A Phase II Trial of TPIV200/huFR-1 (A Multi-Epitope Anti-Folate Receptor Vaccine) Plus Anti-PD-L1 MEDI4736 (Durvalumab) in Patients With Platinum Resistant Ovarian Cancer
Phase: PHASE2
Conditions: Ovarian Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Page 1 of 59 
 
 
Approval date: 10-Oct-2017 
A Phase 2 Trial of TPIV200/huFR-1 (a multi-epitope anti-folate recept 
anti-PD-L1 Antibody durvalumab (MED I4736) in Patients with Platinum 
Cancer 
PROTOCOL FACE PAGE FOR 
MSK THE RAPEUTIC /D IAGNOSTIC PROTOCO 
Principal Investigator/Department: 
Jason Konner, MD 
or vaccine) Plus 
Resistant Ovarian 
L 
Medicine 
Co-Principal 
Dmitriy Zam 
Investigator(s)/Department: 
arin, MD, PhD 
Medicine 
Investigator(s)/Department: 
Carol A. Aghajanian, MD 
Karen A. Cadoo, MD 
Claire Friedman, MD 
Rachel N. Grisham, MD 
Martee L. Hensley, MD, MSc 
David Hyman, MD 
Chrisann Kyi, MD 
Vicky Makker, MD 
Roisin E. O‟Cearbhaill, MD 
Paul Sabbatini, MD 
David R. Spriggs, MD 
William P. Tew, MD 
Elizabeth Butler, PA 
Jessica Gahres, PA 
Katy Nickolaus, PA 
Vania Hom, RN 
Krysten Soldan, RN 
Sara Weissblum, RN 
Jedd Wolchok, MD, PhD 
Mila Gorsky, MD 
Audrey Hamilton, MD 
Paul Hamlin, MD 
Neha Korde, MD 
Louise Ligresti, MD 
Karen Dougherty, APN 
Stuart Lichtman, MD 
Sarah Schweber, MD 
Steven Sugarman, MD 
Wanqing Iris Zhi, MD, PhD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Nursing 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Medicine 
Medicine 
Medicine 
Medicine 
 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 2 of 59 
 
 
 
 
 
Noelia Maamouri, NP 
Jacqueline Bromberg, MD, PhD 
Loren Michel, MD 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Marina Shcherba, DO 
Serena Wong, MD 
Michelle Abboud, NP 
Arlyn Apollo, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
Chau Dang, MD 
Diana Lake, MD 
Rachel Sanford, MD 
Jasmeet Singh, MD 
Alexis Leitenberger, NP 
Alexia Iasonos, PhD 
Jean MarieTorrisi, MD 
Yuliya Lakhman, MD 
Katie Thoren, PhD 
Martin Fleisher, PhD 
Nursing 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Biostatistics 
Radiology  
Radiology 
Laboratory Medicine 
Laboratory Medicine 
Consenting  Professional(s)/Department: 
Carol A. Aghajanian, MD 
Medicine 
Karen A. Cadoo, MD 
Medicine 
Claire Friedman, MD 
Medicine 
Rachel N. Grisham, MD 
Medicine 
Martee L. Hensley, MD, MSc 
Medicine 
David Hyman, MD 
Medicine 
Jason Konner, MD 
Medicine 
Chrisann Kyi, MD 
Medicine 
Vicky Makker, MD 
Medicine 
Roisin E. O‟Cearbhaill, MD 
Medicine 
Paul Sabbatini, MD 
Medicine 
David R. Spriggs, MD 
Medicine 
William P. Tew, MD 
Medicine 
Dmitriy Zamarin, MD, PhD 
Medicine 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 3 of 59 
 
 
 
 
 
Mila Gorsky, MD 
Medicine 
Audrey Hamilton, MD 
Medicine 
Paul Hamlin, MD 
Medicine 
Neha Korde, MD 
Medicine 
Louise Ligresti, MD 
Medicine 
Stuart Lichtman, MD 
Medicine 
Sarah Schweber, MD 
Medicine 
Steven Sugarman, MD 
Medicine 
Wanqing Iris Zhi, MD, PhD 
Medicine 
Jacqueline Bromberg, MD, PhD 
Medicine 
Loren Michel, MD 
Medicine 
Azadeh Namakydoust, MD 
Medicine 
Colette Owens, MD 
Medicine 
Marina Shcherba, DO 
Medicine 
Serena Wong, MD 
Medicine 
Arlyn Apollo, MD 
Medicine 
Pamela Drullinsky, MD 
Medicine 
Zoe Goldberg, MD 
Medicine 
Kenneth Ng, MD 
Medicine 
Tiffany Troso-Sandoval, MD 
Medicine 
Chau Dang, MD 
Medicine 
Diana Lake, MD 
Medicine 
Rachel Sanford, MD 
Medicine 
Jasmeet Singh, MD 
Medicine 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
OneMSK Sites 
Manhattan 
Basking Ridge 
Commack 
Monmouth 
Rockville Centre 
Westchester 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 4 of 59 
 
 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .......................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................... 7 
3.0 
BACKGROUND AND RATIONALE ......................................................................................... 7 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ...................................................................... 14 
4.1 
Design .................................................................................................................................... 14 
4.2 
Intervention ................................................................................................................................... 14 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................... 15 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .................................................................................. 18 
6.1 
Subject Inclusion Criteria ........................................................................................................ 18 
6.2 
Subject Exclusion Criteria ....................................................................................................... 19 
7.0 
RECRUITMENT PLAN ........................................................................................................................ 21 
8.0 
PRETREATMENT EVALUATION .......................................................................................... 21 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................... 24 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ........................................................ 25 
11.0 
TOXICITIES/SIDE EFFECTS ......................................................................................................... 26 
Permitted concomitant medications ............................................................................................... 28 
Excluded Concomitant Medications .................................................................................................... 29 
Gastrointestinal disorders ............................................................................................................... 34 
Endocrine disorders ....................................................................................................................... 34 
Pancreatic disorders ...................................................................................................................... 34 
Neurotoxicity .................................................................................................................................. 34 
Nephritis ............................................................................................................................................... 34 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ............................ 35 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ........................................................................... 44 
14.0 
BIOSTATISTICS ................................................................................................................... 44 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ... 48 
15.1 Research Participant Registration ............................................................................................. 48 
15.2 
Randomization ....................................................................................................................... 49 
16.0 
DAT A M ANAGEMENT ISSUES ............................................................................................ 49 
16.1 
Quality Assurance .................................................................................................................. 49 
16.2 
Data and Safety Monitoring ......................................................................................................... 50 
17.0 
PROTECTION OF HUMAN SUBJECTS ................................................................................ 50 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 5 of 59 
 
 
17.1 
Privacy ................................................................................................................................... 50 
17.2 
Serious Adverse Event (SAE) Reporting .................................................................................... 51 
18.0 
INFORMED CONSENT PROCEDURES ....................................................................................... 56 
19.0 
REFERENCES .......................................................................................................................... 57 
20.0 
APPENDICES ....................................................................................................................... 59 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.1 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
A Phase 2 Trial of TPIV200/huFR-1 (a multi-epitope anti-folate receptor vaccine) Plus anti- 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 6 of 59 
 
 
PD-L1 Antibody durvalumab (MEDI4736) in Patients with Platinum Resistant Ovarian Cancer 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 6 of 59 
 
 
 
 
This is a prospective, non-randomized, phase 2 study which will assess the efficacy and 
safety of a combination vaccine and immune checkpoint inhibitor for platinum resistant 
adnexal (ovarian, fallopian tube, and primary peritoneal) cancer (generally referred to as 
Ovarian Cancer). Forty women with persistent or recurrent high grade epithelial adnexal 
carcinomas, who have had at least one prior platinum chemotherapy regimen and have 
progressed within 6 months of their most recent dose of platinum will be eligible for treatment 
if they have measurable disease and adequate organ function. Patients with clinically 
significant autoimmune disease will be excluded. Treatment cycles will be 28 days and will 
continue until toxicity or disease progression, for up to 12 cycles. 
 
Primary Objective 
 
• 
Determine the effectiveness of the combination by measuring Overall Response Rate 
[ORR = Complete Response (CR) + Partial Response (PR)] by RECIST and 
Progression Free Survival (PFS) rate at 6 months 
 
Secondary Objectives 
 
• 
Disease Control Rate (DCR = CR+PR + stable disease [SD] ≥ 12 weeks) 
• 
Progression Free Survival (PFS) 
• 
Safety of the combination assessed by observed Adverse Events (AE's) and immune- 
related AE's (irAE's). A stopping rule will be employed for excess toxicity. 
• 
Response rate as evaluated by irRECIST criteria 
• 
Measure expression of Folate Receptor-alpha (FRα) and PD-L1 on primary tumors. 
• 
Assess the ability of the combination to elicit an immune response. 
• 
Correlate FRα-specific immune responses and PD-L1 expression with clinical 
efficacy. 
 
Patient Population 
 
• 
Sample size: 40 patients 
• 
Patients with persistent or recurrent high grade adnexal (ovarian, fallopian tube, or 
primary peritoneal) carcinoma, whose disease has progressed within 6 months of 
completing a prior platinum regimen 
• 
Adequate organ function and performance status ECOG 0-1 
• 
At least 1 target lesion, which is measurable by RECIST and was not previously 
irradiated 
 
 
 
 
Treatment Plan: 
 
Patients will receive an intradermal (ID) injection of TPIV200 (500 µg per peptide) and GM- 
CSF (125 µg per peptide) on Day 1 of cycles 1-6. They will also receive intravenous (IV) 
injections of durvalumab (750mg) on Days 1 and 15 of cycles 1-12. Radiologic tumor 
assessment will be repeated every 12 weeks (or 3 cycles) during and after treatment, until 
time of progression. Treatment will continue until progression, intolerance, withdrawal, study 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 7 of 59 
 
 
 
 
completion, or study termination. It is estimated that full accrual will be achieved within 18 
months; 2.5 years is estimated between time of opening and time of last treatment. 
 
40 Patients 
Platinum-Resistant 
Ovarian Cancer 
Cycles 1-6 
Cycles 7-12 
Days 1,15: durvalumab 
(750mg IV over 60 min) 
Days 1,15: durvalumab 
(750mg IV over 60 min) 
Day 1: TPIV + GMCSF 
(500µg/peptide+125µg ID) 
*1 Cycle = 28 Days; Tumor Assessment Q3 Cycles; Biomarkers Baseline and EOS. 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Endpoints 
 
• 
Overall tumor Response Rate (CR+PR) and will be assessed by RECIST 1.1. Pre-defined 
deviations from RECIST will be permitted to allow select patients deemed to be benefitting 
from treatment to receive continued therapy. 
 
• 
Co-primary endpoint supplementary to ORR: Progression Free Survival (PFS) rate at 6 
months. 
Secondary Endpoints 
 
• 
Assess the safety of delivering the doublet, by determining rate of irAE, SAE, therapy 
completion rate, and protocol completion. A stopping rule will halt the study if excess toxicity 
is encountered. 
• 
Disease Control Rate (CR+PR+SD) 
• 
Estimate median PFS 
• 
Response rate as evaluated by irRECIST criteria 
• 
Estimate median Overall Survival (OS). 
• 
Determine the ability of the laboratory parameters to predict response: 
o Tumor tissue FRα expression* 
o Tumor tissue PD-L1 expression** 
o Tumor tissue immune-related gene signature 
o Peripheral blood immune phenotype 
o Peripheral blood gene expression profiling 
o Peripheral blood cellular and serologic responses to FRα 
o Peripheral blood T cell receptor repertoire 
 
* FRα levels (using a Morphotek, Inc. FRA-26B3 IHC Assay Kit) will be performed by 
TapImmune; PD-L1 staining expression (Ventana SP263 assay kit) will be performed by 
AZ/MED I. 
**Immune response monitoring will be performed at MSK. 
 
3.1 
BACKGROUND AND RATIONALE 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 8 of 59 
 
 
 
 
Introduction 
 
Immunotherapy with checkpoint inhibition is improving long-term disease control for patients 
with diverse malignancies (Tolapian 2012; Hamid 2013; Wolchok 2013; Powles 2014), 
including patients with ovarian cancer (OC) (Hodi 2008; Brahmer 2012). The primary 
mediators of adaptive immune blockade, whose targeting in clinical trials have yielded 
results, include CTLA-4 (Hodi 2010; Ribas 2013), PD-1 (Topalian 2012; Hamid 2013; Robert 
2014), and PD-L1 (Brahmer 2012). Responses in tumors such as melanoma, non-small cell 
lung cancer, and renal cell cancer have been impressive. Preclinical data point toward an 
important role of TIL‟s in OC. (Zhang 2003; Sato 2005; Hamanishi 2007) Emerging human 
data in OC demonstrate more modest yet encouraging activity of immune checkpoint 
inhibitors (Hodi 2008; Brahmer 2012). 
Checkpoint Inhibition in OC 
 
Programmed cell death ligand 1 (PD-L1) is part of a complex system of receptors and 
ligands that are involved in controlling T-cell activation. PD-L1 acts at multiple sites in the 
body to help regulate normal immune responses and is utilized by tumors to help evade 
detection and elimination by the host immune system tumor response. In the lymph nodes, 
PD-L1 on antigen-presenting cells binds to PD-1 or CD80 on activated T cells and delivers 
an inhibitory signal to the T cell (Keir et al, 2008; Park et al, 2010). This results in reduced T- 
cell activation and fewer activated T cells in circulation. In the tumor microenvironment, PD- 
L1 expressed on tumor cells binds to PD-1 and CD80 on activated T cells reaching the 
tumor. This delivers an inhibitory signal to those T cells, preventing them from killing target 
cancer cells and protecting the tumor from immune elimination (Zou and Chen, 2008). 
 
In one preclinical study, the 5-year survival rate in OC patients with low expression of PD-L1 
was 80.2% compared with 52.6% in patients with high expression levels of PD-L1 
(Hamanishi et al. 2007). In a Phase 2 study of 20 heavily-pretreated patients with platinum 
resistant OC, nivolumab (anti-PD-1) at 2 dose levels yielded an ORR of 15%; and a 45% 
disease control rate; responses were durable for 2 disease assessments beyond the end of 
treatment in the 2 patients with CR (Hamanishi 2015). On the heels of these results, a 
randomized CTEP trial of nivolumab alone or in combination with ipilimumab for OC has 
been initiated. 
 
