A Phase I/II Evaluation of Olaparib in Combination With Durvalumab (Medi4736) and Tremelimumab in the Treatment of Recurrent Platinum Sensitive or Resistant or Refractory Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Patients Who Carry a BRCA1 or BRCA2 Mutation
Phase: PHASE2
Conditions: BRCA1 Gene Mutation, BRCA2 Gene Mutation, Ovarian Serous Adenocarcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma
Sponsor: Roswell Park Cancer Institute

Document Coversheet 
 
 Study Title: A Phase I/II Evaluation of Olaparib in combination with Durvalumab and Tremelimumab 
in the Treatment of Recurrent Platinum Sensitive or Resistant or Refractory Epithelial Ovarian, 
Fallopian Tube, or Primary Peritoneal Cancer in Patients who Carry a Germline BRCA1 or BRCA2 
Mutation 
Institution/Site:  
Roswell Park Comprehensive Cancer Center 
Document (Approval/Update) Date: 
 04/15/2021 
NCT Number: 
NCT02953457 
Roswell Protocol ID: 
I 288216 
 
 

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE 
AMD 12  04/15/2021
Page 1 of 169
TITLE: A Phase I/II Evaluation of Olaparib in Combination with Durvalumab 
(Medi4736) and Tremelimumab in the Treatment of Recurrent Platinum Sensitive or 
Resistant or Refractory Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal 
Cancer in Patients Who Carry a BRCA1 or BRCA2 Mutation
Roswell Park Cancer Institute
Study Number:
I 288216
Initial Date:
10 June 2016
Amendment 1
07 December 2016
Amendment 2
Amendment 3
Amendment 4
Amendment 5
Amendment 6
Amendment 7
31 August 2017
13 November 2017
27 February 2018 
27 June 2018
21 September 2018
16 January 2019
Amendment 8
24 July 2019
Amendment 9
28 August 2019
Amendment 10 
Amendment 11
Amendment 12
18 November 2019
29 December 2020
15 April 2021
IND Holder:
Roswell Park Cancer Institute
Principal Investigator:
Emese Zsiros, MD
Roswell Park Cancer Institute
Elm & Carlton Streets
Buffalo, New York 14263
716-845-5855
Emese.Zsiros@RoswellPark.org
Sponsor:
Roswell Park Cancer Institute
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
Industry/Other Supporter:
AstraZeneca
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and 
shall remain the exclusive property of the party (ies) mentioned above. The use of such 
confidential information must be restricted to the recipient for the agreed purpose and 
must not be disclosed, published, or otherwise communicated to any unauthorized 
persons, for any reason, in any form whatsoever without the prior written consent of the 
party (ies) above.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 3 of 169
RPCI Study Contacts 
FOR NETWORK SITES: Please contact the RPCI Network Monitor for any study-related 
questions regarding sample handling, processing or shipping.
Name
Institution
Email
Role
Junko Matsuzaki, PhD
Immune Analysis Facility
Cancer Cell Center, Room 
416 Roswell Park Cancer 
Institute Elm and Carlton 
Streets Buffalo, NY 
14263
junko.matsuzaki@roswellpark.org
Immune monitoring
Correlative Sciences 
Pathology Office
Roswell Park Cancer 
Institute,
Elm and Carlton Streets, 
Buffalo, NY 14263
Building: BSB 636
crslabpathteam@roswellpark.org
PD-L1 testing
Pathology
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 4 of 169
List of Abbreviations
AChE
Acetylcholine esterase
ADA
anti-drug antibody
ADCC
antibody-dependent cell-mediated cytotoxicity
AE
adverse event
AESI
adverse event of special interest
ALK
Anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APC
antigen-presenting cells
APF12
Proportion of patients alive and progression free at 12 
months from randomization
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
CDC
Complement dependent cytotoxicity
CI
confidence interval
CL
clearance
Cmax
peak concentration
Cmax,ss
peak concentration at steady state
Cmin
trough concentration
Cmin,ss
trough concentration at steady state
CNS
central nervous system
CR
complete response
CT
computed tomography
CTLA-4
cytotoxic T-lymphocyte-associated antigen-4
DC
disease control
DCR
disease control rate
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DoR
duration of response
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 5 of 169
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDTA
disodium edetate dihydrate
Fc
fragment crystallizable
FFPE
formalin fixed paraffin embedded
FSH
follicle-stimulating hormone
FTIH
first-time-in-human
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GLP
Good Laboratory Practice
HCl
hydrochloride
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IFN
interferon
IGF
insulin-like growth factor
IgG1
immunoglobulin G1
IgG2
immunoglobulin G2
IGSF
immunoglobulin superfamily
IHC
immunohistochemistry 
IL
interleukin
irAE
immune-related adverse event
IRB
Institutional Review Board
irRECIST
immune-related response criteria
IV
Intravenous(ly)
MDSC
Myeloid derived suppressor cells
MedDRA
Medical Dictionary for Regulatory Activities
miRNA
micro ribonucleic acid
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 6 of 169
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology 
Criteria for Adverse Events 
NK
natural killer
NOAEL
no-observed-adverse-effect level
NSCLC
non-small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcome
PVC
polyvinyl chloride
Q2W
every 2 weeks
Q3M
every 3 months
Q3W
every 3 weeks
Q4W
every 4 weeks
Q12W
every 12 weeks
QoL
quality of life
QTc
the time between the start of the Q wave and the end of 
the T wave corrected for heart rate
QTcF
QT interval on ECG corrected using the Frederica’s 
formula
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 7 of 169
RNA
ribonucleic acid
SAE
serious adverse event
SD
stable disease
SID
subject identification
sPD-L1
soluble programmed cell death ligand 1
SOCS3
suppressor of cytokine signaling 3
SUSAR
suspected unexpected serious adverse reaction
t½
half-life
TEAE
treatment-emergent adverse event
TIL
tumor infiltrating lymphocyte
Tmax
time to peak concentration
Tmax,ss
time to peak concentration at steady state
TNF-α
tumor necrosis factor alpha
TSH
thyroid stimulating hormone
ULN
upper limit of normal
USA
United States of America
WFI
water for injection
WHO
World Health Organization
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 8 of 169
SYNOPSIS
Title / Phase
A Phase I/II Evaluation of Olaparib in Combination with 
Durvalumab (Medi4736) and Tremelimumab in the Treatment of 
Recurrent Platinum Sensitive or Resistant or Refractory Epithelial 
Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Patients 
Who Carry a BRCA1 or BRCA2 Mutation.
Roswell Park Cancer Institute Study 
Number
I 288216
Roswell Park Cancer Institute 
Investigator
Emese Zsiros, MD
Sponsor
Roswell Park Cancer Institute
Industry/ Other Supporter
AstraZeneca
Study Drugs
Olaparib
Durvalumab
Tremelimumab
Objectives
Primary:

Phase I: The primary objective of the phase I component 
of this study is:
o
To assess the safety and toxicity of the 
combination of PARP inhibitor olaparib with 
anti-PD-L1 antibody durvalumab and anti-
CTLA4 antibody tremelimumab

Phase II: The primary objective of the phase II 
component of this study is:
o
To assess the impact of the combination of 
olaparib with durvalumab and tremelimumab on 
PFS rates.
Secondary:

To assess the impact of the combination of olaparib with 
durvalumab and tremelimumab on anti-tumor immune 
responses in patients with recurrent platinum sensitive or 
resistant or refractory epithelial ovarian, fallopian tube, 
or primary peritoneal cancer who carry a germline and/or 
somatic BRCA1 or BRCA2 mutation and/or a 
homologous recombination deficiency (HRD)

To assess the impact of the combination of olaparib with 
durvalumab and tremelimumab on PFS and OS in 
patients with recurrent platinum sensitive or resistant or 
refractory epithelial ovarian, fallopian tube, or primary 
peritoneal cancer who carry a germline and/or somatic 
BRCA1 or BRCA2 mutation and/or a HRD.
Study Design
This is an open-label Phase I/II study for combination of the 
PARP inhibitor olaparib with anti-PD-L1 antibody durvalumab 
and anti-CTLA4 antibody tremelimumab, utilizing a 3+3 design 
followed by a Phase II study with a planned enrollment at a 2:1 
ratio of platinum-resistant to platinum-sensitive disease. Patients 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 9 of 169
must have platinum-sensitive or platinum-resistant recurrent or 
persistent or refractory ovarian, fallopian tube, or primary 
peritoneal carcinoma AND have one or more of the characteristics 
listed in the inclusion criteria documented on a validated platform 
(documented genetic test report is required).  Historic report is 
permitted.
Target Accrual and Study Duration
A maximum of 36 participants at multiple sites, including RPCI 
will be enrolled. Accrual is expected to take up to 4 years.
Study Procedures
The following will be performed during the pre-screening period 
Day -42 through Day -1) for PD-L1 status only:

Informed Consent

Preliminary review of eligibility criteria (investigator’s 
opinion)

Obtain archived tumor tissue for PD-L1 assay 
The following will be performed within 28 days prior to first dose 
of study drug (Screening period), unless otherwise specified:

Formal verification of eligibility criteria

Recording of concomitant medications

Recording of adverse events

Medical and surgical history/demographics

Complete physical exam (to include vital signs, height, 
and weight)

ECOG Performance Status

12-lead ECG (in triplicate [2-5 minutes apart])

Tumor/Disease Assessment by CT/MRI (including brain 
MRI only if clinically indicated)

Hematology (Table 6)

Chemistry (Table 7)

CA-125 level

Thyroid function tests: TSH level.  If TSH is abnormal 
fT3 and fT4 will also be collected.

Coagulation (PT, PTT, INR)

Pregnancy test (serum βhCG for pre-menopausal women 
of childbearing potential only)

HIV/Hepatitis B, C serologies

Urinalysis (Table 8) 
Cycle 1 Day 1:

Pregnancy test (serum) in pre-menopausal women of 
child-bearing potential (only if not performed within 7 
days of treatment start).

Physical examination 

Vital signs

Weight

ECOG Performance Status

Single 12-lead ECG– on Cycle 1 Day 1 within 2-3 hours 
prior to start of the first treatment and 0-3 hours after 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 10 of 169
administration of the combination is completed.  In case 
of clinically significant ECG abnormalities, including a 
QTcF value ≥ 470ms, 2 additional 12-lead ECGs should 
be obtained over a brief period (e,g, 30 minutes) to 
confirm the finding.

Recording of adverse events

Recording of concomitant medications

Chemistry (Table 7)

CA-125 level

Thyroid function tests: TSH level.  If TSH is abnormal, 
fT3and fT4 will also be collected.

Hematology (Table 6)

Urinalysis

PAXgene® RNA blood sample collection

Blood for immune monitoring

Blood for circulating soluble factors

Initial durvalumab, tremelimumab, and olaparib 
treatment

Vital Sign monitoring during the infusions
Treatment Phase: Procedures to be conducted during the 
treatment phase of the study are presented in the Schedule of 
Procedures and Observations (see Table 5).
End of Treatment: End of treatment is defined as the last planned 
dosing visit within the 12-month dosing period. For subjects who 
discontinue durvalumab, tremelimumab, or olaparib prior to 12 
months, end of treatment is considered the last visit where the 
decision is made to discontinue treatment. All required procedures 
may be completed within ± 7 days of the end of treatment visit. 
Repeat disease assessment is not required if performed within 28 
days prior to the end of treatment visit (see Table 5).
Statistical Analysis
Sample Size Determination: The potential Phase I study sample 
size ranges from a minimum of n=6 to a maximum of n=12. See 
Table 1 for the dose escalation schema. The phase II portion of the 
study will have a sample size of n=27. Subjects will be enrolled in 
the Phase II study at a ratio of 2:1 of platinum resistant to platinum 
sensitive disease.
Depending on the incidence of DLT(s), following a 3+3 design, the 
sample size is estimated to be 33 to 36 patients. Assuming the true 
DLT rate is much less than 1/3rd, we anticipate enrolling 36 subjects 
(9+27) where the accrual is expected to take up to 4 years.
Efficacy Analysis: Clinical efficacy evaluation will include tumor 
response assessed by irRECIST and RECIST, Progression-free 
Survival and Overall Survival.
The primary endpoint will test the 3 months progression free 
survival rate in the platinum resistant group in conjunction with the 
6-month progression free survival rate in the platinum sensitive 
group.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 11 of 169
Safety Analysis: The primary objective of the Phase I study is 
establishing safety. Assessment of safety and tolerability will be 
performed by closely monitoring the first 6 subjects in the safety 
lead-in cohort. The internal data safety monitoring panel will 
monitor on an ongoing basis, based on data review and regular 
conference calls with the investigators.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 12 of 169
INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Participant Name: (Network sites use participant initials): ___________________________
Medical Record No.: (Network sites use participant ID): _____________________________
Title: A Phase I/II Evaluation of Olaparib in Combination with Durvalumab (Medi4736) 
and Tremelimumab in the Treatment of Recurrent Platinum Sensitive or Resistant or 
Refractory Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Patients 
Who Carry a BRCA1 or BRCA2 Mutation.
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
1.
Patients must have platinum-sensitive or platinum-resistant recurrent or 
persistent or refractory ovarian, fallopian tube, or primary peritoneal 
carcinoma AND have one or more of the following characteristics 
documented on a validated platform (documented genetic test report is 
required). Historic report is permitted.
a) A germline BRCA1 or BRCA2 deleterious alteration.
b) A somatic mutation in BRCA1 or BRCA2 detected in a tumor sample or 
on circulating tumor DNA.
c) Carry a known or likely loss of function alteration in one or more of 
the homologous recombination or mismatch repair pathway genes (see 
section 5.1 for the list of genes).
d) Demonstrate a genomic phenotype of HR deficiency as measured by a 
LOH-high score.
Recurrent ovarian cancer is defined as recurrence of disease in a patient 
who achieved initial complete response to primary therapy. 
Persistent ovarian cancer is defined as having residual disease in the form of 
elevated tumor markers or microscopic or clinically evident disease in a 
patient who has completed and apparently responded to initial chemotherapy.
Refractory ovarian cancer is defined as patients who have failed to achieve 
at least a partial response to therapy including patients with either stable 
disease or disease progression during primary therapy.
Platinum-sensitive is defined as achievement of documented response to 
initial platinum-based treatment and has been off treatment for an extended 
period of time (more than 6 months)
Platinum-resistant is defined as relapse within 6 months of last platinum-
based chemotherapy or progression while on platinum-based therapy.
2.
All patients must have measurable disease as defined by irRECIST. 
Measurable disease is defined as 10 mm in the longest diameter by CT or MRI 
scan (or no less than double the slice thickness) for non- nodal lesions and 
≥ 15 mm in short axis for nodal lesions, 20 mm by chest X-ray, a lymph node 
must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).
3.
Must have archival tissue available for PD-L1 assessment.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 13 of 169
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
4.
Patients should be free of active infection requiring antibiotics (with the 
exception of uncomplicated UTI).
5.
Patients who have the following risk factors are considered to be at increased 
risk for cardiac toxicities and may be enrolled only with increased monitoring 
(refer to Table 5, footnote 5): i) prior treatment with anthracyclines, ii) prior 
treatment with trastuzumab, iii) a New York Heart Association classification 
of II controlled with treatment, iv) prior central thoracic radiation therapy 
(RT), including RT to the heart.
6.
Any hormonal therapy being taken as a treatment for cancer must be 
discontinued at least one week prior to registration. Continuation of hormone 
replacement therapy e.g. thyroid hormone replacement therapy is permitted.
7.
Able to tolerate oral medications and no GI illnesses that would preclude 
absorption of olaparib.
8.
Female patients, age > 18 years at time of study entry.
9.
Have an ECOG Performance Status of 0-1. Refer to Appendix B.
10. Life expectancy of > 6 months.
11. Adequate normal organ and marrow function as defined below:
•
Hemoglobin ≥ 10 g/dL (no blood transfusion in the 28 days prior to entry) 
(olaparib guidelines)
•
WBC > 3 x 109/L
•
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (≥1500 per mm3)
•
Platelet count ≥ 100 x 109/L (≥ 100,000 per mm3)
•
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This 
will not apply to subjects with confirmed Gilbert’s syndrome (persistent 
or recurrent hyperbilirubinemia that is predominantly unconjugated in the 
absence of hemolysis or hepatic pathology), who will be allowed only in 
consultation with their physician
•
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
•
Creatinine ≤ 1.5 x ULN or, serum creatinine CL >51 mL/min (by the 
Cockcroft-Gault equation: see Appendix L)
12. Female subjects must either be of non-reproductive potential (i.e., 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 within 28 days of study treatment, confirmed prior to 
treatment on day 1.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 14 of 169
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
13. Participants of child-bearing potential must agree to use two highly effective 
and acceptable forms of contraception from screening, throughout their 
participation in the study and for 180 days after the last dose of durvalumab + 
tremelimumab combination therapy or 90 days after last dose of durvalumab 
or olaparib, whichever is the longer time period (e.g., hormonal or barrier 
method of birth control). Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should 
inform her treating physician immediately. 
14. Participant or legal representative must understand the investigational nature 
of this study and sign an Independent Ethics Committee/Institutional Review 
Board approved written informed consent form prior to receiving any study 
related procedure.
15. 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.
Investigator Signature: ___________________________________
Date: ___________
Printed Name of Investigator: __________________________________________________
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 15 of 169
INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Participant Name: (Network sites use participant initials): ___________________________
Medical Record No.: (Network sites use participant ID): _____________________________
Title: A Phase I/II Evaluation of Olaparib in Combination with Durvalumab (Medi4736) 
and Tremelimumab in the Treatment of Recurrent Platinum Sensitive or Resistant or 
Refractory Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Patients 
Who Carry a BRCA1 or BRCA2 Mutation
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
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 an investigational product 
during the last 4 weeks (prior use of bevacizumab in the upfront setting 
is allowed).
3.
History of discontinuation of any previous treatment with PARP 
inhibitors, including olaparib, or a PD-1 or PD-L1 inhibitor, including 
durvalumab or anti-CTLA4 antibody, including tremelimumab due to 
toxicity.
4.
Patients with myelodysplastic syndrome/acute myeloid leukemia.
5.
History and/or confirmed ILD/pneumonitis, extensive bilateral lung 
disease on HRCT scan.
6.
Concomitant use of a strong CYP3A inhibitors (e.g., itraconazole, 
telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, 
posaconazole, ritonavir, lopinavir/ritonavir, indinavir, saquinavir, 
nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (e.g., 
amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, 
darunavir/ritonavir, diltiazem, erythromycin, fluconazole. 
Fosamprenavir, imatinib, verapamil).
7.
Concomitant use of strong CYP3A inducers (e.g., phenytoin, 
rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A 
inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin).
8.
History of another primary malignancy except for:

Malignancy treated with curative intent and with no known active 
disease ≥5 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 (e.g. basal cell or squamous cell 
carcinoma of the skin).

