR, aPTT 
X 
 
 
 
 
 
 
 
 
Pregnancy test1 
X 
 
 
 
 
 
 
 
 
Randomization 
X2 
 
 
 
 
 
 
 
 
CDX-1140 
 
 
 
 
 
 
X 
 
 
CDX-301 
 
X 
X 
X 
X 
X 
 
 
 
Research blood 
X4 
 
 
 
 
X4 
X4 
 
Research tissue 
 
 
 
 
 
 
 
X 
 
AE assessment 
 
 
X ------------------------------------ X7,8,9 
X7 
Progression and 
survival 
 
 
 
 
 
 
 
 
 
X 
1. For female patients of childbearing potential only. 
2. After confirmation of eligibility. 
3. 7-12 days after administration of CDX-1140. 
4. First research blood draw will take place at screening or at any point prior to the first dose of CDX-301, second 
on day 8 prior to CDX1140 administration, and third at time of surgery.  
5. Screening should occur no more than 6 weeks prior to surgery, CBC within 3 weeks prior to start of CDX-1140. 
6. Follow-up will occur at standard of care office visits (approx. Q6M) for 24 months after surgery. 
7. AEs will be collected from time of administration of CDX-301 until surgery, or until 60 days after end of 
treatment if surgery doesn’t take place. A phone call or medical record check may take place at the 60 day time 
point (+/- 2 weeks) for AE collection if surgery doesn’t take place. 
8. Follow-up in person visit or call with physician’s office will occur 24-48 hours after administration of CDX-
1140 to evaluate any acute changes.  
9. Assessment of AEs may be done at an outpatient visit 7 +/- 2 days after administration of CDX-1140 or after 
admission for surgery. 
10. Administration of CDX-1140 is on day 8 +/- 1 day. 
 
 
 

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1.0 
INTRODUCTION 
 
1.1 
Study Rationale 
 
The prognosis for pancreatic ductal adenocarcinoma (PDAC) patients is dismal. Therefore, 
the development of new and effective clinical approaches represents a significant unmet 
medical need. Unfortunately, attempts at immunotherapy in PDAC to date have not 
achieved significant clinical benefit as single agents1. This is likely due to the presence of 
a uniquely suppressive tumor microenvironment (TME). Two major drivers of this tumor 
protective microenvironment include a dense fibrotic tumor stroma and robust infiltration 
by tumor-supportive myeloid cells2, 3. High stromal density provides a barrier to the 
delivery of cytotoxic agents and limits T cell infiltration and function4, 5. Additionally, data 
from our group has shown that significant infiltration of PDAC tumors by immune-
suppressive macrophages decreases the efficacy of immunotherapy by inducing 
dysfunction in T cells6-9. While much focus has been on immune suppression within the 
PDAC TME, our recent data described below suggest immune priming by conventional 
dendritic cells (cDCs) may ultimately be the larger barrier to overcome. 
 
Conventional dendritic cells (cDCs) are central for generating tumor antigen specific 
responses in T cells 10. Thus, in animal models and human correlative studies, cDCs have 
been shown to be critical for responsiveness to both checkpoint immunotherapy and the 
induction of tumor immunity by radiation therapy10. Our striking new data has found that 
cDCs are severely dysfunctional in human PDAC patients. This dysfunction is driven by 
two mechanisms: 1) As we recently published (Meyer et al. Nature Comms. 2018 11) PDAC 
patients have impaired development of cDCs in their bone marrow, leading to functional 
depletion of circulating pre-DCs, impaired cross presentation to cytotoxic T lymphocytes 
(CTLs), and poor responsiveness to checkpoint inhibitors11; 2) In recent data (Hedge et al 
Cancer Cell 2020 12), we have shown that even when cDC development is not impaired, 
cDC1s are physically/biochemically excluded from the PDAC TME. We have found that 
treatment with systemic FLT3L and CD40 agonists overcomes cDC exclusion to drive 
tumor immunity that in turn slows tumor progression. 
 
1.2 
Background 
 
 Study disease 
 
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease whose 
incidence is increasing 13, 14. Currently, pancreatic cancer is the third most common 
cause of cancer death in the United States. Only 24% of pancreatic cancer patients 
survive >1 year from diagnosis, and only 9% live for 5 years 13, 15. Current therapies 
are woefully inadequate and costly14, 16. Efforts focusing on early detection are still 
in their infancy17. Proximate solutions to modifiable risk factors, such as smoking 
and obesity, are lacking18, 19. Many standard therapies that are effective for other 
cancers, including immune checkpoint blockade and radiation therapy, have little 
to no effect on survival in pancreatic cancer. In the last decade, multi-agent 

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cytotoxic chemotherapy has modestly improved the median survival at the cost of 
significant toxicity20, 21. Unfortunately, this increase in median survival has not 
translated into an overall survival benefit. New agents and novel approaches are 
desperately needed for pancreatic cancer. Any progress towards an effective 
treatment strategy for pancreatic cancer would be a highly significant healthcare 
advance.  
 
 Summary of Nonclinical Findings for CDX-301 
 
Hundreds of non-clinical studies have documented the biological activities of Flt3L 
in vivo and in vitro. Notably, CDX-301 is human Flt3L.  Administration of 
recombinant human Flt3L into mice and other laboratory species results in a broad 
expansion of HSC. These effects are transient, and hematopoietic values return to 
normal upon stopping recombinant Flt3L treatment. The most distinguishable in 
vivo CDX-301 effects have been observed within the dendritic cell (DC) 
compartment. Large numbers of DCs are generated in murine spleen, bone marrow, 
and the peripheral circulation, and these effects of recombinant Flt3L are far more 
potent than those following treatment with other DC growth promoting cytokines 
such as GM-SCF.  
 
 CDX-1140 Physical, Chemical, and Pharmaceutical Properties 
 
CDX-1140 is a human IgG2κ mAb with a calculated polypeptide molecular weight 
of 144,766 Da and a potential N-linked glycosylation site on the heavy chain. Based 
on the amino acid sequence, glycoform analysis, peptide mapping, and mass 
spectrometry, the overall structure of CDX-1140 is as expected for a human IgG2κ 
mAb with pairs of heavy and light chains stabilized through intra- and inter-chain 
disulfide bonds22. CDX-1140 is generated by in vitro Chinese hamster ovary (CHO) 
cell culture and using standard mAb purification methods. The CDX-1140 
formulated drug substance and drug product are identical in terms of formulation 
and concentration. 
 
 Rationale for CD40 agonism with CDX-1140  
 
Similar to other TNFR/TNFL family members,   CD40 signaling through the 
receptor appears optimal when the CD40L is constrained in a trimeric arrangement, 
thereby enforcing a co-localization or clustering of the CD40 itself, and the 
subsequent recruitment and interaction with TNF receptor associated factors 
(TRAFs). Thus, the requirement for FcR-mediated cross-linking of the agonist 
CD40 mAbs to effect a similar co-localization is reflected in the isotype-
dependence and FcR specificities of the resulting agonist activities. 
 
Two research groups concluded that FcγRIIb engagement was required for anti-
CD40 agonist activity 23, 24; however, it was cross-linking and not the intracellular 
signaling that was required, and cellular distribution as much as affinity was 
important for in vivo activity. Subsequently, it was shown that human IgG2 isotypes 

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of anti-CD40 mAb had greater agonist activities, such as B cell proliferation and 
CD70 up-regulation on DCs, than corresponding IgG1 isotypes and that this was a 
consequence of the IgG2 hinge region and was independent of FcγR binding 25. In 
general, the capacity of a particular mAb to promote colocalization or clustering of 
CD40, whether through FcγR interactions or independent of such interactions, 
favors downstream signaling and agonistic activities. Among several agonist anti-
CD40 mAb currently in oncology clinical trials is the highly agonistic CP-870,893 
mAb 26, 27. While clinical experience with CP-870,893 has provided encouraging 
evidence of activity, this was associated with significant dose-limiting toxicity and 
a maximally tolerated dose (MTD) of 0.2 mg/kg. Such a low dose (≤ 0.2 mg/kg) 
may not be ideal for systemic use, because saturation of CD40 on tissue resident 
DCs or macrophages may not be achieved at these dose levels due to the wide-
spread expression of CD40 on non-immune cells and some tumors28, 29. As these 
authors suggest, perhaps an alternative anti-CD40 mAb better suited for systemic 
use would have somewhat less potent agonist activity than CP-870,893 and thus 
could be used at higher doses, improving the likelihood of fully engaging 
macrophages and DCs in these tissues. As such we anticipate CDX-1140 overcome 
these issues. 
 
