Conditions: EGFR-Mutated Non-Small-Cell Lung Carcinoma Small Cell/Neuroendocrine
Keywords: Targeted Therapy (PARP) Inhibitors Poly (ADP-ribose) Polymerase Monoclonal Antibody
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
Background:

Lung cancers with epidermal growth factor receptor (EGFR) mutations may develop resistance to therapies targeting this protein by evolving/being transformed into small cell or neuroendocrine cancers. There are no standard treatments for it. Researchers want to see if a new combination of drugs can help.

Objective:

To see if the combination of durvalumab and olaparib will cause tumors to shrink.

Eligibility:

Adults age 18 and older who had EGFR-mutated non-small-cell lung carcinoma (NSCLC) that was treated and now transformed to SCLC or another neuroendocrine tumor.

Design:

Participants will be screened under a separate protocol. They may have a tumor biopsy.

Participants will have a physical exam. They will have a review of their symptoms, their medicines, and their ability to do their normal activities. They will have blood tests. They will have an electrocardiogram to evaluate their heart.

Participants will have a computed tomography (CT) scan, a series of x-rays taken of parts of the body.

Participants will get durvalumab on Day 1 of each 28-day cycle. It is given through a small plastic tube that is put in an arm vein. They will take olaparib by mouth twice every day. They will keep a medicine diary.

Participants will take the study drugs until their disease gets worse or they have unacceptable side effects.

About 30 days after they stop taking the study drugs, participants will have a follow-up visit. Then they will be contacted every 6 months for the rest of their life....

Detailed description:
Background:

Targeted therapies designed for specific genetic alterations, known as cancer driver mutations, have changed the treatment paradigm in advanced non-small cell lung carcinoma (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective in NSCLC with activating mutation in the EGFR. Although most patients achieve robust responses to EGFR tyrosine kinase inhibitors (TKIs) with tumor shrinkage and symptomatic relief, drug resistance eventually develops in the majority of patients.

Small cell lung cancer (SCLC) transformation has been reported as one of the mechanisms of acquired resistance to EGFR TKIs.

Several phase III trials showed durable response with poly adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitors in the breast and ovarian cancer with breast cancer gene (BRCA) mutation, a tumor suppressor gene involving homologous recombination repair (HRR) pathway, and several PARP inhibitors are now Food and Drug Administration (FDA) approved for these cancers.

Immune checkpoint blockade appears to be most effective against hypermutated tumors, suggesting that clinical responses correlate with an increased propensity to produce neoantigens.

EGFR-mutated transformed SCLC is an aggressive cancer whose clinical course is similar to that of SCLC. There are no standard treatments for this disease and prospective studies have not been conducted to date. Immune checkpoint inhibitors alone are not effective for EGFR-mutated transformed SCLC. Analyses of EGFR transformed SCLC tumors suggest that these tumors are HRR deficient.

Objective:

To assess the efficacy of a combination of durvalumab and olaparib with respect to best overall response (BOR) according to Response Evaluation Criteria (RECIST 1.1) in patients with EGFR-mutated non-small-cell lung carcinoma (NSCLC) that transform to SCLC and other neuroendocrine carcinomas.

Eligibility:

Subjects with initial diagnosis of EGFR-mutated non-small-cell lung carcinoma (NSCLC) and histologically or cytologically confirmed transformation to small cell/neuroendocrine tumors following treatment with EGFR tyrosine kinase inhibitor.

Subjects should have received platinum-based chemotherapy with or without immunotherapy for small cell/neuroendocrine transformation or refused such therapy.

Age \>=18 years.

Subjects must have measurable disease.

Eastern Cooperative Oncology Group (ECOG) performance status \<= 2

Adequate organ function

Design:

-This is an open label Phase II study evaluating the combination of durvalumab and olaparib

in participants with EGFR-mutated non-small-cell lung carcinoma and histologically or cytologically confirmed transformation to small cell/neuroendocrine tumors following treatment with EGFR tyrosine kinase inhibitor.

Patients will be treated with durvalumab (1,500 mg), intravenous (IV), every 28 days and olaparib (300 mg twice a day (BID) for total daily dose of 600 mg) in a 28-day cycles.

Patients will be evaluated for toxicity every 4 weeks by Common Terminology Criteria for Adverse Events (CTCAE) v5.0, and for response every 8 (+/-1) weeks by RECIST 1.1

Treatment will continue until disease progression or unacceptable toxicity.

Arms:
arm 1: Combination of durvalumab and olaparib

Interventions: intervention 1: Olaparib intervention 2: Durvalumab intervention 3: EKG intervention 4: Tumor biopsy intervention 5: CT chest, abdomen and pelvis intervention 6: MRI chest, abdomen and pelvis
Intervention descriptions: intervention 1: Olaparib tablet will be administered at a total daily dose of 600 mg orally in two divided doses, approximately 12 hours apart. intervention 2: Durvalumab will be administered intravenous (IV) into a peripheral or central vein on Day 1 of every cycle at a flat dose of 1,500 mg. intervention 3: Screening and all cycles Day 1 and Day 15 (+/- 3) days. One cycle is 28 days. intervention 4: Baseline and all cycles Day 15 (+/- 3) days. One cycle is 28 days. intervention 5: Screening and baseline and every 8 (+/-1) weeks after start of therapy. intervention 6: Screening and baseline and every 8 (+/-1) weeks after start of therapy.

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: Olaparib plus Durvalumab
Version Date: 03/11/2024
1
Abbreviated Title: Olaparib plus Durvalumab 
NIH Protocol #: 20-C-0149
Version Date: 03/11/2024
NCT Number: NCT04538378
Title: Phase II Trial of Olaparib (LYNPARZA) plus Durvalumab (IMFINZI) in EGFR-Mutated 
Adenocarcinomas that Transform to Small Cell Lung Cancer (SCLC) and Other Neuroendocrine 
Tumors 
NCI Principal Investigator: 
Anish Thomas, MD 
Developmental Therapeutics Branch (DTB)
National Cancer Institute
10 Center Drive, Room 4-5330
Bethesda, MD 20892
Phone: 240-760-6241
E-mail: anish.thomas@nih.gov 
Commercial Agents:
Drug/Name:
Olaparib 
(Lynparza)
Durvalumab 
(Imfinzi)
IND Number:
IND Exempt
Sponsor:
IND Exempt
Manufacturer:
AstraZeneca
AstraZeneca
Supplier
AstraZeneca
AstraZeneca


Abbreviated Title: Olaparib plus Durvalumab
Version Date: 03/11/2024
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PRÉCIS 
Background:

Targeted therapies designed for specific genetic alterations, known as cancer driver 
mutations, have changed the treatment paradigm in advanced non-small cell lung 
carcinoma (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors 
(TKIs) are effective in NSCLC with activating mutation in the EGFR. Although most 
patients achieve robust responses to EGFR TKIs with tumor shrinkage and symptomatic 
relief, drug resistance eventually develops in the majority of patients.

Small cell lung cancer (SCLC) transformation has been reported as one of the mechanisms 
of acquired resistance to EGFR TKIs.

Several phase III trials showed durable response with poly (ADP-ribose) polymerase 
(PARP) inhibitors in the breast and ovarian cancer with BRCA mutation, a tumor 
suppressor gene involving homologous recombination repair (HRR) pathway, and several 
PARP inhibitors are now FDA approved for these cancers.

Immune checkpoint blockade appears to be most effective against hypermutated tumors, 
suggesting that clinical responses correlate with an increased propensity to produce 
neoantigens.

EGFR-mutated transformed SCLC is an aggressive cancer whose clinical course is similar 
to that of SCLC. There are no standard treatments for this disease and prospective studies 
have not been conducted to date. Immune checkpoint inhibitors alone are not effective for 
EGFR-mutated transformed SCLC. Analyses of EGFR transformed SCLC tumors suggest 
that these tumors are HRR deficient.
Objective:

To assess the efficacy of a combination of durvalumab and olaparib with respect to best 
overall response (BOR) according to Response Evaluation Criteria (RECIST 1.1) in 
patients with EGFR-mutated non-small-cell lung carcinoma (NSCLC) that transform to 
SCLC and other neuroendocrine carcinomas. 
Eligibility:

Subjects with initial diagnosis of EGFR-mutated non-small-cell lung carcinoma (NSCLC) 
and histologically or cytologically confirmed transformation to small cell/neuroendocrine 
tumors following treatment with EGFR tyrosine kinase inhibitor.

Subjects should have received platinum-based chemotherapy with or without 
immunotherapy for small cell/neuroendocrine transformation or refused such therapy.

Age ≥18 years.

Subjects must have measurable disease.

ECOG performance status ≤ 2

Adequate organ function


Abbreviated Title: Olaparib plus Durvalumab
Version Date: 03/11/2024
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Design:

This is an open label Phase II study evaluating the combination of durvalumab and olaparib 
in participants with EGFR-mutated non-small-cell lung carcinoma and histologically or 
cytologically confirmed transformation to small cell/neuroendocrine tumors following 
treatment with EGFR tyrosine kinase inhibitor.

Patients will be treated with durvalumab (1,500 mg), IV, every 28 days and olaparib (300 
mg BID for total daily dose of 600 mg) in a 28-day cycles.

Patients will be evaluated for toxicity every 4 weeks by CTCAE v5.0, and for response 
every 8 (+/-1) weeks by RECIST 1.1

Treatment will continue until disease progression or unacceptable toxicity.


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TABLE OF CONTENTS
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................9
1.
INTRODUCTION .................................................................................................................10
1.1
Study Objectives .............................................................................................................10
1.1.1
Primary Objective....................................................................................................10
1.1.2
Secondary Objectives ..............................................................................................10
1.1.3
Exploratory Objectives ............................................................................................10
1.2
Background and Rationale..............................................................................................10
1.2.1
EGFR-Mutated Adenocarcinoma that Transformed to Small Lung Cell Carcinoma
10
1.2.2
Molecular Mechanisms in EGFR-Mutated Transformed SCLC.............................11
1.2.3
Clinical Course of EGFR-Mutated Transformed SCLC .........................................11
1.2.4
Treatment for EGFR-Mutated Transformed SCLC.................................................12
1.2.5
Mutational Signatures in EGFR-Mutated Adenocarcinomas that Transform to 
Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas ........................................16
1.2.6
Poly (ADP-ribose) Polymerase (PARP)-1 Inhibitors in HRR Deficient Cancer ....20
1.2.7
Olaparib ...................................................................................................................22
1.2.8
Efficacy of Immune Checkpoint Inhibitor in HRR Deficient Cancer .....................24
1.2.9
Durvalumab .............................................................................................................24
1.2.10
Combination Therapy with Durvalumab + Olaparib in SCLC and Transformed 
SCLC
25
1.2.11
Rationale for Combination Therapy with Durvalumab + Olaparib in EGFR 
Transformed SCLC................................................................................................................27
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................28
2.1
Eligibility Criteria ...........................................................................................................28
2.1.1
Inclusion Criteria .....................................................................................................28
2.1.2
Exclusion Criteria ....................................................................................................29
2.1.3
Recruitment Strategies.............................................................................................31
2.2
Screening Evaluation ......................................................................................................31
2.2.1
Screening Activities Performed Prior to Obtaining Informed Consent...................31


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2.2.2
Screening Activities Performed after a Consent for Screening has been Signed....31
2.3
Participant Registration and Status Update Procedures..................................................32
2.3.1
Treatment Assignment Procedures..........................................................................32
2.3.2
Screen Failures.........................................................................................................33
2.4
Baseline Evaluation.........................................................................................................33
3
STUDY IMPLEMENTATION .............................................................................................33
3.1
Study Design...................................................................................................................33
3.2
Drug Administration .......................................................................................................34
3.2.1
Durvalumab .............................................................................................................34
3.2.2
Olaparib ...................................................................................................................34
3.3
Dose Delay or Modifications ..........................................................................................35
3.3.1
Durvalumab .............................................................................................................35
3.3.2
Olaparib ...................................................................................................................35
3.4
Study Calendar................................................................................................................40
3.5
Cost and Compensation ..................................................................................................43
3.5.1
Costs ........................................................................................................................43
3.5.2
Compensation ..........................................................................................................43
3.5.3
Reimbursement........................................................................................................43
3.6
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................43
3.6.1
Criteria for Removal from Protocol Therapy ..........................................................43
3.6.2
Off -Study Criteria...................................................................................................43
3.6.3
Lost to Follow-Up....................................................................................................43
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................44
4.1
Prohibited Medications ...................................................................................................44
4.2
Restricted Concomitant Medications (See Appendix B - Inhibitors and Inducers of 
CYP3A4 for more complete list of Inhibitors and Inducers of CYP3A4) ................................45
4.3
Methods of Contraception...............................................................................................47
5
CORRELATIVE STUDIES FOR RESEARCH ...................................................................48
5.1
Biospecimen Collection ..................................................................................................48
5.2
Collection of Samples .....................................................................................................50
5.3
Correlative Studies for Research.....................................................................................50


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5.3.1
Immune Subsets.......................................................................................................50
5.3.2
Comprehensive Cytokine / Chemokine...................................................................50
5.3.4
Assays for Paraneoplastic Autoantibodies...............................................................51
5.4
Samples for Genetic/Genomic Analysis .........................................................................51
5.4.1
RNA sequencing and whole exome/genome sequencing on tumor tissue and blood
51
5.4.2
Transcriptome Blood ...............................................................................................51
5.4.3
Circulating Tumor DNA (ctDNA) Profiles .............................................................51
5.4.4
NanoString Pan Cancer Immune Panel ...................................................................52
5.4.5
Management of Results ...........................................................................................52
5.4.6
Genetic Counseling..................................................................................................52
5.5
Sample Storage, Tracking and Disposition.....................................................................52
5.5.1
Procedures for Storage of Patient Samples in the DTB Clinical Translational Unit
52
5.5.2
Procedures for Storage of Tissue Specimens in the Laboratory of Pathology ........53
5.5.3
NCI COMPASS Program........................................................................................53
5.5.4
Protocol Completion/Sample Destruction ...............................................................53
6
DATA COLLECTION AND EVALUATION .....................................................................54
6.1
Data Collection ...............................................................................................................54
6.1.1
Olaparib Adverse Events of Special Interest...........................................................54
6.2
Data Sharing Plans..........................................................................................................54
6.2.1
Human Data Sharing Plan .......................................................................................54
6.2.2
Genomic Data Sharing Plan.....................................................................................55
6.3
Response Criteria ............................................................................................................55
6.3.1
Disease Parameters ..................................................................................................55
6.3.2
Methods for Evaluation of Measurable Disease......................................................56
6.3.3
Response Criteria.....................................................................................................57
6.4
Toxicity Criteria..............................................................................................................59
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...60
7.1
Definitions.......................................................................................................................60
7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................60


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7.2.1
Expedited Reporting ................................................................................................60
7.2.2
IRB Requirements for PI Reporting at Continuing Review ....................................60
7.3
NCI Clinical Director Reporting.....................................................................................60
7.4
NIH Required Data and Safety Monitoring Plan............................................................60
7.4.1
Principal Investigator/Research Team.....................................................................60
8
CLINICAL MONITORING..................................................................................................61
9
STATISTICAL CONSIDERATIONS ..................................................................................61
9.1
Study Objectives .............................................................................................................61
9.1.1
Primary Objective....................................................................................................61
9.1.2
Secondary Objectives ..............................................................................................61
9.1.3
Exploratory Objectives ............................................................................................61
9.2
Sample Size Determination.............................................................................................62
9.3
Populations for Analyses ................................................................................................62
9.4
Statistical Analyses .........................................................................................................62
9.4.1
General Approach....................................................................................................62
9.4.2
Analysis of the Primary Endpoints..........................................................................62
9.4.3
Analysis of the Secondary Endpoint........................................................................62
9.4.4
Safety Analyses .......................................................................................................62
9.4.5
Baseline Descriptive Statistics.................................................................................62
9.4.6
Planned Interim Analyses........................................................................................62
9.4.7
Exploratory Analyses...............................................................................................62
10
COLLABORATIVE AGREEMENT ....................................................................................63
10.1
Clinical Trial Agreement.............................................................................................63
11
HUMAN SUBJECTS PROTECTIONS................................................................................63
11.1
Rationale for Subject Selection ...................................................................................63
11.2
Participation of Children .............................................................................................63
11.3
Risk/Benefit Assessment for All Participants .............................................................63
11.3.1
Known Potential Risks ............................................................................................63
11.3.2
Known Potential Benefits........................................................................................65
11.3.3
Assessment of Potential Risks and Benefits............................................................65
11.4
Consent Process and Documentation ..........................................................................65


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12
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................66
12.1
Study Discontinuation and Closure.............................................................................66
12.2
Quality Assurance and Quality Control ......................................................................66
12.3
Conflict of Interest Policy ...........................................................................................67
12.4
Confidentiality and Privacy.........................................................................................67
13
PHARMACEUTICAL INFORMATION .............................................................................68
13.1
Durvalumab (IMFINZI) ..............................................................................................68
13.1.1
Source/Acquisition and Accountability...................................................................68
13.1.2
Administration Procedures ......................................................................................68
13.2
Olaparib (LYNPARZA)..............................................................................................68
13.2.1
Source/Acquisition and Accountability...................................................................68
13.2.2
Administration Procedures ......................................................................................68
14
REFERENCES ......................................................................................................................69
15
APPENDICES .......................................................................................................................72
15.1
Appendix A - Performance Status Criteria..................................................................72
15.2
Appendix B - Inhibitors and Inducers of CYP3A4 .....................................................73
15.3
Appendix C - Patient’s Medication Diary ________________________..................76
15.4
Appendix D - Dosing Modification and Toxicity Management Guidelines (TMGs) 
for Durvalumab Monotherapy, Durvalumab in Combination with other Products, or 
Tremelimumab Monotherapy –September 2023.......................................................................78


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


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1. INTRODUCTION
1.1
Study Objectives
1.1.1
Primary Objective

To assess the efficacy of a combination of durvalumab and olaparib with respect to best 
overall response (BOR) according to Response Evaluation Criteria (RECIST 1.1) in 
patients with EGFR-mutated non-small-cell lung carcinoma (NSCLC) that transform to 
SCLC and other neuroendocrine carcinomas. 
1.1.2
Secondary Objectives

To determine the progression-free survival

To evaluate safety and tolerability of a combination of durvalumab and olaparib

To determine overall survival
1.1.3
Exploratory Objectives

To study immune subsets and cytokine markers of response

To evaluate circulating tumor cells and circulating tumor DNA (ctDNA)

To study paraneoplastic autoantibodies

To perform whole exome sequencing of normal (germline) DNA

To perform molecular profiling of EGFR-mutated transformed small cell/neuroendocrine 
tumors by RNA sequencing and whole exome/genome sequencing of tumor tissue;

To evaluate transcriptome and NanoString Pan Cancer Immune Panel genes in blood.
1.2
Background and Rationale
1.2.1
EGFR-Mutated Adenocarcinoma that Transformed to Small Lung Cell Carcinoma
Targeted therapies designed for specific genetic alterations, known as cancer driver mutations, 
have changed the treatment paradigm in advanced non-small cell lung carcinoma (NSCLC). 
Epidermal growth factor receptor (EGFR) – tyrosine kinase inhibitors (TKIs) are effective in 
NSCLC harboring an activating mutation in the EGFR. Although most patients achieve robust 
responses to EGFR TKIs, with tumor shrinkage and symptomatic relief, acquired drug resistance 
eventually develops in the majority of patients. The most common mechanism of resistance is the 
EGFR Thr790Met gatekeeper mutation. 
Small cell lung cancer (SCLC) transformation has been reported as one of the mechanisms of 
acquired resistance to EGFR TKIs. EGFR-mutated transformed SCLC was first described in 2006 
in a 45-year-old woman with EGFR-mutant lung adenocarcinoma and treated with EGFR TKI 
erlotinib. The tumor responded for 18 months, and biopsy at the time of progression showed SCLC 
with the original EGFR exon 18 deletion mutation [1]. Since this first case, several other case 
series of EGFR-mutated adenocarcinoma transforming to SCLC have been reported. The reported 
incidence of SCLC transformation from EGFR-mutated lung adenocarcinoma varies from 2 to 14 
% in different cohorts [2-5]. 


