FLT3 Ligand (CDX-301), CD40 Agonist Antibody (CDX-1140), and Stereotactic Radiotherapy Versus Standard Therapy for Advanced Non-small Cell Lung Cancer: A Phase I/II Randomized Trial
Phase: PHASE1
Conditions: Non Small Cell Lung Cancer, Lung Cancer
Sponsor: Albert Einstein College of Medicine

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 FLT3 Ligand, CD40 Agonist Antibody, and Stereotactic 
Radiotherapy versus Standard Therapy for Advanced Non- 
small Cell Lung Cancer: A Phase I/II Randomized Trial 
 
Principal Investigators 
 
Nitin Ohri, MD 
Albert Einstein College of Medicine 
Department of Radiation Oncology 
1300 Morris Park Avenue, Mazer 610 
Bronx, NY 10461 
Phone: 718-430-3682 
Fax: 718-430-8618 
Email: nitin.ohri@einsteinmed.org 
Chandan Guha, MD, PhD 
Montefiore Medical Center 
Department of Radiation Oncology 
111 East 210th Street 
Bronx, NY 10467 
Phone: 718-920-4361 
Fax: 718-430-8618 
Email: cguha@montefiore.org  
       Co-Investigators (Radiation Oncology)
Madhur Garg, MD 
Montefiore Medical Center 
Department of Radiation Oncology 
111 East 210th Street 
Bronx, NY 10467 
Email: mgarg@montefiore.org 
Jana Fox, MD 
Montefiore Medical Center 
Department of Radiation Oncology 
111 East 210th Street 
Bronx, NY 10467 
Email: jfox@montefiore.org 
 
William Bodner, MD 
Montefiore Medical Center 
Department of Radiation Oncology 
111 East 210th Street 
Bronx, NY 10467 
Email: wbodner@montefiore.org 
Justin Tang, MD 
Montefiore Medical Center 
Department of Radiation Oncology 
111 East 210th Street 
Bronx, NY 10467 
Email: jtang@montefiore.org 
 
Rafi Kabarriti, MD 
Montefiore Medical Center 
Department of Radiation Oncology 
111 East 210th Street 
Bronx, NY 10467 
Email: rkabarri@montefiore.org 
Johnny Yap, MD 
Montefiore Medical Center 
Department of Radiation Oncology 
111 East 210th Street 
Bronx, NY 10467 
Email: jyap1@montefiore.org
Jonathan Klein, MD 
Montefiore Medical Center 
Department of Radiation Oncology 
111 East 210th Street 
Bronx, NY 10467 
Email: joklein@montefiore.org 
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Co-Investigators (Medical Oncology) 
 
Balazs Halmos, MD 
Montefiore Medical Park at Eastchester 
1695 Eastchester Road 
Bronx, NY 10461 
Email: bahalmos@montefiore.org 
Rasim Gucalp, MD 
Montefiore Medical Center 
111 East 210th Street 
Bronx, NY 10467-2490 
Email: rgucalp@montefiore.org 
 
Haiying Cheng, MD, PhD 
Montefiore Medical Park at Eastchester 
1695 Eastchester Road 
Bronx, NY 10461 
Email: hcheng@montefiore.org 
Stuart Packer, MD 
Montefiore Medical Center 
111 East 210th Street 
Bronx, NY 10467-2490 
Email: spacker@montefiore.org 
 
Roman Perez-Soler, MD 
Montefiore Medical Center 
111 East 210th Street 
Bronx, NY 10467-2490 
Email: rperezso@montefiore.org 
Enrico Castelluci, MD 
Montefiore Medical Center 
111 East 210th Street 
Bronx, NY 10467-2490 
Email: ecastell@montefiore.org 
 
Co-Investigators (Statistics) 
 
Shankar Viswanathan, DrPH, MSc 
Albert Einstein College of Medicine 
1300 Morris Park Avenue, Belfer 1312D 
Bronx, New York 10461 
Email: shankar.viswanathan@einsteinmed.org 
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STUDY SCHEMA 
 
Key Eligibility Criteria: 
 Advanced/metastatic NSCLC, with at least one suitable SBRT target 
 Previous treatment with at least 2 lines of standard systemic therapy 
 ECOG performance status 0-2 
 
1EGFR/ALK positive v. EGFR/ALK negative or unknown 
2Limited Disease (suitable for comprehensive SBRT) v. Extensive Disease 
aIncluding comprehensive SBRT for limited disease 
 
 Safety assessment for Phase I will take place after 6 subjects are randomized to 
Arm 1 and followed for 8 weeks after treatment initiation 
 If ≤ 1 subject out of 6 on Arm 1 experiences a DLT, the study will proceed to 
Phase II 
 The total sample size (Phase I + Phase II) will be 46 subjects 
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Abbreviations 
 
 
ADA 
Anti-drug antibody 
irRC 
Immune-related response criteria 
AE 
Adverse event 
iSD 
Immune stable disease 
AJCC 
American Joint Committee on Cancer 
ITV 
Internal target volume 
ALT 
Alanine transaminase (synonymous with 
iUCR 
Immune unconfirmed complete 
SGPT) 
response 
ANC 
Absolute neutrophil count 
iUPD 
Immune unconfirmed progressive 
AST 
Aspartate transaminase (synonymous 
disease 
with SGOT) 
iUPR 
Immune unconfirmed partial response 
BMP 
Basic Metabolic Panel 
IV 
Intravenous 
CBC 
Complete Blood Count 
kg 
Kilogram 
CFR 
Code of Federal Regulations 
LA-NSCLC 
Locally advanced non-small 
chemoRT 
Chemoradiotherapy 
cell lung carcinoma 
CI 
Confidence interval 
LFTs 
Liver function tests 
CBR 
Clinical benefit rate 
mAb 
Monoclonal antibody 
CR 
Complete response 
mg 
Milligram 
CRF 
Case report form 
mL 
Milliliter 
CT 
Computed tomography 
MRI 
Magnetic resonance imaging 
CT C/A/P 
Computed tomography of the chest, 
MTD 
Maximum tolerated dose 
abdomen, and pelvis 
NCCN 
National Comprehensive Cancer 
CTCAE 
Common Terminology Criteria for 
Network 
Adverse Events 
NSAID 
Non-steroidal anti-inflammatory drug 
CTLA-4 
Cytotoxic T-lymphocyte antigen 4 
NSCLC 
Non-small cell lung cancer 
CTV 
Clinical Target Volume 
ORR 
Objective response rate 
DC 
Dendritic cells 
OS 
Overall survival 
DFS 
Disease-free survival 
PD-1 
Program death receptor-1 
DLT 
Dose-limiting toxicity 
PD-L1 
Programmed death-ligand 1 
DSM 
Data safety and monitoring 
PD-L2 
Programmed death-ligand 2 
DSMC 
Data safety and monitoring committee 
PET 
Positron emission tomography 
ECOG 
Eastern Cooperative Oncology Group 
PFS 
Progression-free survival 
FDA 
Food and Drug Administration 
PHI 
Protected health information 
FDG 
Fludeoxyglucose 
PI 
Principal investigator 
FLT3 
Fms-like tyrosine kinase 3 
PO 
By mouth 
GTV 
Gross tumor volume 
PR 
Partial response 
Gy 
Gray 
PRO 
Patient-reported outcome 
HIPAA 
Health Insurance Portability and 
PTV 
Planning target volume 
Accountability Act 
QoL 
Quality-of-life 
i.v. 
Intravenous 
RECIST 
Response Evaluation Criteria for Solid 
IB 
Investigator’s Brochure 
Tumors 
ICOS 
Inducible costimulator 
RT 
Radiotherapy 
iCPD 
Immune confirmed progressive disease 
RTOG 
Radiotherapy Oncology Group 
iCR 
Immune complete response 
SAE 
Serious adverse event 
IgG2 
Immunoglobulin G, Subclass 2 
SARS-CoV-2 
Severe acute respiratory syndrome 
IMRT 
Intensity modulated radiotherapy 
coronavirus 2 
iPR 
Immune partial response 
SBRT 
Stereotactic body radiotherapy 
irAEs 
Immune-related adverse events 
SD 
Standard deviation (or stable disease) 
IRB 
Institutional review board 
SUV 
Standardized uptake value 
IRB/EC 
Institutional Review Board/Ethics 
ULN 
Upper limit of normal 
Committee 
WBC 
White blood cell 
iRECIST 
Response evaluation criteria in solid 
tumors for immune-based therapeutics 
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Contents 
1.0 OBJECTIVES....................................................................................................................... 7 
1.1 Primary Objective .................................................................................................................................................... 7 
1.2 Secondary Objectives .............................................................................................................................................. 7 
2.0 BACKGROUND .................................................................................................................. 7 
2.1 Non-small Cell Lung Cancer..................................................................................................................................... 7 
2.2 FLT3 Ligand ............................................................................................................................................................... 7 
2.3 Stereotactic Body Radiotherapy (SBRT) ................................................................................................................. 9 
2.4 FLT3 Ligand and SBRT ............................................................................................................................................10 
2.4.1 Preclinical Data .............................................................................................................................................10 
2.4.2 Clinical Data ..................................................................................................................................................11 
2.5 Agonist Anti-CD40 Antibody ................................................................................................................................14 
2.6 FLT3 Ligand, Anti-CD40 Antibody, and Stereotactic Radiotherapy...................................................................16 
2.7 SBRT for NSCLC Patients with Limited Disease Burden .....................................................................................16 
2.8 Quality-of-Life Assessments in NSCLC.................................................................................................................17 
2.9 
Physical Activity Monitoring..............................................................................................................................17 
3.0 PATIENT ELIGIBILITY ........................................................................................................17 
3.1 Inclusion Criteria ....................................................................................................................................................17 
3.2 Exclusion Criteria....................................................................................................................................................18 
4.0 STUDY DESIGN .................................................................................................................19 
4.1 General Design .......................................................................................................................................................20 
4.2 Study Calendars .....................................................................................................................................................21 
4.3 Primary Endpoints..................................................................................................................................................22 
4.4 Secondary Endpoints .............................................................................................................................................22 
5.0 STUDY THERAPY – ARM 1 ................................................................................................22 
5.1 Stereotactic Body Radiotherapy ...........................................................................................................................22 
5.2 CDX-301 and CDX-1140 .........................................................................................................................................27 
  6.0 STUDY THERAPY – ARM 2 ................................................................................................39 
 
7.0 SUBJECT ASSESSMENTS....................................................................................................39 
7.1 Clinical Assessments ..............................................................................................................................................39 
7.2 DLT Definition.........................................................................................................................................................39 
7.3 Radiographic Assessments ....................................................................................................................................41 
7.4 Quality-of-Life Assessments ..................................................................................................................................41 
7.5 Physical Activity Monitoring..................................................................................................................................41 
7.6 Correlative Studies.................................................................................................................................................42 
8.0 STATISTICAL CONSIDERATIONS ........................................................................................42 
8.1 Randomization Procedure ...................................................................................................................................42 
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8.2 Phase I Primary Endpoint – Dose-Limiting Toxicity ............................................................................................42 
8.3 Phase II Primary Endpoint – Progression-free Survival......................................................................................43 
8.4 Secondary Endpoints and Exploratory Analyses ................................................................................................43 
9.0 REGULATORY CONSIDERATIONS ......................................................................................44 
9.1 Protection of Human Subjects ..............................................................................................................................44 
9.2 Compliance with the Protocol and Protocol Revisions .......................................................................................44 
9.3 Remote Consenting ...............................................................................................................................................44 
10.0 DATA HANDLING AND RECORD KEEPING .......................................................................45 
10.1 Confidentiality .....................................................................................................................................................45 
10.2 Source Documents ..............................................................................................................................................45 
10.3 Case Report Forms ..............................................................................................................................................45 
10.4 Data Safety and Monitoring Board ....................................................................................................................45 
11.0 ADVERSE EVENTS...........................................................................................................46 
11.1 Adverse Event Definitions ..................................................................................................................................46 
11.2 Adverse Event Reporting ....................................................................................................................................47 
   12.0 REFERENCES ..................................................................................................................50 
13.0 APPENDICES ..................................................................................................................57 
13.1 Appendix A – ECOG Performance Status...........................................................................................................57 
13.2 Appendix B – Common Terminology Criteria for Adverse Events Version 5.0................................................58 
13.3 Appendix C – iRECIST Criteria .............................................................................................................................59  
13.4 Appendix D – RECIST 1.1 Criteria........................................................................................................................65 
13.5 Appendix E – EORTC QLQ-C30 and LC13 ...........................................................................................................76 
13.6 13.6 Appendix F – Correlative Blood Sample Processing .................................................................................79 
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1.0 OBJECTIVES 
 
1.1 Primary Objective 
 Phase I: To establish the safety of combining FLT3 ligand, CD40 agonist 
antibody, and SBRT for advanced NSCLC that was previously treated with at 
least two lines of systemic therapy. 
 Phase II: To assess the efficacy of combining FLT3 ligand, CD40 agonist 
antibody, and SBRT for advanced NSCLC that was previously treated with at 
least two lines of systemic therapy. 
1.2 Secondary Objectives 
 To evaluate potential surrogate outcomes for clinical efficacy of FLT3 ligand, 
CD40 agonist antibody, and SBRT for advanced NSCLC, including makers of 
immune activation. 
 To characterize PROs for patients with advanced NSCLC who receive standard 
therapy or a combination of FLT3 ligand, CD40 agonist antibody, and SBRT. 
 To explore the predictive value of physical activity metrics for patients with 
advanced NSCLC who receive standard therapy or a combination of FLT3 
ligand, CD40 agonist antibody, and SBRT. 
 
2.0 BACKGROUND 
 
2.1 Non-small Cell Lung Cancer 
Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality in 
the United States and worldwide, causing nearly one million deaths each year1. For the 
approximately 40% of NSCLC patients who present with stage IV disease and other 
patients who progress after presenting with localized disease, standard first-line therapy 
historically was combination chemotherapy, usually with a platinum doublet. Targeted 
therapy is now used as first-line therapy for patients with treatable driver mutations, 
such as activating EGFR mutations, ALK rearrangement, and ROS1 fusion2. For other 
patients, recent randomized trials have demonstrated that the addition of 
immunotherapy to first-line chemotherapy3,4 or use of immunotherapy instead of 
chemotherapy for biomarker-selected patients5 improves outcomes. 
Optimal treatment strategies for advanced NSCLC patients who progress while 
receiving modern first-line systemic therapy are not well-defined. If not included in first- 
line therapy, platinum-based chemotherapy may be an option for fit patients. Other 
chemotherapy options include docetaxel (+/- ramucirumab), gemcitabine, albumin- 
bound paclitaxel, and pemetrexed. Response rates with these agents are approximately 
10%, and disease progression or death typically occurs within a few months6-8. 
2.2 FLT3 Ligand 
Fms-like tyrosine kinase 3 (FLT3) ligand is a potent hematopoietic growth factor 
that mobilizes stem cells and greatly increases the number of circulating dendritic cells 
(DCs) in blood and organs9. FLT3 ligand has been shown to evoke immune responses 
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and cause tumor regression in animal models of fibrosarcoma, breast cancer, prostate 
cancer, and lung adenocarcinoma10-13. 
A key DC subset for cancer immunotherapy are those DCs expressing CD141 in 
humans and the corresponding subset expressing CD103 in mice. This subset is 
responsible for producing T cell attractant chemokines and for “cross-presenting” 
exogenous tumor antigens to CD8+ cytotoxic T cells14. Low levels or the absence of 
CD103+ DCs within the tumor microenvironment is associated with lack of response to 
immunotherapy in murine models15,16. Corresponding to the CD103+ DC subset in mice 
is the CD141+(BDCA3+) subset of human DCs that is similarly important in cross 
presentation of antigens17. Unfortunately, such DCs are often present in very low 
numbers or absent within the tumor microenvironment in humans and a high ratio of 
CD141+ DC associated transcripts within the tumor microenvironment correlates with 
better clinical outcomes18. Therefore, augmenting the presence of CD141+ DCs within 
the tumor microenvironment and providing the appropriate activation and maturation 
signals to the DCs may be an effective mechanism to enhance the anti-tumor and 
clinical activity of immunotherapy agents in patients with cancer. 
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. 
CDX-301 has been shown to expand CD141+(BDCA3+) conventional DCs 
(cDCs)19 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+ DCs20. 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 
tumor21. 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 melanoma22. 
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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, performed at Montefiore Medical Center), 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 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. 
 