 Selected preclinical studies of CDX-301 and CDX-1140 
 
Flt3L Mobilizes Dendritic Cells 
• In mice, Flt3L increases the number of DC in the spleen, lymph nodes and 
peripheral blood. These DC are equivalent to splenic DC from untreated mice 
in presenting alloantigens and/or soluble antigens to T cells in vitro, and in 
priming an antigen-specific T cell response in naïve mice in vivo 30. 
• Flt3L administered subcutaneously at 100 μg/kg/day for 5-7 days was as 
effective as 14 days of such dosing in expanding the numbers of circulating DC 
in rhesus macaques. Numbers of DC peaked at approximately 4 days post 7 
days of treatment and decreased thereafter. The DC were predominantly of 
immature phenotype but were capable of being activated and expressing IL-12 
upon subsequent in vitro culture and stimulation with CD40L 31. 
• Flt3L treatment of humanized mice generated large numbers of human CD141+ 
(BDCA-3) and CD1c+ (BDCA-1) DC, and to a lesser extent plasmacytoid DCs, 
in the blood, spleen, and bone marrow. The CD141+ DC could be efficiently 
activated with poly-ICLC and crosspresentantigen to CD8 T cells 32. 
 
Flt3L Enhances Immune Responses 
• In mice immunized with ovalbumin, administration of Flt3L influences the 
class of antibody produced and enables productive immune responses to 
otherwise tolerogenic protocols 33. 
• Flt3L-treated mice developed lower cellular and humoral immune responses to 
transcutaneous administered hen egg lysozyme (HEL) than did PBS-treated 
control mice. In the presence of cholera toxin, however, Flt3L-treated mice 
developed significantly higher cellular and humoral immune responses to HEL 
when compared to PBS-treated mice 34. 

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Flt3L Enhances Anti-Tumor Responses and Retards Tumor Growth 
• Flt3L completely prevented B10.2 fibrosarcomas in >70% of mice when 
administered on the day of tumor cell inoculation (partial regression was 
observed in most other Flt3L-treated animals). Delaying treatment with a higher 
dose of Flt3L to 1 week after tumor inoculation still resulted in complete 
rejection of established tumors in 72% of mice. Spleen cells from Flt3L-treated 
mice transferred anti-tumor activity, which was abrogated by antibody 
 
 Pancreas Cancer-Specific Studies with CDX-301 and CDX-1140 
 
Mobilizing cDCs into early pancreatic lesions can reverse fibro-inflammatory 
responses  
We tested if increasing cDCs in early stages of PDAC could reassert TH1 and CTL-
mediated disease control. To accomplish this, we stimulated hematopoietic 
mobilization of cDC precursors using Fms-related tyrosine kinase 3 ligand (Flt3L) 
treatment 35-37. Flt3L administration at early stages of tumorigenesis resulted in 
robust infiltration of cDCs in the pancreas, including a 10-fold increase in cDC1s 
and revert disease acceleration and fibro-inflammatory pathology of PDAC in 
mice. Flt3L treatment also resulted in reduced number of pathogenic ROR-γt+ IL-
17A-expressing TH cells and increases in IFN-γ-producing TH1 cells. Flt3L 
treatment increased CD8+ T cell, proximity to lesions, effector function as measured 
by IFN-γ+ and TNF-α+ production, and proliferation. Together these data imply that 
restoring cDC numbers in early stages of PDAC results in a switch from pathogenic 
tumor-promoting TH17 to tumor-restraining TH1 and CD8+ CTL responses to 
neoantigens. 
 
Enhancing cDC infiltration and activation in advanced PDAC leads to disease 
stabilization 
Our observations raised the possibility that Flt3L-based cDC mobilization in 
established pancreatic tumors could benefit anti-tumor immunity. Additionally, our 
previous work has shown that established PDAC in human patients and mouse 
PDAC models can impair cDC1 development in the bone marrow 36 and therapeutic 
strategies might require boosting cDC mobilization to overcome this disruption. 
Thus, we treated PDAC bearing mice bearing advanced tumors with Flt3L. 
Notably, increases in cDC infiltration upon Flt3L treatment were more modest in 
established PDAC compared to premalignant pancreas and in this advanced setting 
FLT3L alone did not change intratumoral CTL infiltration.  
 
To overcome this barrier, we administered CD40-agonist IgGs to improve licensing 
and enhance APC function and survival 38, 39. We found the combination of Flt3L 
with CD40 agonists worked synergistically to drive massive influx of cDC1s and 
cDC2s, with CD40 agonist showing clear superiority and a >64-fold increase in 
cDC1s. Additionally, the combination with Flt3L triggered markedly enhanced 
intratumoral CD8+ CTL and CD4+ TH cell infiltration without TREG induction. 
Notably, the CD40 agonist plus Flt3L treatment elicited integrated anti-tumor 

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responses involving marked increases in infiltrating NK cells, NKT cells and γδT 
cells.  
 
Combining Flt3L administration with CD40 agonism resulted in improved disease 
control beginning a week into treatment in multiple PDAC mouse models. Together 
these data suggest synergistic activities of FLT3L (CDX-301) plus CD40 agonists 
(CDX-1140) can directly improve tumor immunity and retard disease progression 
in mouse models of PDAC.  
 
1.3 
Study Design 
 
 Overall Design 
 
Hypothesis: The combination of CDX-301 and CDX-1140 will work 
synergistically to improve anti-tumor immunity, both within tumor tissue and 
systemically. Specifically, we believe these two agents will combine to increase 
cDCs and T cells within tumor tissues. 
 
Clinical trial design: The trial is a phase II, single institution, open-label, 
randomized trial treating patients with surgically resectable pancreas cancer. 
Patients will be accrued upon designation of surgical resectability by our tumor 
board. Patients will be randomized to receive either CDX-1140 alone or CDX-310 
plus CDX-1140 prior to surgery. Patients will receive a single 7-day cycle of 
treatment followed by surgery 7-12 days after cycle completion. Surgical resection 
tissue will be accessed for endpoint and compared historical controls. 
 
 Justification for Dose 
 
Recombinant human FLT3 ligand, AMG949 originally developed by Immunex and 
subsequently acquired by Amgen, 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, FLT3 ligand 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 
mobilization of immature DCs by FLT3 ligand and the absence of appropriate DC 
maturation signals and/or limited DC access to tumor antigens. 
 
More recently, recombinant human FLT3 ligand (CDX-301) developed by Celldex, 
which is identical in amino acid sequence to AMG949 but produced utilizing a 
serum-free manufacturing process, has been demonstrated to expand and mobilizes 
DCs into the peripheral blood and tissues, including into the tumor 
microenvironment. As of May 28, 2020, healthy volunteers (n=30), allogenic 
hematopoietic stem cell donors (n=4) or cancer patients (n=116), for a total of 150 
subjects, have been treated with CDX-301 as monotherapy or in combination with 
other agents. 

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CDX-301 has been shown to expand CD141+(BDCA3+) conventional DCs (cDCs) 
in healthy volunteers. In these same subjects, CDX-301 was also shown to expand 
precursor cDCs (pre-cDCs) that produce the two major cDC subsets, the 
CD141+(BDCA3+) and the CD1c+ DCs. DC expansion peaks approximately two 
weeks after initiation of FLT3 ligand therapy (see figure below). The intratumoral 
injection of CDX-301 also increases the number of CD141+ DCs in blood and in 
the injected tumor40. CDX-301 also expanded CD141+ DCs and augmented the 
kinetics, magnitude, and frequency of cellular and immune responses to a NY-ESO-
1 vaccine (CDX-1401) in patients with resected melanoma. 
 
 
 
Expansion of two dendritic cell populations in healthy volunteers treated with CDX-301 peaks at 10-14 days after 
treatment initiation. (source: Celldex Therapeutics) 
 
CDX-301 has been evaluated in two Celldex-sponsored clinical studies as 
monotherapy in healthy volunteers and donor/recipients (CDX301-02 and 
CDX301-03), in one study in combination with the antibody-drug conjugate 
glembatumumab vedotin in advanced melanoma (CDX011-05), and in one study 
in combination with CDX-1140 in advanced malignancies (CDX1140-01). CDX-
301 has also been investigated in four investigator-initiated studies: in combination 
with radiotherapy for non-small cell lung cancer (CDX301-53), in combination 
with poly-ICLC and radiotherapy in lymphoma (CDX301-51), in combination with 
poly-ICLC, radiotherapy and pembrolizumab in non-Hodgkin’s lymphoma, 
metastatic breast cancer and head and neck squamous cell carcinoma 
(CDX301-58), and in combination with poly-ICLC and the cancer vaccine CDX-
1401 in malignant melanoma (CDX1401-54).  
CDX-301 has been well 
tolerated. One SAE of grade 3 community-acquired pneumonia in the healthy 
volunteer study CDX301-02 was attributed to CDX-301.  Across all trials, no 
additional SAEs, and no deaths, have been assessed as related to CDX-301. In 
general treatment-related AE following CDX-301 administration are infrequent and 
mild to moderate in severity. Across all trials through August 2019, the most 
common treatment-related AE has been lymphadenopathy in 6 subjects (13%). 
Additional treatment-related grade 1 and grade 2 AEs that have been reported ≥ 5% 
of all patients treated with CDX-301 include: injection site reaction (including 
erythema, rash, reaction or pain; 8%), chills (6%), dyspepsia (6%), fatigue (6%), 
and hot flush (6%).  One case of chills (2%), two cases of fatigue (4%), and two 

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cases of hot flush (4%) were also attributed to CDX-1140; a single case of fatigue 
(2%) was also attributed to glembatumumab vedotin. The CDX-301 Investigator 
Brochure provides additional details. 
 