Adequately treated carcinoma in situ without evidence of disease 
(e.g., breast and cervical cancer in situ).
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 16 of 169
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
9.
Receipt of the last dose of anti-cancer therapy (chemotherapy, 
immunotherapy, endocrine therapy, targeted therapy, biologic therapy, 
tumor embolization, monoclonal antibodies, radiotherapy or, other 
investigational agent) ≤ 21 days prior to the first dose of study drug and 
within 6 weeks for nitrosourea or mitomycin C).
10. Mean QT interval corrected for heart rate (QTcF) ≥470 ms calculated 
from 3 electrocardiograms (ECGs) using Fridericia’s Correction.
11. Patients with history of myocardial infarction within 6 months.
12. 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.
13. Any unresolved toxicity (CTCAE grade ≥2) from previous anti-cancer 
therapy. Subjects with irreversible toxicity that is not reasonably 
expected to be exacerbated by the investigational product may be 
included (e.g., hearing loss, peripherally neuropathy).
14. Any prior Grade ≥3 immune-related adverse event (irAE) while 
receiving any previous immunotherapy agent, or any unresolved irAE 
>Grade 1.
15. 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.
16. Active or prior documented inflammatory bowel disease (e.g., Crohn’s 
disease, ulcerative colitis).
17. Patients with thyroid dysfunction if not adequately controlled.
18. History of primary immunodeficiency.
19. History of allogeneic organ transplant.
20. History of hypersensitivity to durvalumab, tremelimumab, olaparib or, 
any excipient.
21. 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, or test positive for, 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.
22. Known history of previous clinical diagnosis of tuberculosis.
23. History of leptomeningeal carcinomatosis.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 17 of 169
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
24. Receipt of live attenuated vaccination within 30 days prior to study 
entry or within 30 days of receiving durvalumab (e.g. LAIV, MMR, 
VAR, Zoster, yellow fever etc.)
25. Female subjects who are pregnant, breast-feeding, or of reproductive 
potential who are not employing an effective method of birth control 
from screening to 180 days after the last dose of durvalumab + 
tremelimumab + olaparib combination therapy or 90 days after the last 
dose of durvalumab and olaparib therapy, whichever is the longer time 
period.
26. Any condition that, in the opinion of the investigator, would interfere 
with evaluation of study treatment or interpretation of patient safety or 
study results or, is an unsuitable candidate to receive study drug (e.g. 
inability to tolerate oral medications which would preclude absorption 
of olaparib).
27. Symptomatic or uncontrolled brain metastases requiring concurrent 
treatment, inclusive of but not limited to surgery, radiation and/or 
corticosteroids.
28. Subjects with uncontrolled seizures.
29. Dependency on IV hydration or TPN.
Participant meets all entry criteria:
  Yes
  No
If “NO”, do not enroll participant in study.
Investigator Signature: ___________________________________
Date: __________
Printed Name of Investigator: _________________________________________________
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 18 of 169
TABLE OF CONTENTS
1
Background ............................................................................................................................24
1.1
Recurrent Ovarian Cancer ..................................................................................................24
1.2
Durvalumab, Tremelimumab and Olaparib Background ...................................................26
1.2.1
Durvalumab.....................................................................................................................26
1.2.2
Tremelimumab................................................................................................................28
1.2.3
Durvalumab in combination with Tremelimumab..........................................................29
1.2.4
Olaparib...........................................................................................................................30
1.3
Risks and/or Benefits..........................................................................................................30
1.3.1
Potential Benefits ............................................................................................................31
1.3.2
Potential Risks.................................................................................................................33
1.4
Research Hypothesis...........................................................................................................39
2
Study Rationale ......................................................................................................................39
2.1
Durvalumab plus Tremelimumab Combination Therapy Dose Rationale .........................40
2.2
Rationale for 4 Cycles of Combination Therapy Followed by Durvalumab Monotherapy
41
2.3
Rationale for Combination Therapy Doses in this Study ...................................................42
3
Study Objectives.....................................................................................................................42
3.1
Primary Objectives .............................................................................................................42
3.2
Secondary Objectives .........................................................................................................42
4
Methodology ..........................................................................................................................43
4.1
Study Design Overview......................................................................................................43
4.2
Target Accrual and Study Duration....................................................................................46
4.3
Replacement of Participants ...............................................................................................47
5
Participant Selection...............................................................................................................47
5.1
Inclusion Criteria ................................................................................................................47
5.2
Exclusion Criteria ...............................................................................................................50
5.3
Inclusion of Women and Minorities...................................................................................52
6
Treatment Plan .......................................................................................................................52
6.1
Dosing and Administration.................................................................................................52
6.2
Treatment Regimens...........................................................................................................52
6.2.1
Durvalumab + Tremelimumab + Olaparib Combination Therapy .................................52
6.2.2
Olaparib...........................................................................................................................54
6.3
Cohort Management: Dose Escalation Decision Rules......................................................55
6.4
Definition of Dose-Limiting Toxicity ................................................................................55
6.5
Dose Modifications and Toxicity Management .................................................................56
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 19 of 169
6.6
Restrictions, General Concomitant Medication and Supportive Care................................59
6.6.1
Restrictions during the study...........................................................................................59
6.6.2
Permitted Concomitant Medications...............................................................................61
6.6.3
Excluded Concomitant Medications ...............................................................................61
6.6.4
Supportive Care...............................................................................................................64
6.7
Duration of Treatment ........................................................................................................64
6.8
Treatment Discontinuation .................................................................................................64
6.9
Compliance.........................................................................................................................65
7
Investigational Products .........................................................................................................65
7.1
Durvalumab ........................................................................................................................65
7.1.1
Active Substance and Source..........................................................................................65
7.1.2
Drug Shipment ................................................................................................................66
7.1.3
Preparation ......................................................................................................................66
7.1.4
Storage and Stability .......................................................................................................67
7.1.5
Handling and Disposal....................................................................................................67
7.2
Tremelimumab....................................................................................................................67
7.2.1
Active Substance and Source..........................................................................................67
7.2.2
Drug Shipment ................................................................................................................68
7.2.3
Preparation ......................................................................................................................68
7.2.4
Storage and Stability .......................................................................................................69
7.2.5
Handling and Disposal....................................................................................................69
7.3
Olaparib ..............................................................................................................................70
7.3.1
Active Substance and Source..........................................................................................70
7.3.2
Drug Shipment ................................................................................................................70
7.3.3
Preparation ......................................................................................................................70
7.3.4
Storage and Stability .......................................................................................................70
7.3.5
Handling and Disposal....................................................................................................70
8
Study Procedures....................................................................................................................71
8.1
Participant Randomization and Registration ......................................................................71
8.1.1
Pre-Screening Phase (Day -42 to Day -1).......................................................................71
8.1.2
Screening Phase (Day -28 to Day -1)..............................................................................71
8.1.3
Cycle 1 Day 1..................................................................................................................72
8.1.4
Treatment Phase..............................................................................................................73
8.1.5
End of Treatment ............................................................................................................73
8.2
Schedule of Procedures and Observations..........................................................................73
8.3
Description of Study Procedures ........................................................................................80
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 20 of 169
8.3.1
Medical history and physical examination, electrocardiogram, weight and vital signs .80
8.3.2
Physical Examination......................................................................................................80
8.3.3
Electrocardiograms .........................................................................................................80
8.3.4
Vital signs .......................................................................................................................80
8.4
Biological Sampling Procedures.........................................................................................83
8.4.1
Biomarker Sampling and Evaluation Methods ...............................................................83
8.4.2
Estimate of Volume of Blood to be Collected ................................................................88
8.5
Pathology ............................................................................................................................91
8.5.1
Archival Tumor Samples and Fresh Tumor Biopsies.....................................................91
8.5.2
Withdrawal of Informed Consent for Donated Biological Samples...............................92
9
Efficacy evaluations ...............................................................................................................92
9.1
Efficacy Assessment by irRECIST.....................................................................................93
10
Safety Evaluation................................................................................................................94
10.1
Adverse Events ...................................................................................................................94
10.1.1
Definition ........................................................................................................................94
10.1.1.1
Diagnosis Versus Signs and Symptoms ......................................................................94
10.1.1.3
Abnormal Laboratory Values......................................................................................94
10.1.1.4
Preexisting Medical Conditions (Baseline Conditions) ..............................................95
10.1.2
Assessment of Severity ...................................................................................................95
10.1.3
Grading and Relationship to Drug ..................................................................................96
10.1.4
Reporting Adverse Events ..............................................................................................97
10.2
Adverse Events of Special Interest (AESI) ........................................................................98
10.2.1
Durvalumab + Tremelimumab AESIs ............................................................................98
10.2.2
Olaparib Adverse Events of Special Interest (AESIs) ..................................................101
10.2.3
Immune-related Adverse Events...................................................................................101
10.3
Serious Adverse Events ....................................................................................................102
10.3.1
Definition ......................................................................................................................102
10.3.2
Reporting Serious Adverse Events ...............................................................................102
10.4
Investigator Reporting: Notifying the Study Sponsor ......................................................102
10.5
Follow-Up for Serious Adverse Events............................................................................103
10.6
Unanticipated Problems....................................................................................................103
10.6.1
Definition ......................................................................................................................103
10.6.2
Reporting Unanticipated Problems ...............................................................................104
10.7
Reporting of Deaths..........................................................................................................104
10.8
Other Events Requiring Reporting ...................................................................................105
10.8.1
Overdose .......................................................................................................................105
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 21 of 169
10.8.2
Hepatic function abnormality........................................................................................105
10.8.3
Maternal exposure.........................................................................................................105
10.9
FDA Reporting .................................................................................................................106
11
Data and Safety Monitoring..............................................................................................107
12
Statistical Methodology....................................................................................................107
12.1
Sample Size Determination ..............................................................................................107
12.2
Demographics and Baseline Characteristics.....................................................................108
12.3
Safety and Tolerability .....................................................................................................108
12.4
Clinical Efficacy ...............................................................................................................108
12.5
Interim Analysis and Criteria for Early Termination of the Study...................................109
13
Correlative Data Analysis.................................................................................................109
13.1
Translational and Correlative Biomarker Endpoints ........................................................109
14
Ethical and Regulatory Standards.....................................................................................110
14.1
Ethical Principles..............................................................................................................110
14.2
Informed Consent .............................................................................................................110
15
Study Responsibilities ......................................................................................................111
15.1
Data Collection .................................................................................................................111
15.2
Maintenance of Study Documents....................................................................................111
15.3
Study Governance and Oversight .....................................................................................111
16
Administrative Rules ........................................................................................................112
16.1
Revisions to the Protocol..................................................................................................112
16.2
Termination of the Study..................................................................................................112
16.3
Confidentiality ..................................................................................................................112
17
Appendices .......................................................................................................................113
18
References.........................................................................................................................164
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 22 of 169
IN-TEXT TABLES
Table 1
Treatment of Algorithm on True DLT Risk................................................................44
Table 2
Highly Effective Methods of Contraception (<1% failure rate)..................................61
Table 3
Prohibited Medications................................................................................................63
Table 4
Rescue Medications.....................................................................................................64
Table 5
Schedule of Procedures and Observations ..................................................................75
Table 6
Hematology Laboratory Tests.....................................................................................82
Table 7
Clinical Chemistry (serum or plasma) Laboratory Tests ............................................82
Table 8
Urinalysis Tests ...........................................................................................................82
Table 9
Tumor Marker .............................................................................................................83
Table 10
Volume of Blood to be drawn from each Participant..................................................88
Table 11
Guidelines for Routine Adverse Event Reporting for Phase 1 Studies (Regardless of 
Expectedness) ................................................................................................................................97
Table 12
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies (Regardless of 
Expectedness) ................................................................................................................................97
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 23 of 169
APPENDICES
Appendix A
Instructions for Network Sites ...........................................................................113
Appendix B
ECOG Performance Status Scores.....................................................................117
Appendix C
Durvalumab: Dose Calculations ........................................................................118
Appendix D
Durvalumab: Dose Volume Calculations ..........................................................119
Appendix E
Tremelimumab: Dose Calculations....................................................................120
Appendix F
Tremelimumab: Dose Volume Calculations......................................................121
Appendix G
Dosing Modification and Toxicity Management Guidelines for Immune-
Mediated, Infusion-Related and, Non-Immune-Mediated Reactions (MEDI4736 Monotherapy or 
Combination Therapy with Tremelimumab or Tremelimumab Monotherapy): 17 October 2019 
Version 4.03
122
Appendix H
Schedule of study procedures: Follow-up for subjects who have completed 
durvalumab, tremelimumab and olaparib treatment and achieved disease control (until confirmed 
progression of disease) and subjects who have discontinued study treatment due to toxicity in the 
absence of confirmed progression of disease ..............................................................................151
Appendix I
Schedule of study procedures: follow-up for subjects who have discontinued study 
treatment due to confirmed progression of disease at the investigator discretion.......................153
Appendix J
Diary for Medication (Olaparib)........................................................................154
Appendix K
irRECIST Summary...........................................................................................156
Appendix L
Calculation for Creatinine Clearance.................................................................161
Appendix M PAXgene® RNA Tube Freezing/Storage ..............................................................163
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 24 of 169
1
BACKGROUND
1.1
Recurrent Ovarian Cancer
Most patients with epithelial ovarian cancer present with advanced disease at diagnosis (1). The 
standard of care for first-line treatment after primary cytoreductive surgery is the combination of 
a platinum drug with a taxane (2): This combination results in response rates (RR) of 70% in 
patients with suboptimally-debulked disease and, of 80% in optimally cytoreduced patients (2). 
However, disease recurrence is common in this patient population and most patients with recurrent 
ovarian cancer eventually develop platinum-resistant disease (defined as disease recurring within 
6 months after the last treatment with platinum-based chemotherapy) (3).
Platinum-sensitive disease: Carboplatin and paclitaxel (CP) have emerged as standard for re-
challenge in patients with platinum-sensitive recurrent ovarian cancer. Re-challenge with CP has 
been limited by the risk of cumulative peripheral neuropathy. Other carboplatin-based 
combinations, such as gemcitabine and carboplatin (4), and liposomal doxorubicin plus carboplatin 
(5) have been explored. The median PFS of the treatment regimens varies from 8.4 to 12.4 months, 
depending on the study (4-6). Unfortunately, these patients eventually develop platinum-resistant 
disease. Therefore, novel interventions are necessary for patients with platinum-sensitive recurrent 
ovarian cancer.
Platinum-resistant/refractory ovarian cancer is an unmet medical need: In women with 
platinum-resistant disease, RRs range from 10%-25% and duration of response is typically less 
than 6 months to chemotherapeutic agents, such as pegylated liposomal doxorubicin (PLD), 
topotecan, taxanes, etoposide, and gemcitabine (7). Thus, there is an urgent need for the 
development of alternative therapies given the poor response of recurrent disease to traditional 
cytotoxic agents. Two potential therapeutic targets are DNA damage repair and immune 
checkpoint pathways.
Ovarian Cancer and PARP Inhibition: PARP-1 is essential to the repair of DNA single-strand 
breaks via the base excision repair pathway. Poly (ADP-ribose) polymerase (PARP) plays a key 
role in DNA repair mechanisms by detecting and initiating repair after DNA strand breaks. 
Inhibition of PARP in DNA repair-defective tumors (like those with BRCA1 or BRCA2 
mutations) can lead to gross genomic instability and cell death. Recent in vitro and in vivo evidence 
suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers, but also 
as single agents to selectively kill cancers defective in DNA repair, specifically cancers with 
mutation in the breast cancer-associated genes, BRCA1 and BRCA2.
Much of the proof of concept and proof of principle single agent studies performed to date have 
centered on olaparib. Objective responses were observed only in confirmed carriers of BRCA1 or 
BRCA2 mutation, apart from one patient with a strong family history of BRCA mutation who 
declined mutational testing. Of the 60 patients entered, there were 9 partial or complete responses 
by RECIST criteria (8 with ovarian cancer and 1 with breast cancer) (8). A phase II trial evaluating 
two sequential cohorts of women with recurrent ovarian cancer (with confirmed germline BRCA1 
or BRCA2 mutation and measurable disease) enrolled 33 women treated at 400 mg BID and then 
24 women treated at 100 mg BID. Objective response rate (RECIST) was 33% (11/33 patients) in 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 25 of 169
the 400 mg BID cohort and 13% (3/24 patients) in the 100 mg BID cohort (9). In a further phase I 
study, 50 patients with recurrent ovarian cancer, known BRCA1 or BRCA2 mutation and 
measurable disease were treated with doses of olaparib ranging from 40 mg daily for 2 of 3 weeks, 
to 600 mg BID (11 patients). There was then a dose expansion cohort, where all patients received 
olaparib at 200 mg BID (39 patients). Objective response rate was 28% (14/50 patients). Objective 
response rates were reported according to platinum-sensitivity: Platinum-sensitive 46% (6/13 
patients); Platinum-resistant 33% (8/24 patients); and Platinum-refractory 0% (0/13 patients) (10). 
A potential explanation for the variable response according to platinum-sensitivity is the 
development of secondary mutations restoring BRCA 1/2 function (11-15).
Olaparib has also been evaluated as a single agent in a trial that included patients without germline 
BRCA1 or BRCA2 mutation. In this phase II trial, 86 patients were treated and evaluable for 
response (63 with ovarian cancer and 23 with breast cancer). Patients were entered with recurrent 
high grade serous and/or undifferentiated ovarian cancer or triple negative breast cancer. Patients 
were stratified according to whether they had a BRCA1 or BRCA2 mutation or not. In ovarian 
cancer, objective responses were seen in 41% (7/17 patients) with BRCA1 or BRCA2 mutation 
and 24% (11/46 patients) without BRCA1 or BRCA2 mutation (16). A three-arm randomized, 
open label, phase II trial of olaparib 200 mg BID (n=32), olaparib 400 mg BID (n=32) and 
pegylated liposomal doxorubicin (PLD) (n=33), in women with recurrent ovarian cancer, germline 
BRCA1 or BRCA2 mutation and recurrence within 12 months of prior platinum therapy has been 
conducted. PLD was given at 50 mg/m2 every 4 weeks. The primary endpoint was investigator 
assessed progression-free survival. The progression free survival (PFS) and objective response 
rates (RR) were similar between the 3 arms (17). The efficacy of olaparib was consistent with 
previous studies. The efficacy of PLD was greater than expected.
A randomized phase II maintenance trial of olaparib (400 mg BID) vs placebo was conducted in 
women with platinum sensitive recurrent high grade serous ovarian cancer (with and without 
BRCA1 or BRCA2 mutation) who had achieved a response (partial or complete) following 2nd 
line (or greater) platinum-based therapy. The time to progression in the 265 patient cohort was 
extended from 4.8 months to 8.4 months (HR: 0.35, P<0.001). Patients were not required to 
undergo BRCA1 and BRCA2 testing and they were not stratified as to whether they had a BRCA1 
or BRCA2 mutation or not (Ledermann et al, 2011).
Ovarian Cancer and the PD-1/PD-L1 pathway: Tumors employ the programmed cell death 1 
and its ligand (PD-1/PD-L1) inhibitory pathway to paralyze antitumor immune response. PD-L1 
(also known as B7-H1 or CD274) is a coregulatory molecule that is expressed on the surface of 
various types of cells, including immune cells and epithelial cells. By binding to its receptor PD-
1 on lymphocytes, it generates an inhibitory signal toward the T-cell receptor (TCR)-mediated 
activation of lymphocytes. PD-L1 expression in tumor cells has been shown to be an independent 
unfavorable prognostic factor in human ovarian cancer (18). Importantly, PD-L1 expression 
showed the closest relation to unfavorable prognosis among other immunosuppressive molecules 
that have been tested in ovarian cancer (19). Moreover, direct ex-vivo analysis of tumor antigen 
specific CD8+ T cells from tumor-infiltrating lymphocytes (TILs) of ovarian cancer patients 
demonstrated impaired effector function, that was could be restored by blocking the PD-1/PD-L1 
pathway (20). In preclinical models of ovarian cancer, PD-1/PD-L1 pathway blockade also 
enhanced the amplitude of tumor immunity by reprogramming suppressive and stimulatory signals 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 26 of 169
that yielded more powerful cancer control (21, 22). These data suggest that PD-L1 has a role in 
the clinical course of ovarian cancer by affecting the local immune microenvironment and that 
interruption of the PD-1/PD-L1 pathway could restore effective antitumor immunity in ovarian 
cancer patients.
Ovarian Cancer and the CTLA-4 pathway: Tremelimumab is a human monoclonal 
immunoglobulin G2 (IgG2) antibody specific for human cytotoxic T lymphocyte- associated 
antigen 4 (CTLA-4), a co-inhibitory receptor expressed on activated T cells. Tremelimumab has 
been shown to block the inhibitory signal mediated by interaction of human CTLA-4 on activated 
T cells with B7-1 and B7-2 on antigen-presenting cells. This is thought to maintain T cell activation 
in the tumor microenvironment and promote the establishment of tumor-specific immune 
responses. Inhibition of CTLA-4 signaling is a validated approach to cancer therapy, as shown by 
the approval in 2011 of ipilimumab for the treatment of metastatic melanoma based on statistically 
significant and clinically meaningful improvement in OS (23). Like melanoma, ovarian cancer is 
associated with significant tumor heterogeneity, and is also a rational target for immune therapy. 
Although antitumor effects have been observed in patients with epithelial ovarian cancer in 
response to anti-CTLA-4 antibody treatment, evidence of clinical disease regression has not been 
demonstrated.
1.2
Durvalumab, Tremelimumab and Olaparib Background
1.2.1 Durvalumab
The non-clinical and clinical experience is fully described in the current version of the durvalumab 
Investigator’s Brochure (IB Version 15.0).
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that inhibits binding of PD-L1 and is being developed by AstraZeneca/MedImmune for 
use in the treatment of cancer (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document). As 
durvalumab is an engineered mAb, it does not induce antibody-dependent cellular cytotoxicity or 
complement-dependent cytotoxicity. The proposed mechanism of action for durvalumab is 
interference of the interaction of PD-L1.
PD-L1 is expressed in a broad range of cancers with a high frequency, up to 88% in some types of 
cancers. In a number of these cancers, including lung, the expression of PD-L1 is associated with 
reduced survival and an unfavorable prognosis. In lung cancer, only 12% of patients with tumors 
expressing PD-L1 survived for more than 3 years, compared with 20% of patients with tumors 
lacking PD-L1 (24).  Based on these findings, an anti-PD-L1 antibody could be used 
therapeutically to enhance anti-tumor immune responses in patients with cancer. Results of several 
non-clinical studies using mouse tumor models support this hypothesis, where antibodies directed 
against PD-L1 or its receptor PD-1 showed anti-tumor activity (25-28).
Durvalumab has been given to humans as part of ongoing studies as a single drug or in combination 
with other drugs.  As of the data cut-off (DCO) date of (12 July 2019), across the entire clinical 
development program, approximately 8817 patients have received durvalumab in AstraZeneca or 
MedImmune-sponsored interventional studies in multiple tumor types, stages of disease and lines 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 27 of 169
of therapy. Of these, 4067 patients received durvalumab monotherapy, 2423 patients received 
durvalumab in combination with tremelimumab, and 2327 patients received durvalumab in 
combination with an investigational and or an approved product. An estimated 8343 patients have 
been randomized to the various treatment/comparator arms in sponsor-blinded studies. In addition, 
2482 patients have participated in the durvalumab Early Access Programme (EAP; Study 
D4194C00002) for patients with locally advanced, unresectable non-small cell lung cancer 
[NSCLC] whose disease has not progressed following platinum based chemoradiation therapy). 
The cumulative global-marketing patient exposure to durvalumab to (10 mg/kg) to 30 June 2019 
has been estimated to be approximately 12,385 patient-years.
Durvalumab 50 mg/ml was first approved for the treatment of patients with locally advanced or 
metastatic UC in the US on 1 May 2017. On 16 February 2018, durvalumab was approved in the 
US for the treatment of patients with unresectable Stage III NSCLC. On 21 September 2018, 
durvalumab was approved in the EU for the treatment of locally advanced, unresectable NSCLC 
in adults whose tumors express PD-L1 on ≥1% of tumor cells and whose disease has not progressed 
following platinum-based chemoradiation therapy. As of 12 July 2019, durvalumab is approved in 
18 countries for UC and over 45 countries for NSCLC.
Study CD-ON-MEDI4736-1108: As of 16 October 2017, PK data were available for 1009 patients 
following treatment with 0.1 to 10 mg/kg Q2W and 15 mg/kg Q3W (dose-escalation), 10 mg/kg 
Q2W (dose-expansion), and 20 mg/kg Q4W (dose-exploration) durvalumab administered as an IV 
infusion over 60 minutes. The Cmax increased in an approximately dose-proportional manner over 
the dose range examined. The AUC0-14 increased dose-proportionally at doses of 3 to 20 mg/kg 
and more than dose-proportionally at doses of <3 mg/kg, likely due to saturable target-mediated 
clearance (CL). The steady state was achieved at approximately Week 16. Accumulation of 
durvalumab was observed following repeated dosing. Mean accumulation ratio (AR) ranged from 
0.64 to 1.87 and 3.16 to 4.93 for Cmax and Cmin, respectively. Near complete target saturation (sPD-
L1 and membrane bound) is expected with durvalumab ≥3 mg/kg Q2W.
As of 16 October 2017, a total of 849 patients provided evaluable samples for ADA analysis. The 
overall ADA prevalence (the proportion of patients who were evaluable for ADA and were positive 
for durvalumab ADA at any point in time) was 5.3% (45 of 849 patients). The overall ADA 
incidence (the proportion of the study population who were evaluable for ADA and were 
treatment-emergent ADA positive) was 3.1% (26 of 849 patients). Three patients (0.4%, in 3/810 
patients) were neutralizing ADA (nAb) positive. Based on population PK covariate analysis, ADA 
positive status was not associated with a clinically relevant reduction of exposure to durvalumab. 
At the 10 mg/kg Q2W dose, sPD-L1 suppression in ADA positive patients was similar to that 
observed in ADA negative patients. The impact of treatment-emergent ADA on the clinical 
efficacy of durvalumab in urothelial carcinoma (UC) and non-small cell lung cancer (NSCLC) 
patients was not evaluable due to very few patient samples testing positive for treatment-emergent 
ADA.
Durvalumab + tremelimumab: Study D4190C00006: As of 28 February 2017, durvalumab PK 
(n=347) and tremelimumab PK (n=353) data were available from the dose-escalation and dose-
expansion phases following durvalumab Q4W (3, 10, 15, or 20 mg/kg) or Q2W (10 mg/kg) in 
combination with tremelimumab Q4W (1, 3, or 10 mg/kg). An approximately dose-proportional 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 28 of 169
increase in PK exposure (Cmax and AUC 0 to 28 days [AUC0-28]) of both durvalumab and 
tremelimumab was observed over the dose range of 3 to 20 mg/kg durvalumab Q4W and 1 to 10 
mg/kg tremelimumab Q4W. Exposures following multiple doses demonstrated accumulation 
consistent with PK parameters estimated from the first dose. The observed PK exposures of 
durvalumab and tremelimumab following combination were consistent with respective 
monotherapy data, indicating no PK interaction between these 2 agents.
As of 28 February 2017, ADA data were available from 99 patients for durvalumab and95 patients 
for tremelimumab in Study D4190C00006. The ADA prevalence was 7.1% (7/99 patients) for 
durvalumab and 6.3% (6/95 patients) for tremelimumab. The ADA incidence was 2.0% (2/99 
patients) for durvalumab and 5.3% (5/95 patients) for tremelimumab. No patients treated with 
durvalumab tested positive for the presence of nAb. There was no clear relationship between ADA 
and the dose of either durvalumab or tremelimumab, and no apparent association between ADA 
and safety.
1.2.2 Tremelimumab
Tremelimumab is an IgG 2 kappa isotype mAb directed against the cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) also known as CD152 (cluster of differentiation 152). This is an 
immunomodulatory therapy (IMT) that is being developed by AstraZeneca for use in the treatment 
of cancer.
Binding of CTLA-4 to its target ligands (B7-1 and B7-2) provides a negative regulatory signal, 
which limits T-cell activation. Anti-CTLA-4 inhibitors antagonize the binding of CTLA-4 to B7 
ligands and enhance human T-cell activation as demonstrated by increased cytokine (interleukin 
[IL]-2 and interferon [IFN] gamma) production in vitro in whole blood or peripheral blood 
mononuclear cell (PBMC) cultures (29). In addition, blockade of CTLA-4 binding to B7 by anti-
CTLA-4 antibodies results in markedly enhanced T-cell activation and anti-tumor activity in 
animal models, including killing of established murine solid tumors and induction of protective 
anti-tumor immunity. (Refer to the tremelimumab IB, Edition 9.0, for more information). 
Therefore, it is expected that treatment with an anti-CTLA-4 antibody, such as tremelimumab, will 
lead to increased activation of the human immune system, increasing anti-tumor activity in patients 
with solid tumors.
An extensive program of non-clinical and clinical studies has been conducted for tremelimumab 
both as monotherapy and combination therapy with conventional anticancer agents to support 
various cancer indications using different dose schedules. As of the data cutoff date (12 July 2018), 
approximately 1670 patients have been exposed to one or more doses of tremelimumab 
monotherapy across the program; 734 patients from AstraZeneca/MedImmune sponsored studies 
D4884C00001, D4880C00003 (DETERMINE), D4880C00010, D4193C00003 (CONDOR), 
D4881C00024, D4190C00022, D4191C00004 (ARCTIC) and D4191C00011; 967 patients from 
legacy studies (monotherapy). Details on the safety profile of tremelimumab monotherapy are 
summarized in Section 1.3.
Refer to the current tremelimumab IB (IB Version 9.0) for a complete summary of non-clinical 
and clinical information.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 29 of 169
Refer to Section 6.5 for guidance on management of tremelimumab-related toxicities.
Tremelimumab exhibited a biphasic PK profile with a long terminal phase half-life of 22 days. 
Overall, a low incidence of ADAs (<6%) was observed for treatment with tremelimumab.
1.2.3 Durvalumab in combination with Tremelimumab
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity (30) because 
the mechanisms of action of CTLA-4 and PD-1 are non-redundant; therefore, AstraZeneca is also 
investigating the use of durvalumab + tremelimumab combination therapy for the treatment of 
cancer.
Study D4190C00006 is a Phase Ib dose-escalation study to establish safety, PK/PDx, and 
preliminary anti-tumor activity of durvalumab + tremelimumab combination therapy in patients 
with advanced NSCLC. The dosing schedule utilized is durvalumab every 2 weeks (Q2W) or every 
4 weeks (Q4W) up to Week 50 and 48 (12 months), combined with tremelimumab Q4W up to 
Week 24 for 7 doses then every 12 weeks for 2 additional doses for up to 12 months. The study is 
ongoing and continues to accrue.
Study D4190C00006: As of the DCO of 28 February 2017, the ORR per investigator assessment 
in the total dose-escalation group (patients with advanced NSCLC) was 16.7% (17/102; 95% CI: 
10.0, 25.3). ORRs were 28.0% (7/25; 95% CI: 12.1, 49.4) in the PD-L1 high (TC ≥25%) and 
14.0% (8/57; 95% CI: 6.3, 25.8) in the PD-L1 low/negative (TC <25%) group. No objective 
response (OR) was observed at the lowest dose-level combinations of durvalumab 3 or 10 mg/kg 
Q4W + tremelimumab 1 mg/kg. The median TTR was 7.1 weeks and the median DOR had not yet 
been reached. The DCR was 47%. Median OS in the combined tremelimumab 3 mg/kg group 
exceeded that in the tremelimumab 1 and 10 mg/kg groups (16.7 months vs 11.8 and 10.3 months, 
respectively).
In the dose expansion Cohort A (treatment-naive NSCLC selected by PD-L1 status), the ORR was 
15.6% (7/45; 95% CI: 6.5, 29.5). ORRs were 16.7% (3/18; 95% CI: 3.6, 41.4) in the PD-L1 high 
and 12.0% (3/25; 95% CI: 2.5, 31.2) in the PD-L1 low/negative group. A DCR of 57.8% (26/45; 
95% CI: 42.2, 72.3) was observed. The median TTR was 7.3 weeks with a median DOR of 24.4 
weeks. Clinical response was observed in both the PD-L1 high and PD-L1 low/negative subgroups. 
In the As-treated Population, the median PFS was 3.5 months, with a PFS rate of 38.8% at 6 
months. Median OS was not reached, with an OS rate at 6 months of 83.6%.
In the dose expansion Cohort B co-administration group (immunotherapy-naïve, 1L or 2L patients 
with NSCLC, N=19), no objective responses were observed per investigator assessment. A best 
overall response of SD was observed for 9 of the 19 patients (DCR, 47.4%; 95% CI: 24.4, 71.1).
In the dose expansion Cohort B sequential administration group (2L patients with non- squamous 
NSCLC), the ORR per BICR was 14.5% (30/207; 95% CI: 10.0, 20.0). ORRs were 33.9% (19/56; 
95% CI: 21.8, 47.8) in the PD-L1 high and 6.8% (9/132; 95% CI: 3.2, 12.5) in the PD L1 
low/negative subgroup. A DCR of 49.8% (103/207; 95% CI: 42.8, 56.8) was observed. The median 
TTR was 7.2 weeks. The median DOR was not reached. Among the 30 responders, 25 (83.3%) 
had an ongoing response and 11 (36.7%) patients responded for at least 24 weeks. Median PFS 
per BICR (As-treated Population) was 3.4 months (95% CI: 1.7, 3.5) in the total group, 5.4 months 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 30 of 169
(95% CI: 3.4, not estimable) in the PD-L1 high subgroup, and 1.7 months (95% CI: 1.7, 3.5) in 
the PD-L1 low/negative subgroup. The median OS was not reached; however, the overall OS rate 
at 6 months was 68.0% (95% CI: 60.3, 74.5) and higher in the PD-L1 high (81.2%) vs the PD L1 
low/negative (61.3%) subgroup.
Study D4190C00022: As of the 13 January 2017, 40 patients with HCC were evaluable for 
response at ≥16 weeks follow-up. Confirmed ORR was 17.5% (95% CI: 7.3, 32.8). The median 
TTR was 8 weeks (range, 7.6 to 24 weeks). The DCR (defined as any CR + PR + SD >16 weeks) 
was 57.5% (95% CI: 40.9, 73.0).
1.2.4 Olaparib
Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated as monotherapy in patients 
with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-
approved test) advanced ovarian cancer who have been treated with three or more prior lines of 
chemotherapy. The indication is approved under accelerated approval based on objective response 
rate and duration of response. Continued approval for this indication may be contingent upon 
verification and description of clinical benefit in confirmatory trials.
Investigators should be familiar with the current olaparib (AZD2281) Investigator Brochure (IB 
version 17.0). Olaparib (AZD2281, KU-0059436) is a potent Poly-adenosine 5’diphosphoribose 
[poly (ADP ribose] polymerization (PARP) inhibitor (PARP-1, -2 and -3) that is being developed 
as an oral therapy, both as a monotherapy (including maintenance) and for combination with 
chemotherapy and other anti-cancer agents.
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA repair 
mechanisms. PARP enzymes are essential for repairing DNA single strand breaks (SSBs). 
Inhibiting PARPs leads to the persistence of SSBs, which are then converted to the more serious 
DNA double strand breaks (DSBs) during the process of DNA replication. During the process of 
cell division, DSBs can be efficiently repaired in normal cells by homologous recombination repair 
(HR). Tumors with HR deficiencies (HRD), such as serous ovarian cancers, cannot accurately 
repair the DNA damage, which may become lethal to cells as it accumulates. In such tumor types, 
olaparib may offer a potentially efficacious and less toxic cancer treatment compared with 
currently available chemotherapy regimens.
Olaparib has been shown to inhibit selected tumor cell lines in vitro and in xenograft and primary 
explant models as well as in genetic BRCA knock-out models, either as a stand-alone treatment or 
in combination with established chemotherapies. Cells deficient in homologous recombination 
DNA repair factors, notably BRCA1/2, are particularly sensitive to olaparib treatment.
PARP inhibitors such as olaparib may also enhance the DNA damaging effects of chemotherapy 
(31-33). For further information please refer to the current version of the olaparib IB (Version 
17.0).
1.3
Risks and/or Benefits
The proposed study focuses on evaluating the safety of the combination of durvalumab and 
tremelimumab with olaparib and the expanded cohort will determine the efficacy of this 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 31 of 169
combination in treating recurrent ovarian cancer. There is a sound rationale to combine these drugs 
(Section 2) and the results from this study will form the basis for decisions for future studies.
1.3.1 Potential Benefits
1.3.1.1
Durvalumab
The majority of the safety and efficacy data currently available for durvalumab are based on the 
first time in-human, single-agent study (Study 1108) in patients with advanced solid tumors.
NSCLC cohort: Overall, clinical activity was observed in both the PD-L1 high (defined as having 
tumor cells [TC] ≥25%) and PD-L1 low/negative (defined as TC <25%) subgroups, however, 
patients with PD-L1 high tumors had higher objective response rates (ORRs). The ORR per 
blinded independent central review [BICR] was 21.8% and 6.4% in patients with PD-L1 high and 
low/negative tumors, respectively and 15.3% in the overall population regardless of PD-L1 
expression. ORR was 25.9%, 14.3% and 11.5% in the 1L, 2L and 3L+ cohorts, respectively. 
Median duration of response (DOR) was 17.74 months. Median overall survival (OS) was 12.4 
months; median OS was 21.0, 11.8 and 9.3 months in the 1L, 2L and 3L+ cohorts, respectively.  
The OS rate at 24 months was 29.6%.
Head and neck squamous cell carcinoma (HNSCC) cohort: ORR per BICR was 7.3% across 
all patients, 16.7% in patients with PD-L1 high tumors and 2.9% in patients with PD-L1 
low/negative tumors. Median OS was 8.4 months and the OS rate at 24 months was 24.2%.
UC cohort: The ORR per BICR was numerically higher in the PD-L1 high (TC ≥25% or IC ≥25%) 
subgroup (27.7%) compared with the PD-L1 low/negative (TC <25% and IC <25%) subgroup 
(5.9%); and 17.6% overall regardless of PD-L1 expression. The median OS was 10.5 months; the 
OS rate at 24 months was 30.0%.
Hepatocellular carcinoma (HCC) cohort: ORR per Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 was 10%. The median OS was 13.2 months; the OS rate at 24 months 
was 28.2%.
1.3.1.2
Tremelimumab
Across the clinical development program for tremelimumab, a pattern of efficacy has emerged that 
is similar to that of the related anti-CTLA-4 antibody, ipilimumab. Response rates to anti-CTLA-
4 antibodies are generally low, approximately 10%. However, in patients who respond, the 
responses are generally durable, lasting several months even in those with aggressive tumors such 
as refractory metastatic melanoma. Summary efficacy data for completed studies are presented in 
Table 10 of IB Edition 9. 
1.3.1.3
Durvalumab plus Tremelimumab
The preclinical and clinical justification for this combination as noted in Section 1.2.3 also 
supports the synergy of this combination. Available data, such as those presented by Wolchok et 
al, 2013 (38) suggest that the combination of agents targeting PD-1/PD-L1 and CTLA-4 may have 
profound and durable benefits in patients with melanoma. 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 32 of 169
Study D4190C00006 (NSCLC): In the dose expansion Cohort A (treatment-naive NSCLC selected 
by PD-L1 status), the ORR was 15.6% (7/45; 95% CI: 6.5, 29.5). ORRs were 16.7% (3/18; 95% 
CI: 3.6, 41.4) and 12.0% (3/25; 95% CI: 2.5, 31.2) in the PD L1 high and PD-L1 low/negative 
groups, respectively. Median OS was not reached, with an OS rate at 6 months of 83.6%. In the 
dose expansion Cohort B co-administration group (immunotherapy-naïve, 1L or 2L patients with 
NSCLC), no objective responses were observed per investigator assessment. A best overall 
response of SD was observed for 9 of the 19 patients (DCR 47.4%; 95% CI: 24.4, 71.1). In the 
dose expansion Cohort B sequential administration group (2L patients with non-squamous 
NSCLC), the ORR per BICR was 18.8% (40/213; 95% CI: 13.8, 24.7); ORRs were 35.1% (20/57; 
95% CI: 22.9, 48.9) and 11.8% (16/136; 95% CI: 6.9, 18.4) in the PD-L1 high and PD-L1 
low/negative subgroups, respectively. Median PFS per BICR was 3.5, 7.1 and 3.3 months in the 
total, PD-L1 high and PD-L1 low/negative groups, respectively. The median OS was 15.4 months; 
the OS rate at 12 months was 53.8% and higher in the PD-L1 high (71.6%) vs the PD-L1 
low/negative (47.3%) subgroup. In Cohort C (immunotherapy-pretreated, 2L to 4L patients with 
NSCLC), the ORR by investigator assessment was 5.1% (4/78; 95% CI: 1.4, 12.6); ORRs were 
7.7% (2/26; 95% CI: 0.9, 25.1) and 2.9% (1/34; 95% CI: 0.1, 15.3) in the PD-L1 high and PD-L1 
low/negative subgroups, respectively. Median PFS was 1.8, 1.7 and 1.7 months in the total, PD-
L1 high and PD-L1 low/negative groups, respectively. The median OS was 8.4 months; the OS 
rate at 12 months was 34.1% and was similar in the PD-L1 high (31.5%) vs the PD-L1 
low/negative (29.8%) subgroup.
To date, no assay has been established or validated, and no single approach has proven accurate, 
for patient enrichment for checkpoint blockade. However, independent data from multiple sources 
using different assays and scoring methods suggests that PD-L1 expression on tumor cells and/or 
tumor infiltrating cells may be associated with greater clinical benefit.
Data from ongoing studies with durvalumab and other agents targeting the PD-1/PD-L1 pathway 
suggest, as shown in a number of tumor types (e.g., NSCLC, renal cell carcinoma, and melanoma), 
that monotherapy may be more efficacious (in terms of ORR) in patients who are PD-L1-positive.
Given these findings, a number of ongoing studies are assessing the activity of agents in patients 
with PD-L1–positive tumors. There is also an unmet medical need in patients with PD-L1–
negative tumors that needs to be addressed. Data, as of 27 January 2015 from Study 006 show that 
with the addition of tremelimumab to durvalumab, the ORR can be increased to 25% in patients 
with PD-L1 negative NSCLC. As patients with PD-L1 positive disease can also have an increase 
in ORR, from 25% with durvalumab monotherapy, to 36% with the combination of durvalumab 
and tremelimumab, the study will enroll all patients with NSCLC, with an emphasis on those 
determined to be PD-L1 negative.
1.3.1.4
Olaparib
The efficacy of olaparib was investigated in a single-arm study in patients with deleterious or 
suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. A total of 137 
patients with measurable, gBRCAm-associated ovarian cancer treated with three or more prior 
lines of chemotherapy were enrolled. All patients received olaparib at a dose of 400 mg (capsule) 
twice daily as monotherapy until disease progression or intolerable toxicity. Objective response 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 33 of 169
rate (ORR) and duration of response (DOR) were assessed by the investigator according to 
RECIST v1.1. ORR was 34%, complete response (CR) in 2%, partial response (PR) in 32% with 
a median DOR of 7.9 months.
The median age of the patients was 58 years, the majority were Caucasian (94%) and 93% had an 
ECOG PS of 0 or 1. Deleterious or suspected deleterious, germline BRCA mutation status was 
verified retrospectively in 97% (59/61) of the patients for whom blood samples were available by 
the companion diagnostic BRACAnalysis CDxTM, which is FDA approved for selection of 
patients for olaparib treatment.
1.3.2 Potential Risks
1.3.2.1
Durvalumab
Potential risks, based on the mechanism of action of durvalumab and related molecules, include: 
immune-mediated reactions, such as enterocolitis, dermatitis, hepatitis/hepatotoxicity, 
endocrinopathy, pneumonitis, and neuropathy or neurologic events. Additional important potential 
risks include infusion-related reactions, hypersensitivity, anaphylaxis or serious allergic reactions, 
serious infections, and immune complex disease.
Monotherapy pool: Safety data have been pooled for 3 durvalumab monotherapy studies (CD-
ON-MEDI4736-1108, PACIFIC, D4191C00003 [ATLANTIC], D4191C00004
[ARCTIC], D4190C00002, D4193C00001 [HAWK], D4193C00003 [CONDOR] and MYSTIC) 
for patients who received a durvalumab dose of 10 mg/kg Q2W or 20
mg/kg Q4W; a total of 2769 patients are included in this validated pooled data set.

Overall, AEs reported in ≥15% of patients were fatigue, decreased appetite, cough, 
nausea dyspnea, constipation and diarrhea; AEs considered by the investigator as related 
to durvalumab in ≥5% of patients were fatigue, diarrhea, hypothyroidism, pruritus, 
nausea, decreased appetite and rash.

 A total of 44.5% patients reported AEs of Common Terminology Criteria for Adverse 
Events (CTCAE) Grade 3 or higher: Grade 3, 4 and 5 (fatal) events were reported in 
34.5%, 4.7% and 5.2% patients, respectively; Grade 3, 4 and 5 (fatal) events considered 
related to durvalumab were reported in 9.9%, 1.0% and 0.6% patients, respectively.

Grade 3 or 4 events occurring in ≥2% of patients were anemia, dyspnea, hyponatremia, 
fatigue, pneumonia and gamma-glutamyltransferase (GGT) increased; Grade 3 or 4 
events considered related to durvalumab occurring in ≥0.5% patients were fatigue, GGT 
increased, pneumonitis and aspartate aminotransferase (AST) increased.

The most common Grade 5 events were general physical health deterioration (0.5% 
patients), respiratory failure, pneumonia and sepsis (0.4% patients each). The only Grade 
5 events considered related to durvalumab occurring in ≥2 patients were pneumonitis and 
respiratory failure.

A total of 9.4% patients discontinued from study treatment due to an AE. The most 
common events leading to treatment discontinuation (≥5 patients) were pneumonitis, 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 34 of 169
pneumonia, dyspnea, general physical health deterioration, interstitial lung disease (ILD), 
radiation pneumonitis, sepsis and anemia.

A total of 6.5% patients had serious AEs (SAEs) that were considered by the investigator 
as related to durvalumab.

A total of 53.4% patients experienced an AESI. The most common grouped term AESI 
was diarrhea (16.9% patients; of whom 0.7% had events of Grade ≥3). Other common 
AESIs (>10%; grouped term) were dermatitis (15.1% patients; of whom 0.2% had events 
of Grade ≥3); rash (14.5% patients; of whom 0.6% had events of Grade ≥3); hypothyroid 
events (11.3% patients; of whom 0.2% had events of Grade ≥3); and hepatic events 
(10.9% patients; of whom 3.8% had events of Grade ≥3).
PACIFIC: Overall durvalumab monotherapy (10 mg/kg Q2W) was well-tolerated and had a 
manageable safety profile relative to the standard of care (SoC) in this placebo-controlled study 
where durvalumab or placebo was given to patients following concurrent chemoradiation to the 
chest for stage IIIA/IIIB unresectable NSCLC. Generally, the type, incidence, and severity of AEs 
were comparable between the durvalumab and placebo treatment groups. Where not comparable, 
the type, incidence, and severity of events were consistent with the established durvalumab safety 
profile to date (safety monotherapy pool). The exception to this was for events of 
pneumonitis/radiation pneumonitis, for which, as expected in this patient population, there was a 
high background incidence. However, despite a numerical increase in these events for patients 
receiving durvalumab over those receiving placebo, most of these events were low grade. 
Clinically important CTCAE Grade 3 or 4 events were infrequent and balanced between the 2 
treatment groups.
The data incidences for this study are provided in the format of durvalumab vs placebo arms 
respectively. Safety data is presented based on a DCO of 22 March 2018.

AEs experienced during the study with an incidence of >15% were cough (35.2% vs 
25.2%); fatigue (24.0% vs 20.5%); dyspnea (22.3% vs 23.9%); radiation pneumonitis 
(20.2% vs 15.8%); and diarrhea (18.5% vs 19.7%) and pyrexia (15.2% vs 9.4%). 
Combined events of pneumonitis or radiation pneumonitis occurred in 33.9% vs 24.8% of 
patients.

CTCAE Grade 3 or 4 AEs were reported in 32.6% vs 28.2% of patients. CTCAE Grade 3 
pneumonitis or radiation pneumonitis occurred in 3.6% vs 3.0% of patients and there 
were no Grade 4 events.

SAEs were reported in 29.1% vs 23.1% of patients.

AEs with an outcome of death were comparable between treatment groups (4.4% vs 
7.2%). The only AEs with an outcome of death experienced by >1 patient in the 
durvalumab arm were pneumonitis and cardiac arrest. Fatal events of pneumonitis or 
radiation pneumonitis were balanced between the 2 treatment groups.

A total of 15.4% vs 9.8% of patients had an AE that led to permanent discontinuation of 
treatment. AEs leading to discontinuation reported in ≥2 patients were pneumonitis (4.8% 
vs 2.6%), radiation pneumonitis (1.3% vs 1.3%) and pneumonia (1.1% vs 1.3%).

A total of 66.7% vs 49.1% of patients experienced an AESI. AESIs, grouped terms, with 
an overall incidence >15% were dermatitis or rash (33.1% vs 18.4%) and diarrhea (18.5% 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 35 of 169
vs 20.1%). A total of 9.1% vs 3.4% of patients experienced CTCAE Grade 3 or 4 AESIs. 
AESIs with an outcome of death occurred in 4 patients (0.8%) treated with durvalumab 
(all pneumonitis events) and 5 patients (2.1%) treated with placebo (4 patients [1.7%] 
with pneumonitis and 1 patient [0.4%] with eosinophilic myocarditis).
Consistent with the immune-mediated mechanism of action for durvalumab, there was a higher 
incidence of imAEs for patients receiving durvalumab (24.4% vs 8.1% of patients).
1.3.2.2
Tremelimumab
Potential risks, based on the mechanism of action of tremelimumab and related molecules 
(ipilimumab) include: potentially immune-mediated gastrointestinal (GI) events including 
enterocolitis, intestinal perforation, abdominal pain, dehydration, nausea and vomiting, and 
decreased appetite (anorexia); dermatitis including urticaria, skin exfoliation, and dry skin; 
endocrinopathies including hypophysitis, adrenal insufficiency, and hyperthyroidism and 
hypothyroidism; hepatitis including autoimmune hepatitis and increased serum ALT and AST; 
pancreatitis including autoimmune pancreatitis and lipase and amylase elevation; respiratory tract 
events including pneumonitis and interstitial lung disease (ILD); nervous system events including 
encephalitis, peripheral motor and sensory neuropathies, and Guillain-Barré syndrome; cytopenias 
including thrombocytopenia, anemia, and neutropenia; infusion-related reactions; anaphylaxis; 
and serious allergic reactions. The profile of AEs and the spectrum of event severity have remained 
stable across the tremelimumab clinical program and are consistent with the pharmacology of the 
target.
To date, no tumor type or stage appears to be associated with unique AEs (except for vitiligo that 
appears to be confined to patients with melanoma). 
Based on a data cutoff date of 24 January 2016, in Study D4880C00003 (DETERMINE; 
mesothelioma), the proportion of patients with any AE (95.8% in the tremelimumab 10 mg/kg vs 
94.7% in the placebo group) and with AEs with an outcome of death (9.5% vs 6.3%, respectively) 
were similar between tremelimumab and placebo groups. The proportion of patients with AEs 
≥Grade 3 (64.7% in the tremelimumab 10 mg/kg group vs 48.1% in the placebo group), SAEs 
(57.4% vs 45.0%) and AEs leading to discontinuation of treatment (27.4% vs 5.3%) were higher 
compared with the placebo group.
In the TMMD pool, at the dose of tremelimumab 10 mg/kg Q4W used in Study D4880C00003 
(DETERMINE), a lower proportion of patients in the melanoma group had AEs leading to 
discontinuation of treatment (18.2%) compared with patients in the mesothelioma group (27.4%). 
Overall, the incidence of AEs ≥Grade 3 (47.0% vs 64.7% in mesothelioma group) and SAEs 
(43.9% vs 57.4% in mesothelioma group) in patients with melanoma were generally lower than in 
patients with mesothelioma. 
In the TST pool 15 mg/kg group, and overall, the proportion of patients with any AE was similar 
to the TMMD pool.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 36 of 169
1.3.2.3
Durvalumab plus Tremelimumab
No safety studies in animals have been performed combining tremelimumab with durvalumab. As 
both CTLA-4 and PD-L1 have mechanisms of actions that enhance activation of immune cells, 
their potential to induce cytokine release was tested in a whole-blood assay system. Durvalumab 
and tremelimumab, either alone or in combination, did not induce cytokine release in blood from 
any donor.
Durvalumab + tremelimumab pool: Safety data have been pooled for 9 durvalumab and 
tremelimumab combination studies (D4190C00002, D4190C00006, D4190C00010, 
D4190C00011, D4190C00021, D4190C00022, CONDOR, MYSTIC, and ARCTIC) for patients 
who received a dose of 20 mg/kg durvalumab plus 1 mg/kg tremelimumab, or equivalent 
durvalumab 1500 mg + tremelimumab 75 mg fixed dose; a total of 1822 patients are included in 
this pooled data set.

Overall, AEs reported in ≥15% of patients were fatigue, diarrhea, decreased appetite, 
nausea, pruritus, dyspnea, constipation, anemia, pyrexia and, vomiting. AEs reported in 
≥5% of patients that were considered by the investigator as treatment-related were 
fatigue, pruritus, diarrhea, decreased appetite, rash, nausea, hypothyroidism, lipase 
increased, rash maculo-papular, hyperthyroidism, pyrexia, amylase increased and, 
asthenia.

A total of 63.7% patients reported AEs of Grade 3 or higher: Grade 3, 4 and 5 (fatal) 
events were reported in 39.6%, 8.1% and 16.0% patients, respectively; Grade 3, 4 and 5 
(fatal) events considered related to durvalumab were reported in 20.0%, 3.6% and 0.7% 
patients, respectively.

AEs ≥Grade 3 occurring in ≥2% of patients were anemia, hyponatremia, lipase increased, 
pneumonia, dyspnea, diarrhea hypokalemia, fatigue, GGT increased, amylase increased, 
asthenia, AST increased, dehydration, colitis, pulmonary embolism, abdominal pain, 
hyperglycemia, nausea, alanine aminotransferase (ALT) increased and, back pain; 
≥ Grade 3 events considered treatment-related occurring in ≥1% patients were lipase 
increased, diarrhea, amylase increased, colitis, fatigue, pneumonitis, hyponatremia, AST 
increased, ALT increased.

A total of 17.1% patients had SAEs that were considered treatment-related by the 
investigators.

A total of 15.5% patients discontinued from study treatment due to an AE. The most 
common events leading to treatment discontinuation were colitis, diarrhea, pneumonitis 
and bladder cancer.