2.3 Stereotactic Body Radiotherapy (SBRT) 
In recent years, hypofractionated stereotactic body radiotherapy (SBRT) has 
emerged as an effective treatment option for numerous malignancies. SBRT uses the 
principles of intracranial stereotactic radiosurgery (large daily doses delivered precisely 
to a small target volume over a short treatment course) to treat extracranial disease 
sites. For stage I NSCLC, SBRT yields excellent local control rates23-25 and has now 
been proven to prolong survival compared to standard radiotherapy26. Serious adverse 
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events following SBRT for lung tumors are very rare27, except when aggressive SBRT 
regimens are used to treat central lesions28. Importantly, highly-conformal delivery of 
SBRT allows relatively safe treatment of lung tumors in patients with poor pulmonary 
function29. Similarly, SBRT yields low toxicity rates when employed to treat 
extrathoracic disease sites, such as the liver, skeleton, and adrenal gland30-33. 
A wide variety of dosing and fractionation schedules has been used to deliver 
lung SBRT for NSCLC24,25,34,35. Although there is evidence of a dose-response 
relationship when relatively low-dose regimens (BED < 100 Gy) are used,24,25 more 
intense regimens have yielded consistently excellent results and are considered to be 
ablative. These include 10-12.5 Gy x 4-5 fractions, 18-20 Gy x 3 fractions, and 25-34 Gy 
in a single fraction. The National Comprehensive Cancer Network (NCCN) provides 
guidelines for the selection of an SBRT (also known as SABR) schedule as well as 
relevant constraints for normal tissues, which will be adopted for this trial. 
Several recent randomized trials suggest that, for patients with advanced NSCLC 
and limited (“oligometastatic”) disease, radical treatment with SBRT to all active sites of 
disease could delay disease progression and prolong overall survival32,36-38. This 
principal is being tested for patients with oligometastatic NSCLC after first-line systemic 
therapy in NRG-LU002. 
Our group and others have demonstrated that ionizing radiotherapy (RT) has the 
potential to enhance the effectiveness of cancer immunotherapy39-45. RT may serve to 
amplify the tumor-specific peptide repertoire and upregulate cell surface expression of 
MHC determinants and costimulatory molecules46,47. RT may also evoke changes in 
the tumor microenvironment that facilitate the host immune response48,49. These effects 
may be most pronounced when RT is delivered as SBRT, with short courses and high 
daily doses50. We believe that SBRT is a key to enhancing the potential of 
immunotherapy as an effective approach in the treatment of NSCLC. 
 
2.4 FLT3 Ligand and SBRT 
2.4.1 Preclinical Data 
Experiments performed in our department have demonstrated that pretreatment 
of a single lesion with high-dose RT increases the systemic efficacy of FLT3 ligand in a 
murine model of lung adenocarcinoma10. Mice with established, 3-week-old Lewis lung 
tumors were given a single dose of localized primary footpad tumor RT (60 Gy), with or 
without FLT3 ligand (administered daily for 10 days after RT). The combination of RT 
and FLT3 ligand significantly increased survival compared to either treatment alone and 
compared to controls (See Figure Below). Examination of animal lung tissue revealed 
that the lungs of mice treated with RT and FLT3 ligand showed no carcinoma cells but 
had infiltrates of neutrophils, lymphocytes, and mononuclear leukocytes. Lungs from 
other cohorts demonstrated massive tumor cell infiltration (See Figure Below). 
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Local RT acts synergistically with FLT3 ligand in a murine NSCLC model to improve overall survival. 
 
Murine lungs following treatment with RT plus FLT3 ligand demonstrate leukocytic infiltrates without tumor 
cells (left), compared to tumor-laden lungs of mice from other cohorts (right). 
 
 
2.4.2 Clinical Data 
Based on the data summarized above, we recently completed a novel clinical 
trial combining FLT3 ligand and SBRT for the treatment of advanced NSCLC 
(ClinicalTrials.gov Identifier NCT02839265). The study design and results, which were 
presented in preliminary form at the 2018 AACR Annual Meeting51 and at the 2020 
ASCO Annual Meeting, are summarized below. Of note, the FLT3 ligand (CDX-301) 
dosing schedule from our recently completed trial remains unchanged in the present 
study. 
Key Eligibility Criteria: 
 
AJCC stage 3 or 4 histologically proven NSCLC not amenable to curative therapy 
 
Prior treatment with at least one standard chemotherapy regimen or targeted agent prior to 
enrollment 
 
Measurable disease, including: 
o 
at least one tumor or metastasis ≥ 1 cm in greatest dimension that would be amenable to 
SBRT 
o 
at least one measurable lesion that would be outside of the SBRT treatment fields 
 
ECOG performance status 0-2 
 
Study Procedures: 
 
Radiographic assessment with PET/CT at baseline and every 8 weeks 
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 
One-week treatment course: 
o 
5 daily subcutaneous injections of FLT3 ligand (75 μg/kg) 
o 
Stereotactic body radiotherapy (SBRT) to a single tumor or metastasis, delivered in 1, 3, 
or 5 fractions based on NCCN and NRG guidelines 
o 
No other cancer therapy administered until disease progression 
o 
Additional “cycles” of FLT3 ligand and SBRT allowed after 4 months 
Study Endpoints: 
 
Primary endpoint: Progression-free survival 4 months after treatment initiation (PFS4) 
o 
Scored using Immune-related Response Criteria (irRC)52 
o H0: PFS4 ≤ 20% 
H1: PFS4 ≥ 40.5% 
Accept H1 if PFS4 is achieved in 10/29 subjects 
 
Secondary endpoints: 
o 
Adverse events / Dose-limiting toxicities 
o 
Overall Survival 
o 
Radiographic responses in lesions not treated with SBRT 
 
CT: evaluated using irRC52 
 
PET: evaluated using PERCIST53 
 
Total Glycolytic Activity (TGA): volumetric sum of activity in all 
hypermetabolic lesions 
 
Partial Metabolic Response (PMR): Decrease in TGA of at least 45% 
 
Results 
 
29 subjects (described in table below) were enrolled from October 2016 to January 2020. The 
median follow-up duration for living subjects is 16 months 
 
No grade 3 or higher adverse events attributed to study therapy have been observed. 
 
PFS4 was achieved in 17/29 patients (59%), meeting our pre-specified efficacy objective (PFS and 
OS Kaplan-Meier curves below). 
 
Partial responses (“abscopal effects”) were observed in 9 subjects (31%) using PET criteria and in 4 
subjects (14%) using CT criteria (patient example below). 
 
Seven subjects (24%) received a second course of SBRT and CDX-301 after initial study therapy. 
 
Only six subjects (21%) have received additional chemotherapy or immunotherapy after study 
treatment. 
 
Study Conclusions 
 
The combination of FLT3 ligand and SBRT for advanced and previously treated NSCLC is well- 
tolerated. 
 
The combination of FLT3 ligand and SBRT demonstrated activity in advanced NSCLC patients, most 
of whom were previously treated with immunotherapy (checkpoint inhibitors targeting PD1/PD-L1), 
with survival outcomes far superior to published series of NSCLC patients who receive salvage 
chemotherapy after immune checkpoint inhibitor therapy7,54. 
 
Disease extent/multifocality may be a critical prognostic factor. 
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13 
 
100 
 
90 
 
80 
 
70 
 
60 
 
50 
 
40 
 
30 
 
20 
 
10 
 
0 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
Time f rom Study  Treatment (months) 
 
 
 
 
 
 
 
 
 
 
 
Top Left: Patient characteristics 
 
Top Right: Kaplan-Meier PFS and OS curves 
 
Bottom: Sample patient who demonstrated an abscopal 
response after receiving SBRT directed at a small nodule contralateral to the larger primary tumor. 
 
 
 
 
 
 
 
# at Risk: 
23 
19 
15 
13 
12 
11 
9 
# at Risk: 
17 
11 
7 
6 
3 
3 
2 
Survival (%)
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Swimmer plot summarizing subjects’ treatment courses after study enrollment 
 
Exploratory analyses revealing that disease extent at the time of study enrollment was a powerful 
predictor of progression-free survival and overall survival. 8 out of 16 subjects with ≤4 lesions at the time 
of study entry received a second “cycle” of study therapy. 3 of those subjects (#6, #17, and #23 [see 
swimmer plot above]) are alive and without any evidence of active disease on recent scans. 
 
 
2.5 Agonist Anti-CD40 Antibody 
CD40 is a key molecule in the regulation of immune responses whose activity 
can be modulated using antibodies. CD40 is a tumor necrosis factor receptor 
superfamily member expressed on antigen presenting cells, including dendritic cells55, 
as well as a host of other cell types, including a wide range of tumor cells 56. The ligand 
for CD40, CD40L (CD154), is predominately expressed on activated CD4+ helper T 
cells57,58. On dendritic cells, an important function of the interaction of CD40 with CD40L 
expressing CD4+ T-helper cells is the activation and “licensing” of dendritic cells to 
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prime CD8+ effector T cells. Furthermore, CD40-activated macrophages can be 
tumoricidal and, in some cases, deplete tumor stroma59. Thus, CD40 on antigen 
presenting cells plays a critical role in the induction of effective innate and adaptive 
immune responses. The ligation of CD40 on certain malignant cells using CD40 ligand 
or anti-CD40 antibodies may also inhibit proliferation or trigger apoptotic cell death60-62. 
Thus, two independent mechanisms provide opportunities for the use of agonist anti- 
CD40 monoclonal antibodies in cancer therapy: the enhancement of anti-tumor 
immunity and the direct growth inhibition or killing of tumors. 
Anti-CD40 monoclonal antibodies have been tested in several early-phase 
clinical trials63-67. These studies have demonstrated a similar toxicity profile, with 
infusion reactions and transient changes in liver function tests and hematologic 
parameters being most common. CDX-1140 (Celldex) is a fully human IgG2κ 
monoclonal antibody that binds to human CD40 with high affinity and promotes CD40 
signaling68,69. 
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 Meeting70. CDX-1140 
is administered intravenously monthly, and CDX-301 is administered 75 g/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, 
which will be used in the present study. 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 head and neck squamous cell carcinoma 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 
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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. 
 
2.6 FLT3 Ligand, Anti-CD40 Antibody, and Stereotactic Radiotherapy 
The dendritic cell subset expressing CD141 in humans (CD103 in mice) is 
responsible for producing T cell attractant chemokines and for “cross-presenting” 
exogenous tumor antigens to CD8+ cytotoxic T cells14. The absence of such cells is 
associated with lack of response to immunotherapy in murine models15,16 and poor 
clinical outcomes in a variety of cancers18. CDX-301 (FLT3 ligand) has been shown to 
expand CD141+ dendritic cells71. The key rationale for combining CDX-1140 and CDX- 
301 is to increase the number of dendritic cells (especially CD141+ dendritic cells) that 
are available to be activated by CDX-1140. Stereotactic radiotherapy to a single tumor 
or metastasis in this setting is expected to release tumor neoantigens into the 
circulation, augmenting the potential for an effective in situ vaccine. This principle has 
been tested in Dr. Guha’s laboratory at the Albert Einstein College of Medicine72: 
 
 
2.7 SBRT for NSCLC Patients with Limited Disease Burden 
Several phase II randomized trials have recently demonstrated that, for patients 
with “oligometastatic” and non-progressive NSCLC after first-line systemic therapy, 
comprehensive local therapy may delay disease progression and death36-38. This 
hypothesis is now being tested in a large multi-institutional trial (NCT03137771). Radical 
local therapy has also shown promise in other settings of limited metastatic 
disease32,73,74. For advanced/metastatic NSCLC, current NCCN guidelines indicate that 
“definitive local therapy to isolated or limited metastatic sites… is an appropriate option 
in such cases if it can be delivered safely to the involved sites75.” 
For patients in our practice who have limited (typically less than 3-5) sites of 
active disease after several lines of systemic therapy (leaving few appealing systemic 
treatment options), we routinely offer “comprehensive” SBRT as standard of care. As a 
result, all subjects enrolled on this study for whom the treating physicians deem 
comprehensive SBRT to be safe and feasible will receive comprehensive SBRT. 
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2.8 Quality-of-Life Assessments in NSCLC 
Quality-of-life (QoL) is a critical endpoint in clinical trials for advanced lung 
cancer. QoL can be affected dramatically by both the disease and its treatment. In this 
study, we will assess QoL using the EORTC QLQ-C30 tool. The QLQ-C30 is the most 
widely used cancer-specific HRQoL instrument. It contains 30 items and measures 5 
functional dimensions (physical, role, emotional, cognitive, and social), 3 symptom items 
(fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, sleep disturbance, 
appetite loss, constipation, diarrhea, and financial impact), and a global health and 
quality of life (QoL) scale. We will also utilize the EORTC QLQ-LC13, which is a 
disease-specific questionnaire developed and validated to address measurements 
specific to lung cancer76,77. 
2.9 
Physical Activity Monitoring 
Wearable devices that can monitor steps taken, stairs climbed, energy 
expenditure, heart rate, and sleep metrics are now marketed as fitness trackers. Data 
from these user-friendly and inexpensive devices may provide important information to 
clinicians caring for cancer patients78,79. In a series of trials we have performed at 
Montefiore/Einstein, we have discovered that a simple measure – daily step count – can 
provide valuable prognostic information regarding both short-term hospitalization risk80- 
82 and long-term clinical outcomes83. 
 
Baseline activity level (based on step count average and age) can predict clinical outcomes for patients 
treated with chemoradiotherapy for locally advanced NSCLC (left, middle)83 or patients receiving 
palliative systemic therapy for advanced solid tumors (right, preliminary data from an ongoing trial) 
 
Subjects on this trial may opt to wear a commercial fitness tracker (provided by 
the study team) as part of this study. We will assess baseline activity level as a 
prognostic factor for study subjects and also compare rates of activity change for 
subjects who receive study therapy versus standard care, with the expectation that 
study therapy will preserve physical function compared to standard therapy, such as 
cytotoxic chemotherapy. 
 
3.0 PATIENT ELIGIBILITY 
3.1 Inclusion Criteria 
 Histologically proven NSCLC, not classically deemed to be amenable to curative 
therapy based on disease extent at the time of diagnosis or disease progression 
after the initial diagnosis 
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 Age ≥ 18 years 
 Prior treatment with at least two lines of systemic therapy for advanced NSCLC, 
including one line of platinum-based combination chemotherapy 
o Treatment with concurrent chemotherapy and immunotherapy can count 
as two lines of therapy for the purposes of study eligibility. 
 Radiological assessments, including CT within 21 days prior to study entry and PET/CT 
within 42 days prior to study entry, demonstrating measurable disease that includes at 
least one pulmonary or extrapulmonary lesion ≥ 1 cm in greatest dimension that would 
be amenable to SBRT and at least one measurable lesion that would be outside of the 
SBRT treatment fields  
 ECOG performance status 0-2 
 Both men and women enrolled in this trial must agree to use adequate birth 
control measures during the trial and for at least 90 days after last receipt of 
study therapy. Patients and/or partners who are surgically sterile or 
postmenopausal are exempt from this requirement. 
 The following laboratory results, within 21 days prior to study registration: 
o Hemoglobin ≥ 9.0 g/dL 
o Absolute neutrophil count ≥ 1.5 x 109/L 
o Platelet count ≥ 100 x 109/L 
o Serum creatinine ≤ 1.5 x ULN OR creatinine clearance (by Cockcroft- 
Gault formula) > 60 mL/min 
o AST and ALT ≤ 2.5 x ULN 
o Total bilirubin ≤ 2.0 x ULN (except patients with Gilbert’s syndrome, who 
must have a total bilirubin ≤ 3.0 mg/dL) 
o Negative SARS-CoV-2 (COVID-19) PCR test 
 COVID-19 testing may be repeated periodically based on 
institutional policies and must be repeated for any subject with 
unexplained signs (e.g., imaging findings, fever) or symptoms (e.g., 
anosmia) concerning for COVID-19 infection or with recent known 
exposure to COVID-19. 
3.2 Exclusion Criteria 
 Prior therapy with any anti-CD40 antibody or FLT3 ligand 
 Less than 21 days between planned study treatment start and the last receipt 
of chemotherapy, targeted cancer therapy, immunotherapy, radiotherapy 
(excluding palliative radiotherapy), or major surgery. 
 Untreated central nervous system metastases. Patients with a history of brain 
metastases must have had no CNS-directed therapy within the past 60 days and 
radiological assessment within 30 days of study entry demonstrating a lack of 
progressive CNS disease. Patients without a history of brain metastases and 
without symptoms suggestive of brain metastasis do not require staging imaging 
of the brain prior to study enrollment. 
 Known mutation/amplification in FLT3 
 Ongoing use of high dose oral corticosteroids (≥ 2 mg of dexamethasone 
daily or equivalent) or inhaled corticosteroids. Intranasal and/or intraarticular 
corticosteroid use is permitted. 
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 History of non-infectious pneumonitis or any ongoing pneumonitis 
 History of allogeneic organ transplant or active autoimmune disease 
 Other active malignancy for which systemic therapy (excluding hormonal therapy 
for breast or prostate cancer) is indicated. 
 History of myocardial infarction, cerebral vascular accident, thrombosis, or 
pulmonary embolus within 12 months prior to study registration. 
 Uncontrolled intercurrent illness including, but not limited to, symptomatic 
congestive heart failure, unstable angina pectoris, uncontrolled cardiac 
arrhythmia, or psychiatric illness/social situation that would limit compliance with 
study requirements as judged by the treating physicians 
 Active infection requiring systemic therapy, known HIV infection, or positive test 
for hepatitis B surface antigen or hepatitis C (antibody screen and if positive 
confirmed by RNA analysis). If positive results are not indicative of a true active 
or chronic infection, the patient can be enrolled after discussion with, and 
agreement by, the Principal Investigator. 
 Receipt of a live vaccine within 30 days prior to the first dose of study drug. 
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus 
Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not 
allowed. 
 Subjects who are not ambulatory or ambulate using a walker are not eligible for 
the objective activity monitoring component of this study. 
 