The safety, biological activity, and preliminary clinical activity of CDX-1140 as 
monotherapy and in combination with CDX-301 (FLT3 ligand) is being established 
in an ongoing phase I dose escalation and expansion trial (CDX1140-01; 
NCT03329950) whose interim results were presented at the 2019 AACR Annual 
Meeting. CDX-1140 is administered intravenously monthly, and CDX-301 is 
administered 75 μg/kg subcutaneously daily for 5 days the week prior to CDX-1140 
during cycles 1 and 2.  As of May 28th, 2020, a total of 89 patients have been 
administered CDX-1140, with 55 administered CDX-1140 monotherapy, 31 
administered CDX-1140 in combination with CDX-301, and 3 patients 
administered CDX-1140 in combination with pembrolizumab. The Maximum 
Tolerated Dose (MTD) of CDX-1140 was determined to be 1.5 mg/kg. To date in 
the CDX1140-01 trial, 23 patients have been administered CDX-1140 monotherapy 
at 1.5 mg/kg, and 10 have been administered CDX-1140 at 1.5 mg/kg in 
combination with CDX-301. 
 
Although not the primary objective of the study, evidence of anti-tumor activity has 
been observed, with an unconfirmed iRECIST partial response in a patient with 
gastroesophageal adenocarcinoma, treated with CDX-1140 + CDX-301. In 
addition, 2 patients with HNSCC who received CDX-1140 monotherapy have had 
early evidence of an anti-tumor effect with, cavitation and/or necrosis of lesions on 
CT scan.   
 
CDX-1140 is biologically active, with increases in serum cytokine and chemokines 
observed in the study, as well as increased activation markers on dendritic cells and 
B-cells.  Preliminary data indicates that CDX-301 increased the level of serum IL-
12p40. 
 
Most side effects associated with CDX-1140 have occurred in the 24-48 hours 
following the CDX-1140 infusion, consisted of infusion reactions/cytokine release 
syndromes, have been mild to moderate in severity, and have resolved with or 
without medications such as acetaminophen, NSAIDS, and/or anti-nausea 
medication. In a few cases, the side effects have been severe and have required 
hospitalization and treatment with corticosteroids or other immunosuppressive 
medications. Treatment related adverse events that have occurred in > 10% of 
patients are as follows: fatigue, joint pain, nausea, chills, fever, diarrhea, muscle 
pain, vomiting. Transient (usually low-grade) increases in liver transaminases have 
been seen in some patients, but no patient has had to discontinue therapy because 
of increased liver function tests. Cytokine release syndrome (including symptoms 
of fever, hypotension, hypoxia, fatigue, headache, and nausea) and pneumonitis 
have been the most common SAEs reported. Thus far, CDX-301 does not seem to 
add to the side effect profile of CDX-1140. The CDX-1140 Investigator Brochure 
provides additional details. 

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Our recommended phase II dose levels come from a phase I clinical trial that has 
established a MTD for CDX-1140 (Study CDX1140-01), as well as previous 
studies that have studied the MTD for CDX-301. These studies show the majority 
of potential toxicity comes CDX-1140, consistent with the mechanism of action of 
each drug.  
 
CDX-1140 is being studied in one clinical trial. The first in human (FIH) trial 
(Study CDX1140-01) is an open-label, non-randomized, multicenter, dose-
escalation study with expansion cohorts to evaluate the safety, tolerability, 
pharmacokinetics, pharmacodynamic, and clinical activity of intravenous CDX-
1140 as a monotherapy and in combination with subcutaneous CDX-301 (Flt3L) in 
patients with advanced solid tumors and hematologic malignancies.  
 
As of a cut-off date of 9/5/2019, a total of 58 patients have been treated; 41 with 
CDX-1140 monotherapy and 17 patients with CDX-1140 plus CDX-301 
combination therapy. The Maximum Tolerated Dose (MTD) and recommended 
dose and administration schedule for CDX-1140 monotherapy has been defined as 
1.5mg/kg every four weeks.   
 
CDX-301 and CDX-1140 had been used previously, alone and in combination, at 
the doses we are giving without grade 3 or higher AEs.  The combination has also 
been used safely in a dose escalation trial NCT03329950.  Few of these prior studies 
incorporated pancreatic cancer patients, which is why the first six patients on our 
study will be treated as phase I and assessed for potential toxicity.  
 
Initial studies examined the tolerability of CDX-301 alone. Using a standard 3+3 
dose-escalating design, sequential cohorts of 3–6 healthy volunteers received CDX-
301 by daily SC injection at a dose level of 1, 3, 10, 25 or 75 μg/kg for 5 days 
(Cohorts 1–5), 25 μg/kg for 7 days (Cohort 6) or 25 μg/kg for 10 days (Cohort 
7). Transient lymphadenopathy (Grade 1) was seen in six subjects (25 or 
75 μg/kg/day cohorts) and single cases of diarrhea, injection site erythema, 
folliculitis and dry mouth (all Grade 1) were observed. A single subject receiving 
CDX-301 at 75 μg/kg/day for 5 days developed community-acquired pneumonia 
on day 12. No other AE’s were seen.  
 
CDX-301 was given in a subsequent study (25 μg/kg) with a lower dose of RT (2 
Gy x 2) and another immune therapy without toxicity in lymphoma patients 
(Hammerich et al, Nat Med 2019).   
 
 Scientific Rationale for Study Design 
 
The key questions for these CDX-1140 and CDX-301 as anti-cancer agents in 
PDAC patients is what exactly their effects are on tumor infiltrating immune cells. 
While significant pre-clinical and modest clinical data are already present for both 
agents; Without fully understanding their effects in human PDAC tissues it is 

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difficult to predict the optimum ways to employ these agents.  In this study for our 
primary endpoint of changes in intratumoral cDCs we will compare to historical 
tissues and analysis of untreated PDAC patients. Thus, here-in we will simply run 
two arms testing CDX-1140 alone and CDX-301 plus CDX-1140.  
 
1.4 
Risk/Benefit Assessment 
 
 Known Potential Risks  
 
Evidence from mouse and human tolerability studies suggest the study drugs, at the 
doses we are using, have a safety profile supportive of its further development as 
an anti-cancer therapeutic.  
 
Treatment related adverse events that have occurred in > 10% of patients are as 
follows: fatigue, joint pain, nausea, chills, fever, diarrhea, muscle pain, and 
vomiting. Transient changes in liver function tests, platelet count, and lymphocyte 
count have been observed with CDX-1140. Transient increases in liver 
transaminases are expected in the 24-48 hours following the administration of 
CDX-1140. These changes have been mostly low grade and typically return to 
baseline within 1-2 week after the infusion. Important observed risks include 
cytokine release syndrome and pneumonitis. SQ and IV injections may lead to local 
discomfort or pain, and in some cases, infection.  
 
 Known Potential Benefits 
 
If the hypothesis of this study is correct, the experimental therapy will initiate a 
productive immune reaction against the tumor, locally and systemically, which may 
result in partial or complete tumor elimination and/or prevention of metastatic 
disease, however the validity of this hypothesis in humans is not currently known.  
 
Thus far preliminary results of the phase I study of CDX-1140 with CDX-301 have 
been reported in poster form, and show: 
 
• 1 unconfirmed iPR of 4 months duration in combination cohort (CDX-
1140 0.36 mg/kg) – see below 
• 6 patients with iSD; 4 in CDX-1140 monotherapy and 2 in CDX-1140 + 
CDX-301 with a duration of 1.8 months to 5.4 months; 1 iUPD  
in CDX-1140 + CDX301 with a duration of 10+ months 
• Of 62 patients, 38 patients with activity assessments (scans) available 
and 7 have response data pending  
 
Individual patients with encouraging responses are as follows: 

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While there are no established benefits, results from prior preclinical and clinical 
work are encouraging for the potential of benefit.   
 
 Assessment of Potential Risks and Benefits 
 
The benefit-risk assessment of CDX-1140 with CDX-301 should be taken in the 
context of a drug in the early stages of development, and therefore is by definition 
uncertain and evolving. In the early clinical experience to date, this therapy has 
demonstrated an acceptable toxicity profile with evidence of biologic and clinical 
activity consistent with the mechanism of action.  
 
In the best-case scenario, and that predicted by prior animal studies, the potential 
benefit of this therapy is tumor regression. In a population of patients that is 
overwhelmingly incurable, the potential risk benefit ratio appears very favorable.   
 