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1.2.2
Molecular Mechanisms in EGFR-Mutated Transformed SCLC 
Genomic sequencing of both the original tumor and the repeat biopsy samples at the time of 
resistance shows that transformed SCLC tumor samples retain the original EGFR mutation in most 
cases, which suggest that these are not de novo cancers, but a transformed phenotype as a 
mechanism of resistance to treatment [4]. EGFR-mutated transformed SCLC demonstrate many 
features of classical SCLC [6]. The transcriptional profiles of cell lines established from EGFR-
mutated transformed SCLC mimic classical SCLC including neuroendocrine markers. The cell 
lines also show universal alterations of Rb1, the key tumor suppressor involving in de novo SCLC. 
Similar to de novo SCLC, EGFR expression is also lower in transformed SCLC cell lines.
A study by Lee et al. [7] using whole genome sequencing of nine tumors acquired at various time 
points from four patients with EGFR-mutated transformed SCLC showed complete inactivation 
of both Rb1 and TP53 in lung adenocarcinomas prior to transformation. They also found that 
inactivation of both Rb1 and p53 at the initial diagnosis of EGFR-mutated NSCLC was strikingly 
more frequent in the small-cell–transformed group than non-transformed lung adenocarcinoma 
group (82% vs 3%; odds ratio: 131; 95%CI: 19.9 – 859). Among patients registered in a predeﬁned 
cohort (n = 65), an EGFR-mutated lung adenocarcinoma that harbored completely inactivated Rb1 
and p53 had a 43 times greater risk of small cell transformation (relative risk: 42.8; 95% confidence 
interval [CI]: 5.88 – 311). Branch-speciﬁc mutational signature analysis revealed that 
apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC)-induced 
hypermutation was frequent in the branches with small-cell transformation. 
Lin et al. [8] established two cell lines from EGFR-mutated transformed SCLC samples which 
also harbored inactivation of Rb1 and TP53. Interestingly, two distinct morphological phenotypes 
were observed in the two cell lines: a suspension of spheroid aggregates which expressed the 
neuroendocrine markers (“classical subtype SCLC cells”) and an adherent monolayer which had 
characteristics of mesenchymal morphology and cell markers (non-neuroendocrine[non-NE] 
subtype SCLC cells). The cultured classical subtype SCLC cells had slower tumor growth rate 
than non-NE subtype SCLC cells. EGFR protein expression in classic SCLC and non-NE subtype 
SCLC cells were low and showed resistance to EGFR inhibitors, gefitinib and osimertinib. 
Ogino et al. also established cell lines from EGFR-mutated transformed SCLC samples and 
showed classical and non-NE subtypes of SCLC among them as well as universal inactivation of 
TP 53 and Rb1 [9]. 
In a retrospective study of patients with EGFR-mutated transformed SCLC, the most common 
mutations in transformed SCLC were TP53 (38 [79%] of 48 patients), Rb1 (18 [58%] of 31 
patients), and PIK3CA (14 [27%] of 52 patients) [10]. 
1.2.3
Clinical Course of EGFR-Mutated Transformed SCLC
There are no prospective studies that have been addressing the clinical course of EGFR-mutated 
transformed SCLC. Two retrospective studies are available. 
Ferrer et al. [11] conducted a retrospective study of 48 patients with EGFR-mutated transformed 
SCLC and 13 patients with non-EGFR mutated transformed SCLC. Both groups had transformed 
from NSCLC. The median age of EGFR-mutated transformed SCLC group was 61 years, 33 (69%) 
were female, and 28 (62%) were never smoker. The majority of patients (36 of 48) had EGFR 
exon 19 mutation at initial NSCLC diagnosis. Molecular analyses were performed in 38 (79%) 
patients after transformation and 32 (84%) tumors retained the same mutation as the one observed 


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12
initially. One of thirty patients (3%) who harbored exon 19 EGFR mutation at initial diagnosis had 
L858R mutation and five (17%) lost their original EGFR mutation at transformation. One of seven 
(14%) tumors that initially had L858R EGFR mutation lost the original mutation at transformation. 
In 3 patients who initially had EGFR exon 19 mutation, the transformation was associated with 
PI3K mutation and c-MET amplification (one patient), ALK fusion alone (one patient), and ALK 
fusion and EGFR exon 21 and 10 mutations (one patient). The median time to SCLC 
transformation was shorter in EGFR-mutated group compared with non-EGFR mutated 
transformed SCLC group (16 vs. 26 months, P = 0.01). In EGFR-mutated SCLC group, 38 patients 
were treated with TKI and 10 patients were treated with platinum-based chemotherapy before 
transformation.
In the other retrospective study conducted by Marcoux et al. [10], 67 patients with EGFR-mutated 
transformed SCLC were included. Their median age was 56 years, 38 (57%) were female, 49 
(73%) were never smokers. Nine (13%) patients had SCLC or mixed histology at initial diagnosis. 
Forty-five (67%) patients had EGFR exon 19 mutation initially. All the patients with EGFR-
mutated NSCLC were treated with TKI before transformation and all of them retained their 
original mutations at transformation. Median time from NSCLC diagnosis to transformation was 
17.8 months. 
Of four NCI patients with EGFR-mutated transformed SCLC, two patients (CL0196, NCI0402) 
had EGFR exon 19 deletion at initial diagnosis of NSCLC and were treated with TKIs until 
transformation (Table 1). 
Patient CL0083 was initially diagnosed as non-EGFR mutated NSCLC and treated with several 
systemic chemotherapies, and subsequently found to have EGFR exon 21 L858R mutation. The 
patient was started on erlotinib and was found to have exon 20 T790M mutation at resistance with 
erlotinib, and subsequently treated with osimertinib until SCLC transformation. 
Patient #4 was initially diagnosed as EGFR exon 19 mutated stage IV NSCLC and treated with 
erlotinib. Resistance to erlotinib developed 16 months later with EGFR exon 20 T790M mutation. 
Subsequently patient started combination immunotherapy with nivolumab (PD-1 inhibitor), 
ipilimumab (CTLA4 inhibitor) and erlotinib but developed pneumonitis, and subsequently started 
osimertinib (3rd generation EGFR inhibitor). This patient was also treated with investigational 
personalized peptide vaccine, nivolumab and ipilimumab in addition to osimertinib. However, 
disease slowly progressed 21 months after starting osimertinib. Repeat biopsy with right 
supraclavicular lymph node showed transformation to high grade neuroendocrine lung cancer with 
small cell morphology. 
At transformation, three tumors retained their original EGFR mutations (CL0083, NCI0402 and 
#4), whereas the other (CL0196) lost the original EGFR mutation. The time from initial diagnosis 
to transformation were 40.3, 14.5, 18.7 and 40 months, respectively.
1.2.4
Treatment for EGFR-Mutated Transformed SCLC
There are no standard treatments currently for patients with EGFR-mutated transformed SCLC 
and no prospective clinical trials have been conducted. In the retrospective study by Ferrer et al 
described above [11], 42 of 48 (88%) patients in EGFR-mutant SCLC group received at least one 
line of treatment after transformation, mostly platinum-based chemotherapy. Six patients received 
only supportive care at the time of transformation. The partial response rate and the median overall 
survival (OS) rates after diagnosis of NSCLC and transformation were similar between EGFR-


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mutated and non-EGFR-mutated SCLC groups (partial response rate: 45% vs. 40%; median OS: 
28 vs. 37 months after diagnosis of NSCLC and 9 vs. 10 months after transformation, respectively). 
In the other retrospective study by Marcoux et al [10], also, most patients (93%) were treated with 
platinum-based chemotherapy after transformation. Although clinical response rate was 54%, the 
median progression-free survival (PFS) was short at 3.4 months and median OS after 
transformation 10.9 months. These outcomes are similar to that of de novo SCLC.
In the Marcoux series, 17 of 67 patients were treated with immune checkpoint inhibitor such as 
single-agent programmed death-1 inhibitor (PD-1), programmed death-ligand 1 (PD-L1) inhibitor 
or combination with PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitors. 
Interestingly, none of the 17 patients treated responded to the intervention. Among the four NCI 
patients described above, two (CL0083 and NCI0402) were treated with several systemic 
treatments including platinum-based chemotherapy, combination of osimertinib and 
chemotherapy or osimertinib and nivolumab, and phase 2 investigational treatment with no 
responses. These two patients died 13 and 4.6 months after SCLC transformation (Table 1). 
CL0196 was initially treated with platinum-based chemotherapy without any response but has an 
ongoing durable partial response to poly (ADP-ribose) polymerase (PARP) inhibitor olaparib and 
PD-L1 inhibitor durvalumab. Patient #4 remains on treatment with platinum-based chemotherapy 
(4.0 months after transformation).
 


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Patient
Age
Sex
Race
Disease site at initial 
diagnosis
Egfr 
mutation 
at 
diagnosis
Treatment 
before 
transformation
Resp
onse
Time to 
transfor
mation
(months)
Egfr 
mutation 
at 
transfor
mation
Treatme
nt after 
transfor
mation
Resp
onse
Survival 
from
Diagnosis
(months)
Survival 
from 
transfor
mation
(months)
CL0083
57
F
African 
Americ
an
diffuse pleural 
lesions in left chest
left side pleural 
effusion
diffuse bone lesions
exon 21 
(L858R)
exon 20 
(T790M) 
(After 
erlotinib)
1. platinum + 
paclitaxel + 
bevacizumab 
followed by 
maintenance 
bevacizumab
2. pemetrexed + 
bevacizumab
3. topotecan
4. docetaxel
5. erlotinib
6. Osimertinib
1. SD
2. PD
3. SD
4. PD
5. SD
6. PR
40.3
exon 21 
(L858R)
1. 
platinum 
+etoposi
de 
+osimerti
nib
2. 
nivoluma
b 
+osimerti
nib
1. PD
2. PD
53.2
13
CL0196
67
F
White
right upper lobe mass
bilateral hilar and 
mediastinal 
lymphadenopathy
left cervical 
lymphadenopathy
bilateral 
supraclavicular 
lymphadenopathy
exon 19 
deletion
1. pembrolizumab 
(until EGFR result 
came back)
2. Gefitinib
1. NA
2. PR
14.5
no EGFR 
mutation
1. 
platinum 
+ 
etoposide
2. phase 
2 
investiga
tional 
treatment
1. PD
2. PR
27.6+
13.1+
NCI040
2
38
F
African 
Americ
an
Left lower lobe mass
left lower lobe nodule
left hilar 
lymphadenopathy
left subcarinal 
lymphadenopathy
right superior 
mediastinal 
lymphadenopathy
brain lesions
exon 19 
deletion
(E746_A75
0del)
1. osimertinib
1. PR
18.7
exon 19 
deletion
(E746_A7
50del)
1. 
platinum 
+ 
pemetrex
ed
2. phase 
2 
investiga
tional 
treatment
3. 
platinum 
+ 
etoposide
1. PD
2. PD
3. PD
23.3
4.6


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Patient
Age
Sex
Race
Disease site at initial 
diagnosis
Egfr 
mutation 
at 
diagnosis
Treatment 
before 
transformation
Resp
onse
Time to 
transfor
mation
(months)
Egfr 
mutation 
at 
transfor
mation
Treatme
nt after 
transfor
mation
Resp
onse
Survival 
from
Diagnosis
(months)
Survival 
from 
transfor
mation
(months)
#4
30
F
White
Bilateral lung 
nodules
Mediastinal 
lymphadenopathy
Supraclavicular 
lymphadenopathy
Bone lesions
Brain lesion
exon 19
(K745_A7
50del)
exon 20
(T790M) 
(after 
erlotinib)
1. erlotinib
2. nivolumab + 
ipilimumab + 
erlotinib
3. osimertinib
4. investigational 
treatment
5. nivolumab + 
ipilimumab + 
osimertinib
?
40
exon 19
(K745_A7
50del)
1. 
platinum 
+ 
etoposide
?
50.0+
4.0 +
Table 1 Clinical characteristics of patients with EGFR-mutated transformed SCLC
Best response was evaluated according to RECIST, F: female, PR: partial response, SD: stable disease, PD: progressive disease, NA: 
not assessed


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1.2.5
Mutational Signatures in EGFR-Mutated Adenocarcinomas that Transform to Small-Cell 
Lung Cancer and Other Neuroendocrine Carcinomas 
Alexandrov and colleagues derived ‘mutational signature’ from analysis of the genome [12], based 
on the principle that the type of nucleotide substitution and their context (i.e. the bases immediately 
before and after the substitution) may provide important information about the oncogenic process 
operative in the development and progression of cancer. By applying a mathematical algorithm to 
the aggregate of somatic mutations present in the individual cancers, 30 mutational signatures were 
identified initially, and later expanded to 49 signatures [13]. These include signatures that can be 
indicative of specific forms of DNA repair defects in cancer cells (e.g. homologous recombination 
repair [HRR] pathway defect [signature 3], DNA mismatch repair defect [signature 6, 15, 20, and 
26], exposure to mutagenic/carcinogenic stimuli such as UV light [signature 7] and tobacco 
[signature 4 and 29]) [14, 15]. A study using ~1000 invasive breast cancer samples showed that 
biallelic inactivation of BRCA1/2 associates with mutational signature 3 [16]. A signature 3-based 
approach was superior to alternative approaches such as loss of heterogeneity and large-scale 
transition scores in classifying missense BRCA1 or BRCA2 variants known to impair HRR 
pathway. 
To evaluate the HRR pathway defect in EGFR-mutated transformed SCLC, we analyzed the 
mutational signatures in 4 tumors of NCI patients with EGFR-mutated transformed SCLC 
described above (CL0083, CL0196, NCI0402) and 28 tumors from patients with de novo SCLC 
as control. As shown in Figure 1, the EGFR-mutated transformed SCLC group had a significantly 
higher proportion of signature 3 compared with de novo SCLC group (median [interquartile 
range]: 47 [34-49]% vs. 18 [14-27]%, p = 0.015 by Mann-Whitney test), suggesting that the former 
group may have an HRR pathway defect [14]. Signature 3 also inversely correlates with expression 
of genes involved in the HRR pathway such as RAD54B, RMI2, and UBE2T (Figure 2 A-C). Of 
3 patients with EGFR-mutated SCLC, one patient (CL0196) has RAD51 mutation, which mediates 
pairing of homogenous DNA sequencing and strand invasion in HRR pathway [17] and another 
patient (CL0083) has DNA mismatch repair deficiency. As a confirmation, we also compared 
homologous recombination deficiency (HRD) score using whole exome sequencing data [18] in 
EGFR-mutated transformed SCLC (4 tumors) vs. de novo SCLC or extrapulmonary small cell 
cancers (37 tumors) of NCI Clinomics samples. The HRD score in EGFR-mutated transformed 
SCLC were significantly higher than de novo SCLC or extrapulmonary small cell cancers (P = 
0.026 by Wilcoxon test, Figure 3)


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Figure 1. Proportion of signature 3 in patients with SCLC and EGFR transformed SCLC. Two samples were 
available from the patient NCI0402 at different time-points after transformation. trSCLC: EGFR-mutated transformed 
small cell lung carcinoma; PT_NW_trSCLC: patient #4.