4.0 STUDY DESIGN 
 
1EGFR/ALK positive v. EGFR/ALK negative or unknown 
2Limited Disease (suitable for comprehensive SBRT) v. Extensive Disease 
aIncluding comprehensive SBRT for limited disease 
 
 Safety assessment for Phase I will take place after 6 subjects are randomized to 
Arm 1 and followed for 8 weeks after treatment initiation 
 If ≤ 1 subject out of 6 on Arm 1 experiences a DLT, the study will proceed to 
Phase II 
 The total sample size (Phase I + Phase II) will be 46 subjects 
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4.1 General Design 
This is a randomized, open-label phase I/II study. Subjects will be randomized in 
a 1:1 ratio to receive FLT3 ligand, anti-CD40 antibody, and SBRT (Arm 1) versus 
standard care (Arm 2). Subjects on either study arm with limited disease will receive 
SBRT to all evident sites of active disease. Subjects on Arm 1 with extensive disease 
will initially receive SBRT to a single site of disease but may receive additional “cycles” 
of FLT3 ligand, anti-CD40 antibody, and SBRT at later time points. Subjects on Arm 2 
with extensive disease are expected to receive some form of standard systemic therapy 
(e.g., docetaxel). Subjects on Arm 2 with limited disease may also receive standard 
systemic therapy following completion of SBRT to all sites of evident disease, at the 
discretion of the treating physicians. All subjects will be followed closely for treatment- 
related toxicities. Whole-body PET/CT and CT imaging will be performed prior to study 
entry, and restaging CT will be performed every 8 weeks thereafter. 
In the phase I component of this study, subjects will be randomized between 
study arms until 6 subjects have been randomized to Arm 1. Study accrual will then be 
halted until 8 weeks after the last study subject begins treatment. 
If the pre-specified safety criteria are achieved in the Phase I portion of this 
study, the study will proceed to phase II. The total sample size (Phase I and Phase II) 
will be 46 subjects. All 46 subjects will be included in efficacy analyses. 
If the pre-specified safety criteria are not achieved in the Phase I portion of this 
study, the investigators and Celldex will review safety data from this trial as well as 
other trials using CDX-301 and CDX-1140 and determine if the experimental treatment 
regimen should be altered (e.g., by reducing the CDX-1140 dose). The study protocol 
would be amended accordingly, and Phase I component with the new treatment 
regimen would be added. 
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4.2 Study Calendars 
 
4.2.1 Pre-Registration and Pre-treatment Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2.2  Arm 1 (experimental study arm) 
 
 
 
 
 
 
Timing 
CBC, BMP, LFTs 
Within 21 days prior to study entry 
Amylase, Lipase 
Pre-treatment 
Negative SARS-CoV-2 PCR 
Within 21 days prior to study entry 
PET/CT 
Within 42 days prior to study entry 
CT C/A/P 
Within 21 days prior to study entry 
QoL Assessments 
Pre-treatment 
Correlative Study Blood Draw 
Pre-treatment1 
CDX-301 ADA and CDX-1140 PK 
Pretreatment (Arm 1 only)1 
ARM 1 
Week 1 
Week 2 
Week 4 
Week 6 Weeks 91, 172, 252, 332, 412, 492 
History and Physical Examination 
X 
X5X6 
X 
X5X6 
X 
CBC, BMP, LFTs, Amylase, Lipase 
X 
X5X6 
X 
X5X6 
X 
Activity Data Download3 
X 
X 
X 
X 
X 
QoL Assessments 
 
X 
X 
X 
X 
Correlative Study Blood Draw 
  
X7 
  
X7 
X 
CDX-301 ADA and CDX-1140 PK 
  
X7X8X6 
  
X7X6 
  
CT C/A/P 
  
  
  
  
X 
Stereotactic Radiotherapy (SBRT)4 
XXX 
  
  
  
  
FLT3 Ligand (CDX-301) 
XXXXX 
  
  
  
  
CD40 Agonist Antibody (CDX-1140) 
  
X 
  
X 
  
1. +/- 1 week  
2. +/- 2 weeks 
3. For subjects who opt to participate in this part of the study  
4. SBRT should be delivered in 1, 3, or 5 fractions per target  
and may continue beyond Week 1 when treating multiple sites. 
 
Cycles of SBRT(to an untreated lesion)+CDX-301+CDX-1140 may be repeated. 
 
At least 8 weeks must separate the start of each treatment cycle. 
 
CDX-1140 may be omitted from retreatment cycles for subjects with prior 
DLT or intolerable toxicity attributed to CDX-1140. 
 
The schedule of assessments will reset when a new cycle is initiated. 
5. On the day of CDX-1140 infusion 
6. One day after CDX-1140 infusion 
7. Immediately before CDX-1140 infusion  
8. 2 hours after CDX-1140 infusion 
 
1. Must be obtained at least 21 days after last receipt of chemotherapy, targeted 
cancer therapy, immunotherapy, radiotherapy (excluding palliative radiotherapy), 
or major surgery. 
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4.2.3 Arm 2 (control arm) 
 
ARM 2 
Week 1 
Week 2 
Week 4 
Week 6 
Weeks 91, 172, 252, 332, 412, 492 
History and Physical Examination 
X 
X 
X 
X 
X 
CBC, BMP, LFTs, Amylase, Lipase 
X 
X 
X 
X 
X 
Activity Data Download3 
X 
X 
X 
X 
X 
QoL Assessments 
 
X 
X 
X 
X 
Correlative Study Blood Draw 
  
X 
  
X 
X 
CT C/A/P 
  
  
  
  
X 
Stereotactic Radiotherapy (SBRT)4 
X X X 
  
  
  
  
 
 
 
 
 
4.3 Primary Endpoints 
 
Phase I: Dose-limiting toxicity (DLT), as defined in Section 7.2.
 Phase II: Progression-free survival (PFS) duration, defined as time from study registration 
until disease progression (scored using iRECIST84) or death, whichever comes first. 
4.4 Secondary Endpoints 
 Overall survival (OS) duration, defined as time from study registration until death.
 Radiographic responses, scored using iRECIST and RECIST.
 Patient-reported outcomes (PROs), assessed using the EORTC QLQ-C30 and 
QLQ-LC13
 Physical activity metrics, including daily step counts, obtained using wearable 
devices
 Correlative studies, including measures of DC expansion and DC maturation, anti- 
drug antibodies (ADA), and CDX-1140 pharmacokinetics
 
5.0 STUDY THERAPY – ARM 1 
5.1 Stereotactic Body Radiotherapy 
 
5.1.1 Patient Selection – Limited v. Extensive Disease 
Stereotactic body radiotherapy (SBRT) will be administered to all subjects on 
Arm 1 and to subjects with limited disease burden on Arm 2. For the purposes of this 
trial, “limited disease” is defined as disease that, in the estimation of the treating 
physician, can reasonably and safely be addressed in a comprehensive fashion with 
SBRT. This definition will generally align with recent consensus definitions of 
oligometastatic disease, such as having 5 or fewer active lesions85-87. Occasionally, a 
Standard systemic therapy may be administered at any time for subjects with 
extensive disease burden and any time after completion of all planned SBRT for 
subjects with limited disease. 
1. +/- 1 w eek  
2. +/- 2 w eeks 
3. For subjects w ho opt to participate in this part of the study  
4. SBRT is only required for subjects w ith limited disease burden. 
SBRT should be delivered in 1, 3, or 5 fractions per target and may 
continue beyond Week 1 w hen treating multiple sites. 
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study subject with 5 or fewer active lesions may be deemed to be ineligible for 
comprehensive SBRT due to large target size (above 7 cm for lung tumors88 or above 
5 cm for other lesions89,90), target location adjacent to a radiosensitive normal 
structure, or prior radiotherapy exposure. Rarely, comprehensive SBRT a subject with 6 
or more active lesions may be deemed feasible and safe (e.g., two small lung tumors, 
two small liver metastases, and two spine metastases). Any subject with more than 10 
active lesions will be deemed to have extensive disease91. 
 
5.1.2 SBRT Timing 
For subjects on Arm 1, SBRT will be delivered concurrently with FLT3 ligand 
during Week 1 of study therapy. If only one lesion is being treated, SBRT should be 
completed during week 1 (e.g., with daily treatments for a 5-fraction course of 
treatments every other day for a 3-fraction course). In cases where multiple lesions are 
being treated with SBRT (Arm 1 or Arm 2) or if treatment is interrupted due to technical 
issues or intercurrent illness, SBRT may extend beyond Week 1. 
 
5.1.3 Immobilization, Simulation, and Localization 
Patients will be positioned in a stable position capable of allowing accurate 
reproducibility of the target position from treatment to treatment. A variety of 
immobilization systems may be used, including stereotactic frames that surround the 
patient on three sides and large rigid pillows (conforming to patients’ external contours) 
with reference to the stereotactic coordinate system. Patient immobilization must be 
reliable enough to ensure that the gross tumor volume (GTV) does not deviate beyond 
the confines of the planning treatment volume (PTV) with any significant probability (i.e., 
< 5%). 
For thoracic and upper abdominal radiotherapy targets, special considerations 
will be made to account for the effect of internal organ motion (e.g., breathing) on target 
positioning and reproducibility. Acceptable maneuvers include reliable abdominal 
compression, accelerator beam gating with the respiratory cycle, active breath-holding 
techniques, and use of 4D simulation CT to generate internal target volumes (ITVs). 
Internal organ inhibition maneuvers must be reliable enough to ensure that the GTV 
does not deviate beyond the confines of the PTV with any significant probability (i.e., < 
5%). 
Computed tomography will be the primary image platform for targeting and 
treatment planning. Axial acquisitions with gantry 0 degrees and spacing ≤ 3.0 mm 
between scans in the region of the tumor are required. Images will be transferred to the 
treatment planning system for radiotherapy planning. 
Verification CT scans should be obtained immediately before each treatment to 
ensure proper alignment of the geometric center (isocenter) of the simulated fields. 
Verification CT scans and/or portal films during or following each treatment may be 
acquired at the discretion of the treating physician. 
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5.1.4 Target Volumes 
Parenchymal lung tumors greater than 7 cm in maximal diameter and other 
lesions greater than 5 cm in maximal diameter cannot serve as SBRT target lesions for 
this trial. Study subjects with lesions exceeding these size criteria are considered to 
have “Extensive” disease and will not receive SBRT to all active lesions. A smaller 
lesion must be chosen as the SBRT target for such patients. 
Gross tumor volumes (GTVs) for target lesions will be drawn on simulation CT 
imaging, using appropriate window levels. Other imaging modalities (e.g., PET, MRI) 
imaging may be fused to simulation CT scans to aid with localization of target lesions. 
Respiratory motion management for thoracic and upper abdominal tumors is 
required. A deep inspiration breath hold (DIBH) technique may be utilized to eliminate 
respiratory motion. In other cases, 4D CT simulation will be employed. If 4D CT 
simulation is used, GTVs should be generated on each CT phase that will be used for 
treatment (typically 4/10 phases if respiratory gating is employed or 10/10 phases if the 
patient will be treated while breathing freely). These GTVs will be combined to form 
internal target volumes (ITVs). 
No clinical target volumes (CTVs) will be employed in this protocol. 
GTVs or ITVs will be expanded to form planning target volumes (PTVs), using 
expansions of 4-5 mm in all directions. Expansion may be increased by up to 5 
additional mm in the craniocaudal directions if there is concern for unmeasured 
respiratory motion (e.g., in cases of limited 4D CT quality for thoracic or upper 
abdominal targets). 
 
5.1.5 SBRT Dosing 
SBRT doses for this study follow NCCN guidelines75 and cooperative group 
recommendations33. 
 
 
Lung tumors: 
Schedule 
Criteria 
34 Gy x 1 
Peripheral tumor measuring ≤ 
2 cm in greatest dimension and 
> 1 cm from the chest wall 
18 Gy x 3 
Peripheral tumor measuring ≤ 
5 cm and not eligible for 34 Gy 
x 1 fraction 
10 Gy x 5 
Central or peripheral tumor not 
eligible for 34 Gy x 1 fraction or 
18 Gy x 3 fractions 
 
A “central” lung tumor will be defined based on the eligibility criteria for RTOG 081334 (“Seamless Phase 
I/II Study of Stereotactic Lung Radiotherapy (SBRT) for Early Stage, Centrally Located, Non-Small Cell 
Lung Cancer (NSCLC) in Medically Inoperable Patients”): Tumor within or touching the zone of the 
proximal bronchial tree, defined as a volume 2 cm in all directions around the proximal bronchial tree 
(carina, right and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle 
lobe bronchus, lingular bronchus right and left lower lobe bronchi). [See figure below] Tumors that are 
immediately adjacent to mediastinal or pericardial pleura (PTV touching the pleura) also are considered 
central tumors. Tumors that are not “central” are considered to be “peripheral.” 
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Other target lesions: 
Schedule 
Target Lesion Location 
10 Gy x 3 
Spinal or Paraspinal 
10 Gy x 3 
Osseous 
10 Gy x 5 
Mediastinal or Cervical Lymph 
Node 
15 Gy x 3 
Liver 
15 Gy x 3 
Abdominal or Pelvic (lymph 
node or adrenal gland) 
 
 
5.1.6 Target Coverage 
At least 95% of each PTV should receive the full prescription dose. If this cannot 
be achieved while respecting normal tissue constraints, the prescription dose may be 
lowered by up to 30%. Alternatively, the portion of the PTV abutting/overlapping a 
radiosensitive structure may be excluded from the target coverage evaluation structure 
(“PTV_eval”). 
 
5.1.7 Critical Structures 
Normal tissue structures visualized on the simulation CT will be delineated using 
contouring guidelines established by RTOG: 
https://www.rtog.org/CoreLab/ContouringAtlases.aspx 
 
The following normal tissue constraints, adopted from 2020 NCCN guidelines75 
and RTOG 081334, will be used for planning SBRT to lung tumors: 
 
1 Fraction 
3 Fractions 
5 Fractions 
Brachial plexus 
max dose < 17.5 Gy 
max dose < 24 Gy 
max dose < 32 Gy 
Esophagus 
max dose < 15.4 Gy 
max dose < 30 Gy 
max dose < 52.5 Gy 
Great vessels 
max dose < 37 Gy 
max dose < 39 Gy 
max dose < 52.5 Gy 
Heart/pericardium 
max dose < 22 Gy 
max dose < 30 Gy 
max dose < 52.5 Gy 
Lungs 
At least 1500 cc 
receiving < 12.5 Gy 
At least 1500 cc 
receiving < 12.5 Gy 
At least 1500 cc 
receiving < 12.5 Gy 
Skin 
max dose < 26 Gy 
max dose < 24 Gy 
max dose < 32 Gy 
Spinal cord 
max dose < 14 Gy 
max dose < 18 Gy 
max dose < 30 Gy 
Stomach 
max dose < 12.4 Gy 
max dose < 27 Gy 
max dose < 35 Gy 
Trachea and 
proximal bronchi 
max dose < 20.2 Gy 
max dose < 30 Gy 
max dose < 52.5 Gy 
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The following normal tissue constraints, adopted from NRG-BR00133,92, will be 
used for planning SBRT to other target lesions: 
 
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5.2 CDX-301 and CDX-1140 
5.2.1 Dosing and Administration 
CDX-301 
Each 2 mL clear borosilicate glass vial contains 2.5 mg/mL CDX-301 
glycoprotein in a 1.0 mL (with an overfill to 1.2 mL) volume of buffered solution 
composed of 10 mM sodium phosphate, 140 mM NaCl, pH 7.0. CDX-301 Drug Product 
is formulated as a sterile solution intended for single-use subcutaneous administration. 
An initial study drug shipment will be provided following receipt of all required 
documents. Additional supplies should be ordered with at least one week advance 
notice using a form supplied by Celldex. 
All study supplies must be stored in a secured area with limited, approved 
access. CDX-301 temperature must be maintained between 2° to 8°C (36 to 46°F) and 
monitored daily. Deviations in storage conditions must be reported to IIR@celldex.com 
within 24 hours of awareness. 
The individual dose is calculated using the actual baseline body weight of the 
subject according to the calculations below. All subjects will receive 75 µg/kg of CDX- 
301 at each administration. 
Body Weight (kg) x Dose Level (75µg/kg) = Desired Dose (µg) 
Desired Dose (µg) ÷ 2500 µg/mL = Volume of CDX-301 (mL) 
 
For example, for an 80 kg subject, the total dose required to deliver the 75 µg/kg 
dose would be 6000 µg. The calculated volume required from the 2500 µg/ml CDX-301 
stock solution to obtain 6000 µg of CDX-301 would be 2.4 ml. Three vials would be 
needed to administer this dose. 
 