 

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2 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Justification for 
Endpoints 
Primary 
To determine the amount of 
intratumor conventional 
dendritic cells in patients with 
resectable pancreatic cancer 
treated with neoadjuvant CDX-
1140 vs. patients with 
resectable pancreatic cancer 
treated with neoadjuvant CDX-
301 + CDX-1140. 
intratumoral cDCs in surgical 
tissues 
The immune therapy 
activates and increases the 
number of dendritic cells, 
which in mouse studies 
correlates with improved 
clinical outcome.  
Exploratory 
To report immunologic 
correlates in both groups 
before and after therapy. 
Immunologic correlates will be 
assessed by multiplex IHC, 
FACS, and CyTOF, performed 
on tumor tissue and blood. 
Global immune profiling by 
CyTOF, single cell RNASeq 
analysis, and histologic 
assessments,  
local control rate, distant 
metastasis-free survival, overall 
survival, margin negative 
resection rate. 
Immune correlates are 
important indicators of 
therapeutic effect, and may 
correlate with clinical 
response.  
To assess local control of 
resectable pancreatic cancer 
treated with neoadjuvant CDX-
1140 vs. resectable pancreatic 
cancer treated with 
neoadjuvant CDX-301 + CDX-
1140. 
To assess distant metastasis-
free survival of patients with 
resectable pancreatic cancer 
treated with neoadjuvant CDX-
1140 vs. resectable pancreatic 
cancer treated with 
neoadjuvant CDX-301 + CDX-
1140. 
To assess overall survival of 
patients with resectable 
pancreatic cancer treated with 
neoadjuvant CDX-1140 vs. 
resectable pancreatic cancer 
treated with neoadjuvant CDX-
301 + CDX-1140. 
To assess extent of resection in 
patients with resectable 

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pancreatic cancer treated with 
neoadjuvant CDX-1140 vs. 
resectable pancreatic cancer 
treated with neoadjuvant CDX-
301 + CDX-1140. 
To assess the safety and 
tolerability profile of CDX-
1140 vs. CDX-301 plus CDX-
1140 in surgically resectable 
pancreatic cancer patients. 
adverse events 
AE profile for this patient 
population. 
 
 
3 
STUDY POPULATION 
 
3.1 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed surgically resectable pancreatic ductal 
adenocarcinoma, but not adenosquamous/squamous pancreas cancers (as determined 
by operating surgeon or tumor board).  Patients who have previously received 
chemotherapy for his/her pancreas cancer within the past 6 months and who are now 
deemed resectable are also eligible for this trial. 
 
2. At least 18 years of age. 
 
3. ECOG performance status ≤ 1 (see Appendix A) 
 
4. Normal bone marrow and organ function as defined below: 
a. Absolute neutrophil count ≥ 1,500 /cumm 
b. Platelets ≥ 100,000 /cumm 
c. Hemoglobin ≥ 9.0 g/dL 
d. AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN 
e. Creatinine clearance ≤ 1.5 x IULN or glomerular filtration rate of ≥ 60 mL/min 
f. INR ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR 
or PTT is within therapeutic range of intended use of anticoagulants 
g. aPTT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR 
or PTT is within therapeutic range of intended use of anticoagulants 
h. Albumin ≥ 3.0mg/dL 
 
5. The effects of CDX-301 and CDX-1140 on the developing human fetus are unknown.  
For this reason, women of childbearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control, abstinence) prior to study 
entry, for the duration of study participation, and for 3 months after the last dose of 
either study drug.  Should a woman become pregnant or suspect she is pregnant while 
participating in this study or for 3 months after the last dose of either study drug, she 
must inform her treating physician immediately. 
 

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6. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. Immmune deficienties such as HIV. 
 
2. A history of other malignancy with the exception of malignancies for which all 
treatment was completed at least 2 years before registration and the patient has no 
evidence of disease. 
 
3. Currently receiving any other investigational agents or has received any other 
investigational agents within 4 weeks or 5 half-lives of the planned first dose of study 
treatment. 
 
4. Receipt of chemotherapy within 2 weeks of planned first dose of study treatment. 
 
5. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to CDX-301 or CDX-1140 or other agents used in the study. 
 
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(for > 1 month of 10 mg prednisone daily, or equivalent) or any other form of 
immunosuppressive therapy not routinely associated with chemotherapeutic regimen. 
 
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, immunosuppression, autoimmune conditions, or underlying pulmonary 
disease. 
 
8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, immunosuppression, autoimmune conditions, or underlying pulmonary 
disease. 
 
9. Has an autoimmune disease requiring systemic treatment within the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).  
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment. 
 
10. Known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) 
or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected). 
 
11. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
 
12. Has a known history of active TB (bacillus tuberculosis). 

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13. Major surgery within 28 days prior to the first study treatment. 
 
14. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
pregnancy test within 14 days of study entry. 
 
15. History of bone marrow or solid organ transplant.  
 
16. Patients with a history of myocardial infarction, cerebral vascular accident, thrombosis 
or pulmonary embolus within 12 months prior to the first dose of study treatment are 
excluded from this study. 
 
17. Patients with known mutations/amplifications in Flt3 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.  
 
 
4 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
 

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4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
4.4 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently randomized to the study intervention or entered in the study.  A 
minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants, to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities.  Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse event (if applicable).   
 
4.5 
Strategies for Recruitment and Retention 
 
All patients with pancreatic cancer are discussed in our weekly multidisciplinary tumor 
board and clinical trial options are reviewed. WUSM department of surgery preforms 
greater than 100 pancreatic cancer resections per year. Many of these patients would be 
eligible for this trial. We anticipate an accrual rate of approximately 15 patients per year. 
To have outreach meetings in the community to explain the radiation therapy and clinical 
trial options available at Washington University. We will accrue without respect to race, 
gender or socioeconomic background. 
 
4.6 
Measures to Minimize Bias:  Randomization 
 
Consenting and eligible patients will be randomized on a 1:1 basis to receive CDX-1140 
followed by surgery or CDX-301 + CDX-1140 followed by surgery until 12 patients 
evaluable for the primary objective have been randomized to each arm.  The randomization 
table will be generated by the statistician using a statistical software and will be uploaded 
to REDCap to randomize patients. 
 
 
5 
TREATMENT PLAN 
 
5.1 
Premedication Administration 
 
 CDX-1140 
 
Prophylactic premedication is required for all patients: diphenhydramine 25/50 mg 
(or equivalent anti-histamine), 500 to 750 mg paracetamol (acetaminophen), and 
naproxen sodium 250 mg (or equivalent NSAID) at least 30 minutes prior to CDX-
1140 administrations. Ranitidine 150 mg (or equivalent) may also be incorporated 
into the premedication regimen.  Prophylactic premedication with corticosteroids 

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is to be avoided because of the potential to attenuate the anti-tumor activity of 
CDX-1140.  
 
CDX-1140 will be administered intravenously over 90 minutes using a 0.22 micron 
in-line filter. 
 
CDX-1140 post-infusion medication is also required for all patients.  In the 24-48 
hours following the CDX-1140 infusion, alternate oral acetaminophen (1000 mg) 
and non-steroidal anti-inflammatory (e.g., ibuprofen 200 mg) q6H. An anti-
histamine and anti-emetic may also be utilized if clinically indicated.  Patients 
should be evaluated to determine if continuation of post-infusion medication is 
needed on the day after CDX-1140 dosing. Note that the potential for toxicity with 
these drugs and appropriate precaution should be utilized in patients with risk 
factors for toxicity, e.g. patients with peptic ulcers, increased LFTs, or increased 
creatinine. Also, care should be taken to medicate for no longer than is necessary 
in order to avoid potential confounding factors in determining adverse event 
causality (e.g. increased LFTs). 
 
All patients should be monitored for 4 to 6 hours post administration of CDX-1140 
with standard post-infusion monitoring. 
 
 CDX-301 
 
Injection site reactions have been infrequent and mild with CDX-301. Pre-
medication with diphenhydramine has been reported to be effective in the 
prevention of pruritic and erythemic reactions and may be considered for subjects 
who experience local reactions after treatment with CDX-301. Injection site 
reactions may also be treated with analgesics (i.e., Tylenol). If there is injection site 
pain, a numbing cream such as Emla cream can be used prior to administration of 
CDX-301. 
 
5.2 
Study Intervention Administration 
 
Patients randomized to the CDX-1140 monotherapy arm will receive a single IV infusion 
at a dose of 1.5 mg/kg, with surgery to follow 7-12 days after administration of CDX-1140. 
 
Patients randomized to the CDX-301 + CDX-1140 arm will receive CDX-301 at 75 
mcg/kg/day as a subcutaneous injection every day for 5 days (Days 1-5) with CDX-1140 
IV at 1.5 mg/kg on Day 8.  Patients will be required to be present in clinic for each injection. 
Surgery will be 7-12 days after administration of CDX-1140. 
 
5.3 
Definitions of Evaluability 
 
Patients must undergo collection of blood and tissue at the time of resection in order to be 
evaluable for the primary objective of determining amount of intratumor cDC.  Patients 
who are not evaluable for the primary objective will not count towards analysis of this 

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objective and will be replaced. However, these patients will continue on study/in follow-
up to be followed for toxicity and local control, DMFS, and OS regardless of whether they 
had resection. 
  