 
Durvalumab: anti-PD-L1 Monoclonal Antibody 
 
Durvalumab, formerly called MEDI4736, is a human mAb of the IgG1κ subclass that inhibits 
binding of PD-L1 to PD-1 and CD80. Durvalumab is composed of 2 identical heavy chains 
and 2 identical light chains, with an overall molecular weight of approximately 149 kDa. 
Antibodies of the IgG1 isotype have the potential to trigger effector functions such as ADCC 
and CDC. However, durvalumab carries 3 point mutations in its constant domain that reduce 
binding to C1q as well as the affinity of the Fc domain for the ADCC-inducing Fcγ receptors 
(Oganesyan et al, 2008). 
 
Preclinical analyses reveal the following features: 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 9 of 59 
 
 
 
 
• 
Durvalumab binds to PD-L1 and blocks its interaction with PD-1 and CD80 
• 
In vitro, durvalumab can relieve PD-L1-mediated suppression of human T-cell 
activation 
• 
Durvalumab does not trigger ADCC or CDC in cell-based functional assays 
• 
Durvalumab inhibits tumor growth in a xenograft model via a T-cell dependent 
mechanism 
• 
An anti-mouse PD-L1 antibody demonstrated improved survival in a syngeneic tumor 
model when given as monotherapy and resulted in complete tumor regression in > 
50% of treated mice when given in combination with chemotherapy 
 
To date, several hundred patients with a range of solid tumors have been treated on 
integrated monotherapy studies with durvalumab. These trials (CD-ON-MEDI4736-1108, 
D4190C00002, and D4190C00007) have yielded information on clinical safety, efficacy, and 
PK, as summarized below. (Investigator‟s Brochure, durvalumab (MEDI4736), vol. 8.0) 
 
Pharmacokinetics 
 
Study CD-ON-MEDI4736-1108: As of 09Feb2015, PK data were available for 378 subjects  
in the dose-escalation and dose-expansion phases of Study CD-ON-MEDI4736-1108 
following treatment with durvalumab 0.1 to 10 mg/kg every 2 weeks (Q2W) or 15 mg/kg  
every 3 weeks (Q3W). The maximum observed concentration (Cmax) increased in an 
approximately dose-proportional manner over the dose range of 0.1 to 15 mg/kg. The area 
under the concentration-time curve from 0 to 14 days (AUC0-14) increased in a greater than 
dose-proportional manner over the dose range of 0.1 to 3 mg/kg and increased  dose- 
proportionally at ≥ 3 mg/kg. These results suggest durvalumab exhibits nonlinear PK likely 
due to saturable target-mediated CL at doses < 3 mg/kg and approaches linearity at doses ≥ 
3 mg/kg. Near complete target saturation (soluble programmed cell death ligand 1 [sPD-L1] 
and membrane bound) is expected with durvalumab ≥ 3 mg/kg Q2W. Exposures after 
multiple doses showed accumulation consistent with PK parameters estimated from the first 
dose. In addition, PK simulations indicate that following durvalumab 10 mg/kg Q2W dosing, > 
90% of subjects are expected to maintain PK exposure ≥ 40 μg/mL throughout the dosing 
interval. 
 
As of 09Feb2015, a total of 388 subjects provided samples for anti-drug antibody (ADA) 
analysis. Only 8 of 388 subjects (1 subject each in 0.1, 1, 3, and 15 mg/kg cohorts, and 4 
subjects in 10 mg/kg cohort) were ADA positive with an impact on PK/pharmacodynamics in 
1 subject in the 3 mg/kg cohort. 
 
Safety 
 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune 
checkpoint inhibitor class. No tumor types appeared to be associated with unique AEs. 
Immune-related AEs (irAEs), which are important risks of immune checkpoint inhibitors, have 
been observed with durvalumab and include colitis, pneumonitis, hepatitis/hepatotoxicity, 
neuropathy/neuromuscular toxicity, endocrinopathy, dermatitis, and nephritis. In addition, 
pancreatitis is an important potential risk particularly with durvalumab and tremelimumab 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 10 of 59 
 
 
 
 
(anti-CTLA-4) combination therapy. These events are manageable by available/established 
treatment guidelines as described in the study protocols. 
Study CD-ON-MEDI4736-1108: The safety profile of durvalumab monotherapy in the 694 
subjects with advanced solid tumors treated at 10 mg/kg Q2W in Study CD-ON-MEDI4736- 
1108 has been broadly consistent with that of the overall 1,279 subjects who have received 
durvalumab monotherapy (not including subjects treated with blinded investigational product) 
across the clinical development program. The majority of treatment-related AEs were 
manageable with dose delays, symptomatic treatment, and in the case of events suspected 
to have an immune basis, the use of established treatment guidelines for immune-mediated 
toxicity. As of 07May2015, among the 694 subjects treated with durvalumab 10 mg/kg Q2W 
in Study CD-ON-MEDI4736-1108, a total of 378 subjects (54.5%) experienced a treatment- 
related AE, with the most frequent (occurring in ≥ 5% of subjects) being fatigue (17.7%), 
nausea (8.6%), diarrhea (7.3%), decreased appetite (6.8%), pruritus (6.3%), rash (6.1%),  
and vomiting (5.0%). A majority of the treatment-related AEs were Grade 1 or Grade 2 in 
severity with ≥ Grade 3 events occurring in 65 subjects (9.4%). 
 
Treatment-related ≥ Grade 3 events reported in 3 or more subjects (≥ 0.4%) were fatigue (12 
subjects, 1.7%); increased aspartate aminotransferase (AST; 7 subjects, 1.0%);  increased 
gamma-glutamyltransferase (GGT; 6 subjects, 0.9%); increased alanine aminotransferase 
(ALT; 5 subjects, 0.7%); and colitis, vomiting, decreased appetite, and hyponatremia (3 
subjects, 0.4% each). Six subjects had treatment-related Grade 4 AEs (upper gastrointestinal 
hemorrhage, increased AST, dyspnea, neutropenia, colitis, diarrhea, and pneumonitis) and 1 
subject had a treatment-related Grade 5 event (pneumonia). Treatment-related serious 
adverse events (SAEs) that occurred in ≥ 2 subjects were colitis and pneumonitis (3 subjects 
each). A majority of the treatment-related SAEs were ≥ Grade 3 in severity and resolved with 
or without sequelae. AEs that resulted in permanent discontinuation of durvalumab were 
considered as treatment related in 18 subjects (2.6%), with colitis being the most frequent 
treatment-related AE resulting in discontinuation (3 subjects). A majority of the treatment- 
related AEs resulting in discontinuation of durvalumab were ≥ Grade 3 in severity and 
resolved with or without sequelae. 
Study D4191C00003/ATLANTIC: The safety profile of durvalumab monotherapy in Study 
CD-ON-MEDI4736-1108 is generally consistent with that of Study D4191C00003/ATLANTIC 
in subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) treated 
with durvalumab 10 mg/kg Q2W. As of 05May2015, 264 of 303 subjects (87.1%) reported 
any AE in Study D4191C00003/ATLANTIC. Overall,  events reported in ≥ 10% of subjects 
were dyspnea (18.8%), fatigue (17.8%), decreased appetite (17.5%), cough (14.2%), pyrexia 
(12.2%), asthenia (11.9%), and nausea  (11.2%). Nearly two-thirds of the subjects 
experienced AEs that were Grade 1 or 2 in severity and manageable by general treatment 
guidelines as described in the current durvalumab study protocols. Grade 3 or higher AEs 
were reported in 107 of 303 subjects (35.3%). A total of 128 subjects (42.2%) reported AEs 
that were considered by the investigator as related to investigational product. Treatment- 
related AEs (all grades) reported in ≥ 2% of subjects were decreased appetite (6.6%); fatigue 
(5.9%); asthenia (5.0%); nausea (4.6%); pruritus (4.3%); diarrhea, hyperthyroidism, 
hypothyroidism, and pyrexia (3.3% each); rash (2.6%); weight decreased (2.3%); and 
vomiting (2.0%). Treatment-related Grade 3 AEs reported in ≥ 2 subjects were pneumonitis 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 11 of 59 
 
 
 
 
(3 subjects) and increased GGT (2 subjects). There were no treatment-related Grade 4 or 5 
AEs. Ninety-four of 303 subjects (31.0%) reported any SAE. SAEs that occurred in ≥ 1.0% of 
subjects were dyspnea (6.6%); pleural effusion, general physical health deterioration (2.3% 
each); pneumonia (2.0%); hemoptysis, pulmonary embolism (1.3% each); and pneumonitis, 
respiratory failure, disease progression (1.0% each). Nine subjects had an SAE considered 
by the investigator as related to durvalumab. Each treatment-related SAE occurred in 1 
subject each with the exception of pneumonitis, which occurred in 3 subjects. Fifteen of 303 
subjects (5.0%) have died due to an AE (pneumonia [3 subjects]; general physical health 
deterioration, disease progression, hemoptysis, dyspnea [2 subjects each]; pulmonary 
sepsis, respiratory distress, cardiopulmonary arrest [verbatim term (VT)], hepatic failure, and 
sepsis [1 subject each]). None of these events was considered related to durvalumab. 
Twenty-three of 303 subjects (7.6%) permanently discontinued durvalumab treatment due to 
AEs. Events that led to discontinuation of durvalumab in ≥ 2 subjects were dyspnea, general 
physical health deterioration, and pneumonia. Treatment-related AEs that led to 
discontinuation were increased ALT and increased hepatic enzyme, which occurred in 1 
subject each. 
Efficacy 
 
Partial efficacy data are available for 2 monotherapy studies (CD-ON-MEDI4736-1108 and 
D4190C00007). 
Study CD-ON-MEDI4736-1108: Overall, 456 of 694 subjects treated with durvalumab 10 
mg/kg Q2W were evaluable for response (defined as having ≥ 24 weeks follow-up, 
measurable disease at baseline, and ≥ 1 follow-up scan, or discontinued due to  disease 
progression or death without any follow-up scan). In PD-L1 unselected patients, the objective 
response rate (ORR), based on investigator assessment per Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1, ranged from 0% in uveal melanoma (n = 23) to 20.0% in 
bladder cancer (n = 15), and disease control rate at 24 weeks (DCR-24w) ranged from 4.2% 
in triple-negative breast cancer (TNBC; n = 24) to 39.1% in advanced cutaneous melanoma 
(n = 23). PD-L1 status was known for 383 of the 456 response evaluable subjects. Across 
the PD-L1-positive tumors, ORR was highest for bladder cancer, advanced cutaneous 
melanoma, hepatocellular carcinoma (HCC; n = 3 each, 33.3% each), NSCLC (n = 86, 
26.7%), and squamous cell carcinoma of the head and neck (SCCHN; n = 22, 18.2%). In the 
PD-L1-positive subset, DCR-24w was highest in advanced cutaneous melanoma (n = 3, 
66.7%), NSCLC (n = 86, 36.0%), HCC and bladder cancer (n = 3 each, 33.3% each), and 
SCCHN (n = 22, 18.2%). 
Study D4190C00007: Of the 32 subjects with myelodysplastic syndrome (MDS) treated in 
Study D4190C00007, 21 subjects had at least 1 post-baseline disease assessment. Among 
these subjects, the best overall responses were marrow complete remission (mCR) in 4 
subjects (19.0%); stable disease (SD) in 4 subjects (19.0%); and progressive disease (PD) in 
5 subjects (23.8%). The remaining 8 subjects (38.1%) did not meet the criteria for complete 
remission (CR), mCR, partial remission (PR), SD, or PD at the date of assessment. 
Fixed Dosing 

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A population PK model was developed for durvalumab using monotherapy  data  from  a 
Phase 1 study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid 
tumors). Population PK analysis indicated only minor impact of body weight (WT) on PK of 
durvalumab (coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed 
dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted steady state PK 
concentrations (5th, median and 95th percentiles) using the population PK model. A fixed 
dose of 750 mg was selected to approximate 10 mg/kg (based on median body WT of ~75 
kg). A total of 1000 patients were simulated using body WT distribution of 40–120 kg. 
Simulation results demonstrate that body WT-based and fixed dosing regimens yield similar 
median steady state PK concentrations with slightly less overall between-subject variability 
with fixed dosing regimen. 
 
Similar findings have been reported by others [Ng et al 2006, Wang et al. 2009, Zhang et al, 
2012,Narwal et al 2013]. Wang and colleagues investigated 12 monoclonal antibodies and 
found that fixed and body size-based dosing perform similarly, with fixed dosing being better 
for 7 of 12 antibodies [3]. In addition, they investigated 18 therapeutic proteins and peptides 
and showed that fixed dosing performed better for 12 of 18 in terms of reducing the between- 
subject variability in pharmacokinetic/pharmacodynamics parameters [Zhang et al 2012]. 
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar pharmacokinetic exposure and variability, 
we considered it feasible to switch to fixed dosing regimens. Based on average body WT of 
75 kg, a fixed dose of 750 mg Q2W durvalumab (equivalent to 10 mg/kg Q2W), 1500 mg 
Q4W durvalumab (equivalent to 20 mg/kg Q4W) is included  in  the  current  study.  Fixed 
dosing of durvalumab is recommend only for subjects with > 30kg body weight due to 
endotoxin exposure. Patients with a body weight less than or equal to 30 kg should be 
dosed using a weight-based dosing schedule (Appendix A). 
 
 
FRα and the FRα Vaccine TPIV200 
 
One reason that responses in OC appear to be less robust than for other solid tumors may 
be its relatively low mutational burden (TCGA 2011). The success of immune checkpoint 
inhibition may partly relate to the breadth of the mutational landscape (Rizvi 2015), with 
melanoma and NSCLC having the highest mutation loads among solid tumors, providing a 
feast of immunologic targets. Mutational load and neoantigen landscape may be predictive of 
response to CTLA-4 inhibitors in patients with melanoma (Snyder 2014). 
 
An important question in OC is whether the efficacy of checkpoint inhibition can be improved 
by enhancing immunologic targets. Only a few tumor-associated antigens (TAAs) have been 
identified in OC. One notable example is the folate receptor alpha (FRα), which presents an 
compelling opportunity for targeted immunotherapy. The human FRα is over-expressed in a 
majority of ovarian cancers (70-90%), but is rarely found in healthy adult tissues. While it is a 
self antigen, several promiscuous epitopes of FRα have been identified to prompt a T cell 
response in 70% of patients with ovarian and breast cancers (Knutson 2006). 