CDX-301 liquid should be withdrawn from the vial gently, avoiding foaming and 
excess shearing. As the maximum volume of any individual injection will be 2.0 ml, the 
dose may be split into up to 3 separate syringes/subcutaneous injections as needed to 
administer the required volume. 
CDX-301 will be administered as a daily subcutaneous injection. The injection 
site may be rotated between the extremities. CDX-301 injections should not be given to 
areas of skin with conditions such as scarring, tattoos or persistent injection site 
reactions that will not allow easy access for study drug administration or evaluation of 
localized adverse events. CDX-301 administration will be performed within the clinical 
setting by trained staff personnel. 
 
CDX-1140 
Each vial to be used for intravenous administration 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. 
CDX-1140 must be stored at ≤ -65°C (-85°F) until use. CDX-1140 should be 
protected from light. However, sufficient light protection is provided by the secondary 
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container (carton); no specific light protection is needed during preparation of the dosing 
solution and infusion. 
Upon removal from storage at ≤ -65°C, vials should be thawed at ambient 
temperature for approximately 1.5 hours. After equilibration to room temperature and 
before use, the vial should be gently swirled to ensure uniform mixing of the contents. 
Do not invert or shake vials. Solution should be gently withdrawn (avoiding foaming and 
excess shearing). 
CDX-1140 should be administered as a 90-minute infusion using a volumetric 
pump with a 0.22 micron pore size, low-protein binding polyethersulfone (PES) 
membrane in-line filter. 
The CDX-1140 dose will be calculated using the actual baseline body weight of 
the patient. The following formula should be used to calculate the volume of CDX-1140 
required for each administration: 
 
Body Weight (kg) x Desired Dose (mg/kg) ÷ 3 mg/mL = Volume of CDX-1140 (mL) 
 
For example, for an 80 kg subject, the total dose required to deliver the 1.5 
mg/kg dose would be 120 mg. the calculated volume required from the 3 mg/mL CDX- 
1140 stock solution to obtain 120 mg would be 40 mL. As each vial of CDX-1140 
contains a withdrawable volume of 10 mL, administration of the 1.5 mg/kg dose would 
require 4 vials of CDX-1140. 
 
5.2.2 Treatment Schedule 
CDX-301 and CDX-1140 will only be administered to subjects on Arm 1. Subjects 
on Arm 2 will not “crossover” if disease progression is observed. The Study Calendar 
(Section 4.2) describes the timing of study drug administrations. 
Some subjects on Arm 1 may receive more than one “cycle” of CDX-301, CDX- 
1140, and SBRT (targeting a lesion not previously treated with SBRT). The decision to 
administer treatment cycles beyond cycle 1 must be agreed upon by the treating 
physicians, the principal investigators, and the study subject. Additional treatment 
cycles will not be offered to subjects who develop disease progression within four 
months of receiving a previous cycle of study therapy or to subjects who have no 
evidence of active disease. Subjects who previously experienced DLT or intolerable 
toxicity related to CDX-1140 may be treated with CDX-301 and SBRT and without CDX- 
1140 in subsequent treatment cycles. 
For subjects who receive more than one cycle of study therapy, the schedule of 
events will reset at the beginning of each cycle. At least 8 weeks must separate the start 
of each treatment cycle. 
 
CDX-301 
Five injections of CDX-301 should be administered daily during Week 1 
(Monday-Friday) of a treatment cycle. If that is not possible due to department closure 
for a national holiday, inclement weather, or another reason that is not treatment-related 
toxicity, CDX-301 treatment may extend to Week 2 (though not beyond 10 days after 
the first CDX-301 dose). 
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CDX-1140 
The first CDX-1140 will take place 4 days (+/- 1 day) after the last dose of CDX- 
301. As CDX-301 will typically be given from Monday-Friday, CDX-1140 will usually be 
given on a Tuesday. The second dose of CDX-1140 will be given 4 weeks (+/- 3 days) 
after the first CDX-1140 dose. CDX-1140 will not be administered on a Friday, as a 
clinic visit the day after each CDX-1140 dose is required. 
5.2.3 Medications to be given before/after study drug administration 
CDX-301 
No premedication is required for CDX-301. 
No medication is required after CDX-301 injections. 
 
CDX-1140 
Prophylactic premedication is required, at least 30 minutes prior to administration 
of CDX-1140: 
 diphenhydramine 25/50 mg (or equivalent antihistamine) 
 500 to 750 mg paracetamol (acetaminophen) 
 naproxen sodium 250 mg (or equivalent NSAID), at least 30 minutes prior to 
CDX-1140 administrations. 
 Ranitidine 150 mg (or equivalent) and/or an anti-emetic (ondansetron 8 mg, 
or equivalent) may also be incorporated into the premedication regimen. 
 Prophylactic premedication with corticosteroids is to be avoided because of 
the potential to attenuate the anti-tumor activity of CDX-1140. 
 
Post-infusion medication is required over the 24-48 hours after each CDX-1140 
infusion: 
 Alternating oral acetaminophen (1000 mg) and non-steroidal anti- 
inflammatory (e.g., ibuprofen 200 mg) q6h. 
 An antihistamine and anti-emetic may also be utilized if clinically indicated. 
 Patients should be evaluated to determine if continuation of post-infusion 
medication is needed when they are seen on the Cycle 1 Day 2 visit. 
 The potential for toxicity with these drugs should be recognized, and 
appropriate precaution should be utilized in patients with risk factors for 
toxicity, such as patients with peptic ulcers, increased LFTs, or increased 
creatinine. Also, care should be taken to medicate for no longer than 
is necessary, to avoid adverse events. 
 
5.2.4 Potential Toxicities and Toxicity Management 
Potential toxicity and guidance for the management of toxicity is summarized 
below. However, the CDX-1140 and CDX-301 Investigator Brochures (IB) are the 
Single Reference Safety Documents that provide complete and relevant information 
about the known safety profile of CDX-1140 and CDX-301. 
 
CDX-301 
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CDX-301 was generally well-tolerated in all prior studies, including our prior study 
of CDX-301 and SBRT for advanced NSCLC, which utilized the same CDX-301 
dose/schedule as the present trial. The most frequently observed toxicities related to 
CDX-301 have been asymptomatic lymphadenopathy and mild injection site reactions. 
Injection site reactions have been infrequent and mild with CDX-301. No injection 
site reactions were observed in our recent trial combining CDX-301 and SBRT (29 
subjects, 180 injections). Generally mild to moderate injection site reactions were 
reported in studies using AMG949. Pre-medication with diphenhydramine has been 
reported to be effective in the prevention of pruritic and erythemic reactions93 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. Patients will be monitored for 30 minutes following each 
CDX-301 injection. 
Leukocytosis, especially monocytosis, is expected during administration of CDX- 
301. Hematological parameters, including WBC and differential, should be monitored in 
subjects receiving CDX-301. CDX-301 should not be administered if marked 
leukocytosis, e.g. WBCs greater than 50,000 cells/mm3, is observed. 
 
CDX-1140 
The CDX1140-01 study was the first clinical trial with CDX-1140, and therefore 
there is limited clinical experience to define expected toxicities. Management of drug- 
related adverse events and serious adverse events should be in accordance with the 
institution’s standard of care and guidelines for managing immune related toxicities94. 
CDX-1140 infusion should take place in a monitored setting that has ready 
access to an intensive care unit in case of a severe infusion reaction. All subjects 
should be monitored for 2 hours after each administration of CDX-1140; patients who 
experience any treatment-related adverse events during the observation period should 
be further monitored as clinically appropriate. CDX-1140 will be administered once 
every four weeks. CDX-1140 will be administered intravenously over 90 minutes using a 
0.22 micron in-line filter. The dose of study treatments will be calculated based on 
actual weight at screen and may remain constant throughout the study, unless greater 
than 10% change in weight is observed. The infusion duration can be increased by 30- 
minute intervals up to 180 minutes if warranted due to prior infusion reactions. 
In the phase I trial testing CDX-1140, infusions were generally well-tolerated. 
Drug-related adverse events have been observed in the post-infusion period, typically 
within 24-48 hours after completing the infusion. Symptoms have included fever, 
fatigue, nausea, chills, and arthralgias. As of May 28th, 2020, there were 4 grade 2 and 
2 grade 3 cytokine release syndrome adverse events. These adverse events were 
treated with corticosteroids, and in one case, tocilizumab. It is therefore recommended 
that medication to treat infusion reactions, including severe infusion reactions/cytokine 
release syndrome, be readily available at the time of the study drug infusion. All patients 
should be monitored for 2 hours after each administration of CDX-1140; patients who 
experience any treatment-related adverse events during the observation period should 
be further monitored as clinically appropriate. 
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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 (Version 5.0) 
guidelines, http://ctep.cancer.gov. Serum should be obtained at the time of an infusion 
reaction/cytokine release syndrome. Patients who experience a grade 4 infusion 
reaction or a grade 3 infusion reaction lasting > 6 hours will permanently discontinue 
CDX-1140, and the adverse event will be considered a DLT. 
 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, including an infusion reaction of Grade 2, during the 4 to 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. Tocilizumab should be considered for patients with 
severe or prolonged infusion reactions/cytokine release syndrome who are 
not responding to appropriate therapy. 
 
Subjects with peri-infusional reactions 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 
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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. 
5.2.5 Dose Modifications 
CDX-301 
There will be no CDX-301 dose modifications. If discontinued, CDX-301 will not 
be reinstituted. CDX-301 should not be administered if marked leukocytosis, e.g., WBCs 
greater than 50,000 cells/mm3, is observed. Any ≥ Grade 3 injection site reactions 
thought related to CDX-301 warrant discontinuation of CDX-301 treatment and will be 
considered a DLT. If CDX-301 is discontinued due to a DLT, treatment with CDX-1140 
may continue in the absence of a CDX-1140-related DLT. 
 
CDX-1140 
CDX-1140 dose modifications are not allowed. The second CDX-1140 infusion 
should only be administered if the subject is receiving ≤ 10 mg/day prednisone or 
equivalent for treatment of drug related toxicity, and all toxicity related to prior treatment 
(including laboratory abnormalities) has resolved to ≤ grade 1, with the following 
exceptions: 
 Subjects may receive treatment in the presence of grade 2 fatigue 
 Subjects who have not experienced a grade 3 drug-related skin AE may 
receive treatment in the presence of grade ≤ 2 skin toxicity 
 Subjects with baseline grade 1 AST/ALT or total bilirubin elevation may 
receive treatment in the presence of grade 2 AST/ALT or total bilirubin 
elevation 
 Grade 2 drug-related pulmonary toxicity, diarrhea, or colitis, must have 
resolved to baseline before treatment is received 
 Patients with drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement may receive treatment 
 Asymptomatic lymphopenia 
 Clinically asymptomatic increased amylase or lipase. The medical monitor 
should be consulted in the event of grade 4 elevations in amylase or lipase. 
 
5.2.6 Additional Warnings and Precautions 
CDX-301 
Drug-drug Interactions 
Interactions between CDX-301 and other drugs have not been fully evaluated. 
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Allergic Reaction 
CDX-301 is a fully human protein, and it is unlikely that it will induce a 
hypersensitivity reaction. No such reactions have been observed in the CDX-301 
programs to date; nor were any such reactions reported in the AMG949 clinical 
development program. If such reactions were to be observed, possible manifestations 
could include fever, chills, rash, rigors, pruritus, or other symptoms. 
 
Immunogenicity 
None of the 30 healthy volunteers treated in the Phase I trial with CDX-301 (5 to 
10-day regimen) developed anti-rhuFlt3L antibody. In the Celldex-sponsored pilot study, 
CDX301-03, none of the four donors administered CDX-301 had detectable anti- 
rhuFLT3L antibodies at any collection time point. 
The immunogenicity of CDX-301 has also been investigated in two investigator- 
sponsored studies. In CDX301-51, the effects of intratumoral injection of CDX-301 and 
poly-ICLC were studied in low grade B-cell lymphoma. Samples were collected from 15 
patients for anti-CDX-301 immunogenicity testing. One patient has been found positive 
for anti-CDX-301 immunoreactivity. To date, no neutralizing responses have been 
observed. Immunogenicity samples were collected from 30 patients in CITN-07 
(CDX1401-54). Of the 144 total samples collected, none were found to exhibit a specific 
anti-CDX-301 response. 
Approximately 16% of subjects treated with AMG949 in Immunex sponsored 
studies and tested for immune response were noted to develop anti-rhuFlt3L antibody. 
Anti-rhuFlt3L antibodies appeared to develop more frequently in studies with greater 
exposure to AMG949. However, none of the anti-rhuFlt3L antibodies were neutralizing. 
In theory, neutralizing antibodies could develop following administration of CDX- 
301, with potential consequences of neutralizing subsequent CDX-301 effects, 
neutralization of endogenous Flt3L activity that could result in bone marrow 
suppression, inhibition or enhancement of immune responses, and/or result in immune 
complex mediated disease. Although this scenario is considered extremely unlikely to 
occur with CDX-301, patients will continue to be monitored for anti-CDX-301 antibodies 
and whether these antibodies are neutralizing. 
 
Coagulation 
No thrombotic events have been reported as potentially related to CDX-301 in 
the Celldex clinical development program to date. Thrombotic events 
(hypercoagulability, IV line thrombosis, and venous thrombosis) were observed rarely in 
oncology patients (n = 6) receiving AMG949 and was more common when combined 
with GM-CSF or G-CSF. Low grade thrombocytopenia has also been observed 
following AMG949 administration. Evaluation of coagulation parameters and clotting 
factors in several of these patients did not reveal any abnormalities. 
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Autoimmune Disease 
Subjects with a known history of autoimmune disorders should not be given 
CDX-301, until further studies have determined the safety profile of CDX-301 in this 
patient population. Pre-clinical studies have demonstrated that rhuFlt3L may have a 
complicated role in regulating autoimmune diseases and can either exacerbate or 
ameliorate autoimmune disease manifestations. Therefore, CDX-301 may have the 
potential to exacerbate autoimmune disorders by its immunomodulatory effects. 
Subjects administered CDX-301 will be monitored for the development of 
potential autoimmune phenomena, such as hyper- or hypothyroidism. 
 
Development of Immune Tolerance 
CDX-301-mediated increases in immature dendritic cells and/or Treg cells could 
potentially be tolerogenic. Therefore, CDX-301 could potentially have deleterious effects 
in an infectious disease setting or other pre-existing or developing disease. AMG949 
worsened the outcome in a mouse Streptococcus pneumoniae pneumonia challenge 
model95, indicating that rhuFlt3L treatment could pose a risk for increased lung injury 
associated with S pneumoniae pneumonia. Study subjects should be monitored for the 
development of infections conditions. 
rhuFlt3L may also be associated with a differential response to vaccines. In 
another murine model, intramuscular injection of rhuFlt3L in combination with a hepatitis 
B vaccine suppressed the antibody response to the vaccine in a dose-dependent 
manner, although in situ delivery by plasmid increased the antibody response96. In a 
clinical study in which healthy volunteers were administered hepatitis B vaccine and 
either placebo or AMG949, there was no inter-group difference in hepatitis B antibody 
responses, demonstrating that AMG949 neither augmented or tolerized humoral 
responses to the vaccine. 
 
Leukemia 
There are data showing that prophylactic treatment with rhuFlt3L can prevent or 
abrogate leukemic activity97. There also are data showing the expression of Flt3 and the 
Flt3L receptor, on some leukemias, and extensive data that support an association 
between an increase in proliferation or suppression of apoptosis in clinical leukemias 
that bear constitutively activated Flt3 mutations. These mutations do not appear to be 
causal for AML98-101. It is not known whether the addition of rhuFlt3L to patients with 
leukemia expressing Flt3 will promote leukemic proliferation, or whether the ligand can 
promote the development of leukemia in people without pre-existing leukemia. Since the 
effect of administered rhuFlt3L is transient, it would seem unlikely to have any persistent 
effects and no cases of leukemia were reported after rhuFlt3L administration in previous 
studies. 
 
Pregnancy, Carcinogenesis, and Teratogenicity 
The effects of CDX-301 on fertility, pregnancy, or the unborn fetus have not been 
determined. It is not known if CDX-301 is excreted in milk or can cross the placenta. For 
this reason, pregnant and nursing women should not receive CDX-301. Women of 
childbearing potential treated with CDX-301 must take adequate contraceptive 
measures. 
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CDX-1140 
Most side effects associated with CDX-1140 to date have occurred in the 24-48 
hours following the CDX-1140 infusion, been mild to moderate, 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 
include fatigue, arthralgia, nausea, chills, fever, diarrhea, myalgia, vomiting, AST 
increase, and ALT increase. 
 