All patients who receive any study treatment are evaluable for the exploratory objective of 
safety and tolerability.  Patients are evaluated from first receiving study treatment until 
time of resection, or until 60 days after end of treatment if resection doesn’t take place. 
 
In order to be evaluable for the exploratory objective evaluating immunologic correlates, 
patients must have blood and tissue collected before and after therapy. 
 
In order to be evaluable for the exploratory objectives of assessing local control, DMFS, 
and OS, patients must have received at least one dose of study treatment. 
 
In order to be evaluable for the exploratory objective of assessing extent of resection, 
patient must have received at least one dose of study treatment and undergone resection. 
 
5.4 
Concomitant Therapy and Supportive Care Guidelines 
 
The investigational drugs are not known or predicted to interact with other drugs, and are 
not broken down by CYP enzymes.  
 
Infusion reactions may occur when giving any IV medication. Recommendations for the 
management of peri-infusional reactions are provided below and may be modified based 
on local treatment standards and guidelines, as appropriate. Infusion reactions should be 
graded according to NCI-CTCAE guidelines, http://ctep.cancer.gov. Obtain serum at the 
time of an infusion reaction.  
 
For Grade 1 symptoms: (Mild transient reaction; infusion interruption not indicated; 
intervention not indicated)  
 
Remain at bedside and monitor patient until recovery from symptoms.  
 
For Grade 2 symptoms: (infusion interruption indicated but responds promptly to 
symptomatic treatment [e.g., antihistamines, nonsteroidal anti-inflammatory drugs, 
narcotics, corticosteroids, i.v. fluids]; prophylactic medications indicated for ≤ 24 hours)  
 
Stop the CDX-1140 infusion, begin an i.v. infusion of normal saline, and treat the patient 
with diphenhydramine 50 mg i.v. (or equivalent) and/or 500 to 1000 mg 
paracetamol/acetaminophen; remain at bedside and monitor patient until resolution of 
symptoms. Corticosteroid therapy may also be administered as appropriate. If the infusion 
is interrupted, then restart the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate may be increased to 
100% of the original infusion rate. Monitor patient closely. If symptoms recur then no 
further CDX-1140 will be administered at that visit. The amount of study drug infused 
must be recorded on the case report form (CRF). Patients who experience an adverse event, 

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including an infusion reaction of Grade 2, during the 4-6 hour observation period that does 
not resolve during this time should be observed for 24 hours or until the adverse event 
resolves with vital sign measurements every 4 hours and additional evaluations as 
medically indicated for the management of the adverse event.  
 
For Grade 3 or Grade 4 symptoms: (Grade 3: prolonged [i.e., not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae [e.g., 
renal impairment, pulmonary infiltrates]. Grade 4: life-threatening consequences; urgent 
intervention indicated).  
 
Immediately discontinue infusion of CDX-1140. Begin an i.v. infusion of normal saline, 
and treat the patient as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for i.v. administration, and/or diphenhydramine 50 mg i.v. with 
methylprednisolone 100 mg i.v. (or equivalent), as needed. Patient should be monitored 
until the Investigator is comfortable that the symptoms will not recur. Investigators should 
follow their institutional guidelines for the treatment of anaphylaxis. Patients who 
experience an infusion reaction of Grade ≥ 3, regardless of resolution, will be observed for 
24 additional hours or until the adverse event resolves with vital sign measurements every 
4 hours and additional evaluations as medically indicated for the management of the 
adverse event. In the case of late-occurring hypersensitivity symptoms (e.g., appearance of 
a localized or generalized pruritus within 1 week after treatment), symptomatic treatment 
may be given (e.g., oral antihistamine, or corticosteroids). CDX-1140 will be permanently 
discontinued for patients with Grade 4 infusion reactions or Grade 3 infusion reactions 
lasting more than 6 hours.  
 
5.5 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative serum or urine pregnancy test within 14 days prior to the first day of study 
treatment.  
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during treatment with the 
investigational agents.  
 
If a patient is suspected to be pregnant, the study agent should be immediately 
discontinued.  In addition, a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy 
with the study agent or 3 months thereafter, the investigator must be notified in order to 
facilitate outcome follow-up. 

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5.6 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
Treatment may also be discontinued early for the following reasons: 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will still be followed as 
indicated in the study calendar. 
 
5.7 
Duration of Follow-up 
 
Patients will be followed every  6 months for 2 years or until death, whichever occurs first.  
Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event. 
 
5.8 
Lost to Follow-Up 
 
A participant will be considered lost to follow-up if he or she fails to return for three 
scheduled visits and is unable to be contacted by the study team. 
 
The following actions must be taken if the participant fails to return to clinic for a required 
study visit: 
o The study team will attempt to contact the participant and reschedule the missed 
visit within 1 week and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study. 
o Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 

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address).  These contact attempts should be documented in the participant’s medical 
record or study file. 
o Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 
5.9 
Protocol Stopping Criteria 
 
The principal investigator will closely monitor and analyze study data as they become 
available and will make determinations regarding the presence and severity of adverse 
events. The administration of study injections and new enrollments will be halted and the 
QASMC promptly notified if any of the following events occurs: 
 
1. One (or more) subject(s) experiences a Grade 3 or 4 adverse event that is classified 
as probably or definitely related to treatment with CDX-301 or CDX-1140; this 
excludes Grade 3 arthralgia and myalgia that has been adequately treated with a 
short course of steroids. 
 
2. One (or more) subject(s) experiences a SAE that is classified as probably or 
definitely related to treatment with CDX-301 or CDX-1140;  
3. Two (or more) subjects experience the same Grade 2 or higher adverse event  that 
is classified as probably or definitely related to study treatment: this criterion 
applies to cytokine-release syndrome, infusion-related reactions, laboratory 
abnormalities or other clinical adverse experiences. This excludes adverse events 
of arthralgia and myalgia that have been adequately treated with a short course of 
steroids. 
4. Any other observation occurs that in the opinion of the PI results in a 
recommendation to halt enrollment. 
 
If one of these events does occur, study enrollments would only resume if review of the 
adverse events that caused the halt resulted in a recommendation to permit further study 
treatment and study enrollments. 
 
 
6 
DOSE DELAYS/DOSE MODIFICATIONS 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 4 weeks of the scheduled 
interruption, at PI discretion. A hold longer than 4 weeks will be allowed at PI discretion.  
 
There will be no dose modifications for CDX-1140 as it is given as a single dose.   
 
CDX-301 will be discontinued for any grade 3 and grade 4 events that are deemed at least possibly 
related to it. If discontinued, the patient may still remain on study.  Any missing doses are made 
up, if feasible.  Since this is an immune therapy and the dose-response relationship is not likely to 
be linear, the therapy will be held rather than dose reduced for patients experiencing an AE.    

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Toxicity 
Possibly, probably or 
definitely attributed to 
CDX-301 
Treatment Interruption and Dose Reduction Instructions 
Lymphadenopathy 
No treatment modification, since lymphadenopathy is not 
dangerous or indicative of a poor outcome.  
Injection site erythema 
No treatment modification. Rotate injection site. Treat with 
topical antibiotic ointment.  
Folliculitis 
No treatment modification. Treat with topical antibiotic 
ointment. 
Dry mouth 
No treatment modification.  
Other holds and modifications may be made at the discretion of the PI. 
 
 
7 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below.  Please refer to Appendix B for definitions and Appendix C for a grid of reporting 
timelines. 
 
Adverse events will be tracked from start of treatment through time of surgery (or 60 days after 
end of treatment if surgery doesn’t take place).  All adverse events must be recorded on the toxicity 
tracking case report form (CRF) with the exception of: 
• Baseline adverse events, which shall be recorded on the medical history CRF 
 
Refer to the data submission schedule in Section 10.0 for instructions on the collection of AEs in 
the EDC. 
 
Reporting requirements for Washington University study team may be found in Section 7.1.   
 
7.1 
Sponsor-Investigator Reporting Requirements 
 
 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. 
 
 Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 

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The Washington University Sponsor-Investigator (or designee) is required to notify 
the QASMC of any unanticipated problems involving risks to participants or others 
occurring at WU or any BJH or SLCH institution that has been reported to and 
acknowledged by HRPO.  (Unanticipated problems reported to HRPO and 
withdrawn during the review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu.  Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
 Reporting to Celldex Therapeutics 
 
Any serious adverse event (SAE) or follow-up to an SAE, including death due to 
any cause other than progression of the cancer under study, whether or not related 
to study drug, must be reported to Celldex Therapeutics within 1 business day. 
 
The investigator must inform Celldex Therapeutics in writing using a MedWatch 
3500a form of any SAE within 24 hours of the investigator becoming aware of the 
event.  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. 
 
“Adverse Event” or “AE” shall mean any untoward medical occurrence in a study 
subject who is administered the Study Drug regardless of whether or not a causal 
relationship with the Study Drug exists.  By way of example and without limitation, 
an AE can be any unfavorable and unintended sign (for example, an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the 
Study Drug. 
  