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Approval date: 10-Oct-2017 
Page 13 of 59 
 
 
 
 
Based on these observations, a multi-epitope anti-FRα vaccine (huFR-1 or TPIV200 – 
TapImmune, Inc.) was developed by identifying the five most highly antigenic moieties of 
FRα identified in a group of un-vaccinated patients with OC and breast cancer, as compared 
with normal volunteers. Using these 5 oligopeptide antigens, TPIV200 was designed, 
generated, and validated in animal models, and subsequently tested in human subjects 
(Investigators Brochure, TPIV200, TapImmune, Inc.). 
 
In a phase 1 study, 22 women in remission from OC or breast cancer were vaccinated with 
TPIV200 admixed GM-CSF in a single syringe. (Proc ASCO 2015) One cycle of 
cyclophosphamide was given in an effort to reduce T-regs. The safety profile of TPIV200 was 
excellent. Immune responses were measured, using IFN-γ ELIspot assays in the 21 patients 
who had adequate numbers of specimens. Robust increases in FRα specific T cell immune 
responses were detected in all evaluable patients. All 5 of the constituent peptides were 
found to be immunogenic and all patients appeared to have developed immune responses to 
at least 2 and, in the majority, more than 3 of the vaccine peptides. Vaccination with peptide 
also led to generation of T cells that recognize naturally processed antigen from the FRα 
protein. Clinical efficacy could not be evaluated, since all patients were in clinical remission. 
T-regs were not measurably reduced. 
While many attempts to target FRα in OC have not yielded benefits, the validity of FRα as a 
therapeutic target for OC has been bolstered by the impressive clinical activity of 
mirvetuximab soravtansine (IMGN853), in recurrent OC in a phase 1 trial reported at ASCO 
2015. IMGN853 is an antibody-mytansoid conjugate, which is FRα-specific (Ab 2015; Moore 
2015). Levels of FRα measured by immunohistochemistry correlated with response. 
Although FRα can be detected in small amounts in healthy adult lung and kidney, pulmonary 
toxicities were rare and renal toxicity was not observed. 
 
 
Furthermore no significant pulmonary or renal toxicity was encountered in studies using 
farletuzumab (Konner 2010), an anti-FRα MAb, shown to induce ADCC in preclinical models, 
despite radiolabeling studies confirming tumor-targeting (Smith-Jones 2008); nor was such 
toxicity seen in clinical trials with vintafolide, a folate-vinca conjugate, also demonstrated to 
home to tumors by radio-imaging SPECT studies (Naumann 2013). 
Hypothesis 
 
In clinical trials, peptide vaccines have demonstrated measurable immunogenicity in OC 
patients vaccinated against the FRα as well as other TAA's. Vaccines alone however have  
yet to demonstrate compelling evidence of clinical efficacy (Tse 2014). For this study, we 
hypothesize that the therapeutic potential of anti-cancer vaccines is hindered by immune 
checkpoints in the suppressive tumor microenvironment, and furthermore that immune 
checkpoint inhibition may overcome these restraints. In the proposed study, patients with 
platinum resistant OC will be vaccinated with TPIV200 and given concurrent durvalumab. It is 
expected that these agents will be tolerable at full doses of each, given their mild, and non- 
overlapping toxicity profiles. Safety and efficacy will be evaluated. Immunologic assays will  
be utilized to characterize the specific cellular and humoral immune responses generated 

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Page 14 of 59 
 
 
 
 
against vaccinated peptides and other potential TAA's to evaluate for evidence of epitope 
spreading. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is an MSKCC investigator-initiated, single-center, non-randomized, open-label, phase 
2 study to evaluate the activity of TPIV200 + durvalumab in patients with recurrent or 
persistent platinum resistant OC. The safety and tolerability of this doublet will also be 
evaluated. 
 
Each cycle will be 28 days in duration. Patients will receive study treatment until disease 
progression, intolerable toxicity, elective withdrawal from the study, study completion, or 
study termination. 
 
Efficacy assessments will be performed every 3 cycles (or 12 weeks) from initiation of study 
treatment until disease progression is documented. 
 
Safety will be evaluated through the monitoring of all serious and non-serious AEs and 
irAE‟s, graded according to the current version of National Cancer Institute‟s Common 
Terminology Criteria for Adverse Events (CTCAE v. 4.03). A safety stopping rule will be used 
to terminate the study early if excess toxicity is encountered. 
 
 
4.3 
Intervention 
 
Eligible patients will undergo screening and baseline procedures per the Study Schedule. 
Study inclusion and exclusion criteria will be applied per section 6.0. Enrolled patients will 
receive durvalumab IV (intravenous Sec on Days 1 and 15) during Cycles 1-12 and 
TPIV200+GM-CSF ID (3 intradermal injections on Day 1) during Cycles 1-6. Each cycle will 
be 28 days in duration. Patients will receive study treatment until disease progression, 
intolerable toxicity, elective withdrawal from the study, study completion, or study termination. 
Efficacy assessments will be performed at the initiation of study treatment and then every 3 
cycles (or 12 weeks) until radiologic and/or clinical disease progression. Patients who 
discontinue treatment for reasons other than progression may continue efficacy assessments 
until progression is demonstrated. Patients who demonstrate radiologic progression by 
RECIST criteria may be considered for continued therapy (but not primary efficacy analysis)  
if they are deemed to be clinically benefiting, according to predetermined permitted criteria 
(section 12.4). Safety will be evaluated in this study through the monitoring of all serious and 
non-serious AEs and irAEs, graded according to the current version of the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTC v.4.03). 
The order of administration on Days 1 of Cycles 1-6 is durvalumab followed by TPIV200. 
Durvalumab (750mg) will be infused IV over 1 hour on Days 1 and 15 of Cycles 1-12. On 
Cycle 1 Day 1, TPIV200 should be administered as soon as possible after the 60 (+/-5) min 
post-infusion vital sign check. For subsequent doses, post-infusion vitals are not required 
(unless patient has experienced hypersensitivity to durvalumab), and TPIV200 should be 
administered as soon as possible after the end of durvalumab infusion. 

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Page 15 of 59 
 
 
 
 
TPIV200 (500µg per peptide) will be admixed with 125µg granulocyte-macrophage colony 
stimulating factor (GM-CSF) [adjuvant] and injected ID on Day 1 of Cycles 1-6. The 
peptide/GM-CSF mixture will be injected at 3 sites ID, preferably on the forearm. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 
FRα peptide vaccine with adjuvant (GM-CSF) 
 
5.1.1 
FRα peptide vaccine 
 
Background: The tumor antigen targeted by the vaccine is folate receptor alpha 
(FRα), a high affinity folate-binding protein that is overexpressed on 70-90% of 
ovarian tumors. The vaccine contains five peptides: FR30, FR56, FR76, FR113, and 
FR238 [Investigator Brochure, TapImmune, Inc.]. 
Formulation: The vaccine including the 5 peptides formulated together will be 
provided as a single lyophilized glass vial.  Each vial will contain 0.550 mg of each of 
the 5 peptides for a total of 2.75 mg.  The peptide and formulation are GMP quality. 
Storage: Vaccine vials should be stored at -20ºC at controlled temperature. 
 
Refer to the FRα vaccine (TapImmune, Inc.) investigator brochure for detailed 
information about the vaccine. 
 
 
5.1.2 
Sargramostim (Leukine®, GM-CSF) 
 
Background: Sargramostim stimulates proliferation, differentiation and functional 
activity of neutrophils, eosinophils, monocytes, and macrophages. 
Formulation: Commercially available 
 
Injection, powder for reconstitution: 250 µg [contains mannitol 40 mg/mL and sucrose 
10 mg/mL] 
 
Liquid injection: 500 µg/mL [contains mannitol, tromethamine, benzyl alcohol] 
 
Preparation, storage, and stability: Store intact vials under refrigeration at 2ºC to 
8ºC (36ºF to 46ºF), do not freeze. Do not shake. Sargramostim powder for injection 
may be reconstituted with 0.5mL preservative free Sterile Water for Injection (SWFI) 
or bacteriostatic water for injection (with benzyl alcohol 0.9%) for a final concentration 
of 500 µg /mL. Preparations made with SWFI should be administered as soon as 
possible, and discarded within 6 hours of reconstitution. Preparations made with 
bacteriostatic water may be stored for up to 20 days at 2ºC to 8ºC. Gently swirl to 
reconstitute; do not shake. 
Refer to the manufacturer‟s labeling information for Leukine®. 
 
5.1.3 
Preparation of vaccine for ID injections: 

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IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 16 of 59 
 
 
 
 
The ID syringes for injection of the FRα peptide vaccine with adjuvant (GM-CSF) will 
be prepared prior to each injection by a site pharmacist according to the instructions 
below (preparation). The pharmacist will then have the syringes delivered to bedside 
for injection as soon as practical but no more than 6 hours after preparation. 
Preparation of the FRα peptide vaccine with adjuvant (GM-CSF) 
 
Thaw peptide vials in the refrigerator or at room temperature for 1 to 2 hours.  Bring 
vaccine to room temperature, before preparing the dose.  When reconstituting, mix 
the solution in the vial by gentle swirling; do not shake. 
Do not refreeze vaccine peptides after thawing 
 
• 
Remove a vial of GM-CSF from the refrigerator and allow to reach 
room temperature. 
• 
Add 0.5 mL of water for injection to reconstitute lyophilized GM-CSF to 
a concentration of 500 µg/mL.  If liquid product is used, there is no 
need to reconstitute; the concentration is 500 µg/mL. 
• 
Add 1.1 mL of water for injection to reconstitute lyophilized peptide 
vial. 
• 
Mix vial as needed to resolubilize the peptides. 
• 
Allow the vial to sit upright for a minute. 
• 
Withdraw 0.275 mL of GM-CSF and add to the peptide vial containing 
2.75 mg of peptide.  Swirl to mix. 
• 
Load THREE tuberculin syringes with ~0.41 mL of the peptide/GM- 
CSF mixture. 
Labeling and delivery of syringes 
 
Label each syringe with: 
• 
Patient ID 
• 
Time of preparation (HH:MM) 
Have the labeling confirmed by a second pharmacist 
Deliver the 3 syringes immediately for injection to the patient. 
 
 
5.2 
Durvalumab 
 
The Pharmaceutical Development  R & D Supply Chain Management section 
of  AstraZeneca/MedImmune will supply durvalumab (MEDI4736) to the investigator as a 
concentrate for solution for infusion. 
Formulation/packaging/storage 

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Page 17 of 59 
 
 
 
 
Durvalumab is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 m M trehalose 
dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. 
 
The investigational product is supplied as a vialed liquid solution in clear 10R glass vials 
closed with an elastomeric stopper and a flip-off cap overseal. Each vial contains 500 mg 
(nominal) of active investigational product at a concentration of 50 mg/mL (500 mg/vial). The 
solution will be diluted with 0.9% (w/v) saline for IV infusion. 
 
Unopened vials of liquid durvalumab must be stored at 2°C to 8°C (36°F to 46°F). 
Durvalumab must be used within the individually assigned expiry date on the label. 
In use storage and stability 
 
Total in-use storage time from needle puncture of durvalumab vial to start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2-8°C (36-46°F). If in-use 
storage time exceeds these limits, a new dose must be prepared from new vials. Infusion 
solutions must be allowed to equilibrate to room temperature prior to commencement of 
administration. Durvalumab does not contain preservatives and any unused portion must be 
discarded. 
 
 
Study drug preparation 
 
Calculate the dose volume of durvalumab and number of vials needed for the subject to 
achieve the accurate dose of 750mg. 
Preparation of infusion bags 
 
The preparation of infusion bags should be done under aseptic conditions by trained 
personnel; it should not be prepared on the ward. 
 
An additional volume of 0.9% (w/v) saline equal to the calculated volume of durvalumab to be 
added to the IV bag must be removed from the bag prior to addition of durvalumab. 
 
The calculated volume of durvalumab is then added to the IV bag, and the bag is mixed by 
gentle inversion to ensure homogeneity of the dose in the bag. 
Prior to the start of the infusion, ensure that the bag contents are at room temperature to 
avoid an infusion reaction due to the administration of the solution at low temperatures. 
Vials should be used for specific subjects and should not be shared between subjects. 
 
Patient weight at baseline should be used for dosing calculations in patients ≤30 kg unless 
there is a ≥10% change in weight. Dosing day weight can be used for dosing calculations 
instead of baseline weight per institutional standard. 
Dose administration 
 
Durvalumab will be administered at room temperature (approximately 25°C ) by controlled 
infusion via an infusion pump into a peripheral vein or central access device. 

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Page 18 of 59 
 
 
 
 
Following preparation of durvalumab, the entire contents  of the IV bag should be 
administered as an IV infusion over approximately 60 minutes (±5 minutes), using a 0.2-μm 
in-line filter.  Less than 55 minutes is considered a deviation. 
 
The IV line will be flushed with a volume of normal saline equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed. 
Since the compatibility of durvalumab with other IV medications and solutions, other than 
normal saline (0.9% [weight/volume] sodium chloride for injection) or dextrose, is not known, 
the durvalumab solution should not be infused through an IV line in which other solutions or 
medications are being administered. 
Monitoring of dose administration 
 
Subjects will be monitored during and after the infusion with assessment of vital signs at the 
times specified in the Schedule of Assessment (Section 8.0). 
 
In the event of a Grade ≤ 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50%, or interrupted until resolution of the event (up to 4 hours) and re-initiated 
at 50% of the initial rate until completion of the infusion. For subjects with a Grade ≤ 2 
infusion-related reaction, subsequent infusions may be administered at 50% of the initial 
rate.  Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent 
medications per institutional standard may be administered at the discretion of the 
investigator.  If the infusion-related reaction is Grade ≥ 3 or higher in severity, study drug will 
be discontinued. 
 
As with any antibody, allergic reactions to dose administration are possible.  Appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognize and treat anaphylaxis.  The 
study site must have immediate access to emergency resuscitation teams and equipment in 
addition to the ability to admit subjects to an intensive care unit if necessary. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
1. 
Subjects must have recurrent or persistent platinum-resistant epithelial ovarian, 
fallopian tube, or primary peritoneal carcinoma with measureable disease (as defined 
by RECIST 1.1.) who have received at least one prior platinum-based therapy. 
 
Platinum-based therapy is defined as treatment with carboplatin, cisplatin or another 
organoplatinum compound. 
 
Platinum-resistant is defined as having had disease progression within 6 months or 
most recent platinum therapy, or having disease progression while receiving previous 
platinum-based chemotherapy. 

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Page 19 of 59 
 
 
 
 
Histologic documentation of diagnosis of carcinoma is required and the following 
histologic subtypes are eligible: high grade serous, clear cell, endometrioid, 
carcinoma, adenocarcinoma, mixed (including above subtypes only). 
 