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Figure 2: Correlation between the proportion of signature 3 and expression of RAD54B, RIM2, UBE2T. We 
used Spearman correlation test to evaluate the correlation. One sample from NCI0402 obtained before transformation 
was labeled as NSCLC. trSCLC: EGFR-mutated transformed small cell lung cancer; TMM: trimmed mean of M-
value; FPKM: fragments per kilobase million


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Figure 3: HRD score in EGFR-mutated transformed SCLC and de novo SCLC or extrapulmonary small cell 
cancers. We used Wilcoxon test to analyze statistical differences between EGFR-mutated transformed SCLC vs. 
others. HRD score was calculated as previously described [18]. HRD: homologous recombination deficiency; LOH; 
loss of heterozygosity; Telomeric AI; Telomeric allelic imbalance; LST; large-scale state transitions; SCLC: small 
cell lung cancer, trSCLC: EGFR-mutated transformed small cell lung cancer.
1.2.6
Poly (ADP-ribose) Polymerase (PARP)-1 Inhibitors in HRR Deficient Cancer
Proteomic profiling previously identified PARP-1 as a candidate drug target for SCLC [19]. PARP is 
recruited to DNA single-strand breaks (SSB) where it PARylates multiple substrates including 
histones to facilitate the relaxation of chromatin, as well as itself. PARP inhibitors stay bound 
within the PARP active site and the PARP protein is trapped on the DNA long enough to be 


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encountered by the replication machinery, and this results in a stalling of the replication fork, its 
collapse and the generation of DNA double strand breaks [20, 21]. Important consequence of this 
and the proposed basis of PARP inhibitor monotherapy activity is the generation of DNA double-
strand breaks that would normally be repaired by the HRR pathway. In cancers with HRR 
deficiency, PARP trapping will result in significant genomic instability until it is no longer 
sustainable and tumor cell death results [22]. Several phase III trials showed durable response with 
PARP inhibitors in the breast and ovarian cancer with BRCA mutation, a tumor suppressor gene 
involving HRR pathway, and several PARP inhibitors are now FDA approved for these cancers 
[23-25].
Although PARP inhibitors are active in SCLC, the subsets of tumors that respond is not fully 
defined. In a phase I study, 23 patients with SCLC previously treated with ≥ 1 systemic therapy 
were treated with talazoparib [26]. Two (8%) patients had PR with duration response of 12.0 and 
15.3 weeks, and further 4 patients (16%) has SD lasting at least 16 weeks. In a randomized phase 
II study of cisplatin and etoposide with veliparib or placebo in previously-untreated extensive-
stage SCLC (N=128) [27], the median PFS and OS were not significantly different between two 
groups (median PFS: 6.1 months for veliparib vs. 5.5 months for placebo, P = 0.06; median OS: 
10.3 vs. 8.9 months, P = 0.17). In a randomized, double-blind, phase II study of temozolomide in 
combination with veliparib or placebo in patients with refractory/relapsed SCLC (N=104) [28], no 
significant difference in 4-month PFS were noted between the two groups (36% for veliparib vs 
27% for placebo, P = 0.19). The median OS was also not improved significantly (8.2 vs. 7.0 
months, P = 0.50). In this study, significantly prolonged PFS (5.7 vs. 3.6 months, P = 0.009) and 
OS (12.2 vs. 7.5 months, P = 0.014) were observed in patients with SLFN11-positive tumors 
treated with temozolomide and veliparib. SLFN11 is a putative DNA/RNA helicase belonging to 
the Schlafen family of proteins which induces lethal S-phase arrest in response to DNA damage. 
Studies in patient-derived xenograft SCLC models have also demonstrated that SLFN11 
expression measured by immunohistochemistry correlates with treatment responses to PARP 
inhibitors [29].
A recent preclinical report also showed that EGFR-mutated non-SCLC cells that acquired TKIs 
resistance exhibited PARP dependence for survival and PARP inhibitors sensitivity [30].
Authors demonstrated the 7 of 8 non-SCLC cell lines that acquired TKIs resistance with T790M 
mutation, MET amplification or epithelial to mesenchymal transition had lower half maximum 
inhibitory concentration, decreased colony survival, more tumor growth suppression efficacy, and 
increased gamma-H2AX foci (a biomarker for DNA double-strand breaks) with multiple PARP 
inhibitors compared with their TKI sensitive cell lines (Figure 4). Interestingly, the PARP 
inhibitor sensitivity did not depend on PARP-trapping and DNA repair pathway, but NOX-
dependent reactive oxygen species (ROS) though RAC1 (a small G-protein in the Rho family 
which is an activator of NOX-enzymes) PARPylation.


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Figure 4. EGFR-mutated NSCLC lines are more sensitive to PARP inhibitors/inhibition. Several TKI-resistant 
EGFR-mutated non-SCLC cell lines had significant lower IC50 of rucaparib, niraparib, and olaparib compared with 
their TKI-naïve cell lines. Several TKI-resistant EGFR-mutated non-SCLC cell lines and heterotopic tumor xenograft 
from established and patient-delivered tumor cell lines were more sensitive to olaparib with significant higher levels 
of gamma-H2AX (a biomarker for DNA double-strand breaks) and tumor control. These data were published by 
Marcar L et al [30]
1.2.7
Olaparib
Olaparib (AZD2281, KU-0059436) is a potent polyadenosine 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 ovarian 
cancers in patients with BRCA1/2 mutations, 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.
For full information, refer to investigator brochure.
1.2.7.1
Risks of Olaparib
1.2.7.1.1 Myelodysplastic Syndrome/Acute Myeloid Leukaemia (MDS/AML)
The incidence of MDS/AML in patients treated in clinical trials with olaparib monotherapy, 
including long-term survival follow up, was <1.5%, with higher incidence in patients with 
BRCAm PSR ovarian cancer who had received at least two prior lines of platinum chemotherapy 


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and were followed up for 5 years. The majority of events had a fatal outcome. The duration of 
therapy with olaparib in patients who developed MDS/AML varied from<6 months to >4 years. 
All patients had potential contributing factors for the development of MDS/AML, having received 
previous chemotherapy with platinum agents. Many had also received other DNA-damaging 
treatments. The majority of reports were in gBRCAm carriers and some of the patients had a 
history of more than one primary malignancy or of bone marrow dysplasia. If MDS and/or AML 
are confirmed while on treatment with olaparib, it is recommended that olaparib should be 
discontinued and the patient be treated appropriately.
1.2.7.1.2 Hematological Toxicity 
Anaemia and other hematological toxicities were generally low grade (CTCAE Grade 1 or 2), 
however, there were reports of CTCAE Grade 3 and higher events. Anaemia was the most common 
CTCAE Grade ≥3 adverse reaction reported in clinical studies with first onset generally reported 
in the first 3 months of treatment. An exposure-response relationship between olaparib and 
decreases in haemoglobin has been demonstrated. In clinical studies with olaparib monotherapy, 
the incidence of CTCAE Grade ≥2 shifts (decreases) from baseline in haemoglobin was 21%, 
absolute neutrophils 17%, platelets 5%, lymphocytes 26% and leucocytes 19% (all % 
approximate).The incidence of elevations in MCV from low or normal at baseline to above the 
ULN was approximately 68%. Levels appeared to return to normal after treatment discontinuation 
and did not appear to have any clinical consequences. Baseline testing, followed by monthly 
monitoring of complete blood counts is recommended for the first 12 months of treatment with 
olaparib, and periodically after this time to monitor for clinically significant changes in any 
parameter during treatment which may require dose interruption or reduction and/or further 
treatment.
1.2.7.1.3 Other Laboratory Findings
In clinical studies with olaparib the incidence of CTCAE Grade ≥2 shifts (elevations) from baseline 
in blood creatinine was approximately 11%. Data from a double-blind placebo-controlled study 
showed median increase up to 23% from baseline remaining consistent over time and returning to 
baseline after treatment discontinuation, with no apparent clinical sequelae; 90% of patients had 
creatinine values of CTCAE Grade 0 at baseline and 10% were CTCAE Grade 1 at baseline. The 
increase in blood creatinine level might be explained by inhibition of renal transporters such as 
OCT2, MATE1 and MATE2K by olaparib, as blood creatinine levels were found to return to 
baseline after treatment discontinuation.
1.2.7.1.4 Nausea and Vomiting
Nausea was generally reported very early, with first onset within the first month of olaparib 
treatment in the majority of patients. Vomiting was reported early, with first onset within the first 
two months of olaparib treatment in the majority of patients. Both nausea and vomiting were 
reported to be intermittent for the majority of patients and can be managed by dose interruption, 
dose reduction and/or antiemetic therapy. Antiemetic prophylaxis is not required.
1.2.7.1.5 Venous Thromboembolism
In clinical studies, the incidence of deep vein thrombosis and pulmonary embolism was 0.7% and 
1.4%, respectively. Venous thromboembolism has been identified as an ADR associated with 
olaparib. A higher number of VTEs were noted in the olaparib arm of PROfound, PROpel, and 
PAOLA-1, and this imbalance appears to be associated with populations that have a higher risk of 


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VTEs, including an older male population with prostate cancer who also received continuous 
androgen deprivation treatment, and patients who received bevacizumab in combination with 
olaparib. Due to differences in follow-up time, patient selection, patient monitoring, and medical 
care, a direct comparison with the published literature data including published clinical trials, 
observational trials, and observational studies is challenging. However, the incidence of VTEs 
observed in PROfound, PROpel, and PAOLA-1 are consistent with the incidence reported in 
prostate cancer patients from the literature (Wong et al 2018, Deka et al 2019, Nguyen-Nielsen et 
al 2014, Sun et al 2016) and in the bevacizumab SmPC (described as a ‘very common’ ADR; 
Avastin SmPC 2022)
1.2.7.1.6 New Primary Malignancies Other Than MDS/AML
New primary malignancies have been reported in <1.0% of patients. There were other contributing 
factors/potential alternative explanations for the development of the new primary malignancy in 
all cases, including documented BRCA mutation, treatment with radiotherapy and extensive 
previous chemotherapy including carboplatin, taxanes, anthracyclines and other alkylating and 
DNA damaging agents.
For information on all identified and potential risks with olaparib always refer to the current 
version of the olaparib IB.
1.2.8
Efficacy of Immune Checkpoint Inhibitor in HRR Deficient Cancer
Immune checkpoint blockade appears to be most effective against hypermutated tumors, 
suggesting that clinical responses correlate with an increased propensity to produce neoantigens. 
BRCA1-mutated triple-negative breast cancer and high grade serous ovarian cancer exhibit an 
increased somatic mutational load and greater numbers of tumor-infiltrating lymphocytes, with 
increased expression of immunomodulatory genes including PD-1 and CTLA4, when compared 
BRCA1–wild-type tumors [31, 32]. In vivo studies also show that the combination of PD-1 and 
CTLA-4 inhibitors with cisplatin profoundly attenuate the growth of BRCA1-deficient breast 
tumors in vivo and improve overall survival [31, 33]. 
1.2.9
Durvalumab
Durvalumab (MEDI4736) is a selective, high-affinity human immunoglobulin G1 monoclonal 
antibody that blocks PD-L1 binding to PD-1 and CD80, thereby enhancing the function of tumor-
directed T cells.
A population PK model was developed for durvalumab using monotherapy data from a Phase I 
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 the 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 
1,000 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-patient variability with fixed dosing regimen. 
Similar findings have been reported by others [34-37]. Wang and colleagues investigated 12 
monoclonal antibodies and found that fixed and body size-based dosing perform similarly, with 


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fixed dosing being better for 7 of 12 antibodies [35]. 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-patient variability in pharmacokinetic/pharmacodynamics parameters [36]. 
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced 
dosing errors. Given expectation of similar pharmacokinetic exposure and variability, we 
considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 kg, a 
fixed dose of 1,500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) is included in the current 
study.
1.2.9.1
Risks with durvalumab 
Risks with durvalumab include, but are not limited to, diarrhea/colitis pneumonitis/ILD, 
endocrinopathies (hypo- and hyper-thyroidism, type I diabetes mellitus (which may present with 
diabetic ketoacidosis), diabetes insipidus, encephalitis, subcutaneous injection site reaction, 
hypophysitis and adrenal insufficiency) hepatitis/increases in transaminases, nephritis/increases in 
creatinine, pancreatitis/increases in amylase and lipase, rash/pruritus/dermatitis (including 
pemphigoid), myocarditis, myositis/polymyositis, enterocolitis, pancreatitis, proctitis, hepatic 
enzyme increased, other rare or less frequent inflammatory events including neurotoxicity, 
infusion-related reactions, hypersensitivity reactions, infections/serious infections, non-infective 
encephalitis, immune-mediated arthritis, uveitis and cytokine release syndrome.
For information on all identified and potential risks with durvalumab please always refer to the 
current version of the durvalumab investigator brochure. 
In monotherapy clinical studies adverse events (AEs) (all grades) reported very commonly (≥ 10% 
of patients) are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, 
vomiting, back pain, pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, rash, and 
pruritus. Approximately 4% of patients experienced an AE that resulted in permanent 
discontinuation of durvalumab and approximately 7% of patients experienced a serious adverse 
events (SAE) that was considered to be related to durvalumab by the study investigator. The 
majority of treatment-related AEs were manageable with dose delays, symptomatic treatment, and 
in the case of events suspected to have an immune basis, the use of established treatment guidelines 
for immune-mediated (Appendix D).
1.2.10 Combination Therapy with Durvalumab + Olaparib in SCLC and Transformed SCLC 
We evaluated the efficacy of a combination of durvalumab, a PD-L1 inhibitor, and olaparib, a 
PARP inhibitor, in patients with relapsed SCLC in a phase II open-label, single-arm study [38]. In 
this study patients were treated with 1,500 mg every 28 days and olaparib 300 mg twice daily. 
After a median follow up of 11.1 months, one of 19 evaluable patients had confirmed CR and PR 
and four patients had SD. The median PFS was 1.8 months (95%CI: 0.9 – 2.4 months) and the 
median OS was 4.1 months (95%CI: 2.4 – 9.2 months). The study did not meet its primary endpoint 
and the objective response rate (ORR) of 10.5%. The confirmed ORR is similar to that of PD-1 
inhibitor nivolumab alone in this setting [39]. The results of this study are in line with the findings 
from phase II basket study which administered olaparib as monotherapy for 4 weeks followed by 
combination with durvalumab in relapsed SCLC patients at least 12 weeks after platinum-based 
therapy [40]. Among 38 patients, 2 patients had responses (5%) and the 12-week disease control 
rate was 29%. 


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Interestingly, one of the cases with partial response in the NCI study had EGFR-mutated 
transformed SCLC (CL0196 described above; Figure 5). The patient was initially diagnosed as 
metastatic EFGR exon 19 deleted-lung adenocarcinoma and had received the PD-1 inhibitor 
pembrolizumab before the EGFR mutation results were available with no response, followed by a 
PR on gefitinib. Disease progression after one year of gefitinib was confirmed as transformed 
SCLC and did not respond to 2 cycles of carboplatin and etoposide. Subsequently the patient 
received olaparib plus durvalumab and had an 89% tumor shrinkage from baseline and remains on 
treatment at one year now. The patient’s post-treatment biopsies displayed a dense T-cell infiltrate 
in clusters and aggregates extending deeply into the tumor with extensive tumor cell necrosis 
accompanied by increased PD-L1 expression on tumor and tumor-infiltrating immune cells 
suggesting a possible immune response driving the tumor response. In an international multicenter 
phase II basket study of olaparib and durvalumab, one instance of paired biopsy specimens 
obtained before and after olaparib run-in (that is, by olaparib alone) showed significant increase in 
PD-L1 expression and tumor infiltrating lymphocytes in a patient whose cancer responded to the 
combination [41].
Additionally, cell lines derived from patient #4 described above shows sensitivity to PARP 
inhibitors olaparib and rucaparib. The patient’s tumor shows prominent proportion of signature 3 
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Figure 5. Clinical course and response with combination treatment with durvalumab and olaparib in a patient 
with EGFR-mutated transformed SCLC (CL0196). (A) timeline of treatment; (B) CT scan at pre-treatment, 1 
months and 3 months after treatment. Red circles and arrows indicate right upper lobe mass and paraaortic lymph 
node, respectively; (C): Pre- and on-treatment biopsies stained immunohistochemically for the presence of PD-L1, 
CD3+ and CD8+ T cells (40X magnification)
1.2.11 Rationale for Combination Therapy with Durvalumab + Olaparib in EGFR Transformed 
SCLC
EGFR-mutated transformed SCLC is an aggressive cancer whose clinical course is similar to that 
of de novo SCLC. There are no standard treatments for this disease and prospective studies have 
not been conducted to date. Based on retrospective data reported by Marcoux et al, immune 
checkpoint inhibitors alone are not effective for EGFR-mutated transformed SCLC. Albeit in a 
limited number of patients, we have observed an enrichment of signature 3 indicative of defects in 
HRR pathways and a prevalence of mutations in DNA damage repair genes. We have also 
observed preclinical activity of PARP inhibitors in a patient derived cell line and durable ongoing 
partial response to olaparib and durvalumab in a patient with transformed SCLC. Taken together, 


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these provide rationale for a small pilot study testing combination of PARP inhibitor and immune 
checkpoint inhibitor in EGFR-mutated transformed SCLC.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
Eligibility Criteria
2.1.1
Inclusion Criteria 

Subjects with initial diagnosis of EGFR-mutated non-small-cell lung carcinoma (NSCLC) 
and histologically or cytologically confirmed transformation to small cell or 
neuroendocrine tumor following treatment with EGFR tyrosine kinase inhibitor.

Subjects should have received platinum-based chemotherapy with or without 
immunotherapy for small cell/neuroendocrine transformation or refused such therapy.

Age ≥18 years.

Patients must have measurable disease per RECIST 1.1. See Section 6.3 for the evaluation 
of measurable disease.

ECOG performance status ≤ 2 (Appendix A).

Adequate hematological function within 28 days prior to enrollment as defined below:
white blood cell (WBC) count ≥ 3 × 109/L, 
absolute neutrophil count (ANC) ≥ 1.0 ×109/L, 
platelet count ≥75 × 109/L, and 
Hgb ≥9 g/ dL if no blood transfusion within 4 weeks prior to enrollment OR >10 
g/dL if no blood transfusion within 2 weeks prior to enrollment.

Adequate hepatic function within 28 days prior to enrollment as defined by:
a total bilirubin level ≤ 1.5 × ULN; for subjects with documented/suspected 
Gilbert’s disease, bilirubin ≤ 3 × ULN 
an AST level ≤2.5×ULN, (≤ 5X ULN if liver metastasis)
an ALT level ≤2.5 ×ULN, (≤ 5X ULN if liver metastasis). 