Celldex Therapeutics, Inc., considers an SAE to be any adverse event that is life-
threatening or that results in any of the following outcomes: death; inpatient 
hospitalization or prolongation of existing hospitalization; persistent or significant 
disability/incapacity; or a congenital anomaly/birth defect. 
 
“Suspected Unexpected Serious Adverse Reaction” or “SUSAR” shall mean any 
Serious Adverse Event, the nature, severity or frequency of which is not consistent 
with information in the most current investigator’s brochure.  
 
Elective or previously scheduled hospitalizations for pre-existing conditions that 
have not worsened after initiation of treatment should not be classified as SAEs.  
For example, an admission for a previously scheduled hernia repair would not be 
classified as an SAE. 
 
Completed SAE reports are to be submitted to: 

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Celldex Therapeutics, Inc. 
Pharmacovigilance 
Hotline: 908-323-2233 
Fax No.: 781-644-6434 
Email: SAE@celldex.com  
 
7.1.3.1 Reporting Pregnancy 
 
Pregnancy per se is not considered an AE unless there is cause to believe 
that the study drug may have interfered with the effectiveness of a 
contraceptive medication or if the outcome of the pregnancy meets SAE 
criteria (miscarriage or congenital anomaly/birth defect), it should be 
reported as an SAE.  Hospitalization for normal delivery of a healthy 
newborn is not an SAE.   
 
Each pregnancy that occurs in female subjects or female partners of male 
subjects while on the study drug or within three months following 
completion of the study drug must be reported to the Celldex within 24 
hours of the Investigator becoming aware of its occurrence.  If a subject 
becomes pregnant, drug administration must be discontinued immediately.  
The pregnancy should be followed up to determine outcome (including 
spontaneous or voluntary termination), details of the birth, and the presence 
or absence of any birth defects, congenital abnormalities, or maternal or 
newborn complications.  Follow-up and documentation must occur even if 
the subject withdraws from the study or the study is completed.  Every effort 
should be made to gather information regarding the pregnancy outcome 
until 8 weeks postpartum.  It is the responsibility of the Investigator to 
obtain all pregnancy information. 
 
 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA 
DIFFER FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It 
is the responsibility of the Washington University Sponsor-Investigator to report to 
the FDA as follows: 
 
• Report any unexpected fatal or life-threatening suspected adverse reaction 
(refer to Appendix B for definitions) no later than 7 calendar days after 
initial receipt of the information.   
• Report a suspected adverse reaction that is both serious and unexpected 
(SUSAR, refer to Appendix B) no later than 15 calendar days after it is 
determined that the information qualifies for reporting.  Report an adverse 
event (refer to Appendix B) as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the drug and the adverse 
event, such as: 

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o A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure 
o One or more occurrences of an event that is not commonly associated 
with drug exposure but is otherwise uncommon in the population 
exposed to the drug 
o An aggregate analysis of specific events observed in a clinical trial that 
indicates those events occur more frequently in the drug treatment 
group than in a concurrent or historical control group 
• Report any findings from epidemiological studies, pooled analysis of 
multiple studies, or clinical studies that suggest a significant risk in humans 
exposed to the drug no later than 15 calendar days after it is determined 
that the information qualifies for reporting. 
• Report any findings from animal or in vitro testing that suggest significant 
risk in humans exposed to the drug no later than 15 calendar days after it 
is determined that the information qualifies for reporting.  
• Report any clinically important increase in the rate of a serious suspected 
adverse reaction of that listed in the protocol or IB within 15 calendar days 
after it is determined that the information qualifies for reporting. 
 
Submit each report as an IND safety report in a narrative format or on FDA Form 
3500A or in an electronic format that FDA can process, review, and archive.  Study 
teams must notify the Siteman Cancer Center Protocol Development team of each 
potentially reportable event within 1 business day after initial receipt of the 
information, and must bring the signed 1571 and FDA Form 3500A to the Siteman 
Cancer Center Protocol Development team no later than 1 business day prior to the 
due date for reporting to the FDA. 
 
Each notification to FDA must bear prominent identification of its contents (“IND 
Safety Report”) and must be transmitted to the review division in the Center for 
Drug Evaluation and Research (CDER) or in the Center for Biologics Evaluation 
and Research (CBER) that has responsibility for review of the IND.  Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such (“Follow-up IND Safety 
Report”).  
 
7.2 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 7.1 include: 
• planned hospitalizations 
• hospitalizations < 24 hours 
• respite care 
• events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
 

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8 
PHARMACEUTICAL INFORMATION 
 
8.1 
CDX-301 
 
 CDX-301 Description 
 
CDX-301 is recombinant human Flt3L, which stimulates dendritic cell 
development.  More specifically, CDX-301 is a soluble glycoprotein, which, after 
the leader sequence has been cleaved off, consists of 153 amino acids representing 
most of the protein’s extracellular domain except for the C-terminal three amino 
acids, 
and 
whose 
calculated 
molecular 
weight 
is 
17,445 
kD 
(C777H1224N213O229S8). It exists as numerous isoforms, some of which are 
separated by isoelectric focusing in the pI range of 3.5 to 5.5. There are two N-
glycosylation sites (N100 and N123), which are partially occupied by complex 
carbohydrate structures and five O-glycosylation sites (S136, S137, T138, S144 
and T151), three of which are always occupied.  
 
CDX-301 drug product is formulated as a sterile solution intended for single-use 
parenteral administration. Each vial contains a nominal 2.5 mg/mL CDX-301 
protein in a 1 mL volume of buffered solution composed of sodium phosphate and 
sodium chloride, with a pH of 7.0.  
 
 Pharmacokinetics and Drug Metabolism 
 
CDX-301 half life, efficacy and safety of CDX-301, recombinant human Flt3L, at 
expanding dendritic cells and hematopoietic stem cells in healthy human volunteers 
has been reported 41 and is shown in breif below.  
 
 

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 Supplier(s) 
 
The drug will be supplied free of charge by Celldex. 
 
 Dosage Form and Preparation 
 
CDX-301 is formulated as an injectable solution, for SQ administration.  CDX-301 
vials should not be shaken. CDX-301 liquid should be withdrawn from vial gently, 
avoiding foaming and excess shearing. CDX-301 should be used as soon as possible 
once drawn into a syringe within 4 hours). Each CDX-301 vial is single use only. 
Partially used vials or solutions must not be used to prepare another dose and 
instead should be handled for destruction according to the study sites’ regulations 
for the disposal of biological agents. CDX-301 is injected subcutaneously using 
standard procedures, in either abdominal or gluteal subcutaneous tissue.   
 
 Storage and Stability 
 
CDX-301 will be stored in a refrigerator at 2 to 8°C and protected from light. CDX-
301 should not be frozen. 
 
 Administration 
 
Patients should be given CDX-301 SQ, in either the stomach or gluteal 
subcutaneous tissue.  The injection can be performed any time during the day, but 
preferably will be given at roughly the same time each day.  
 
 Special Handling Instructions 
 
No special handling instructions. 
 
8.2 
CDX-1140 
 
 CDX-1140 Description 
 

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CDX-1140 is an agonistic antibody against CD40.  Specifically, CDX-1140 is a 
recombinant fully human IgG2 anti-CD40 mAb generated by in vitro Chinese 
Hamster Ovary (CHO) cell culture and using standard mAb purification processes. 
The product is composed of two identical pairs of polypeptide chains, each pair 
having one fully-human kappalight (23,227 Da) and one fully-human IgG2 heavy 
chain (49,172 Da). The heavy and light chains expected molecular weights are 
based on the amino acid sequence of each chain. The N-terminal amino-acid 
sequences of the variable regions have been confirmed by sequence analysis.  
 
No animal-derived raw materials are used during the cell culture, purification, and 
formulation of the drug substance. A low pH step and a nanofiltration step are used 
for virus inactivation and reduction. Testing for adventitious agents is performed in 
accordance to the Food and Drug Administration (FDA) Points to Consider in the 
Manufacture and Testing of Monoclonal Antibody Products for Human Use (1997).  
 
The Drug Product manufacturing process consists of sterile filtration (2 x 0.22 μm 
filters in series) of the CDX-1140 formulated bulk Drug Substance, aseptic filling 
into Type 1 vials, stoppering with gray butyl stoppers, and capped with 
polypropylene flip-off caps. Each vial contains a nominal 3.0 mg/mL CDX-1140 
protein in a 10.0 mL volume of buffered solution composed of sodium phosphate, 
potassium phosphate, potassium chloride, sodium chloride, and Polysorbate 80, 
with a pH of 7.0.  
 
The final Drug Product dosage form is provided in a 10-mL Type 1 vial with a gray 
butyl stopper and a polypropylene flip-off cap, containing a sterile, single-use liquid 
with a nominal 3.0 mg/mL of CDX-1140 to be used for intravenous administration. 
The drug product vials are stored at ≤ - 65°C (-85°F). The CDX-1140 formulated 
drug substance and drug product are identical in terms of formulation and 
concentration.  
 