Cytokine Release Syndrome 
2 patients who received CDX-1140 monotherapy and 4 patients who received 
CDX-1140 in combination with CDX-301 have experienced cytokine release syndrome. 
Symptoms included fever, hypotension, hypoxia, fatigue, headache, and nausea. 
 
Pneumonitis 
4 patients who received CDX-1140 monotherapy experienced severe treatment- 
related pneumonitis, with 3 of the 4 developing pneumonitis during the first week of 
treatment. These patients developed shortness of breath, and imaging of the lungs 
demonstrated new inflammatory changes. Two patients required intubation. All four 
patients were treated with high dose corticosteroids, and two of the patients 
subsequently died, due to a documented infection in one patient and presumed infection 
in the other. Two patients demonstrated clinical improvement temporally associated with 
the administration of tocilizumab. Of note, tocilizumab has not been incorporated into 
the treatment guidelines for management of pneumonitis associated with immune 
checkpoint blockade therapy,102 but there is a case series suggesting that tocilizumab is 
effective in the management of corticosteroid-refractory pneumonitis irAEs103. Based on 
the rapid response temporally associated with the administration of tocilizumab in the 
cases discussed above, and the case series suggesting that tocilizumab may be 
beneficial in treating checkpoint-related pneumonitis, tocilizumab should be considered 
as a therapeutic option in those patients with CDX-1140 related, steroid-refractory 
pneumonitis, as well as for other high grade steroid-refractory adverse events. 
 
Thrombosis 
CD40 is functionally expressed on platelets and endothelial cells, and CD40 
signaling could theoretically promote a pro-thrombotic state. In the CDX1140-01 study, 
1 patient developed a deep vein thrombosis and pulmonary embolism that was 
considered related to CDX-1140. Administration of CP-870,893, another agonist anti- 
CD40 mAb, was associated with transient increases in D-dimer and thrombin- 
antithrombin 3 complex formation levels at the 2 highest doses tested (0.2 and 0.3 
mg/kg) in the Phase 1 study63. Standard coagulation parameters were not affected by 
CP-870,893. One patient with a prior history of deep vein thrombosis had a drug-related 
thromboembolic dose-limiting toxicity. 
 
Elevated liver enzymes 
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Increases in liver function tests in the 24-48 hours following the CDX-1140 are an 
expected pharmacodynamic effect of the drug. The increases are usually low-grade, 
but can be grade 3, and liver function tests typically return to approach baseline within a 
week. Treatment of these transient changes is not indicated. More significant changes 
in laboratory tests may be followed more closely, if clinically warranted, and may require 
intervention per irAE guidelines102,104 if the changes are associated with clinical 
symptoms or persistent 
 
Decreased lymphocyte and monocyte counts 
Decreases in lymphocyte and monocyte counts are a pharmacodynamic effect of 
CDX-1140, occurring within 24-48 hours of a dose and typically recovering by 1 week. 
Decreases in B cells, as determined by flow cytometry, predominates. 
 
Other Adverse Events 
Based on a review of the relevant literature and the proposed mechanism of 
action of CDX-1140 in binding to CD40 expressing cells and enhancing immune 
reactions, the following additional adverse effects may be encountered: 
 Infusion reactions/cytokine release syndrome/hypersensitivity reactions 
 As mentioned above, infusion reactions are likely to occur and may include 
chills, rigors, fever, rash, nausea, vomiting, myalgias, headache, and 
hypotension. Obtain serum at the time of an infusion reaction/cytokine release 
syndrome. 
 As discussed above, patients are to be pre-medicated with antihistamine, 
acetaminophen, and/or NSAID at least 30 minutes prior to CDX-1140 
administrations. Prophylactic premedication with corticosteroids is to be 
avoided with CDX-1140 because of the potential to attenuate antitumor 
activity. In the 24 hours following the CDX-1140 infusion, alternate 
oral acetaminophen (1000 mg) and non-steroidal anti-inflammatory (e.g., 
ibuprofen 200 mg) q6h. An antihistamine and anti-emetic may also be utilized 
if clinically indicated. 
 Immune-related adverse events (irAEs) 
 An irAE is defined as a clinically significant adverse event of any organ that is 
associated with study drug exposure, of unknown etiology, and is consistent 
with an immune-mediated mechanism. Serologic, immunologic, and histologic 
(biopsy) data should be used to support an irAE diagnosis. Appropriate efforts 
should be made to rule out neoplastic, infectious, metabolic, toxin, or other 
etiologic causes of the adverse event. Most commonly irAEs involve skin, 
gastrointestinal (GI) tract, endocrine organs and liver, but can involve any 
organ system. irAEs typically clinically manifest several weeks to a few 
months following initiation of immune enhancing anti-tumor therapy. Possible 
clinical manifestations include: 
o Constitutional: fever, fatigue 
o GI: diarrhea, colitis, constipation, hematochezia, melena, abdominal pain, 
pancreatitis 
o Skin: rash, pruritus, alopecia, desquamation 
o Liver: elevated liver enzymes, hepatitis 
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o Endocrine: hypothyroidism, hyperthyroidism, adrenal insufficiency, 
hypophysitis, hypogonadism, diabetes 
o Ocular: conjunctivitis, iritis, uveitis 
o Others: neuropathy, including Guillain-Barre syndrome, hemolytic anemia, 
thrombocytopenia, pneumonitis 
 
Guidelines have been published for the management of irAEs associated with 
immunotherapy,102,104,105 and investigators should be familiar with the workup and 
treatment of irAEs. Obtain serum at the time of any ≥ Grade 3 suspected drug related 
irAE. 
 
5.2.7 Concomitant Therapy 
Subjects may continue to use any ongoing medications not prohibited by the 
inclusion/exclusion criteria. However, efforts should be made to maintain stable doses 
of concomitant medications during study treatment. Subjects must be instructed not to 
take any medications, including over-the-counter products, without first consulting with 
the investigator. 
Investigators may prescribe concomitant medications or treatments deemed 
necessary to provide adequate supportive care. However, while on study, when 
clinically appropriate, subjects should strictly follow the study-prescribed treatment 
regimen in accordance with the following guidance: 
 Concurrent administration of any anticancer therapies and/or other investigational 
agents are prohibited throughout the treatment period.
o Following treatment, but prior to documented progression of disease, additional 
anticancer therapies should be avoided if clinically feasible. If additional 
anticancer therapies are needed, it should be discussed and agreed upon with 
the Principal Investigator prior to administration. 
o Following progression of disease, subjects may receive any appropriate alternate 
therapies. 
 During study treatment, subjects may receive supportive care to include 
bisphosphonates, hematologic, and anti-infectious support and pain management.
 Thoracentesis or paracentesis may be performed if needed for comfort. If surgical 
intervention or localized radiation become indicated (either for palliation or down- 
staging of previously non-resectable tumor), these interventions are permitted, but 
should be avoided if clinically feasible until after the second response assessment, 
following consultation with the Principal Investigator. A tumor response assessment 
should be conducted prior to any intervention, in order to document progression 
and/or confirm an objective response. Subjects who undergo surgical resection or 
radiation in the absence of progression may continue to receive study treatment until 
remaining lesions meet criteria for progression of disease. Platelet counts should be 
checked immediately before any invasive intervention, as CDX-1140 may a 
decrease in platelet count in the days following each infusion.
 Immunosuppressive agents are prohibited during the study, with the following 
exceptions:
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o Immunosuppressive agents and the use of systemic corticosteroids are permitted in the 
context of treating AEs. Subjects receiving corticosteroids for treatment of drug-related 
AEs must be at ≤ 10 mg/day prednisone or equivalent prior to re- initiation of study 
therapy. 
o Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption). 
 Vaccinations:
o Non-study vaccinations are prohibited until at least 28 days after the last dose of 
CDX-301. Otherwise, any vaccination containing live, attenuated, or inactivated 
virus may be permitted if clinically indicated. However, this must be discussed 
with the Principal Investigator prior to administration and may require a study 
drug washout period prior to and after administration of the vaccine. Inactivated 
influenza vaccination is permitted on study without restriction. 
o  Some of the systemic adverse events attributed SARS-CoV2 vaccines, such as 
fever, fatigue, arthralgias, and myalgias, overlap with the adverse events 
associated with CDX-1140. Administration of the SARS-CoV2 vaccine in close 
temporal association with CDX-1140 may confound causality assessments for 
any accompanying adverse events. Therefore, administration of the SARS-
CoV2 vaccination and CDX-1140 should be separated by at least 1 week, if 
possible. For CDX-301, if possible, the vaccine should be administered either at 
least 1 week prior to the initiation of CDX-301 or at least 3 weeks after the first 
dose in a cycle, and if eligible for another cycle of treatment, at least 1 week 
prior to the next cycle. The recommendation is based on the biological activity of 
CDX-301, which induces a transient increase in hematopoietic cells, including 
dendritic cell, that peaks at approximately 2 weeks from the initiation of 
treatment and then rapidly declines. No data is available on the potential impact 
of CDX-1140 or CDX-301 on the immunogenicity or adverse event profile of the 
SARS-CoV2 vaccines, therefore decisions to vaccinate patients while 
participating in this study will be individualized and based on the judgement of 
the treating investigator.  
 Prophylactic premedication is required prior to CDX-1140 administration: 
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 is to be avoided because of the potential to 
attenuate the anti-tumor activity of CDX-1140.
 Post-infusion medication is required following CDX-1140 administration: 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 when they are 
seen on the Cycle 1 Day 2 visit. Note, 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 
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potential confounding factors in determining adverse event causality (e.g. increased 
LFTs).
 The effect of CDX-1140 on the absorption, metabolism, or excretion of other drugs 
has not been studied. As CDX-1140 is a human monoclonal antibody, inhibition or 
induction of cytochrome P450 (CYP) enzymes or other typical drug metabolizing 
enzymes is unexpected, and thus, interaction with other medications metabolized 
through these pathways is unlikely.
 For patients in Part 2, concomitant administration of CDX-301 with growth factors 
such as G-CSF should be done with caution and the CBC followed closely.
 
6.0 STUDY THERAPY – ARM 2 
Stereotactic Body Radiotherapy for Limited Disease 
Subjects on Arm 2 with “limited disease”, as defined in Section 5.1.1, will be 
treated with SBRT to all sites of known active disease. SBRT details are provided in 
Section 5.1. SBRT will be delivered in the same fashion for both study arms. 
 
Other radiotherapy 
Subjects on Arm 2 with disease that is not amenable to comprehensive SBRT 
may be treated with any form of palliative radiotherapy, including SBRT, to address 
symptoms or prevent symptom progression. Treatment details will be left to the 
discretion of the managing physicians but are expected to align with institutional 
standards and established guidelines75,106. 
 
Systemic therapy 
Subjects on Arm 2 with extensive disease burden are expected to receive a 
standard treatment regimen. Approved options at this time include docetaxel (+/- 
ramucirumab), pemetrexed, and gemcitabine75. Selection of the systemic treatment 
regimen will be left to the discretion of the treating physician. Assessments for subjects 
receiving standard systemic therapy should follow the Study Calendar (Section 4.2). 
Subjects on Arm 2 with limited disease may receive systemic therapy after 
completion of SBRT or may undergo surveillance without active therapy. Systemic 
therapy should not be initiated until all planned SBRT is completed. 
 
7.0 SUBJECT ASSESSMENTS 
7.1 Clinical Assessments 
Clinical assessments will take place according to the schedules depicted in the 
Study Calendars (Section 4.2) and will include complete histories and physical 
examinations. History and physicals may be obtained remotely. Additional visits may 
take place, and events that are noted at those visits (e.g., treatment-related toxicity) will 
be included in data analyses. 
Adverse events will be scored at each clinic visit using CTCAE version 5.0. Any 
new or worsening toxicities will be classified as “unrelated” or “related” to study 
treatment (See Section 11.1). Adverse events will be documented in this manner for 
subjects on both study arms, so that adverse event rates with study therapy in Arm 1 
can be compared to adverse event rates with standard therapy in Arm 2. 
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7.2 DLT Definition 
The definition of a dose-limiting toxicity (DLT) will be nearly identical to the 
definition used in the recent study combining CDX-301 and CDX-114070. A DLT will be 
defined as any of the following outcomes, attributed to study therapy (including SBRT) 
and occurring within 8 weeks after initiation of initial study therapy: 
 Death
 Any ≥ Grade 3 non-hematological toxicity, with the following exceptions:
o Grade 3 alopecia, vitiligo, or endocrinopathies controlled by hormone 
replacement therapy 
o Grade 3 nausea that resolves to ≤ grade 2 with or without treatment within 72 
hours 
o Grade 3 vomiting and diarrhea that resolves to ≤ grade 2 with or without 
treatment within 72 hours 
o Grade 3 fatigue that resolves to ≤ grade 2 within 5 days 
o Grade 3 hypertension in the absence of maximal medical therapy 
o Grade 3 adverse event of tumor flare (defined as local pain, irritation, or rash 
localized at sites of known or suspected tumor) of ≤ 7 days in duration 
o Grade 3 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis. It is recommended to consult with the 
Principal Investigator for grade 4 amylase or lipase abnormalities 
o Grade 3 clinically significant laboratory abnormalities that are asymptomatic and 
can be reversed within 72 hours, however: 
o Any Grade 4 ALT or AST elevation will be a DLT 
o Any Grade 3 ALT or AST elevation that lasts longer than 7 days will be a DLT 
o ALT or AST > 8 X ULN regardless of duration will be considered a DLT 
o ALT or AST > 5 X ULN that lasts longer than 14 days will be considered a DLT 
o ALT or AST of > 3 X ULN with a concurrent total bilirubin > 2 X ULN will be 
considered a DLT in the absence of another cause (other than study drug) of 
these elevations. 
 Any of the following hematologic toxicities:
o Grade 4 anemia (regardless of duration) 
o Grade 4 neutropenia persisting > 5 days 
o Grade 3 thrombocytopenia with hemorrhage 
o Grade 4 thrombocytopenia 
o Any other ≥ Grade 3 hematologic adverse event not returning to baseline or ≤ 
grade 1 prior to the next planned study drug dose, excluding asymptomatic 
lymphopenia which will not be considered a DLT 
 ≥ Grade 3 infusion reaction
o Excluding grade 3 infusion reactions resolving within 6 hours with or without 
treatment 
 ≥ Grade 3 related injection site reaction will be considered a DLT and no further 
treatment with CDX-301 will be permitted
 Any ≥ grade 2 eye pain or reduction of visual acuity that does not improve to ≤ grade 
1 severity within 2 weeks of the initiation of topical therapy or requires systemic 
treatment
 Treatment delay of > 2 weeks due to drug-related toxicity that is not improving will be 
considered a DLT.
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7.3 Radiographic Assessments 
Pre-registration imaging will be obtained prior to study entry and will consist of a 
whole-body PET/CT (within 42 days) and a diagnostic CT of the chest, abdomen, pelvis 
(within 21 days). The surveillance imaging schedule is detailed in the Study Calendars 
(Section 4.2) and includes CT of the chest, abdomen, and pelvis every 8 weeks for one  
year. CT imaging of the pelvis may be omitted for patients with no history of metastatic 
lesions in the anatomical area. Intravenous and oral contrast will be used, unless a 
contraindication to contrast administration exists. Additional imaging studies (e.g., FDG-
PET, MRI) may be added at any time to assess disease that is not well-visualized on 
CT and/or if there is concern for disease progression. The surveillance imaging 
schedule beyond year 1 will be left to the discretion of the treating physicians but should 
follow current guidelines75. 
Subjects with a history of brain metastases will undergo surveillance for the 
development of new/progressive brain metastases. Imaging timing and details will be 
left to the discretion of the treating physicians but will generally follow current 
guidelines107 and most often include high-resolution MRI of the brain with i.v. contrast 
every 2-3 months. Prompt MRI of the brain is recommended for any study subject who 
develops symptoms suggestive of new/worsening brain metastasis. 
Tumor response and progression-free survival (PFS) will be assessed using 
iRECIST criteria (Appendix) and secondarily using RECIST criteria. 
7.4 Quality-of-Life Assessments 
Quality-of-life (QoL) will be assessed using the EORTC QLQ-C30 and EORTC 
QLQ-LC13. Of note, these tools are available in multiple languages. In the rare case 
where a study subject is not fluent in any language in which the QLQ-C30 and QLQ- 
LC13 are available, QoL assessments will be omitted. In cases where QoL 
assessments are due but cannot be completed in clinic for logistical reasons, QoL 
surveys may be administered over the telephone. 
The EORTC QLQ-C30 and EORTC QLQ-LC13 are described in Section 2.9, and 
the assessment schedule is displayed in the Study Calendars (Section 4.2). The 
complete surveys are included in the Appendix. The statistical plans for QoL analysis 
are described in Section 8.3. 
7.5 Physical Activity Monitoring 
A commercially available fitness tracker (e.g., Garmin Vivofit, shown below on 
left) will be provided at no cost to the patient and placed on the patient’s wrist at the 
time of study registration. The device will be activated and synced with a computer or 
mobile device, and the device will be set to show the time. Patients will be shown how 
to remove the device (like removing a wristwatch), in case they wish to remove it 
temporarily or permanently. However, patients will be asked to keep the device on 
continuously throughout the course of the study. The device is waterproof, so patients 
will not need to remove it when bathing. The device has a battery life of over one year, 
so patients will not need to charge it. Data will be synced automatically every time the 
patient enters one of the Medical Oncology or Radiation Oncology clinics using a 
wireless access client (shown below on right). In cases where the data is not synced 
automatically, a study team member will sync the data using a mobile device.
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        Wearable activity monitor (left) and wireless access client (right) 
7.6 Correlative Studies 
We will collect blood samples at regular intervals (See Section 4.2) to facilitate 
monitoring immune responses, such as DC expansion and maturation. We will also 
follow T-cell inducible costimulator (ICOS) expression. ICOS is a member of the 
immunoglobulin superfamily. Responses to immunotherapy have been associated with 
increased ICOS expression on CD8+ T-cells, particularly following CTLA-4 blockade108- 
111. We will follow serum levels of high-mobility group box 1 (HMGB1), whose release 
has been linked to antitumor immune responses112,113. Flow cytometry will be 
performed to track measures of DC maturation such as CD83 and CD86 expression114. 
Other correlative studies will be performed in collaboration with Dr. Guha’s laboratory 
and the study sponsor. Details regarding blood processing for peripheral blood 
mononuclear cell (PBMC) isolation are shown in the Appendix. 
Due to potential transient lymphocytic effects of the SARS-CoV2 vaccine, correlative 
blood should not be drawn within a 5-day period after administration. 
Testing for anti-drug antibody (ADA) and CDX-1140 pharmacokinetics will be 
performed at baseline and prior to, two hours after, and one day after each CDX-1140 
infusion. These tests will be performed at Celldex Lab in Fall River, MA. Approximately 10 
mL of blood will be collected in serum-separating tubes (SST). After clotting at room 
temperature for 30 minutes, the samples will be spun at 3000 RPM at 4°C for 15 minutes. 
Plasma will be aliquoted into 3-4 cryovials and frozen -80°C. Study samples will be shipped 
to Celldex at convenient intervals or at Celldex’s request.  
 