Adequate renal function within 28 days prior to enrollment as defined by:
Creatinine OR
Measured or calculated 
creatinine clearance 
(CrCl) (eGFR may also 
be used in place of 
CrCl) A
< 1.5x institution upper limit of normal OR
> 51 mL/min/1.73 m2 for participant with creatinine levels
> 1.5 X institutional ULN
A Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard.


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o
The effects of the study treatment on the developing human fetus are unknown; 
thus, women of childbearing potential must agree to use 1 highly effective form of 
contraception (see section 4.3.1.3) and their partners must use a male condom, or 
they must totally/truly abstain from any form of sexual intercourse from the time 
of screening throughout the total duration of the protocol treatment and for at least 
6 months after the last dose of the study drugs. Male participants and their partners 
must use a highly effective form of contraception (see section 4.3.1.3) from the time 
of screening throughout the total duration of the protocol treatment and for 3 
months after the last dose of study treatment.

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. 
o
Postmenopausal or evidence of non-childbearing status for women of childbearing 
potential: negative urine or serum pregnancy test within 28 days of enrollment and 
confirmed prior to treatment on day 1. Postmenopausal is defined as: amenorrheic 
for 1 year (12 months in a row) or more following cessation of exogenous hormonal 
treatments; luteinizing hormone (LH) and follicle stimulating hormone (FSH) 
levels in the post-menopausal range for women under 50, radiation-induced 
oophorectomy with last menses >1 year ago; chemotherapy-induced menopause 
with more than one-year interval since last menses; surgical sterilization for female 
participants (bilateral oophorectomy or hysterectomy) or male partners. 

Patients with symptomatic brain metastases will be excluded from trial secondary to poor 
prognosis. However, patients who have had treatment for their brain metastasis and whose 
brain disease is stable without steroid therapy for 2 weeks may be enrolled. Imaging to rule 
out brain metastases is not required for screening but should be performed prior to study 
enrollment if clinically indicated.

Subjects must be able to understand and willing to sign a written informed consent 
document
2.1.2
Exclusion Criteria

Patients who are receiving any other investigational agents. Patients may be on other 
clinical trials or treatment during screening to determine eligibility

Systemic anti-cancer treatment or major surgery within 2 weeks prior to enrollment.

Palliative radiation within 24 hours prior to enrollment.

High-dose consolidative chest radiation within 2 weeks prior to enrollment.

Major surgical procedure (as defined by the Investigator) within 28 days prior to 
enrollment. Note: local surgery of isolated lesions for palliative intent is acceptable.

Patients receiving any medications or substances that are moderate and strong inhibitors or 
inducers of CYP3A4. A list of CYP3A4 inhibitors and inducers is provided in Appendix 
B. Note: dihydropyridine calcium - channel blockers are permitted for management of 
underling disease.

History of auto-immune disease requiring steroid maintenance, or history of primary 
immunodeficiency.


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
Current or prior use of immunosuppressive medication within 14 days before the 
enrollment, with the exception 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. In the case of short-term use of systemic corticosteroids (less 
than 24 hours within 28 days) of greater than 10 mg/day of prednisone or an equivalent 
corticosteroid, the required washout period prior to enrollment is 7 days.

Patients with myelodysplastic syndrome/acute myeloid leukemia; or baseline clinical 
features suggestive of myelodysplastic syndrome or acute myelogenous leukemia.

Persistent toxicities (≥ CTCAE grade 2) with the exception of alopecia, caused by previous 
cancer therapy.

History of allergic reactions attributed to compounds of similar chemical or biologic 
composition of olaparib or durvalumab.

Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged 
by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, 
congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or 
patients with congenital long QT syndrome.

Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and TB testing), hepatitis B (known 
positive HBV surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved 
HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and 
absence of HBsAg) and patients positive for hepatitis C (HCV) antibody are eligible only 
if polymerase chain reaction is negative for HBV or HCV RNA.

HIV-positive patients on antiretroviral therapy are ineligible because of potential 
pharmacokinetic interactions with study drugs. However, patients with long-standing (>5 
years) HIV on antiretroviral therapy > 1 month (undetectable HIV viral load and CD4 count 
> 150 cells/μL) may be eligible if the PI determines no anticipated clinically significant 
drug-drug interactions.

History of allogenic organ transplantation, bone marrow transplant or double umbilical 
cord blood transplantation (dUCBT).

Uncontrolled intercurrent illness or medical condition including, but not limited to, 
ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia requiring medications ((except chronic atrial fibrillation/flutter with 
controlled vascular rate), or psychiatric illness/social situations that may impair the 
patient’s tolerance of study treatments and, in the judgment of the investigator, would make 
the patient inappropriate for the study.

Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication based 
on primary investigator decision.

Pregnant women are excluded from this study because olaparib is a PARP inhibitor agent 
with the potential for teratogenic or abortifacient effects. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 


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with durvalumab and olaparib, breastfeeding should be discontinued if the mother is treated 
with study drugs. 
2.1.3
Recruitment Strategies
This study will be posted on the CCR website, www.clinicaltrials.gov, as well as on NIH websites 
and NIH social media forums. Outside providers and colleagues may directly refer patients for 
screening into this study.
2.2
Screening Evaluation
2.2.1
Screening Activities Performed Prior to Obtaining Informed Consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in person or telephone communications with prospective subjects 

Review of existing medical records to include H&P, laboratory studies, etc. 

Review of existing MRI, x-ray, or CT images

Review of existing photographs or videos

Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes.
2.2.2
Screening Activities Performed after a Consent for Screening has been Signed
The following activities will be performed only after the subject has signed the study consent OR 
the consent for study 01-C-0129 (provided the procedure is permitted on that study) on which 
screening activities may also be performed. . Assessments performed at outside facilities or on 
another NIH protocol within the timeframes below may also be used to determine eligibility once 
a patient has signed the consent.
Within 28 days prior to enrollment unless otherwise noted below:

Complete medical history and physical examination, including height, weight, vital signs, and 
ECOG performance status.

Three EKGs 

Laboratory Evaluation: CBC with differential, sodium, potassium, chloride, bicarbonate, 
BUN, glucose, albumin, calcium, magnesium, phosphorus, AST/ALT, total bilirubin, gamma 
glutamyl transferase, serum creatinine, PT/PTT, total protein, urine or serum HCG. Urinalysis: 
Hb/erythrocytes/blood, protein/albumin, glucose

Activated partial thromboplastin time (APTT) 

International normalized ratio (INR) 

HIV (only for patients with long-standing (>5 years) HIV on antiretroviral therapy > 1 month), 
HBV and HCV viral load by PCR (only for participants with previous HBV or HCV infections)

CD4 count (only for patients with long-standing (>5 years) HIV on antiretroviral therapy > 1 
month)


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
TB testing (if infection is suspected)

CT of chest, abdomen and pelvis (or MRI of chest, abdomen and pelvis if clinically indicated)

Tumor measurements

Histologic or cytologic confirmation of small cell/neuroendocrine tumors transformation from 
any certified laboratory (at any time point prior to enrollment). 

Documentation of initial EGFR mutation status which was determined using standard assays 
such as PCR and NGS (at any time point prior to enrollment).

Concomitant medication review

Pregnancy test for women of child bearing potential
2.3
Participant Registration and Status Update Procedures
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration 
& 
Status 
Updates 
found 
at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
2.3.1
Treatment Assignment Procedures
Cohorts
Number
Name
Description
1
Cohort 1
Subjects with EGFR-mutated transformed small cell lung cancer or 
neuroendocrine tumors.
Arms
Number
Name
Description
1
Arm 1
Combination of durvalumab and olaparib.
Arm assignment
Subjects in Cohort 1 will be directly assigned to Arm 1.
2.3.2
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details and eligibility criteria.
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
transient underlying condition not related to the condition under study may be rescreened once 
after the underlying condition has resolved.


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2.4
Baseline Evaluation
Tests done at screening do not need to be repeated on baseline if performed in designated time 
frame prior to start of study treatment.
Within 14 days prior to first dose:

CT of chest, abdomen and pelvis (if for clinical reason patient had MRI of chest, abdomen 
and pelvis at screening for evaluation of the disease, MRI will continue to be used for 
evaluation of disease during this trial) 

Tumor measurements

Optional tumor research biopsy

Baseline symptoms evaluation

Amylase, lipase

Collection of available unstained slides or a block from previous biopsies/surgeries for 
research

Collection of research blood for paraneoplastic autoantibodies assays and whole 
exome/genome sequencing 
3
STUDY IMPLEMENTATION
3.1
Study Design
The proposed study is an open label, single-arm phase II study of durvalumab in combination with 
olaparib, in patients with EGFR-mutated transformed small cell or neuroendocrine tumors.
Treatment with durvalumab and olaparib will be delivered in cycles consisting of 4 weeks (+/- 3 
days) and start on cycle 1 day 1. 
Durvalumab (1,500 mg) will be given IV every 28 days and olaparib (300 mg BID for total daily 
dose of 600 mg) will be administered orally on every day of every cycle.
Treatment will continue until off treatment criteria are met (see section 3.6.1)
If one of the study drugs is permanently discontinued because of toxicity, the patient may continue 
the other study drug per PI discretion until off treatment criteria are met (section 3.6.1). 
Patients will be monitored for disease status every 8 (+/- 1) weeks with imaging. 
Patients may undergo optional biopsies for research purposes at the following time points: 
pretreatment, on cycle 1 day 15 (+/- 4 days) and at disease progression.
3.2
Drug Administration
3.2.1
Durvalumab
Durvalumab will be administered IV into a peripheral or central vein on Day 1 of every cycle at a 
flat dose of 1,500 mg.
The entire contents of the 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. 


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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 (otherwise requires new infusion 
preparation).
The IV line will be flushed with a volume of 0.9% Sodium Chloride equal to the priming volume 
of the infusion set after the contents of the IV bag are fully administered 
In the event of a ≤ Grade 2 infusion-related reaction, the infusion rate of durvalumab 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 may be administered at the 
discretion of the investigator. If the infusion related reaction is ≥ Grade 3 in severity, durvalumab 
will be discontinued. 
As with any antibody, allergic reactions are possible. Therefore, 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.
3.2.2
Olaparib
Olaparib tablet will be administered at a total daily dose of 600 mg orally in two divided doses, 
approximately 12 hours apart. The dose should be taken at the same times each day with 
approximately 1 cup (240 mL) of water. Olaparib could be taken with or without regard to meals, 
with a light meal/snack (i.e. 2 pieces of toast or a couple of crackers).
The olaparib tablets should be swallowed whole and not chewed, crushed, dissolved or divided.
Missing up to 15% of the doses for any given cycle is allowed. 
Olaparib will be dispensed at the start of each cycle. Patients will be provided with a Medication 
Diary for olaparib (Appendix C), instructed in its use, and asked to bring the diary with them to 
each appointment.
If vomiting occurs shortly after the olaparib tablet is swallowed, the dose should only be replaced 
if the intact tablet can be seen. Should any patient miss a scheduled dose, the patient will be allowed 
to take the scheduled dose up to a maximum of 2 hours after that scheduled dose time. If greater 
than 2 hours after the scheduled dose time, the missed dose should not be taken, and the patient 
should take their allotted dose at the next scheduled time.
No routine prophylactic anti-emetic treatment is required at the start of study treatment. See 
Section 3.3.2.2 Management of nausea and vomiting. Patients will be provided with ondansetron 
and instructed to take 8 mg of ondansetron with small meal or snack to prevent nausea and 
vomiting approximately 30 minutes prior to each dose of olaparib if nausea or vomiting occurs 
and as required thereafter.
3.3
Dose Delay or Modifications
In case of unbearable toxicity definitely attributed to one of the study drugs, patient will be taken 
off this drug and per PI discretion may continue treatment with the other drug only.
For patients who are benefiting from combination therapy, since we don’t know which agent is 
driving the response (i.e. either of the drugs alone or the combination), in the event that one drug 


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is causing toxicities and have to be discontinued, it is reasonable to continue the other drug to see 
if the patient might benefit from it.
When, at the beginning of a treatment cycle, treatment delay related to one of the drug is indicated, 
treatment with the other drug may continue without delay per PI discretion. 
If, in the opinion of the investigator, a toxicity is considered to be due solely to one drug, the dose 
of the other drug does not require modification.
3.3.1
Durvalumab
Guidelines for the management of immune-mediated adverse events (imAE), infusion-related 
reactions, and non-immune-mediated reactions for durvalumab are provided in the durvalumab 
Toxicity Management Guidelines (TMGs). Please see Appendix D.
Patients should be thoroughly evaluated, and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered potentially 
immune related.
Following the first dose of durvalumab, subsequent administration of durvalumab can be modified 
based on toxicities observed as described in the Dosing Modification and Toxicity Management 
Guidelines in Appendix D. These guidelines have been prepared to assist the Investigator in the 
exercise of his/her clinical judgment in treating these types of toxicities. These guidelines apply to 
AEs considered causally related to durvalumab monotherapy by the reporting investigator.
3.3.2
Olaparib
Summary of dose holding/interruptions and dose de-escalation recommendations for olaparib in 
case of olaparib-related adverse events (graded according to NCI-CTCAE v5.0).
Any toxicity observed during the course of the study could be managed by interruption of the dose 
of study treatment or dose reductions. Repeat dose interruptions are allowed as required, for a 
maximum of 4 weeks on each occasion. Study treatment can be dose reduced to 250 mg twice 
daily as a first step and to 200 mg twice daily as a second step. If the reduced dose of 200 mg twice 
daily is not tolerable, no further dose reduction is allowed and treatment with olaparib should be 
discontinued. 
Once dose is reduced, escalation is not permitted (except following concomitant treatment with 
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3.3.2.1
Management of Hematological Toxicity
3.3.2.1.1 Management of Anemia
Table 2
Management of anemia
Haemoglobin
Action to be taken
Hb < 10 but ≥ 8 g/dl 
(CTCAE Grade 2)
First occurrence:
Give appropriate supportive treatment and investigate causality. 
Investigator judgement to continue olaparib with supportive treatment 
(e.g. transfusion) or interrupt dose for a maximum of 4 weeks. Study 
treatment can be restarted if Hb has recovered to > 9g/dl.
Subsequent occurrences:
If Hb< 10 but ≥ 9 g/dl investigator judgement to continue olaparib 
with supportive treatment (e.g. transfusion) or dose interrupt (for max 
of 4 weeks) and upon recovery dose reduction may be considered (to 
250 mg twice daily as a first step and to 200 mg twice daily as a 
second step).
If Hb< 9 but ≥ 8 g/dl, dose interrupt (for max of 4 weeks) until Hb ≥ 9 
g/dl and upon recovery dose reduction may be considered (to 250 mg 
twice daily as a first step and to 200 mg twice daily as a second 
step). 
Hb < 8 g/dl
(CTCAE Grade 3)
Give appropriate supportive treatment (e.g. transfusion) and 
investigate causality. 
Interrupt olaparib for a maximum of 4 weeks until improved to Hb ≥ 
9 g/dl.
Upon recovery dose reduce to 250 mg twice daily as a first step and 
to 200 mg twice daily as a second step in the case of repeat Hb 
decrease.
Common treatable causes of anemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed. In some cases, management 
of anemia may require blood transfusions. For cases where patients develop prolonged 
hematological toxicity (≥2-week interruption/delay in study treatment due to grade 3 or worse 
anemia and/or development of blood transfusion dependence), refer to section 3.3.2.1.3. 


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3.3.2.1.2 Management of Neutropenia, Leukopenia And Thrombocytopenia
Table 3
Management of Neutropenia, Leukopenia and Thrombocytopenia
Toxicity
Study treatment dose adjustment
CTCAE Grade 1-2
Investigator judgement to continue treatment or if dose interruption, 
this should be for a maximum of 4 weeks; appropriate supportive 
treatment and causality investigation
CTCAE Grade 3-4
Dose interruption until recovered to CTCAE gr 1 or better for a 
maximum of 4 weeks. If repeat CTCAE grade 3-4 occurrence, dose 
reduce olaparib to 250 mg twice daily as a first step and 200 mg 
twice daily as a second step
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 CTCAE 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 (7 days for pegylated G-CSF) of 
the last dose of study treatment unless absolutely necessary.
Platelet transfusions, if indicated, should be done according to local hospital guidelines.
For cases where patients develop prolonged hematological toxicity (≥2-week interruption/delay in 
study treatment due to CTCAE grade 3 or worse), refer to section 3.3.2.1.3. 
3.3.2.1.3 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 CTCAE grade 3 or worse anemia 
and/or development of blood transfusion dependence
≥2-week interruption/delay in study treatment due to CTCAE grade 3 or worse neutropenia 
(ANC < 1 x 109/L)
≥2-week interruption/delay in study treatment due to CTCAE grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (Platelets < 50 x 
109/L)
Check weekly differential blood counts including reticulocytes and peripheral blood smear. 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. Olaparib treatment should be discontinued if blood counts do not recover to CTCAE 
grade 1 or better within 4 weeks of dose interruption.
Olaparib treatment should be discontinued if patient’s diagnosis of MDS and/or AML is 
confirmed.