 Pharmacokinetics and Drug Metabolism 
 
CDX-1140 has previously been described: Vitale et al, Cancer Immunol 
Immunother 2019 42 
 
(https://link.springer.com/article/10.1007%2Fs00262-018-2267-0).  
 
Summary of Nonclinical Findings  
CDX-1140 is an agonist anti-CD40 human IgG2κ mAb being developed as a cancer 
therapeutic. The main findings from the in vitro pharmacology studies are as 
follows:  
• 
CDX-1140 bound specifically to human CD40 with high affinity but not to 10 
TNFRSF members with the closest homology to CD40.  
• 
CDX-1140 does not block CD40 ligand (CD40L) binding to CD40.  
• 
CDX-1140 bound to human and cynomolgus macaque CD40.  

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• 
CDX-1140 activated CD40 signaling in a CD40-expressing HEK-293 NF- kB 
reporter cell line in vitro.  
• 
CDX-1140 promoted B cell activation in vitro as measured by proliferation, 
upregulation of activation markers CD86 and HLA-DR, and induction of IL-
12p40 production by dendritic cells (DCs).  
• 
Based on in vitro B cell and DC activation, the MABEL is estimated to be 
approximately 0.004 mg/kg for CDX-1140.  
• 
CDX-1140 agonist activity is independent of Fc receptor (FcR) interactions.  
• 
Prolonged incubation (6 days) of human peripheral blood mononuclear cells 
(PBMCs) with CDX-1140 led to the accumulation of various cytokines and 
chemokines, most prominently TNF-α, MIP-1α, and MIP-1β, with lower levels 
of IL-1RA, IL-6, and IL-10. Depletion of CD14+ monocytes, but not B cells, 
eliminated the production of TNF-α.  
• 
CDX-1140 was assessed for the capacity to induce cytokines in whole blood 
from healthy human donors when added in soluble form, or adsorbed to 
microtiter plates from wet solution, or adsorbed to microtiter plates by drying 
down completely. Overall, very little specific cytokine induction was observed 
with CDX-1140 relative to the human IgG2 isotype control under any 
condition, although donor to donor variability was observed with some 
activation greater than the negative control.  
• 
CDX-1140 upregulated CD95 on Ramos lymphoma cells and the addition of 
CD40L enhanced the CD95 expression when combined with suboptimal lower 
CDX-1140 concentrations. A similar synergy was observed between CDX-
1140 and CD40L in DC and B cell activation assays.  
• 
CDX-1140 was compared in vitro to CP*, an mAb having the same amino acid 
sequence as CP-870,893, an agonist anti-CD40 IgG2 mAb in clinical 
development by Roche. CDX-1140 was similar, though generally lower 
compared to CP* in the upregulation of CD86 on B cells and induction of IL-
12p40 by DC.  
• 
The main findings from the in vivo pharmacology studies are as follows:  
• 
CDX-1140 significantly increased the duration of survival of severe combined 
immunodeficiency (SCID) mice implanted subcutaneously with human B cell 
lymphoma Daudi, Ramos or Raji cells.  
• 
When Ramos lymphoma cells were co-implanted with human PBMCs in SCID 
mice, the survival of the mice was extended further compared to the absence of 
added PBMCs, suggesting a contribution from immune responses.  
 
Effects of on peripheral blood immune cells have been preliminarily examined, as 
shown below.   

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Effects on pro-inflammatory cytokines have been examined, as shown below:  
 

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 Supplier(s) 
 
The drug will be supplied free of charge by Celldex. 
 
 Dosage Form and Preparation 
 
CDX-1140 is formulated as an injectable solution, for IV administration.  The 
morning that a patient is due for treatment, research personnel will remove a vial 
from the -85°F freezer and place it in the refrigerator at 2-8 degrees °C.  When a 
patient arrives for treatment, research personnel will remove the vial and deliver it 
to the patient’s treatment location. After equilibration to room temperature and 
before use, the vial should be gently swirled (but not inverted or shaken) to ensure 
uniform mixing of the contents. Solution should be gently withdrawn (avoiding 
foaming and excess shearing). Once the sterile vials are entered (i.e., once CDX-
1140 is drawn into a syringe), the drug should be used as soon as possible (typically 
within 3 hours if kept at room temperature or within 6 hours if refrigerated; or in 
accordance with any applicable institutional guidance). The infusion should take 
place at a standard rate appropriate for the type of IV access, lasting between 1-15 
minutes.  
 
 Storage and Stability 
 
Vials of CDX-1140 are shipped in insulated shippers and must be stored at ≤ - 65°C 
(-85°F) until use and protected from light – storage at -85°F will be done by the 
primary investigators. The day of treatment, CDX-1140 can be stored at room 
temperature for up to 3 hours, or refrigerated (at 2-8 degrees) for up to 6 hours if 
necessary.   
 
 Administration 
 

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Each vial to be used for intravenous administration contains a premixed solution, 
containing 3.0 mg/mL CDX-1140 protein in a 10.0 mL volume of buffered solution.  
Injections can be performed through any standard IV method (peripheral IV, PICC, 
PORT, or any other IV access that is in place or most convenient for the patient).  
Patients should be given CDX-1140 IV once per month.  
 
 Special Handling Instructions 
 
No special handling instructions. 
 
 
9 
CORRELATIVE STUDIES 
 
9.1 
Fresh Tumor Tissue 
 
 Collection of Specimen  
 
Tumor tissue will be collected at the time of surgical resection. Tissue received 
from the OR is brought to the pathology processing table.  At this point, the tissue 
is sectioned and “bread loaved” by a pathologist.  Current best practice for 
correlative studies will take a central plane cross-section from the tumor if not 
interfering with clinical pathological assessments.  Tumor tissue will then be 
transported to the research labrotory on wet ice in DMEM media. A smaller portion 
(~20% of available biomarker tissue) will directly cryopreserved in liquid N2 or on 
dry ice.  
 
Processing labrotory is located at BJCIH 7th floor, room 7202 (DeNardo-lab). 
 
 Handling of Specimen(s) 
 
Tumor tissues will be divided into two pieces. Twenty percent of tissue will be 
directly cryopreserved in liquid N2 or on dry ice, while eighty percent of the tissue 
will be placed in DMEM Media in wet ice.  Samples will be transported on wet and 
dry ice to the research labrotory for processing. Research processing laboratory is 
located at BJCIH 7th floor, room 7202 (DeNardo-lab). 
 
9.2 
Archived Tumor Tissue 
 
Archival tissue will be retrieved from pathology thru the SCC request system.  This will 
also be used to inspect potential sampling biases or problems. 
 
9.3 
Research Blood 
 
Blood will be collected at three time points: 
• At screening 
• Prior to first therapeutic dose of CDX-1140, on the day of infusion 

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• At the time of surgery. 
 
For each blood collection three 10ml green-top (sodium heparin) tubes will be collected 
for PBMCs and plasma along with one red-top sera (no-anticoagulant) tubes. Samples will 
be transported on wet ice to the research laboratory for processing.  
 
Processing laboratory is located at BJCIH 7th floor, room 7202 (DeNardo-lab). 
 
Additionally, no more than 10 mL of blood will be collected at any standard follow-up 
visit to analyze for CDX-301 ADAs.  This blood will be collected in to a single red top 
tube, labeled with patient ID, date, and visit time point, and will be taken directly to the 
DeNardo lab for cryopreservation and batch shipping to Celldex. 
 
9.4 
Specimen Analysis 
 
First, we will assess the impact of CDX-1140 compared to CDX-301/CDX-1140 on 
multiple parameters of PDAC local and systemic tumor immunity. Second, we expect 
diverse objective responses to therapy; blood and PDAC tissues parameters can be 
correlated with patient outcomes to identify the biological parameters that indicate 
therapeutic benefit. 
 
Our tissue collections will include pre- treatment and time of surgery blood and sera, as 
well as tumor tissue collected at the time of surgery. Tissue collection will be mandatory 
for all patients. Tumor tissues will be divided into cryopreserved, formalin-fixed paraffin-
embedded (FFPE), and flow cytometry/CyTOF samples. We will directly assess how no-
treatment vs CDX-1140 vs CDX-301/CDX-1140 alters immune cell tumor infiltration 
using high-density flow cytometry and CyTOF. We optimized two 14-parameter flow 
cytometry protocols to assess T-cell infiltration, activation, and exhaustion, and myeloid 
cell and DC infiltration and two 35 parameter CyTOF panel (see Figure). This will be 
complemented by Single Cell RNA sequencing when tissue it sufficient.  Conventional 
dendritic cells are defined by the  lack of expression of CD3, CD19, CD20, CD16, CD56, 
and the expression of CD45, CD11c, MHCII high and either CD1c or CD141. 
 