A total of 68.6% patients had AESIs. The most common grouped term AESI was 
dermatitis/rash (38.4% patients, of whom 1.4% had events of Grade ≥3). Other common 
(>10%) AESIs by grouped term were diarrhea/colitis (28.5% patients, of whom 5.8% had 
events of Grade ≥3); hepatic events (15.5% patients, of whom 5.7% had events of Grade 
≥3); hypothyroid events (11.5% patients, of whom 0.2% had events of Grade ≥3); and 
pancreatic events (11.5% patients, of whom <6.9% had events of Grade ≥3).
In the literature (38), using the combination of the same class of drugs (e.g., anti PD-1 and anti-
CTLA4 antibodies), specifically nivolumab + ipilimumab in a study involving patients with 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 37 of 169
malignant melanoma, the safety profile of this combination had shown occurrences of AEs 
assessed by the Investigator as treatment-related in 93% of treated patients, with the most frequent 
events being rash (55% of patients), pruritus (47% of patients), fatigue (38% of patients), and 
diarrhea (34% of patients).  Grade 3 or 4 AEs, regardless of causality, were noted in 72% of 
patients, with Grade 3 or 4 events assessed by the Investigator as treatment-related in 53%. The 
most frequent of these Grade 3 or 4 events assessed by the Investigator as treatment-related include 
increased lipase (in 13% of patients), AST (in 13%), and ALT levels (in 11%). Frequent Grade 3 
or 4 selected AEs assessed by the Investigator as treatment-related in the combination therapy 
included hepatic events (in 15% of patients), GI events (in 9%), and renal events (in 6%). Isolated 
cases of pneumonitis and uveitis were also observed.
1.3.2.4
Olaparib
Olaparib 400 mg (capsule) twice daily as monotherapy, has been studied in 300 patients with 
gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior 
lines of chemotherapy. In the 223 patients with gBRCA-mutated ovarian cancer who received 3 
or more prior lines of chemotherapy (including 137 patients in Study 1 with measurable disease) 
adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and 
discontinuation in 7%. There were 8 (4%) patients with adverse reactions leading to death, two 
were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, 
intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Adverse reactions reported 
in ≥20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had 
received 3 or more prior lines of chemotherapy who were treated with olaparib 400 mg twice daily 
were anemia, abdominal pain/discomfort, decreased appetite, nausea, vomiting, diarrhea, 
dyspepsia, fatigue/asthenia, nasopharyngitis, upper respiratory infection, arthralgia, and myalgia. 
Abnormal laboratory findings were decrease in hemoglobin, absolute neutrophil count, platelets, 
lymphocytes, mean corpuscular volume elevation and, increase in creatinine. The median exposure 
to olaparib in these patients was 158 days. The following adverse reactions and laboratory 
abnormalities have been identified in ≥10 to <20% of the 223 patients receiving olaparib and not 
included in the table: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, 
headache, urinary tract infection, dyspnea, and rash. The following adverse reactions and 
laboratory abnormalities have been identified in ≥1 to <10% of the 223 patients receiving olaparib 
and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, 
hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, 
vulvovaginal disorder, dry skin/ eczema, pruritis, hypertension, venous thrombosis (including 
pulmonary embolism), and hot flush.
In a randomized trial of olaparib 400 mg (capsule) twice daily as maintenance monotherapy (53 
patients) compared to placebo (43 patients) in patients with platinum sensitive, relapsed, high-
grade serous ovarian cancer following treatment with 2 or more platinum-containing regimens, the 
median duration on treatment with laparib was 11.1 months for patients with a gBRCA mutation 
compared to 4.4 months for patients with gBRCA mutation on placebo. Adverse reactions led to 
dose interruptions in 26% of those receiving olaparib and 7% of those receiving placebo; dose 
reductions in 15% of olaparib and 5% of placebo patients; and discontinuation in 9% of olaparib 
and 0% in placebo patients. One (2%) patient on olaparib died as a result of an adverse reaction. 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 38 of 169
Adverse Reactions Reported in ≥20% of Patients with gBRCA-Mutated Ovarian Cancer in the 
Randomized Trial were anemia, abdominal pain/discomfort, decreased appetite, nausea, vomiting, 
diarrhea, dyspepsia, fatigue/asthenia, nasopharyngitis, upper respiratory infection, arthralgia, 
myalgia, back pain, headache, cough and dermatitis/rash. Laboratory Abnormalities observed were 
decrease in hemoglobin, absolute neutrophil count, platelets, mean corpuscular volume elevation, 
and increase in creatinine.
Myelodysplastic syndrome/Acute Myeloid Leukemia (overall 22 out of 2618 patients i.e. 1%) and 
pneumonitis (<1%) occurred in patients exposed to olaparib, and some cases were fatal.
Potential overlapping toxicity between olaparib, durvalumab, and tremelimumab are: diarrhea, 
enterocolitis, myalgia, arthralgia, fatigue, and rash. However, based on published studies, anti-
CTLA-4 appears to be associated with more frequent and severe side effects.
1.3.2.5
Fixed Dosing for Durvalumab and Tremelimumab
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.
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 
through Phase 3 (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma) [Wang 
et al. 2014]. Population PK model indicated minor impact of body WT on PK of tremelimumab 
(coefficient of ≤ 0.5). The WT-based (1 mg/kg Q4W) and fixed dosing (75 mg/kg Q4W; based on 
median body WT of ~75 kg) regimens were compared using predicted PK concentrations (5th, 
median and 95th percentiles) using population PK model in a simulated population of 1000 
patients with body weight distribution of 40 to 120 kg. Similar to durvalumab, simulations 
indicated that both body WT-based and fixed dosing regimens of tremelimumab yield similar 
median steady state PK concentrations with slightly less between-subject variability with fixed 
dosing regimen.
Similar findings have been reported by others (39-42). Wang and colleagues (41) 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. 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 (42).
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 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 39 of 169
fixed dose of 750 mg Q2W durvalumab (equivalent to 10 mg/kg Q2W), 1500 mg Q4W 
durvalumab (equivalent to 20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg 
Q4W) is included in the current study.
Fixed dosing of durvalumab and tremelimumab is recommended only for subjects with > 30 kg 
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.
1.3.2.6
Dose for Olaparib
Olaparib capsule formulation is approved in the United States as monotherapy in patients with 
deleterious or suspected deleterious germline BRCA mutated advanced ovarian cancer who have 
been treated with three or more prior lines of chemotherapy at a dose of 400 mg BID (capsule 
form). The indication is approved under accelerated approval based on objective response rate and 
duration of response.
A tablet formulation of olaparib has been used in all newer clinical trials with a recommended 
monotherapy dose of 300 mg BID.
1.4
Research Hypothesis
The combination of olaparib, durvalumab, and tremelimumab will be safe and, tolerable with 
acceptable toxicity.
The combination of olaparib, durvalumab, and tremelimumab will improve the PFS in patients 
with BRCA germline and/or somatic mutations who have platinum- sensitive or platinum-resistant 
ovarian cancer.
The combination of olaparib, durvalumab, and tremelimumab will improve the antitumor response 
in patients with BRCA germline and/or somatic mutations who have recurrent platinum-sensitive 
or platinum-resistant ovarian cancer.
The combination of olaparib, durvalumab, and tremelimumab will have significant effects on the 
density, location, and antitumor properties of immune cells in the ovarian tumor 
microenvironment.
2
STUDY RATIONALE
Epithelial ovarian cancer (EOC) is the leading cause of mortality related to gynecologic cancer in 
USA with a majority of patients presenting with advanced disease at the time of diagnosis. There 
is an urgent need for the development of alternative therapies given the poor response of recurrent 
disease to available therapies. The current study focuses on evaluating the MTD and safety profile 
of a novel combination of three drugs. 
PD-L1 has a role in the clinical course of ovarian cancer by affecting the local immune 
microenvironment and that interruption of the PD-1/PD-L1 pathway could restore effective 
antitumor immunity in ovarian cancer patients. The rationale for combining durvalumab and 
tremelimumab is that the mechanisms of CTLA 4 and PD-1 are non-redundant; suggesting that 
targeting both pathways may have additive or synergistic activity (30). In fact, combining 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 40 of 169
immunotherapy agents has been shown to result in improved response rates (RRs) relative to 
monotherapy. For example, the concurrent administration of nivolumab and ipilimumab to patients 
with advanced melanoma induced higher objective response rates (ORRs) than those obtained with 
single-agent therapy. Importantly, responses appeared to be deep and durable (38). Similar results 
have been observed in an ongoing study of durvalumab + tremelimumab in NSCLC (43), with 
further updated details presented in this clinical study protocol.
PARP inhibitors selectively kill cancer cells defective in DNA repair, specifically cancers with 
mutation in the breast cancer-associated genes, BRCA1 and BRCA2. Therefore, with non-
redundant modes of action, targeting these three different pathways may have additive or 
synergistic activity leading to superior tumor control compared to monotherapy, thus improving 
progression free survival (PFS) and overall survival (OS) in women with recurrent/persistent 
platinum-resistant ovarian, primary peritoneal, or fallopian tube cancers who carry a germline 
and/or somatic BRCA1 or BRCA2 Mutation.
2.1
Durvalumab plus Tremelimumab Combination Therapy Dose Rationale
The durvalumab + tremelimumab doses and regimen selected for this study are based on the goal 
of selecting an optimal combination dose of durvalumab and tremelimumab that would yield 
sustained target suppression (sPD-L1), demonstrate promising efficacy, and have an acceptable 
safety profile.
In order to reduce the dosing frequency of durvalumab to align with the Q4W dosing of 
tremelimumab, while ensuring an acceptable PK/PDx, safety, and efficacy profile, cohorts were 
narrowed to 15 and 20 mg/kg durvalumab Q4W. PK simulations from the durvalumab 
monotherapy data indicated that a similar area under the plasma drug concentration-time curve at 
steady state (AUCss; 4 weeks) was expected following both 10 mg/kg Q2W and 20 mg/kg Q4W 
durvalumab. The observed durvalumab PK data from the D4190C00006 study were well in line 
with the predicted monotherapy PK data developed preclinically. This demonstrates similar 
exposure of durvalumab 20 mg/kg Q4W and 10 mg/kg Q2W, with no alterations in PK when 
durvalumab and tremelimumab (doses ranging from 1 to 3 mg/kg) are dosed together. While the 
median Cmax at steady state (Cmax,ss) is expected to be higher with 20 mg/kg Q4W (approximately 
1.5 fold) and median trough concentration at steady state (Cmin,ss) is expected to be higher with 10 
mg/kg Q2W (approximately 1.25 fold), this is not expected to impact the overall safety and 
efficacy profile, based on existing preclinical and clinical data.
Monotonic increases in PDx activity were observed with increasing doses of tremelimumab 
relative to the activity observed in patients treated with durvalumab monotherapy. There was 
evidence of augmented PDx activity relative to durvalumab monotherapy with combination doses 
containing 1 mg/kg tremelimumab, inclusive of both the 15 mg/kg and 20 mg/kg durvalumab plus 
1 mg/kg tremelimumab combinations.
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse events 
(AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs. Between the 
10 mg/kg durvalumab + 1 mg/kg tremelimumab and 10 mg/kg durvalumab + 3 mg/kg 
tremelimumab cohorts treated at the Q2W schedule, the number of patients reporting any AE, 
Grade 3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg durvalumab + 3 mg/kg 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 41 of 169
tremelimumab cohort than the 10 mg/kg durvalumab + 1 mg/kg tremelimumab cohort. A similar 
pattern was noted in the Q4W regimens, suggesting that, as the dose of tremelimumab increased 
above 1 mg/kg, a higher rate of treatment-related events may be anticipated. Further, the SAEs 
frequently attributed to immunotherapy, pneumonitis and colitis, were more commonly seen in 
cohorts using either 3 or 10 mg/kg of tremelimumab compared to the 1-mg/kg dose cohorts. 
Together, these data suggest that a combination using a tremelimumab dose of 1 mg/kg appeared 
to minimize the rate of toxicity when combined with durvalumab. As a result, all combination 
doses utilizing either the 3 or 10 mg/kg doses of tremelimumab were eliminated in the final dose 
selection.
In contrast, cohorts assessing higher doses of durvalumab with a constant dose of tremelimumab 
did not show an increase in the rate of AEs. The data suggested that increasing doses of durvalumab 
may not impact the safety of the combination as much as the tremelimumab dose. Further, safety 
data between the 10-mg/kg and 20-mg/kg cohorts were similar, with no change in safety events 
with increasing dose of durvalumab.
In Study D4190C00006, of all treatment cohorts, the cohort of 11 patients treated in the 20 mg/kg 
durvalumab + 1 mg/kg tremelimumab group had the fewest AEs, Grade ≥3 AEs, SAEs, and 
treatment discontinuations due to AEs, but still showed strong evidence of clinical activity. This 
cohort had a lower number of treatment-related Grade ≥3 AEs or treatment-related SAEs. No dose-
limiting toxicities were reported.
Preliminary clinical activity of the durvalumab and tremelimumab combination did not appear to 
change with increasing doses of tremelimumab. The 15- and 20-mg/kg durvalumab Q4W cohorts 
demonstrated objective responses at all doses of tremelimumab and increasing doses of 
tremelimumab did not provide deeper or more rapid responses.
Efficacy data suggested that the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort may 
demonstrate equivalent clinical activity to other dose combinations. A total of 5 of 11 patients in 
the 20 mg/kg durvalumab + 1 mg/kg tremelimumab cohort were evaluable for efficacy with at 
least 8 weeks of follow-up. Of these, there were 2 patients (40%) with partial response (PR), 
1 patient (20%) with stable disease (SD), and 1 patient (20%) with progressive disease (PD) (The 
fifth patient had only a single scan, which was conducted outside the window for these 
evaluations).
Additionally, of all cohorts, the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort had 
the fewest AEs, Grade ≥3 AEs, SAEs, and treatment discontinuations due to AEs, but still showed 
some evidence of clinical activity. Altogether, the data suggested that a 20 mg/kg durvalumab + 
1 mg/kg tremelimumab dose combination should be selected for further development.
2.2
Rationale for 4 Cycles of Combination Therapy Followed by Durvalumab 
Monotherapy
Long-term follow up on melanoma patients treated with ipilimumab, an anti-CTLA-4 targeting 
antibody (dosed every 3 weeks [Q3W] for 4 doses and then discontinued), shows that patients 
responding to ipilimumab derive long-term benefit, with a 3-year OS rate of approximately 22%. 
Furthermore, the survival curve in this population reached a plateau at 3 years and was maintained 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 42 of 169
through 10 years of follow up (44). Similar data have been presented for other anti-PD-1/PD-L1 
targeting antibodies:

Nivolumab (anti-PD-1) was dosed Q2W for up to 96 weeks in a large Phase I dose 
escalation and expansion study, and showed responses were maintained for a median of 
22.94 months for melanoma (doses 0.1 mg/kg to 10 mg/kg), 17 months for NSCLC (doses 
1, 3, and 10 mg/kg), and 12.9 months for renal cell carcinoma patients (doses 1 and 10 
mg/kg) at the time of data analysis (45, 46) 

Furthermore, responses were maintained beyond treatment discontinuation in the majority 
of patients who stopped nivolumab treatment (either due to protocol specified end of 
treatment, complete response [CR], or toxicity) for up to 56 weeks at the time of data 
analysis (47).

MPDL3280a (anti-PD-L1) and the combination of nivolumab with ipilimumab, in which 
patients were dosed for a finite time period and responses maintained beyond treatment 
discontinuation have been reported (38, 48)
Similar long-term results may be expected with use of other immune-mediated cancer therapeutics 
including anti-CTLA-4 antibodies such as tremelimumab, anti PD-L1 antibodies such as 
durvalumab, or the combination of the two.
2.3
Rationale for Combination Therapy Doses in this Study
Therefore, in this study, durvalumab will be given Q4W for up to 1 year, tremelimumab Q4W for 
the 1st 4 cycles in combination with olaparib (300 mg [or lower in the case of de-escalation] BID 
for up to 1 year). 
3
STUDY OBJECTIVES
3.1
Primary Objectives
Phase I: The primary objective of the Phase I component of this study is:

To assess the safety and toxicity of the combination of PARP inhibitor olaparib with anti-
PD-L1 antibody durvalumab and anti-CTLA4 antibody tremelimumab.
Phase II: The primary objective of the Phase II component of this study is:

To assess the impact of the combination of olaparib with durvalumab and tremelimumab 
on PFS rates.
3.2
Secondary Objectives

To assess the impact of the combination of olaparib with durvalumab and tremelimumab 
on anti-tumor immune responses in patients with recurrent platinum sensitive or resistant 
or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer who carry a 
germline and/or somatic BRCA1 or BRCA2 mutation and/or a homologous recombination 
deficiency (HRD).
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 43 of 169

To assess the impact of the combination of olaparib with durvalumab and tremelimumab 
on PFS and OS in patients with recurrent platinum sensitive or resistant or refractory 
epithelial ovarian, fallopian tube, or primary peritoneal cancer who carry a germline and/or 
somatic BRCA1 or BRCA2 mutation and/or a HRD.
4
METHODOLOGY
4.1
Study Design Overview
This is an open-label Phase I/II study for combination of the PARP inhibitor olaparib with anti-
PD-L1 antibody durvalumab and anti-CTLA4 antibody tremelimumab, utilizing a 3+3 design. 
Fixed doses of durvalumab (1500 mg Q4W for up to 1 year) and tremelimumab (75 mg Q4W for 
4 cycles) will be utilized with the recommended dose of olaparib for BRCA mutated ovarian 
cancer (300 mg BID for up to 1 year) in the first 6 patients in a Phase I safety run part of this study 
(Safety lead-in Cohort) followed by a Phase II part of the study (expansion cohort), enrolling 27 
additional subjects. In case of >1 DLT out of the 6 patients, tremelimumab will be eliminated from 
this combination study as many of the toxicities from durvalumab and tremelimumab overlap but 
based on published studies, tremelimumab is associated with more frequent and severe side effects. 
Data suggested that increasing doses of durvalumab may not impact the safety of the combination 
as much as the tremelimumab dose. The dose of tremelimumab utilized here is the lowest effective 
dose and therefore de-escalation not recommended. If the DLT is olaparib related, de-escalation 
plan is to decrease to 250 mg and then to 200 mg as shown in Table 1, following the 3+3 rule.
Update: The Phase 1 portion of this study has been completed and reviewed. 6 patients were 
treated at Dose level -1 (durvalumab 1500 mg + tremelimumab 75 mg + Olaparib 250 mg) with 
no dose limiting toxicities observed.  Based on this, the dose for the Phase II Expansion cohort 
was determined as durvalumab 1500 mg IV Q4W up to 1 year + tremelimumab 75 mg IV Q4W 
4 cycles + olaparib 250 mg PO BID up to 1 year. 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 44 of 169
Table 1
Treatment of Algorithm on True DLT Risk
Phase I:
Cohort
Dose Level
N
# of 
DLTs*
Action Based on # of DLTs
Total #
0, 1
+ 3
1/6 DLT: Phase II Expansion cohort
≥ 2
Eliminate tremelimumab: Phase II-T Expansion 
cohort
or
If DLT due to olaparib, dose de-escalate olaparib as 
follows:
0/3 DLT: Phase II-O 
Expansion cohort:
durvalumab 1500 mg + 
tremelimumab 75 mg + 
olaparib 250 mg
1/3 DLT:
 +3 at same dose
1/6 DLT: Phase II-O 
Expansion cohort: 
durvalumab 1500 mg + 
tremelimumab 75 mg + 
olaparib 250 mg
Phase I 
Lead-in 
cohort
durvalumab 
1500 mg + 
tremelimumab 
75 mg + olaparib 
300 mg
3
+3
durvalumab 1500 mg + 
tremelimumab 75 mg + 
olaparib 250 mg
≥2/3 or ≥2/6 DLTs: +3 
with further de-
escalation:
 durvalumab 1500 mg + 
tremelimumab 75 mg + 
olaparib 200 mg
6 to 12 
depending 
on DLTs
*DLT – dose limiting toxicity in the first two cycles of treatment.
For further description of Table 1, please refer to Section 6.3..
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 45 of 169
Phase II (Dose determined after completion of the Phase I portion of the study):
Cohort
Dose Level
N
# of DLTs
Action Based on # of 
DLTs
Total #
Phase II  
Expansion cohort 
(2:1 ratio of 
platinum-
resistant to 
platinum-
sensitive)
durvalumab 1500 mg 
+ tremelimumab 
75 mg + olaparib 250 
mg 
27
N/A
N/A
18 platinum-
resistant and 
9 platinum-
sensitive)
The study schema is depicted in Figure 1.
Figure 1
Study Schema
Screening/ Enrollment
Phase I (3 + 3)
(safety lead-in cohort, 
n=6 subjects)
Phase II 
(Expansion Cohort, 
n=27 subjects
Immune Response Monitoring:
PFS, OS
Enrollment into the study will be at a 2:1 ratio of platinum-resistant to platinum-sensitive disease 
only in the Phase II study. Enrollment into the safety lead-in cohort of the Phase I part will not be 
constrained to a 2:1 ratio of platinum-resistant to platinum-sensitive disease. Estimated total 
sample size including the Phase I lead-in and Phase II expansion cohorts, n = 33 to 39. It has been 
observed that ovarian cancer patients with BRCA1 and BRCA2 mutations tend to be more 
sensitive to platinum agents and possibly PARP inhibitors than wild-type BRCA ovarian cancers. 
In an initial proof-of-concept study of 50 BRCA1/BRCA2-mutated patients treated with 200 mg 
BID olaparib, objective response rates for platinum-sensitive and platinum-resistant cases were 
46% and 33%. Therefore, in this combination drug therapy study, the Phase II study is planned to 
enroll at a 2:1 ratio of platinum-resistant to platinum-sensitive disease.
Durvalumab will be administered every 4 weeks (Q4W) for up to 1 year (13 cycles) and 
tremelimumab will be administered every 4 weeks (Q4W) for up to 4 doses/cycles. Olaparib will 
be administered 300 mg BID (or lower in the event of de-escalation) for up to 1 year. Study 
treatments will be continued for up to 1 year or until disease progression, whichever occurs sooner. 
Each cycle for durvalumab and tremelimumab is 4 weeks. Olaparib is continuous dosing. For the 
first 4 cycles (16 weeks), a patient will receive all three drugs and then continue with only 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 46 of 169
durvalumab (9 more cycles) with daily olaparib.  In the event of disease progression while the 
patient is receiving durvalumab and Ooaparib alone (i.e. after completion of the first 4 doses of 
tremelimumab), the patient may be given an additional 4 doses of tremelimumab per the 
investigator’s discretion in combination with the ongoing durvalumab and olaparib. 
Primary Endpoint

Phase I component: Safety and tolerability: DLTs will be defined based on the rate of drug-
related grade 3-5 adverse events. These will be assessed using the NCI CTCAE v4.0.

Phase II component: To assess the impact of the combination of olaparib with durvalumab 
and tremelimumab on PFS rates compared the PFS achieved with the last treatment.
Secondary Endpoints

To assess the impact of the combination of olaparib with durvalumab and tremelimumab 
on anti-tumor immune responses 

To assess the impact of the combination of olaparib with durvalumab and tremelimumab 
on OS

Assessment of anti-tumor immune response of the treatment combination by evaluating 
translational and correlative biomarker endpoints. Archival tissue and on-treatment tumor 
biopsies and peripheral blood will be utilized for this assessment.

Olaparib treatment of BRCA1/2+ve platinum resistant ovarian cancer patients leads to the 
release of a unique repertoire of tumor antigens that will be cross-presented to the immune 
system leading to generation of humoral and T cell responses. We will initially focus on 
auto-antibody analysis of pre- and post- treatment samples from the patients on the clinical 
trial, using a previously validated “seromics” approach by our group (Gnjatic et al, 
2010)(49). The results generated by the analysis of pre- and post-treatment sera may be 
useful individually or as signature sets as (i) diagnostic markers, preferentially 
immunogenic in HR-deficient ovarian cancer, (ii) prognostic markers, associated with 
favorable or unfavorable clinical outcome in HR-deficient ovarian cancer, and (iii) 
potential targets of immune responses for the development of new immunotherapeutic 
reagents in HR-deficient ovarian cancer. 
o
Immunoscore: archival and on-treatment biopsies.
o
Analysis of T-cell responses.
o
Analysis of potential resistance mechanism: sequencing studies (e.g. for HR 
deficiency), gene expression studies and analysis for secondary genetic and 
epigenetic events.
All participants will sign an informed consent prior to study related tests. All participants will meet 
the inclusion and exclusion criteria summarized in Section 5.1 and Section 5.2.
4.2
Target Accrual and Study Duration
A maximum of 36 participants at multiple sites, including RPCI will be enrolled.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 47 of 169
During the initial enrollment of the first two patients in dose level 1, due to the safety assessments 
after the first patients, there is a waiting period of at least 4 weeks before the second patient can 
be enrolled. Assuming an average enrollment of 1 patient per site per month:

Enrollment Period: 12 months

Duration of Treatment: 12 months 

Length of Study: 24 months. 

Accrual is expected to take up to 4 years.
4.3
Replacement of Participants
Patients who are not considered fully evaluable per protocol for the primary objective of safety 
and tolerability may be replaced. The period for evaluating DLTs will be from the time of first 
administration of durvalumab, tremelimumab, and olaparib until at least two cycles of durvalumab 
(8 weeks). Subjects who do not remain on the study up to this time for reasons other than DLT 
will be replaced with another subject at the same dose level. The compliance requirement for 
olaparib is 75% of the planned dose during the first 8 weeks. This applies to both Phase I and Phase 
II part of the study. There will be no replacement of patients during retreatment.
5
PARTICIPANT SELECTION
5.1
Inclusion Criteria
To be included in this study, participants must meet the following criteria:
1. Patients must have platinum-sensitive or platinum-resistant recurrent or persistent or 
refractory ovarian, fallopian tube, or primary peritoneal carcinoma AND have one or more 
of the following characteristics documented on a validated platform (documented genetic 
test report is required). Historic report is permitted.
a.
A germline BRCA1 or BRCA2 deleterious alteration.
b. A somatic mutation in BRCA1 or BRCA2 detected in a tumor sample or on 
circulating tumor DNA.
c.
Carry a known or likely loss of function alteration in one or more of homologous 
recombination or mismatch repair pathway genes (See Table below for the list of 
genes).
d. Demonstrate a genomic phenotype of HR deficiency as measured by a LOH-high 
score.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 48 of 169
Gene List
ATM
CDKN2A
FANCO
PTEN
ATR
CHEK1
FANCP
RAD50
BAP1
CHEK2
FAM175A 
(ABRA1)(ABRAXAS)
RAD51
BARD1
FANCA
MLH1
RAD51B
BMPR1A
FANCB
MRE11A
RAD51C
BRCA1
FANCC
MSH2 
RAP80
BRCA2
FANCE
MSH6
RAD51D
BRCC36
FANCD2
MUTYH
RBBP8 
BRCC45 (MERIT 40)
FANCF
NBN
RET
BRIP1 (FANCJ)
FANCG
PALB2 (FANCN)
STK11
CDH1
FANCI
PI3K
VHL
CDK4
FANCL
PMS2
XRCC2
CDK12
FANCM
PRSS1
XRCC3
Recurrent ovarian cancer is defined as recurrence of disease in a patient who achieved 
initial complete response to primary therapy. 
Persistent ovarian cancer is defined as having residual disease in the form of elevated 
tumor markers or microscopic or clinically evident disease in a patient who has completed 
and apparently responded to initial chemotherapy.
Refractory ovarian cancer is defined as patients who have failed to achieve at least a 
partial response to therapy including patients with either stable disease or disease 
progression during primary therapy.
Platinum-sensitive is defined as achievement of documented response to initial platinum-
based treatment and has been off treatment for an extended period of time (more than 6 
months).
Platinum-resistant is defined as relapse within 6 months of last platinum-based 
chemotherapy or progression while on platinum-based therapy.
2. All patients must have measurable disease as defined by irRECIST. Measurable disease is 
defined as 10 mm in the longest diameter by CT or MRI scan (or no less than double the 
slice thickness) for non- nodal lesions and ≥ 15 mm in short axis for nodal lesions, 20 mm 
by chest X-ray, a lymph node must be ≥ 15 mm in short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm).
3. Must have archival tissue available for PD-L1 assessment.
4. Patients should be free of active infection requiring antibiotics (with the exception of 
uncomplicated UTI).
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 49 of 169
5. Patients who have the following risk factors are considered to be at increased risk for 
cardiac toxicities and may be enrolled only with increased monitoring (refer to Table 5, 
footnote 5): i) prior treatment with anthracyclines, ii) prior treatment with trastuzumab, iii) 
a New York Heart Association classification of II controlled with treatment, iv) prior 
central thoracic radiation therapy (RT), including RT to the heart.
6. Any hormonal therapy being taken as a treatment for cancer must be discontinued at least 
one week prior to registration. Continuation of hormone replacement therapy e.g. thyroid 
hormone replacement therapy is permitted.
7. Able to tolerate oral medications and no GI illnesses that would preclude absorption of 
olaparib.
8. Female patients, age > 18 years at time of study entry.
9. Have an ECOG Performance Status of 0-1. Refer to Appendix B.
10. Life expectancy of > 6 months.
11. Adequate normal organ and marrow function as defined below:
o
Hemoglobin ≥ 10 g/dL (no blood transfusion in the 28 days prior to entry (olaparib 
guidelines)
o
WBC > 3 x 109/L
o
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (≥1500 per mm3)
o
Platelet count ≥ 100 x 109/L (≥ 100,000 per mm3)
o
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply 
to subjects with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or 
hepatic pathology), who will be allowed only in consultation with their physician
o
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
o
Creatinine ≤ 1.5 x ULN or, Serum Creatinine CL > 51 mL/min (by the Cockcroft-
Gault equation: see Appendix L).
12. Female subjects must either be of non-reproductive potential (i.e., 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 within 28 days of study 
treatment, confirmed prior to treatment on day 1.
13. Participants of child-bearing potential must agree to use two highly effective and 
acceptable forms of contraception from screening, throughout their participation in the 
study and for 180 days after the last dose of durvalumab + tremelimumab combination 
therapy or 90 days after last dose of durvalumab or olaparib, whichever is the longer time 
period (e.g., hormonal or barrier method of birth control). Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately. 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 50 of 169
14. Participant or legal representative must understand the investigational nature of this study 
and sign an Independent Ethics Committee/Institutional Review Board approved written 
informed consent form prior to receiving any study related procedure.
15. 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.
5.2
Exclusion Criteria
Participants will be excluded from this study for the following:
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 an investigational product during the last 4 
weeks (prior use of bevacizumab in the upfront setting is allowed).
3. History of discontinuation of any previous treatment with PARP inhibitors, including 
olaparib, or a PD-1 or PD-L1 inhibitor, including durvalumab or anti-CTLA4 antibody, 
including tremelimumab due to toxicity.
4. Patients with myelodysplastic syndrome/acute myeloid leukemia. 
5. History and/or confirmed ILD/pneumonitis, extensive bilateral lung disease on HRCT 
scan.
6. Concomitant use of a strong CYP3A inhibitors (e.g., itraconazole, telithromycin, 
clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritonavir, 
lopinavir/ritonavir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate 
CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, 
darunavir/ritonavir, diltiazem, erythromycin, fluconazole. Fosamprenavir, imatinib, 
verapamil).
7. Concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, 
St. John’s Wort) and moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, 
modafinil, nafcillin).
8. History of another primary malignancy except for:
o
Malignancy treated with curative intent and with no known active disease ≥5 years 
before the first dose of study drug and of low potential risk for recurrence.
o
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease (e.g. basal cell or squamous cell carcinoma of the skin).
o
Adequately treated carcinoma in situ without evidence of disease (e.g., breast and 
cervical cancer in situ).
9. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine 
therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 51 of 169
radiotherapy or other investigational agent) ≤ 21 days prior to the first dose of study drug 
and within 6 weeks for nitrosourea or mitomycin C).
10. Mean QT interval corrected for heart rate (QTcF) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using Fridericia’s Correction.
11. Patients with history of myocardial infarction within 6 months.
12. 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.
13. Any unresolved toxicity (CTCAE grade ≥2) from previous anti-cancer therapy. Subjects 
with irreversible toxicity that is not reasonably expected to be exacerbated by the 
investigational product may be included (e.g., hearing loss, peripherally neuropathy).
14. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous 
immunotherapy agent, or any unresolved irAE >Grade 1.
15. 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.
16. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative 
colitis) 
17. Patients with thyroid dysfunction if not adequately controlled.
18. History of primary immunodeficiency.
19. History of allogeneic organ transplant.
20. History of hypersensitivity to durvalumab, tremelimumab, olaparib or, any excipient.
21. 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, or test positive for,  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.
22. Known history of previous clinical diagnosis of tuberculosis.
23. History of leptomeningeal carcinomatosis.
24. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days 
of receiving durvalumab (e.g. LAIV, MMR, VAR, Zoster, yellow fever etc.).
25. Female subjects who are pregnant, breast-feeding, or of reproductive potential who are not 
employing an effective method of birth control from screening to 180 days after the last 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 52 of 169
dose of durvalumab + tremelimumab + olaparib combination therapy or 90 days after the 
last dose of durvalumab and olaparib therapy, whichever is the longer time period.
26. Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results or, is an unsuitable 
candidate to receive study drug (e.g. inability to tolerate oral medications which would 
preclude absorption of olaparib).
27. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of 
but not limited to surgery, radiation and/or corticosteroids.
28. Subjects with uncontrolled seizures.
29. Dependency on IV hydration or TPN.
5.3
Inclusion of Women and Minorities
Women of all races and ethnic groups are eligible for this study.
6
TREATMENT PLAN
6.1
Dosing and Administration
Patients will receive IV infusions of fixed doses of durvalumab (1500 mg Q4W for up to 
13 doses/cycles) and tremelimumab (75 mg Q4W for up to 4 doses) in combination with olaparib 
(300 mg BID or lower in case of de-escalation) orally. Study drugs will be continued for up to 
1 year or until disease progression, whichever occurs sooner. After Phase I completion, dose of 
olaparib for Phase II was determined to be 250 mg BID.
For cohorts receiving all 3 drugs (durvalumab, tremelimumab, and olaparib):
In the event that the patient experiences disease progression during the time that they are receiving 
durvalumab and olaparib alone (i.e. after first 4 doses of tremelimumub have been completed), an 
additional 4 doses of tremelimumab may be added to ongoing durvalumab and olaparib at the 
investigator’s discretion.  
6.2
Treatment Regimens
6.2.1 Durvalumab + Tremelimumab + Olaparib Combination Therapy
Patients will receive 1500 mg durvalumab via IV infusion Q4W for up to 13 doses/cycles and 
75 mg tremelimumab via IV infusion Q4W for up to 4 doses/cycles. Olaparib will be given orally, 
300 mg BID (or lower in case of de-escalation), for up to 12 months. Tremelimumab + durvalumab 
should be given at least 1 hour after the patient has taken their olaparib morning dose. 
Tremelimumab will be administered first. Durvalumab infusion will start approximately 1 hour 
after the end of tremelimumab infusion. The duration will be approximately 1 hour for each 
infusion.
A 1-hour observation period is required after the first infusion of durvalumab and tremelimumab. 
If no clinically significant infusion reactions are observed during or after the first cycle, subsequent 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 53 of 169
infusion observation periods can be at the Investigator’s discretion (suggested 30 minutes after 
each durvalumab and tremelimumab infusion).
Based on average body weight of 75 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 
20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) is included in the 
current study. For participants weighing ≤ 30 kg, refer to Appendix C (Durvalumab) and Appendix 
E (Tremelimumab).
6.2.1.1
Monitoring of dose administration
Patients will be monitored during and after the infusion with assessment of vital signs at the times 
specified in the Study Protocol.

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 and re-initiated at 50% of the 
initial rate until completion of the infusion.