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3.3.2.2
Management of Non-Hematological Toxicity
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion. If 
the interruption is any longer than this the study Sponsor must be informed. Where toxicity 
reoccurs following re-challenge with study treatment, 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 study treatment.
Study treatment can be dose reduced to 250 mg twice daily as a first step and to 200 mg twice 
daily as a second step. Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 adverse 
event occurs which the investigator considers to be related to administration of study treatment.
Management of new or worsening pulmonary symptom
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormalities occur in 
the absence of a clear diagnosis, an interruption in study treatment dosing is recommended and 
further 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 study treatment can be restarted, if deemed appropriate by the investigator.
Management of nausea and vomiting
Events of nausea and vomiting are known to be associated with olaparib treatment. These events 
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 for nausea and 
within the first 6 months of treatment for vomiting. For nausea, the incidence generally plateaus 
at around 9 months, and for vomiting at around 6 to 7 months.
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. Alternatively, 
olaparib tablets can be taken with a light meal/snack (i.e. 2 pieces of toast or a couple of crackers).
As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), generally a 
single agent antiemetic should be considered e.g. dopamine receptor antagonist, antihistamines or 
dexamethasone.
Interruptions for intercurrent non-toxicity related events
Study treatment dose interruption for conditions other than toxicity resolution should be kept as 
short as possible. If a patient cannot restart study treatment within 4 weeks for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be discussed 
with AZ.
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF. 
Study treatment should be stopped at least 3 days prior to planned surgery. After surgery study 
treatment can be restarted when the wound has healed. No stoppage of study treatment is required 
for any needle biopsy procedure.


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Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
radiation treatment. Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered.
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, patients should 
be advised to use caution while driving or using machinery if these symptoms occur. 
Table 4 Dose reductions for study treatment
Initial Dose
Following re-challenge post 
interruption: 
Dose reduction 1
Dose reduction 2
300 mg twice daily
250 mg twice daily
200 mg twice daily
3.3.2.3
Renal Impairment
If subsequent to study entry and while still on study therapy, a patient’s estimated CrCl falls below 
the threshold for study inclusion (≥51 ml/min), retesting should be performed promptly. 
A dose reduction is recommended for patients who develop moderate renal impairment (creatinine 
clearance calculated per institutional standard or based on a 24-hour urine test of between 31 and 
50 ml/min) for any reason during the course of the study: the dose of olaparib should be reduced 
to 200 mg twice daily.
Because the CrCl determination is only an estimate of renal function, in instances where the CrCl 
falls to between 31 and 50 mL/min, the investigator should use his or her discretion in determining 
whether a dose change, or discontinuation of therapy is warranted.
Olaparib has not been studied in patients with severe renal impairment (creatinine clearance ≤ 30 
ml/min) or end-stage renal disease; if patients develop severe impairment or end stage disease is 
it recommended that olaparib be discontinued.


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3.4
Study Calendar
All Cycles
Cycle=28 
(+/- 3) days
Screening1
Baseline1 
Day 11
Day 
152
30 
Days 
Safety 
FU11, 13
Long 
Term 
FU12,13
Durvalumab3
X
Olaparib4
X4
Medical History
X
Height
X
Histologic confirmation of the disease 
X
EKG
X5
X
Physical exam, weight and ECOG
X
X
X
X
Vital Signs
X
X
X
X
Screening labs 6
X
Protocol labs 7
X
X
X
Amylase, lipase
X
X
APTT
X
X16
INR
X
 X16, 17
TB testing (if infection is suspected)
X
HIV, HBV, HCV viral load by PCR (if 
history of HIV, HBV, HCV)
X
CD4 count 15
X
Radiologic Evaluation8
X
X
X8
X
Tumor measurements8
X
X
X8
X
Serum or urine pregnancy test
X
X
X
X
Concomitant medications
X
X
X
Adverse event evaluation
X
X
X
Baseline symptoms evaluation
X
Bone marrow evaluation 18
X
Tumor biopsy9
X
X


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All Cycles
Cycle=28 
(+/- 3) days
Screening1
Baseline1 
Day 11
Day 
152
30 
Days 
Safety 
FU11, 13
Long 
Term 
FU12,13
Collection of available unstained slides 
or a block
X
Research blood for Immune subsets10
X10
X
Research blood for cytokine / 
chemokine 10
X10
X
Research blood for circulating tumor 
cells 10 
X10
X
Research blood for circulating tumor 
DNA 14 
X
X
Research blood for whole 
exome/genome sequencing
X
Research blood for transcriptome 10
X
X
Assays for paraneoplastic 
autoantibodies 
X
Research blood for NanoString Pan 
Cancer Immune Panel 10
X10
X10
Phone call or e-mail for survival every 
6 month
X
1 Baseline and C1D1 evaluations do not need to be repeated if performed at screening or baseline 
in designated time frame. All evaluations will be done within 7 days before treatment initiation on 
Day 1 of every cycle. If treatment does not start within 28 days after enrollment, screening 
evaluations will be repeated.
2 Day 15 (+/- 2 days) visit is only on Cycle 1
3 Durvalumab via IV infusion on Day 1 of each cycle. 
4 Olaparib PO, BID every day of every cycle. 
5 Three EKGs during screening
6 Laboratory Evaluation: CBC with differential, sodium, potassium, chloride, bicarbonate, BUN, 
glucose, albumin, calcium, magnesium, phosphorus, AST/ALT, total bilirubin, gamma glutamyl 
transferase, serum creatinine, PT/PTT, total protein, urine or serum HCG. Urinalysis: 
Hb/erythrocytes/blood, protein/albumin, glucose.


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7 Protocol labs: CBC with differential, Sodium, Potassium, Chloride, Bicarbonate, BUN, serum 
creatinine, glucose, albumin, calcium, magnesium, phosphorus, AST, ALT, alkaline phosphatase, 
total bilirubin, LDH, TSH, free T4, Urine protein to creatinine ratio (UPCR) or urinalysis, TBNK 
lymphocyte subsets, total protein. Urinalysis: Hb/erythrocytes/blood, protein/albumin, glucose
8 CT/MRI of chest, abdomen and pelvis at screening/baseline and every 8 (+/-1) weeks after start 
of study therapy. If patient is taken off treatment for reason other than disease progression, imaging 
will continue during follow-up until disease progression.
9 Optional tumor biopsies on baseline, cycle 1 day 15 (+/-4) days and at disease progression. 
Leftover sample from one of the biopsies may be used for disease confirmation.
10 Pre-treatment on cycle 1 day 1, cycle 1 day 15 and cycle 3 day 1, and at disease progression.
11 Follow up visit is planned to be performed at 30 (+/- 7) days after treatment discontinuation to 
evaluate patient’s safety. 
12 After safety FU visit, subjects will be followed every 6 months (± 1 month) for survival by 
phone call or e-mail. Note: if patients are taken off treatment for reason other than disease 
progression, they will be invited for imaging studies every 8 (+/-1) weeks during follow up period 
until disease progression. Outside images are acceptable. 
13 If subjects are not willing to come to NIH for FU visits, they will be contacted by phone call or 
e-mail or any other approved NIH platform in compliance with local policies) for survival and 
adverse events.
14 Research blood for circulating tumor DNA will be collected on cycle 1 day 1, cycle 1 day 15 
and day 1 of subsequent cycles
15 Patients with long-standing (>5 years) HIV on antiretroviral therapy > 1 month only
16 If clinically indicated
17 For patients taking warfarin it is recommended that INR be monitored carefully at least once per 
week for the first month, then monthly if the INR is stable.
18 Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
hematological toxicities. Bone marrow analysis should include an aspirate for cellular 
morphology, cytogenetic analysis and flow cytometry, and a core biopsy for bone marrow 
cellularity. If it is not possible to conduct cytogenetic analysis or flow cytometry on the bone 
marrow aspirate, then attempts should be made to carry out the tests on a blood sample.


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3.5
Cost and Compensation
3.5.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not covered 
by insurance company. Medicines that are not part of the study treatment will not be provided or 
paid for by the NIH Clinical Center.
3.5.2
Compensation
N/A
3.5.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation. Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate. The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.
3.6
Criteria for Removal from Protocol Therapy and Off Study Criteria
Prior to removal from study, efforts must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy.
3.6.1
Criteria for Removal from Protocol Therapy

Progressive disease 

Excessive toxicity (see section 3.3)

Patient request to be withdrawn from treatment

PI discretion

Positive pregnancy test

Drugs become unavailable
3.6.2
Off -Study Criteria

Death

Patient request to be withdrawn from study

PI discretion

Lost to follow up

PI decision to end the study

Permanent loss of capacity to consent

Screen failure
3.6.3
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff. 


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The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:

The site will attempt to contact the participant and reschedule the missed visits and counsel 
the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (telephone calls and if necessary, an IRB 
approved certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record 
or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
All routine and appropriate supportive care (including blood products) will be provided during this 
study, as clinically indicated, and in accordance with the standard of care practices. Clinical 
judgment should be utilized in the treatment of any AE experienced by the patient.
4.1
Prohibited Medications
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy (Hormone 
replacement therapy (HRT) is acceptable), radiotherapy (unless palliative), biological therapy or 
other novel agent) is to be permitted while the patient is receiving study medication. (Note: Patients 
may continue the use of bisphosphonates or denosumab for bone disease.) 
Live virus and live bacterial (including live attenuated) vaccines should not be administered while 
the patient is receiving study medication and during the 30-day follow up period. An increased 
risk of infection by the administration of live virus and bacterial vaccines has been observed with 
conventional chemotherapy drugs and the effects with olaparib are unknown.


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4.2
Restricted Concomitant Medications (See Appendix B - Inhibitors and Inducers of 
CYP3A4 for more complete list of Inhibitors and Inducers of CYP3A4)
Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which it is allowed ):
Strong CYP3A inhibitors: 
itraconazole, telithromycin, 
clarithromycin, boosted protease 
inhibitors, indinavir, saquinavir, 
nelfinavir, boceprevir, telaprevir
Moderate CYP3A inhibitors: 
ciprofloxacin, erythromycin, 
diltiazem, fluconazole, verapamil 
Strong or moderate CYP3A inhibitors should not be 
taken with olaparib. If there is no suitable alternative 
concomitant medication, then the dose of olaparib 
should be reduced for the period of concomitant 
administration. The dose reduction of olaparib should be 
recorded in the CRF with the reason documented as 
concomitant CYP3A inhibitor use. 
•
Strong CYP3A inhibitors – reduce the dose of 
olaparib to 100 mg twice daily for the duration 
of concomitant therapy with the strong inhibitor 
and for 5 half-lives afterwards.
•
Moderate CYP3A inhibitors - reduce the dose of 
olaparib to 150 mg twice daily for the duration 
of concomitant therapy with the moderate 
inhibitor and for 3 half-lives afterwards.
•
After the washout of the inhibitor is complete, 
the olaparib dose can be re-escalated.
Strong inducers: phenobarbital, 
phenytoin, rifampicin, rifabutin, 
rifapentine, carbamazepine, 
nevirapine, enzalutamide and St 
John’s Wort
Moderate CYP3A inducers: 
bosentan, efavirenz and modafinil
Strong or moderate CYP3A inducers should not be 
taken with olaparib.
If the use of any strong or moderate CYP3A inducers 
are considered necessary for the patient’s safety and 
welfare this could diminish the clinical efficacy of 
olaparib.
If a patient requires use of a strong or moderate CYP3A 
inducer, then they must be monitored carefully for any 
change in efficacy of olaparib


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Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which it is allowed ):

CYP3A4 substrates: 
hormonal contraceptive, 
simvastatin, cisapride, 
cyclosporine, ergot 
alkaloids, fentanyl, 
pimozide, sirolimus, 
tacrolimus and quetiapine

CYP2B6 substrates: 
bupropion, efavirenz

OATP1B1substrates: 
bosentan, glibenclamide, 
repaglinide, statins and 
valsartan

OCT1, MATE1 and 
MATE2K substrates: 
metformin

OCT2 substrates: serum 
creatinine

OAT3 substrates: 
furosemide, methotrexate
Effect of olaparib on other drugs
Based on limited in vitro data, olaparib may increase the 
exposure to substrates of CYP3A4, OATP1B1, OCT1, 
OCT2, OAT3, MATE1 and MATE2K.
 Based on limited in vitro data, olaparib may reduce the 
exposure to substrates of 2B6.
Caution should be observed if substrates of these 
isoenzymes or transporter proteins are co-administered.
Anticoagulant therapy
Patients who are taking warfarin may participate in this 
trial; however, it is recommended that international 
normalised ratio (INR) be monitored carefully at least 
once per week for the first month, then monthly if the 
INR is stable. Subcutaneous heparin and low molecular 
weight heparin are permitted.
Palliative radiotherapy
Palliative radiotherapy may be used for the treatment of 
pain at the site of bony metastases that were present at 
baseline, provided the investigator does not feel that 
these are indicative of clinical disease progression 
during the study period. Study treatment should be 
discontinued for a minimum of 3 days before a patient 
undergoes therapeutic palliative radiation treatment. 
Study treatment should be restarted within 4 weeks as 
long as any bone marrow toxicity has recovered. 


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Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which it is allowed ):
Administration of other anti-cancer 
agents
Patients must not receive any other concurrent anti-
cancer therapy, including investigational agents, while 
on study treatment. Patients may continue the use of 
bisphosphonates or denosumab for bone. 
Any natural/herbal products or 
other traditional remedies
The use should be discouraged, but use of these 
products, as well as any medication or vaccine including 
over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the patient is receiving at 
the time of enrolment or receives during the study must 
be recorded along with:

Reason for use

Dates of administration including start and end 
dates

Dosage information including dose and 
frequency
4.3
Methods of Contraception
4.3.1.1
Female Patient of Child-Bearing Potential
Female patients of childbearing potential who are not abstinent and intend to be sexually active 
with a non-sterilized male partner must use at least 1 highly effective method of contraception (see 
section 4.3.1.3) from the time of screening throughout the total duration of the protocol treatment 
and the drug washout period (6 months after the last dose of protocol therapy). Cessation of birth 
control after this point should be discussed with a responsible physician. Periodic abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of birth control.
Male partners of female patients (of childbearing potential) must also use a male condom plus 
spermicide or total/true abstinence throughout this period. 
Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral 
salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. 
Women will be considered post-menopausal if defined as: amenorrheic for 1 year or more 
following cessation of exogenous hormonal treatments; luteinizing hormone (LH) and follicle 
stimulating hormone (FSH) levels in the post-menopausal range for women under 50, radiation-
induced oophorectomy with last menses >1 year ago; chemotherapy-induced menopause with 
more than one-year interval since last menses; surgical sterilization (bilateral oophorectomy or 
hysterectomy).
4.3.1.2
Male Patients with a Female Partner of Childbearing Potential
Non-sterilized male patients who are not abstinent and intend to be sexually active with a pregnant 
woman or with a woman of childbearing potential must use a male condom plus spermicide or 
total/true abstinence from the time of screening throughout the total duration of the study treatment 
and at least 3 months after the last dose of study treatment). However, periodic abstinence, the 


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rhythm method, and the withdrawal method are not acceptable methods of contraception. Male 
patients should refrain from sperm donation throughout this period.
Female partners (of childbearing potential) of male patients must also use a highly effective 
method of contraception throughout this period (see section 4.3.1.3). 
4.3.1.3
Effective Methods
Acceptable non-hormonal birth control methods:

Total/true abstinence: When the patient refrains from any form of sexual intercourse and 
this is in line with their usual and/or preferred lifestyle; this must continue for the total 
duration of the study treatment and for at least 6 months (for female patients) or at least 3 
months (for male patients) after the last dose of study treatment. Periodic abstinence (eg, 
calendar ovulation, symptothermal, post-ovulation methods, or declaration of abstinence 
solely for the duration of a trial) and withdrawal are not acceptable methods of 
contraception.

Vasectomised sexual partner PLUS male condom (with participant assurance that partner 
received post-vasectomy confirmation of azoospermia).

Tubal occlusion PLUS male condom.

Intrauterine device (provided coils are copper-banded) PLUS male condom.
Acceptable hormonal methods:

Mini pill PLUS male condom: Progesterone-based oral contraceptive pill using 
desogestrel. Cerazette (Merck Sharp & Dohme) is currently the only highly efficacious 
progesterone-based pill available.

Combined pill PLUS male condom: Normal and low-dose combined oral pills.

Injection PLUS male condom: Medroxyprogesterone injection (eg, Depo-Provera 
[Pfizer]).

Implants PLUS male condom: Etonorgestrel-releasing implants (eg, Nexplanon [Merck 
Sharp & Dohme]).

Patch PLUS male condom: Norelgestromin/ethinyl estradiol transdermal system (eg, 
Xulane).

Intravaginal device (eg, ethinyl estradiol-/etonogestrel-releasing intravaginal devices such 
as NuvaRing [Merck Sharp & Dohme]) PLUS male condom.