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On archival FFPE tissues we will complement flow 
cytometry with multiplex IHC on FFPE tissue. We 
optimized several multiplex IHC panels using the 
PerkinElmer OPAL system. These panels can identify 
changes in T-cell infiltration and proliferation (e.g., 
CD3+/CD8+/Ki67+) and proximity to tumor cells 
(CK19). For imaging and deconvolution we will capture 
images and conduct quantitative analysis using HALO 
pattern recognition software. 
 
We will analyze blood leukocyte populations using two 
optimized 36-parameter CyTOF panels designed for 
adaptive and innate immune cells, respectively. We will 
focus on evidence of increased T-cell activation 
corresponding with tumor reactivity (similar to results 
from human checkpoint studies43, 44). This will include 
analyses of T-cell proliferation (Ki67), lineage 
transcription factors (e.g., GATA3, T-bet, Eomes), 
effector function (Granzyme B, perforin), memory 
status 
(e.g., 
KLRG1, 
CD28, 
CD127), 
and 
exhaustion/checkpoint marker expression (e.g., 41BB, 
LAG3, TCF1 and SLMF6). We will perform unguided 
analysis of this CyTOF data using PhenoGraph and X-
Shift to identify uniquely changing T-cell subsets, and 
Citirs to determine potential biomarkers of treatment 
response.  
 
 
10 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
 
Figure. (A) T-cell CyTOF panel. 
(B) CyTOF data from human PDAC 
tissues (n=6) analyzed for T-cell 
subsets by PhenoGraph. 

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Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Medical History Form 
Prior to starting treatment 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Surgery Form 
Time of surgery 
Research Specimen Form 
Baseline, time of CDX-1140 treatment, time of surgery 
Follow Up Form 
Every 6 months for 2 years; 60 days after EOT if surgery 
is not performed  
Progression Form 
Time of disease progression 
Death Form 
Time of death 
MedWatch Form 
See Section 7.0 for reporting requirements 
 
10.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 7.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
 
11 
MEASUREMENT OF EFFECT 
 
Primary Endpoint: This study is powered to detect a two-fold change in intratumoral 
conventional dendritic cells between CDX-1140 vs. CDX-301 plus CDX-1140 treated patients. 
This is a critical endpoint to ensure CDX-301 plus CDX-1140 is having its intended biological 
effect and thus has a likelihood of impacting tumor immunity and patient outcomes.  
 
Correlative Secondary Endpoints: These will include global immune profiling by CyTOF, 
single cell RNASeq analysis, and histologic assessments. Critical to this assessment will be 
comparative analysis of the impact of CDX-1140 vs. CDX-301 plus CDX-1140 on T cell and cDC 
number and phenotype.  
 
 
Exploratory endpoints: These will include local control rate, distant metastasis-free survival 
(DMFS), overall survival (OS), and margin negative resection rate. Proportions of local control 
and margin negative resection for all treated patients.  
 
 
12 
DATA AND SAFETY MONITORING 

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In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least one patient has been enrolled) or one 
year after accrual has opened (if no patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities separated by cohorts  
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 
13 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design 
 
This is a two-arm randomized Phase II trial. All the enrolled patients with resectable 
pancreatic cancer will undergo surgery. Patients will be 1:1 randomized to one of two 
treatments: neoadjuvant CDX-1140 vs. CDX-301 plus CDX-1140.  
 

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13.2 
Sample Size Calculation 
 
The primary endpoint is intratumoral conventional dendritic cells (cDCs) at surgery. The 
sample size calculation is based on the primary endpoint only. Our pilot data in animal 
models showed that the mean and standard deviation of the number of intratumoral cDCs 
per gram of tissue in CD40 agonist IgGs was 44726 with a standard deviation of 37895, 
and for mice treated with CDX-301 plus CD40 agonist, the mean cDCs per gram of tissue 
was 2716742 with a standard deviation of 1322448. Assuming a similar therapeutic effect 
on cDCs and similar distribution among samples, 12 patients per arm will have at least 
99.9% power to detect the intratumoral cDCs difference as measured by CyTOF between 
two arms using a two-sided two-group T-test at the type I error of 5%. We plan to enroll 
12 patients evaluable for the primary objective per arm for a total of 24 evaluable patients. 
An interim analysis can be performed at 5 patients per arm or greater; 5 patients per arm 
will have >80% power to detect changes in cDCs. 
 
13.3 
Accrual 
 
We perform surgery in 80-110 patients per year at Washington University with similar 
characteristics and estimate approximately 30-40 patients/year may be eligible for and will 
participate in this trial. We anticipate enrollment of approximately 1-3 patients per month.  
 
13.4 
Statistical Analyses 
 
 Patient Disposition 
 
The number of patients discontinued, the reasons for discontinuation, and the 
amount of therapy administered will be summarized by patient and by reason for 
discontinuation by arm. 
 
 Protocol Deviations 
 
All significant deviations will be summarized by patient and by type of deviation. 
 
 Demographics and Baseline Characteristics 
 
Subject demographic and clinical characteristics will be summarized to 
characterize the population. Descriptive summaries will include means, standard 
deviations, medians, ranges for continuous variables and frequency and percentage 
for categorical variables. They are presented by total and each arm, respectively. 
 
 Endpoint Analysis 
 
The primary endpoint is intratumoral cDCs in surgical tissues. Conventional 
dendritic cells are defined by the lack of expression of CD3, CD19, CD20, CD16, 
CD56, and the expression of CD45, CD11c, MHCII high and either CD1c or 
CD141.  Kruskal-Wallis test will be used to compare the difference between two 

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arms.  
 
Exploratory endpoints include global immune profiling by CyTOF, single cell 
RNASeq analysis, and histologic assessments. Kruskal-Wallis test will be used to 
compare the difference on T cell and cDC number and phenotype between two 
arms.  
 
Additional exploratory endpoints include local control rate, distant metastasis-free 
survival (DMFS), overall survival (OS), and margin negative resection rate. 
Proportions of local control and  margin negative resection for all treated patients 
and their associated 95% confidence intervals will be calculated assuming a 
binomial distribution. Chi-square or Fisher’s exact test will be used to compare the 
difference between two arms.  
 
OS is defined as the time from the date of treatment to the date of death, censored 
at the last follow-up otherwise. DMFS is defined as the time from treatment to the 
date of distant metastasis or death, whichever occurs first. The alive patients 
without distant metastasis is censored at the last follow-up. The Kaplan-Meier 
method will be used to calculate the probability of OS and DMFS. The log-rank 
test will be considered to compare the difference of OS and DMFS between two 
arms. 
 
Data on the toxicity in each arm will be collected for each subject, including 
frequency, type, and severity of adverse events. All analyses will be conducted 
using SAS (SAS Institute, Cary, NC) at the two-sided 5% significance level.  
 
 
 

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14 
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We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials Core 
which provided protocol development services. The Siteman Cancer Center is supported in part 
by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 

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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 

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APPENDIX B: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 

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o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 

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APPENDIX C: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Celldex 
Serious AND 
unexpected suspected 
adverse reaction 
 
 
Report no later than 15 
calendar days after it is 
determined that the 
information qualifies for 
reporting 
 
Serious adverse events 
regardless of 
relatedness 
 
 
 
Report to Celldex within 24 
hours of the investigator 
becoming aware of the event.   
Unexpected fatal or 
life-threatening 
suspected adverse 
reaction 
 
 
Report no later than 7 
calendar days after initial 
receipt of the information 
 
Unanticipated 
problem involving risk 
to participants or 
others 
Report within 10 working days.  If the 
event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 
1 working day. 
Report via email after IRB 
acknowledgment 
 
 
Pregnancy 
 
 
 
Each pregnancy that occurs in 
female subjects or female 
partners of male subjects while 
on the study drug or within 3 
months following completion 
of the study drug must be 
reported to Celldex within 24 
hours of the investigator 
becoming aware of its 
occurrence. 
Major deviation 
Report within 10 working days.  If the 
event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 
1 working day. 
 
 
 
A series of minor 
deviations that are 
Report within 10 working days.   
 
 
 

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Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Celldex 
being reported as a 
continuing 
noncompliance 
Protocol exception 
Approval must be obtained prior to 
implementing the change 
 
 
 
Clinically important 
increase in the rate of 
a serious suspected 
adverse reaction of 
that list in the protocol 
or IB 
 
 
Report no later than 15 
calendar days after it is 
determined that the 
information qualifies for 
reporting 
 
Complaints 
If the complaint reveals an unanticipated 
problem involving risks to participants or 
others OR noncompliance, report within 
10 working days.  If the event results in 
the death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working 
day.  Otherwise, report at the time of 
continuing review. 
 
 
 
Breach of 
confidentiality 
Within 10 working days. 
 
 
 
Incarceration 
If withdrawing the participant poses a 
safety issue, report within 10 working 
days.   
 
If withdrawing the participant does not 
represent a safety issue and the patient 
will be withdrawn, report at continuing 
review. 
 
 
 
 

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Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Celldex 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 
which is typically due 
every 6 months. 
The most current 
toxicity table from the 
DSM report is provided 
to the FDA with the 
IND’s annual report. 
 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the time of 
continuing review. 
 
 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review.