2. 
Age ≥ 18 years 
 
3. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
 
4. 
Resolution of (non-laboratory) adverse effects of recent surgery, radiotherapy, or 
chemotherapy to Grade ≤1 prior to first study treatment (with the exception of  
alopecia or neuropathy; chemotherapy-induced peripheral neuropathy up to Grade ≤2 
will be permitted). 
 
5. 
Patients must have measurable disease. Measurable disease is defined by RECIST 
(version 1.1). Measurable disease is defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded) and 
has not been previously irradiated. Each lesion must be ≥ 10 mm when measured by 
CT, MRI or caliper measurement by clinical exam; or ≥ 20 mm when measured by 
chest x-ray. Lymph nodes must be ≥ 15 mm in short axis when measured by CT or 
MRI. 
 
6. 
Adequate normal organ and marrow function defined by the following laboratory 
results obtained within 14 days prior to first treatment: 
 
▪ 
Absolute neutrophil count (ANC) ≥ 1.5 x 10
9/L (> 1500 per mm
3) 
▪ 
Platelet ≥ 100 x 109/L (>100,000 per mm3) 
▪ 
Hemoglobin ≥ 9.0 g/dL 
▪ 
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  (Unless 
Gilbert‟s Syndrome, without concurrent clinically significant liver disease) 
▪ 
AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver 
metastases are present, in which case it must be ≤ 5x ULN 
▪ 
Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft 
and Gault 1976) or by 24-hour urine collection for determination of creatinine 
clearance: 
 
Creatinine CL 
(mL/min) 
= W eight (kg) x (140 – Age) 
 
x 0.85 
72 x serum creatinine (mg/dL) 
 
7. 
Female subjects must either be of non-reproductive potential (ie, post-menopausal by 
history: ≥60 years old and no menses for ≥1 year without an alternative medical 
cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of 
bilateral oophorectomy) or must have a negative serum pregnancy test upon study 
entry. 
 
8. 
Subject is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including 
follow up. 
 
6.3 
Subject Exclusion Criteria 

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Page 20 of 59 
 
 
 
 
1. 
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site); Previous enrollment in the present study. 
 
2. 
Participation in another clinical study with receipt of an investigational product during 
the last 4 weeks 
3. 
Any previous treatment with a PD-1 or PD-L1 inhibitor, including durvalumab 
 
4. 
History of another primary malignancy except for: 
 
• 
Malignancy treated with curative intent and with no known active disease ≥3 
years before the first dose of study drug and of low potential risk for recurrence 
 
• 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease 
 
• 
Adequately treated carcinoma in situ without evidence of disease (eg, cervical 
cancer in situ) 
 
• 
Adequately treated stage 1 breast or stage 1 low grade endometrial cancer. 
 
5. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal 
antibodies, other investigational agent) < 21 days prior to the first dose of study drug. 
 
6. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using Fridericia‟s  Correction 
 
7. Current or prior use of immunosuppressive medication within 28 days before the first 
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or 
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of 
prednisone, or an equivalent corticosteroid. Steroid pre-medication for CT scan contrast 
or study drug, is allowable, regardless of dose. 
 
8. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous 
immunotherapy agent, or any unresolved irAE > Grade 1 
 
9. Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects 
with vitiligo, Grave‟s disease, or psoriasis not requiring systemic treatment (within the 
past 2 years) are not excluded. 
 
10. Active or prior documented inflammatory bowel disease (e.g., Crohn‟s disease, ulcerative 
colitis) 
 
11. History of primary immunodeficiency 
 
12. History of allogeneic organ transplant 
 
13. History of hypersensitivity to durvalumab or any excipient 

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Page 21 of 59 
 
 
 
 
 
14. History of hypersensitivity to TPIV200 
 
15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina 
pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding 
diatheses including any subject known to have evidence of acute or chronic hepatitis B, 
hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations 
that would limit compliance with study requirements or compromise the ability of the 
subject to give written informed consent 
 
16. Known history of previous clinical diagnosis of tuberculosis 
 
17. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days 
of receiving durvalumab 
 
18. Subjects who are pregnant, breast-feeding or of reproductive potential who are not 
employing an effective method of birth control 
 
19. Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results 
 
20. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive 
of but not limited to surgery, radiation and/or corticosteroids. 
 
21. Subjects with uncontrolled seizures. 
 
22. Known hypersensitivity reaction to the GM-CSF adjuvant 
 
23. Patients who have developed any evidence of clinical or radiologic pneumonitis, 
COP/BOOP, or other lung injury, during treatment with prior FRα-targeting therapy, such 
as mirvetuximab soravtansine (IMGN853), or with any prior cancer immunotherapy. 
7.0 
RECRUITMENT PLAN 
 
Potential research subjects will be identified by a member of the patient‟s treatment team, the 
protocol investigator or research team within the Gynecologic Medical Oncology Group at 
Memorial Sloan Kettering Cancer Center (MSKCC). Patient recruitment will occur in the 
Gynecologic Medical Oncology clinics at MSKCC. The investigator will discuss the study with 
suitable participants, and should the patient consent to proceed with protocol therapy, will 
enroll their patients in the research study. Approximately 2-4 patients will accrue onto this 
study per month. All participants will be women. 
 
8.1 
PRETREATMENT EVALUATION 
 
Within 28 days prio r to tre atme nt start: 
• Written informed consent/assignment of  subject identification number 
• History and Physical examination with Adverse event/serious adverse event assessment 
• Review of concomitant medications 
• Vital signs (blood pressure, heart rate and temperature), weight and height 
• Performance status 

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• Toxicity assessment 
• Radiographic tumor measurements (CT C/A/P, MRI, Chest X-ray) 
• Request archival tumor (10-20 PPFE slides or tissue block). 
 
Within 14 days prior to treatment start: 
• Complete Blood Count (CBC) with differential and platelets 
• Comprehensive profile (BUN, creatinine (or creatinine clearance), sodium, potassium, 
chloride, CO2, calcium, total bilirubin, total protein, albumin, alkaline phosphatase, AST, 
ALT) 
• 
Thyroid function tests (TSH and fT3 and fT4) g 
• Coagulation tests: prothrombin time, APTT and INR (PT/PTT) 
• Magnesium 
• LDH 
• Amylase 
• Lipase 
• Uric Acid 
•  CA125 
• Gamma GTP 
• Body weight 
• Urinalysis 
• Pregnancy test (in women of child bearing potential) 
• 12 lead ECG (in triplicate) 
• Research bloods 
 
Single tracing ECGs should be taken within an hour prior to the start of the infusion and at least 
one time point 0 to 3 hours after the  infusion for Cycle 1 Day 1  and Cycle 5 Day 1. The 
screening ECG may be used in place of pre-infusion Cycle 1 Day 1 ECG, if it was performed 
within 14 days prior. 
 
ECGs recorded during the screening period will be obtained in triplicate (with 2-5 minute lag time 
between each); ECGs recorded during the treatment phase will be single tracing. All 12-lead 
ECGs should be recorded while the subject is in the supine position. A 12-lead ECG will be 
recorded for all subjects on study days noted in Section 10.0. The same method of assessment 
should be used throughout the study. Twelve-lead ECGs will be obtained after the subject has 
been resting in a supine position for at least 5 minutes in each case. On Cycle 5 Day 1, ECGs 
will be recorded within an hour prior to start of infusion and at least one time point 0 to 3 hours 
after the infusion. 
 
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured on 
study days noted in the Schedule of Assessments. On durvalumab treatment days, vital signs 
will be measured within an hour prior to start of durvalumab administration, at 30 minutes during 
the infusion (± 5 minutes), at the end of infusion (+ 5 minutes), and at 30 minutes (± 5 minutes) 
and 60 minutes (± 5 minutes) post-infusion. If the infusion takes longer than 60 minutes, then 
blood pressure and pulse measurements should follow the principles described here, or more 
frequently if clinically indicated. For subsequent doses (at dose levels of 10 mg/kg or less), the 
1-hour observation period will not be required unless a subject experiences an infusion-related 
reaction. 

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Page 23 of 59 
 
 
 
 
The following clinical laboratory tests will be performed (see the Schedule of Assessments, 
Section 10.0 for the time points of each test): 
 
• 
Coagulation parameters: Activated partial thromboplastin time and International normalized 
ratio (INR) to be assessed at baseline and as clinically indicated 
 
• 
Pregnancy test (female subjects of childbearing potential only) 
 
o Urine human chorionic gonadotropin 
 
o Serum beta-human chorionic gonadotropin (at screening only) 
 
• 
Thyroid Stimulating Hormone 
 
o free T3 and free T4 only if TSH is abnormal 
 
• 
Other laboratory tests 
 
o Hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody 
 
o HIV antibody 
 
 
Table 1. Hematology Laboratory Tests 
Basophils 
Mean corpuscular volume 
Eosinophils 
Monocytes 
Hematocrit 
Neutrophils 
Hemoglobin 
Platelet count 
Lymphocytes 
Red blood cell count 
Mean corpuscular hemoglobin 
Total white cell count 
Mean corpuscular hemoglobin 
concentration 
 
 
 
 
 
Table 2. Clinical chemistry (Serum or Plasma) Laboratory Tests 
Albumin 
Glucose 
Alkaline phosphatase 
Lactate  dehydrogenase 
Alanine  aminotransferase 
Lipase 
Amylase 
Magnesium 
Aspartate  aminotransferase 
Potassium 
Bicarbonate 
Sodium 

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Table 2. Clinical chemistry (Serum or Plasma) Laboratory Tests 
 
 
 
 
 
 
 
 
 
a    If Total bilirubin is ≥2xULN (and no evidence of Gilbert‟s syndrome) then fractionate into direct and indirect 
bilirubin 
b At baseline and as clinically indicated 
 
 
 
 
 
 
 
 
 
 
 
a   Microscopy should be used as appropriate to investigate white blood cells and use the high power field for 
red blood cells 
9.0 
TREATMENT/INTERVENTION PLAN 
 
Forty patients may be treated. An initial safety lead-in (described in detail under Safety 
Analysis in Section 14.0) will require that at least 4 patients are observed for at least 4 
weeks. The first 3 patients must be staggered by 3 weeks. No more than 3 patients will be 
enrolled during each 3 week period thereafter. 
 
All subjects will receive TPIV200+GM-CSF and durvalumab. Each cycle will be 28 days in 
duration. The order of administration on Days 1 of Cycles 1-6 is durvalumab followed by 
TPIV200.  Patients will receive study treatment until disease progression, intolerable toxicity, 
elective withdrawal from the study, study completion, or study termination . 
 
Durvalumab (750mg) will be infused intravenously (IV) over 1 hour on Days 1 and 15 of 
Cycles 1-12. 
 
TPIV200 (500µg per peptide) will be admixed with 125µg Granulocyte-macrophage colony 
stimulating factor (GM-CSF) and injected intradermally (ID) on Day 1 of Cycles 1-6. The 
peptide/GM-CSF mixture will be injected into at least 3 sites ID, preferably on the forearm. 
For patients with a history of breast cancer who have not had lymph node dissections on one 
side, the forearm on the side without node dissections will be used unless the patient prefers 
to use the upper outer leg. For patients with prior bilateral lymph node dissection, a site on 
the outer upper leg should be used. 
Albumin 
Glucose 
Calcium 
Total bilirubina 
Chloride 
Total protein 
Creatinine 
Urea or blood urea nitrogen, depending on local practice 
Gamma glutamyl transferaseb 
Uric acid 
Table 3. Urinalysis Testsa 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Colour and appearance 

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Page 25 of 59 
 
 
 
 
Efficacy assessments will be performed every 3 cycles from initiation of study treatment until 
disease progression. Patients who discontinue treatment for reasons other than progression 
may continue efficacy assessments until progression. 
 
Safety will be evaluated in this study through the monitoring of all serious and non-serious 
AEs and irAEs, graded according to the current version of the National Cancer Institute 
Common Terminology Criteria for Adverse Events. A stopping rule will be applied to halt the 
study if excess toxicity is encountered. 
Pre- and post-treatment blood and serum samples, as well as archival tumor tissue (when 
available) will be collected for biomarker analysis (as per Appendix D). 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
All assessments to be performed pre-infusion unless stated otherwise. A Cycle is 28 Days. 
 
Parameter 
Screening 
Cycle 1 
Cycles 2-6 
Cycles 7-12 
End of 
Treatment 
Follow-up 
Day 
28 days 
beforea 
14 days 
before 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 1 
Day 15 
Consent 
x 
Medical 
History 
x 
Concomitant 
Medications 
x 
x 
x 
x 
x 
x 
x 
x 
Request 
Archival 
tumor tissue 
x 
Physical 
Examination 
x 
x 
x 
x 
ECOG 
x 
Weight 
x 
x 
x 
x 
Vital Signs 
(BP, HR, and 
temperature), 
height 
x 
x 
x 
x 
x 
x 
x 
Adverse 
Event 
Assessment 
x 
x 
x 
x 
x 
x 
x 
x 
CBC 
x 
x 
x 
x 
x 
Comp 
x 
x 
X 
x 
X 
x 
x 
TSH 
x 
x 
X 
x 
X 
x 
x 
Free T3 & 
Free T4b 
x 
x 
X 
x 
X 
x 
PT/PTT 
x 
As clinically indicated 
CA-125 
x 
Every 6 weeks for the first 
6 cycles 
As clinically 
indicated 
GGT 
x 
x 
As clinically indicated 
Amylase, 
LDH, Lipase, 
Uric Acid, 
Magnesium 
x 
x 
x 
x 
x 
x 
x 
HIV G 
x 
Hepatitis H 
x 
Urinalysis 
x 
x 
x 

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Page 26 of 59 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a  If screening laboratory assessments are performed w ithin 3 days prior to Day 1 they do not need to be repeated at Cycle 1 
Day 1. A +/- 3 Day window is allowed for all scheduled treatments and associated parameters, unless otherw ise specified. 
b  Draw free T3 and free T4 only if TSH is abnormal, beginning no later than f irst subsequent draw . May discontinue if TSH 
normal on 2 consecutive blood draws. 
c   Research bloods will consist of 4 CPT tubes, and w ill be drawn at 4 time points. The baseline draw  may be on Cycle 1 Day 1, or up to 
14 days prior. The on-treatment research bloods may be draw n on Cycle 1 Day 15, Cycle 2 Day 15, and Cycle 3 Day 1 (C1D15, 
C2D15, and C3D1), or up to 7 days prior. For all of these blood draws, the tubes must be transported to the Immunotherapy Core Lab 
at ZRC (Zuckerman Research Center) by 5 PM on the same day. 
d ECGs should be taken within an hour prior to the start of the infusion and at least one time point 0 to 3 hours after the infusion. For 
Cycle 1 Day 1, the screening ECG may be used in place of pre-infusion ECG, if it w as performed w ithin 14 days prior. ECGs recorded 
during the screening period will be obtained in triplicate (with 2-5 minute lag time betw een each); ECGs recorded during the treatment 
phase will be single tracing. 
e  Radiographic disease assessment have a +/- 7 day window . Patients who are off study and have not progressed/withdraw n consent 
w ill have scans done every 12 weeks until POD 
f    A follow-up call or visit will be done 90 days (+/- 2 weeks) after the last treatment. 
G  If unknow n 
H Hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
The dose delay instructions provided in this section are intended to serve as guidelines to 
allow ongoing treatment for patients experiencing clinical benefit without signs or symptoms 
of progression while ensuring patient safety. Patients may temporarily suspend dosing of 
study drug for up to 14 days if they experience toxicity that is considered related to study 
drug and requires that a dose be held. Patients who miss ≥ 28 consecutive days of 
scheduled study treatment because of drug-related AEs will be discontinued from the study. 
Exceptions may be made after discussion with and approval by the Principal Investigator. 
 