Levonorgestrel-releasing intrauterine system (eg, Mirena [Bayer]) PLUS male condom.
5
CORRELATIVE STUDIES FOR RESEARCH
5.1
Biospecimen Collection
The primary goal of the correlative studies is to identify potential predictive biomarkers of 
response to immune checkpoint inhibition with a PARP inhibitor. Although PD-L1 expression in 
tumor was highly predictive of response to a PD-1 inhibitor, nivolumab in treatment-naive lung 
cancer patients (50% in PD-L1–positive patients v. 0% in PD-L1–negative patients), this was not 
the case for pretreated patients (15% in PD-L1–positive vs 14% in PD-L1–negative). Pretreatment 
biopsy samples will provide important information on development of predictive biomarkers in 
cancer patients. Other correlative study aims include investigation of proof-of-concept biomarkers 
of immune checkpoint inhibition and DNA damage repair inhibition in recurrent cancer. These 


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will be performed in an exploratory fashion.
Test/assay
Sample 
volume 
(approx.)
Type of tube a
Collection point
Location of 
specimen 
analysis
Immune subsets
16 mL 
blood
2 x 8 mL CPT: 
blue and black top
Pre-treatment C1D1
C1D15
C3D1
disease progression
DTB Clinical 
Translational 
Unit
Comprehensive 
cytokine / 
chemokine
20 mL 
blood
2 x 10 mL EDTA
tubes (lavender 
top)
Pre-treatment C1D1
C1D15
C3D1
disease progression
DTB Clinical 
Translational 
Unit
Enumeration of 
circulating tumor 
cells
20 mL 
blood
2 x 10 mL 10 ml 
CellSave
Pre-treatment C1D1
C1D15
C3D1
Disease progression
DTB Clinical 
Translational 
Unit
Assays for 
paraneoplastic 
autoantibodies
10 mL 
blood
10 mL red top tube Baseline
DTB Clinical 
Translational 
Unit
RNA sequencing 
and whole 
exome/genome 
sequencing
NA
Tumor sample
Pre-treatment C1D1
C1D15
DTB Clinical 
Translational 
Unit /NCI 
COMPASS 
Whole 
exome/genome 
sequencing
3 mL
blood
1 x 3 ml light blue 
citrate tube
Baseline
DTB Clinical 
Translational 
Unit / NCI 
COMPASS
Transcriptome 
2.5 mL 
blood
2.5 mL PAXgene 
RNA tube
Pre-treatment C1D1 
C1D15
C3D1
Disease progression
DTB Clinical 
Translational 
Unit
Circulating tumor 
DNA Profiles
10 mL 
blood
Cell-
free DNA BCT 
Streck tubes
C1D1
C1D15
Day 1 of 
subsequent cycles
DTB Clinical 
Translational 
Unit
NanoString Pan 
Cancer Immune 
Panel
2.5 mL 
blood
2.5 mL PAXgene 
RNA tube
Pre-treatment C1D1 
C1D15 
C3D1
Disease progression
DTB Clinical 
Translational 
Unit


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Test/assay
Sample 
volume 
(approx.)
Type of tube a
Collection point
Location of 
specimen 
analysis
a.
Please note that tubes and media may be substituted based on availability with the 
permission of the PI or laboratory investigator.
5.2
Collection of Samples
5.2.1
Blood
Blood samples will be collected at time points indicated in the Study Calendar 3.4. Blood samples 
will be sent to and processed by the DTB Clinical Translational Unit. 
5.2.2
Tumor samples
Optional baseline and post-treatment biopsies will be performed at time points indicated in Study 
Calendar 3.4. Frozen tumor samples will be procured by the DTB Clinical Translational Unit. 
Tissue for formalin fixation will be sent to the Laboratory of Pathology. Formalin-fixed samples 
will be analyzed for disease first, leftover will be used for research. 
5.3
Correlative Studies for Research 
5.3.1
Immune Subsets
PBMCs will be processed and stored at the DTB Clinical Translational Unit and will be assessed 
using multi-parameter flow cytometry for immune subsets including but not necessarily limited to 
Tregs, MDSC, effector and exhausted CD8+ T-cells. Assessment will include functional markers, 
i.e. PD-1, TIM3, CTLA-4 and/or CD40.
5.3.2
Comprehensive Cytokine / Chemokine
The cytokine analysis will be done at the DTB Clinical Translational Unit. 
5.3.3
Enumeration and Gene Expression of Circulating Tumor Cells
Blood will be collected to correlate changes in circulating tumor cells (CTC) [42] enumeration 
with clinical response. CTC will be investigated using ferrofluidic enrichment and multi-parameter 
flow cytometric detection. CTCs are identified by positive expression of epithelial markers and a 
viability marker and negative expression of hematopoietic markers. Immune markers including 
but not limited to functional markers, i.e. PD-1 or PD-L1 in CTC will be studied
5.3.4
Assays for Paraneoplastic Autoantibodies
SCLC is the most frequent cancer histology associated with paraneoplastic syndromes. SCLC 
associated paraneoplastic syndromes are thought to be related to immune-mediated tissue 
destruction due to neural antigen expression from cancer cells and are associated with more 
favorable outcomes [43]. One red top tube (10 ml) will be collected and frozen at baseline for 
future evaluation of paraneoplastic autoantibodies. The antibodies of interest include Anti-Hu, 
Anti-Ri, Anti-amphiphysin, antineuronal antibodies Ma1 and Ma2 and antiYo or anti-Purkinje cell 
antibody. Since these antibodies are not truly paraneoplastic antibodies, as they can also occur in 
the non-paraneoplastic setting, but their baseline levels will be of use in the work-up of patients 


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who develop paraneoplastic syndromes on the trial. The analysis will be done at the DTB Clinical 
Translational Unit.
5.4
Samples for Genetic/Genomic Analysis
5.4.1
RNA sequencing and whole exome/genome sequencing on tumor tissue and blood
Emerging data suggest that tumor mutational loads and neo-antigens may correlate with clinical 
response to immune checkpoint inhibition[44] [45]. It has been reported that mutated peptides 
resulting from DNA mutations are recognized by CD8+ T-cells and CD4+ T-cells in a large 
fraction of melanoma patients, and these neo-antigen-specific T cell responses are likely to 
contribute to the clinical effects of cancer immunotherapy[44] [46] [47]. Patient samples will 
undergo whole exome sequencing of tumor and normal (germline) DNA and RNA sequencing to 
elucidate DNA damage repair genes, the mutational loads resulting from mutations in genes 
involved in DNA damage repair pathways and potential neo-antigens as an exploratory endpoint.
5.4.2
Transcriptome Blood
In order to address the exploratory goal of characterizing predictive biomarkers of response, 
genomic analysis including but not limited to RNAseq may be performed.
5.4.3
Circulating Tumor DNA (ctDNA) Profiles
Subclone architecture and genomic evolution of SCLC under treatment has not been well studied 
primarily due to lack of tumor specimens because of the aggressiveness of the disease, particularly 
longitudinal samples acquired during treatment. Recent findings showed high concordance of 
ctDNA and metastatic tumor whole-exome sequencing [48]. Mean variant allele frequency of 
clonal mutations from pre-treatment ctDNA is associated with PFS and OS [49]. SCLC is 
characterized by early hematogenous spread, which makes ctDNA sequencing a promising 
modality for genomic profiling. Plasma samples from patients with SCLC may be used to quantify 
somatic variants in ctDNA. The ctDNA can detect genomic alterations including single nucleotide 
variants, copy number alterations, and insertions or deletions in genes that are frequently mutated 
in SCLC, including TP53, RB1, and others. These liquid biopsies can potentially improve disease 
subclassification, improve monitoring of disease burden and depth of response to treatment, and 
provide early warning of disease relapse in patients with SCLC.
5.4.4
NanoString Pan Cancer Immune Panel
 Peripheral blood will be analyzed for 730 immune genes and 40 control genes using the 
NanoString Pan Cancer Immune Panel.
5.4.5
Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the American 
College of Medical Genetics and Genomics recommendations for the return of incidental findings 
that is current at the time of primary analysis. (A list of current guidelines is maintained on the 
CCR intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists. 
Subjects will be contacted at that time with a request to provide a sample to be sent to a CLIA 
certified laboratory.
For additional information on consenting, ordering and results for samples analyzed through the 
NCI COMPASS Program, refer to CCR SOP ADGC-5, Tumor/Normal Whole Exome 


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Sequencing: Consenting, Ordering, and Obtaining Results found at 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825#CCRPolicies/Sta
ndardOperatingProcedures(SOPs)-ADGC. 
5.4.6
Genetic Counseling
If the research findings are verified in the CLIA certified lab, the subject will be offered the 
opportunity to come to NIH (at our expense) to have genetic education and counseling with the 
NCI Genetics Branch to explain this result. If the subject does not want to come to NIH, a referral 
to a local genetic healthcare provider will be provided (at their expense). This is the only time 
during the course of the study that incidental findings will be returned. No interrogations regarding 
clinically actionable findings will be made after the primary analysis
5.5
Sample Storage, Tracking and Disposition
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples 
will not be sent outside the National Institutes for Health (NIH) without appropriate approvals 
and/or agreements, if required. 
5.5.1
Procedures for Storage of Patient Samples in the DTB Clinical Translational Unit
Contact the Lab by email (Min-Jung Lee: min-jung.lee@nih.gov; and Sunmin Lee: 
leesun@mail.nih.gov) when the patient is scheduled and by phone as soon as the blood is drawn 
at 240-760-6330. A lab member will come to pick up the blood. Please keep blood at ambient 
temperature. Members of the lab will enter the samples into a secure password protected patient’s 
sample tracking database (Translational Pharmacodynamics Research Group Patient Sample 
Management System) and process the samples. 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol. It is critical that the 
sample remains coded and linked to patient information such as race, age, dates of diagnosis and 
death, and histological information about the tumor, in order to correlate with these variables.
Blood samples will be stored initially in the DTB Clinical Translational Unit in the Magnuson 
Clinical Center. If, at any time, a subject withdraws from the study and does not wish for their 
existing samples to be utilized, the individual must provide a written request. Following receipt of 
this request, the samples will be destroyed (or returned to the patient, if so requested).
When a patient withdraws consent the participant’s data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved.
The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will be 
made per the requirements of section 7.2 
5.5.2
Procedures for Storage of Tissue Specimens in the Laboratory of Pathology
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly, and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation. Unutilized excess tissue that is not embedded 
in paraffin is stored in formalin for up to three months, in accordance with College of American 
Pathologists/Joint Commission on Accreditation of Healthcare Organizations (CAP/JCAHO) 


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guidelines, and then discarded. Following completion of the diagnostic workup, the slides and 
tissue blocks are stored indefinitely in the LP’s clinical archives. All specimens are catalogued and 
retrieved utilizing the clinical laboratory information systems, in accordance with CAP/JCAHO 
regulations. The use of any stored specimens for research purposes is only allowed when the 
appropriate IRB approval has been obtained. In some cases, this approval has been obtained via 
the original protocol on which the patient was enrolled.
5.5.3
NCI COMPASS Program
Participants may undergo genetic analysis through the NCI COMPASS program for tumor-
normal exome and transcriptome. For additional information on consenting, ordering and results, 
refer to CCR SOP ADGC-5, Tumor/Normal Whole Exome Sequencing: Consenting, Ordering, 
and Obtaining Results found at 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 
5.5.4
Protocol Completion/Sample Destruction
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are 
remaining at the completion of the protocol will be stored in the conditions described in sections 
above. The study will remain open so long as sample or data analysis continues. Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed. 
If the patient withdraws consent the participant’s data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved.
The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will be 
per the requirements of section 7.2. 
6
DATA COLLECTION AND EVALUATION 
6.1
Data Collection
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and timeliness. 
The principal investigator, associate investigators/research nurses and/or a contracted data 
manager will assist with the data management efforts. Primary and final analyzed data will have 
identifiers so that research data can be attributed to an individual human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.
Document AEs from the first study intervention, Study Day 1 of Cycle 1 through 30 days after the 
study agent (s) was/were administered. Beyond 30 days after the last intervention, only adverse 
events which are serious and related to the study intervention need to be recorded.


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An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:
•
Results in discontinuation from the study
•
Is associated with clinical signs or symptoms 
•
Requires treatment or any other therapeutic intervention
•
Is associated with death or another serious adverse event, including hospitalization. 
•
Is judged by the Investigator to be of significant clinical impact
If any abnormal laboratory result is considered clinically significant, the investigator will provide 
details about the action taken with respect to the test drug and about the patient’s outcome.
Adverse Events of grade 1 will not be collected.
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1. 
6.1.1
Olaparib Adverse Events of Special Interest
Adverse events of special interest [AESI] are events of scientific and medical interest specific to 
the further understanding of Olaparib’s safety profile and require close monitoring and rapid 
communication by the investigators to AstraZeneca. Adverse Events of Special Interest for 
olaparib comprise the Important Identified Risk of MDS/AML, and the Important Potential Risks 
of new primary malignancy (other than MDS/AML) and pneumonitis. 
6.2
Data Sharing Plans
6.2.1
Human Data Sharing Plan
The PI will share coded linked human data generated in this research for future research 

in a NIH-funded or approved public repository clinicaltrials.gov and dbGaP

in BTRIS 

in publication and/or public presentations

with approved outside collaborators under appropriate agreements

at the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
6.3
Response Criteria
For the purposes of this study, patients should be re-evaluated for response every 8 weeks (+/- 1 
week).


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Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [50, 51]. Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria.
6.3.1
Disease Parameters
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as: 

By chest x-ray: >20 mm; 

By CT scan: 
o
Scan slice thickness 5 mm or under as >10 mm 
o
Scan slice thickness >5 mm: double the slice thickness 

With calipers on clinical exam: >10 mm. 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pneumonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions.
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease.


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Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or 
in rare cases unequivocal progression of each should be noted throughout follow-up.
6.3.2
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during 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.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
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). 
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 
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 during 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.
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response when 


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biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint.
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
6.3.3
Response Criteria
6.3.3.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum of diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study.
6.3.3.2
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator).
6.3.3.3
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 


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


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Non-Target Lesions
New Lesions
Overall Response
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised
6.3.3.4
Duration of Response
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.
6.4
Toxicity Criteria
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. 
All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy 
of 
the 
CTCAE 
version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50).
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
Definitions
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP Office of Compliance and Training / IRB Reporting
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 
Non-Compliance 
Human 
Subjects 
Research 
found 
at: 


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https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.3
NCI Clinical Director Reporting 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB will also be reported to the NCI 
Clinical Director/designee; therefore, a separate submission for these reports is not necessary.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease. 
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH Required Data and Safety Monitoring Plan
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a weekly basis when patients are being actively treated on 
the trial to discuss each patient. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in section 
7.2.1 will be submitted within the appropriate timelines. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.
8
CLINICAL MONITORING 
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through independent 
verification of study data with source documentation focusing on:

Informed consent process

Eligibility confirmation

Drug administration and accountability

Adverse events monitoring

Response assessment.
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center.


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This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct. 
9
STATISTICAL CONSIDERATIONS
9.1
Study Objectives
9.1.1
Primary Objective

To assess the efficacy of a combination of durvalumab and olaparib with respect to best 
overall response (BOR) according to Response Evaluation Criteria (RECIST 1.1) in 
patients with EGFR-mutated non-small-cell lung carcinoma that transform to SCLC and 
other neuroendocrine carcinomas. 
9.1.2
Secondary Objectives

To determine the progression-free survival (PFS)

To evaluate safety and tolerability of a combination of durvalumab and olaparib 

To determine overall survival (OS)
9.1.3
Exploratory Objectives

To study immune subsets and cytokine markers of response

To evaluate circulating tumor cells and circulating tumor DNA (ctDNA)

To study paraneoplastic autoantibodies

To perform whole exome sequencing of normal (germline) DNA

To perform molecular profiling of EGFR-mutated transformed small cell/neuroendocrine 
tumors by RNA sequencing and whole exome/genome sequencing of tumor tissue;

To evaluate transcriptome and NanoString Pan Cancer Immune Panel genes in blood.
9.2
Sample Size Determination
In patients with EGFR-mutated transformed SCLC and other neuroendocrine tumors, it would be 
desirable if the fraction of patients who are able to achieve a response were consistent with 25% 
and more than 5%. In this small pilot cohort of 12 evaluable patients who receive durvalumab and 
olaparib, if there are 2 or more who exhibited a clinical response, the probability of this occurring 
is 11.8% if the true probability of response is 5%, and 84.2% if the true probability of response is 
25%. In addition, the one-sided lower 90% confidence interval bound on 2/12 is 4.5% with 2/12 
responses, thus demonstrating marginally improved results compared to 5%, and the upper one-
sided 90% confidence interval bound on 2/12 is 38.6%, demonstrating consistency with 25%. Thus, 
if 2/12 (17%) or more of these patients achieve a response, this would be more consistent with 25% 
or more probability of this being the case than with 5% or less probability of this being the case, 
and thus would be considered an acceptable fraction.
It is expected that 12 evaluable patients can be accrued in 3 years. We will plan for a small number 
of inevaluable participants (2), intending to initiate intervention in up to 14 participants. Note: To 
allow for  screen failures, a total of 25 will be set for the purposes of the NIH accrual ceiling.


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9.3
Populations for Analyses
All patients who received at least one dose of both treatments and had at least one post-baseline 
tumor assessment will be evaluated for response. In addition, any treated patients who exhibited 
clinical progression before being evaluated for clinical response will be included in the analysis.
9.4
Statistical Analyses
9.4.1
General Approach
The clinical response rate of patients will be reported along with a confidence interval.
9.4.2
Analysis of the Primary Endpoints
The clinical response rate of evaluable patients will be reported along with a 95% confidence 
interval.
9.4.3
Analysis of the Secondary Endpoint
PFS and OS will be estimated by the Kaplan-Meier method. The median PFS and OS will be 
reported along with a 95% confidence interval.
9.4.4
Safety Analyses
Patients will be assessed for toxicity by reporting the grades of toxicity and the type of toxicity 
observed for all patients. 
9.4.5
Baseline Descriptive Statistics
Baseline demographic characteristics will be reported.
9.4.6
Planned Interim Analyses
None
9.4.7
Exploratory Analyses
Exploratory Objectives:

To study immune subsets and cytokine markers of response

To evaluate circulating tumor cells and circulating tumor DNA (ctDNA)

To study paraneoplastic autoantibodies

To perform whole exome sequencing of normal (germline) DNA

To perform molecular profiling of EGFR-mutated transformed small cell/neuroendocrine 
tumors by RNA sequencing and whole exome/genome sequencing of tumor tissue;

To evaluate transcriptome and NanoString Pan Cancer Immune Panel genes in blood.
Each these objectives will be evaluated in an exploratory fashion, with descriptive statistics 
obtained where appropriate. If any statistical tests are performed, the results will be reported 
without adjustment for multiple comparisons but may be reported in the context of the number of 
tests performed.