For patients 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 patients 
to an intensive care unit if necessary.
6.2.1.2
Duration of Treatment and Criteria for Retreatment
For patients receiving durvalumab + tremelimumab + olaparib, retreatment is allowed (once 
only) for patients meeting the retreatment criteria below. The same treatment guidelines followed 
during the initial 12-month treatment period will be followed during the retreatment period, 
including the same dose and frequency of treatments and the same schedule of assessments. 
Similar to the initial treatment, in the event of disease progression while the patient is receiving 
durvalumab and olaparib alone (i.e. after completion of the first 4 doses of tremelimumab), the 
patient may be given an additional 4 doses of tremelimumab per the investigator’s discretion, in 
combination with the ongoing durvalumab and olaparib. 
Patients receiving the combination of durvalumab, tremelimumab, and olaparib may undergo 
retreatment in the clinical scenarios described below:

Patients who achieve and maintain disease control (i.e., irCR, irPR, or irSD) through to the 
end of the 12-month treatment period may restart treatment with the combination upon 
evidence of PD according to irRECIST during follow-up.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 54 of 169

Before restarting their assigned treatment, the Investigator should ensure that the patient:
o
Does not have any significant, unacceptable, or irreversible toxicities that indicate 
continuing treatment will not further benefit the patient.
o
Still fulfills the eligibility criteria for this study, including re-consenting to restart 
durvalumab, tremelimumab, and olaparib.
o
Has not have received an intervening systemic anticancer therapy after their assigned 
treatment discontinuation.
o
Has had a baseline tumor assessment within 28 days of restarting their assigned 
treatment; all further scans should occur with the same frequency as during the initial 
12 months of treatment (relative to the date of randomization) until study treatment is 
stopped (maximum of 12 months of further treatment).
During the retreatment period, patients receiving durvalumab + tremelimumab + olaparib may 
resume durvalumab dosing at 1500 mg Q4W with 75 mg of tremelimumab Q4W for 4 doses each. 
Patients will then continue with durvalumab monotherapy at 1500 mg Q4W, beginning at Week 
16, 4 weeks after the last dose of combination therapy (a total of 9 additional doses). Olaparib will 
be administered throughout this retreatment period at 300 mg BID (or the MTD in case of dose 
de-escalation) for up to 1 year.
Treatment through progression is at the Investigator’s discretion, and the Investigator should 
ensure that patients do not have any significant, unacceptable, or irreversible toxicities that indicate 
that continuing treatment will not further benefit the patient. A patient with a confirmed 
progression receiving durvalumab + tremelimumab + olaparib cannot continue therapy or obtain 
retreatment if dosing is ongoing in the combination portion of therapy (Q4W dosing) and 
progression occurs in a target lesion that has previously shown a confirmed response.
Patients who AstraZeneca and/or the Investigator determine may not continue treatment will enter 
follow-up. There will be no replacement of patient during retreatment.
6.2.2 Olaparib
Subjects will be administered olaparib in line with normal clinical practice, at 300 mg BID, in 
combination with fixed doses of durvalumab and tremelimumab. It is expected that subjects will 
receive this combination therapy for up to 1 year or until disease progression, whichever occurs 
sooner. After completion of the Phase I portion of the study, the safe dose of olaparib to be used 
in the Phase II study for this combination therapy was determined to be 250 mg BID.
6.2.2.1
Dose administration
Patients will take 2 tablets of 150 mg each (total 300 mg), orally, twice daily. In case of the reduced 
200 mg dose group, patients will take 2 tablets of 100 mg and for the 250 mg dose group, one 150 
mg and one 100 mg tablet. The olaparib tablets should be swallowed whole and not chewed, 
crushed, dissolved or divided. Durvalumab + tremelimumab should be given at least 1 hour after 
the patient has taken their olaparib morning dose.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 55 of 169
6.2.2.2
Monitoring of dose administration
Patients will be monitored for the first dose, similar to as described for durvalumab and 
tremelimumab (refer to Section 6.2.1.1) and subsequent doses will be taken by the patient at home.
Reported adverse events (AEs) and potential risks are described in Section 1.3.2. Appropriate dose 
modifications are described in Section 6.5.
6.3
Cohort Management: Dose Escalation Decision Rules
Refer to Section 4.1
Fixed doses of durvalumab, tremelimumab, and olaparib will be used in the first 6 patients in a 
Phase I safety run part of this study (Safety lead-in Cohort) followed by a Phase II part of the study 
(expansion cohort), enrolling 27 additional subjects (18 platinum-resistant patients and 9 platinum-
sensitive patients). In case of >1 DLT out of the 6 patients, tremelimumab will be eliminated from 
this combination study (The DLT must be related to tremelimumab). The dose of tremelimumab 
utilized here is the lowest effective dose and therefore de-escalation not recommended. If the DLT 
is olaparib related, de-escalation plan is to decrease to 250 mg and then to 200 mg as shown in 
Table 1, following the 3+3 rule. 
6.4
Definition of Dose-Limiting Toxicity
Dose-limiting toxicities (DLTs) will be evaluated during the Phase I portion of the trial. The period 
for evaluating DLTs will be from the time of first administration of durvalumab, tremelimumab, 
and olaparib until two cycles of durvalumab (8 weeks). Subjects who do not remain on the study 
up to this time for reasons other than DLT will be replaced with another subject at the same dose 
level. Grading of DLTs will follow the guidelines provided in the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03.
A DLT will be defined as any Grade 3 or higher toxicity that occurs during the DLT evaluation 
period. Toxicity that is clearly and directly related to the primary disease or to another etiology is 
excluded from this definition. The following will be DLTs:

Any Grade 4 irAE

Any ≥ Grade 3 colitis

Any Grade 3 or 4 noninfectious pneumonitis irrespective of duration

Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the initiation 
of maximal supportive care

Any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to Grade 2 
within 3 days after onset of the event despite optimal medical management including 
systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline within 14 days

Liver transaminase elevation > 5 × ULN or total bilirubin > 5 × ULN

Bone marrow findings consistent with myelodysplastic syndrome/acute myeloid leukemia

Any ≥ Grade 3 non-irAE, except for the exclusions listed below
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 56 of 169
The definition excludes the following conditions:

Grade 3 fatigue lasting ≤ 7 days

Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the subject is asymptomatic

Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc)

Concurrent vitiligo or alopecia of any AE grade

Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management

Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 3 days. Grade 3 or Grade 4 febrile neutropenia will be 
a DLT regardless of duration or reversibility

Grade 3 or 4 lymphopenia

Grade 3 thrombocytopenia that is not associated with clinically significant bleeding that 
requires medical intervention, and improves by at least 1 grade within 3 days

Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 3 days
Immune-related AEs are defined as AEs of an immune nature (i.e., inflammatory) in the absence 
of a clear alternative etiology. In the absence of a clinically significant abnormality, repeat 
laboratory testing will be conducted to confirm significant laboratory findings prior to designation 
as a DLT. 
6.5
Dose Modifications and Toxicity Management
For adverse events (AEs) that are considered at least partly due to administration of durvalumab 
or tremelimumab or olaparib, the following dose adjustment guidance may be applied:

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 or tremelimumab or olaparib along with 
appropriate continuing supportive care. If ≥2 DLTs due to tremelimumab, tremelimumab 
will be eliminated for the Phase II expansion cohort. There will be no dose adjustment.
In addition, there are certain circumstances in which durvalumab or tremelimumab should be 
permanently discontinued.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 57 of 169
Management of toxicity of durvalumab and tremelimumab 
Based on the mechanism of action of durvalumab or tremelimumab 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 closely 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.
Toxicity management guidelines for immune-mediated reactions, for infusion-related reactions, 
and for non-immune-mediated reactions are detailed in Appendix G.
In addition, management guidelines for adverse events of special interest (AESIs) are detailed in 
Section 10.2. All toxicities will be graded according to NCI CTCAE v4.03.
Management of toxicity of olaparib
Any toxicity observed during the course of the study could be managed by interruption and/ or 
dose reduction of the dose if deemed appropriate by the Investigator. Repeat dose interruptions are 
allowed as required, for a maximum of 14 days on each occasion. If the interruption is any longer 
than this the AstraZeneca study team must be informed. Olaparib must be interrupted until the 
patient recovers completely or the toxicity reverts to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (current version) grade 1 or less.
Where toxicity reoccurs following re-challenge with olaparib, and where further dose interruptions 
are considered inadequate for management of toxicity, then the patient should be considered for 
dose reduction or must permanently discontinue treatment with olaparib. Dose de-escalation will 
be to 250 mg BID and then to 200 mg BID if needed.
Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 adverse event occurs which the 
Investigator considers to be at least possibly related to administration of olaparib.
Management of anemia
Adverse events of anemia CTCAE grade 1 or 2 (Hemoglobin (Hb) > 8 g/dL) should be 
investigated and managed as deemed appropriate by the investigator with or without interruption 
of study drug or change in dose, taking into account previous history of anemia. Common treatable 
causes of anemia (e.g., iron, vitamin B12 or folate deficiencies and hypothyroidism) should be 
excluded.  In some cases, management of anemia may require blood transfusions. However, if a 
patient develops anemia CTCAE grade 3 (Hb < 8 g/dL) or worse, study treatment should be 
interrupted for up to maximum of 4 weeks to allow for bone marrow recovery and the patient 
should be managed appropriately.  Study treatment can be restarted at the same dose if Hb has 
recovered to > 10 g/dL.  Any subsequently required anemia related interruptions, considered likely 
to be dose related, or coexistent with newly developed neutropenia, and or thrombocytopenia, will 
require study treatment dose reductions by 250 mg bd as a first step and to 200 mg bd as a second 
step.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 58 of 169
If a patient has been treated for anemia with multiple blood transfusions without study treatment 
interruptions and becomes blood transfusion dependent as judged by investigator, study treatment 
should be permanently discontinued.
Management of neutropenia and leukopenia
Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by the 
investigator with close follow up and interruption of study drug if CTC grade 3 or worse 
neutropenia occurs.  Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is 
not recommended, however, if a patient develops febrile neutropenia, study treatment should be 
stopped and appropriate management including G-CSF should be given according to local hospital 
guidelines.  Please note that G-CSF should not be used within at least 24 h of the last dose of study 
treatment.
Study treatment can be restarted at the same dose if an adverse event of neutropenia or leukopenia 
have been recovered up to CTC AE grade >1 (ANC > 1.5 x 109/L).  Growth factor support should 
be stopped at least 24h before restarting study drug (7 days for pegylated G-CSF).
Any subsequent interruptions will require study treatment dose reductions.
Management of thrombocytopenia
An adverse event of thrombocytopenia should be managed as deemed appropriate by the 
investigator. If a patient develops thrombocytopenia CTCAE grade 3 or worse study treatment 
should be interrupted for a maximum of 4 weeks. In some cases, management of thrombocytopenia 
may require platelet transfusions. Platelet transfusions should be done according to local hospital 
guidelines.
Management of prolonged hematological toxicities while on study treatment
If a patient develops prolonged hematological toxicity such as:

≥2 week interruption/delay in study treatment due to CTC grade 3 or worse anemia and/or 
development of blood transfusion dependence

≥2 week interruption/delay in study treatment due to CTC grade 3 or worse neutropenia 
(ANC < 1 x 109/L)

≥2 week interruption/delay in study treatment due to CTC grade 3 or worse 
thrombocytopenia (Platelets < 50 x 109/L)
Weekly differential blood counts including reticulocytes (calculate reticulocyte index (RI), RI = 
reticulocyte count x hematocrit (Hct)/normal Hct; a value of 45 is usually used for normal Hct) 
and peripheral blood smear should be performed. If any blood parameters remain clinically 
abnormal after 4 weeks of dose interruption, the patient should be referred to hematologist for 
further investigations. Bone marrow analysis and/or blood cytogenetic analysis should be 
considered at this stage according to standard hematological practice.
Myelodysplastic syndrome and/or Acute Myeloid Leukemia (MDS/AML is an important potential 
risk for olaparib. Development of a confirmed MDS or other clonal blood disorder should be 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 59 of 169
reported as an SAE and full reports must be provided by the investigator to AstraZeneca Patient 
Safety. Study treatment should be discontinued if diagnosis of MDS/AML is confirmed.
The dose of olaparib must not be adjusted under any other circumstances unless the AstraZeneca 
Study Physician gives prior agreement.
Management of new or worsening pulmonary symptoms
 If new or worsening pulmonary symptoms (e.g. dyspnea) or radiological abnormality occurs, an 
interruption in olaparib dosing is recommended and a diagnostic workup (including a high-
resolution CT scan) should be performed, to exclude pneumonitis. Following investigation, if no 
evidence of abnormality is observed on CT imaging and symptoms resolve, then olaparib treatment 
can be restarted, if deemed appropriate by the investigator. If significant pulmonary abnormalities 
are identified, these need to be discussed with the AstraZeneca Study Physician.
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF.
Olaparib should be stopped before surgery and re-started after wound has healed following 
recovery.
No stoppage of olaparib is required for any biopsy procedures.
Olaparib should be discontinued for a minimum of 7 days before a patient undergoes therapeutic 
palliative radiation treatment.
Management of nausea and vomiting
Events of nausea and vomiting are known to be associated with olaparib treatment.  In study 
D0810C00019 nausea was reported in 71% of the olaparib treated patients and 36% in the placebo 
treated patients and vomiting was reported in 34% of the olaparib treated patients and 14% in the 
placebo treated patients.  They are generally mild to moderate (CTCAE grade 1 or 2) severity, 
intermittent and manageable on continued treatment.  The first onset generally occurs in the first 
month of treatment with the incidence of nausea and vomiting not showing an increase over the 
treatment cycles.
No routine prophylactic anti-emetic treatment is required at the start of study treatment, however, 
patients should receive appropriate anti-emetic treatment at the first onset of nausea or vomiting 
and as required thereafter, in accordance with local treatment practice guidelines.
6.6
Restrictions, General Concomitant Medication and Supportive Care
6.6.1 Restrictions during the study
Contraception
The following restrictions apply while the patient is receiving study treatment and for the specified 
times before and after:
Female patient of child-bearing potential
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 60 of 169
Females of childbearing potential who are sexually active with a non-sterilized male partner must 
use at least 1 highly effective method of contraception (Table 2) from the time of screening and 
must agree to continue using such precautions for 180 days after the last dose of durvalumab + 
tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy. 
Non-sterilized male partners of a female patient must use male condom plus spermicide throughout 
this period. Cessation of birth control after this point should be discussed with a responsible 
physician. Not engaging in sexual activity for the total duration of the drug treatment and the drug 
washout period is an acceptable practice; however, periodic abstinence, the rhythm method, and 
the withdrawal method are not acceptable methods of birth control.  Female patients should also 
refrain from breastfeeding throughout this period.
N.B.: Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.
Women will be considered post-menopausal if they have been amenorrheic for 12 months without 
an alternative medical cause. The following age-specific requirements apply: 

Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal treatments 
and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-
menopausal range for the institution or underwent surgical sterilization (bilateral 
oophorectomy or hysterectomy). 

Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
Highly effective methods of contraception, defined as one that results in a low failure rate (i.e., 
less than 1% per year) when used consistently and correctly, are described in Table 2. Note that 
some contraception methods are not considered highly effective (e.g. male or female condom with 
or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper 
containing intrauterine device; progestogen-only oral hormonal contraceptive pills where 
inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which 
is considered highly effective]; and triphasic combined oral contraceptive pills).
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 61 of 169
Table 2
Highly Effective Methods of Contraception (<1% failure rate)
Barrier/Intrauterine methods
Hormonal Methods

Copper T intrauterine device

Levonorgesterel-releasing intrauterine 
system (e.g., Mirena®)a

Etonogestrel implants (e.g. Implanon 
or Norplant)

Intravaginal device (e.g., 
ethinylestradiol and etonogestrel)

Medroxyprogesterone injection (e.g., 
Depo-Provera)

Normal and low dose combined oral 
contraceptive pill

Norelgestromin/ethinylestradiol 
transdermal system

Cerazette (desogestrel)
a This is also considered a hormonal method
Blood Donation
Subjects should not donate blood while participating in this study, or for at least 90 days following 
the last dose of durvalumab or tremelimumab or olaparib concomitant treatments.
Food Intake Restrictions
Avoid grapefruit and Seville oranges during olaparib treatment and 3 months following the last 
dose of trial treatment, which may increase olaparib plasma concentrations. Olaparib tablet 
formulation can be taken with no regard to food.
The Principal Investigator must be informed as soon as possible about any medication taken from 
the time of screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be recorded 
in the eCRF.
Restricted, prohibited, and permitted concomitant medications are described in the following 
tables.
6.6.2 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 in Section 6.6.3 below.
6.6.3 Excluded Concomitant Medications
The following medications are considered exclusionary during the study:
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 62 of 169
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. 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 including, 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 obstructive pulmonary disease, radiation, nausea, etc.).  
4. Live attenuated vaccines within 30 days of durvalumab and tremelimumab dosing (i.e., 30 
days prior to the first dose, during treatment with durvalumab and tremelimumab for 30 
days post discontinuation of durvalumab and tremelimumab. Inactivated vaccines, such as 
the injectable influenza vaccine, are permitted.
5. Use of strong CYP3A inhibitors must be avoided: The use of any natural/herbal products 
or other “folk remedies” should be discouraged but use of these products, as well as use of 
all vitamins, nutritional supplements and all other concomitant medications must be 
recorded in the eCRF.

Olaparib is an FDA approved drug for the treatment of patients with deleterious 
germline BRCA mutated advanced ovarian cancer. Based on in vitro data and 
clinical exposure data, olaparib is considered unlikely to cause clinically significant 
drug interactions through inhibition or induction of cytochrome P450 enzyme 
activity. In vitro data have, however, also shown that the principal enzyme 
responsible for the formation of the 3 main metabolites of olaparib is CYP3A4 and 
consequently, to ensure patient safety, the following potent inhibitors of CYP3A4 
must not be used during this study for any patient receiving olaparib.

While this is not an exhaustive list, it covers the known potent inhibitors, which 
have most often previously been reported to be associated with clinically significant 
drug interactions: ketoconazole, itraconazole, ritonavir, idinavir, saquinavir, 
telithromycin, clarithromycin and nelfinavir. For patients taking any of the above, 
the required wash-out period prior to starting olaparib is one week.
6.  Use of strong CYP3A inducers must be avoided: In addition, to avoid potential reductions 
in exposure due to drug interactions and therefore a potential reduction in efficacy, the 
following CYP3A4 inducers must be avoided: Phenytoin, rifampicin, rifapentine, 
rifabutin, carbamazepine, phenobarbitone, nevirapine, modafinil and St John’s Wort 
(Hypericum perforatum). For patients taking any of the above, the required wash-out 
periods prior to starting olaparib are: phenobarbitone 5 weeks, and for any of the others, 3 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 63 of 169
weeks. After randomization, if the use of any potent inducers or inhibitors of CYP3A4 are 
considered necessary for the patient’s safety and welfare, the Investigator must contact the 
AstraZeneca Study Physician. A decision to allow the patient to continue in the study will 
be made on a case-by-case basis.
7. Olaparib in combination with other myelosuppressive anticancer agents, including DNA 
damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.
Table 3
Prohibited Medications
Prohibited Medication/
Class of Drug
Usage
Additional investigational anticancer therapy 
concurrent with those under investigation in this study
Should not be given while the patient is on IP treatment 
mAbs against CTLA-4, PD-1, or PD-L1
Should not be given whilst the patient is on IP 
treatment through 90 days after the last dose of IP.
Any concurrent chemotherapy, local therapy (except 
palliative radiotherapy for non-target lesions, e.g., 
radiotherapy, surgery, radiofrequency ablation), 
biologic therapy, or hormonal therapy for cancer 
treatment
Should not be given whilst the patient is on IP 
treatment (including SOC). Concurrent use of 
hormones for non-cancer related conditions (e.g., 
insulin for diabetes and hormone replacement therapy) 
is acceptable.
Immunosuppressive medications, including, but not 
limited to, systemic corticosteroids at doses exceeding 
10 mg/day of prednisone or its equivalent, 
methotrexate, azathioprine, and tumor necrosis factor α 
blockers  
Should not be given whilst the patient is on IP 
treatment (including SOC). Use of immunosuppressive 
medications for the management of IP related AEs or 
in patients with contrast allergies is acceptable. In 
addition, use of inhaled, topical, and intranasal 
corticosteroids is permitted.
Live attenuated vaccines
Should not be given through 30 days after the last dose 
of IP (including SOC) during the study
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 64 of 169
6.6.4 Supportive Care
Table 4
Rescue Medications
Rescue and Supportive Care Medication/
Class of Drug
Usage
Concomitant medications or treatments (e.g., 
acetaminophen or diphenhydramine) deemed 
necessary by the Investigator to provide adequate 
prophylactic or supportive care, except for those 
medications identified as “excluded” 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
Participants may be pretreated for nausea and vomiting with appropriate anti-emetics.
6.7
Duration of Treatment
Participants may remain on study for up to 1 year from the time of first treatment administration 
receiving a total of 13 doses of durvalumab and 4 doses of tremelimumab at Q4W and daily 
olaparib in the absence of disease progression (irRECIST), unacceptable toxicity and withdrawal 
from study, intercurrent illness that prevents further administration of treatment, participant 
demonstrates an inability/refusal to comply with oral medication regime or, participant withdraws 
from study.
6.8
Treatment Discontinuation
Upon treatment discontinuation all end of treatment evaluations and tests will be conducted. All 
participants who discontinue due to an AE must be followed until the event resolves or stabilizes. 
Appropriate medical care should be provided until signs and symptoms have abated, stabilized, or 
until abnormal laboratory findings have returned to acceptable or pre-study limits. The final status 
of the AE will be reported in the participant’s medical records and the appropriate eCRF.
An individual subject will not receive any further investigational product if any of the following 
occur in the subject in question:
1. Withdrawal of consent or lost to follow-up. 
a.
If consent is withdrawn, the subject will not receive any further investigational 
product or further study observation.
2. Adverse event that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing
3. Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a safety 
risk.
4. Pregnancy or intent to become pregnant.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 65 of 169
5. Any AE that meets criteria for discontinuation as defined in Section 10.1.
6. Adverse Event or DLT that, in the opinion of the Investigator, contraindicates further 
dosing (See Section 6.4 for definition of DLT).
7. Grade ≥ 3 infusion reaction.
8. Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal; e.g., refusal to adhere to scheduled visits.
9. Initiation of alternative anticancer therapy including another investigational agent.
10. Confirmation of PD and investigator determination that the subject is no longer benefiting 
from treatment.
11. Development of intercurrent, non-cancer related illnesses that prevent either continuation 
of therapy or regular follow up.
Subjects who are permanently discontinued from further receipt of investigational product, 
regardless of the reason (withdrawal of consent, due to an AE, other), will be identified as having 
permanently discontinued treatment. 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety per Section 10 and Appendix H or Appendix I, including the collection of any 
protocol-specified blood specimens, unless consent is withdrawn or the subject is lost to follow-
up or started on standard therapy or enrolled in another clinical study. All subjects will be followed 
for survival. Subjects who decline to return to the site for evaluations will be offered follow-up by 
phone every 3 months as an alternative.
6.9
Compliance
Participants will be provided with a medication diary for olaparib to monitor compliance 
(Appendix J). The compliance requirement for olaparib is75% at any time on study treatment.
7
INVESTIGATIONAL PRODUCTS
7.1
Durvalumab
7.1.1 Active Substance and Source
Durvalumab (MEDI4736), IMFINZI™, will be supplied by AstraZeneca as a 500 mg vial solution 
for infusion after dilution. The solution contains 50 mg/mL durvalumab, 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% (weight/volume) 
polysorbate 80; it has a pH of 6 and density of 1.054 g/mL. The nominal fill volume is 10 mL. 
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug 
product should be kept in original packaging until use to prevent prolonged light exposure. 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 66 of 169
7.1.2 Drug Shipment
Durvalumab will be provided by the Investigational Products Supply section of 
AstraZeneca/MedImmune and shipped to the participating site.
The date of receipt and the amount of drug received will be documented. Drug shipment records 
will be retained by the investigational pharmacist or designee.
7.1.3 Preparation
Preparation of durvalumab doses for administration with an IV bag
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique. Total time from needle puncture of the durvalumab 
vial to the start of administration should not exceed: 

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
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. 
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been 
observed. Dose of 1500 mg durvalumab for patients >30 kg will be administered using an IV bag 
containing 0.9% (w/v) saline, with a final durvalumab concentration ranging from 1 to 20 mg/mL 
and delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter. 30 mL of 
durvalumab (i.e., 1500 mg of durvalumab) is added to the IV bag such that final concentration is 
within 1 to 20 mg/mL (IV bag volumes 100 to 1000 mL). Mix the bag by gently inverting to 
ensure homogeneity of the dose in the bag.
For patients < 30 kg: Calculate the dose volume of durvalumab and tremelimumab and number of 
vials needed for the subject to achieve the accurate dose ( Appendix C and Appendix E).
Durvalumab will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral or central vein. 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, or 0.22-μm in-line filter. Less than 55 minutes 
is considered a deviation.
The IV line will be flushed with a volume of IV solution (0.9% [w/v] 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.
Standard infusion time is 1 hour. However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature. The table below summarizes time 
allowances and temperatures.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 67 of 169
Durvalumab hold and infusion times
Maximum time from needle puncture to start of 
administration
4 hours at room temperature, 24 hours at 2°C to 8°C
Maximum time for IV bag infusion, including 
interruptions
8 hours at room temperature
In the event that either preparation time or infusion time exceeds the time limits outlined in the 
table, a new dose must be prepared from new vials. Durvalumab does not contain preservatives, 
and any unused portion must be discarded.
7.1.4 Storage and Stability
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited-access facility, as specified by the Sponsor and in 
accordance with the applicable regulatory requirements.
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Drug storage temperature will be maintained and recorded, as applicable.
7.1.5 Handling and Disposal
The Investigator or designee will be responsible for dispensing and accounting for all 
investigational drug provided by the sponsor exercising accepted medical and pharmaceutical 
practices. Study drugs must be handled as cytotoxic agents and appropriate precautions taken per 
the institution’s environmentally safe handling procedures. All investigational drugs will be 
dispensed in accordance with the Investigator’s prescription or written order.
All products dispensed will be recorded on a product accountability record. Records of product lot 
numbers and dates received will be entered on a product accountability form. This record will be 
reviewed by the Sponsor’s staff or representative during periodic monitoring visits. It is the 
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained.
Used vials (excess drug) will be destroyed according to standard practices after properly 
accounting for the dispensing. Partially used vials of study drug will not be re-used for other 
participants.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
7.2
Tremelimumab
7.2.1 Active Substance and Source
Tremelimumab will be supplied by AstraZeneca either as a 400-mg or a 25-mg vial solution for 
infusion after dilution.  The solution contains 20 mg/mL tremelimumab, 20 mM histidine/histidine 
hydrochloride, 222 mM trehalose dihydrate, 0.27 mM disodium edetate dihydrate, and 0.02% 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 68 of 169
weight/volume (w/v) polysorbate 80; it has a pH of 5.5 and density of 1.034 g/mL.  The nominal 
fill volume is 20.0 mL for the 400-mg vial and 1.25 mL for the 25-mg vial. Investigational product 
vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug product should be kept 
in original container until use to prevent prolonged light exposure.
7.2.2 Drug Shipment
Tremelimumab will be provided by the Investigational Products Supply section of 
AstraZeneca/MedImmune and shipped to the participating site.
The date of receipt and the amount of drug received will be documented. Drug shipment records 
will be retained by the investigational pharmacist or designee.
7.2.3 Preparation
Preparation of tremelimumab doses for administration with an IV bag
The dose of tremelimumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique. Total time from needle puncture of the 
tremelimumab vial to the start of administration should not exceed: 

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
It is recommended that the prepared final IV bag be stored in the dark at 2ºC-8°C (36°F-46°F) 
until needed. If storage time exceeds these limits, a new dose must be prepared from new vials. 
The refrigerated infusion solutions in the prepared final IV bag should be equilibrated at room 
temperature for about 2 hours prior to administration. Tremelimumab does not contain 
preservatives and any unused portion must be discarded.
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin IV bags have 
been observed. Doses of 75 mg tremelimumab for patients >30 kg will be administered using an 
IV bag containing 0.9% (w/v) saline, with a final tremelimumab concentration ranging from 
0.1 mg/mL to 10 mg/mL and delivered through an IV administration set with a 0.2 μm or 0.22 μm 
in-line filter. 3.8 mL of tremelimumab (i.e., 75 mg of tremelimumab) is added to the IV bag such 
that final concentration is within 0.1 mg/mL to 10 mg/mL (IV bag volumes 50 to 500 mL). Mix 
the bag by gently inverting to ensure homogeneity of the dose in the bag.
For patients <30 kg, Calculate the dose volume for tremelimumab and number of vials needed for 
subject to achieve the accurate dose (Appendix C and Appendix E).
Tremelimumab will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral or central vein. Following preparation of 
tremelimumab, the entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 minutes 
is considered a deviation.
The IV line will be flushed with a volume of 0.9% (w/v) 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 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 69 of 169
according to institutional policy to ensure the full dose is administered and document if the line 
was not flushed.
Standard infusion time is 1 hour. However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature. The table below summarizes time 
allowances and temperatures.
Tremelimumab hold and infusion times
Maximum time from needle puncture to start of 
administration
4 hours at room temperature, 24 hours at 2°C to 8°C
Maximum time for IV bag infusion, including 
interruptions
8 hours at room temperature
In the event that either preparation time or infusion time exceeds the time limits outlined in the 
table, a new dose must be prepared from new vials. Tremelimumab does not contain preservatives, 
and any unused portion must be discarded.
7.2.4 Storage and Stability
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited-access facility, as specified by the Sponsor and in 
accordance with the applicable regulatory requirements.
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Tremelimumab vials must be protected from light.
Drug storage temperature will be maintained and recorded, as applicable.
7.2.5 Handling and Disposal
The Investigator or designee will be responsible for dispensing and accounting for all 
investigational drug provided by the sponsor exercising accepted medical and pharmaceutical 
practices. Study drugs must be handled as cytotoxic agents and appropriate precautions taken per 
the institution’s environmentally safe handling procedures. All investigational drugs will be 
dispensed in accordance with the Investigator’s prescription or written order.
All products dispensed will be recorded on a product accountability record. Records of product lot 
numbers and dates received will be entered on a product accountability form. This record will be 
reviewed by the Sponsor’s staff or representative during periodic monitoring visits. It is the 
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained.
Used vials (excess drug) will be destroyed according to standard practices after properly 
accounting for the dispensing. Partially used vials of study drug will not be re-used for other 
participants.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 70 of 169
7.3
Olaparib
7.3.1 Active Substance and Source
Olaparib will be supplied as film-coated 100 mg and 150 mg tablets for oral administration 
(100 mg tablets to be used for dose reduction).
7.3.2 Drug Shipment
Olaparib 
will 
be 
provided 
by 
the 
Investigational 
Products 
Supply 
section 
of 
AstraZeneca/MedImmune and shipped to the participating site. Olaparib tablets are supplied in 
high-density polyethylene (HDPE) bottles containing desiccant. Bottles contain 32 tablets in each.
The date of receipt and the amount of drug received will be documented. Drug shipment records 
will be retained by the investigational pharmacist or designee.
7.3.3 Preparation
Tablet taken orally, no preparation needed. The olaparib tablets should be swallowed whole and 
not chewed, crushed, dissolved or divided. Durvalumab + tremelimumab should be given at least 
1 hour after the patient has taken their olaparib morning dose.
7.3.4 Storage and Stability
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited-access facility, as specified by the Sponsor and in 
accordance with the applicable regulatory requirements.
Store olaparib at controlled room temperature (15°C - 25°C).  Excursion data available to confirm 
tablets suitable for use if stored up to 50°C for 7 days.
Drug storage temperature will be maintained and recorded, as applicable.
7.3.5 Handling and Disposal
The Investigator or designee will be responsible for dispensing and accounting for all 
investigational drug provided by the sponsor exercising accepted medical and pharmaceutical 
practices. Study drugs must be handled as cytotoxic agents and appropriate precautions taken per 
the institution’s environmentally safe handling procedures. All investigational drugs will be 
dispensed in accordance with the Investigator’s prescription or written order.
All products dispensed will be recorded on a product accountability record. Records of product lot 
numbers and dates received will be entered on a product accountability form. This record will be 
reviewed by the Sponsor’s staff or representative during periodic monitoring visits. It is the 
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained.
Excess drug will be destroyed according to standard practices after properly accounting for the 
dispensing. Partially used vials of study drug will not be re-used for other participants.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 71 of 169
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
8
STUDY PROCEDURES
Before study entry, throughout the study, and following study drug discontinuation, various 
clinical and diagnostic laboratory evaluations are outlined. The purpose of obtaining these detailed 
measurements is to ensure adequate safety and tolerability assessments. Clinical evaluations and 
laboratory studies may be repeated more frequently if clinically indicated. The Schedules of 
Assessments during the screening and treatment period is provided in Table 5.
Unless otherwise defined in the written protocol text, all procedures/assessments will be conducted 
in accordance with RPCI Clinical Research Services Standard Operating Procedures.
8.1
Participant Randomization and Registration
Enrollment will be non-randomized, competitive multicenter, sequential enrollment with central 
patient registration. Enrollment will be under ongoing review by an internal data safety-monitoring 
panel.
Eligibility of each participant will be established prior to enrollment.
Informed consent MUST be completed prior to receiving any study related procedures.
8.1.1 Pre-Screening Phase (Day -42 to Day -1)

Written Informed Consent and assignment of subject identification number

Preliminary eligibility fulfillment (investigator’s opinion)

Obtain archived tumor tissue for PD-L1 assay
8.1.2 Screening Phase (Day -28 to Day -1)
Screening procedures will be performed up to 28 days before Cycle 1 Day 1, unless otherwise 
specified. All subjects must first read, understand, and sign the IRB/REB/IEC-approved ICF 
before any study-specific screening procedures are performed. After signing the ICF, completing 
all screening procedures, and being deemed eligible for entry, subjects will be enrolled in the study. 
Procedures that are performed prior to the signing of the ICF and are considered standard of care 
may be used as screening assessments if they fall within the 28-day screening window.
The following procedures will be performed during the Screening Visit:

Formal verification of eligibility criteria

Medical and surgical history/demographics

Complete physical exam 

ECOG Performance Status

Vitals signs, weight and height 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 72 of 169

12-lead ECG (in triplicate [2-5 minutes apart])

Recording of concomitant medications 

Disease assessment imaging by CT/MRI (including brain MRI only if clinically indicated)

Clinical laboratory tests for:
o
Hematology (see Table 6)
o
Clinical chemistry with creatinine clearance (see Table 7)
o
TSH, (fT3 & fT4 if TSH is abnormal)
o
Coagulation (PT, PTT, INR)
o
Serum pregnancy test for pre-menopausal women of childbearing potential only
o
HIV/Hepatitis B, C serologies
o
CA-125 level
o
Urinalysis (Table 8)

Recording of Adverse events
8.1.3 Cycle 1 Day 1

Serum hCG pregnancy test for premenopausal women with child-bearing potential.  Does 
not need to be repeated if performed within 7 days of Cycle 1 Day 1. 

Targeted Physical examination 

Vital signs

Weight

ECOG Performance Status

Single 12- lead ECG– within 2-3 hours prior to the start of the first study treatment and 0-
3hrs after administration of the combination is completed.  In case of clinically significant 
ECG abnormalities, including a QTcF value ≥ 470ms, 2 additional 12-lead ECGs should 
be obtained over a brief period (e.g. 30 minutes) to confirm the finding.  

Recording of Adverse events

Recording of Concomitant medications

Clinical Chemistry (Table 7)

Thyroid function tests: TSH.  If TSH is abnormal, then fT3 and fT4 will also be collected.

Hematology (Table 6)

CA-125 level

Urinalysis (Table 8)
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 73 of 169

PAXgene® RNA blood sample

Blood for immune monitoring

Blood for circulating soluble factors

Initial durvalumab, tremelimumab, and olaparib treatment

Vital Sign monitoring during infusions (see Table 5 for time points)
8.1.4 Treatment Phase
Procedures to be conducted during the treatment phase of the study are presented in the Schedule 
of Procedures and Observations (Table 5). Screening procedures performed within 72 hours of 
Cycle 1 Day 1 (C1D1) do not need to be repeated on C1D1.
8.1.5 End of Treatment
End of treatment is defined as the last planned dosing visit within the 12-month dosing period. For 
subjects who discontinue durvalumab or tremelimumab or olaparib prior to 12 months, end of 
treatment is considered the last visit where the decision is made to discontinue treatment. All 
required procedures may be completed within ± 7 days of the end of treatment visit. Repeat disease 
assessment is not required if performed within 28 days prior to the end of treatment visit.
Follow-up assessments for subjects who have completed durvalumab, tremelimumab, and olaparib 
treatment and achieved disease control, or have discontinued durvalumab or tremelimumab or 
olaparib due to toxicity in the absence of confirmed progressive disease are provided in Appendix 
H.
Follow-up assessments for subjects who have discontinued durvalumab or tremelimumab 
treatment due to confirmed PD are presented in Appendix I.
All subjects will be followed for survival until the end of the study regardless of further treatments, 
or until the sponsor ends the study.
8.2
Schedule of Procedures and Observations
The schedule of procedues and observations for this study is summarized in Table 5 below.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 74 of 169
Screening and Treatment Period (up to 12 months):

Durvalumab 1500 mg Q4W, maximum of 13 doses, IV administration, last infusion 
Cycle 13 Day 1.

Tremelimumab 75 mg Q4W (equivalent to 1 mg/kg Q4W), maximum of 4 doses, IV 
administration, last infusion Cycle 4 Day 1.  In the event of progressive disease on 
durvalumab and olaparib alone (i.e. after completion of initial 4 doses of tremelimumab), 
an additional 4 doses of tremelimumab may be added to the ongoing durvalumab and 
olaparib per the investigator’s discretion.  See section 6.1.  Patients receiving additional 
tremelimumab doses will be monitored for toxicity.

Olaparib 300 mg BID (or lower in the event of de-escalation), oral administration, up to 
1 year. (After Phase I completion, Phase II dose was determined to be 250 mg BID for 
this combination).
Tremelimumab + durvalumab should be given at least 1 hour after the patient has taken their 
olaparib morning dose. The olaparib tablets should be swallowed whole and not chewed, crushed, 
dissolved or divided. Tremelimumab will be administered first. Durvalumab infusion will start 
approximately 1 hour after the end of tremelimumab infusion. The duration will be approximately 
1 hour for each infusion.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 75 of 169
Table 5
Schedule of Procedures and Observations
All assessments to be performed pre-infusion unless stated otherwise.
Evaluation1
Pre-
Screening
(Day -42 to 
Day -1)
Screening
(Day -28 to 
Day -1)
Cycle 1
Day 1
Cycle 1
Day 15
(± 3 days)
Cycle 2-13,
Day 1
(± 3 days)
End of 
Treatment 
Visit19 (± 7 days)
Written Informed 
Consent and 
assignment of subject 
identification number
X
Preliminary 
eligibility fulfillment 
(investigator opinion)
X
Formal verification 
of eligibility criteria
X
Recording of 
Concomitant 
Medications
X
X
X
X
X
Recording of 
Adverse Events8
X
X
X
X
X
Clinical 
Assessments
Medical & Surgical 
History
X
Physical 
Examination 
including vital signs, 
height and weight5
X
X
X
X

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 76 of 169
All assessments to be performed pre-infusion unless stated otherwise.
Evaluation1
Pre-
Screening
(Day -42 to 
Day -1)
Screening
(Day -28 to 
Day -1)
Cycle 1
Day 1
Cycle 1
Day 15
(± 3 days)
Cycle 2-13,
Day 1
(± 3 days)
End of 
Treatment 
Visit19 (± 7 days)
Vital Sign 
Monitoring during 
infusions6
X
X
ECOG Performance 
Status
X
X
X
X
X
Laboratory 
Procedures
Hematology10
X
X
X
X
Serum Chemistry18, 10
X
X
X
X
CA-125 level10
X
X20
X20
Obtain archived 
tumor tissue for PD-
L1 assay (see section 
8.5.1.1 for further 
detail)
X
Hepatitis B & C; 
HIV
X
Serum hCG3
X
X3
Thyroid function 
tests9, 10
X
X20
Urinalysis11, 10
X
X
X
Coagulation 
parameters12
X

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 77 of 169
All assessments to be performed pre-infusion unless stated otherwise.
Evaluation1
Pre-
Screening
(Day -42 to 
Day -1)
Screening
(Day -28 to 
Day -1)
Cycle 1
Day 1
Cycle 1
Day 15
(± 3 days)
Cycle 2-13,
Day 1
(± 3 days)
End of 
Treatment 
Visit19 (± 7 days)
PAXgene® RNA 
tube (whole blood 
sample for 
mRNA/miRNA 
profiling)13
X
X13
Blood for immune 
monitoring14
X
X
X
Blood for circulating 
soluble factors15
X
X15
Imaging/Other 
Procedures
Brain MRI
X2
12-Lead 
Electrocardiogram  
(see section 8.3.3 for 
further detail)7
X7
X7
X7
Tumor Biopsy
X16

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 78 of 169
Tumor/Disease 
Assessment by 
irRECIST (CT or 
MRI)
X17
X17
X17
All assessments to be performed pre-infusion unless stated otherwise.
Evaluation1
Pre-
Screening
(Day -42 to 
Day -1)
Screening
(Day -28 to 
Day -1)
Cycle 1
Day 1
Cycle 1
Day 15
(± 3 days)
Cycle 2-13,
Day 1
(± 3 days)
End of 
Treatment 
Visit19 (± 7 days)
Study Drug 
Administration
Durvalumab 
administration
X
X
Tremelimumab 
administration
X
X4
Olaparib 
administration
           X   -------------- BID continuous dosing, up to 1 year----------------------
1.
Assessments to be performed at the times stipulated in the table and as clinically required in the management of the subject.
2.
To be done only if clinically indicated.
3.
Serum hCG to be obtained at screening, on Cycle 1 Day 1 and as clinically indicated once on treatment in pre-menopausal women of child-bearing 
potential only.  Serum hCG only needs to be repeated on Cycle 1 Day 1 if screening test is not done within 7 days of treatment start.
4.
Cycle 2, 3 and 4 only.
5.
Full physical exam at screening; targeted physical exam at other time points.  Patients with increased risk for cardiac toxicities (listed as inclusion 
criteria #9) will undergo targeted physical exam every 2 weeks and echocardiography if clinically indicated.  Refer to section 8.3.2.  Height 
required at screening visit only.  Vital signs include blood pressure, pulse, temperature and respiratory rate.
6.
Subjects will have their blood pressure, pulse, temperature and respiratory rate measured before, during and after the infusion at the following times 
(based on a 60-minute infusion for both durvalumab and tremelimumab).  Refer to Section 8.3.4.

At the beginning of the infusion (at 0 minutes)

At 30 minutes during the infusion (± 5 minutes)

At the end of the infusion (at 60 minutes ± 5 minutes)

In the 1 hour observation period post-infusion: 30 and 60 minutes post the end of the infusion (± 5 minutes)-for the first infusion only and 
then for subsequent infusions as clinically indicated.
If the infusion takes longer than 60 minutes, then the vital signs measurements should be collected every 30 minutes (± 5 minutes) and as 
described above or more frequently if clinically indicated.
7.
12-lead ECG will be obtained at the following time points: 

Screening (3 ECGs will be done 2-5 minutes apart during the screening visit)

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 79 of 169

On Cycle 1 Day 1, a single ECG should be performed within 2-3 hours prior to the start of the first study treatment and 0-3hrs after 
administration of the combination is completed.

On Treatment ECG: On Cycle 5 Day 1 OR at least one time after starting study treatment, a single ECG will be performed prior to 
administration of study treatment.