Patients may suspend dosing of study drug for radiation therapy or surgery that is considered 
by the treating physicians to be of clinical benefit for the patient. After completion of the 
intervention, patients may restart the study drug as long as all criteria for dosing are met and 
there is no evidence of disease progression (unless approved by PI and sponsor as noted 
previously). 
 
 
 
 
11.1 
Durvalumab 
 
For adverse events (AEs) that are considered at least partly due to administration of 
durvalumab the following dose adjustment guidance may be applied: 
Pregnancy 
Test 
x 
As clinically indicated 
Research 
bloods c 
X 
X 
X 
X 
X 
12- Lead 
ECG d 
X 
x 
Cycle 5 Day 1 
Durvalumab 
x 
x 
x 
x 
x 
x 
TPIV200 
x 
x 
Radiographic 
disease 
assessment e 
x 
Every 3 cycles (or 12 weeks) 
Every 12 
weeks 
Follow-up call 
or visit f 
x 

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Page 27 of 59 
 
 
 
 
• 
Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity where required). 
 
• 
If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of durvalumab along with appropriate continuing supportive care. 
If medically appropriate, dose modifications are permitted for durvalumab (see below). 
 
• 
All dose modifications should be documented with clear reasoning and documentation of the 
approach taken. 
 
• 
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued. 
• 
Following the first dose of durvalumab, subsequent administration of durvalumab can be 
modified based on toxicities observed (see APPENDIX A).  Dose reductions are not 
permitted. 
• 
Based on the mechanism of action of durvalumab leading to T-cell activation and 
proliferation, there is the possibility of observing immune related Adverse Events (irAEs) 
during the conduct of this study.  Potential irAEs include immune-mediated enterocolitis, 
dermatitis, hepatitis, and endocrinopathies. Subjects should be monitored for signs and 
symptoms of irAEs.  In the absence of an alternate etiology (e.g., infection or PD) signs or 
symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy should be considered to 
be immune-related. 
• 
Dose modification recommendations and toxicity management guidelines for immune- 
mediated reactions, for infusion-related reactions, and for non-immune-mediated reactions 
are detailed in Tables 1, 2, and 3, respectively. 
 
• 
In addition, management guidelines for adverse events of special interest (AESI‟s) are 
detailed in Section 11.4.1.3. All toxicities will be graded according to NCI CTCAE v4.03. 

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Page 28 of 59 
 
 
 
 
Contraception 
 
Females of childbearing potential who are sexually acti ve with a nonsterilised male partner 
must use 2 methods of effective contraception from screening, and must agree to continue 
using such precautions for 90 days after the final dose of investigational product, or for at 
least 90 days following the last infusion of durvalumab or until after 4-5X the half-life of 
durvalumab or until the time specified in the prescribing information of durvalumab, 
whichever occurs longest; cessation of birth control after this point should be discussed with 
a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of birth control. 
 
• Females of childbearing potential are defined as those who are not surgically steri le (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal (defined as 12 months with no menses without an alternative medical 
cause). 
 
• Subjects must use 2 acceptable methods of effecti ve contraception as described in 
Table 5. 
 
• Nonsterilised males who are sexually acti ve with a female partner of childbearing 
potential must use 2 acceptable methods of effecti ve contraception (see Table 5) from 
Day 1 and for 90 days after receipt of the final dose of investigational product. 
 
Effective methods of contraception (two methods must be used) 
 
 
Barrier Methods 
Intrauterine Device Methods 
Hormonal 
Methods 
 
 
Male condom plus spermicide 
Copper T 
Implants 
Cap plus spermicide 
Progesterone Ta 
Hormone shot or 
injection 
Diaphragm plus spermicide 
Levonorgestrel- releasing 
intrauterine system (e.g., Mirena®)a 
 
a 
This is also considered a hormonal method. 
Combined pill 
Minipill  
Patch 
 
 
 
Permitted concomitant medications 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except for 
those medications identified as “excluded” as listed below. 

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Excluded Concomitant Medications 
 
The following medications are considered exclusionary during the study. 
 
1. Any investigational anticancer therapy other than the protocol specified therapies 
 
2. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment, other than the 
protocol specified therapies. Concurrent use of hormones for noncancer-related 
conditions (e.g., insulin for diabetes 
and hormone replacement therapy) is 
acceptable. NOTE: Local treatment of isolated lesions for palliative intent is 
acceptable (e.g., by local surgery or radiotherapy) 
 
3. Immunosuppressive medications includi ng, but not limited to systemic corticosteroids 
at doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, 
azathioprine, and TNF-α blockers. Use of immunosuppressive medications for the 
management of investigational product-related AEs or in subjects with contrast 
allergies is acceptable. In addition, use of inhaled and intranasal corticosteroids is 
permitted. A temporary period of steroids will be allowed for different indications, at 
the discretion of the principal investigator (e.g., chronic obstructi ve pulmonary 
disease, radiation, nausea, etc). 
 
4. Live attenuated vaccines within 30 days of durvalumab dosing (ie, 30 days prior to 
the first dose, during treatment with durvalumab and for 30 days post discontinuation 
of durvalumab. Inacti vated vacci nes, such as the injectable influenza vaccine, are 
permitted. 
 
 
 
Table 4. Prohibited and Rescue Medications 
Rescue/supportive  medication/class  of 
drug: 
Usage: 
Concomitant 
medications or treatments 
(eg, acetaminophen or diphenhydramine) 
deemed necessary by the Investigator to 
provide 
adequate 
prophylactic 
or 
supportive 
care, 
except 
for 
those 
medications identified as “prohibited” as 
listed above 
To   be administered   as prescribed   by the 
Investigator 
Best supportive care (including antibiotics, 
nutritional support, growth factor support, 
correction of metabolic disorders, optimal 
symptom control, and pain management 
[including palliative radiotherapy, etc]) 
Should be used when necessary for all patients 

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Page 30 of 59 
 
 
 
 
 
 
 
11.2 
TPIV200+GM-CSF 
 
Deviations from schedule: Deviations are permitted with the following windows: 3 day  
forward or backward during vaccinations 1-6. If a deviation is allowed, the patient should plan 
to return to the original vaccination schedule with the next visit. 
 
Dose reduction or delay is not permitted. Patient will be followed if study treatment is 
discontinued for toxicity. Study treatment should be discontinued for unacceptable toxicity, 
defined by: 
• 
Grade 3 allergic reaction, or higher with the exception of fever. (Grade 2 allergic reaction 
is defined as rash, flushing, urticaria, or dyspnea; Grade 3 allergic reaction is defined as 
symptomatic bronchospasm, requiring parenteral medication, with or without urticaria, 
allergy related edema or angioedema; Grade 4 allergic reaction is defined as 
anaphylaxis.) 
 
• 
Grade 2 or higher autoimmune reaction (Grade 2 is defined as evidence of autoimmune 
reaction involving a non-essential organ or function (e.g. hypothyroidism) requiring 
treatment other than immunosuppressive drugs. Grade 3 is a reversible autoimmune 
reaction involving a major organ (e.g. colitis) 
 
• 
≥ Grade 3 hematologic or non-hematologic toxicity including fever. (Grade 3 fever is > 
40ºC for < 24 hours). 
 
• 
Grade 3 injection site reaction. (Grade 3 is defined as ulceration or necrosis that is 
severe or prolonged, or requiring surgery). 
 
11.3 
General 
 
The toxicity profiles of the different investigational agents are generally non-overlapping. 
Emergence of novel toxicities resulting from the combination is not expected, but patients will 
be carefully monitored for unexpected events. 
 
 
 
It is expected that patients with nausea, emesis, diarrhea, or constipation will receive 
appropriate medical management without dose modification. However, patients with 
persistent (≥ 24 hours) Grade ≥3 toxicity in spite of optimal medical management require 
delay in subsequent therapy for a maximum of 2 weeks until recovered to Grade 1. Dose 
delay for durvalumab will follow the toxicity management algorithm Tables found in Appendix 
A. 
 
Other non-hematologic toxicities with an impact on organ function of Grade ≥2 require delay 
in subsequent therapy for a maximum of 28 days until recovered to Grade 1, or pre-therapy 
baseline. 
Hematopoietic Growth Factors and Blood Products 

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Erythropoietin, darbepoetin alfa, romiplostim and/or hematopoietic colony-stimulating factors 
for treatment of cytopenias should be administered according to institutional guidelines. 
Transfusion thresholds for blood product support will be in accordance with institutional 
guidelines. 
11.4 
Assessment of Safety 
 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
Safety Parameters 
 
11.4.1 Definition of adverse events 
 
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice 
(GCP) E6(R1) defines an AE as: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
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 
medicinal product, whether or not considered related to the medicinal product. 
 
An AE includes but is not limited to any clinically significant worsening of a subject‟s 
pre-existing condition. An abnormal laboratory finding (including ECG finding) that requires 
an action or intervention by the investigator, or a finding judged by the investigator to 
represent a change beyond the range of normal physiologic fluctuation, should be reported 
as an AE. 
 
Adverse events may be treatment emergent (ie, occurring after initial receipt of  
investigational product) or nontreatment emergent. A nontreatment-emergent AE is any new 
sign or symptom, disease, or other untoward medical event that begins after written informed 
consent has been obtained but before the subject has received investigational product. 
 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition, that did  
not worsen from baseline, is not considered an AE (serious or nonserious). An untoward 
medical event occurring during the prescheduled elective procedure or routinely scheduled 
treatment should be recorded as an AE or SAE. 
 
The term AE is used to include both serious and non-serious AE‟s. 
 
11.4.2 Definition of Serious Adverse Events (SAE’s) 
 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, 
treatment, wash-out, follow-up), at any dose of the study drugs that fulfils one or more of the 
following criteria: 
 
• 
Results in death 
• 
Is immediately life-threatening 

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• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital abnormality or birth defect in offspring of the subject 
• 
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
Medical or scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in this situation. Examples of medically important events are intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalizations; or development of drug dependency or drug 
abuse. 
 
The causality of SAE‟s (their relationship to all study treatment/procedures) will be assessed 
by the investigator(s) and communicated to the FDA and  AstraZeneca in parallel. 
11.4.3 Definition of Adverse Events of Special Interest 
 
An adverse event of special interest (AESI) is one of scientific and medical interest specific 
to understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. 
The rapid reporting of AESIs allows ongoing surveillance of these e vents in order to 
characterize and understand them in association with the use of this investigational product. 
 
AESIs for durvalumab include but are not limited to events with a potential inflammatory or immune- 
mediated mechanism and which may require more frequent monitoring and/or interventions such as 
steroids, immunosuppressants and/or hormone replacement therapy. These AESIs are being closely 
monitored in clinical studies with durvalumab monotherapy and combination therapy. An immune- 
related adverse event (irAE) is defined as an adverse event that is associated with drug exposure 
and is consistent with an immune-mediated mechanism of action and where there  is  no  clear 
alternate etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, 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 irAE. 
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Physician. 
AESIs observed with durvalumab include: 
• 
Colitis 
• 
Pneumonitis 
• 
ALT/AST increases / hepatitis / hepatotoxicity 
• 
Neuropathy  /  neuromuscular  toxicity  (i.e.  events  of  encephalitis,  peripheral  motor  and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
• 
Endocrinopathy   (i.e.   events of   hypophysitis,   adrenal insufficiency,   and   hyper-   and 
hypothyroidism) 
• 
Dermatitis 

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• 
Nephritis 
• 
Pancreatitis   (or labs suggestive of pancreatitis  - increased serum lipase, increased serum 
amylase) 
Further information on these risks (e.g. presenting symptoms) can be found in the current version of 
the durvalumab Investigator Brochure. 
Pneumonitis 
 
Adverse events of pneumonitis are of interest for AstraZeneca/Medimmune, as pneumonitis 
has been reported with anti-PD-1 MAbs (Topalian et al, NEJM 2012). Initial work-up should 
include high-resolution CT scan, ruling out infection, and pulse oximetry. Pulmonary 
consultation is highly recommended. 
 
Guidelines for the management of subjects with immune-mediated events including 
pneumonitis are outlined in Section 6.6.1. 
11.4.4 Hypersensitivity Reactions 
 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti- 
PD-L1 and anti-PD-1 therapy (Brahmer et al 2012). As with the administration of any foreign 
protein and/or other biologic agents, reactions following the infusion of MAbs can be caused 
by various mechanisms, including acute anaphylactic (immunoglobulin E-mediated) and 
anaphylactoid reactions against the MAb, and serum sickness. Acute allergic reactions may 
occur, may be severe, and may result in death. Acute allergic reactions may include 
hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, 
hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, 
hypertension, myalgia, vomiting and unresponsiveness. 
 