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10 COLLABORATIVE AGREEMENT
10.1 Clinical Trial Agreement
A CTA has been executed between NCI, NIH and AstraZeneca (CTA 1165). 
11  HUMAN SUBJECTS PROTECTIONS 
11.1 Rationale for Subject Selection
No individual who meets the criteria for eligibility will be excluded from participation based on 
their race, ethnicity, gender, or socioeconomic status. Particular attention will be made to acquire 
a broad and diversified population.
11.2 Participation of Children
Children (younger than 18 years) will not be included in this protocol due to the limited data on 
study drugs in children and the different biology of childhood malignancy.
11.3 Risk/Benefit Assessment for All Participants 
11.3.1 Known Potential Risks 
11.3.1.1 Study Drug Risks
The primary risk to patients participating in this research study is from the toxicity of study drugs.
All care will be taken to minimize study treatment side effects, but they can be unpredictable in 
nature and severity. Patients will be examined and evaluated prior to enrollment. All evaluations 
to monitor the treatment of patients will be recorded in the patient’s medical record. 
For risk information, refer to investigator brochures.
11.3.1.2 Risk of Biopsy
All care will be taken to minimize risks that may be incurred by tumor sampling. However, there 
are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained 
fully during informed consent.
Biopsies may be done under sedation. Potential side effects of sedation include headache, nausea 
and drowsiness. These side effects usually go away quickly.
11.3.1.3 Risks of Exposure to Ionizing Radiation 
This research study has three optional CT guided biopsies and 6 CTs. The amount of radiation 
exposure from these procedures is equal to approximately 9 rem.
11.3.1.4 Risks from CT contrast
Itching, hives or headaches are possible risks associated with contrast agents that may be used 
during CT imaging. Symptoms of a more serious allergic reaction include shortness of breath and 
swelling of the throat or other parts of the body. Very rarely, the contrast agents used in CT can 
cause kidney problems for certain participants, such as those with impaired kidney function.
11.3.1.5 Risks from Electrocardiograms
Other than possibly experiencing some minor skin irritation from the electrodes, there are no 
anticipated risks related to complete the electrocardiogram and/or the echocardiogram.


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11.3.1.6 Research Blood Collection Risks
Risks of blood draws include pain and bruising in the area where the needle is placed, 
lightheadedness, and rarely, fainting and infection. When large amounts of blood are collected, 
low red blood cell count (anemia) can develop. Up to 106 mL of blood may be collected at each 
visit with a maximum of 414 mL in an 8-week period.
11.3.1.7 Urine Collection Risks
There are no risks associated with urine collection.
11.3.1.8 MRI and MRI Contrast Risks
Participants are at risk for injury from the MRI magnet if they have metal in their body. There is 
a possibility that participants may experience claustrophobia. There are risks of back discomfort 
related to lying in the scanner. 
The most common side effects from MRI contrast (gadolinium) include injection site pain, 
nausea, itching, rash, headaches and dizziness. Serious but rare side effects such as gadolinium 
toxicity and nephrogenic systemic fibrosis, or NSF, are most often seen in individuals with 
severe kidney problems.
11.3.1.9 Other Risks
Risks include the possible occurrence of any of a range of side effects which are listed in the 
Consent Document or this protocol document. Frequent monitoring for adverse effects will help 
to minimize the risks associated with administration of the study agents.
11.3.1.10
Non-Physical Risks of Genetic Research
Risk of receiving unwanted information
Anxiety and stress may arise as a result of the anticipation that unwanted information regarding 
disease related DNA sequencing or disease tendencies, or misattributed paternity. Patients will be 
clearly informed that the data related to DNA sequencing and genetic analysis is coded, 
investigational and will not be shared with patients, family members or health care providers.
Risk related to possibility that information may be released
This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency 
or trait can be released to members of the public, insurers, employers, or law enforcement agencies. 
Although there are no plans to release results to the patients, family members or health care 
providers, this risk will be included in the informed consent document.
11.3.2 Known Potential Benefits
The study drugs may help to control the disease. The results may help the investigators learn more 
about the disease and develop new treatments for patients with this disease.
11.3.3 Assessment of Potential Risks and Benefits
SCLC and other neuroendocrine tumors treatment need improved therapy options. Current studies 
suggest that combination of durvalumab and olaparib may have tremendous anti-tumor efficacy. 
A number of clinically appropriate strategies to minimize risks to patients have been built into the 
protocol through the means of inclusion/exclusion criteria, monitoring strategies, and management 


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guidelines. Overall, the potential benefit of the combination of durvalumab and olaparib in subjects 
with solid tumors outweigh the risks associated with this drug.
The potential benefit to a patient that participates in this study is better control of their tumor 
growth and disease recurrence which may or may not have a favorable impact on symptoms and/or 
survival.
Potential adverse reactions attributable to the administration of the study drugs utilized in this trial 
are discussed in the package inserts. All care will be taken to minimize side effects, but they can 
be unpredictable in nature and severity.
11.4 Consent Process and Documentation
The informed consent document will be provided as a physical or electronic document to the 
participant for review prior to consenting. A designated study investigator will carefully explain 
the procedures and tests involved in this study, and the associated risks, discomforts and benefits. 
In order to minimize potential coercion, as much time as is needed to review the document will be 
given, including an opportunity to discuss it with friends, family members and/or other advisors, 
and to ask questions of any designated study investigator. A signed informed consent document 
will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant. Whether in person or remote, the privacy of the subject will be 
maintained. Consenting investigators (and participant, when in person) will be located in a private 
area (e.g., clinic consult room). When consent is conducted remotely, the participant will be 
informed of the private nature of the discussion and will be encouraged to relocate to a more private 
setting if needed. 
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document. When required, witness signature will be 
obtained similarly as described for the investigator and participant.
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the following to obtain the required signatures:

Adobe platform (which is not 21 CFR Part 11 compliant); or, 

iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the same 
screen may be used when in the same location but is not required. 
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) 
found 
at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.


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12 REGULATORY AND OPERATIONAL CONSIDERATIONS
12.1 Study Discontinuation and Closure
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
associate investigators and regulatory authorities. If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional 
Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension. 
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping 

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA).
12.2 Quality Assurance and Quality Control
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Council for Harmonisation 
Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities.
12.3 Conflict of Interest Policy
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 


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a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial. The study leadership in conjunction with the NCI has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest.
12.4 Confidentiality and Privacy
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records.
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by the clinical site(s) and by NCI CCR research staff will be secured and password protected. At 
the end of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants.


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13 PHARMACEUTICAL INFORMATION
13.1 Durvalumab (IMFINZI) 
For detailed information, refer to investigator brochure.
13.1.1 Source/Acquisition and Accountability
Commercial supplies of durvalumab (IMFINZI) will be supplied by AstraZeneca Inc. and 
delivered directly to the NIH Pharmacy. Individual IV bags will be prepared for each study 
participant according to assigned dose by NIH Pharmacy personnel. IV bags will be delivered from 
NIH Pharmacy to patient unit where drug will be infused to the patient.
13.1.2 Administration Procedures
Refer to section 3.2.1.
13.2 Olaparib (LYNPARZA)
For detailed information, refer to investigator brochure.
13.2.1 Source/Acquisition and Accountability
Commercial supplies of olaparib (LYNPARZA) will be supplied by AstraZeneca and delivered 
directly to the NIH Pharmacy. Individual bottles with tablets will be prepared for each study 
participant according to assigned dose by NIH Pharmacy personnel. Patients will pick up bottles 
at NIH Pharmacy and will return bottles and not-used tablets after completion of every cycle 
together with Medication Diary to Study Coordinator. After review of leftover tablets and 
Medication Diary, unused tablets will be returned to pharmacy and disposed by pharmacy 
personnel.
13.2.2 Administration Procedures
See Section 3.2.2.


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Thomas, A., et al., Durvalumab in Combination with Olaparib in Patients with Relapsed 
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Inc. . 2011-2012. 1810-1818 


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


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15.2 Appendix B - Inhibitors and Inducers of CYP3A4
CYP3A4 INDUCERS (PROHIBITED)
Armodafenil1 
Barbiturates2 
Bosentan1 
Carbamazepine 
Dexamethasone1 
Efavirenz 
Fosphenytoin1 
Glucocorticoids2 (see note) 
Modafinil2 
Nafcillin1 
Nevirapine 
Oxcarbazepine 
Pentobarbital1 
Phenobarbital 
Phenytoin 
Pioglitazone2 
Primidone1 
Rifabutin 
Rifampin 
Rifapentine1 
St. John’s wort2 
Troglitazone3 
Note: Topical steroids are permitted. Please contact overall PI if systemic steroids are clinically indicated 
while on trial. 
1 Cited in [52] 
2 Cited in Flockhart Table http://medicine.iupui.edu/clinpharm/ddis/table.asp. 
3 Weak inhibitors per Lacy et al. May be used with caution. 
Note: Drugs without a superscript are cited in both the Lacy and Flockhart references.
CYP3A4 INHIBITORS 
Strong Inhibitors 
(prohibited)
Moderate Inhibitors
(use with caution, avoid if 
possible)
Weak Inhibitors
(use with caution, avoid if 
possible)
Amprenavir1 
Atazanavir1 
Clarithromycin 
Conivaptan1 
Delavirdine1 
Fosamprenavir1 
Fospropofol1 
Imatinib1 
Indinavir 
Isoniazid1 
Itraconazole 
Ketoconazole 
Miconazole1 
Nefazodone 
Nelfinavir 
Nicardipine1 
Posaconazole1 
Propofol1 
Quinidine1 
Amiodarone1 
Aprepitant 
Cimetidine1 
Clotrimazole1 
Cyclosporine1 
Desipramine1 
Doxycycline1 
Efavirenz1 
Erythromycin 
Fluconazole 
Fosaprepitant1 
Grapefruit juice 
Haloperidol1 
Lidocaine1 
Metronidazole1 
Norfloxacin1 
Sertraline1 
Tetracycline1 
Verapamil 
Chloramphenicol2 
Ciprofloxacin2 
Diethyldithiocarbamate2 
Fluvoxamine2 
Gestodene2 
Mibefradil2 
Mifepristone 
Norfluoxetine2 
Star fruit2 
Troleandomycin2 


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Strong Inhibitors 
(prohibited)
Moderate Inhibitors
(use with caution, avoid if 
possible)
Weak Inhibitors
(use with caution, avoid if 
possible)
Ritonavir 
Saquinavir2 
Telithromycin 
Voriconazole1 
1 Cited in [52] 
2 Cited in Flockhart Table http://medicine.iupui.edu/clinpharm/ddis/table.asp. 
Note: Drugs without a superscript are cited in both the Lacy and Flockhart references.
CYP3A4 Substrates (allowed – take note of possible interactions)
Alfentanil 
Alfuzosin 
Alprazolam 
Ambrisentan 
Amiodarone 
Amlodipine 
Aprepitant 
Aripiprazole 
Armodafinil 
Astemizole2 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Budesonide 
Buprenorphine 
Buspirone 
Busulfan 
Cafergot2 
Caffeine2 
Carbamazepine 
Cerivastatin2 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Ciclesonide 
Cilostazol 
Cisapride 
Dexlansoprazole 
Dextromethorphan2 
Diazepam 
Dihydroergotamine 
Diltiazem 
Disopyramide 
Docetaxel 
Domperidone2 
Doxorubicin 
Eletriptan 
Efavirenz 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erlotinib 
Erythromycin 
Escitalopram 
Esomeprazole 
Estradiol 
Estrogens conjugated 
synthetic 
Estrogens, conjugated 
equine 
Estrogens esterified 
Estropipate 
Eszopiclone 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestane 
Felbamate 
Isradipine 
Itraconazole 
Ixabepilone 
Ketamine 
Ketoconazole 
Lansoprazole 
Lapatinib 
Lercanidipine2 
Levonorgestrel 
Lidocaine 
Lovastatin2 
Lopinavir 
Maraviroc 
Medroxyprogesterone 
Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methylprednisolone 
Miconazole 
Midazolam 
Mirtazapine 
Modafinil 
Montelukast 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nilotinib 
Nimodipine 
Ranolazine 
Rifabutin 
Repaglinide 
Risperidone2 
Ritonavir 
Salmeterol 
Saquinavir 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Solifenacin 
Spiramycin 
Sufentanil 
Sunitinib 
Tacrolimus 
Tadalafil 
Tamoxifen 
Tamsulosin 
Temsirolimus 
Telithromycin 
Teniposide 
Terfenadine2 
Testosterone2 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tinidazole 
Tipranavir 
Tolterodine 
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CYP3A4 Substrates (allowed – take note of possible interactions)
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Codeine2 
Colchicine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Darifenacin 
Darunavir 
Dasatinib 
Delavirdine 
Dexamethasone 
Felodipine 
Fentanyl 
Finasteride2 
Flunisolide 
Flurazepam 
Flutamide 
Fluticasone 
Fosamprenavir 
Fosaprepitant 
Gefitinib 
Haloperidol 
Hydrocortisone2 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide dinitrate 
Isosorbide mononitrate 
Nitrendipine2 
Nisoldipine 
Norethindrone 
Norgestrel 
Omeprazole 
Ondansetron 
Paclitaxel 
Paricalcitol 
Pazopanib 
Pimozide 
Primaquine 
Propranolol2 
Progesterone 
Quazepam 
Quetiapine 
Quinidine 
Quinine 
Rabeprazole 
Tramadol 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zaleplon2 
Ziprasidone2 
Zolpidem 
Zonisamide 
Zopiclone 
* Note: [52] 
** Substrates cited in Flockhart Table http://medicine.iupui.edu/clinpharm/ddis/table.asp. Accessed Nov 
2011 


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15.3 Appendix C - Patient’s Medication Diary ________________________
Cycle___________________ Patient’s ID ___________________
INSTRUCTIONS TO THE PATIENT:
1.
Complete one form for each cycle of treatment
2.
You will take olaparib twice a day every day during 28-day cycle
3.
Record the date and time you took the tablets and the number of tablets that you took.
4.
If you have any comments or notice any side effects, please record them in the comments column.
5.
Please bring this form and your bottles (even they are empty) when you come for your clinic 
visits.
Oral olaparib 
(every 12 hours)
Day
Date
Time
# of 
Tablets
Time
# of 
Tablets
Comments
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15


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Oral olaparib 
(every 12 hours)
Day
Date
Time
# of 
Tablets
Time
# of 
Tablets
Comments
16
17
18
19
20
21
22
23
24
25
26
27
28
Patient’s signature: ___________________________________________________


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15.4 Appendix D - Dosing Modification and Toxicity Management Guidelines (TMGs) for Durvalumab Monotherapy, 
Durvalumab in Combination with other Products, or Tremelimumab Monotherapy –September 2023
General Considerations Regarding Immune-Mediated Reactions
These guidelines are provided as a recommendation to support investigators in the management of potential immune-mediated adverse events (imAEs). 
Immune-mediated events can occur in nearly any organ or tissue, therefore, these guidelines may not include all the possible immune-mediated reactions. Investigators are 
advised to take into consideration the appropriate practice guidelines and other society guidelines (e.g., National Comprehensive Cancer Network (NCCN), European 
Society of Medical Oncology (ESMO)) in the management of these events. Refer to the section of the table titled “Other -Immune-Mediated Reactions” for general guidance 
on imAEs not noted in the “Specific Immune-Mediated Reactions” section.
Early identification and management of imAEs is essential to ensure safe use of the study drug. Monitor patients closely for symptoms and signs that may be clinical 
manifestations of underlying imAEs. Patients with suspected imAEs should be thoroughly evaluated to rule out any alternative etiologies (e.g., disease progression, 
concomitant medications, infections). In the absence of a clear alternative etiology, all such events should be managed as if they were immune-mediated. Institute medical 
management promptly, including specialty consultation as appropriate. In general, withhold study drug/study regimen for severe (Grade 3) imAEs. Permanently discontinue 
study drug/study regimen for life-threatening (Grade 4) imAEs, recurrent severe (Grade 3) imAEs that require systemic immunosuppressive treatment, or an inability to 
reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids. 
Based on the severity of the imAE, durvalumab and/or tremelimumab should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroid 
should be tapered over ≥ 28 days. More potent immunosuppressive agents should be considered for events not responding to systemic steroids. Alternative 
immunosuppressive agents not listed in this guideline may be considered at the discretion of the investigator based on clinical practice and relevant guidelines. With long-
term steroid and other immunosuppressive use, consider the need for glucose monitoring.
Dose modifications of study drug/study regimen should be based on severity of treatment-emergent toxicities graded per NCI CTCAE version in the applicable study 
protocol.
Considerations for Prophylaxis for Long Term use of Steroids for Patients Receiving Immune Checkpoint Inhibitor Immunotherapy

Infection Prophylaxis: Pneumocystis jirovecii pneumonia (PJP), antifungal and Herpes Zoster reactivation

Gastritis: Consider prophylaxis for patients at high risk of gastritis (e.g. NSAID use, anticoagulation) when the patient is taking steroid therapy

Osteoporosis: Consider measures for prevention and mitigation of osteoporosis .
Relevant Society Guidelines for Management of imAEs
These society guidelines are provided as references to serve in support of best clinical practice and the TMGs. Please note, these were the current versions of these 
guidelines at the time of updating TMGs. Please refer to the most up to date version of these guidelines.
1.
Brahmer JR, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother 
Cancer 2021;9:e002435
2.
Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical 
Oncology (ASCO) Guideline Update. J Clin Oncol 2022;39:4073-4126.
3.
Haanen J, et al. Management of toxicities from immunotherapy: European Society for Medical Oncology (ESMO) clinical practice guidelines for diagnosis, 
treatment, and follow-up. Annals Oncol 2022;33 (12):1217-1238.


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General Considerations Regarding Immune-Mediated Reactions
4.
Sangro B, et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol 2020;72(2):320-341.
5.
Thompson JA, et al. National Comprehensive Cancer Network Guidelines: Management of immunotherapy-related toxicities version1.2022. Published February 
28, 2022.
Pediatric Considerations Regarding Immune-Mediated Reactions
Dose Modifications
Toxicity Management
The criteria for permanent discontinuation of study drug/study regimen based on 
CTCAE grade/severity is the same for pediatric patients as it is for adult patients, 
as well as to permanently discontinue study drug/study regimen if unable to reduce 
corticosteroid ≤ a dose equivalent to that required for corticosteroid replacement 
therapy within 12 weeks of initiating corticosteroids. 
−
All recommendations for specialist consultation should occur with a 
pediatric specialist in the specialty recommended.
−
The recommendations for steroid dosing (i.e., mg/kg/day) provided for adult 
patients should also be used for pediatric patients.
−
The recommendations for intravenous immunoglobulin (IVIG) and 
plasmapheresis use provided for adult patients may be considered for 
pediatric patients.
−
The infliximab 5 mg/kg IV one time dose recommended for adults is the 
same as recommended for pediatric patients ≥ 6 years old. For subsequent 
dosing and dosing in children < 6 years old, consult a pediatric specialist.
−
For pediatric dosing of mycophenolate mofetil, consult a pediatric specialist.
−
With long-term steroid and other immunosuppressive use, consider need for 
PJP prophylaxis, gastrointestinal protection, and glucose monitoring.