8.0 STATISTICAL CONSIDERATIONS 
 
8.1 Randomization Procedure 
At the time of study registration, subjects will be stratified by EGFR/ALK mutation 
status and disease burden and then will be randomized 1:1 between the two study arms 
using a modified permuted block treatment allocation scheme115. Block sizes of 2 (65%) 
and 4 (35%) will be considered. Study subjects and study personnel will NOT be blinded 
with respect to the randomization result. 
 
8.2 Phase I Primary Endpoint – Dose-Limiting Toxicity 
A stopping rule for safety will be implemented as follows: After 6 subjects are 
randomized to Arm 1 (which will take place after approximately 12 total subjects are 
enrolled), accrual will be temporarily suspended for DLT monitoring. 8 weeks after the 
6th subject on Arm 1 starts treatment, the study will proceed to Phase II if no more than 
one out of six subjects on Arm 1 has experienced a DLT (defined in Section 7.2). 
If the pre-specified safety criteria are not achieved in the Phase I portion of this 
study, the investigators and Celldex will review safety data from this trial as well as 
other trials using CDX-301 and CDX-1140 and determine if the experimental treatment 
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regimen should be altered (e.g., by reducing the CDX-1140 dose). The study protocol 
would be amended accordingly, and Phase I component with the new treatment 
regimen would be added. 
At the conclusion of the trial, study therapy will be considered safe and worthy of 
further study if no more than 4 out of 23 subjects on Arm 1 experience a DLT. The 
target Grade 3 toxicity rate is no more than 12.5%, and a toxicity rate greater than 35% 
is considered clinically unacceptable. This design has the following operating 
characteristics: The probability of accepting the treatment for further study if the true 
toxicity rate is unacceptably high (>35%) is at most 5%. In contrast, there is at least an 
85% probability of accepting the treatment for further study if the true toxicity rate is less 
than 12.5%. 
The proportion of patients on Arm 1 who develop a DLT will be computed, along 
with Clopper-Pearson 95% exact confidence intervals. Frequencies of specific 
treatment-related adverse events (including delayed adverse events) and event grades 
will be characterized using counts and percentages. 
 
8.3 Phase II Primary Endpoint – Progression-free Survival 
The primary study hypothesis is that treatment with FLT3 ligand, CD40 agonist 
antibody, and SBRT (Arm 1) will improve progression-free survival (PFS) compared to 
standard therapy (Arm 2). Based on published data for patients with advanced NSCLC 
who require treatment after several lines of standard therapy, we expect that the median 
PFS duration for subjects on Arm 2 will be 5 months. Based on our recent study using 
FLT3 ligand and SBRT and the expectation that CD40 agonist antibody will enhance 
treatment efficacy, we hypothesize that the median PFS duration for subjects on Arm 1 
will be 10 months. This improvement is approximately equivalent to a hazard reduction 
of 50%. We are employing a randomized phase II screening design, using α = 0.20 
(wherein a p-value <0.20 indicates a positive trial). We anticipate that study accrual will 
take place over 24 months, and we will analyze treatment efficacy 12 months after 
accrual is completed. We do not expect any subjects to be lost to follow-up before the 
primary endpoint occurs. Based on these assumptions, our total sample size of 46 
subjects yields study power of 81% using a two-sided log-rank test. 
We will compare the distributions of PFS between treatment arms using a two- 
sided log-rank test. The rates at various timepoints (e.g., every 6 months after 
randomization) and median PFS durations for each arm will be estimated using the 
Kaplan-Meier method. Associated 95% confidence intervals (CI) will be calculated using 
Greenwood’s formula. Cox proportional hazards models will be used to estimate the 
impact of study therapy on PFS duration. 
 
8.4 Secondary Endpoints and Exploratory Analyses 
Overall survival (OS) rates and median OS durations will be estimated using the 
Kaplan-Meier method. Exploratory comparisons of OS distributions between study arms 
will be performed using a two-sided log-rank test and Cox proportional hazards models. 
Radiographic response rates will be characterized using descriptive statistics. 
The clinical benefit rate (CBR) will be defined as the percentage of subjects who 
achieve best response of confirmed CR or PR, or stable disease (SD) for at least four 
months. CBR in Arm 1 and Arm 2 will be compared using chi-square testing or Fisher 
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exact test, as appropriate. Objective response rate (ORR) will be defined as the 
percentage of subjects who do not receive comprehensive SBRT who achieve best 
response of confirmed CR or PR. ORR in Arm 1 and Arm 2 will be compared using chi- 
square testing or Fisher exact test, as appropriate. 
Quality-of life (QoL) will be assessed using the EORTC QLQ-C30 and EORTC 
QLQ-LC13. Summary statistics (mean, standard deviation, median, 25th and 75th 
percentiles, and range) and the mean change from baseline of linear-transformed 
scores will be reported for all the items and subscales of the EORTC QLQ-C30 
questionnaire and the QLQ-LC13, according to the EORTC scoring manual guidelines 
and the. Completion and compliance rates will be summarized at each timepoint by 
treatment arm. Only patients with a non-missing baseline assessment and at least one 
non-missing post-baseline assessment will be included in the analyses. 
Daily step count averages at baseline and at various timepoints after study 
registration will be characterized using descriptive statistics. To test the hypothesis that 
study therapy preserves physical function compared to standard therapy, a linear mixed 
effects model with random coefficients using a restricted maximum likelihood procedure 
will be used to model daily step count as a function of study arm, using adjustment 
variables such as age and gender. 
Exploratory multivariable and subgroup analyses of PFS and OS predictors will 
be performed. Adjustment/grouping variables will include baseline disease burden, 
performance status, NSCLC subtype, and prior response to immunotherapy. 
 
9.0 
REGULATORY CONSIDERATIONS 
9.1 
Protection of Human Subjects 
The Investigator must ensure that patients or their legally acceptable representatives 
are clearly and fully informed about the purpose, potential risks and other critical issues 
regarding clinical trials in which they volunteer to participate. Preparation of the consent 
form is the responsibility of the Investigator and must include all elements required by 
CFR 21 Part 50.25 and the local IRB. 
9.2 Compliance with the Protocol and Protocol Revisions 
The study must be conducted as described in this approved protocol. All revisions to the 
protocol must be provided to the PI. The PI should not implement any deviation or change to 
the protocol without prior review and documented approval/favorable opinion from the IRB/IEC 
of an Amendment, except where necessary to eliminate an immediate hazard(s) to study 
patients. The investigator must ensure that patients or their legally acceptable representatives 
are clearly and fully informed about the purpose, potential risks and other critical issues 
regarding clinical trials in which they volunteer to participate. Preparation of the consent form is 
the responsibility of the PI. 
 
 
 
 
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10.0 DATA HANDLING AND RECORD KEEPING 
10.1 Confidentiality 
 
Information about study subjects will be kept confidential and managed according 
to the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA). Those regulations require a signed subject authorization informing the subject 
of the following: 
 What protected health information (PHI) will be collected from subjects in this 
study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior 
to the revocation of subject authorization. For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission 
to collect at least vital status (i.e. that the subject is alive) at the end of their 
scheduled study period. 
10.2 Source Documents 
Source data is all information, original records of clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial. Source data are contained in source documents Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial. 
 
10.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the 
study. All data requested on the CRF must be recorded. All missing data must be 
explained. If a space on the CRF is left blank because the procedure was not done or 
the question was not asked, write “N/D”. If the item is not applicable to the individual 
case, write “N/A”. All entries should be printed legibly in black ink. If any entry error has 
been made, to correct such an error, draw a single straight line through the incorrect 
entry and enter the correct data above it. All such changes must be initialed and dated. 
DO NOT ERASE OR WHITE OUT ERRORS. For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date it. 
 
10.4 Data Safety and Monitoring Board 
The Albert Einstein College of Medicine/Albert Einstein Cancer Center Data 
Safety Monitoring Committee (DSMC) has the responsibility for ensuring data and 
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safety monitoring along with the PI who is ultimately responsible for the ongoing 
monitoring and safety of clinical protocols. The primary functions of the AECC DSMC 
are as follows: 
1. To review and ensure protocol compliance with dose escalation in phase I trials 
2. To review/assure protocol compliance for all trials that have two-stage phase II 
designs, 
3. Reviewing all internal and external serious adverse reports, investigator alerts, 
action letters, and other safety reports for trials being performed at AECC- 
affiliated institutions and; 
To implement and to determine the adequacy of DSM plans of all approved protocols. 
 
The DSMC is an independent committee and meets on a bimonthly basis. 
During its bimonthly meeting, the DSMC will review serious (grade 3 or higher) adverse 
events from this study. In the event that the DSMC decides that a protocol revision is 
warranted, the committee will immediately notify the principal investigator of this study. 
The DSMC has the authority to close trials to patient accrual should the risk to patients 
be excessive or outweigh the potential benefits of the study. All study suspensions and 
closures will be forwarded to the IRB/CCI and study sponsor from the DSMC. The 
DSMC will review all safety data from Phase I before the study proceeds to Phase II. 
 
11.0 ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a subject 
administered a study treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a study treatment, whether or not related to the 
study treatment. All observed or volunteered AEs regardless of suspected causal 
relationship to the study treatment will be reported as described in the following 
sections. For the purposes of this current study, “study treatment” is defined as CDX- 
1140, CDX 301, and radiotherapy. AEs for subjects on arm 2 who receive standard 
therapy (e.g., chemotherapy) will also be reported. 
11.1 Adverse Event Definitions 
Adverse Event (AE): any new, undesirable medical experience or change of an existing 
condition that occurs during or after treatment, whether or not considered product- 
related. 
 
Serious Adverse Event (SAE): An AE occurring at any dose that results in any of the 
following outcomes (CFR 312.32) 
 Death 
 Life-threatening adverse experience 
 Inpatient hospitalization or prolongation of existing hospitalization excluding 
those for study therapy administration, transfusional support, disease staging/re- 
staging procedures, thoracentesis / paracentesis, or placement of an indwelling 
catheter, unless associated with other serious events 
 Persistent or significant disability or incapacity 
 Congenital anomaly / birth defect. 
 
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The definition of SAE also includes important medical event. Medical and scientific 
judgment should be exercised in deciding whether expedited reporting is appropriate in 
other situations, such as important medical events that may not be immediately life- 
threatening or result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above. 
These should also usually be considered serious. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. A new diagnosis of cancer during the course of treatment 
should be considered an important medical event. 
 
Causality: the relationship of each AE to study drug will be defined as “unrelated” or 
“related” to study treatment using the following definitions: 
 Unrelated: There is little or no possibility that the study treatment(s) caused the 
reported AE; and other factor(s) including concurrent illnesses, progression and 
expression of the disease state, concurrent medications, or a reaction to 
concurrent medications appear to explain the AE. 
 Related: There exists at least a reasonable possibility that the study treatment(s) 
caused or contributed to the AE; an inability to identify an alternate etiology for an 
AE should not, by itself, justify a “related” attribution. 
 
Unexpected Adverse Event: An AE that is not mentioned in the Investigator's Brochure 
or package insert or the specificity or severity of which is not consistent with the 
investigator's brochure or package insert. 
 
Life-threatening: Any adverse experience that places the patient or subject, in the view 
of the investigator, at immediate risk of death from the reaction as it occurred. It does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 
AEs will use the descriptions and grading scales found in the revised Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 
 
11.2 Adverse Event Reporting 
Study site personnel must notify the PI and the sponsor immediately of any SAE 
experienced by a patient. In general, SAEs assessed as clearly being due to disease 
progression, and not due to study drug(s), should be excluded from AE reporting. 
Study-specific clinical outcomes of death because of disease progression are exempt 
from SAE reporting, unless the investigator deems them related to use of the study 
drug. Hospitalization for study drug administration is not an SAE. 
The following steps will be taken to report promptly and document accurately any 
SAE, even if it may not appear to be related to the study treatment: 
 Report the SAE to the PI and the treating physician by email, telephone or fax 
within 24 hours of becoming aware that a patient has experienced an SAE. 
 Record the SAE accurately on the AE page of the patient’s CRF. 
 Using the standard IRB-SAE report form, submit all known patient information 
within 24 hours of SAE occurrence to the clinical trial office to submit to IRB and 
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DSMC. Date and sign each report before submission. Include the following 
information (or as much as possible to obtain and still report the event within 24 
hours): 
o Study protocol number and indication 
o Study site and investigator’s identification 
o Patient’s ID (patient number and initials), age or date of birth, and sex 
o Date of enrollment 
o Description of SAE, including date of onset and duration, severity, and 
outcome 
o Date of first and most recent (last) dose administered 
o Action taken regarding study treatment 
o Relationship of SAE to study treatment 
o Concomitant medications, including regimen and indication 
o Intervention, including concomitant medications used to treat SAE 
o Pertinent laboratory data/diagnostic tests conducted and date 
o Pertinent medical history of patient 
o Date of hospital admission/discharge 
o Date of death (if applicable) 
 
Within 10 days of initial IRB notification, the PI is required to submit a completed 
Adverse Event Report to the IRB. The treating physicians should perform appropriate 
diagnostic tests and therapeutic measures and submit all follow-up substantiating data, 
such as diagnostic test reports and autopsy report to the PI, IRB, and DSMB. 
 