Any other time point as clinically indicated.
In case of clinically significant ECG abnormalities, including a QTcF value ≥ 470ms, 2 additional 12-lead ECGs should be obtained over a brief 
period (e.g. 30 minutes) to confirm the finding.
8.
For AEs/SAEs reported during pre-screening, additional information such as medical history and concomitant medications may be needed.
9.
TSH level will be obtained at screening, on Cycle 1 Day 1 and as clinically indicated.  Free T3 and free T4 level will only be measured if TSH is 
abnormal.  Thyroid function tests should also be measured if there is clinical suspicion of an adverse event related to the endocrine system.  Refer 
to Section 8.3.4.
10. Refer to Table 6 in Section 8.3.4.  If screening laboratory assessments are performed within 3 days prior to Cycle 1 Day 1, they do not need to be 
repeated.  Results for safety bloods must be available and reviewed before commencing an infusion.
11. Refer to Table 8 in Section 8.3.4.  Urinalysis to be performed at screening, on day 1 of each cycle and as clinically indicated.
12. Prothrombin time, APTT and INR to be performed at screening and as clinically indicated.  Refer to Section 8.3.4.
13. PAXgene® RNA tube will be collected on day 1 of cycles 1 & 2 (±3 days) and day 1 of cycles 3, 5, 7, 9, 11, & 13 (±7 days).    Refer to Section 
8.4.2.2.
14. Blood for immune monitoring will be collected on Cycle 1 Day 1, Cycle 1 Day 15, and Day 1 of cycles 2-13.    Refer to Section 8.4.2.1.
15. Refer to Section 8.4.2.3.  Blood for Circulating Soluble Factors will be collected on Cycle 1 Day 1, Cycle 2 Day 1 and Cycle 4 Day 1 only.
16. Tumor biopsy will be performed on cycle 4 day 1 (± 7 days and if clinically appropriate) after completion of CT scan for biopsy site determination 
or at the time of progression (if clinically appropriate).  Refer to Section 8.5.1.2.
17. CT (preferred) or MRI scans, preferably with IV contrast, are collected during screening (for baseline), as close to and prior to initiation of study 
treatment.  Timing of on-treatment CT/MRI scans is pre-dose C4D1 (± 7 days) for biopsy site determination and every 3 cycles thereafter (i.e. Day 
1 of Cycles 7, 10, 13 ± 7 days) or as clinically indicated until progressive disease or off-study.  Response according to irRECIST criteria (irCR, 
irPR) requires a confirmatory scan preferably at the next regularly scheduled imaging visit and no earlier than 6 weeks after the prior assessment of 
CR, PR, or SD is deemed by irRECIST.  End of Treatment disease assessment does not need to be repeated if performed within 28 days prior to 
end of treatment.
18. Refer to Table 7 for details.
19. Refer to Appendix H and Appendix I for follow-up visits.
20. Results from CA-125 and thyroid function test do not need to be available prior to dosing patient on dosing days.

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 80 of 169
8.3
Description of Study Procedures
8.3.1 Medical history and physical examination, electrocardiogram, weight and vital signs
Findings from medical history (obtained at screening) and physical examination shall be given a 
baseline grade according to the procedure for AEs. Increases in severity of pre-existing conditions 
during the study will be considered AEs, with resolution occurring when the grade returns to the 
pre-study grade or below.
Physical examinations will be performed on study days noted in the Schedule of Assessments.
8.3.2 Physical Examination
Physical examinations will be performed according to the assessment schedule. Full physical 
examinations will include assessments of the head, eyes, ears, nose, and throat and the respiratory, 
cardiovascular, 
GI, 
urogenital, 
musculoskeletal, 
neurological, 
dermatological, 
hematologic/lymphatic, and endocrine systems. Height will be measured at Screening only. 
Targeted physical examinations are to be utilized by the Investigator on the basis of clinical 
observations and symptomatology. Situations in which physical examination results should be 
reported as AEs are described in Section 10.
8.3.3 Electrocardiograms
Resting 12-lead ECGs will be recorded at screening, on Cycle 1 Day1 within 2-3 hours prior to 
the start of the first study treatment and 0-3hrs after administration of the combination is 
completed,  on Cycle 5 day 1 OR at least one time after starting study treatment and as clinically 
indicated throughout the study. ECGs should be obtained after the patient has been in a supine 
position for 5 minutes and recorded while the patient remains in that position.
At Screening, triplicate ECGs (2-5 minutes apart) will be obtained on which QTcF must be 
<470 ms.
For all other time points, a single ECG will be performed.  In case of clinically significant ECG 
abnormalities, including a QTcF value ≥ 470 ms, 2 additional 12-lead ECGs should be obtained 
over a brief period (e.g., 30 minutes) to confirm the finding.
Situations in which ECG results should be reported as AEs are described in Section 10.
8.3.4 Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules.
On infusion days, patients receiving durvalumab + tremelimumab + olaparib treatment will be 
monitored during and after infusion of IP as presented in the bulleted list below:
Supine BP will be measured using a semi-automatic BP recording device with an appropriate cuff 
size, after the patient has rested for at least 5 minutes. BP, pulse, temperature and respiratory rate 
will be collected from patients receiving durvalumab + tremelimumab treatment before, during, 
and after each infusion at the following times (based on a 60-minute infusion):
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 81 of 169

Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [i.e., the beginning of the infusion]).

Approximately 30 minutes during the infusion (halfway through infusion).

At the end of the infusion (approximately 60 minutes ±5 minutes).

A 1-hour observation period is required after the first infusion of durvalumab and 
tremelimumab.
Tremelimumab will be administered first. Durvalumab infusion will start approximately 1 hour 
after the end of tremelimumab infusion. The duration will be approximately 1 hour for each 
infusion. A 1-hour observation period is required after the first infusion of durvalumab and of 
tremelimumab. If no clinically significant infusion reactions are observed during or after the first 
cycle, subsequent infusion observation periods can be at the Investigator’s discretion (suggested 
30 minutes after each durvalumab and tremelimumab infusion).
If the infusion takes longer than 60 minutes, then vital signs measurements should follow the 
principles as described above or be taken more frequently if clinically indicated. The date and time 
of collection and measurement will be recorded on the appropriate eCRF. Additional monitoring 
with assessment of vital signs is at the discretion of the Investigator per standard clinical practice 
or as clinically indicated.
Only the first dose of olaparib (oral) will be administered and monitored as above at the clinic. 
Subsequent doses will be taken by the patient and will keep a log book.
Situations in which vital signs results should be reported as AEs are described in Section 10. 
Clinical Laboratory Tests
The following clinical laboratory tests will be performed (see the Schedule of Assessments):

Coagulation parameters: Activated partial thromboplastin time and International 
normalized ratio to be assessed at screening and as clinically indicated 

Pregnancy test (pre-menopausal female subjects of childbearing potential only)
o
Serum beta-human chorionic gonadotropin (at screening visit within 7 days prior 
to first treatment and as clinically indicated thereafter

Thyroid Stimulating Hormone
o
Free T3 and free T4 only if TSH is abnormal

Other laboratory tests
o
Hepatitis B surface antigen, hepatitis C antibody
o
HIV screening test
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 82 of 169
Table 6
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 7
Clinical Chemistry (serum or plasma) Laboratory Tests
Albumin
Glucose
Alkaline phosphatase
Lactate dehydrogenase
Alanine aminotransferase
Lipase
Amylase
Magnesium
Aspartate aminotransferase
Potassium
Bicarbonate
Sodium
Calcium 
Total bilirubin a
Chloride
Total protein
Creatininec
Urea or blood urea nitrogen, depending on local practice
Gamma glutamyltransferase b
Uric acid
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
c Creatinine ≤ 1.5 x ULN or, Serum Creatinine CL > 51 mL/min (by the Cockroft-Gault equation). Refer to Inclusion 
Criterion #10.
Table 8
Urinalysis Tests
Bilirubin
pH
RBC, WBC
Protein
Glucose
Specific gravity
Ketones
Colour and appearance
a  Microscopy should be used as appropriate to investigate white blood cells and use the high power field for red blood 
cells.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 83 of 169
Table 9
Tumor Marker
Tumor Marker
CA-125 Level
8.4
Biological Sampling Procedures
8.4.1 Biomarker Sampling and Evaluation Methods
Tumor samples will be examined to evaluate biomarkers by immunohistochemistry (IHC) and 
mRNA/miRNA expression profiling. This may include but is not limited to, the expression level 
and localization of immunosuppressive proteins such as PD-Ll on tumor cells, tumor infiltrating 
lymphocytes (TlLs), and/or markers of inflammatory/immune cell signatures, e.g. CTLA-4 CD3, 
CD4, CDS, CD45RO, IFN-gamma, FoxP3, and granzyme Band OX40. Any relationships between 
biomarker expression with subject response to treatment with durvalumab, tremelimumab, and 
olaparib will be evaluated. Additionally, analyses of tumor mutations and polymorphisms using 
archival tumor tissue may be performed through relevant methodologies in order to assess genetic 
alterations and their potential relationships with treatment outcome to durvalumab, tremelimumab, 
and olaparib. Further, selected gene sequencing of samples may be employed to evaluate genetic 
alterations and relationships with treatment outcome with durvalumab, tremelimumab, and 
olaparib.
8.4.1.1
PD-L1 Testing
To ensure comparability of data across all studies of durvalumab and, to gain real world experience 
on the performance of this assay, it is strongly encouraged that all studies that include PD-L1 
testing utilize the Ventana SP263 assay. Testing should be restricted to the Ventana SP263 assay 
and should be performed in accordance with the package insert on the Ventana Benchmark 
platform (Ultra or XT).
The Ventana SP263 assay is fully analytically validated test characterized through to the 
completion of reader precision studies in the non-small cell lung cancer (NSCLC) and squamous 
cell carcinoma of the head & neck (SCCHN). For these tumors, the Ventana SP263 assay has a 
fully reproducibility data package supporting cut-off and scoring algorithm. Following completion 
of ATLANTIC and HAWK clinical trials, the assay will be associated with clinical utility. In other 
cancer types (bladder, pancreatic, gastric, hepatocellular, triple negative breast, ovarian, 
esophageal, nasopharyngeal, glioblastoma, soft tissue sarcoma, cholangiocarcinoma, small cell 
lung, melanoma and cervical HPV+ cancers), the Ventana SP263 assay has only limited clinical 
performance data.
Sample collection for PD-L1 testing

The preferred tumor sample for the determination of a patient’s PD-L1 status is the one 
taken following the completion of the most recent prior line of therapy. Samples taken at 
this time reflect the current PD-L1 status of the tumor and considered clinically most 
relevant.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 84 of 169

Archived tissue will be utilized for PD-L1 testing as assessment. The age of the sample / 
date of collection should be captured.

Patients will be asked to undergo one fresh biopsy for on-treatment assessment on Cycle 4 
Day 1 (± 7 days) if considered clinically appropriate by their treating physician or at time 
of progression (if considered clinically appropriate).

Samples should be collected via a core needle of 18 gauge or larger or be collected by an 
incisional or excisional tumor biopsy. Where institutional practice uses a smaller gauge 
needle, samples should be evaluated for tumor cell quantity (i.e. >100 tumor cells) to allow 
for adequate PD-L1 immunohistochemistry analyses.

Samples submitted for PD-L1 testing should be formalin fixed and embedded in paraffin. 
Samples from fine needle aspirates (FNA) are not appropriate for PD-L1 analysis.
Sample data collection for PD-L1 testing
The following fields of data should be collected from the site/institution collecting and shipping 
the samples:

Patient identifier (e-code or unique identifier)

Specimen identifier (written on the specimen)

Site identifier

Specimen collection date

Type of specimen submitted

Quantity of specimen

Date of sectioning

Archival or fresh tumor

Tumor type

Primary tumor location

Metastatic tumor location (if applicable)

Fixative
The following fields of data should be collected from PD-L1 testing laboratory:

Are the negative and positive controls stained correctly

Is the H&E material acceptable

Is morphology acceptable

Total percent positivity of PD-L1 in tumor cells

PD-L1 status (positive, negative or NA) in tumor cells 

Total percent positivity of PD-L1 in infiltrating immune cells
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 85 of 169
Sample processing and, if indicated, submission process for PD-L1 testing
Preparing Stored samples for testing

Archived sample should be retrieved from the Paraffin Archive/Bio-Bank storage location. 
These blocks should undergo quality review, prior to evaluation or shipment. Where it is 
not possible or indicated to ship the block to a testing laboratory, unstained slides should 
be prepared from the paraffin-embedded tumor sample block (described below) prior to 
evaluation or shipment.
Preparing newly acquired samples for PD-L1 testing

Tumor biopsy will be performed according to institutional practice on Cycle 4 Day 1 (± 7 
days) (if clinically appropriate), or time of progression (if clinically appropriate). Where 
clinically acceptable, a minimum of 2 core biopsies should be collected and processed to 
FFPE in a single block. The provision of 4 cores is advised in order to provide sufficient 
tissue for PD-L1 assessment (2 for FFPE and 2 for flash freezing (refer to Laboratory 
Manual, version 2.0 for processing instructions). Archived tissue will be utilized for 
assessment. Tumor biopsy samples will be examined to evaluate the correlation between 
clinical activity and the expression level of PD-Ll and tumor-infiltrating lymphocytes 
changes in biopsies pre and post treatment.
Flash Frozen Tissue for DNA (refer to Section 8.5.1.2)

Samples collected at RPCI will be processed and stored (-80°C) at the Correlative Science 
Pathology Office and will be batch shipped on dry ice to the RPCI Immune Analysis 
Facility.

NETWORK SITES: Follow directions above for sample collection and processing. The 
cryogenic tubes will be labeled with the Subject ID # (unique to Network patients), 
initials, the participant’s study number, clinical study number, protocol time point, and 
protocol day. The samples will immediately be frozen in liquid nitrogen as per the lab 
manual and stored at -80ºC until requested for batch mailing. Samples are to be batch 
shipped frozen, on dry ice.
o
Note: Samples cannot be frozen in glass tubes – cryogenic vials must be used.
o
Frozen samples will be shipped via Fed Express Overnight on dry ice with 
delivery on Mon-Fri. NO SATURDAY DELIVERY. Do not ship on a Friday or 
the day before a holiday.
o
Address shipments and any questions regarding specimen processing to:
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 86 of 169
Roswell Park Cancer Center
Immune Analysis Facility at the Center for Immunotherapy
CCC Bldg. 4th Floor, Rm. 416
Attn: Study Number – I 288216
Elm & Carlton Streets
Buffalo, NY 14263
Tel: 716-845-8459
Junko.Matsuzaki@RoswellPark.org

It is recommended that core needle tumor biopsies are collected using an 18 gauge or larger 
needle and the process should be image guided. Excisional or incisional samples are also 
adequate. If smaller gauge needle is used, then the number of cores collected should be 
increased to allow sufficient material for successful PD-L1 testing (>100 tumor cells) and 
embedded in the same block. If available, a single excisional biopsy of at least 4 mm in 
diameter may substitute for all core biopsies.
Fixation of biopsy samples for PD-L1 testing

Previously frozen tissue is not acceptable for processing to FFPE for PD-L1 testing. To fix 
newly acquired tissue, place immediately (within 30 min of excision) into an adequate 
volume of 10% v/v neutral buffered formalin (NBF). Samples should remain in fixative for 
24 – 48 hours at room temperature. 

It is vital that there is an adequate volume of fixative relevant to the tissue (at least a 10-
volume excess) and that large specimens (if any) are incised prior to fixation to promote 
efficient tissue preservation. 
Embedding in paraffin for PD-L1 testing

An overnight processing schedule into paraffin wax is recommended (as per institutional 
guidelines)

Storage of tumor blocks for PD-L1 testing
o
FFPE blocks should be stored at ambient temperature and protected from light until 
shipment by courier at ambient temperature. FFPE blocks are stable under these 
conditions for an indefinite period.
Quality control of samples to be used for PD-L1 testing

Tissue should be assessed by the site pathologist prior to PD-L1 testing.  

Each sample should be reviewed for:

Adequate fixation

Good preservation of morphology

Presence of tumor tissue
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 87 of 169

Histopathology consistent with indication

Greater than 100 tumor cells are required to determine PD-L1 status – tumor cell content 
must be reviewed prior to testing in order for PD-L1 obtain a valid result.
PD-L1 testing laboratory (Department of Pathology in the Pathology Resource Network at RPCI):
Roswell Park Cancer Institute
Elm & Carlton Streets
Correlative Science Pathology Office
Gratwick Basic Science Building, S-636
Attn: Protocol Lab Team, I 288216 Samples
Buffalo, NY 14263
(716) 845-8917
Email: CRSLabPathTeam@RoswellPark.org 
For Network Sites, samples are to be sent to the central lab (Immune Analysis Facility). Additional 
details for sample collection, processing, storage, and shipment is provided in the Laboratory 
Manual [RPCI Immune Analysis Facility study Laboratory Manual (Version 2.0)]. Samples will 
be analyzed in RPCI’s Core Pathology Laboratory (Pathology Resource Network).

When submitting sample for PD-L1 testing the recommendation is to ship the block in 
order for sectioning to occur at the laboratory. Blocks should be shipped containing enough 
material to be provided to allow a minimum of 5, and preferably 10, sections to be cut 
(each 4-micron thick) to be used for PD-L1 testing.
Sectioning instructions

Where it is not possible or indicated to ship the block to laboratory for PD-L1 testing, 
unstained slides should be prepared from the paraffin-embedded tumor sample block as 
described below:

A minimum of 5-10 x 4 micron (μm) thick, unstained sections should be provided for PD-
L1 testing

A new disposable microtome blade must be used for each block to prevent contamination.

Apply one section per slide to positively-charged Superfrost™ glass slides.

The sections should be dried overnight between room temperature and 37°C. Do not dry 
sections at temperatures above 37°C.
Sections should be stored at ambient temperature and protected from light until use or shipment to 
testing lab by courier at ambient temperature. It is recommended that slides are cut freshly prior to 
PD-L1 testing and they are used within 90 days of being cut to obtain PD-L1 status.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 88 of 169
This is required for both observational and interventional clinical studies collecting clinical 
samples.
8.4.2 Estimate of Volume of Blood to be Collected
Table 10
Volume of Blood to be drawn from each Participant
Assessment
Sample 
volume 
(mL)
No. of 
samples
Total 
volume 1 
Year 
(mL)
Collection tube
Clinical chemistry
Hematology
4
4
14
14
56
56
gold top
purple top
Thyroid Function test
Coagulation
4
4
14
1
56
4
gold top
light-blue top
PAXgene® RNA tube
Blood for Immune Monitoring
Circulating soluble factors 
2.5
70 
5
8
15
3
20
1050
15
PAXgene® tube
6 green tops and 1 red top
purple top
Total
93.5
69
1257
Please refer to the study Laboratory Manual (version 2.0) for additional details on processing 
and storage.
Samples will be kept at room temperature prior to processing.
8.4.2.1
Blood for Immune Monitoring
Blood samples will be collected via venipuncture for immune monitoring (to check for T cell 
phenotype, humoral and T cell responses using flow cytometry, ELISPOT and ELISA). Samples 
will be collected using (6) 10 mL green-top collection tubes and, (1) 4 mL red-top collection tube.
Samples will be obtained, prior to infusion, on:

Cycle 1 Day 1

Cycle 1 Day 15 (± 3 days)

Day 1 of Cycles 2-13 (± 3 days)

At the follow up visit if the patient discontinued durvalumab treatment due to confirmed 
progression of disease, at the discretion of the investigator.
Samples will be kept at room temperature prior to processing.
Samples collected at RPCI will be sent to the Immune Analysis Facility for processing (refer to 
Laboratory Manual, version 2.0 for additional details).
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 89 of 169
Roswell Park Cancer Center
Immune Analysis Facility at the Center for Immunotherapy
CCC Bldg. 4th Floor, Rm. 416
Attn: Study Number – I 288216
Elm & Carlton Streets
Buffalo, NY 14263
Tel: 716-845-8459
Junko.Matsuzaki@RoswellPark.org 
NETWORK SITES: Follow directions above for sample collection and processing. The 
cryogenic tubes will be labeled with the Subject ID # (unique to Network patients), initials, the 
participant’s study number, clinical study number, protocol time point, dose, and protocol day. 
The samples will immediately be frozen at -80ºC or below (samples are to be stored until requested 
for batch mailing), unless otherwise indicated. Samples are to be batch shipped frozen, on dry ice, 
unless otherwise indicated.
Note: Samples cannot be frozen in glass tubes – cryogenic vials must be used.
Frozen samples will be shipped via Fed Express Overnight on dry ice with delivery on Mon-Fri. 
NO SATURDAY DELIVERY. Do not ship on a Friday or the day before a holiday.
Address shipments and any questions regarding specimen processing to:
Junko Matsuzaki PhD, Director-Immune Analysis Facility
Immune Analysis Facility at the Center for Immunotherapy
Cancer Cell Center, Room 416
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, NY 14263
junko.matsuzaki@roswellpark.org
Samples will be analyzed at the IAF, where all samples will be archived.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
8.4.2.2
Blood for mRNA/miRNA Profiling
Blood samples will be collected via venipuncture for mRNA/miRNA profiling. Samples will be 
collected using (1) 2.5 mL PAXgene® RNA tube.
Samples will be obtained, prior to infusion, on:

Cycle 1 Day 1 (± 3 days)

Cycle 2 Day 1 (± 3 days)
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 90 of 169

Day 1 of Cycles 3, 5, 7, 9, 11 &13 (± 7 days)
Samples will be kept at room temperature prior to processing.
Samples collected at RPCI will be sent to the Immune Analysis Facility for processing (refer to 
Laboratory Manual, version 2.0 for additional details).
Roswell Park Cancer Center
Immune Analysis Facility at the Center for Immunotherapy
Cancer Cell Center, Room 416
Attn: Study Number – I 288216
Elm & Carlton Streets
Buffalo, NY 14263
Tel: 716-845-8459
junko.matsuzaki@roswellpark.org 
NETWORK SITES: Follow directions above for sample collection and processing. The 
cryogenic tubes will be labeled with the Subject ID # (unique to Network patients), initials, the 
participant’s study number, clinical study number, protocol time point, dose, and protocol day. 
The samples will be frozen  following the procedure outlined in Appendix M  (samples are to be 
stored until requested for batch mailing). Samples are to be batch shipped frozen, on dry ice.
Note: Samples cannot be frozen in glass tubes – cryogenic vials must be used.
Frozen samples will be shipped via Fed Express Overnight on dry ice with delivery on Mon-Fri. 
NO SATURDAY DELIVERY. Do not ship on a Friday or the day before a holiday.
Address shipments and any questions regarding specimen processing to:
Junko Matsuzaki PhD, Director-Immune Analysis Facility
Immune Analysis Facility at the Center for Immunotherapy
Cancer Cell Center, Room 416
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, NY 14263
junko.matsuzaki@roswellpark.org
Samples will be analyzed at the IAF, where all samples will be archived.
8.4.2.3
Blood for Circulating Soluble Factors
Blood samples will be collected via venipuncture for analysis of circulating soluble factors. 
Samples will be collected using (1) 5 mL purple top EDTA collection tube. Samples will be 
obtained, prior to infusion, on:

Cycle 1 Day 1 

Cycle 2 Day 1 (± 3 days)

Cycle 4 Day 1 (± 3 days)
Samples will be kept at room temperature prior to processing.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 91 of 169
Samples collected at RPCI will be sent to the Immune Analysis Facility for processing (refer to 
Laboratory Manual, version 2.0 for additional details).
Roswell Park Cancer Center
Immune Analysis Facility at the Center for Immunotherapy
Cancer Cell Center, Room 416
Attn: Study Number – I 288216
Elm & Carlton Streets
Buffalo, NY 14263
Tel: 716-845-8459
junko.matsuzaki@roswellpark.org 
NETWORK SITES: Follow directions above for sample collection and processing. The 
cryogenic tubes will be labeled with the Subject ID # (unique to Network patients), initials, the 
participant’s study number, clinical study number, protocol time point, dose, and protocol day. 
The samples will immediately be frozen at -80ºC or below (samples are to be stored until 
requested for batch mailing). Samples are to be batch shipped frozen, on dry ice.
Note: Samples cannot be frozen in glass tubes – cryogenic vials must be used.
Frozen samples will be shipped via Fed Express Overnight on dry ice with delivery on Mon-Fri. 
NO SATURDAY DELIVERY. Do not ship on a Friday or the day before a holiday.
Address shipments and any questions regarding specimen processing to:
Junko Matsuzaki PhD, Director-Immune Analysis Facility
Immune Analysis Facility at the Center for Immunotherapy
Cancer Cell Center, Room 416
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, NY 14263
junko.matsuzaki@roswellpark.org
Samples will be analyzed at the IAF, where all samples will be archived.
8.5
Pathology
8.5.1 Archival Tumor Samples and Fresh Tumor Biopsies
8.5.1.1
Archival tumor samples
Archival tumor samples are required for all subjects and must be deemed available during the 
screening period. The quantity (5-10 unstained slides with tissue sections of 4µm thick on charged 
glass slides), and quality of archival tumor samples should be confirmed during screening period.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 92 of 169
For Network Sites, de-identified tissue samples using study-specific subject ID number and tissue 
accession# (GCP requires at least 2 identifiers) are to be sent to the central lab (Immune Analysis 
Facility). Additional details for sample collection, processing, storage, and shipment is provided 
in the Laboratory Manual [RPCI Immune Analysis Facility study Laboratory Manual (Version 
2.0)]. Samples will be analyzed in RPCI’s Core Pathology Laboratory.
8.5.1.2
Fresh tumor biopsies
Tumor lesions planned for biopsy must not be used as index lesions for assessment of disease and 
tumor response. Excisional biopsies are preferred where clinically appropriate. Otherwise, subjects 
will undergo 4 image-guided core biopsies (18 g or larger, if clinically appropriate). Two tissue 
cores will be placed in formalin and processed to FFPE. The remaining 2 cores will be immediately 
frozen in liquid nitrogen and then stored at -80°C. Network sites will ship the samples in formalin 
at room temperature on the same day as collection to the central lab (IAF) as per lab manual. Flash 
frozen samples can be batch shipped to the Central Lab on dry ice.
Additional details for sample collection, processing, storage, and shipment is provided in the 
Laboratory Manual [RPCI Immune Analysis Facility study Laboratory Manual (Version 2.0)].
Tumor biopsy will be performed on Cycle 4 Day 1 ± 7 days (if clinically appropriate), or at time 
of progression (if clinically appropriate). Archived sample will be utilized for baseline assessment.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
8.5.2 Withdrawal of Informed Consent for Donated Biological Samples
If a subject withdraws consent to the use of donated samples, the samples will be disposed 
of/destroyed, and the action documented. As collection of the biological samples is an integral part 
of the study, then the subject is withdrawn from further study participation.
The Principal Investigator:

Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed/destroyed, the action documented and 
the signed document returned to the study site

Ensures that the subject is informed about the sample disposal
9
EFFICACY EVALUATIONS
Disease Evaluation and Methods
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 93 of 169
The response to immunotherapy may differ from the typical responses observed with cytotoxic 
chemotherapy, including the following (50, 51):

Response to immunotherapy may be delayed

Response to immunotherapy may occur after PD by conventional criteria

The appearance of new lesions may not represent PD with immunotherapy

SD while on immunotherapy may be durable and represent clinical benefit.
Based on the above-described unique response to immunotherapy and based on guidelines from 
regulatory agencies, e.g., European Medicines Agency’s “Guideline on the evaluation of anti-
cancer medicinal products in man” (52) for immune modulating anti-cancer compounds, the study 
may wish to implement the following in addition to standard RECIST 1.1 criteria (53):

RECIST will be modified so that PD must be confirmed at the next scheduled visit, 
preferably, and no earlier than 4 weeks after the initial assessment of PD in the absence 
of clinically significant deterioration. Treatment with durvalumab, tremelimumab, and 
olaparib would continue between the initial assessment of progression and confirmation 
for progression.

In addition, subjects may continue to receive durvalumab, tremelimumab, and olaparib 
beyond confirmed PD in the absence of clinically significant deterioration and if 
investigators consider that subjects continue to receive benefit from treatment.
Modification of RECIST as described may discourage the early discontinuation of 
durvalumab/olaparib 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 1.1 criteria.
Of note, clinically significant deterioration is considered to be a rapid tumor progression that 
necessitates treatment with anti-cancer therapy other than durvalumab/olaparib or with 
symptomatic progression that requires urgent medical intervention (e.g., central nervous system 
metastasis, respiratory failure due to tumor compression, spinal cord compression).
9.1
Efficacy Assessment by irRECIST
Tumor response will be assessed using the Immune-Related Response Criteria (irRECIST) as 
described by Nishino et al, 2013 (54) and Bohnsack et al, 2014 (55). The Principal Investigator is 
responsible for ensuring that all staff involved in the study is familiar with the content of this 
section.
Tumor response will be assessed by irRECIST. Conventional RECIST 1.1 (53) will also be 
documented during the trial, however; RECIST 1.1 will not be used to determine disease 
progression.
Refer to Appendix K for a summary of irRECIST.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 94 of 169
10 SAFETY EVALUATION
10.1 Adverse Events
10.1.1 Definition
An adverse event or adverse experience (AE) is any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of ‘unrelated’, ‘unlikely’, 
‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
10.1.1.1 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
10.1.1.2 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
10.1.1.3 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 x the upper limit of normal associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event CRF.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 95 of 169
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated blood potassium level of 7 mEq/L should be recorded as 
“hyperkalemia”
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
10.1.1.4 Preexisting Medical Conditions (Baseline Conditions)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
10.1.2 Assessment of Severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of AEs 
and SAEs. Severity will be graded according to the NCI CTCAE v4.03. The determination of 
severity for all other events not listed in the CTCAE should be made by the investigator based 
upon medical judgment and the severity categories of Grade 1 to 5 as defined below.
Grade 1 (mild):

An event that is usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living.
Grade 2 (moderate):

An event that is usually alleviated with additional specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject.
Grade 3 (severe)

An event that requires intensive therapeutic intervention. The event interrupts usual 
activities of daily living, or significantly affects the clinical status of the subject.
Grade 4 (life threatening)

An event, and/or its immediate sequelae, that is associated with an imminent risk of death 
or with physical or mental disabilities that affect or limit the ability of the subject to perform 
activities of daily living (eating, ambulation, toileting, etc.).
Grade 5 (fatal):

Death (loss of life) as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a measure 
of intensity whereas seriousness is defined by the criteria in Section 10.1.2. A Grade 3 AE need 
not necessarily be considered an SAE. For example, a Grade 3 headache that persists for several 
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 96 of 169
hours may not meet the regulatory definition of an SAE and would be considered a nonserious 
event, whereas a Grade 2 seizure resulting in a hospital admission would be considered an SAE.
10.1.3 Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 4 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP
Version 4 of the CTCAE is identified and located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
AEs not covered by specific terminology listed should be reported with common medical 
terminology, and documented according to the grading scales provided in the CTCAE Version 4.
The relationship of event to study drug will be documented by the Investigator as follows:

Unrelated: The event is clearly related to other factors such as the participant’s clinical 
state, other therapeutic interventions or concomitant drugs administered to the participant.

Unlikely: The event is doubtfully related to investigational agent(s). The event was most 
likely related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs.

Possible: The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the participant’s 
clinical state, other therapeutic interventions or concomitant drugs.

Probable: The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot 
be reasonably explained by other factors such as the participant’s clinical state, therapeutic 
interventions or concomitant drugs.

Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, 
improves upon stopping the drug, or reappears on re-exposure.
N.B.: When making the assessment on causality, it should be taken into consideration that 
immune-therapeutic agents have the potential to cause very late and/or permanent effects on the 
immune system, i.e., a causal relationship could exist despite a lack of apparent temporal 
relationship. Information provided in the IB and/or in "Background" of this protocol may support 
these evaluations.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 97 of 169
10.1.4 Reporting Adverse Events
Table 11
Guidelines for Routine Adverse Event Reporting for Phase 1 Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
X
X
Unlikely
X
X
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
Table 12
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
Routine AEs occurring between the start date of intervention until 90 days after the last 
intervention, or until the event has resolved, the study participant is lost to follow-up, the start of 
a new treatment, or until the study investigator assesses the event(s) as stable or irreversible, will 
be reported. New information will be reported after it is received.
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.
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. After 
90 days, only subjects with ongoing investigational product-related SAEs will continue to be 
followed for safety.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 98 of 169
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.
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 + tremelimumab+ 
olaparib. 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 
sponsor and AstraZeneca/MedImmune Drug Safety.
10.2 Adverse Events of Special Interest (AESI)
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 events in order to characterize and 
understand them in association with the use of this investigational product.
10.2.1 Durvalumab + Tremelimumab AESIs
AESIs for durvalumab and tremelimumab 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 regard to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Sponsor.
AESIs observed with durvalumab and tremelimumab include:

Diarrhea / Colitis and intestinal perforation

Pneumonitis / ILD

ALT/AST increases / hepatitis / transaminase increases / 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 / hypopituitarism, adrenal insufficiency, and 
hyper- and hypothyroidism and type I diabetes mellitus)
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 99 of 169

Rash / Dermatitis

Nephritis / Blood creatinine increases

Pancreatitis (or labs suggestive of pancreatitis - increased serum lipase, increased serum 
amylase)

Myocarditis

Myositis / Polymyositis

Intestinal Perforation

Other inflammatory responses that are rare / less frequent with a potential immune-
mediated etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and other 
events involving the eye (e.g., keratitis and optic neuritis) skin (e.g., scleroderma, vitiligo 
and pemphigoid) , hematological (e.g., hemotological anemia and immune 
thrombocytopenic purpura) and rheumatological events (polymyalgia rheumatic and 
autoimmune arthritis), vasculitis, non-infectious meningitis and non-infectious 
encephalitis.
Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the durvalumab and tremelimumab Investigator Brochure. For durvalumab and tremelimumab, 
AESIs will comprise the following:
Pneumonitis
AEs of pneumonitis are also of interest for AstraZeneca, as pneumonitis has been observed with 
use of anti-PD-1 mAbs (but not with anti-PD-L1 mAbs). Initial work-up should include a high-
resolution CT scan, ruling out infection, and pulse oximetry. Pulmonary consultation is highly 
recommended. Guidelines for the management of patients with immune-related AEs (irAEs) 
including pneumonitis are provided in Appendix G.
Infusion reactions
AEs of infusion reactions (also termed infusion-related reactions) are of special interest to 
AstraZeneca and are defined, for the purpose of this protocol, as all AEs occurring from the start 
of IP infusion up to 48 hours after the infusion start time. For all infusion reactions, SAEs should 
be reported to AstraZeneca Patient safety as described in Section 10.4.
Hypersensitivity reactions
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-PD-
L1 and anti-PD-1 therapy (45). 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 (IgE-mediated) and anaphylactoid reactions against the mAbs 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 the management 
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 100 of 169
of patients with hypersensitivity (including anaphylactic reaction) and infusion-related reactions 
are provided in Section 6.2.1.1.
Hepatic function abnormalities (hepatotoxicity)
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 IP. Guidelines for management of patients with hepatic 
function abnormality are provided in Appendix G.
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 tremelimumab are provided in Appendix G.
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 G.
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 G.
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 G.
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 G.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 101 of 169
10.2.2 Olaparib Adverse Events of Special Interest (AESIs)
Adverse Events of Special Interest (AESIs) for olaparib are the Important Potential Risks of 
MDS/AML, new primary malignancy (other than MDS/AML) and pneumonitis.
ANY event of MDS/AML, new primary malignancy, or pneumonitis should be reported to 
AstraZeneca Patient Safety whether it is considered a non-serious AE [e.g. non-melanoma skin 
cancer] or SAE, and regardless of investigator’s assessment of causality or knowledge of the 
treatment arm.
A questionnaire will be sent to any investigator reporting an AESI, as an aid to provide further 
detailed information on the event. During the study there may be other events identified as AESIs 
that require the use of a questionnaire to help characterize the event and gain a better understanding 
regarding the relationship between the event and study treatment.
10.2.3 Immune-related Adverse Events
Based on the mechanism of action of durvalumab and tremelimumab leading to T-cell activation 
and proliferation, there is a possibility of observing irAEs during the conduct of this study. 
Potential irAEs may be similar to those seen with the use of ipilimumab, BMS-936558 (anti-PD-
1 mAb), and BMS-936559 (anti-PD-L1 mAb) and may include immune-mediated enterocolitis, 
dermatitis, hepatitis (hepatotoxicity), pneumonitis, and endocrinopathies (23, 45, 56) These AEs 
are inflammatory in nature and can affect any organ. With anti-PD-L1 and anti-CTLA-4 
combination therapy, the occurrence of overlapping or increasing cumulative toxicities that 
include irAEs could potentially occur at higher frequencies than with either durvalumab or 
tremelimumab monotherapy. Patients should be monitored for signs and symptoms of irAEs. In 
the absence of an alternate etiology (e.g., infection or PD), an immune-related etiology should be 
considered for signs or symptoms of enterocolitis, dermatitis, pneumonitis, hepatitis, and 
endocrinopathy. In addition to the dose modification guidelines provided in Appendix G – 
Table A), it is recommended that irAEs are managed according to the general treatment guidelines 
outlined for ipilimumab (57). These guidelines recommend the following:

Patients should be evaluated to identify any alternative etiology.

In the absence of a clear alternative etiology, all events of an inflammatory nature should 
be considered immune related.

Symptomatic and topical therapy should be considered for low-grade events.

Systemic corticosteroids should be considered for a persistent low-grade event or for a 
severe event.

More potent immunosuppressives should be considered for events not responding to 
systemic steroids (e.g., infliximab or mycophenolate).

If the Investigator has any questions in regard to an AE being an irAE, the Investigator 
should immediately contact the Study Sponsor.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 102 of 169
10.3 Serious Adverse Events
10.3.1 Definition
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following:

Death.

A life-threatening adverse event (experience). Any AE that places a participant or 
participants, in the view of the Investigator or sponsor, at immediate risk of death from the 
reaction as it occurred. It does NOT include an AE that, had it occurred in a more severe 
form, might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.

A congenital anomaly or birth defect.

Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
participant and may require medical or surgical 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 SAEs (their relationship to all study treatment/procedures) will be assessed by the 
investigator(s) and communicated to AstraZeneca.
10.3.2 Reporting Serious Adverse Events
All new SAEs occurring from the date the participant signs the study consent until 90 days after 
the last intervention or a new treatment is started, whichever comes first, will be reported. The 
RPCI SAE Source Form is to be completed with all available information, including a brief 
narrative describing the SAE and any other relevant information. 
SAEs that are unexpected and possibly, probably or definitely related must be reported as an 
Unanticipated Problem. Please refer to Section 10.6 for details on reporting Unanticipated 
Problems.
10.4 Investigator Reporting: Notifying the Study Sponsor
All SAEs 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 + tremelimumab + olaparib or, until the initiation of alternative anticancer therapy. 
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 103 of 169
The investigator and/or Sponsor are responsible for informing the Ethics Committee and/or the 
Regulatory Authority of the SAE as per local requirements.
The investigator and/or sponsor must inform the FDA, via a MedWatch form, of any serious or 
unexpected adverse events that occur in accordance with the reporting obligations of 21 CFR 
312.32, and will concurrently forward all such reports to AstraZeneca. A copy of the MedWatch 
report must be faxed to AstraZeneca at the time the event is reported to the FDA. It is the 
responsibility of the sponsor to compile all necessary information and ensure that the FDA receives 
a report according to the FDA reporting requirement timelines and to ensure that these reports are 
also submitted to AstraZeneca at the same time.
* A cover page should accompany the MedWatch form indicating the following:

“Notification from an Investigator Sponsored Study”

The investigator IND number assigned by the FDA

The investigator’s name and address

The trial name/title and AstraZeneca ISS reference number (ESR-16-11751)
* 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:
AEMailboxClinicalTrialTCS@astrazeneca.com
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca and the FDA.
Serious adverse events that do not require expedited reporting to the FDA still need to be reported 
to AstraZeneca 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.
10.5 Follow-Up for Serious Adverse Events
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as stable 
or irreversible. New information will be reported when it is received.
10.6 Unanticipated Problems
10.6.1 Definition
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:

Unexpected (in terms of nature, severity, or frequency) given:
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 104 of 169
a) The research procedures that are described in the study-related documents, including 
study deviations, as well as issues related to compromise of participant privacy or 
confidentiality of data.
b) The characteristics of the participant population being studied.

Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research).

Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized and if in relation to an AE is also deemed Serious per Section 10.3.
10.6.2 Reporting Unanticipated Problems
The Reportable New Information (RNI) Form will be submitted to the CRS Quality Assurance 
(QA) Office within 1 business day of becoming aware of the Unanticipated Problem.  After review, 
CRS QA Office will submit the RNI to the IRB.
When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CRS QA Office with an updated Reportable New Information Form.  The site 
Investigator or designated research personnel will report all unanticipated problems, whether 
related or unrelated to the investigational agent(s) to the IRB in accordance with their local 
institutional guidelines.
10.7 Reporting of Deaths
All deaths that occur during the study, or within the protocol defined 90 day post last dose of 
durvalumab + tremelimumab + olaparib (follow up period), must be reported as follows:

Death that is clearly the result of disease progression should be documented but should not 
be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported to as a SAE within 24 hours (see Section 10.3.2for 
further details). The report should contain a comment regarding the co-involvement of 
progression of disease, if appropriate, and should assign main and contributory causes of 
death.

Deaths with an unknown cause should always be reported as a SAE.
Deaths that occur following the protocol-defined 90-day post-last-dose of durvalumab + 
tremelimumab + olaparib follow-up period will be documented as events for survival analysis but 
will not be reported as an SAE.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 105 of 169
10.8 Other Events Requiring Reporting
10.8.1 Overdose
An overdose is defined as a subject receiving a dose of durvalumab + tremelimumab + olaparib in 
excess of that specified in the Investigator’s Brochure, unless otherwise specified in this protocol.
Any overdose of a study subject with durvalumab + tremelimumab + olaparib, 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 10.4 for contact information). If the overdose results in an AE, the AE must 
also be recorded as an AE (see Section 10.1). 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 10.3). There is 
currently no specific treatment in the event of an overdose of durvalumab or tremelimumab or 
olaparib.
The investigator will use clinical judgment to treat any overdose.
10.8.2 Hepatic function abnormality
Hepatic function abnormality (as defined in Section 10.2.1) 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 10.3.2 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 investigation 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.
10.8.3 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 pregnancy, normal birth, or congenital 
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 106 of 169
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, i.e., 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.
10.9 FDA Reporting
When RPCI is the IND holder the following describes the FDA reporting requirements by timeline 
for AEs and new safety findings that meet the criteria outlined below:
Within 7 Calendar Days
Any adverse event that meets ALL the following criteria:

Related or possibly related to the use of the study drug;

Unexpected; and

Fatal or life-threatening.
Within 15 Calendar Days
Any adverse event that meets ALL the following criteria:

Related or possibly related to the use of the study drug;

Unexpected; and

Serious but not fatal or life-threatening;
Or, meets ANY of the following criteria:

A previous adverse event that is not initially deemed reportable but is later found to fit the 
criteria for reporting (report within 15 days from when event was deemed reportable).

Any findings from other studies, including epidemiological studies, pooled analysis of 
multiple studies, or other clinical studies conducted with the study drug that suggest a 
significant risk in humans exposed to the drug.

Any findings from animal or in vitro testing that suggest a significant risk for human 
participants including reports of mutagenicity, teratogenicity, or carcinogenicity or reports 
of significant organ toxicity at or near the expected human exposure.

Any clinically important increase in the rate of occurrence of a serious, related or possibly 
related adverse event over that listed in the protocol or investigator brochure.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 107 of 169
Sponsors are also required to identify in IND safety reports, all previous reports concerning similar 
adverse events and to analyze the significance of the current event in the light of the previous 
reports.
Reporting Process
The principal investigator or designee will complete and submit a FDA Form 3500A MedWatch 
for any event that meets the above criteria. Forms will be submitted to the CRS QA Office via 
email to CRSQA@RoswellPark.org.  Network sites: See Appendix A.
11 DATA AND SAFETY MONITORING
The Phase 1 portion of this study will be reviewed at the scheduled RPCI Early Phase Clinical 
Trial (EPCT) Program meetings and the minutes are forwarded to the IRB for review.
During the Phase II portion of this study, The RPCI Data, Safety Monitoring and Accrual Board 
(DSMAB) will assess the progress of the study, the safety data, and critical efficacy endpoints. 
The DSMAB will review the study annually and will make recommendations that include but not 
limited to; (a) continuation of the study, (b) modifications to the design, (c) suspension of, or (d) 
or termination of the study.
12 STATISTICAL METHODOLOGY
Phase I: The primary objective of the Phase I component of this study is:

To assess the safety and toxicity of the combination of PARP inhibitor olaparib with anti-
PD-L1 antibody durvalumab and anti-CTLA4 antibody tremelimumab
Phase II: The primary objective of the Phase II component of this study is:

To assess the impact of the combination of olaparib with durvalumab and tremelimumab 
on PFS rates.
The secondary objectives of the Phase II component of study are:

To assess the impact of the combination of olaparib with durvalumab and tremelimumab 
on anti-tumor immune responses in patients with recurrent platinum sensitive or resistant 
or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer who carry a 
germline and/or somatic BRCA1 or BRCA2 mutation.

To assess the impact of the combination of olaparib with durvalumab and tremelimumab 
on PFS and/or OS in patients with recurrent platinum sensitive or resistant or refractory 
epithelial ovarian, fallopian tube, or primary peritoneal cancer who carry a germline and/or 
somatic BRCA1 or BRCA2 mutation. 
12.1 Sample Size Determination
The potential Phase I study sample size ranges from a minimum of n=6 to a maximum of n=12. 
See Table 1 for the dose escalation schema. The Phase II portion of the study will have a sample 
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 108 of 169
size of n=27. Subjects will be enrolled in the Phase II study at a ratio of 2:1 of platinum resistant 
to platinum sensitive disease.
Depending on the incidence of DLT(s), following a 3+3 design, the sample size is estimated to be 
33 to 36 patients. Assuming the true DLT rate is much less than 1/3rd, we anticipate enrolling 36 
subjects (9+27) where the accrual is expected to take up to 4 years.
12.2 Demographics and Baseline Characteristics
Descriptive statistics (as appropriate: n, percent, mean, median, min and max) will be used to 
summarize demographic and baseline characteristics.
12.3 Safety and Tolerability
The primary objective of the Phase I study is establishing safety. Assessment of safety and 
tolerability will be performed by the internal data safety monitoring panel on an ongoing basis, 
based on data review and regular conference calls with the investigators.
DLT: All patients who receive at least two cycles of durvalumab + tremelimumab and 8 weeks of 
olaparib treatment and respective safety assessments, as well as, all patients who discontinue the 
study prematurely due to DLT are considered fully evaluable per protocol for DLT (see Section 
4.3 for patient replacement). Patients must also have received at least 75% of the planned dose of 
olaparib during the DLT evaluation period (except for patients who discontinued prematurely due 
to DLT) to be evaluable for DLT.
Safety set: All patients who received at least one dose of durvalumab + tremelimumab + olaparib 
will be evaluated for safety and tolerability.
Appropriate summaries of AEs, laboratory data and vital sign data will be presented. AEs will be 
listed individually per patient according to CTCAE version 4.03, and the number of patients 
experiencing each AE will be summarized using descriptive statistics.
The MTD is defined as the highest dose studied, for which the observed incidence of DLT is less 
than 33%. Frequencies of toxicities will be tabulated according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
12.4 Clinical Efficacy
Clinical efficacy evaluation will include tumor response assessed by irRECIST, Progression-free 
Survival and overall survival.
The primary endpoint will test the 3-month progression free survival rate in the platinum resistant 
group in conjunction with the 6-month progression free survival rate in the platinum sensitive 
group. The overall test follows the approach of London and Change(58)  Let 
 denote the 3 month 
𝜋1
progression free response rate for the platinum-resistant strata and let 
denote the 6 month 
𝜋2
progression free response rate for the platinum sensitive strata. Our overall test is of the form 𝐻0:𝜋1
versus the alternative
. Using the approach of 
= 0.55,  𝜋2 = 0.65 
 𝐻1:𝜋1 > 0.55,  𝜋2 > 0.65
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 109 of 169
London and Chang our test statistic takes the form 
, where  denotes the 
𝑇=
𝑅‒ ∑2
𝑖𝑁𝑖𝜋𝑖0
𝑁∑2
𝑖= 1𝜋𝑖0(1 ‒ 𝜋𝑖0)𝑃𝑖
𝑅
combined number of non-progressors across strata, 
 and 
 represent the null 
 𝜋10 = 0.55
 𝜋20 = 0.65
values for strata 1 and 2 above, 
 
 and 
 represent the strata sample sizes 
𝑁= 𝑁1 + 𝑁2 𝑁1 = 18
𝑁2 = 9
and 
 and  
 represent the strata distribution proportions, respectively. The 
𝑃1 = 2/3
𝑃2 = 1/3
distributional properties of  are given in London and Chang (58). Given 
 and a fixed 
𝑇
𝛼= 0.10
sample size of 
 we will be able to detect a difference of 0.2 and 0.15 between the null and 
𝑁= 27
alternative progression free survival rate values per strata one and two, respectively at 0.72 power 
based on an exact multinomial test about .
𝑇
All patients who received at least two cycles of durvalumab + tremelimumab and 8 weeks of 
olaparib, as well as baseline and at least one post-baseline disease assessment will be evaluated for 
clinical efficacy. Tumor Responses by irRECIST and RECIST, progression free survival and 
overall survival will be summarized and analyzed descriptively via summary frequencies and 
Kaplan-Meier estimators.
12.5 Interim Analysis and Criteria for Early Termination of the Study
This is a Phase I/II study and as such will be monitored and discussed by RPCI’s Phase 1 
Committee, which meets on a regular basis per the RPCI Data Safety Monitoring Plan. Drug safety 
will be monitored and evaluated continuously throughout the study including 30-day safety follow-
up period by obtaining, reviewing and analyzing data on AEs, changes in laboratory values, vital 
signs, electrocardiograms (ECGs), and physical examination findings. Potential early termination 
decisions are an inherent part of the Phase 1 study monitoring. The Phase II study does not have 
an interim analysis point.
13 CORRELATIVE DATA ANALYSIS
13.1 Translational and Correlative Biomarker Endpoints
Archival and on-treatment tumor biopsies and peripheral blood will be utilized for this assessment.

Olaparib treatment of BRCA1/2+ve platinum resistant ovarian cancer patients leads to the 
release of a unique repertoire of tumor antigens that will be cross-presented to the immune 
system leading to generation of humoral and T cell responses. We will initially focus on 
auto-antibody analysis of pre- and post- treatment samples from the patients on the clinical 
trial, using a previously validated “seromics” approach by our group (49). The results 
generated by the analysis of pre- and post-treatment sera may be useful individually or as 
signature sets as (i) diagnostic markers, preferentially immunogenic in HR-deficient 
ovarian cancer, (ii) prognostic markers, associated with favorable or unfavorable clinical 
outcome in HR-deficient ovarian cancer, and (iii) potential targets of immune responses 
for the development of new immunotherapeutic reagents in HR-deficient ovarian cancer.

Immunoscore: pre- and post-treatment biopsies.

Analysis of T-cell responses.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 110 of 169

Analysis of potential resistance mechanism: sequencing studies (e.g. for HR deficiency), 
gene expression studies and analysis for secondary genetic and epigenetic events.
14 ETHICAL AND REGULATORY STANDARDS
14.1 Ethical Principles
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC). Each participant (or legal guardian) shall read, understand, and sign an 
instrument of informed consent prior to performance of any study-specific procedure. It is the 
responsibility of the investigator to ensure that the participant is made aware of the investigational 
nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
study specific information according to Health Insurance Portability and Accountability Act 
regulations (where applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated. The clinical trial should be 
conducted in accordance with the ethical principles embodied in the Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research, consistent with good 
clinical practice and the applicable regulatory requirements and according to the guidelines in this 
protocol, including attached appendices.
14.2 Informed Consent
The Investigator (or IRB specified designee) is responsible for obtaining written consent from each 
participant or the participant's legally authorized representative in accordance with GCP guidelines 
using the approved informed consent form, before any study specific procedures (including 
screening procedures) are performed. The informed consent form acknowledges all information 
that must be given to the participant according to applicable GCP guidelines, including the purpose 
and nature of the study, the expected efficacy and possible side effects of the treatment(s), and 
specifying that refusal to participate will not influence further options for therapy. Any additional 
information that is applicable to the study must also be included. Additional national or 
institutionally mandated requirements for informed consent must also be adhered to. The 
participant should also be made aware that by signing the consent form, processing of sensitive 
clinical trial data and transfer to other countries for further processing is allowed.
The Investigator shall provide a copy of the signed consent form to the participant and the signed 
original shall be maintained in the Investigator File. A copy of the signed consent form must be 
filed in the participant file. At any stage, the participant may withdraw from the study and such a 
decision will not affect any further treatment options.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 111 of 169
15 STUDY RESPONSIBILITIES
15.1 Data Collection
Data entry into the database is to be completed in a timely fashion (within 30 days) after the 
participant’s clinic visit. If an AE is considered serious it is captured on both the Adverse Event 
page and the Serious Adverse Event Source Form, which is handled in an expedited fashion.
Data management activities will be performed using eClinical. eClinical is a suite of software tools 
that enables the collection, cleaning and viewing of clinical trial data. CRS data management will 
design the study-specific database and facilitate its development by the eClinical Information 
Technology team. Once the database design is approved by the Investigator, Statistician, and 
Clinical Research Coordinator, the database will be put into production and data entry can begin. 
Data can be entered and changed only by those with the rights to do so into the eCRFs (via the 
EXPeRT Module). eClinical is compliant with all relevant technical aspects of relevant GCP 
guidelines.

The system can generate accurate copies of stored data and audit trail information in human 
readable form.

System access is limited to authorized individuals through the controlled assignment of 
unique ID and password combinations.

The system is designed to periodically force users to change their passwords and verifies 
that user ID and password combinations remain unique.

The system automatically generates a permanent time-stamped audit trail of all user 
interactions.
When data entry is complete, data management will review the data and will query any missing, 
incomplete, or invalid data points for resolution by the Clinical Research Coordinator and 
Investigator. Once all queries have been resolved, the data can be released to the statistician for 
analysis.
15.2 Maintenance of Study Documents
Essential documents will be retained per RPCI’s policy for 6 years from the study termination 
date. These documents could be retained for a longer period, however, if required by the applicable 
local regulatory requirements or by an agreement with RPCI.
15.3 Study Governance and Oversight
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 112 of 169
16 ADMINISTRATIVE RULES
16.1 Revisions to the Protocol
RPCI may make such changes to the protocol as it deems necessary for safety reasons or as may 
be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to the 
IRB/ERC for written approval before implementation.
16.2 Termination of the Study
It is agreed that, for reasonable cause, either the RPCI Investigators or the Sponsor, may terminate 
this study, provided a written notice is submitted within the time period provided for in the Clinical 
Trial Agreement. In addition, RPCI may terminate the study at any time upon immediate notice if 
it believes termination is necessary for the safety of participants enrolled in the study.
16.3 Confidentiality
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 113 of 169
17 APPENDICES
Appendix A
Instructions for Network Sites
1.
CONTACT INFORMATION
All questions related to the protocol or study implementation should be directed to:
Roswell Park Cancer Institute
CRS Quality Assurance (QA) Network Office
CRSNetworkCoordinators@RoswellPark.org 
1930 GBSB Buffalo, New York 14263
Telephone:
Monday - Friday; 8:00 AM to 4:30 PM EST
716-845-3155
After hours, weekends, and holidays request the RPCI Investigator
716-845-2300
Fax: 716-845-8743
2.
INFORMED CONSENT

Informed consent must be obtained by the site Investigator/designee from any participants 
wishing to participate, prior to any procedures or treatment.

An informed consent template is provided by RPCI and can be amended to reflect 
institutional requirements.

All consent changes must be reviewed by Roswell Park CRS QA Network Office prior to 
submission to the site IRB.

The informed consent must be IRB approved.

Always check that the most up to date version of the IRB approved consent is being used.

Within 5 business days, notify the Roswell Park CRS QA Network Office of all participant 
withdrawals or consent to limited study participation and appropriately document the 
discontinuation and the reason(s) why.
3.
PARTICIPANT REGISTRATION
The participant completes the Gender, Race, and Ethnicity Form and this is placed in the study 
binder.
RPCI does not grant exceptions to eligibility criteria.
Phase 1 Protocol Registration Instructions
Contact the RPCI Network Monitor to verify that a slot is available in the open cohort when a 
participant has been identified. Do not have the participant sign consent prior to verifying an 
open slot.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 114 of 169

After the participant signs consent, the Subject Screening and Enrollment Log must be 
faxed or emailed CRSNetworkCoordinators@RoswellPark.org) to the Roswell Park QA 
Coordinator Monitor within 1 business day. The Roswell Park QA Coordinator/Monitor 
will confirm receipt of the Subject Screening and Enrollment Log and email the participant 
ID number.

When the participant has met eligibility, a signed eligibility checklist and other requested 
documentation will be faxed or emailed to the Roswell Park Network QA Coordinator.

Within 1 business day of receipt of the eligibility check list, the Roswell Park Network QA 
Coordinator will fax or email the cohort assignment and dose level.

An email must be sent by the site to confirm receipt of the cohort assignment and to provide 
the planned treatment start date.
Phase 2 Protocol Registration Instructions
The 
Subject 
Screening 
and 
Enrollment 
Log 
must 
be 
faxed 
or 
emailed 
(CRSNetworkCoordinators@RoswellPark.org) to the Roswell Park CRS QA Network Office 
within 1 business day of the date the participant is consented. Once the Investigator has determined 
that eligibility has been met, complete the eligibility check list and fax or email it to the Roswell 
Park Network QA Coordinator at 716-845-8743.
4.
STUDY DEVIATIONS

If a deviation has occurred to eliminate hazard, this must be reported to the RPCI Network, 
site IRB and any other regulatory authority involved in the study.

ALL study deviations will be recorded on the Study Deviation Log.

Participants inadvertently enrolled with significant deviation(s) from the study-specified 
criteria will be removed from the study, at the discretion of the Principle Investigator.
The Reportable New Information (RNI) Form will be submitted to the CRS Network QA 
Coordinator within 1 business day of becoming aware of the Unanticipated Problem.  
5.
STUDY DOCUMENTATION

Study documents must be filled out completely and correctly. Ditto marks are not allowed.

If an entry has been documented in error put a single line through the entry and initial and 
date the change. The Roswell Park Network QA Coordinator must be able to read what has 
been deleted.

Do NOT use white-out, magic marker, scratch-outs.

Do NOT erase entries.

Use only black ink for documentation on the accountability form and any other study 
forms.

It is the responsibility of RPCI to inform the Investigator/ institution as to when these 
documents no longer need to be retained. If, for any reason, the Investigator desires to no 
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 115 of 169
longer maintain the study records, they may be transferred to another institution, another 
investigator, or to RPCI upon written agreement between the Investigator and RPCI.
6.
DRUG ACCOUNTABILITY
Drug accountability must be strictly maintained.

Responsibility rests solely with the Investigator but can be delegated as appropriate (e.g., to 
pharmacy personnel).

A drug accountability record form (DARF) will record quantities of study drug received, 
dispensed to participants and wasted, lot number, date dispensed, participant ID number 
and initials, quantity returned, balance remaining, manufacturer, expiration date, and the 
initials of the person dispensing the medication.

Study drug supply will only be used in accordance with the IRB approved study.

Drug accountability forms are protocol and agent specific, they are study source documents 
and will be used to verify compliance with the study.

An inventory count must be performed with each transaction. Any discrepancies shall be 
documented and explained.

Drug accountability forms must be stored with study related documents.

Each medication provided for this study and each dosage form and strength must have its 
own DARF.

Dispensing the wrong study supply is considered a medication error.

NEVER replace investigational agents with commercial product.

Do NOT “transfer”, “borrow” or “replace” supplies between studies.
If any questions regarding study drugs associated with this trial, network sites should contact: 
Denise Wells-Johnson
716-845-3298
Denise.WellsJohnson@roswellpark.org
7.
SERIOUS ADVERSE EVENT REPORTING
The site Investigator or designated research personnel will report all SAEs, whether related or 
unrelated to the investigational agent(s) to the IRB in accordance with their local institutional 
guidelines. The site will notify the Roswell Park Network QA Coordinator within 1 business day 
of being made aware of the SAE. A preliminary written report must follow within 1 business day 
of the first notification using the following forms:

RPCI SAE Source form

MedWatch 3500A 
A complete follow-up report must be sent to the RPCI Network Monitor when new information 
becomes available.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 116 of 169

If this is a Phase 1 study the site Investigator or designated research personnel will 
complete and send the Serious Adverse Event / Possible Dose Limiting Toxicity Memo 
to notify the appropriate RPCI personnel of an SAE or potential DLT via email: 
Phase1DLTnetwork@Roswellpark.org.
8.
UNANTICIPATED PROBLEM REPORTING
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the criteria 
in Section 10.6.
For all adverse events occurring that are unanticipated and related or possibly related to the 
research drug, biologic or intervention, the participating physician or delegated research staff from 
each site will notify their local IRB in accordance with their local institutional guidelines. The 
site must also notify the Roswell Park Network QA Coordinator within 1 business day of being 
made aware of the Unanticipated Problem by completing the RPCI Unanticipated Problem 
Report Form and faxing or emailing it to the Roswell Park Network QA Coordinator.
9.
DATA AND SAFETY MONITORING
Weekly or bi-weekly teleconferences will be scheduled to review participant adverse events and 
study status. The site Investigator and study coordinator are expected to attend.
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 117 of 169
Appendix B
ECOG Performance Status Scores
Description
Status
Fully active, able to carry on all pre-disease performance without restriction.
0
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light housework, office work.
1
Ambulatory and capable of all self-care but unable to carry out any work activities.
2
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4
Dead
5
APPROVED RPCI IRB
4/16/2021

Roswell Park Cancer Institute Study Number: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 118 of 169
Appendix C
Durvalumab: Dose Calculations
For durvalumab dosing done depending on subject weight ≤ 30 kg:
1. Cohort dose: X mg/kg
2. Subject weight: Y kg
3. Dose for subject: XY mg = X (mg/kg) × Y (kg)
4. Dose to be added into infusion bag: 
Dose (mL) = XY mg / 50 (mg/mL) 
where 50 mg/mL is durvalumab nominal concentration 
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 mL). 
Dose adjustments for each cycle only needed for greater than 10% change in weight.
5. The theoretical number of vials required for dose preparation is the next greatest whole 
number of vials from the following formula:
Number of vials = Dose (mL) / 10 (mL/vial)
Example:
1. Cohort dose: 10 mg/kg
2. Subject weight: 30 kg
3. Dose for subject: 300 mg = 10 (mg/kg) × 30 (kg)
4. Dose to be added into infusion bag: 
Dose (mL) = 300 mg / 50 (mg/mL) = 6mL
5. The theoretical number of vials required for dose preparation: 
Number of vials = 6 (mL) / 10 (mL/vial) = 1 vial
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 119 of 169
Appendix D
Durvalumab: Dose Volume Calculations
For durvalumab flat dosing:
1. Cohort dose: X g
2. Dose to be added into infusion bag: 
Dose (mL) = X g × 1000 / 50 (mg/mL) 
where 50 mg/mL is durvalumab nominal concentration.
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 mL). 
3. The theoretical number of vials required for dose preparation is the next greatest whole number of vials from 
the following formula:
Number of vials = Dose (mL) / 10 (mL/vial)
Example: 
1. Cohort dose: 1.5 g
2. Dose to be added into infusion bag: 
Dose (mL) = 1.5 g ×1000 / 50 (mg/mL) = 30mL
3. The theoretical number of vials required for dose preparation: 
Number of vials = 30 (mL) / 10 (mL/vial) = 3 vials
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 120 of 169
Appendix E
Tremelimumab: Dose Calculations
For tremelimumab dosing done depending on subject weight (≤ 30 kg):
1. Cohort dose: X mg/kg
2. Subject weight: Y kg
3. Dose for subject: XY mg = X (mg/kg) × Y (kg)
4. Dose to be added into infusion bag: 
Dose (mL) = XY mg / 20 (mg/mL) 
where 20 mg/mL is tremelimumab nominal concentration.
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 mL). Dose 
adjustments for each cycle are only needed for greater than 10% change in weight.
5. The theoretical number of vials required for dose preparation is the next greatest whole number of vials from 
the following formula:
Number of vials = Dose (mL) / 20 (mL/vial)
Example: 
1. Cohort dose: 1 mg/kg
2. Subject weight: 30 kg
3. Dose for subject: 30 mg = 1 (mg/kg) × 30 (kg)
4. Dose to be added into infusion bag: 
Dose (mL) = 30 mg / 20 (mg/mL) = 1.5 mL
5. The theoretical number of vials required for dose preparation: 
Number of vials = 1.5 (mL) / 20 (mL/vial) = 1 vials
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 121 of 169
Appendix F
Tremelimumab: Dose Volume Calculations
For tremelimumab flat dosing:
1. Cohort dose: X mg
2. Dose to be added into infusion bag: 
Dose (mL) = X mg / 20 (mg/mL) 
where 20 mg/mL is tremelimumab nominal concentration 
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 mL). 
3. The theoretical number of vials required for dose preparation is the next greatest whole number of vials from 
the following formula:
Number of vials = Dose (mL) / 20 (mL/vial)
Example: 
1. Cohort dose: 75 mg
2. Dose to be added into infusion bag: 
Dose (mL) = 75 mg / 20 (mg/mL) = 3.8 mL
3. The theoretical number of vials required for dose preparation: 
Number of vials = 3.8 (mL) / 20 (mL/vial) = 1 vial
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 122 of 169
Appendix G
Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, 
Infusion-Related and, Non-Immune-Mediated Reactions (MEDI4736 Monotherapy or Combination 
Therapy with Tremelimumab or Tremelimumab Monotherapy): 17 October 2019 Version 4.03 
Dose Modifications
Toxicity Management
Drug administration modifications of study drug/study regimen will be 
made to manage potential immune-related AEs based on severity of 
treatment-emergent toxicities graded per NCI CTCAE v4.03. (unless 
indicated otherwise)
In addition to the criteria for permanent discontinuation of study 
drug/study regimen based on CTC grade/severity (table below), 
permanently discontinue study drug/study regimen for the following 
conditions:

Inability to reduce corticosteroid to a dose of ≤10 mg of 
prednisone per day (or equivalent) within 12 weeks  of the 
start of the immune-mediated adverse event (imAE)

Grade 3 recurrence of a previously experienced Grade 3 
treatment-related imAE following resumption of dosing
Grade 1
No dose modification
Grade 2
Hold study drug/study regimen dose until Grade 2 
resolution to Grade ≤1.
If toxicity worsens, then treat as Grade 3 or Grade 4.
Study drug/study regimen can be resumed once event 
stabilizes to Grade ≤1 after completion of steroid taper.
Patients with endocrinopathies who may require 
prolonged or continued steroid replacement can be 
retreated with study drug/study regimen on the 
following conditions:
1.
The event stabilizes and is controlled.
2.
The patient is clinically stable as per Investigator or 
treating physician’s clinical judgement.
3.
Doses of prednisone are at ≤10 mg/day or 
equivalent.
Grade 3
Depending on the individual toxicity, study drug/study 
regimen may be permanently discontinued. Please refer 
to guidelines below.
Grade 4
Permanently discontinue study drug/study regimen.

Note: For  asymptomaticamylase or lipase levels of 
>2.0×ULN, hold study drug/study regimen, and if 
complete work up shows no evidence of pancreatitis, 
study drug/study regimen may be continued or resumed.

Note: Study drug/study regimen should be permanently 
discontinued in Grade 3 events with high likelihood for 
morbidity and/or mortality – e.g., myocarditis, or other 
similar events even if they are not currently noted in the 
guidelines. Similarly, consider whether study drug/study 
regimen should be permanently discontinued in Grade 2 
events with high likelihood for morbidity and/or mortality – 
e.g., myocarditis, or other similar events even if they are not 
currently noted in the guidelines – when they do not rapidly 
improve to Grade <1 upon treatment with systemic steroids 
and following full taper
It is recommended that management of immune-mediated adverse 
events (imAEs) follows the guidelines presented in this table:

It is possible that events with an inflammatory or immune 
mediated mechanism could occur in nearly all organs, some 
of them not noted specifically in these guidelines

Whether specific immune-mediated events (and/or laboratory 
indicators of such events) are noted in these guidelines or 
not, patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, concomitant 
medications, and infections) to a possible immune-mediated 
event. . In the absence of a clear alternative etiology; all 
events should be considered potentially immune related. 
General recommendations follow

Symptomatic and topical therapy should be considered for 
low-grade (Grade 1 or 2, unless otherwise specified) events.

For persistent (>3 to 5 days) low-grade (Grade 2) or severe 
(Grade ≥3) events, promptly start prednisone 1 to 
2 mg/kg/day PO or IV equivalent.

Some events with high likelihood for morbidity and/or 
mortality – e.g., myo-carditis, or other similar events even if 
they are not currently noted in the guidelines – should 
progress rapidly to high dose IV corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the event is 
Grade 2, and if clinical suspicion is high and/or there has 
been clinical confirmation. Consider, as necessary, 
discussing with the study physician, and promptly pursue 
specialist consultation. 

If symptoms recur or worsen during corticosteroid tapering 
(28 days of taper), increase the corticosteroid dose 
(prednisone dose [e.g., up to 2 to 4 mg/kg/day PO or IV 
equivalent]) until stabilization or improvement of symptoms, 
then resume corticosteroid tapering at a slower rate (>28 days 
of taper).
−
More potent immunosuppressives such as TNF inhibitors 
(e.g., infliximab) (also refer to the individual sections of the 
imAEs for specific type of immunosuppressive) should be 
considered for events not responding to systemic steroids. 
Progression to use of more potent immunosuppressives 
should proceed more rapidly in events with high likelihood 
for morbidity and/or mortality – e.g., myocarditis, or other 
similar events even if they are not currently noted in the 
guidelines – when these events are not responding to 
systemic steroids.

With long-term steroid and other immunosuppressive use, 
consider need for Pneumocystis jirovecii pneumonia (PJP, 
formerly known as Pneumocystis carnii pneumonia) 
prophylaxis, gastrointestinal protected, and glucose 
monitoring.

Discontinuation of study drug/study regimen is not mandated 
for Grade 3/Grade 4 inflammatory reactions attributed to 
local tumor response (e.g., inflammatory reaction at sites of 
metastatic disease and lymph nodes). Continuation of study 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 123 of 169

Note: There are some exceptions to permanent 
discontinuation of study drug for Grade 4 events (i.e. 
hyperthyroidism, hypothyroidism, Type I diabetes mellitus)
drug/study regimen in this situation should be based upon a 
benefit/risk analysis for that patient.
AE  Adverse event; CTC  Common Toxicity Criteria; CTCAE  Common Terminology Criteria for Adverse Events; imAE  Immune-mediated 
adverse event; IV  intravenous; NCI  National Cancer Institute; PO  By mouth.
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
Any Grade
1.1.1.1.1
General 
Guidance
For Any Grade:

Monitor patients for signs and 
symptoms of pneumonitis or 
ILD (new onset or worsening 
shortness of breath or cough). 
Patients should be evaluated 
with imaging and pulmonary 
function tests, including other 
diagnostic procedures as 
described below.

Initial work-up may include 
clinical evaluation, 
monitoring of oxygenation via 
pulse oximetry (resting and 
exertion), laboratory work-up, 
and high- resolution CT scan.
Grade 1
(asymptomatic, clinical or 
diagnostic observations only; 
intervention not indicated)
No dose modifications required. 
However, consider holding study 
drug/study regimen dose as 
clinically appropriate and during 
diagnostic work-up for other 
etiologies.
For Grade 1 (radiographic 
changes only):

Monitor and closely follow up 
in 2 to 4 days for clinical 
symptoms, pulse oximetry 
(resting and exertion), and 
laboratory work-up and then 
as clinically indicated.

Consider Pulmonary and 
Infectious Disease consults.
Pneumonitis/Interstitial Lung 
Disease (ILD)
Grade 2
(symptomatic; medical 
intervention indicated; limiting 
instrumental ADL)
Hold study drug/study regimen 
dose until Grade 2 resolution to 
Grade ≤1.

If toxicity worsens, then treat 
as Grade 3 or Grade 4.

If toxicity improves to Grade 
≤1, then the decision to 
reinitiate study drug/study 
regimen will be based upon 
treating physician’s clinical 
judgment and after 
completion of steroid taper.
For Grade 2 (mild to moderate 
new symptoms):

Monitor symptoms daily and 
consider hospitalization.

Promptly start systemic 
steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV 
equivalent).

Reimage as clinically 
indicated.

If no improvement within 3 to 
5 days, additional workup 
should be considered and 
prompt treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day started

If still no improvement within 
3 to 5 days despite IV 
methylprednisolone at 2 to 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 124 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
4 mg/kg/day, promptly start 
immunosuppressive therapy 
such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg 
every 2 weeks). Caution: It is 
important to rule out sepsis 
and refer to infliximab label 
for general guidance before 
using infliximab.

Once the patient is improving, 
gradually taper steroids over 
≥28 days and consider 
prophylactic antibiotics, 
antifungals, or anti-PJP 
treatment (refer to current 
NCCN guidelines for 
treatment of cancer-related 
infections)a

Consider pulmonary and 
infectious Disease consults.

Consider, as necessary, 
discussing with study 
physician.
Grade 3 or 4
(Grade 3: severe symptoms; 
limiting self-care ADL; oxygen 
indicated)
(Grade 4: life-threatening 
respiratory compromise; urgent 
intervention indicated [e.g., 
tracheostomy or intubation])
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4 (severe or new 
symptoms, new/worsening 
hypoxia, life-threatening):

Promptly initiate empiric IV 
methylprednisolone 1 to 
4 mg/kg/day or equivalent.

Obtain Pulmonary and 
Infectious Disease consults 
Consider as necessary, 
discussing with study 
physician.

Hospitalize the patient.

Supportive care (e.g., 
oxygen).

If no improvement within 3 to 
5 days, additional workup 
should be considered and 
prompt treatment with 
additional 
immunosuppressive therapy 
such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg 
every 2 weeks dose) started. 
Caution: rule out sepsis and 
refer to infliximab label for 
general guidance before using 
infliximab.

Once the patients is 
improving, gradually taper 
steroids over ≥28 days and 
consider prophylactic 
antibiotics, antifungals, and, 
in particular, anti-PJP 
treatment (refer to current 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 125 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
NCCN guidelines for 
treatment of cancer-related 
infections). a
Any Grade
General Guidance
For Any Grade:

Monitor for symptoms that 
may be related to 
diarrhea/colitis (abdominal 
pain, cramping, or changes in 
bowel habits such as 
increased frequency over 
baseline or blood in stool) or 
related to bowel perforation 
(such as sepsis, peritoneal 
signs, and ileus).

When symptoms or 
evaluation indicate a 
perforation is suspected, 
consult a surgeon experienced 
in abdominal surgery 
immediately without any 
delay.

Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., 
disease progression, other 
medications, or infections), 
including testing for 
clostridium difficile toxin, etc.

Steroids should be considered 
in the absence of clear 
alternative etiology, even for 
low-grade events, in order to 
prevent potential progression 
to higher grade event, 
including perforation.

Use analgesics carefully; they 
can mask symptoms of 
perforation and peritonitis.
Grade 1
(Diarrhea: stool frequency of
<4 over baseline per day)
(Colitis: asymptomatic; clinical 
or diagnostic observations only)
No dose modifications.
For Grade 1:

Monitor closely for worsening 
symptoms.

Consider symptomatic 
treatment, including 
hydration, electrolyte 
replacement, dietary changes 
(e.g., American Dietetic 
Association colitis diet), and 
loperamide. Use probiotics as 
per treating physician’s 
clinical judgment.
Diarrhea/Colitis 
Large intestine 
perforation/Intestine 
perforation
Grade 2
(Diarrhea: stool frequency of 4 
to 6 over baseline per day) 
Hold study drug/study regimen 
until resolution to Grade ≤1

If toxicity worsens, then treat 
as Grade 3 or Grade 4.
For Grade 2:

Consider symptomatic 
treatment, including 
hydration, electrolyte 
replacement, dietary changes 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 126 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
(Colitis: abdominal pain; mucus 
or blood in stool)
(Perforation: symptomatic; 
medical intervention indicated*)
* “medical intervention” is not 
invasive

If toxicity improves to Grade 
≤1, then study drug/study 
regimen can be resumed after 
completion of steroid taper.
(e.g., American Dietetic 
Association colitis diet), and 
loperamide and/or 
budesonide.