Guidelines for management of subjects with hypersensitivity (including anaphylactic reaction) 
and infusion-related reactions are outlined in Appendix A. 
11.4.5 Hepatic function abnormalities (hepatotoxicity) 
 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-1 
antibodies (Brahmer et al 2012).  Inflammatory hepatitis has been reported in 3% to 9% of 
subjects treated with anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab).  The clinical 
manifestations of ipilimumab-treated subjects included general weakness, fatigue, nausea 
and/or mild fever and increased liver function tests such as AST, ALT, alkaline phosphatase, 
and/or total bilirubin. 
 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 
3 × ULN and concurrent increase in total bilirubin to be greater than 2 × ULN. Concurrent 
findings are those that derive from a single blood draw or from separate blood draws taken 
within 8 days of each other. Follow-up investigations and inquiries will be initiated promptly 
by the investigational site to determine whether the findings are reproducible and/or whether 
there is objective evidence that clearly supports causation by a disease (e.g., cholelithiasis 
and bile duct obstruction with distended gallbladder) or an agent other than the 

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investigational product. Guidelines for management of subjects with hepatic function 
abnormality are outlined in Appendix A. 
Cases where a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2x ULN may need 
to be reported as SAE‟s, These cases should be reported as SAEs if, after evaluation they 
meet the criteria for a Hy‟s Law case or if any of the individual liver test parameters fulfill any 
of the SAE criteria. 
Gastrointestinal disorders 
Diarrhea/colitis 
is 
the most commonly observed 
treatment emergent SAE when 
tremelimumab is used as monotherapy. In rare cases, colon perforation may occur that 
requires surgery (colectomy) or can lead to a fatal outcome if not properly managed. 
Guidelines on management of diarrhea and colitis in patients receiving durvalumab are 
provided in Appendix A. 
Endocrine disorders 
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- 
and hypothyroidism. Guidelines for the management of patients with immune-mediated 
endocrine events are provided in Appendix A. 
Pancreatic disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase 
elevation. Guidelines for the management of patients with immune-mediated pancreatic 
disorders are provided in Appendix A. 
Neurotoxicity 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis. Guidelines for the management of 
patients with immune-mediated neurotoxic events are provided in Appendix A. 
Nephritis 
Consult with Nephrologist.   Monitor for signs and symptoms that may be related to changes 
in renal function (e.g. routine urinalysis, elevated serum BUN and creatinine, decreased 
creatinine clearance, electrolyte imbalance, decrease in urine output, proteinuria, etc) 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, infections etc.) 
Steroids should be considered in the absence of clear alternative etiology even for low grade 
events (Grade 2), in order to prevent potential progression to higher grade event. 
Guidelines for the management of patients with immune-mediated neurotoxic events are 
provided in Appendix A. 
11.4.6 Criteria for Hy’s Law (FDA Guidance 2009) 
 
• 
The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug 
or placebo 

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• 
Among trial subjects showing such aminotransferase elevations, often with 
aminotransferases much greater than 3 x ULN, one or more also show elevation of 
serum total bilirubin to >2 x ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
 
• 
No other reason can be found to explain the combination of increased aminotransferases 
and total bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or 
another drug capable of causing the observed injury. 
12.1 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Antitumor Effect 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [22]. Changes in the largest diameter (unidimensional measurement) of the 
tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in 
the RECIST criteria. 
12.1 
Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment on study. 
 
Evaluable for objective response. Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
reevaluated will be considered evaluable for response. These patients will have their 
response classified according to the definitions stated below. (Note: Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Tar get Disease Response. Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least 
one cycle of therapy, and have had their disease reevaluated will be considered evaluable  
for non-target disease. The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 
12.2 
Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest x- 
ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area will not be considered 
measurable unless progression is documented or a biopsy is obtained to confirm 
persistence at least 90 days following completion of radiation therapy. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 

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recommended to be no greater than 5 mm). At baseline and in follow-up, only  the short axis 
will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic 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 non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
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.  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. 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. If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum. The baseline sum diameters will be used as reference to  further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
 
12.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment 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 followup. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 

Memorial Sloan Kettering Cancer Center 
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Conventional CT and MR I: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If 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), but NOT 
lung. 
 
CA125: CA125 alone cannot be used to assess response. If CA125 is initially above the 
upper normal limit, it must normalize for a patient to be considered in complete clinical 
response. 
 
12.4 
Response Criteria 
Evaluation of Target Lesions 
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 the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the 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 progressions). 
 
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. 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note: If CA125 is initially above the upper normal limit, it must normalize for a patient to be 
considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
CA125 level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or Principal Investigator). 
Evaluation of Best Overall Response 

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Page 38 of 59 
 
 
 
 
The best overall response is the best response recorded from the start of the treatment  until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response 
assignment will depend on the achievement of both measurement and confirmation  criteria. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non- 
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions 
may be 
accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objecti ve evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document the 
objective progression even after disconti nuation of treatment. 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 

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Page 39 of 59 
 
 
 
 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequi vocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* „Non-CR/non-PD‟ is preferred over „stable disease‟ for non-target disease since 
SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised 
 
 
 
 
Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). The 
duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
Progression-Free Survival 
 
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to 
time of recurrence, progression, or death, whichever occurs first. 
Survival 
 
Survival is defined as the duration of time from start of treatment to time of death or the date 
of last contact 
Permitted Deviations from RECIST 
 
The study's efficacy objecti ves will be evaluated according to the standard, 
unmodified REC IST v1.1 criteria described in section 12.3, and that, within the 
context of this protocol, the only purpose of the modifications to the criteria is to allow 
certain patients to conti nue the study treatment despite meeting REC IST criteria for 
progression of disease. 
 
The response to immunotherapy may differ from the typical responses observed with 
cytotoxic chemotherapy including the following (Wolchok et al 2009, Nishino et al 2013): 
 
• 
Response to immunotherapy may be delayed 

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• 
Response to immunotherapy may occur after POD by conventional criteria 
• 
The appearance of new lesions may not represent POD with immunotherapy 
• 
SD while on immunotherapy may be durable and represent clinical benefit. 
 
 
As long as they are receiving treatment on protocol, patients will be permitted to continue 
study treatment after RECIST v 1.1 criteria for POD are met if they meet all of the following 
criteria: 
 
• 
Absence of symptoms and signs indicating unequivocal progression of disease 
• 
No decline in ECOG performance status 
• 
Absence of tumor growth at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions 
 
• 
Patients for whom approved therapies exist must provide written consent to acknowledge 
deferring these treatment options in favor of continuing study treatment at the time of 
initial apparent progression 
 
Patients in whom radiographic disease progression is confirmed at the subsequent tumor 
assessment may be considered for continued study treatment at the discretion of the 
investigator if they continue to meet the criteria above and have evidence of clinical benefit. 
 
Modification of RECIST as described may discourage the early discontinuation of  
durvalumab + TPIV200 and provide a more complete evaluation of its anti-tumor activity than 
would be seen with conventional response criteria.  Nonetheless, the efficacy analysis will be 
conducted by programmatically deriving each efficacy endpoint based on RECIST v 1.1 
criteria. 
Patients who have permanently discontinued study treatment must discontinue study 
participation if they experience disease progression per RECIST v 1.1. 
 
The primary reason for study treatment discontinuation should be documented on the eCRF. 
 
Of note, clinically significant deterioration is considered to be a rapid tumor progression that 
necessitates treatment with anti-cancer therapy other than durvalumab + TPIV200 or with 
symptomatic progression that requires urgent medical intervention (e.g., central nervous 
system metastasis, respiratory failure due to tumor, spinal cord compression). 
 
irRECIST 
 
Immune-related RECIST (irRECIST) guidelines according to Bohnsack et al. (48) are 
presented below. 
 
I. 
Baseline Assessments in irRECIST 
 
In irRECIST, baseline assessment and measurement of measurable/non-measurable and 
target/non-target lesions and lymph nodes are in line with RECIST 1.1. 

Memorial Sloan Kettering Cancer Center 
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II 
Follow-up Assessments in irRECIST 
 
A. Follow-up recording of target and new measurable lesions 
A key difference in irRECIST is that the appearance new lesions does not 
automatically indicate progression.  Instead, all measured lesions (baseline-selected 
target lesions and new measurable lesions) are combined into the total measured 
tumor burden (TMTB) at follow up.  Baseline-selected target lesions and new 
measurable lesions are NOT assessed separately. Measurements of those lesions are 
combined into the TMTB, and one combined assessment provided. 
 
In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions total, 
per time point), new lesions must meet criteria as defined for baseline target lesion selection 
and meet the same minimum size requirements of 10 mm in long diameter and minimum 15 
mm in short axis for new measurable lymph nodes. New measurable lesions should be 
prioritized according to size, and the largest lesions elected as new measured lesions. 
 
B. Follow-up non-target assessment 
RECIST 1.1 definitions for assessment of non-target lesions apply.  The response of non- 
target lesions primarily contributes to the overall response assessments of irCR and irNon- 
CR/Non-PD (irNN). Non-target lesions do not affect irPR and irSD assessments. Only a 
massive and unequivocal worsening of non-target lesions alone, even without progress in the 
TMTB is indicative of irPD.  In alignment with RECIST 1.1, baseline selected non-target 
lesions can never convert to measurable lesions, not even if they increase in size at 
subsequent time points and become measurable. Only true new lesions can be measured 
and contribute to the TMTB. 
C. Follow-up for New Non-Measurable Lesions 
All new lesions not selected as new measurable lesions are considered new non-measurable 
lesions and are followed qualitatively. Only a massive and unequivocal progression of new 
non-measurable lesions leads to an overall assessment of irPD for the time point. Persisting 
new non-measurable lesions prevent irCR. 
III 
Overall Assessments for irRECIST 
 
The irRECIST overall tumor assessment is based on TMTB of measured target and 
new lesions, non-target lesion assessment and new non-measurable lesions. 
At baseline, the sum of the longest diameters (SumD) of all target lesions (up to 2 lesions per 
organ, up to total 5 lesions) is measured.  At each subsequent tumor assessment (TA), the 
SumD of the target lesions and of new, measurable lesions (up to 2 new lesions per organ, 
total 5 new lesions) are added together to provide the total measurable tumor burden (TMTB). 
 
Overall Asse ssments by irRECIST 
Complete 
Response (irCR) 
Complete disappearance of all measurable and non-measurable lesions. Lymph 
nodes must decrease to < 10 mm in short axis. 

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Partial Response 
(irPR) 
Decrease of ≥ 30% in TMTB relative to baseline, non-target lesions are irNN, 
and no unequivocal progression of new non-measurable lesions 
• 
If new measurable lesions appear in subjects with no ta rge t le sion s a t 
ba se line, irPD will be assessed. That irPD time point will be considered a 
new baseline, and all subsequent time points will be compared to i t for 
response assessment. irPR is possible if the TMTB of new measurable 
lesions decreases by ≥ 30% compared to the first irPD documentation 
• 
irRECIST can be used in the a djuva nt se tting, in subjects with no visible 
disease on CT/MRI scans. The appearance of new measurable lesion(s) 
automatically leads to an increase in TMTB by 100% and leads to irPD. 
These subjects can achieve a response i f the TMTB decreases at follow-up, 
as a sign of delayed response. 
• 
Based on the above, sponsors may consider enrolling subjects with no 
measurable disease and/or no visible disease in studies with response 
related endpoints. 
Stable Disease 
(irSD) 
Failure to meet criteria for irCR or irPR in the absence of irPD 
Progressive 
Disease (irPD) 
Minimum 20% increase and minimum 5 mm absolute increase in TMTB 
compared to nadir, or irPD for non-target or new non-measurable lesions. 
Confirmation of progression is recommended minimum 4 weeks after the first 
irPD assessment. An irPD confirmation scan may be recommended for subjects 
with a minimal TMTB %-increase over 20% and especially during the flare time- 
window of the first 12 weeks of treatment, depending on the compound efficacy 
expectations, to account for expected delayed response. 
• 
In irRECIST a substantial and unequivocal increase of non-ta rge t le sion s is 
indicative of progression. 
• 
IrPD may be assigned for a subject with multiple ne w non-me a sura ble 
le sion s if they are considered to be a sign of unequivocal massi ve 
worsening 
Other 
irNE: used in exceptional cases where insufficient data exist. 
irND: in adjuvant setting when no disease is detected 
irNN:, no target disease was identified at baseline, and at follow-up the subject 
fails to meet criteria for irCR or irPD 
 
 
12.5 Biomarker  Assessment 
 
The study will include analyses of archival tumor tissue and peripheral blood to define the 
biomarkers that could predict/correlate with response. Research bloods will be collected pre- 
treatment at 4 pre-specified time points: Day 1, Day 15 (C1D15), Day 43 (C2D15) , and Day 85 
(C3D1) with a window of -14 Days for the Day 1 Draw and -7 Days for every subsequent draw. Four 
CPT tubes will be collected at each time point. CPT tubes will be supplied to participating Regional 
and Alliance sites. Once the CPT tubes are drawn, the tubes will be couriered at room temperature 
to Immune Monitoring Core facility at ZRC (Zuckerman Research Center, 415 East 68th St., Room 
1513). If this is not feasible, patients may have the CPT draws performed at 53rd street or any other 
participating site within specified windows. 
 
12.5.1 Tissue FRα expression (TapImmune) 
 
Archival tissue slides will be shipped to the sponsor (Tap Immune) to assess the levels of FRa 
expression by IHC. 
 
12.5.2 Tissue PD-L1 expression (AstraZeneca/MEDImmune) 

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Archival tissue slides will be shipped to the sponsor (Astra Zeneca/MEDImmune) to assess the 
levels of PD-L1 expression in tumor cells and tumor-infiltrating immune cells. 
 
12.5.3 Tissue gene expression profiling and IHC (MSKCC, Zamarin, Wolchok lab) 
 
By using Nanostring nCounter PanCancer Immune Profiling Panel, and immunofluorescence 
microscopy, archival tumor tissue will be assessed for tumor infiltration with various immune cell 
subsets, including CD8 cells, CD4+ effector cells (FoxP3-), CD4+ regulatory T cells (FoxP3+), and 
myeloid cells (CD68+). Tumors will also be assessed for the expression of the known activating co- 
stimulatory receptors such as 4-1BB (CD137), OX40, GITR, CD40, and ICOS, as well as known 
immune inhibitory components such as PD-L1, indoleamine dioxygenase  (IDO),  B7-H3,  B7-H4, 
LAG3, TIM-3, PD-1, CTLA-4, VISTA, and BTLA. The expression of each gene will be treated as a 
continuous variable. For exploratory biomarker analyses, patients will be dichotomized on the basis 
of the primary efficacy endpoint. 
 