Reporting to Celldex is required in addition to reporting to the FDA and does not 
replace the requirement to notify the FDA if required. The PI will inform Celldex in 
writing using an SAE form or MEDWATCH 3500A form of any SAE within 24 hours of 
being aware of the event. The written report must be completed and supplied to Celldex 
by facsimile or email within 24 hours/1 business day. The initial report must be as 
complete as possible, including an assessment of the causal relationship between the 
event and the investigational product(s), if available. Information not available at the 
time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report. 
Completed SAE reports are to be submitted to: 
 
Celldex Therapeutics, Inc. 
Pharmacovigilance 
Facsimile : 781-644-6434 
Email: SAE@celldex.com (note - check for removal of HIPAA identifiers prior 
to sending information. 
For questions regarding SAE reporting: 908-323-2233 (SAE Hotline) 
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Caburlotto G, Lleo MM, Hilton T, et al: Effect on human cells of environmental 
Vibrio parahaemolyticus strains carrying type III secretion system 2. Infect Immun 78:3280-7, 
2010 
112. 
Apetoh L, Ghiringhelli F, Tesniere A, et al: The interaction between HMGB1 and 
TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev 220:47- 
59, 2007 
113. 
Tesniere A, Panaretakis T, Kepp O, et al: Molecular characteristics of 
immunogenic cancer cell death. Cell Death Differ 15:3-12, 2008 
114. 
Harada S, Kimura T, Fujiki H, et al: Flt3 ligand promotes myeloid dendritic cell 
differentiation of human hematopoietic progenitor cells: possible application for cancer 
immunotherapy. Int J Oncol 30:1461-8, 2007 
115. 
Zelen M: The randomization and stratification of patients to clinical trials. Journal 
of chronic diseases 27:365-375, 1974 
116. 
Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. American journal of clinical oncology 5:649-656, 1982 
117. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria 
in solid tumours: revised RECIST guideline (version 1.1). European journal of cancer 45:228- 
247, 2009 
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13.0 APPENDICES 
 
13.1 Appendix A - ECOG Performance Status 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed 
or chair. 
5 
Dead 
 
Adapted from Oken 1982116. 
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13.2 Appendix B – Common Terminology Criteria for Adverse Events 
Version 5.0 
 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_ 
Quick_Reference_5x7.pdf 
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13.3 Appendix C – iRECIST Criteria 
Tumors may respond differently to immunotherapies compared with 
chemotherapeutic drugs, raising questions about the assessment of changes in tumor 
burden—a mainstay of evaluation of cancer therapeutics that provides key information 
about objective response and disease progression. Immunotherapeutics may result in 
infiltration of immune cells leading to transient increase in the size in malignant lesions, 
or undetectable lesions becoming detectable. A consensus guideline—iRECIST—was 
developed by the RECIST working group for the use of modified Response Evaluation 
Criteria in Solid Tumors (RECIST version 1.1) in cancer immunotherapy trials, to ensure 
consistent design and data collection, facilitate the ongoing collection of trial data, and 
ultimate validation of the guideline84. This guideline describes a standard approach to 
solid tumor measurements and definitions for objective change in tumor size for use in 
trials in which an immunotherapy is used. The criteria are identical to those of RECIST 
1.1 in many respects but have been adapted to account for instances where an 
increase in tumor burden, or the appearance of new lesions, does not reflect true tumor 
progression. 
To assess objective response or future progression, it is necessary to estimate 
the overall tumor burden at baseline and use this as a comparator for subsequent 
measurements. All baseline evaluations should be performed as close as possible to 
the treatment start and never more than 4 weeks before the beginning of the treatment. 
Assessments should be identified on a calendar schedule and should not be affected by 
delays in therapy. The same method of assessment and the same technique should be 
used to characterize each identified and reported lesion at baseline and during follow- 
up. Imaging based evaluation should always be done rather than clinical examination, 
unless the lesion(s) being followed cannot be imaged but are assessable by clinical 
exam. (See “Methods of Lesion Measurement” for further guidance.) 
 
Measurable Disease: 
Measurable tumor lesions (nodal, subcutaneous, lung parenchyma, solid organ 
metastases) are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 20 mm with chest x-ray and as ≥ 10 
mm with CT scan or clinical examination. 
 Malignant lymph nodes must be ≥15 mm in the short axis to be considered 
measurable; only the short axis will be measured and followed. All other pathological 
nodes (those with short axis ≥ 10 mm but < 15 mm) should be considered non-target 
lesions. Nodes that have a short axis < 10 mm are considered non-pathological and 
should not be recorded or followed.
 Bone lesions: Bone scan, PET scan, or plain films are not considered adequate 
imaging techniques to measure bone lesions. However, these techniques can be 
used to confirm the presence or disappearance of bone lesions. Bone lesions are 
considered measurable only if assessed by CT scan and have an identifiable soft 
tissue component that meets these requirements (soft tissue component ≥ 10 mm by 
CT scan). Blastic bone lesions are non-measurable.
 Cystic lesions: Lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor non- 
measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to
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represent cystic metastases can be considered as measurable lesions, if they meet 
the definition of measurability described above. However, if noncystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 Previously irradiated lesions are not considered measurable unless progression has 
been documented in the lesion.
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Non-measurable Disease: 
All other lesions (or sites of disease), including small lesions are considered non- 
measurable disease. Bone lesions without a measurable soft tissue component, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, lymphangitic involvement of lung or skin 
and abdominal masses followed by clinical examination are all non-measurable. 
Lesions in previously irradiated areas are non-measurable, unless progression has 
been demonstrated. 
 
Target Lesions: 
 When more than one measurable tumor lesion is present at baseline all lesions up to 
a maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.
 Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.
 At baseline, the sum of the target lesions (longest diameter of tumor lesions plus 
short axis of lymph nodes: overall maximum of 5) is to be recorded.
 
Special notes on the assessment of target lesions: 
 Target lesions that become ‘too small to measure’: After baseline, a value should be 
provided on the CRF for all identified target lesions for each assessment, even if 
very small. If extremely small and faint lesions cannot be accurately measured but 
are deemed to be present, a default value of 5 mm may be used. If lesions are too 
small to measure and indeed are believed to be absent, a default value of 0 mm may 
be used.
 Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that 
when lymph nodes are included as target lesions, the ‘sum’ of lesions may not be 
zero even if complete response criteria are met, since a normal lymph node is 
defined as having a short axis of < 10mm. For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions.
 Lesions that split or coalesce on treatment: When non-nodal lesions 'fragment', the 
longest diameters of the fragmented portions should be added together to calculate 
the target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each
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individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the 'coalesced lesion'. 
 
Non-Target Lesions: 
 All other measurable/non-measurable lesions (or sites of disease) including 
pathological lymph nodes should be identified as non-target lesions and should also 
be recorded at baseline.
 Measurements are not required but these lesions should be noted at baseline and 
should be followed as “present” or “absent”.
 
New lesions: 
New lesions should be assessed and categorized as measurable or non-measurable 
using RECIST 1.1 principles. Five lesions (no more than two per organ) should be 
measured and recorded as New Lesions-Target (NLT) and New Lesion-Non-Target 
(NLNT) but should not be included in the sum of measures of the original target lesions 
identified at baseline. 
 
Methods of lesion measurement: 
 Clinical exam: Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm as assessed using calipers (e.g. skin nodules). For the case 
of skin lesions, documentation by color photography including a ruler to estimate the 
size of the lesion is recommended. If feasible, imaging is preferred.
 Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression 
is an important endpoint, since CT is more sensitive than X-ray, particularly in 
identifying new lesions. However, lesions ≥ 20 mm on chest X-ray may be 
considered measurable if they are clearly defined and surrounded by aerated lung.
 CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined measurability 
of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or 
less. When CT scans have slice thickness greater than 5 mm, the minimum size for 
a measurable lesion should be twice the slice thickness. MRI is also acceptable in 
certain situations (e.g. for body scans). Other specialized imaging or other 
techniques may also be appropriate for individual case. For example, while PET 
scans are not considered adequate to measure lesions, PET-CT scans may be used 
providing that the measures are obtained from the CT scan and the CT scan is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast).
 Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. If new lesions are identified by ultrasound in the 
course of the study, confirmation by CT is advised.
 Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials 
where recurrence following complete response or surgical resection is an endpoint.
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 Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response.
 Cytology, histology: These techniques can be used to differentiate between PR and 
CR in rare cases if required by protocol (for example, residual lesions in tumor types 
such as germ cell tumors, where known residual benign tumors can remain). When 
effusions are known to be a potential adverse effect of treatment (e.g. with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment when the 
measurable tumor has met criteria for response or stable disease is advised to 
differentiate between response or stable disease and progressive disease.
 
Response Definitions: 
 Immune Complete Response (iCR): disappearance of target and non-target lesions 
and normalization of tumor markers. Pathological lymph nodes must have short axis 
measures <10 mm (Note: continue to record the measurement even if < 10 mm and 
considered CR). Residual lesions (other than nodes < 10 mm) thought to be non- 
malignant should be further investigated (by cytology specialized imaging or other 
techniques as appropriate for individual cases4 before CR can be accepted. 
Confirmatory scans should be performed at least 4 weeks after iCR.
 Immune Partial Response (iPR): at least a 30% decrease in the sum of measures 
(longest diameter for tumor lesions and short axis measure for nodes) of target 
lesions, taking as reference the baseline sum of diameters. Non target lesions must 
be non-PD. Confirmatory scans should be performed at least 4 weeks after iPR.
 Immune Stable Disease (iSD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as reference the smallest sum of 
diameters on study.
 Immune Unconfirmed Progressive Disease (iUPD): at least a 20% increase in the 
sum of diameters of measured lesions taking as references the smallest sum of 
diameters recorded on study (including baseline) AND an absolute increase of ≥ 5 
mm. Appearance of new lesions will also constitute iUPD (including lesions in 
previously unassessed areas). In exceptional circumstances, unequivocal 
progression of non-target disease may be accepted as evidence of iUPD, where the 
overall tumor burden has increased sufficiently to merit discontinuation of treatment 
or where the tumor burden appears to have increased by at least 73% in volume. 
Modest increases in the size of one or more non-target lesions are NOT considered 
unequivocal progression. Confirmatory scans should be performed at least 4 weeks, 
but no longer than 8 weeks, after iUPD.
 Immune Confirmed Progressive Disease (iCPD): iCPD is confirmed if further 
increase in tumor burden, compared to the last assessment, is seen as evidenced 
by one or more of the following:
o Continued increase in tumor burden (from iUPD) in the lesion category (target, 
non-target disease or new lesions) where RECIST 1.1 definitions of progression 
had previously been met 
 Continued progression in target disease with an increase of at least 5 mm in 
the absolute value of the sum of measures of target disease 
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 Continued unequivocal progression in non-target disease with an increase in 
tumor burden 
 Increase in size of previously identified new lesion (s) (an increase of at least 
5 mm in the absolute value of the sum of those considered to be target new 
lesions) or additional new lesions. 
o RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) 
where progression was not previously identified, including the appearance of 
additional new lesions. 
 
Notes on confirmation of progression: 
 Treatment beyond initial RECIST 1.1-defined progression (ie, iUPD) is permitted 
only for patients who are clinically stable. Such patients may continue treatment until 
the next assessment (≥ 4 weeks but no longer than 8 weeks later). An assignment of 
clinical stability requires that no worsening of performance status has occurred, that 
no clinically relevant increases in disease-related symptoms such as pain or 
dyspnea occur that are thought to be associated with disease progression (these 
symptoms are generally understood to mean a requirement for increased palliative 
intervention), and that no requirement for intensified management of disease-related 
symptoms exists, including increased analgesia, radiotherapy, or other palliative 
care. The imaging findings and the recommendation to continue with treatment 
despite iUPD should be discussed with the patient before a decision is made about 
whether or not to continue therapy. All decisions regarding continuation or 
discontinuation of therapy should be made by the patient and their health-care 
provider.
o Patients who have iUPD and are not clinically stable should be designated as not 
clinically stable in the case report form to allow the best overall response to be 
calculated and the date of iUPD to be used in estimates of progression-free 
survival. 
 If iUPD is not confirmed at the next assessment, but instead tumor shrinkage occurs 
(compared with baseline) which meets the criteria of iCR, iPR, or iSD, then the bar is 
reset so that iUPD needs to occur again (compared with nadir values) and then be 
confirmed (by further growth) at the next assessment for iCPD to be assigned.
 If no change in tumor size or extent from iUPD occurs, then the timepoint response 
would again be iUPD.
 iUPD can be assigned multiple times as long as iCPD is not confirmed at the next 
assessment.
 The prior documentation of iUPD does not preclude assigning iCR, iPR, or iSD in 
subsequent time-point assessments or as best overall response (BOR) providing 
that iCPD is not documented at the next assessment after iUPD.
 The date of disease progression should be the first date at which progression criteria 
are met (ie, the date of iUPD) provided that iCPD is confirmed at the next 
assessment. If iUPD occurs, but is disregarded because of later iSD, iPR, or iCR, 
that iUPD date should not be used as the progression event date.
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Integration of Target, Non-Target and New Lesions into Time-point iResponse 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
(NLs) 
Time Point (TP) Response 
No prior iUPD* Prior iUPD*; ** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non-iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/Non-iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non-iUPD 
No 
iSD 
iSD 
iUPD with no 
change OR 
decrease 
from last TP 
iUPD with no 
change OR 
decrease from last 
TP 
Yes 
NA 
NLs confirms iCPD if NLs were 
previously identified and increase in 
size (≥ 5 mm in sum of measurements 
for New Lesion-Target or any increase 
for New Lesion – Non-target) or 
number. If no change in NLs (size or 
number) from last TP, remains iUPD 
iSD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed 
based in further increase in size of 
non-target disease (need not meet 
RECIST 1.1 criteria for unequivocal 
PD) 
iUPD 
Non-iCR/Non-iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed 
based on: 
o further increase in sum of 
measurements of at least 5 mm, 
otherwise remains iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed 
based on further increase in: 
o previously identified target lesion 
iUPD sum of measurements ≥5 mm 
and / or 
o non-target lesion iUPD (prior 
assessment - need not be unequivocal 
PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed 
based on further increase in: 
o previously identified target lesion 
iUPD ≥ 5 mm and / or 
o previously identified non-target lesion 
iUPD (need not be unequivocal) and 
/or 
o size or number of new lesions 
previously identified 
Non-iUPD/PD Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed 
based on 
o increase in size or number of new 
lesions previously identified 
* in any lesion category. ** previously identified in assessment immediately prior to this TP. 
 
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13.4 Appendix D – RECIST 1.1 Criteria 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements. All baseline evaluations should be performed as close as possible to 
the treatment start and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging based 
evaluation should always be done rather than clinical examination, unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical exam. (See “Methods of 
Lesion Measurement” for further guidance.) 
At baseline, lesions should be identified as either “Target” or “Non-Target” as follows: 
Target Lesions: 
 Up to a maximum of five measurable target lesions total (with a maximum of two target 
lesions per organ) should be identified as target lesions and will be recorded and 
measured at baseline. (This means in instances where patients have only one or two 
organ sites involved a maximum of two and four lesions respectively will be recorded.)
 Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, and should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be 
selected.
 All target lesion measurements should be recorded in metric notation, using calipers  
if clinically assessed.
 A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for 
all target lesions will be calculated and reported as the baseline sum diameters. The 
baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. (See “Tumor response 
evaluation”.)
 
Non-Target Lesions: 
 All other measurable/non-measurable lesions (or sites of disease) including 
pathological lymph nodes should be identified as non-target lesions and should also 
be recorded at baseline. It is acceptable to record multiple non-target lesions involving 
the same organ as a single item on the case report form (e.g. ‘multiple enlarged pelvic 
lymph nodes’ or ‘multiple liver metastases’).
 Non-target lesions should be followed as ‘present’, ‘absent’, or in rare cases 
‘unequivocal progression’. (See “Tumor response evaluation”.) While some non- 
target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively.
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MEASURABILITY OF TUMOR AT BASELINE 
 Measurable: Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
of:
o 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
o 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable). 
o 20 mm by chest X-ray. 
Note: To be considered pathologically enlarged and measurable, a lymph node must 
be  15mm in short axis when assessed by CT scan (for lymph nodes, only the short 
axis is measured and followed). 
 Non-measurable: All other lesions, including small lesions (longest diameter < 10mm 
or pathological lymph nodes with  10 to < 15 mm short axis) as well as truly non- 
measurable 
lesions. 
Lesions 
considered 
truly 
non-measurable 
include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, and abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques.
 
Special considerations regarding lesion measurability: 
 Malignant lymph nodes: Lymph nodes merit special mention since they are normal 
anatomical structures which may be visible by imaging even if not involved by 
tumour. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane 
of acquisition may be axial, saggital or coronal). The smaller of these measures is the 
short axis. At baseline and in follow-up, only the short axis will be measured and 
followed. To be considered pathologically enlarged and measurable, a lymph node 
must be 15mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). All other pathological nodes (those with 
short axis 10mm but <15 mm) should be considered non-target lesions. Nodes that 
have a short axis <10mm are considered non-pathological and should not be recorded 
or followed.
 Bone lesions: Bone scan, PET scan or plain films are not considered adequate 
imaging techniques to measure bone lesions. However, these techniques can be used 
to confirm the presence or disappearance of bone lesions. Lytic bone lesions or 
mixed lytic-blastic lesions, with identifiable soft tissue components, that can be 
evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition 
of measurability described above. Blastic bone lesions are non-measurable.
 Cystic lesions: Lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor non- 
measurable) since they are, by definition, simple cysts. ‘Cystic lesions’ thought to 
represent cystic metastases can be considered as measurable lesions, if they meet 
the definition of measurability described above. However, if noncystic lesions are 
present in the same patient, these are preferred for selection as target lesions.
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 Lesions with prior local treatment: Tumor lesions situated in a previously irradiated 
area, or in an area subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the lesion.
 