Promptly start prednisone 1 to 
2 mg/kg/day PO or IV 
equivalent.

If event is not responsive 
within 3 to 5 days or worsens 
despite prednisone at 1 to 2 
mg/kg/day PO or IV 
equivalent, GI consult should 
be obtained for consideration 
of further workup, such as 
imaging and/or colonoscopy, 
to confirm colitis and rule out 
perforation, and prompt 
treatment with IV 
methylprednisolone 2 to 4 
mg/kg/day started.

If still no improvement within 
3 to 5 days despite 2 to 4 
mg/kg IV 
methylprednisolone, promptly 
start immunosuppressives 
such as infliximab at 5 mg/kg 
once every 2 weeks a. 
Caution: it is important to 
rule out bowel perforation and 
refer to infliximab label for 
general guidance before using 
infliximab.

Consider, as necessary, 
discussing with study 
physician if no resolution to 
Grade ≤1 in 3 to 4 days.

Once the patient is improving, 
gradually taper steroids over 
≥28 days and consider 
prophylactic antibiotics, 
antifungals, and anti-PJP 
treatment (refer to current 
NCCN guidelines for 
treatment of cancer-related 
infections).a
Grade 3 or 4
(Grade 3: Diarrhea stool 
frequency of ≥7 over baseline 
per day;
Grade 4 Diarrhea: life 
threatening consequences)
Permanently discontinue study 
drug/study regimen- for Grade 3 if 
toxicity does not improve to Grade 
<1 within 14 days; study 
drug/study regimen can be 
resumed after completion of 
steroid taper.
Grade 4
For Grade 3 or 4:

Promptly initiate empiric IV 
methylprednisolone 2 to 
4 mg/kg/day or equivalent.

Monitor stool frequency and 
volume and maintain 
hydration.

Urgent GI consult and 
imaging and/or colonoscopy 
as appropriate.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 127 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
Grade 3 Colitis: severe 
abdominal pain, change in 
bowel habits, medical 
intervention indicated, 
peritoneal signs 
Grade 4: Colitis: life-threatening 
consequences, urgent 
intervention indicated
(Grade 3 Perforation: severe 
symptoms, elective* operative 
intervention indicated; Grade 4 
Perforation: life-threatening 
consequences, urgent 
intervention indicated)
*This guidance anticipates that 
Grade 3 operative interventions  
of perforations are usually not 
elective
Permanently discontinue study 
drug/study regimen

If still no improvement within 
3 to 5 days of IV 
methylprednisolone 2 to 4 
mg/kg/day or equivalent, 
promptly start further 
immunosuppressives (e.g. 
infliximab at 5 mg/kg once 
every 2 weeks). Caution: 
Ensure GI consult to rule out 
bowel perforation and refer to 
infliximab label for general 
guidance before using 
infliximab. If perforation is 
suspected, consult a surgeon 
experienced in abdominal 
surgery immediately without 
any delay.

Once the patient is improving, 
gradually taper steroids over 
≥28 days and consider 
prophylactic antibiotics, 
antifungals, and anti-PJP 
treatment (refer to current 
NCCN guidelines for 
treatment of cancer-related 
infections a
 Any Elevations in AST, ALT 
or TB  as Described Below
General Guidance
For Any Elevations Described:

Monitor and evaluate liver 
function test: AST, ALT, 
ALP, and TB.

Evaluate for alternative 
etiologies (e.g., viral hepatitis, 
disease progression, 
concomitant medications).
 (AST or ALT > to 3 × ULN if 
baseline normal, 1.5-
3.0×baseline if baseline 
abnormal; and/or TB > to 
1.5 × ULN if baseline normal, 
>1.0-1.5×baseline if baseline 
abnormal)
No dose modifications.

If it worsens, then treat as 
described for elevations in the 
row below.

Continue LFT monitoring per 
protocol.
Hepatitis (elevated LFTs)
Infliximab should not be used for 
management of immune-related 
hepatitis.
 (AST or ALT > 3 to 5 × ULN 
if baseline normal, >3-
5×baseline if baseline 
abnormal;  and/or TB >1.5 to 
3.0 × ULN if baseline normal, 
>1.5- 3.0×baseline if baseline 
abnormal
Hold study drug/study regimen 
dose until resolution to AST or 
ALT ≤3.0×ULN and/or TB 
≤1.5×ULN if baseline normal, or 
to AST or ALT ≤3.0×baseline 
and/or TB ≤1.5×baseline if 
baseline abnormal.

If toxicity worsens, then treat 
as described for elevation in 
the row below.

If toxicity improves to AST 
or ALT ≤3.0×ULN and/or TB 
≤1.5×ULN if baseline 
normal, or to AST or ALT 
≤3.0×baseline and/or TB 

Regular and frequent 
checking of LFTs (e.g., every 
1 to 2 days) until elevations of 
these are improving or 
resolved.

If no resolution to AST or 
ALT ≤3.0×ULN and/or TB 
≤1.5×ULN if baseline normal, 
or to AST or ALT 
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline 
abnormal in 1 to 2 days, 
consider, as necessary, 
discussing with study 
physician.
PLEASE SEE 
shaded area 
immediately below 
this section to find 
guidance for 
management of 
“Hepatitis (elevated 
LFTS)” in HCC 
patients
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 128 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
≤1.5×baseline if baseline 
abnormal , resume study 
drug/study regimen after 
completion of steroid taper.

If event is persistent (>3 to 5 
days) or worsens, promptly 
start prednisone 1 to 
2 mg/kg/day PO or IV 
equivalent.

If still no improvement within 
3 to 5 days despite 1 to 
2 mg/kg/day of prednisone 
PO or IV equivalent, consider 
additional work-up and start 
prompt treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day.

If still no improvement within 
3 to 5 days despite 2 to 
4 mg/kg/day of IV 
methylprednisolone, promptly 
start immunosuppressives 
(mycophenolate mofetil) a 
Discuss with study physician 
if mycophenolate mofetil is 
not available. Infliximab 
should NOT be used.

Once the patient is improving, 
gradually taper steroids over 
≥28 days and consider 
prophylactic antibiotics, 
antifungals, and anti-PJP 
treatment (refer to current 
NCCN guidelines for 
treatment of cancer-related 
infections).a
AST or 
ALT >5.0×ULN if baseline 
normal, >5×baseline if 
baseline abnormal; and/or 
TB >3.0×ULN if baseline 
normal; >3.0×baseline if 
baseline abnormal
For elevations in transaminases 
≤8×ULN and/or in TB ≤5×ULN if 
baseline normal, or for elevations 
in transaminases ≤8×baseline 
and/or TB ≤5×baseline if baseline 
abnormal:

Hold study drug/study 
regimen dose until resolution 
to AST or ALT ≤3.0×ULN 
and/or TB ≤1.5×ULN if 
baseline normal, or to AST or 
ALT ≤3.0×baseline and/or TB 
≤1.5×baseline if baseline 
abnormal

Resume study drug/study 
regimen if elevations 
downgrade to AST or ALT 
≤3.0×ULN and/or TB 
≤1.5×ULN if baseline normal, 
or to AST or ALT 
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline 

Promptly initiate empiric IV 
methylprednisolone at 1 to 
4 mg/kg/day or equivalent.

If still no improvement within 
3 to 5 days despite 1 to 
4 mg/kg/day 
methylprednisolone IV or 
equivalent, promptly start 
treatment with 
immunosuppressive therapy 
(mycophenolate mofetil). 
Discuss with study physician 
if mycophenolate is not 
available. Infliximab should 
NOT be used.

Request Hepatology consult, 
and perform abdominal 
workup, and imaging as 
appropriate.

Once the patient is improving, 
gradually taper steroids over 
≥28 days and consider 
prophylactic antibiotics, 
antifungals, and anti-PJP 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 129 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
abnormal, within 14 days and 
after completion of steroid 
taper.

Permanently discontinue 
study drug/study regimen if 
the elevations do not 
downgrade as described in 
bullet above within 14 days

For elevations in 
transaminases >8×ULN or 
elevations in TB >5×ULN if 
baseline normal, or for 
elevations in transaminases 
>8×baseline and/or TB 
>5×baseline if baseline 
abnormal, permanently 
discontinue study drug/study 
regimen. Permanently 
discontinue study drug/study 
regimen for any case meeting 
Hy’s law criteria (AST and/or 
ALT >3 × ULN + bilirubin 
>2 × ULN without initial 
findings of cholestasis (i.e., 
elevated alkaline P04) and in 
the absence of any alternative 
cause.b
treatment (refer to current 
NCCN guidelines for 
treatment of cancer-related 
infections).a
Hepatitis (elevated LFTs)
Infliximab should not be used 
for management of immune-
related hepatitis
See instructions at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any time) 
occurs in setting 
Elevations in AST, ALT or TB 
as Described Below
General Guidance
For Any Elevations Described:

Monitor and evaluate liver 
function test: AST, ALT, 
ALP, and TB.

Evaluate for alternative 
etiologies (e.g., viral hepatitis, 
disease progression, 
concomitant medications, 
worsening of liver cirrhosis 
[e.g., portal vein thrombosis]).

For HBV+ patients: evaluate 
quantitative HBV viral load, 
quantitative HBsAg, or 
HBeAg

For HCV+ patients: evaluate 
quantitative HCV viral load

Consider consulting 
hepatologist/Infectious 
Disease specialist regarding 
change/implementation in/of 
antiviral medications for any 
patient with an elevated HBV 
viral load >2000 IU/ml

Consider consulting 
hepatologist/Infectious 
Disease specialist regarding 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 130 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
change/implementation in/of 
antiviral HCV medications if 
HCV viral load increased by 
≥2-fold

For HCV+ with HBcAB+: 
Evaluate for both HBV and 
HCV as above
 Isolated AST or ALT >ULN 
and ≤5.0×ULN, whether normal 
or elevated at baseline

No dose modifications.

If ALT/AST elevations 
represents significant 
worsening based on 
investigator assessment, then 
treat as described for 
elevations in the row below.
For all transaminase elevations, 
see instructions at bottom of 
shaded area if transaminase rise is 
not isolated but (at any time) 
occurs in setting of either 
increasing bilirubin or signs of 
DILI/liver decompensation
of either increasing bilirubin or 
signs of DILI/liver 
decompensation 
 Isolated AST or ALT 
>5.0×ULN and ≤8.0×ULN, if 
normal at baseline
Isolated AST or ALT 
>2.0×baseline and ≤12.5×ULN, 
if elevated >ULN at baseline

Hold study drug/study 
regimen dose until resolution 
toAST or ALT ≤5.0×ULN.

If toxicity worsens, then treat 
asdescribed for elevations in 
the rows below. 

If toxicity improves to AST or 
ALT ≤5.0×ULN, resume 
study drug/study regimen after 
completion of steroid taper.

Regular and frequent 
checking of LFTs (e.g., every 
1 to 3 days) until elevations of 
these are improving or 
resolved.

Recommend consult 
hepatologist; consider 
abdominal ultrasound, 
including Doppler assessment 
of liver perfusion.

Consider, as necessary, 
discussing with study 
physician.

If event is persistent (>3 to 5 
days) or worsens, and 
investigator suspects toxicity 
to be immune-mediated AE, 
recommend to start 
prednisone 1 to 2 mg/kg/day 
PO or IV equivalent.

If still no improvement within 
3 to 5 days despite 1 to 
2 mg/kg/day of prednisone 
PO or IV equivalent, consider 
additional workup and 
treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day.
THIS shaded area 
is guidance only for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 131 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management

If still no improvement within 
3 to 5 days despite 2 to 
4 mg/kg/day of IV 
methylprednisolone, consider 
additional abdominal workup 
(including liver biopsy) and 
imaging (i.e., liver 
ultrasound), and consider 
starting immunosuppressives 
(i.e., mycophenolate mofetil).a 
Discuss with study physician 
if mycophenolate mofetil is 
not available. Infliximab 
should NOT be used.
 Isolated AST or ALT 
>8.0×ULN and ≤20.0×ULN, if 
normal at baseline
Isolated AST or ALT 
>12.5×ULN and ≤20.0×ULN, if  
elevated >ULN at baseline

Hold study drug/study 
regimen dose until resolution 
to AST or ALT ≤5.0×ULN 
Grade ≤1 

Resume study drug/study 
regimen if elevations 
downgrade to AST or ALT 
≤5.0×ULN within 14 days 
and after completion of 
steroid taper.

Permanently discontinue 
study drug/study regimen if 
the elevations do not 
downgrade to AST or ALT 
≤5.0×ULN within 14 days

Permanently discontinue 
study drug/study regimen for 
any case meeting Hy’s law 
criteria, in the absence of any 
alternative cause.b

Regular and frequent 
checking of LFTs (e.g., every 
1-2 days) until elevations of 
these are improving or 
resolved.

Consult hepatologist (unless 
investigator is hepatologist); 
obtain abdominal ultrasound, 
including Doppler assessment 
of liver perfusion; and 
consider liver biopsy.

Consider, as necessary, 
discussing with study 
physician.

If investigator suspects 
toxicity to be immune-
mediated, promptly initiate 
empiric IV 
methylprednisolone at 1 to 
4 mg/kg/day or equivalent.

If no improvement within 3 to 
5 days despite 1 to 
4 mg/kg/day 
methylprednisolone IV or 
equivalent, obtain liver biopsy 
(if it has not been done 
already) and promptly start 
treatment with 
immunosuppressive therapy 
(mycophenolate mofetil). 
Discuss with study physician 
if mycophenolate is not 
available. Infliximab should 
NOT be used.

Once the patient is improving, 
gradually taper steroids over 
≥28 days and consider 
prophylactic antibiotics, 
antifungals, and anti-PCP 
treatment (refer to current 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 132 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
NCCN guidelines for 
treatment of cancer-related).a
 (Isolated AST or ALT 
>20×ULN,  whether normal or 
elevated at baseline)

Permanently discontinue 
study drug/study regimen.
Same as above 
(except would recommend 
obtaining liver biopsy early)
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal at 
baseline; or 2×baseline, if >ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR):
-
Manage dosing for  each level of transaminase rise as instructed for the next highest level of transaminase rise
-
For example, manage dosing for second level of transaminase rise (i.e.,  AST or ALT >5.0×ULN and ≤8.0×ULN, if normal at 
baseline, or AST or ALT >2.0×baseline and ≤12.5×ULN, if elevated >ULN at baseline) as instructed for the third level of 
transaminase rise (i.e., AST or ALT >8.0×ULN and ≤20.0×ULN, if normal at baseline, or AST or ALT >12.5×ULN and 
≤20.0×ULN, if  elevated >ULN at baseline)
-
For the third and fourth levels of transaminase rises, permanently discontinue study drug/study regimen
Any Grade
General Guidance
For Any Grade:

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, or 
proteinuria).

Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., 
disease progression or 
infections).

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.
Nephritis or renal dysfunction
(elevated serum creatinine)
Grade 1
(Serum creatinine > 1 to 1.5 × 
baseline; > ULN to 1.5 × ULN)
No dose modifications.
For Grade 1:

Monitor serum creatinine 
weekly and any accompanying 
symptoms.

If creatinine returns to 
baseline, resume its 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 133 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
regular monitoring per 
study protocol.

If creatinine worsens, 
depending on the 
severity, treat as Grade 2, 
3, or 4.

Consider symptomatic 
treatment, including hydration, 
electrolyte replacement, and 
diuretics.
Grade 2
(serum creatinine >1.5 to 3.0 × 
baseline; >1.5 to 3.0 × ULN)
Hold study drug/study regimen 
until resolution to Grade ≤1 or 
baseline.

If toxicity worsens, then treat 
as Grade 3 or 4.

If toxicity improves to Grade 
≤1 or baseline, then resume 
study drug/study regimen 
after completion of steroid 
taper.
For Grade 2:

Consider symptomatic 
treatment, including hydration, 
electrolyte replacement, and 
diuretics.

Carefully monitor serum 
creatinine every 2 to 3 days 
and as clinically warranted.

Consult nephrologist and 
consider renal biopsy if 
clinically indicated.

If event is persistent (>3 to 5 
days) or worsens, promptly 
start prednisone 1 to 2 
mg/kg/day PO or IV 
equivalent.

If event is not responsive 
within 3 to 5 days or worsens 
despite prednisone at 1 to 2 
mg/kg/day PO or IV 
equivalent, additional workup 
should be considered and 
prompt treatment with IV 
methylprednisolone at 2 to 
4 mg/kg/day started.

Once the patient is improving, 
gradually taper steroids over 
≥28 days and consider 
prophylactic antibiotics, 
antifungals, and anti-PJP 
treatment (refer to current 
NCCN guidelines for 
treatment of cancer-related 
infections).a

When event returns to 
baseline, resume study 
drug/study regimen and 
routine serum creatinine 
monitoring per study protocol.
Grade 3 or 4
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4:

Carefully monitor serum 
creatinine on daily basis.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 134 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
(Grade 3: serum creatinine 
>3.0 × baseline; >3.0 to 
6.0 × ULN)
(Grade 4: serum creatinine >6.0 
× ULN)

Consult nephrologist and 
consider renal biopsy if 
clinically indicated.

Promptly start prednisone 1 to 
2 mg/kg/day PO or IV 
equivalent.

If event is not responsive 
within 3 to 5 days or worsens 
despite prednisone at 1 to 2 
mg/kg/day PO or IV 
equivalent, additional workup 
should be considered and 
prompt treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day started.

Once the patient is improving, 
gradually taper steroids over 
≥28 days and consider 
prophylactic antibiotics, 
antifungals, and anti-PJP 
treatment (refer to current 
NCCN guidelines for 
treatment of cancer-related 
infections).a
Any Grade
(refer to NCI CTCAE v 4.03 for 
definition of severity/grade 
depending on type of skin rash)
General Guidance
For Any Grade:

Monitor for signs and 
symptoms of dermatitis (rash 
and pruritus).

IF THERE IS ANY 
BULLOUS FORMATION, 
THE STUDY PHYSICIAN 
SHOULD BE CONTACTED 
AND STUDY DRUG 
DISCONTINUED. IF 
SUSPECT STEVENS-
JOHNSON SYNDROME 
OR TOXIC EPIDERMAL 
NECROLYSIS.
Grade 1
No dose modifications.
For Grade 1:

Consider symptomatic 
treatment, including oral 
antipruritics (e.g., 
diphenhydramine or 
hydroxyzine) and topical 
therapy (e.g., urea cream).
Rash or dermatitis
(including Pemphigoid)
Grade 2
For persistent (>1 to 2 weeks) 
Grade 2 events, hold scheduled 
study drug/study regimen until 
resolution to Grade ≤1 or baseline.

If toxicity worsens, then treat 
as Grade 3.
For Grade 2:

Obtain Dermatology consult.

Consider symptomatic 
treatment, including oral 
antipruritics (e.g., 
diphenhydramine or 
hydroxyzine) and topical 
therapy (.e.g., urea cream).
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 135 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management

If toxicity improves to Grade 
≤1 or baseline, then resume 
drug/study regimen after 
completion of steroid taper.

Consider moderate-strength 
topical steroid.

If no improvement of rash/skin 
lesions occurs within 3 to 
5 days or is worsening despite 
symptomatic treatment and/or 
use of moderate strength 
topical steroid,  consider, as 
necessary, discussing with 
study physician and promptly 
start systemic steroids such as 
prednisone 1 to 2 mg/kg/day 
PO or IV equivalent.

Consider skin biopsy if the 
event is persistent for >1 to 
2 weeks or recurs.
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen 
until resolution to Grade ≤1 or 
baseline.
If temporarily holding the study 
drug/study regimen does not 
provide improvement of the Grade 
3 skin rash to Grade ≤1 or baseline 
within 30 days, then permanently 
discontinue study drug/study 
regimen.
For Grade 4:
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4:

Consult Dermatology.

Promptly initiate empiric IV 
methylprednisolone 1 to 
4 mg/kg/day or equivalent.

Consider hospitalization.

Monitor extent of rash [Rule 
of Nines].

Consider skin biopsy 
(preferably more than 1) as 
clinically feasible.

Once the patient is improving, 
gradually taper steroids over 
≥28 days and consider 
prophylactic antibiotics, 
antifungals, and anti-PCP 
treatment (refer to current 
NCCN guidelines for 
treatment of cancer-related 
infections).a

 Consider, as necessary, 
discussing with study 
physician.
Endocrinopathy
(e.g., hyperthyroidism, 
thyroiditis, hypothyroidism, Type 
1 diabetes mellitus hypophysitis, 
hypopituitarism, and adrenal 
insufficiency; exocrine event of 
amylase/lipase increased also 
included in this section)
Any Grade
(depending on the type of 
endocrinopathy, refer to NCI 
CTCAE v4.03 for defining the 
CTC grade/severity)
General Guidance
For Any Grade:

 Consider consulting an 
endocrinologist for endocrine 
events.

Consider, as necessary, 
discussing with study 
physician.

Monitor patients for signs and 
symptoms of 
endocrinopathies. Non-
specific symptoms include 
headache, fatigue, behavior 
changes, changed mental 
status, vertigo, abdominal 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 136 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
pain, unusual bowel habits, 
polydipsia, polyuria. 
hypotension, and weakness.

Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., 
disease progression including 
brain metastases, or 
infections).

 Depending on the suspected 
endocrinopathy, monitor and 
evaluate thyroid function tests: 
TSH, free T3 and free T4 and 
other relevant endocrine  and 
related labs (e.g., blood 
glucose and ketone levels, 
HgA1c).

For asymptomatic elevations 
in serum amylase and lipase 
>ULN and <3×ULN, 
corticosteroid treatment is not 
indicated as long as there are 
no other signs or symptoms of 
pancreatic inflammation.

If a patient experiences an AE 
that is thought to be possibly 
of autoimmune nature (e.g., 
thyroiditis, pancreatitis, 
hypophysitis, or diabetes 
insipidus), the investigator 
should send a blood sample for 
appropriate autoimmune 
antibody testing.
Grade 1
No dose modifications.
For Grade 1 (including those 
with asymptomatic TSH 
elevation):

Monitor patient with 
appropriate endocrine function 
tests.

For suspected 
hypophysitis/hypopituitariusm, 
consider consultation of an 
endocrinologist to guide 
assessment of early morning 
ACTH, cortisol, TSH, and free 
T4; also consider 
gonadotropins, sex hormones, 
and prolactin levels, as well as 
cosyntropin stimulation test 
(though it may not be useful in 
diagnosing early secondary 
adrenal insufficiency). 

If TSH < 0.5 × LLN, or TSH 
>2 × ULN or consistently out 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 137 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
of range in 2 subsequent 
measurements, include free T4 
at subsequent cycles as 
clinically indicated and 
consider  consultation of an 
endocrinologist. 
Grade 2
For Grade 2 endocrinopathy other 
than hypothyroidism and Type 1 
diabetes mellitus, hold study 
drug/study regimen dose until 
patient is clinically stable.

If toxicity worsens, then treat 
as Grade 3 or Grade 4.
Study drug/study regimen can be 
resumed once event stabilizes and 
after completion of steroid taper.
Patients with endocrinopathies 
who may require prolonged or 
continued steroid replacement 
(e.g. adrenal insufficiency) can be 
retreated with study drug/study 
regimen on the following 
conditions:
1.
The event stabilizes and 
is controlled.
2.
The patient is clinically 
stable as per investigator 
or treating physician’s 
clinical judgement.
3.
Doses of prednisone are 
≤10 mg/day or 
equivalent.
For Grade 2 (including those 
with symptomatic 
endocrinopathy):

Consult endocrinologist to 
guide evaluation of endocrine 
function, and , as indicated by 
suspected endocrinolopathy 
and as clinically indicated, 
consider pituitary scan.

For all patients with abnormal 
endocrine work up, except  
those with isolated 
hypothyroidism or Type I DM, 
and as guided by an 
endocrinologist, consider 
short-term corticosteroids 
(e.g., 1 to 2 mg/kg/day 
methylprednisolone or IV 
equivalent) and prompt 
initiation of treatment with 
relevant hormone replacement 
(e.g., , hydrocortisone,  sex 
hormones). 

Isolated hypothyroidism may 
be treated with replacement 
therapy, without study 
drug/study regimen 
interruption, and without 
corticosteroids.

Isolated Type I diabetes 
mellitus (DM) may be treated 
with appropriate diabetic 
therapy, without study 
drug/study regimen 
interruption, and without 
corticosteroids.

Once  patients on steroids are 
improving, gradually taper  
immunosuppressive steroids 
(as appropriate and with 
guidance of endocrinologist) 
over ≥28 days and consider 
prophylactic antibiotics, 
antifungals, and anti-PJP 
treatment (refer to current 
NCCN guidelines for 
treatment of cancer-related 
infections).a

For patients with normal 
endocrine workup (laboratory 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 138 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
assessment or MRI scans), 
repeat laboratory 
assessments/MRI as clinically 
indicated.
Grade 3 or 4
For Grade 3 or 4 endocrinopathy 
other than hypothyroidism and 
Type I diabetes mellitus, hold 
study drug/study regimen dose 
until endocrinopathy symptom(s) 
are controlled.
Study drug/study regimen can be 
resumed once event stabilizes and 
after completion of steroid taper.
Patients with endocrinopathies 
who may require prolonged or 
continued steroid replacement 
(e.g. adrenal insufficiency) can be 
treated with study drug/study 
regimen on the following 
conditions: 
1. The event stabilizes and is 
controlled
2. The patient is clinically stable 
as per investigator or treating 
physician’s clinical judgement
3. Doses of prednisone are < 10 
mg/day or equivalent
For Grade 3 or 4:

Consult endocrinologist to 
guide evaluation of endocrine 
function and, as indicated by 
suspected endocrinopathy and 
as clinically indicated, 
consider pituitary scan. 
Hospitalization recommended

For all patients with abnormal 
endocrine work up, except 
those with isolated 
hypothyroidism  or Type I 
DM, and as guided by an 
endocrinologist, promptly 
initiate empiric IV 
methylprednisolone1 to 
2 mg/kg/day or equivalent, as 
well as relevant hormone 
replacement  (e.g., 
hydrocortisone, sex 
hormones).

For adrenal crisis, severe 
dehydration, hypotension, or 
shock, immediately initiate IV 
corticosteroids with 
mineralocorticoid activity.

Isolated hypothyroidism may 
be treated with replacement 
therapy, without study 
drug/study regimen 
interruption, and without 
corticosteroids. 

Isolated Type I diabetes 
mellitus may be treated with 
appropriate diabetic therapy, 
without study drug/study 
regimen interruption, and 
without corticosteroids.

Once patients on steroids are 
improving, gradually taper 
immunosuppressive steroids 
(as appropriate and with 
guidance of endocrinologist) 
over ≥28 days and consider 
prophylactic antibiotics, 
antifungals, and anti-PJP 
treatment (refer to current 
NCCN guidelines for 
treatment of cancer-related 
infections).a
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 139 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
Any Grade
(depending on the type of 
neurotoxicity, refer to NCI 
CTCAE v4.03 for defining the 
CTC grade/severity)
General Guidance
For Any Grade:

Patients should be evaluated to 
rule out any alternative 
etiology (e.g., disease 
progression, infections, 
metabolic syndromes, or 
medications).

Monitor patient for general 
symptoms (headache, nausea, 
vertigo, behavior change, or 
weakness).

Consider appropriate 
diagnostic testing 
(e.g., electromyogram and 
nerve conduction 
investigations).

Perform symptomatic 
treatment with Neurology 
consult as appropriate.
Grade 1
No dose modifications
For Grade 1:

See “Any Grade” 
recommendations above.
Grade 2
For acute motor neuropathies or 
neurotoxicity, hold study 
drug/study regimen dose until 
resolution to Grade ≤1.
For sensory 
neuropathy/neuropathic pain, 
consider holding study drug/study 
regimen dose until resolution to 
Grade ≤1.

If toxicity worsens, then treat 
as Grade 3 or 4.
Study drug/study regimen can be 
resumed once event improves to 
Grade ≤1 and after completion of 
steroid taper.
For Grade 2:

Consider, as necessary, 
discussing with the study 
physician.

Obtain Neurology consult.

Sensory 
neuropathy/neuropathic pain 
may be managed by 
appropriate medications (e.g., 
gabapentin or duloxetine).

Promptly start systemic 
steroids prednisone 1 to 
2 mg/kg/day PO or IV 
equivalent.

If no improvement within 3 to 
5 days despite 1 to 
2 mg/kg/day prednisone PO or 
IV equivalent, consider 
additional workup and 
promptly treat with additional 
immunosuppressive therapy 
(e.g., IV IG).
Neurotoxicity
(to include but not be limited to 
limbic encephalitis and 
autonomic neuropathy, excluding 
Myasthenia Gravis and Guillain-
Barre)
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen 
dose until resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if Grade 3 
imAE does not resolve to Grade 
≤1 within 30 days.
For Grade 3 or 4:

Consider, as necessary, 
discussing with study 
physician.

Obtain Neurology consult.

Consider hospitalization.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 140 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
For Grade 4:
Permanently discontinue study 
drug/study regimen.

Promptly initiate empiric IV 
methylprednisolone 1 to 
2 mg/kg/day or equivalent.

If no improvement within 3 to 
5 days despite IV 
corticosteroids, consider 
additional workup and 
promptly treat with additional 
immunosuppressants (e.g., IV 
IG).

Once stable, gradually taper 
steroids over ≥28 days.
Peripheral neuromotor 
syndromes
(such as Guillain-Barre and 
myasthenia gravis)
Any Grade
General Guidance
For Any Grade:

The prompt diagnosis of 
immune-mediated peripheral 
neuromotor syndromes is 
important, since certain 
patients may unpredictably 
experience acute 
decompensations that can 
result in substantial morbidity 
or in the worst case, death. 
Special care should be taken 
for certain sentinel symptoms 
that may predict a more severe 
outcome, such as prominent 
dysphagia, rapidly progressive 
weakness, and signs of 
respiratory insufficiency or 
autonomic instability.

Patients should be evaluated to 
rule out any alternative 
etiology (e.g., disease 
progression, infections, 
metabolic syndromes or 
medications). It should be 
noted that the diagnosis of 
immune-mediated peripheral 
neuromotor syndromes can be 
particularly challenging in 
patients with underlying 
cancer, due to the multiple 
potential confounding effects 
of cancer (and its treatments) 
throughout the neuraxis. Given 
the importance of prompt and 
accurate diagnosis, it is 
essential to have a low 
threshold to obtain a 
Neurology consult.

Neurophysiologic diagnostic 
testing (e.g., electromyogram 
and nerve conduction 
investigations, and “repetitive 
stimulation” if myasthenia is 
suspected) are routinely 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 141 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
indicated upon suspicion of 
such conditions and may be 
best facilitated by means of a 
Neurology consultation.

It is important to consider that 
the use of steroids as the 
primary treatment of Guillain-
Barre is not typically 
considered effective. Patients 
requiring treatment should be 
started with IV IG and 
followed by plasmapheresis if 
not responsive to IV IG.
Grade 1
No dose modifications
For Grade 1:

Consider, as necessary, 
discussing with the study 
physician.

Care should be taken to 
monitor patients for sentinel 
symptoms of a potential 
decompensation as described 
above.

Obtain a neurology consult.
Grade 2
Hold study drug/study regimen 
dose until resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days 
or if there are signs of respiratory 
insufficiency or autonomic 
instability.
For Grade 2:

Consider, as necessary, 
discussing with the study 
physician.

Care should be taken to 
monitor patients for sentinel 
symptoms of a potential 
decompensation as described 
above.

Obtain a Neurology consult

Sensory 
neuropathy/neuropathic pain 
may be managed by 
appropriate medications (e.g., 
gabapentin or duloxetine).

MYASTHENIA GRAVIS:

Steroids may be 
successfully used to treat 
myasthenia gravis. It is 
important to consider 
that steroid therapy 
(especially with high 
doses) may result in 
transient worsening of 
myasthenia and should 
typically be administered 
in a monitored setting 
under supervision of a 
consulting neurologist.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 142 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management

Patients unable to 
tolerate steroids may be 
candidates for treatment 
with plasmapheresis or 
IV IG. Such decisions 
are best made in 
consultation with a 
neurologist, taking into 
account the unique needs 
of each patient.

If myasthenia gravis-like 
neurotoxicity is present, 
consider starting AChE 
inhibitor therapy in 
addition to steroids. Such 
therapy, if successful, 
can also serve to 
reinforce the diagnosis.

GUILLAIN-BARRE:

It is important to 
consider here that the use 
of steroids as the primary 
treatment of Guillain-
Barre is not typically 
considered effective.

Patients requiring 
treatment should be 
started with IV IG and 
followed by 
plasmapheresis if not 
responsive to IV IG.
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen 
dose until resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if Grade 3 
imAE does not resolve to Grade 
≤1 within 30 days or if there are 
signs of respiratory insufficiency 
or autonomic instability.
For Grade 4:
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4 (severe or life-
threatening events):

Consider, as necessary, 
discussing with study 
physician.

Recommend hospitalization.

Monitor symptoms and obtain 
Neurology consult.

MYASTHENIA GRAVIS:

Steroids may be 
successfully used to treat 
myasthenia gravis. They 
should typically be 
administered in a 
monitored setting under 
supervision of a 
consulting neurologist.

Patients unable to 
tolerate steroids may be 
candidates for treatment 
with plasmapheresis or 
IV IG.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 143 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management

If myasthenia gravis-like 
neurotoxicity present, 
consider starting AChE 
inhibitor therapy in 
addition to steroids. Such 
therapy, if successful, 
can also serve to 
reinforce the diagnosis.

GUILLAIN-BARRE:

It is important to 
consider here that the use 
of steroids as the primary 
treatment of Guillain-
Barre is not typically 
considered effective.

Patients requiring 
treatment should be 
started with IV IG and 
followed by 
plasmapheresis if not 
responsive to IV IG.
Myocarditis
Any Grade
General Guidance
Discontinue drug permanently if 
biopsy-proven immune-mediated 
myocarditis
For Any Grade:

The prompt diagnosis of 
immune-mediated 
myocarditis is important, 
particularly in patients with 
baseline cardiopulmonary 
disease and reduced cardiac 
function

Consider, as necessary, 
discussing with the study 
physician.

Monitor patients for signs and 
symptoms of myocarditis 
(new onset or worsening chest 
pain, arrhythmia, shortness of 
breath, peripheral edema). As 
some symptoms can overlap 
with lung toxicities, 
simultaneously evaluate for 
and rule out pulmonary 
toxicity as well as other 
causes (e.g., pulmonary 
embolism, congestive heart 
failure, malignant pericardial 
effusion). A Cardiology 
consultation should be 
obtained early, with prompt 
assessment of whether and 
when to complete a cardiac 
biopsy, including any other 
diagnostic procedures.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 144 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management

Initial work-up should include 
clinical evaluation, BNP, 
cardiac enzymes, ECG, 
echocardiogram (ECHO), 
monitoring of oxygenation via 
pulse oximetry (resting and 
exertion), and additional 
laboratory work-up as 
indicated. Spiral CT or 
cardiac MRI can complement 
ECHO to assess wall motion 
abnormalities when needed.

Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., 
disease progression, other 
medications, or infections)
Grade 1
(asymptomatic with laboratory 
(e.g., BNP) or cardiac imaging 
abnormalities)
No dose modifications required 
unless clinical suspicion is high, in 
which case hold study drug/study 
regimen dose during diagnostic 
work-up for other etiologies. If 
study drug/study regimen is held, 
resume after complete resolution 
to Grade 0.
For Grade 1 (no definitive 
findings):

Monitor and closely follow up 
in 2 to 4 days for clinical 
symptoms,  BNP, cardiac 
enzymes, ECG, ECHO, pulse 
oximetry (resting and 
exertion), and laboratory 
work-up as clinically 
indicated.

Consider using steroids if 
clinical suspicion is high.
Grade 2, 3 or 4
(Grade 2: Symptoms with mild 
to moderate activity or exertion)
 (Grade 3: Severe with 
symptoms at rest or with 
minimal activity or exertion; 
intervention indicated)
(Grade 4: Life-threatening 
consequences; urgent
intervention indicated (e.g., 
continuous IV therapy or 
mechanical hemodynamic 
support))
For Grade 2:Hold study 
drug/study regimen dose until 
resolution to Grade 0. If toxicity 
rapidly improves to Grade 0, then 
the decision to reinitiate study 
drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. If toxicity does not 
rapidly improve, permanently. 
discontinue study drug/study 
regimen.
For Grade 3-4:
 permanently discontinue study 
drug/study regimen.
For Grade 2-4:

Monitor symptoms daily, 
hospitalize.

Promptly start IV 
methylprednisolone 2 to 
4 mg/kg/day or equivalent 
after Cardiology consultation 
has determined whether and 
when to complete diagnostic 
procedures including a cardiac 
biopsy.

Supportive care (e.g., 
oxygen).

If no improvement within 3 to 
5 days despite IV 
methylprednisolone at 2 to 
4 mg/kg/day, promptly start 
immunosuppressive therapy 
such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg 
every 2 weeks). Caution: It is 
important to rule out sepsis 
and refer to infliximab label 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 145 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
for general guidance before 
using infliximab.

Once the patient is improving, 
gradually taper steroids over 
≥28 days and consider 
prophylactic antibiotics, 
antifungals, or anti-PJP 
treatment (refer to current 
NCCN guidelines for 
treatment of cancer-related 
infections).a
Myositis/Polymyositis 
(“Poly/myositis”)
Any Grade
General Guidance
For Any Grade:

Monitor patients for signs and 
symptoms of poly/myositis. 
Typically, muscle 
weakness/pain occurs in 
proximal muscles including 
upper arms, thighs, shoulders, 
hips, neck and back, but 
rarely affects the extremities 
including hands and fingers; 
also difficulty breathing 
and/or trouble swallowing can 
occur and progress rapidly. 
Increased general feelings of 
tiredness and fatigue may 
occur, and there can be new-
onset falling, difficulty getting 
up from a fall, and trouble 
climbing stairs, standing up 
from a seated position, and/or 
reaching up.

If poly/myositis is suspected, 
a Neurology consultation 
should be obtained early, with 
prompt guidance on 
diagnostic procedures. 
Myocarditis may co-occur 
with poly/myositis; refer to 
guidance under Myocarditis. 
Given breathing 
complications, refer to 
guidance under 
Pneumonitis/ILD. 
Given possibility of an 
existent (but previously 
unknown) autoimmune 
disorder, consider 
Rheumatology consultation.

Consider, as necessary, 
discussing with the study 
physician.