12.5.4 PBMC immunophenotyping (MSKCC: IMF) 
 
By using multi-parameter flow cytometry, we will explore whether peripheral blood biomarkers could 
serve as early predictors of clinical benefit and provide targets for further combinations, with a 
particular focus on targetable markers of T cell activation (ICOS, CD137, OX40, GITR),  and 
inhibition (LAG3, TIM3, PD-1, BTLA, VISTA), as well as percentages of peripheral inhibitory immune 
subsets such as MDSCs and Tregs. 
 
12.5.5 PBMC gene expression analyses 
 
RNA extracted from PBMCs collected at baseline and on-treatment will be analyzed on the 
Nanostring platform using Nanostring nCounter PanCancer Immune Profiling Panel, to define gene 
signatures associated with clinical benefit. 
 
12.5.6 PBMC vaccine-specific immune responses (MSKCC: IMF) 
 
Whole blood will be collected at baseline and at 4 and 8 weeks post-therapy initiation. CD8 and CD4 
cells will be analyzed for development of FRa-specific T cell responses by restimulation with FRa 
peptide and intracellular cytokine staining. 
 
12.5.7 PBMC T cell receptor (TCR) repertoire analyses (MSKCC: IMF, Zamarin, Wolchok lab) 
 
DNA isolated from PBMC‟s will be send for deep sequencing of TCR CDR regions at Adaptive 
Biotechnologies to determine whether maintenance or emergence of  particular  oligoclonal 
populations of T cells in the periphery is predictive of clinical benefit. 
 
12.5.8 Serologic assays (MSKCC, Fleisher, Thoren). 
 
Sera collected at baseline and at 4 and 8 weeks post-therapy will be analyzed for development of 
serologic responses to FRa. Using Surface Plasmon Resonance, these antibodies will be 
characterized for titers, isotype, and affinity to FRa, These measures will be correlated to clinical 
outcomes. 
 
12.5.9 Identify HLA class I-binding peptides from FRα that are recognized by patient lymphocytes 
prior to and after therapy. Assess which out of the 5 peptides correlates with the number of 
lymphocytes prior to and after therapy. 

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13.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
Patients may withdraw from the study at any time. Any patient who withdraws will be 
encouraged to return to the study center for a treatment completion visit. Patients who 
discontinue early should return within 30 days following the final dose of study treatment. The 
primary reason for discontinuation must be recorded in the medical record. 
 
Patients may be withdrawn from the study if they experience any of the following: 
 
• 
Disease progression, per investigator assessment 
• 
Intolerable toxicity of study drugs 
Other reasons for patient discontinuation may include, but are not limited to, the following: 
 
• 
Change in patient eligibility 
• 
Non-compliance 
• 
Patient decision 
• 
If the patient becomes pregnant 
• 
If treatment is delayed for more than 28 consecutive days 
The investigator has the right to discontinue a patient from the study for any medical 
condition that the investigator determines may jeopardize the patient‟s safety if he or she 
continues in the study; for reasons of noncompliance (e.g., missed doses, visits); or if the 
investigator determines it is in the best interest of the patient. 
 
 
14.1 
BIOSTATISTICS 
 
This study aims to assess the activity of durvalumab + TPIV200 in patients with recurrent or 
persistent ovarian or fallopian tube or primary peritoneal cancer. 
 
Prior monotherapy studies of immune checkpoint inhibitors in ovarian cancer have yielded 
overall response rates in the range of 10-15%, and may serve as a basis for historical 
comparison of the doublet tested here. 
 
Study 
N 
ORR (CR+PR) 
DCR (ORR+SD) 
Prior Therapy 
Nivolumab (anti-P D-1) 
1 mg/kg q 2 weeks (cohort 1) 
3 mg/kg q 2 weeks (cohort 2) 
10 
10 
15% (3/20): 
10% (1 PR) 
20% (2 CR) 
50% (5 SD +1 PR) 
40% (2 SD +2 CR) 
≥ 2 priors 
Platinum Resistant 
A velum ab (anti-P D-L1) 
Phase Ib expansion cohort 
10 mg/kg q 2 weeks 
75 
10.7% (8 PR) 
55% (33 SD +8 PR) 
med 4 priors(1-11) 
Platinum Resistant 
Pembrolizumab  (anti-PD-1) 
Phase Ib expansion cohort 
10 mg/kg q 2 weeks 
26 
11.5% (1 CR, 2 PR) 
35% (9 SD+1CR+2 PR) 
>80% > 4 priors 
PD-L1+ (IHC) 
 
 
ORR (defined as CR+PR) will be the primary endpoint. A 10% ORR will be considered low 
and 25% or higher will be considered promising for further studies. Forty patients provide 
90% power and Type I error of 10% using a Simon two stage design. There will be an interim 
analysis after 27 patients and if 3 or more responders (CR+PR) are observed out of 27 

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Page 45 of 59 
 
 
 
 
patients then the study will continue to the second stage. At the end of the study we require 7 
or more responders out of 40 patients to declare this study positive and the agent worthy for 
further investigation. 
 
Unacceptable response rate:  0.1 
Desirable response rate:  0.25 
Error rates: Type I =  0.1 ; Type II =  0.1 
 
# 
responses 
required in 
Stage I 
# patients 
accrued 
at stage I 
# 
responses 
required in 
Stage I 
Total 
sample 
size 
>=3 
27 
>=7 
40 
 
 
If the test for ORR is significant, then the PFS rate at 6 months will also be tested against the 
historical control estimate. For PFS rate at 6 months, we consider a 15% rate as low, and a 
rate of 35% or higher as indicative of promising activity. This test of PFS rate will be 
performed only if the ORR analysis is significant, and thus PFS assessment is  
supplementary to ORR assessment. At the end of the study, if 10 or more out of 40 patients 
are considered progression free at 6 months, then the combination will be considered worthy 
of further study. This study will have 94% power and 7% Type I error to show activity in terms 
of 6 months PFS rate. The overall Type I error of the study is bounded by the 10% error rate 
of the first hypothesis of ORR. The hierarchy in the two hypotheses for ORR and PFS 
ensures the overall error rate to be smaller than 10% (Bretz 2009) 
 
Based on historical accrual rates in similar populations, we anticipate successful enrollment 
of 3-4 patients per month yielding a total accrual time of 18 months. Accrual will continue 
until 40 (evaluable patients are defined in section 12.1), unless the interim analysis after 27 
patients does not support continuation. 
Efficacy Variables 
The intent of this protocol is to assess the vaccine-checkpoint inhibitor combination for 
activity in patients with recurrent platinum-resistant epithelial adnexal carcinomas. There are 
no treatment comparisons involved. For the purpose of this study „platinum resistance‟ will 
refer to patients who have exhibited progressive disease (clinical, radiologic, or serologic) 
within 6 months of completing a previous course of platinum therapy (primary, secondary, or 
other). 
 
The principal parameters employed to evaluate the efficacy of the combination are: 
• 
The rate of ORR and duration of overall objective response (ORR = CR + PR). 
• 
The frequency and severity of observed adverse effects. 
• 
Progression-free survival rate at 6 months for all patients evaluable for this endpoint. 
Patients who have have measurable disease  present at baseline, have received at least 
one cycle of therapy, and have had their disease reevaluated will be considered 
evaluable for response and PFS. The primary efficacy analysis will include only patients 
who are evaluable for response. Patients without post baseline assessment of response 
will be included in a sensitivity analysis as non responders for ORR, and events for PFS. 
For safety, all patients who received at least one cycle of therapy will be included. 
 
Definitions of Statistics to be Reported 

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• 
Disease Control Rate (DCR), defined as the percentage of patients with complete 
response (CR) + partial response (PR) + stable disease (SD) ≥12 weeks from the 
start of treatment will be reported and the 90% confidence interval will be estimated 
using exact binomial proportions. This will be done following RECIST criteria. 
• 
Progression free survival (PFS), defined as the duration of time from start of 
treatment to time of recurrence, progression, or death due to any cause, whichever 
occurs first. Patients will be censored at last follow up date. The Kaplan Meier 
estimate of median PFS will be reported as well as the PFS rate at 6 months 
• 
Overall survival (OS), defined as the duration of time from start of treatment until the 
date of death due to any cause. Patients will be censored at last follow up date. The 
Kaplan Meier estimate of median OS will be reported. 
• 
Duration of response (DOR), defined as the time from which measurement criteria are 
met for CR or PR (whichever status is recorded first using RECIST) until the first date 
of documented disease progression, will be estimated using the Kaplan Meier 
method. Patients without documented progression will be censored at last follow up. 
• 
The rate of response using immune response criteria (refer to irRECIST description in 
section 12.3, which defines responders and non responders) and the 90% confidence 
interval will be estimated using exact binomial proportions. 
• 
Adverse events by the current version of Common Terminology Criteria for Adverse 
Events version 4 (CTCAE v4.03) will be tabulated in order to assess the safety profile 
and tolerability therapy in treated patients. 
 
Safety Analysis 
 
A stopping rule will be incorporated into this single stage design in order to address safety. 
 
The rates of irAE, SAE, therapy completion rate, and protocol completion will also be 
reported. 
 
Safety will be measured by the frequency of grade 3 or 4 treatment-related clinically 
significant toxicities (NCI Common Terminology Criteria for Adverse Events version 3.0), 
aside from Grade 3 or 4 hematologic or laboratory abnormalities, unless they are deemed 
unexpected or clinically significant. We assume that a 20% rate of clinically significant 
treatment-related adverse event, such as persistent or unexpected renal injury or pulmonary 
toxicity, or clinically significant laboratory abnormality, is an unacceptable toxicity rate. The 
trial will be terminated at any point if at least 7 out of 40 patients experience a grade 3/4 
protocol-related adverse event that is unique to the combination. Using this stopping rule, the 
probability of stopping the trial early for various hypothetical toxicity rates is as follows: 
 
True toxicity rate 
10% 
15% 
20% 
25% 
30% 
Probability of early stopping 
10% 
40% 
71% 
90% 
98% 
 
Frequencies of toxicities will be tabulated. The grade 3 or 4 treatment-related non- 
hematologic/non-laboratory toxicity will be estimated at the end of the trial along with the 
95% confidence interval. With 40 patients, these rates can be estimated within ±16%. 
 
In addition to the Stopping Rule described above, a four-week safety monitoring period will 
begin once 4-6 patients begin treatment. No subsequent patients may receive protocol 
therapy until the 4th treated patient completes 4 weeks on study. If any of the first 4 
treated patients is invaluable for toxicity through week 4, the monitoring period will 
extend to the 5th patient, etc, for a maximum of 6 patients. Once at least 4 patients 
have been observed for at least 4 weeks, treatment of subsequent enrollees may 

Memorial Sloan Kettering Cancer Center 
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Page 47 of 59 
 
 
 
 
then resume at the discretion of the Principle Investigator. Observance of 1 or more 
unexpected, cli nically-significant SAE that is possibly, probably, or definitely related 
to protocol therapy should prompt consideration to amend or terminate the protocol. 
 
Methods of Efficacy Analysis 
Efficacy measures such as Overall Response rate (ORR) and PFS rate at 6 months and 
median progression free survival (PFS) will be estimated. Clinical Benefit Rate (CBR) will be 
defined as ORR + Stable Disease (SD) rate. 
 
As per the standard of reference set by the Gynecologic Oncology Group for platinum 
resistant ovarian cancer, if a new agent has a true response rate of 10% or less, it would be 
considered of little clinical significance. Conversely, if the true response rate is at least 25%, 
further investigation is clearly indicated. These are the reference ORR numbers used to 
assess novel agents in the GOG-0126 queue, through which nearly 40 treatments have been 
evaluated. As a means of comparison, and to further justify this ORR goal, the clinical data  
for several relevant cytotoxic and biologic agents are tabulated here. 
 
Rx 
ORR (%) 
[PR + CR] 
CB/DCR (%) 
[ORR + SD] 
PFS 
(m) 
Response 
Duration (m) 
# of Patients 
(n) 
Reference 
Topotecan 
6.5 
3.1 
124 
Gordon, JCO 2001 
Liposomal Dox 
12.5 
2.1 
130 
Gordon, JCO 2001 
Gemcitabine 
17 
54 
4.8 
17 
D‟Agostino, Gyn Onc 
2002 
Docetaxel 
22 
22 
Rose, Gyn Onc 2003 
Weekly 
Paclitaxel 
21 
67 
3.6 
21 
Markman, Gyn Onc 
2006 
Nivolumab 
15 
3.5 
20 
Hamanishi, ASCO 2015 
Pembrolizumab 
11.5 
35 
>6.2-8.3 
26 
Varga, ASCO 2015 
Avelumab 
10.7 
55 
75 
Disis, ASCO 2015 
Bev 
16 
4.4 
36 
Cannistra, JCO 2007 
Chemo
a
 
12 
3.4 
2.1-2.8 
182 
Pujade, JCO 2014 
Chemo + Bev 
27 
6.7 
4.2-5.5 
179 
Pujade, JCO 2014 
Olaparib
b
 
31 
73 
7.4 
193 
Kaufman, JCO 2015 
IMGN853 
13-22c 
61 
23 
Borghaei, ASCO 2015 
CB/DCR = Clinical Benefit or Disease Control Rate 
 
aThe chemotherapy dosing regimens used in the AURELIA trial were as follows: 
• 
Paclitaxel 80 mg/m2 IV on days 1, 8, 15, and 22 every 4 weeks 
• 
Pegylated liposomal doxorubicin 40 mg/m2  IV on day 1 every 4 weeks 
• 
Topotecan 4 mg/m2 IV on days 1, 8, and 15, every 4 weeks or 1.25 mg/m2 on days 1 to 5 
every 3 weeks 
bAll patients had germline deleterious mutations in BRCA 1/ 2. 
cAn additional 7/23 patients (30%) had a decrease in CA -125 marker. 
 