METHODS OF LESION MEASUREMENT 
 Clinical exam: Clinical lesions will only be considered measurable when they are 
superficial and  10mm diameter as assessed using calipers (e.g. skin nodules). For 
the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested. As noted above, when lesions can be 
evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the study.
 Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression 
is an important endpoint, since CT is more sensitive than X-ray, particularly in 
identifying new lesions. However, lesions on chest X-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung.
 CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined measurability 
of lesions on CT scan based on the assumption that CT slice thickness is 5mm or  
less. When CT scans have slice thickness greater than 5 mm, the minimum size for 
a measurable lesion should be twice the slice thickness. MRI is also acceptable in 
certain situations (e.g. for body scans). If there is concern about radiation exposure at 
CT, MRI may be used instead of CT in selected instances.
 FDG-PET: While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement 
CT scanning in assessment of progression. (See “Tumor Response Evaluation”.)
 Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced 
in their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will 
be taken from one assessment to the next. If new lesions are identified by ultrasound 
in the course of the study, confirmation by CT or MRI is advised.
 Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials  
where recurrence following complete response or surgical resection is an endpoint.
 Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response.
 Cytology, histology: These techniques can be used to differentiate between PR and 
CR in rare cases if required by protocol (for example, residual lesions in tumor types  
such as germ cell tumors, where known residual benign tumors can remain). When 
effusions are known to be a potential adverse effect of treatment (e.g. with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the
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neoplastic origin of any effusion that appears or worsens during treatment can be 
considered if the measurable tumor has met criteria for response or stable disease 
in order to differentiate between response (or stable disease) and progressive 
disease. 
 
TUMOR RESPONSE EVALUATION 
 
Evaluation of target lesions: 
Target lesions will be assigned an overall response assessment at each evaluation time 
point according to the following definitions: 
 Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm.
 Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.
 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance 
of one or more new lesions is also considered progression).
 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
 
Special notes on the assessment of target lesions 
 Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10mm on study. This means 
that when lymph nodes are included as target lesions, the ‘sum’ of lesions may not be 
zero even if complete response criteria are met, since a normal lymph node is defined 
as having a short axis of < 10mm. For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions.
 Target lesions that become ‘too small to measure’: While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded 
at each subsequent evaluation, even when very small (e.g. 2 mm). However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning 
an exact measure and may report them as being ‘too small to measure’. When this 
occurs it is important that a value be recorded on the case report form. If it is the opinion 
of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0mm. If the lesion is believed to be present and is faintly seen but too 
small to measure, a default value of 5mm should be assigned. (Note: It is less likely 
that this rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the retroperitoneum; 
however, if a lymph node is believed to be present
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and is faintly seen but too small to measure, a default value of 5mm should be 
assigned in this circumstance as well). This default value is derived from the 5mm 
CT slice thickness (but should not be changed with varying CT slice thickness). The 
measurement of these lesions is potentially non-reproducible, therefore providing 
this default value will prevent false responses or progressions based upon 
measurement error. To reiterate, however, if the radiologist is able to provide an actual 
measure, that should be recorded, even if it is below 5mm. 
 Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate 
the target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’.
 
Evaluation of non-target lesions: 
Non-target lesions will be assigned an overall response assessment at each evaluation 
time point according to the following definitions: 
 Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10mm short 
axis).
 Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits.
 Progressive Disease (PD): Unequivocal progression (see comments below) of 
existing non-target lesions. (Note: the appearance of one or more new lesions is 
also considered progression).
 
Special notes on assessment of progression of non-target disease: 
 When the patient also has measurable disease: In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR 
in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy (see further details below). A modest ‘increase’ in the size 
of one or more non-target lesions is usually not sufficient to quality for unequivocal 
progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore 
be extremely rare.
 When the patient has only non-measurable disease: The same general concepts 
apply here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease 
burden. Because worsening in non-target disease cannot be easily quantified (by 
definition: if all lesions are truly non-measurable) a useful test that can be applied when 
assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable 
disease: i.e., an increase in tumor burden representing an additional
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73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ 
to ‘large’, an increase in lymphangitic disease from localized to widespread, or may 
be described in protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal 
progression’ is seen, the patient should be considered to have had overall PD at that 
point. While it would be ideal to have objective criteria to apply to non-measurable 
disease, the very nature of that disease makes it impossible to do so, therefore the 
increase must be substantial. 
 
New lesions: 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. 
 There are no specific criteria for the identification of new radiographic lesions; 
however, the finding of a new lesion should be unequivocal: i.e. not attributable to 
differences in scanning technique, change in imaging modality or findings thought to 
represent something other than tumour (for example, some ‘new’ bone lesions may 
be simply healing or flare of pre-existing lesions). This is particularly important when 
the patient’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, 
which it is not.
 A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease progression. 
An example of this is the patient who has visceral disease at baseline and while on 
study has a CT or MRI brain ordered which reveals metastases. The patient’s brain 
metastases are considered to be evidence of PD even if he/she did not have brain 
imaging at baseline.
 If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the 
date of the initial scan.
 While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 
in assessment of progression (particularly possible ‘new’ disease). New lesions on the 
basis of FDG-PET imaging can be identified according to the following algorithm:
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. (A ‘positive’ FDG-PET scan lesion means one which is 
FDG avid with an uptake greater than twice that of the surrounding tissue on the 
attenuation corrected image.) 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan). If the positive FDG-PET at follow-up 
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corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
 
Evaluation of overall response: 
It is assumed that at each protocol specified time point, an overall response assessment 
occurs. The patient’s overall response assignment will depend on the findings of both 
target and non-target disease and will also take into consideration the appearance of new 
lesions. 
 
Table 1 provides a summary of the overall response status calculation at each time 
point for patients who have measurable disease at baseline. When patients have non- 
measurable (therefore non-target) disease only, Table 2 is to be used. 
 
Special notes on evaluation of overall response: 
 Missing assessments and inevaluable designation:
– When no imaging/measurement is done at all at a particular time point, the 
patient is not evaluable (NE) at that time point. 
– If only a subset of lesion measurements are made at an assessment, usually the 
case is also considered NE at that time point, unless a convincing argument can 
be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response. This would be most likely to happen in the case 
of PD. For example, if a patient had a baseline sum of 50mm with three measured 
lesions and at follow-up only two lesions were assessed, but those gave a sum of 
80 mm, the patient will have achieved PD status, regardless of the contribution of 
the missing lesion. 
 ‘Symptomatic deterioration’: Patients with a global deterioration of health status 
requiring discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as ‘symptomatic deterioration’. Every effort 
should be made to document objective progression even after discontinuation of 
treatment. Symptomatic deterioration is not a descriptor of an objective response: it is 
a reason for stopping study therapy. The objective response status of such patients is 
to be determined by evaluation of target and non-target disease as shown in Table 1 
and Table 2.
 In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends upon this determination, 
it is recommended that the residual lesion be investigated 
(fine needle 
aspirate/biopsy) before assigning a status of complete response. FDG-PET may be 
used to upgrade a response to a CR in a manner similar to a biopsy in cases where 
a residual radiographic abnormality is thought to represent fibrosis or scarring.
 For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment. If at the next scheduled assessment, progression is 
confirmed, the date of progression should be the earlier date when progression was 
suspected.
 Confirmation of response: In the event of complete or partial responses, efforts should 
be made to obtain a confirmatory scan (no sooner than 28 days later).
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Table 1: Overall response: patients with target +/–non-target disease. 
Target lesions 
Non-target lesions 
New lesions Overall 
 
 
 
 
PR 
Non-PD 
or 
not 
all 
evaluated 
SD 
Non-PD 
or 
not 
all 
No 
PR 
 
No 
SD 
 
 
 
 
 
CR = complete response, PR = partial response, SD = stable disease, PD 
= progressive disease, and NE = inevaluable. 
 
 
Table 2: Overall response: patients with non-target disease only. 
Non-target lesions New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PD = progressive disease, and NE = inevaluable. 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as endpoint for assessment of efficacy in some trials 
so to assign this category when no lesions can be measured is not advised. 
response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
evaluated 
Not all evaluated Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
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FREQUENTLY ASKED QUESTIONS 
What should be done if several unique lesions at baseline become confluent at a 
follow-up evaluation? 
Measure the longest diameter of the confluent mass and record to add into the sum of 
the longest diameters. 
How large does a new lesion have to be to count as progression? Does any small 
sub-centimeter lesion qualify, or should the lesion be at least measurable? 
New lesions do not need to meet ‘measurability criteria’ to be considered valid. If it is clear 
on previous images (with the same technique) that a lesion was absent then its definitive 
appearance implies progression. If there is any doubt (because of the techniques or 
conditions) then it is suggested that treatment continue until next scheduled assessment 
when, generally, all should be clear. Either it gets bigger and the date of progression is 
the date of the first suspicion, or it disappears and one may then consider it an artifact 
with the support of the radiologists. 
How should one lesion be measured if on subsequent exams it is split into two? 
Measure the longest diameter of each lesion and add this into the sum. 
Does the definition of progression depend on the status of all target lesions or 
only one? 
As per the RECIST 1.1 guideline, progression requires a 20% increase in the sum of 
diameters of all target lesions AND a minimum absolute increase of 5 mm in the sum. 
What is the criterion for a measurable lesion if the CT slice thickness is > 5 mm? 
RECIST 1.1 recommends that CT scans have a maximum slice thickness of 5 mm and 
the minimum size for a measurable lesion is twice that: 10 mm (even if slice thickness is 
< 5 mm). If scanners with slice thickness > 5 mm are used, the minimum lesion size 
must have a longest diameter twice the actual slice thickness. 
What should we record when target lesions become so small they are below the 
10 mm ‘measurable’ size? 
Target lesion measurability is defined at baseline. Thereafter, actual measurements, even 
if < 10 mm, should be recorded. If lesions become very small, some radiologists indicate 
they are ‘too small to measure’. This guideline advises that when this occurs, if the lesion 
is actually still present, a default measurement of 5 mm should be applied. If in fact the 
radiologist believes the lesion has gone, a default measurement of 0 mm should be 
recorded 
If a patient has several lesions which have decreased in size to meet PR criteria 
and one has actually disappeared, does that patient have PD if the ‘disappeared’ 
lesion reappears? 
Unless the sum meets the PD criteria, the reappearance of a lesion in the setting of PR 
(or SD) is not PD. The lesion should simply be added into the sum. If the patients had 
had a CR, clearly reappearance of an absent lesion would qualify for PD. 
When measuring the longest diameter of target lesions in response to treatment, 
is the same axis that was used initially used subsequently, even if there is a 
shape change to the lesion that may have produced a new longest diameter? 
The longest diameter of the lesion should always be measured even if the actual axis is 
different from the one used to measure the lesion initially (or at different time point 
during follow-up). The only exception to this is lymph nodes: as per RECIST 1.1 the 
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short axis should always be followed and as in the case of target lesions, the vector of 
the short axis may change on follow-up 
Target lesions have been selected at baseline and followed but then one of these 
target lesions then becomes non-evaluable (i.e. different technique used). What is 
the effect this has on the other target lesions and the overall response? 
What may be done in such cases is one of the following: 
(a) If the patient is still being treated, call the centre to be sure that future evaluations 
are done with the baseline technique so at least SOME courses are fully evaluable 
(b) If that is not possible, check if there IS a baseline exam by the same technique 
which was used to follow patients in which case if you retrieve the baseline measures 
from that technique you retrieve the lesion evaluability 
(c) If neither (a) nor (b) is possible then it is a judgement call about whether you delete 
the lesion from all forms or consider the impact of the lesion overall is so important that 
its being non-evaluable makes the overall response interpretation inevaluable without it. 
Such a decision should be discussed in a review panel. It is NOT recommended that the 
lesion be included in baseline sums and then excluded from follow-up sums since this 
biases in favour of a response. 
What if a single non-target lesion cannot be reviewed, for whatever reason; does 
this negate the overall assessment? 
Sometimes the major contribution of a single non-target lesion may be in the setting of 
CR having otherwise been achieved: failure to examine one non-target in that setting 
will leave you unable to claim CR. It is also possible that the non-target lesion has 
undergone such substantial progression that it would override the target disease and 
render patient PD. However, this is very unlikely, especially if the rest of the measurable 
disease is stable or responding. 
A patient has a 32% decrease in sum cycle 2, a 28% decrease cycle 4 and a 33% 
decrease cycle 6. Does confirmation of PR have to take place in sequential scans 
or is a case like this confirmed PR? 
It is not infrequent that tumour shrinkage hovers around the 30% mark. In this case, most 
would consider PR to have been confirmed looking at this overall case. Had there been 
two or three non-PR observations between the two time point PR responses, the most 
conservative approach would be to consider this case SD. 
A patient has a lesion measurable by clinical exam and by CT scan. Which should 
be followed? 
CT scan. Always follow by imaging if that option exists since it can be reviewed and 
verified 
A lesion which was solid at baseline has become necrotic in the centre. How 
should this be measured? 
The longest diameter of the entire lesion should be followed. Eventually, necrotic lesions 
which are responding to treatment decrease in size. In reporting the results of trials, you 
may wish to report on this phenomenon if it is seen frequently since some agents (e.g. 
angiogenesis inhibitors) may produce this effect. 
If I am going to use MRI to follow disease, what is minimum size for 
measurability? 
MRI may be substituted for contrast enhanced CT for some sites, but not lung. The 
minimum size for measurability is the same as for CT (10 mm) as long as the scans are 
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performed with slice thickness of 5mm and no gap. In the event the MRI is performed with 
thicker slices, the size of a measurable lesion at baseline should be two times the slice 
thickness. In the event there are inter-slice gaps, this also needs to be considered in 
determining the size of measurable lesions at baseline. 
Can PET–CT be used with RECIST? 
At present, the low dose or attenuation correction CT portion of a combined PET–CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. 
However, if your site has documented that the CT performed as part of a PET–CT is of 
the same diagnostic quality as a diagnostic CT (with IV and oral contrast) then the PET– 
CT can be used for RECIST measurements. Note, however, that the PET portion of the 
CT introduces additional data which may bias an investigator if it is not routinely or serially 
performed. 
 
Adapted from Eisenhauer 2009117. 
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13.5 Appendix E – EORTC QLQ-C30 and LC13 
 
 
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13.6 Appendix F – Correlative Blood Sample Processing 
Purpose 
To freeze and store PBMC from patients. 
Methods 
Human peripheral blood mononuclear cells (PBMC) from whole blood will be isolated using a density 
gradient centrifugation (Ficoll-Paque) and prepared to be ready to use or stored in a cryoprotective 
media. 
This method has shown an acceptable % cell recovery, viability and yield for further flow cytometry 
analysis. 
Time 
90 minutes 
Reagents 
1. 14-20 ml whole blood in heparinized tubes (sodium heparin green lid) 
2. RPMI-1640 medium with 2mM L- glutamine and 5% FBS 
3. Ficoll Histopaque 1.077 (Sigma) 
4. Phosphate-buffered saline (dPBS) 
5. 2ml Cryovials 
6. 50 ml tubes 
7. Sterile pipets 
8. Centrifuge eppendorf 5810R 
Procedure 
1. Mix all blood tubes in a 50 ml tube. Take note of the approximate 
blood volume. 
2. Centrifuge collection tubes at 200 x g for 10 min at RT. 
3. Carefully remove plasma and collect 3ml. Centrifuge the isolated 
plasma at 1,000 x g for 10 minutes. Aliquot the plasma supernatant 
in 1ml x3 cryovials and store at -80C. 
4. Replace the plasma removed for an equal volume of RPMI 5% FBS. 
Add the same volume of RPMI 5% FBS (no more than 35 ml final 
volume). 
5. Gently transfer the diluted blood in a 50 ml tube containing 15 ml of 
Ficoll-Paque with the help of a 25ml sterile pipet. 
6. Centrifuge 30 min at 1800 rpm (or 400 x g), room temperature 
(acceleration: 4, brake: 0). 
7. Transfer the lymphocyte-containing band (buffy coat) into a new 
50ml tube using a 1 ml micropipet. 
8. Wash the total lymphocyte population with 3V of RPMI 1640 
containing 5% FBS two times. Between washes, pellet down the 
cells, centrifuge 10 min at 1800 rpm, 4C (acceleration: 9 brake: 9). 
9. Count number of cells before the last centrifugation (final volume= 
10ml). 
10. 
If the cells will be cryopreserved then resuspend cells in the 
corresponding volume of cRPMI (or ExVivo media) to have at least 
2-3x10e7 cells/ml and continue with cryopreservation protocol. 
11. 
If the cells will be directly used for FACS then resuspend cells 
in 3ml of cRPMI and incubate at 37C for up to 2h for the cells to 
recover. 
12. 
Collect the cells by centrifuging and resuspend with PBS to its 
corresponding volume (1x10e6 cells/100 ul) and continue with 
FACS protocol. 
Notes 
15ml of ficoll is sufficient for 
isolate pbmcs from 35ml blood 
solution (blood + RPMI) 
Label should include study 
number, sample identification, the 
date, and “PBMC”. 
It is important to avoid the blood 
to get mixed with the ficoll. 
Cc = cells x 10e4 x VF = cells/ml 
square x dil 
Reference: Standard Operating Protocol - HIMC 
Title: Isolation of Plasma – Undiluted, Pre-Ficoll Revised: 8/12/2013 – Version 1.2 
Authors: R. Gupta, A. Puleo, & H. Maecker 
 
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