Initial work-up should include 
clinical evaluation, creatine 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 146 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
kinase, aldolase, LDH, 
BUN/creatinine, erythrocyte 
sedimentation rate or C-
reactive protein level, urine 
myoglobin, and additional 
laboratory work-up as 
indicated, including a number 
of possible 
rheumatological/antibody 
tests (i.e., consider whether a 
rheumatologist consultation is 
indicated and could guide 
need for rheumatoid factor, 
antinuclear antibody, anti-
smooth muscle, antisynthetase 
[such as anti-Jo-1], and/or 
signal-recognition particle 
antibodies). Confirmatory 
testing may include 
electromyography, nerve 
conduction studies, MRI of 
the muscles, and/or a muscle 
biopsy. Consider Barium 
swallow for evaluation of 
dysphagia or dysphonia.

Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., 
disease progression, other 
medications, or infections).
Grade 1
(mild pain)
No dose modification
For Grade 1:

Monitor and closely follow 
up in 2 to 4 days for clinical 
symptoms and initiate 
evaluation as clinically 
indicated

Consider neurology consult.

Consider, as necessary, 
discussing with the study 
physician
Grade 2
(moderate pain associated with 
weakness; pain limiting 
instrumental activities of daily 
living [ADLs])
Hold study drug/study regimen 
dose until resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days 
or if there are signs of respiratory 
insufficiency.
For Grade 2:

Monitor symptoms daily and 
consider hospitalization.

Obtain Neurology consult, 
and initiate evaluation.

Consider, as necessary, 
discussing with the study 
physician.

If clinical course is rapidly 
progressive (particularly if 
difficulty breathing and/or 
trouble swallowing), promptly 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 147 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
start IV methylprednisolone 2 
to 4 mg/kg/day systemic 
steroids along with receiving 
input from Neurology 
consultant 

If clinical course is not 
rapidly progressive, start 
systemic steroids (e.g., 
prednisone 1 to 2 mg/kg/day 
PO or IV equivalent); if no 
improvement within 3 to 5 
days, continue additional 
work up and start treatment 
with IV methylprednisolone 2 
to 4 mg/kg/day

If after start of IV 
methylprednisolone at 2 to 
4 mg/kg/day there is no 
improvement within 3 to 5 
days, consider start of 
immunosuppressive therapy 
such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg 
every 2 weeks). Caution: It is 
important to rule out sepsis 
and refer to infliximab label 
for general guidance before 
using infliximab.

Once the patient is improving, 
gradually taper steroids over 
≥28 days and consider 
prophylactic antibiotics, 
antifungals, or anti-PJP 
treatment (refer to current 
NCCN guidelines for 
treatment of cancer-related 
infections).a
Grade 3 or 4
(pain associated with severe 
weakness; limiting self-care 
ADLs)
For Grade 3:
Hold study drug/study regimen 
dose until resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if Grade 3 
imAE does not resolve to Grade 
≤1 within 30 days or if there are 
signs of respiratory insufficiency.
For Grade 4:
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4 (severe or life-
threatening events):

Monitor symptoms closely; 
recommend hospitalization.

Obtain Neurology consult, 
and complete full evaluation.

Consider, as necessary, 
discussing with the study 
physician.

Promptly start IV 
methylprednisolone 2 to 
4 mg/kg/day systemic steroids 
along with receiving input 
from Neurology consultant.

If after start of IV 
methylprednisolone at 2 to 
4 mg/kg/day there is no 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 148 of 169
Specific Immune-mediated Reactions
Adverse Events
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
improvement within 3 to 5 
days, consider start of 
immunosuppressive therapy 
such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg 
every 2 weeks). Caution: It is 
important to rule out sepsis 
and refer to infliximab label 
for general guidance before 
using infliximab.

Consider whether patient may 
require IV IG, 
plasmapheresis.

Once the patient is improving, 
gradually taper steroids over 
≥28 days and consider 
prophylactic antibiotics, 
antifungals, or anti-PJP 
treatment (refer to current 
NCCN guidelines for 
treatment of cancer-related 
infections).a
a
ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD.
b
FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation.
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; 
AST Aspartate aminotransferase; BUN Blood urea nitrogen; C  Computed tomography; CTCAE Common Terminology Criteria for Adverse 
Events; ILD Interstitial lung disease; imAE immune-mediated adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; 
LFT Liver function tests; LLN Lower limit of normal; MRI Magnetic resonance imaging; NCI National Cancer Institute; NCCN National 
Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia) ; PO By mouth; 
T3 Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of 
normal.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 149 of 169
Infusion-related Reactions
Severity Grade of the Event
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
Any Grade
General Guidance
For Any Grade:

Manage per institutional standard at the 
discretion of investigator.

Monitor patients for signs and symptoms 
of infusion-related reactions (e.g., fever 
and/or shaking chills, flushing and/or 
itching, alterations in heart rate and blood 
pressure, dyspnea or chest discomfort, or 
skin rashes) and anaphylaxis 
(e.g., generalized urticaria, angioedema, 
wheezing, hypotension, or tachycardia).
Grade 1 or 2
For Grade 1:
The infusion rate of study drug/study regimen 
may be decreased by 50% or temporarily 
interrupted until resolution of the event.
For Grade 2:
The infusion rate of study drug/study regimen 
may be decreased 50% or temporarily 
interrupted until resolution of the event.
Subsequent infusions may be given at 50% of 
the initial infusion rate.
For Grade 1 or 2:

Acetaminophen and/or antihistamines 
may be administered per institutional 
standard at the discretion of the 
investigator.

Consider premedication per institutional 
standard prior to subsequent doses.

Steroids should not be used for routine 
premedication of Grade ≤2 infusion 
reactions.
Grade 3 or 4
For Grade 3 or 4:
Permanently discontinue study drug/study 
regimen.
For Grade 3 or 4:

Manage severe infusion-related reactions 
per institutional standards (e.g., IM 
epinephrine, followed by IV 
diphenhydramine and ranitidine, and IV 
glucocorticoid).
CTCAE Common Terminology Criteria for Adverse Events; IM Intramuscular; IV Intravenous; NCI National Cancer Institute.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 150 of 169
Non-immune-mediated Reactions
Severity Grade of the Event
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
Any Grade
Note: Dose modifications are not required for 
AEs not deemed to be related to study 
treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not 
deemed to be clinically significant.
Treat accordingly, as per institutional 
standard.
Grade 1
No dose modifications.
Treat accordingly, as per institutional 
standard.
Grade 2
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline.
Treat accordingly, as per institutional 
standard.
Grade 3
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline.
For AEs that downgrade to ≤Grade 2 within 7 
days or resolve to ≤Grade 1 or baseline within 
14 days, resume study drug/study regimen 
administration.  Otherwise, discontinue study 
drug/study regimen.
Treat accordingly, as per institutional 
standard.
Grade 4
Discontinue study drug/study regimen (Note: 
For Grade 4 labs, decision to discontinue 
should be based on accompanying clinical 
signs/symptoms, the Investigator’s clinical 
judgment, and consultation with the Sponsor.).
Treat accordingly, as per institutional 
standard.
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with 
Study Physician.”
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 151 of 169
Appendix H
Schedule of study procedures: Follow-up for subjects who have completed durvalumab, 
tremelimumab and olaparib treatment and achieved disease control (until confirmed progression of 
disease) and subjects who have discontinued study treatment due to toxicity in the absence of confirmed 
progression of disease
Time Since Last Dose of Durvalumab or Tremelimumab or Olaparib
Day (±3)
Months (±1 week)
Evaluation
30
2
3
4
6
8
10
12 Months and Every 6 Months 
(±2 weeks)
Physical examination a
X
Vital signs (temperature, 
respiratory 
rate, 
blood 
pressure, pulse) b
X
Weight
X
Urine hCG or serum βhCG
X
AE/SAE assessment
X
X
X
Concomitant medications
X
X
X
Palliative radiotherapy
As clinically indicated 
ECOG performance status
X
X
X
X (and month 9)
X
Subsequent 
anti-cancer 
therapy
X
X
X
X
X
X
X
X
Survival 
status: 
phone 
contact with subjects who 
refuse 
to 
return 
for 
evaluations and agree to be 
contacted
X
X
X
X
X
X
X (every 2 months)
Hematology c
X
X
X
Chemistry d
X
X
X
Thyroid function tests (TSH, 
and fT3 and fT4)e 
X
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 152 of 169
Time Since Last Dose of Durvalumab or Tremelimumab or Olaparib
Day (±3)
Months (±1 week)
Evaluation
30
2
3
4
6
8
10
12 Months and Every 6 Months 
(±2 weeks)
Tumour assessment (CT or 
MRI)
For subjects who achieve disease control following 12 months of treatment, tumour assessments should be 
performed every 12 weeks relative to the date of first infusion thereafter until confirmed PD by irRECIST by 
investigational site review.  Please refer to Table 5 for timings of confirmatory scans.  
For subjects who discontinue durvalumab + tremelimumab due to toxicity (or symptomatic deterioration), 
tumour assessments should be performed relative to the date of first infusion as follows: every 12 weeks until 
confirmed PD by irRECIST by investigational site review or started on standard therapy or another 
clinical study.  Please refer to Table 5 for timings of confirmatory scans.  
Upon confirmed PD or initiation of standard therapy, scans should be conducted according to local standard clinical 
practice.
a
Full physical exam (refer to Section 8.3.2).
b
Refer to Section 8.3.4.
c
Refer to Section 8.3.5, Table 6..
d
Refer to Section 8.3.5, Table 7.
c
Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an adverse 
event related to the endocrine system.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 153 of 169
Appendix I
Schedule of study procedures: follow-up for subjects who have discontinued study 
treatment due to confirmed progression of disease at the investigator discretion
Time Since Last Dose of Durvalumab or Tremelimumab or Olaparib
Day (±3)
Months (±1 week)
Evaluation
30
2
3
4
6
8
10
12 Months and Every 6 Months 
(±2 weeks)
Physical examination a
X
Vital signs (temperature, respiratory 
rate, blood pressure, pulse) b
X
Weight
X
AE/SAE assessment
X
X
X
Concomitant medications
X
Palliative radiotherapy
As clinically indicated
ECOG performance status c
X
Subsequent anti-cancer therapy
X
X
X
X
X
X
X
X
Survival status: phone contact with 
subjects who refuse to return for 
evaluations and agree to be contacted
X
X
X
X
X
X
X (every 2 months)
Hematology d
X
Chemistry e
X
Thyroid function tests (TSH, and fT3 
and fT4)  f
X
miRNA/mRNA (to examine immune 
cell gene expression profiles in 
circulation), if applicable
X
blood for immune monitoring
X
Tumour assessment (CT or MRI)
For subjects who continue on durvalumab + tremelimumab post-confirmed progression at the 
investigator’s discretion (following consultation with the sponsor), tumour assessments should be 
performed relative to the date of first infusion per Table 5 until durvalumab + tremelimumab is stopped.
For subjects who discontinue durvalumab + tremelimumab following confirmed progression, scans 
should be conducted according to local clinical practice and submitted for central review until a new 
treatment is started (these scans are optional).
a
Full physical exam (refer to Section 8.3.2)
b
Refer to Section 8.3.4.
c
Refer to Section 8.3.4, Table 6.
d
Refer to Section 8.3.4, Table 7.
e
PS to be collected if available at the 2 monthly calls to obtain subsequent anti-cancer therapy and survival status
f
Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an adverse 
event related to the endocrine system.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 154 of 169
Appendix J
Diary for Medication (Olaparib)
Study No.: ____________________
Patient Name: ______________________________
Drug Name: ___________________
Cycle (Please circle one.):
1
2
3
4
5
6
7
8
9
10
11
12    
Medical Record No.: __________________________
Study Medication Calendar
Please complete this calendar on a daily basis immediately after you take your pills. Fill in the date for each day and the time the pill is 
taken in the AM and PM space (not check mark) and write the total number of pills you take each day. 
Start Date: _________________
Cycle Day
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Date
Dose
AM
Number of pills 
taken (Please Note 
time)
PM
Cycle Day
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Date
Dose
AM
Number of pills 
taken(Please Note 
time)
PM
Cycle Day
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Date
Dose
AM
Number of pills 
taken(Please Note 
time)
PM
Cycle Day
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Date
Dose
AM
Number of pills 
taken(Please Note 
time)
PM
Please remember to bring this calendar and your pill bottle (including any unused pills) with you to your next clinic appointment.
_______________________________________________________________________________________
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 155 of 169
Coordinator’s Use Only
% 𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒=(
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑃𝑖𝑙𝑙𝑠 𝐷𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑‒ 𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑃𝑖𝑙𝑙𝑠 𝑅𝑒𝑡𝑢𝑟𝑛𝑒𝑑
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑃𝑖𝑙𝑙𝑠 𝑆𝑐ℎ𝑒𝑑𝑢𝑙𝑒𝑑
) × 100
_____% 𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒=  (
               ‒                 
        
) × 100
Patient signature: __________________________________________
Date: ____________
CRC signature: ____________________________________________
Date: ____________
Investigator signature:
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 156 of 169
Appendix K
irRECIST Summary
Tumor response assessment using the Immune-Related response Criteria as described by Nishino et al, 2013* 
and Bohnsack et al, 2014**.
1.0
Baseline
1.1
Measurable Lesion Definitions and Target Lesion Selection

All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all 
involved organs, will be identified as target lesions and recorded and measured at baseline

Measurable lesions must be accurately measured in at least one dimension with a minimum size of:
o
10 mm in the longest diameter by CT or MRI scan (or no less than double the slice thickness) for 
non- nodal lesions and ≥ 15 mm in short axis for nodal lesions.
o
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable).
o
20 mm by chest X-ray

A sum of the longest diameter (short axis for lymph nodes) of all target lesions will be calculated and 
reported as the baseline sum diameters. This will be used as reference to further characterize the objective 
tumor response of the measurable dimension of the disease.
1.2
Non-measurable Lesion Definitions

Non-target lesions will include:
o
Measurable lesions not selected as target lesions
o
All sites of non-measurable disease, such as neoplastic masses that are too small to measure 
because their longest uninterrupted diameter is < 10 mm (or < two times the axial slice thickness), 
i.e., the longest perpendicular diameter is ≥ 10 and < 15 mm.
o
Other types of lesions that are confidently felt to represent neoplastic tissue, but are difficult to 
measure in a reproducible manner. These include bone metastases, leptomeningeal metastases, 
malignant ascites, pleural or pericardial effusions, ascites, inflammatory breast disease, 
lymphangitis cutis/pulmonis, cystic lesions, ill-defined abdominal masses, skin lesions, etc.

All lesions or sites of disease not recorded as target lesions (e.g., small lesions and non-measurable lesions) 
should be identified as non-target lesions and indicated as present in the source documents at baseline. 
There is no limit to the number of non-target lesions that can be recorded at baseline. The general location 
will also be documented on the images, drawing a regularly-shaped Region of Interest. 

Measurements of the non-target lesions will not be performed, but the presence or absence of each should 
be noted throughout follow-up and evaluation.
1.3
Target and Non-Target Lymph Node Lesion Definitions

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 recommended to be no greater than 5 mm). At baseline 
and in follow-up, only the short axis will be measured and followed.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 157 of 169
1.4
Non-Target Lesion Selection

All lesions or sites of disease not recorded as target lesions should be recorded as non-target lesions at 
baseline. There is no limit to the number on non-target lesions that can be recorded at baseline.
1.5
Bone Lesions

Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure bone 
lesions. However, these techniques can be used to confirm the presence or disappearance of bone lesions.

Regardless of the imaging modality blastic bone lesions will not be selected as target lesions. Lytic or 
mixed lytic-blastic lesions with a measurable soft tissue component ≥ 10 mm can be selected as target 
lesions.
1.6
Brain Lesions

Brain Lesions detected on brain scans can be considered as both target or non-target lesions.
1.7
Cystic and Necrotic Lesions as Target Lesions

Lesions that meet the criteria for radiographically defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts.

Lesions that are partially cystic or necrotic can be selected as target lesions.

The longest diameter of such a lesion will be added to the Total Measured Tumor Burden (TMTB) 1 of 
all target lesions at baseline. 

If other lesions with a non-liquid/non-necrotic component are present, those should be preferred.
1.8
Lesions with Prior Local Treatment

During target lesion selection the radiologist will consider information on the anatomical sites of previous 
intervention (e.g. previous irradiation, RF-ablation, TACE, surgery, etc.).

Lesions undergoing prior intervention will not be selected as target lesions unless there has been a 
demonstration of progress in the lesion.
1.9
No Disease at Baseline

If a patient has no measurable and no non-measurable disease at baseline the radiologist will assign ‘No 
Disease’ (irND) as the overall tumor assessment for any available follow-up time-points unless new 
measurable lesions are identified and contribute to the TMTB.
2.0
Follow-Up
2.1
Recording of Target and New Measurable Lesion Measurements

The longest diameters of non-nodal target and new non-nodal measurable lesions, and short axes of nodal 
target and new nodal measurable lesions will be recorded. Together they determine the Total Measured 
Tumor Burden (TMTB) at follow-up.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 158 of 169
𝐓𝐌𝐓𝐁 % 𝐜𝐡𝐚𝐧𝐠𝐞=
𝐁𝐚𝐬𝐞𝐥𝐢𝐧𝐞 𝐓𝐮𝐦𝐨𝐫 𝐁𝐮𝐫𝐝𝐞𝐧‒ 𝐂𝐮𝐫𝐫𝐞𝐧𝐭 𝐓𝐮𝐦𝐨𝐫 𝐁𝐮𝐫𝐝𝐞𝐧
𝐁𝐚𝐬𝐞𝐥𝐢𝐧𝐞 𝐓𝐮𝐦𝐨𝐫 𝐁𝐮𝐫𝐝𝐞𝐧
 × 𝟏𝟎𝟎
2.1
Definition of New Measurable Lesions

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 shall be prioritized according to size, and the largest lesions shall be 
selected as new measured lesions.
2.2
Non-Target Lesion Assessment

The RECIST 1.1 definitions for the assessment of non-target lesions apply (i.e., measurements of the non-
target lesions will not be performed, but the presence or absence of each should be noted throughout 
follow-up and evaluation).

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.
2.3
New Non-Measurable Lesions Definition and Assessment

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.
2.4
irRECIST Overall Tumor Assessments
The irRECIST overall tumor assessment is based on the TMTB (total measured tumor burden) of measured target 
and new lesions, non-target lesion assessment and new non-measurable lesions.
Time point response assessments will be performed on Cycle 4 Day 1 (± 7 days)  and then every 3 cycles.
Conventional RECIST 1.1 will also be documented during the trial however; RECIST 1.1 will not be used to 
determine disease progression. The irRECIST will be used for tumor response assessment at time of continuing 
review and will be used for IRB reporting and formal analysis.

irCR: Complete disappearance of all measurable and non-measurable lesions. Lymph nodes must 
decrease to < 10 mm in short axis. Confirmation of response is not mandatory.

irPR: Decrease of ≥ 30% in TMTB relative to baseline, non-target lesions are irNN, and no unequivocal 
progression of new non-measurable lesions.

irSD: Failure to meet criteria for irCR or irPR in the absence of irPD.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 159 of 169

irNN: No target disease was identified at baseline and at follow-up the patient fails to meet criteria for 
irCR or irPD.

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.

irNE: Used in exceptional cases where insufficient data exists.

irND: In adjuvant setting when no disease is detected.
New Lesions: the presence of new lesion(s) does not define progression. The measurements of the new lesion(s) 
are included in the sum of the measurements (the sum of the measurements = the sum of the longest diameters of 
all target lesions and new lesions, if any).
2.5
Confirmation Measurement
A confirmatory assessment is required no less than 6 weeks after a PR or CR is deemed by irRECIST
3.0
Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation. 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 follow-up. 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.

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.

Conventional CT and MRI: 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) however, conventional CT scan is the preferred modality to 
determine response to treatment.
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there 
are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, 
and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, 
the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and 
site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline 
and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the irRECIST 
or RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and 
diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if 
possible.

Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at 
a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 160 of 169
in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances.

Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are initially above 
the upper normal limit, they must normalize for a participant to be considered in complete clinical 
response.
Nishino M, Giobbie-Hurder A, et al. Developing a Common Language for Tumor Response to Immunotherapy: 
Immune-Related Response Criteria Using Unidimensional Measurements. Clin Cancer Res 2013, 19 (14): 
3936-3943.
** Bohnsack O, Ludajic K, and Hoos A. Adaptation of the Immune Related Response Criteria: irRECIST et al, 
2014, 1070P-, Ann Oncol 2014, 25 (suppl 4): 1070P iv369 doi:10.1093/annonc/mdu342.23. 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 161 of 169
Appendix L
Calculation for Creatinine Clearance
Cockroft-Gault Equation*
Men: CrCl = [(140-YR) x IBW] / (SCr x 72)
Women: CrCl = 0.85 x [(140-YR) x IBW] / (SCr x 72)
Note: At Roswell Park, clinical lab chemistries are performed with plasma.
Where:
CrCl is creatine clearance (mL/min)
IBW is ideal body weight (kg)
SCr is serum creatinine (mg/dL)
YR is age (years)
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 162 of 169
*Cockcroft D, W, Gault M, H, Prediction of Creatinine Clearance from Serum Creatinine. Nephron. 
1976; 16 (1):31-41)
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 163 of 169
Appendix M PAXgene® RNA Tube Freezing/Storage 
1) Collect blood into PAX tube
2) Let tubes stand UPRIGHT for a minimum of 2 hours and a maximum of 72 hours at RT (18-25C) 
Tubes should be placed in a wire or plastic rack.  DO NOT USE Styrofoam. 
3) Transfer specimens to -20C freezer for 24 hours
4) After 24 hours move tubes to -70 to -80C freezer for storage until batch shipment
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 164 of 169
18 REFERENCES
1.
Cannistra SA. Cancer of the ovary. N Engl J Med. 2004;351(24):2519-29. doi: 10.1056/NEJMra041842. 
PubMed PMID: 15590954.
2.
Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, Mannel RS, DeGeest K, 
Hartenbach EM, Baergen R, Gynecologic Oncology G. Phase III trial of carboplatin and paclitaxel compared with 
cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology 
Group study. J Clin Oncol. 2003;21(17):3194-200. doi: 10.1200/JCO.2003.02.153. PubMed PMID: 12860964.
3.
Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen GB, Wheeler S, Swart AM, 
Qian W, Torri V, Floriani I, Jayson G, Lamont A, Trope C, Icon, Collaborators AGO. Paclitaxel plus platinum-
based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: 
the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361(9375):2099-106. PubMed PMID: 12826431.
4.
Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H, Lacave AJ, Wagner U, Stahle A, Stuart G, Kimmig 
R, Olbricht S, Le T, Emerich J, Kuhn W, Bentley J, Jackisch C, Luck HJ, Rochon J, Zimmermann AH, Eisenhauer 
E, Ago O, Ncic CTG, Eortc GCG. Gemcitabine plus carboplatin compared with carboplatin in patients with 
platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the 
EORTC GCG. J Clin Oncol. 2006;24(29):4699-707. doi: 10.1200/JCO.2006.06.0913. PubMed PMID: 16966687.
5.
Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, Gebski V, Heywood M, Vasey PA, Volgger B, 
Vergote I, Pignata S, Ferrero A, Sehouli J, Lortholary A, Kristensen G, Jackisch C, Joly F, Brown C, Le Fur N, 
du Bois A. Pegylated liposomal Doxorubicin and Carboplatin compared with Paclitaxel and Carboplatin for 
patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol. 2010;28(20):3323-9. doi: 
10.1200/JCO.2009.25.7519. PubMed PMID: 20498395.
6.
Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, Sovak MA, Yi J, Nycum LR. 
OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without 
bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube 
cancer. J Clin Oncol. 2012;30(17):2039-45. doi: 10.1200/JCO.2012.42.0505. PubMed PMID: 22529265; 
PMCID: PMC3646321.
7.
Markman M, Bookman MA. Second-line treatment of ovarian cancer. The oncologist. 2000;5(1):26-35. 
PubMed PMID: 10706647.
8.
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, 
O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS. Inhibition of poly(ADP-ribose) 
polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123-34. doi: 
10.1056/NEJMoa0900212. PubMed PMID: 19553641.
9.
Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, Scott C, Weitzel 
JN, Oaknin A, Loman N, Lu K, Schmutzler RK, Matulonis U, Wickens M, Tutt A. Oral poly(ADP-ribose) 
polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-
of-concept trial. Lancet. 2010;376(9737):245-51. doi: 10.1016/S0140-6736(10)60893-8. PubMed PMID: 
20609468.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 165 of 169
10.
Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, De Greve J, Lubinski J, Shanley 
S, Messiou C, A'Hern R, Tutt A, Ashworth A, Stone J, Carmichael J, Schellens JH, de Bono JS, Kaye SB. 
Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating 
with platinum-free interval. J Clin Oncol. 2010;28(15):2512-9. doi: 10.1200/JCO.2009.26.9589. PubMed PMID: 
20406929.
11.
Edwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA, Boyd J, Reis-Filho JS, Ashworth 
A. Resistance to therapy caused by intragenic deletion in BRCA2. Nature. 2008;451(7182):1111-5. doi: 
10.1038/nature06548. PubMed PMID: 18264088.
12.
Norquist B, Wurz KA, Pennil CC, Garcia R, Gross J, Sakai W, Karlan BY, Taniguchi T, Swisher EM. 
Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian 
carcinomas. J Clin Oncol. 2011;29(22):3008-15. doi: 10.1200/JCO.2010.34.2980. PubMed PMID: 21709188; 
PMCID: PMC3157963.
13.
Sakai W, Swisher EM, Jacquemont C, Chandramohan KV, Couch FJ, Langdon SP, Wurz K, Higgins J, 
Villegas E, Taniguchi T. Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-
mutated ovarian carcinoma. Cancer Res. 2009;69(16):6381-6. doi: 10.1158/0008-5472.CAN-09-1178. PubMed 
PMID: 19654294; PMCID: PMC2754824.
14.
Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, Villegas E, Jacquemont C, 
Farrugia DJ, Couch FJ, Urban N, Taniguchi T. Secondary mutations as a mechanism of cisplatin resistance in 
BRCA2-mutated cancers. Nature. 2008;451(7182):1116-20. doi: 10.1038/nature06633. PubMed PMID: 
18264087; PMCID: PMC2577037.
15.
Swisher EM, Sakai W, Karlan BY, Wurz K, Urban N, Taniguchi T. Secondary BRCA1 mutations in 
BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res. 2008;68(8):2581-6. doi: 
10.1158/0008-5472.CAN-08-0088. PubMed PMID: 18413725; PMCID: PMC2674369.
16.
Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, Hirte H, Huntsman D, 
Clemons M, Gilks B, Yerushalmi R, Macpherson E, Carmichael J, Oza A. Olaparib in patients with recurrent 
high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, 
multicentre, open-label, non-randomised study. The Lancet Oncology. 2011;12(9):852-61. doi: 10.1016/S1470-
2045(11)70214-5. PubMed PMID: 21862407.
17.
Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, Amnon A, Bell-McGuinn KM, Chen 
LM, Friedlander M, Safra T, Vergote I, Wickens M, Lowe ES, Carmichael J, Kaufman B. Phase II, open-label, 
randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase 
inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent 
ovarian cancer. J Clin Oncol. 2012;30(4):372-9. doi: 10.1200/JCO.2011.36.9215. PubMed PMID: 22203755.
18.
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura 
K, Minato N, Honjo T, Fujii S. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are 
prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A. 2007;104(9):3360-5. doi: 
10.1073/pnas.0611533104. PubMed PMID: 17360651; PMCID: PMC1805580.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 166 of 169
19.
Hamanishi J, Mandai M, Abiko K, Matsumura N, Baba T, Yoshioka Y, Kosaka K, Konishi I. The 
comprehensive assessment of local immune status of ovarian cancer by the clustering of multiple immune factors. 
Clinical immunology. 2011;141(3):338-47. doi: 10.1016/j.clim.2011.08.013. PubMed PMID: 21955569.
20.
Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, Eppolito C, Qian F, Lele S, 
Shrikant P, Old LJ, Odunsi K. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by 
LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A. 2010;107(17):7875-80. doi: 
10.1073/pnas.1003345107. PubMed PMID: 20385810; PMCID: PMC2867907.
21.
Duraiswamy J, Freeman GJ, Coukos G. Therapeutic PD-1 pathway blockade augments with other 
modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. Cancer Res. 
2013;73(23):6900-12. 
doi: 
10.1158/0008-5472.CAN-13-1550. 
PubMed 
PMID: 
23975756; 
PMCID: 
PMC3851914.
22.
Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with 
tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 2013;73(12):3591-603. doi: 
10.1158/0008-5472.CAN-12-4100. PubMed PMID: 23633484; PMCID: PMC3686913.
23.
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, 
Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg 
D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol 
GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 
2010;363(8):711-23. doi: 10.1056/NEJMoa1003466. PubMed PMID: 20525992; PMCID: PMC3549297.
24.
Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer may contribute 
to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells 
maturation. Med Oncol. 2011;28(3):682-8. doi: 10.1007/s12032-010-9515-2. PubMed PMID: 20373055.
25.
Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, Rietz C, Flies DB, Lau JS, Zhu G, Tamada 
K, Chen L. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. 
Cancer Res. 2005;65(3):1089-96. Epub 2005/02/12. PubMed PMID: 15705911.
26.
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the 
escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 
2002;99(19):12293-7. Epub 2002/09/10. doi: 10.1073/pnas.192461099. PubMed PMID: 12218188; PMCID: 
Pmc129438.
27.
Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, Kurihara C, Kawaguchi A, Nagao 
S, Azuma M, Yagita H, Miura S. Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic 
cancer model. Int J Oncol. 2009;35(4):741-9. Epub 2009/09/03. PubMed PMID: 19724910.
28.
Zhang P, Su D-M, Liang M, Fu J. Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) 
surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis. Molecular Immunology. 
2008;45(5):1470-6. doi: http://dx.doi.org/10.1016/j.molimm.2007.08.013.
29.
Tarhini AA, Kirkwood JM. Tremelimumab (CP-675,206): a fully human anticytotoxic T lymphocyte-
associated antigen 4 monoclonal antibody for treatment of patients with advanced cancers. Expert opinion on 
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 167 of 169
biological therapy. 2008;8(10):1583-93. Epub 2008/09/09. doi: 10.1517/14712598.8.10.1583. PubMed PMID: 
18774925.
30.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature reviews Cancer. 
2012;12(4):252-64. doi: 10.1038/nrc3239. PubMed PMID: 22437870; PMCID: PMC4856023.
31.
Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson 
I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A. Targeting the DNA repair defect in BRCA mutant 
cells as a therapeutic strategy. Nature. 2005;434(7035):917-21. Epub 2005/04/15. doi: 10.1038/nature03445. 
PubMed PMID: 15829967.
32.
McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S, Giavara S, O'Connor MJ, Tutt AN, 
Zdzienicka MZ, Smith GC, Ashworth A. Deficiency in the repair of DNA damage by homologous recombination 
and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66(16):8109-15. Epub 2006/08/17. 
doi: 10.1158/0008-5472.can-06-0140. PubMed PMID: 16912188.
33.
Menear KA, Adcock C, Boulter R, Cockcroft XL, Copsey L, Cranston A, Dillon KJ, Drzewiecki J, 
Garman S, Gomez S, Javaid H, Kerrigan F, Knights C, Lau A, Loh VM, Jr., Matthews IT, Moore S, O'Connor 
MJ, Smith GC, Martin NM. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-
phthalazin- 1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. Journal of medicinal 
chemistry. 2008;51(20):6581-91. Epub 2008/09/20. doi: 10.1021/jm8001263. PubMed PMID: 18800822.
34.
Antonia S, Gettinger S, Chow  L, Juergens R, Borghaei H, Shen Y. Nivolumab (anti-PD-1; BMS-936558; 
ONO-4538) and ipilimumab in first-line NSCLC. J Clin Oncol. 2014;32 (suppl).
35.
Kirkwood JM, Lorigan P, Hersey P, Hauschild A, Robert C, McDermott D, Marshall MA, Gomez-
Navarro J, Liang JQ, Bulanhagui CA. Phase II trial of tremelimumab (CP-675,206) in patients with advanced 
refractory or relapsed melanoma. Clin Cancer Res. 2010;16(3):1042-8. doi: 10.1158/1078-0432.CCR-09-2033. 
PubMed PMID: 20086001.
36.
Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D, Suman VJ, Moon J, Sondak VK, Atkins MB, 
Eisenhauer EA, Parulekar W, Markovic SN, Saxman S, Kirkwood JM. Meta-analysis of phase II cooperative 
group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for 
future phase II trials. J Clin Oncol. 2008;26(4):527-34. Epub 2008/02/01. doi: 10.1200/jco.2007.12.7837. 
PubMed PMID: 18235113.
37.
Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, 
Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, 
Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical 
trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin 
Oncol. 2013;31(5):616-22. doi: 10.1200/JCO.2012.44.6112. PubMed PMID: 23295794; PMCID: PMC4878048.
38.
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, 
Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, 
Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in 
advanced melanoma. N Engl J Med. 2013;369(2):122-33. doi: 10.1056/NEJMoa1302369. PubMed PMID: 
23724867.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 168 of 169
39.
Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an investigational anti-
interferon-alpha monoclonal antibody, in systemic lupus erythematosus. Clin Pharmacokinet. 2013;52(11):1017-
27. doi: 10.1007/s40262-013-0085-2. PubMed PMID: 23754736; PMCID: PMC3824374.
40.
Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of pertuzumab in cancer 
patients based on population pharmacokinetic analysis. Pharm Res. 2006;23(6):1275-84. doi: 10.1007/s11095-
006-0205-x. PubMed PMID: 16715358.
41.
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing of 
monoclonal 
antibodies 
in 
adult 
clinical 
trials. 
J 
Clin 
Pharmacol. 
2009;49(9):1012-24. 
doi: 
10.1177/0091270009337512. PubMed PMID: 19620385.
42.
Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of therapeutic 
peptides and proteins in adults. J Clin Pharmacol. 2012;52(1):18-28. doi: 10.1177/0091270010388648. PubMed 
PMID: 21233304.
43.
Antonia S, Goldbertg S, Balmanoukian AS, Narwal R, Robbins P, D'Angelo G. A Phase 1 open-label 
study to evaluate the safety and tolerability of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) 
antibody, in combination with tremelimumab in patients with advanced non-small cell lung cancer (NSCLC).  
European Society of Medical Oncology (ESMO) Meeting; September 26-30, 2014; Madrid, Spain.
44.
Schadendorf D, Hodi F, Robert C, al. e. A study of MPDL3280A, an engineered PD-L1 antibody in 
patients with locally advanced or metastatic tumours European Cancer Congress 2013 (ECCO-ESMO-ESTRO); 
September 27-October 1, 2013; Amsterdam, The Netherlands.
45.
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, 
Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman 
AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-
L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455-65. doi: 
10.1056/NEJMoa1200694. PubMed PMID: 22658128; PMCID: PMC3563263.
46.
Drake C, McDermott D, Sznol M, Choueiri T, Kluger H, JD P. Survival, safety, and response duration 
results of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a phase I trial in patients with previously treated 
metastatic renal cell carcinoma (mRCC): Long-term patient follow-up. J Clin Oncol. 2013;31 (suppl).
47.
Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence 
DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia 
GD, Gupta A, Pardoll DM, Sosman JA, Hodi FS. Survival, Durable Tumor Remission, and Long-Term Safety in 
Patients With Advanced Melanoma Receiving Nivolumab. Journal of Clinical Oncology. 2014. doi: 
10.1200/jco.2013.53.0105.
48.
Herbst R, Gordon M, Fine G, Sosman J, Soria J, Hamid O. . A study of MPDL3280A, an engineered PD-
L1 antibody in patients with locally advanced or metastatic tumours J Clin Oncol. 2013;31 (suppl 15).
49.
Gnjatic S, Ritter E, Buchler MW, Giese NA, Brors B, Frei C, Murray A, Halama N, Zornig I, Chen YT, 
Andrews C, Ritter G, Old LJ, Odunsi K, Jager D. Seromic profiling of ovarian and pancreatic cancer. Proc Natl 
Acad Sci U S A. 2010;107(11):5088-93. doi: 10.1073/pnas.0914213107. PubMed PMID: 20194765; PMCID: 
PMC2841879.
APPROVED RPCI IRB
4/16/2021

Roswell Park Protocol No.: I 288216
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
AMD 11 12/29/2020
Page 169 of 169
50.
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a common 
language for tumor response to immunotherapy: immune-related response criteria using unidimensional 
measurements. Clin Cancer Res. 2013;19(14):3936-43. doi: 10.1158/1078-0432.CCR-13-0895. PubMed PMID: 
23743568; PMCID: PMC3740724.
51.
Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack O, Nichol 
G, Humphrey R, Hodi FS. Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-
Related Response Criteria. Clinical Cancer Research. 2009;15(23):7412-20. doi: 10.1158/1078-0432.ccr-09-
1624.
52.
European Medicines Agency. Guideline on the evaluation of anticancer medicinal products in man. 
Oncolocy Working Party. 2012;EMA/CHMP/205/95/Rev.4.
53.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther 
S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation 
criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer. 2009;45(2):228-
47. doi: http://dx.doi.org/10.1016/j.ejca.2008.10.026.
54.
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a Common 
Language for Tumor Response to Immunotherapy: Immune-Related Response Criteria Using Unidimensional 
Measurements. Clinical Cancer Research. 2013;19(14):3936-43. doi: 10.1158/1078-0432.ccr-13-0895.
55.
Bohnsack O, Hoos A, Ludajic K. 1070PADAPTATION OF THE IMMUNE RELATED RESPONSE 
CRITERIA: IRRECIST. Annals of Oncology. 2014;25(suppl 4):iv369. doi: 10.1093/annonc/mdu342.23.
56.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, 
Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman 
WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia 
GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. 
The New England journal of medicine. 2012;366(26):2443-54. Epub 2012/06/05. doi: 10.1056/NEJMoa1200690. 
PubMed PMID: 22658127.
57.
Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of 
response with ipilimumab. J Clin Oncol. 2012;30(21):2691-7. doi: 10.1200/JCO.2012.41.6750. PubMed PMID: 
22614989.
58.
London WB, Chang MN. One- and two-stage designs for stratified phase II clinical trials. Statistics in 
medicine. 2005;24(17):2597-611. doi: 10.1002/sim.2139. PubMed PMID: 16118809.
APPROVED RPCI IRB
4/16/2021