Given the inherent difficulty in detecting meaningful overall survival (OS) data in patients who 
will likely frequently receive multiple, and divergent downstream agents after end of study, 
including possible enrollment in additional clinical trials, PFS is considered an appropriate 
endpoint for meaningful clinical efficacy. (Broglio 2009) This approach has been adopted for 
ovarian cancer. (Bast 2007; Markman 2007) 
 
Secondary objectives: 
• 
Determine the ability of the laboratory parameters to predict response: 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 48 of 59 
 
 
 
 
o Tumor tissue FRα expression* 
o Tumor tissue PD-L1 expression** 
o Tumor tissue immune-related gene signature 
o Peripheral blood immune phenotype 
o Peripheral blood gene expression 
o Peripheral blood cellular and serologic responses to FRα 
o Peripheral blood T cell receptor repertoire 
 
• 
For exploratory biomarker analyses, patients will be dichotomized on the basis of clinical 
benefit (CB) rate (CR+PR+SD) as the outcome measure. All biomarkers will be treated as 
continuous variables and minimum p value approach will be used to define the appropriate 
cutoffs. For tissue based biomarkers, CBR will be correlated to the level of tissue expression 
of FRa, PD-L1, or specific genes/gene signatures identified from transcriptional profiling. 
Levels of gene expression and their relationship to CB will be assessed graphically in order 
to explore potential cutoffs for expression that related to CB. For peripheral blood 
biomarkers, changes in specific biomarkers (e.g. change in ICOS level expression on 
lymphocytes) from baseline levels will be assessed graphically in order to explore potential 
cutoffs for expression that related to CB. 
• 
Identify HLA class I-binding peptides from FRα that are recognized by patient lymphocytes 
prior to and after therapy. Assess which out of the 5 peptides correlates with  the number of 
lymphocytes prior to and after therapy. This aim is exploratory and hypothesis generating. 
• 
Determine whether the elicitation of FRα-specific immune responses correlated with clinical 
efficacy. Binary variables such as +/- MDSC‟s, or +/- FR-specific T Cells measured at weeks 
2, 6, and 12 will be assessed with PFS in a Cox model taking into account the time- 
dependent nature of these biomarkers obtained during treatment. Depending on the number 
of events, the sample size might limit definitive conclusions and this analysis is exploratory. 
• 
Analyze whether FRα-specific antibodies elicited by protocol therapy can be detected by 
surface plasmon resonance (Dr. Thoren, Fleischer laboratory) 
 
 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/).  The completed signature page of the written consent/RA or 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 49 of 59 
 
 
 
 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
15.3 
Randomization 
 
NA 
 
16.1 
DAT A M ANAGEMENT ISSUES 
 
A research study assistant (RSA) will be assigned to study. The responsibilities of the RSA 
include project compliance, data collection, extraction and data entry, data reporting, 
coordination of the activities of the protocol study team and, and of the flow of regulatory 
paperwork. 
 
The data collected for the study will be entered into a secure database (CRDB). All routine 
blood test results required per the protocol will be captured in CRDB in addition to  baseline 
medical conditions and disease information, response assessments, off-study 
documentation, and toxicity grade and attribution. Source documentation will be available to 
support the computerized patient record. 
 
MSKCC will hold the IND and will be responsible for all safety monitoring. All SAEs will be 
reported to the MSKCC IRB. The safety of the study will be monitored by the MSKCC Data 
and Safety Monitoring Committee. 
 
Weekly registration reports will be generated by the RSA and reviewed by the PI to monitor 
patient accruals and completeness of registration data. Routine data quality reports will be 
generated to assess missing data and inconsistencies. 
 
Accrual rates and extent and accuracy of evaluations and follow up will be monitored 
periodically throughout the study. Recurrent lapses in data collection, deviations or violations 
will be discussed with the study team and a corrective plan will be generated. Accrual goals 
and factors impacting accrual goals will be discussed at the weekly New Patient/Protocol 
meetings. 
 
If accrual proceeds more quickly than anticipated, it may be slowed or staggered at the 
discretion of the Principal Investigator, to account for safety concerns or data management 
resources. 
16.2 
Quality Assurance 
 
The data and safety monitoring plan at Memorial Sloan Kettering Cancer Center was 
approved by the National Cancer Institute in September 2001. The plan addressed the new 
policies set forth by the NCI and the document entitled "Policy of the National Cancer  
Institute for data and safety monitoring of clinical trials" which can be found at 
http://grants.nih.gov/grants/guide/noticefiles/not98-084.html. The DSM plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC data and 
safety monitoring plan can be found on the MSKCC Internet at 
http://inside2/clinresearch/Documents/MSKCC Data and Safety Monitoring Plans.pdf. 

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Page 50 of 59 
 
 
 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff  
education on clinical research QA) and departmental procedures for quality control, plus  
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. Memorial Sloan Kettering Cancer Center has set up three distinct 
monitoring processes for our clinical trials program. There are two sub-committees that have 
the responsibility of data and safety monitoring. These are joint sub-committees with dual- 
reporting responsibilities. The Data and Safety Monitoring Committee (DSMC) is the sub- 
committee responsible for monitoring all Phase 1, 2, 1/2, pilot and non-phase clinical trials. 
The Data and Safety Monitoring Board (DSMB) is the sub-committee responsible for 
monitoring Phase 3 randomized clinical trials. The Therapeutic Response Review Committee 
(TRRC) is the sub-committee of Research Council responsible for the independent 
therapeutic response review for participants in IRB/PB approved clinical trials where 
therapeutic efficacy is a stated primary objective, typically phase 2 and 3 trials. Formal 
monitoring of such studies is designed to ensure that the interests of the  participants are 
being scrutinized on a regular basis, and that the trial is progressing in a satisfactory manner. 
 
The DSMC convenes once per quarter and monitors the risk participants are exposed to, the 
progress of the study, the adequacy of the data storage and whether sufficient data are being 
entered into the CRDB. The DSMC monitors phase 1, 2, 1/2, pilot and non-phase trials that 
are not being monitored by an industrial sponsor, and which meet the NCI definition of a 
Clinical Trial. This trial will qualify for monitoring by the DSMC. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required, and the monitoring procedures will be 
established at the time of protocol activation. A detailed description of the data to be 
collected, process of data collection (i.e., data manager and/or data management office), 
database that will be utilized for data collection and storage (e.g., Clinical Research 
Database (CRDB), user-supported software), reporting requirements of the data to the 
institution (IRB), the sponsor and/or governing agency. 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research. The MSKCC 
Data and Safety Monitoring Plans can be found on the MSKCC Intranet at:  
http://smskpsps9/dept/ocr/OCR%20W   ebsite%20Documents/Clinical%20Research%20Qualit   
y%20Assurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitori   ng%20Plan.p  
df 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
17.2 
Privacy 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
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Page 51 of 59 
 
 
 
 
MSK‟s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
 
 
SAE reporting is required as soon as the participant signs consent.  SAE reporting is 
required for 90-days after the participant‟s last investigational treatment or intervention. Any 
events that occur after the 90-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 „Reporting of Serious 
Adverse Events‟, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org.  All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org.  All other reports should be sent to sae@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject‟s name (generate the report with only initials if it will be sent outside of 
MSK) 

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IRB Number: 16-011 A(5) 
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Page 52 of 59 
 
 
 
 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject‟s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI‟s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above.  If appropriate, the report will be 
forwarded to the FDA by the SAE staff through the IND Office. 
 
Ethical conduct of the study 
 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements Subject data protection. 
17.3.1 Recording of adverse events and serious adverse events 
 
Adverse events will be recorded via Electronic CRDB (Clinical Records Database) using a 
recognized medical term or diagnosis that accurately reflects the event. Adverse events will 
be assessed by the investigator for severity, relationship to the investigational product, 
possible etiologies, and whether the event meets criteria of a fatal  SAE/ or SUSAR and 
therefore requires immediate notification to the regulatory authority (FDA) and 
AstraZeneca/MedImmune Patient Safety in parallel within 5 calendar days; All other non-fatal 
or non-SUSAR SAE‟s can be sent to the regulatory agency and AstraZeneca within 10 days 
on a monthly basis. 
 
The following variables will be collected for each AE: 
 
• 
AE (verbatim) 
• 
The date (and time when clinically relevant) when the AE started and stopped 
• 
Changes in NCI CTCAE grade and the maximum CTC grade attained 
• 
Whether the AE is serious or not 

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Page 53 of 59 
 
 
 
 
• 
Investigator causality rating against durvalumab (yes or no) 
• 
Investigator causality rating against TPIV200 + GM-CSF (yes or no) 
• 
Action taken with regard to durvalumab 
• 
Action taken with regard to TPIV200 + GM-CSF 
• 
Outcome 
 
In addition, the following variables will be collected for SAEs as applicable: 
 
• 
Date AE met criteria for serious AE 
• 
Date Investigator became aware of serious AE 
• 
AE is serious due to 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Description of AE 
• 
Causality assessment in relation to Study procedure(s) 
• 
Causality assessment in relation to TPIV200 + GM-CSF 
 
Events, which are unequivocally due to disease progression, should not be reported 
as an AE during the study. 
 
17.2.1.1 Study recording period and follow-up for adverse events and serious 
adverse events 
 
Adverse events and serious adverse events will be recorded from time of signature of 
informed consent, throughout the treatment period and including the follow-up period (90 
days after the last dose of durvalumab or TPIV200, whichever is later). 
 
During the course of the study all AEs and SAEs should be proactively followed up for each 
subject. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
 
If a subject discontinues from treatment for reasons other than disease progression, and 
therefore continues to have tumor assessments, drug or procedure-related SAEs must be 
captured until the patient is considered to have confirmed PD and will have no further tumor 
assessments. 
 
The investigator is responsible for following all SAEs until resolution, until the subject returns 
to baseline status, or until the condition has stabilized with the expectation that it will remain 
chronic, even if this extends beyond study participation. 
17.2.1.2 Follow-up of unresolved adverse events 
 
Any AEs that are unresolved at the subject‟s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF. 

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Page 54 of 59 
 
 
 
 
After 90 days, only subjects with ongoing investigational product-related SAEs will continue 
to be followed for safety. 
 
AstraZeneca/MedImmune retains the right to request additional information for any subject 
with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
17.2.1.3 Post study events 
 
After the subject has been permanently withdrawn from the study, there is no obligation for 
the investigator to actively report information on new AE or SAEs occurring in former study 
subjects after the 90-day safety follow-up period for patients treated with durvalumab. 
However, if an investigator learns of any SAEs, including death, at any time after the subject 
has been permanently withdrawn from study, and he/she considers there is a reasonable 
possibility that the event is related to study treatment, the investigator should notify the study 
sponsors: the TapImmune Medical Director and AstraZeneca/MedImmune Drug Safety. 
 
 
 
 
17.2.1.4 Reporting of serious adverse events 
 
All SAEs or SUSARs will be reported, whether or not considered causally related to the 
investigational product, or to the study procedure(s). The reporting period for SAEs is the 
period immediately following the time that written informed consent is obtained through 90 
days after the last dose of durvalumab or until the initiation of alternative anticancer therapy. 
The investigator is responsible for informing the Ethics Committee and/or the Regulatory 
Authority of the SAE as per local requirements. 
 
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of 
events in relation to all study medications and if the SAE is related to disease 
progression, as determined by the principal investigator. 
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s  
designated mailbox within 24 hours of notification: 
AE MailboxClinicalTrialTCS@astrazeneca.com and to the TapImmune Medical Director at  
pyeramian@tapimmune.com. 
If a non-serious AE becomes serious, this and other relevant follow-up information must also 
be provided to AstraZeneca, TapImmune, and the FDA. 
Serious adverse events that do not require expedited reporting to the FDA still need to be 
reported to AstraZeneca and TapImmune preferably using the MedDRA coding language for 
serious adverse events.  This information should be reported on a monthly basis and under 
no circumstance less frequently than quarterly. 
17.2.1.5 Other events requiring reporting 
Overdose 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 55 of 59 
 
 
 
 
An overdose is defined as a subject receiving a dose of durvalumab in excess of that 
specified in the Investigator‟s Brochure, unless otherwise specified in this protocol. 
 
Any overdose of a study subject with durvalumab, with or without associated AEs/SAEs, is 
required to be reported within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca/MedImmune Patient Safety or designee using the designated Safety e-mailbox 
(see Section 11.4 for contact information). If the overdose results in an AE, the AE must also 
be recorded as an AE (see Section 11.4). Overdose does not automatically make an AE 
serious, but if the consequences of the overdose are serious, for example death or 
hospitalization, the event is serious and must be recorded and reported as an SAE (see 
Section 11.4). There is currently no specific treatment in the event of an overdose of 
durvalumab. 
 
The investigator will use clinical judgment to treat any overdose. 
 
 
 
 
Hepatic function abnormality 
 
Hepatic function abnormality (as defined in Section 11.4) in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” 
within 24 hours of knowledge of the event to the sponsor and AstraZeneca/MedImmune 
Patient Safety using the designated Safety e-mailbox (see Section 11.4 for contact 
information), unless a definitive underlying diagnosis for the abnormality (e.g., cholelithiasis 
or bile duct obstruction) that is unrelated to investigational product has been confirmed. 
 
• 
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study subject will 
be based on the clinical judgment of the investigator. 
 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
subject must be interrupted immediately. Follow-up investigations and inquiries must be 
initiated by the investigational site without delay. 
 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune. 
Pregnancy 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the IPs should be discontinued 
immediately. 
 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled 
as SAEs. Elective abortions  without complications  should not be handled as  AEs. The 
outcome   of   all   pregnancies   (spontaneous   miscarriage,   elective   termination,   ectopic 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 56 of 59 
 
 
 
 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented 
even if the patient was discontinued from the study. 
 
If any pregnancy occurs in the course of the study, then the Investigator or other site 
personnel should inform the appropriate AstraZeneca representatives within 1 day, ie, 
immediately, but no later than 24 hours of when he or she becomes aware of it. 
 
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 to 
5 calendar days for SAEs and within 30 days for all other pregnancies. 
 
The same timelines apply when outcome information is available. 
 
Pregnancy in a subject who has received investigational product is required to be reported 
within 24 hours of knowledge of the event to the sponsor and AstraZeneca/MedImmune 
Patient Safety or designee using the designated Safety e-mailbox (see Section 17.2.1.4 for 
contact information) and to the TapImmune Medical Director. 
 
Subjects who become pregnant during the study period must not receive additional doses of 
investigational product but will not be withdrawn from the study. The pregnancy will be 
followed for outcome of the mother and child (including any premature terminations) and 
should be reported to AstraZeneca/MedImmune Patient Safety and to the TapImmune 
Medical Director or designee after outcome. 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain  
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-011 A(5) 
Approval date: 10-Oct-2017 
Page 57 of 59 
 
 
 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
19.0 
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20.0     APPENDICES 
 
• 
Appendix A: Durvalumab Dosing Modification and Toxicity Management Guidelines 
(Tables 1,2,3) 
• 
Appendix B: Schedule of study procedures: follow-up for subjects who have 
completed durvalumab treatment and achieved disease control (until confirmed 
progression of disease) and subjects who have discontinued durvalumab due to 
toxicity in the absence of confirmed progression of disease 
• 
Appendix C: Schedule of study procedures: follow-up for subjects who have 
discontinued durvalumab treatment due to confirmed progression of disease