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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology with similar 
clinical presentation (e.g. infection, 
progressive disease).
−
Monitor patients for signs (e.g. tachypnoea) 
and symptoms of pneumonitis or ILD (new 
onset or worsening shortness of breath or 
cough). Evaluate patients with imaging and 
pulmonary function tests, including other 
diagnostic procedures as described below. 
−
Suspected pneumonitis should be confirmed 
with radiographic imaging and other 
infectious and disease-related etiologies 
excluded, and managed as described below.
−
Initial work-up may include clinical 
evaluation, monitoring of oxygenation via 
pulse oximetry (resting and exertion), 
laboratory work-up (including clinically 
relevant culture specimens to rule out 
infection), and high- resolution computed 
tomography (CT) scan.
−
Consider Pulmonary and Infectious Diseases 
consults.
Grade 1
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 
−
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.
Pneumonitis/Interstitial 
Lung Disease (ILD)
Grade 2
Hold study drug/study regimen dose until Grade 2 resolution to 
Grade ≤1.

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 
For Grade 2
−
Monitor symptoms daily and consider 
hospitalization as clinically indicated.
−
Consider Pulmonary and Infectious Diseases 
Consults.


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completion of steroid taper (<10 mg prednisone or 
equivalent).
−
Promptly start systemic steroids (e.g., 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent).
−
Consider HRCT or chest CT with contrast, 
Repeat imaging as clinically indicated.
−
If no improvement within 2 to 3 days, 
additional workup should be considered and 
prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
started.
−
If no improvement within 2 to 3 days despite 
IV methylprednisolone at 2 to 4 mg/kg/day, 
promptly start immunosuppressive therapy. 
such as tumor necrosis factor (TNF) 
inhibitors (e.g., infliximab at 5 mg/kg IV 
once, may be repeated at 2 and 6 weeks after 
initial dose at the discretion of the treating 
provider or relevant practice guidelines). 
Caution: It is important to rule out sepsis and 
refer to infliximab label for general guidance 
before using infliximab. 
−
Consider discussing with Clinical Study 
Lead.
Grade 3 or 4
Permanently discontinue study drug/study regimen.
For Grade 3 or 4
−
Hospitalize the patient
−
Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day or 
equivalent.
−
Obtain Pulmonary and Infectious Diseases 
Consults; consider discussing with Clinical 
Study Lead, as needed.
−
Consider starting anti-infective therapy if 
infection is still a consideration on the basis 
of other diagnostic testing despite negative 
culture results
−
Supportive care (e.g., oxygen).
−
If no improvement within 2 days, additional 
workup should be considered and prompt 
treatment with additional 
immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg IV, 


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may be repeated at 2 and 6 weeks after 
initial dose at the discretion of the treating 
provider or relevant practice guidelines). 
Caution: rule out sepsis and refer to 
infliximab label for general guidance before 
using infliximab.
Diarrhea/Colitis
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade
−
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.
−
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (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).
−
Consider further evaluation with imaging 
study with contrast.
−
Consult a gastrointestinal (GI) specialist for 
consideration of further workup
−
WHEN SYMPTOMS OR EVALUATION 
INDICATE AN INTESTINAL 
PERFORATION IS SUSPECTED, 
CONSULT A SURGEON 
EXPERIENCED IN ABDOMINAL 
SURGERY IMMEDIATELY WITHOUT 
ANY DELAY. 
−
PERMANENTLY DISCONTINUE 
STUDY DRUG FOR ANY GRADE OF 
INTESTINAL PERFORATION. 
−
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 events, including 
intestinal perforation. 
−
Use analgesics carefully; they can mask 
symptoms of perforation and peritonitis.


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Grade 1
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), loperamide, and other 
supportive care measures. 
−
If symptoms persist, consider checking 
lactoferrin and/or calprotectin; if positive, 
treat as Grade 2 below. If negative and no 
infection, continue Grade 1 management.
Grade 2
Hold study drug/study regimen until resolution to Grade ≤1

If toxicity improves to Grade ≤1, then study drug/study 
regimen can be resumed after completion of steroid taper 
(<10 mg prednisone, or equivalent).
For Grade 2
−
Consider symptomatic treatment, including 
hydration, electrolyte replacement, dietary 
changes (e.g., American Dietetic Association 
colitis diet), and loperamide and/or 
budesonide.
−
Consider further evaluation with imaging 
study with contrast.
−
Consider consult of a gastrointestinal (GI) 
specialist for consideration of further 
workup.
−
Promptly start prednisone 1 to 2 mg/kg/day 
PO or IV equivalent.
−
If no improvement within 3 days despite 
therapy with 1 to 2 mg/kg IV prednisone 
equivalent, reconsult GI specialist and, if 
indicated, promptly start additional 
immunosuppressant agent such as infliximab 
at 5 mg/kg IV, may be repeated at 2 and 6 
weeks after initial dose at the discretion of 
the treating provider or relevant practice 
guidelines. Caution: it is important 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.
−
Consider, as necessary, discussing with 
Clinical Study Lead if no resolution to Grade 
≤1 in 3 to 4 days.


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Grade 3 or 4
Grade 3

For patients treated with durvalumab monotherapy, 
hold study drug/study regimen until resolution to 
Grade ≤1; study drug/study regimen can be resumed 
after completion of steroid taper (<10 mg prednisone 
per day, or equivalent). 

For patients treated with durvalumab in combination 
with other products (not tremelimumab), decision to 
be made at the discretion of the study investigator, in 
discussion with AstraZeneca Clinical Study Lead.

For patients treated with durvalumab in 
combination with tremelimumab or 
tremelimumab monotherapy:
A. Permanently discontinue tremelimumab for 
Grade 3 diarrhea/colitis. HOLD durvalumab 
until resolution to Grade < 1; durvalumab alone 
can be resumed after completion of steroid taper 
(<10 mg prednisone per day or equivalent)
B. Permanently discontinue both durvalumab and 
tremelimumab for 1) Grade 4 diarrhea colitis or 
2) Any grade of intestinal perforation. 
Grade 4 
Permanently discontinue study drug/study regimen.
For Grade 3 or 4
−
Urgent GI consult and imaging and/or 
colonoscopy as appropriate.
−
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent.
−
Monitor stool frequency and volume and 
maintain hydration.
−
If still no improvement within 2 days, 
continue steroids and promptly add further 
immunosuppressants. (e.g., infliximab at 5 
mg/kg IV, may be repeated at 2 and 6 weeks 
after initial dose at the discretion of the 
treating provider or relevant practice 
guidelines). 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.
Hepatitis 
Infliximab should not 
be used for 
management of 
immune-related 
hepatitis.
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., viral 
hepatitis, disease progression, concomitant 
medications).
−
Monitor and evaluate transaminases 
(aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], alkaline 
phosphatase [ALP], and total bilirubin.
PLEASE SEE


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ALT or AST ≤ 3 x 
ULN or total 
bilirubin ≤ 1.5 x 
ULN

No dose modifications.

If it worsens, then consider holding therapy.
−
Continue transaminase and total bilirubin 
monitoring per protocol.
ALT or AST > 3 ≤ 5 
x ULN or total 
bilirubin > 1.5 ≤ 3 x 
ULN 

Hold study drug/study regimen dose until ALT or AST ≤ 3 
x ULN or total bilirubin ≤ 1.5 x ULN. Resume study 
drug/study regimen after completion of steroid taper (<10 
mg prednisone or equivalent).

Permanently discontinue study drug/study regimen for any 
case meeting Hy’s law laboratory criteria (AST or ALT 
>3 × ULN AND bilirubin >2 × ULN without initial 
findings of cholestasis (i.e., elevated ALP) and in the 
absence of any alternative cause.
−
Regular and frequent checking of 
transaminases and total bilirubin (e.g., every 
1 to 2 days) until LFT elevations improve or 
resolve.
−
Consider checking creatinine phosphokinase 
(CPK) and aldolase (to rule out myositis).
−
If no resolution to ALT or AST ≤ 3 x ULN 
or total bilirubin ≤ 1.5 x ULN in 1 to 2 days, 
consider discussing with Clinical Study 
Lead, as needed.
−
If event is persistent (>2 to 3 days) or 
worsens, promptly start prednisone 1 to 
2 mg/kg/day PO or IV equivalent.
ALT or AST > 5-≤ 
10 x ULN

Hold study drug/study regimen . Resume study drug/study 
regimen if elevations downgrade to ALT or AST ≤ 3 x 
ULN or total bilirubin ≤ 1.5 x ULN after completion of 
steroid taper (<10 mg prednisone, or equivalent). 

If in combination with tremelimumab, do not restart 
tremelimumab.
−
Promptly initiate empiric IV 
methylprednisolone at 1 to 2 mg/kg/day or 
equivalent.
−
Check CPK and aldolase (to rule out 
myositis).
−
Perform Hepatology Consult, abdominal 
workup, and imaging as appropriate
−
If still no improvement within 2 to 3 days 
despite 1 to 2 mg/kg/day methylprednisolone 
IV or equivalent, promptly start treatment 
with an additional immunosuppressant.(e.g., 
mycophenolate mofetil 0.5 – 1 g every 12 
hours then taper in consultation with 
hepatology consult or relevant practice 
guidelines). Discuss with Clinical Study Lead 
if mycophenolate is not available. Infliximab 
should NOT be used.


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Concurrent ALT or
AST > 3 x ULN and
total bilirubin
> 2 x ULN d
ALT or AST
> 10 x ULN OR total
bilirubin > 3 x
ULN
Permanently discontinue study drug/study regimen.
−
Promptly initiate empiric IV 
methylprednisolone at 1 to 2 mg/kg/day 
or equivalent.
−
If still no improvement within 2 to 3 days 
despite 1 to 2 mg/kg/day 
methylprednisolone IV or equivalent, 
promptly start treatment with an 
additional immunosuppressant.(e.g., 
mycophenolate mofetil 0.5 – 1 g every 12 
hours then taper in consultation with 
hepatology consult or relevant practice 
guidelines). Discuss with Clinical Study 
Lead if mycophenolate is not available. 
Infliximab should NOT be used.
−
Perform Hepatology Consult, abdominal 
workup, and imaging as appropriate.
Hepatitis 
(elevated transaminases 
and total
bilirubin)
Infliximab should not 
be used for 
management of 
immune-related 
hepatitis. 
Any Elevations of 
AST, ALT, or T. Bili 
as Described Below
General Guidance
For Any Elevations Described
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., viral 
hepatitis, disease progression, concomitant 
medications, worsening of liver cirrhosis 
[e.g., portal vein thrombosis]).
−
Monitor and evaluate liver function test: 
AST, ALT, ALP, and T. Bili.
−
For hepatitis B (HBV) + patients: evaluate 
quantitative HBV viral load, quantitative 
Hepatitis B surface antigen (HBsAg), or 
Hepatitis B envelope antigen (HBeAg).
−
For hepatitis C (HCV) + patients: evaluate 
quantitative HCV viral load.
−
Consider consulting Hepatology or 
Infectious Diseases specialists regarding 
changing or starting antiviral HBV 
medications if HBV viral load is >2000 
IU/ml.
−
Consider consulting Hepatology or 
Infectious Diseases specialists regarding 
changing or starting antiviral HCV 
medications if HCV viral load has increased 
by ≥2-fold.
THIS shaded area 
is guidance only for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients (or 
secondary tumour 
involvement of the 
liver with abnormal 
baseline values 
[BLV])


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−
For HCV+ with Hepatitis B core antibody 
(HBcAb) +: Evaluate for both HBV and 
HCV as above.
 Isolated AST or ALT 
>ULN and ≤2.5 BLV 

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
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
 Isolated AST or ALT 
>2.5 BLV and 
≤5×BLV and ≤ 20 
ULN

Hold study drug/study regimen dose until resolution to 
AST or ALT ≤2.5×BLV.

If toxicity worsens, then treat as described for elevations in 
the rows below. If toxicity improves to AST or ALT 
≤2.5×BLV, resume study drug/study regimen after 
completion of steroid taper (<10 mg prednisone, or 
equivalent).
−
Regular and frequent checking of 
Transaminases and total bilirubin (e.g., 
every 1 to 3 days) until elevations of these 
are improving or resolved.
−
Consider checking creatinine phosphokinase 
(CPK) and aldolase (to rule out myositis).

Recommend consult hepatologist; consider 
abdominal ultrasound, including Doppler 
assessment of liver perfusion.
−
Consider, as necessary, discussing with 
Clinical Study Lead.
−
If event is persistent (>2 to 3 days) or 
worsens, and investigator suspects toxicity 
to be an imAE, start prednisone 1 to 
2 mg/kg/day PO or IV equivalent.
−
If still no improvement within 2 to 3 days 
despite 1 to 2 mg/kg/day of prednisone PO 
or IV equivalent, consider additional 
workup. If still no improvement within 2 to 
3 days despite 2mg/kg/day of IV 
methylprednisolone, consider additional 
abdominal workup (including liver biopsy) 
and imaging (i.e., liver ultrasound), and 
consider starting additional 
immunosuppressants. (e.g., mycophenolate 
mofetil 0.5 – 1 g every 12 hours then taper in 


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consultation with hepatology consult or 
relevant practice guidelines). Discuss 
Clinical Study Lead if mycophenolate 
mofetil is not available. Infliximab should 
NOT be used.
ALT or AST
>5-7X BLV and ≤ 
20X ULN OR 
concurrent 2.5-5X 
BLV and ≤20XULN 
and total bilirubin > 
1.5 - < 2 x ULN d

Withhold durvalumab and permanently discontinue 
tremelimumab 

Resume study drug/study regimen if elevations 
downgrade to AST or ALT ≤2.5×BLV and after 
completion of steroid taper (<10 mg prednisone, or 
equivalent).

Permanently discontinue study drug/study regimen if the 
elevations do not downgrade to AST or ALT ≤2.5×BLV 
within 14 days
−
Regular and frequent checking of LFTs (e.g., 
every 1-2 days) until elevations of these are 
improving or resolved.
−
Check CPK and aldolase (to rule out 
myositis)
−
Consult hepatologist (unless investigator is 
hepatologist); obtain abdominal ultrasound, 
including Doppler assessment of liver 
perfusion; and consider liver biopsy.
−
Consider discussing with Clinical Study 
Lead, as needed.
−
If investigator suspects toxicity to be 
immune-mediated, promptly initiate empiric 
IV methylprednisolone at 1 to 2 mg/kg/day 
or equivalent.
−
If no improvement within 2 to 3 days despite 
1 to 2 mg/kg/day methylprednisolone IV or 
equivalent, obtain liver biopsy (if it has not 
been done already) and promptly start 
treatment with an additional 
immunosuppressant. (e.g. mycophenolate 
mofetil 0.5 – 1 g every 12 hours then taper in 
consultation with a hepatologist or relevant 
practice guidelines). Discuss with Study 
Clinical Lead if mycophenolate is not 
available. Infliximab should NOT be used.
 ALT or AST
> 7 X BLV OR > 20
ULN whichever 
occurs
first OR bilirubin >
3ULN 
Permanently discontinue study drug/study regimen.
Same as above 
(except recommend obtaining liver biopsy early)


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Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression, infections, recent IV 
contrast, medications, fluid status).
−
Consider Consulting a nephrologist.
−
Consider imaging studies to rule out any 
alternative etiology.
−
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, decreased urine 
output, or proteinuria).
−
Follow urine protein/creatinine ratio every 3-
7 days.
Grade 1
No dose modifications.
For Grade 1
−
Monitor serum creatinine weekly and any 
accompanying symptoms.

If creatinine returns to baseline, 
resume its regular monitoring per 
study protocol.

If creatinine worsens, depending 
on the severity, treat as Grade 2, 3, 
or 4.
−
Consider hydration, electrolyte replacement, 
and diuretics, as clinically indicated.
−
Consider nephrologist consult if not resolved 
within 14 days, or earlier as clinically 
indicated
Nephritis and/or renal 
dysfunction
Grade 2
Hold study drug/study regimen until resolution to Grade ≤1 or 
baseline. 

If toxicity improves to Grade ≤1 or baseline, then resume 
study drug/study regimen after completion of steroid taper 
(<10 mg prednisone, or equivalent).
For Grade 2
−
Consider including hydration, electrolyte 
replacement, and diuretics as clinically 
indicated.
−
Follow urine protein/creatinine ratio every 3-
7 days.
−
Carefully monitor serum creatinine and as 
clinically warranted.


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−
Consult nephrologist and consider renal 
biopsy if clinically indicated.
−
Start prednisone 0.5 – 1 mg/kg/day if other 
causes are ruled out.
−
If event is persistent beyond 5 days or 
worsens, increase to prednisone up to 2 
mg/kg/day PO or IV equivalent.
−
If event is not responsive within 5 days or 
worsens despite prednisone at 1 to 2 
mg/kg/day PO or IV equivalent, consider 
additional workup. 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 daily.
−
Follow urine protein/creatinine ratio every 3-
7 days.
−
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 
of steroids or worsens despite prednisone at 
1 to 2 mg/kg/day PO or IV equivalent, 
consider additional workup and prompt 
treatment with an immunosuppressant.
Dermatologic Adverse 
Events
(Including Pemphigoid)
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
definition of 
severity/grade 
depending on type of 
skin rash)
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology.
−
Monitor for signs and symptoms of 
dermatitis (rash and pruritus).
−
HOLD STUDY DRUG IF GRADE 3 
PEMPHIGOID OR SEVERE 
CUTANEOUS ADVERSE REACTION 
(SCAR) IS SUSPECTED. 
−
PERMANENTLY DISCONTINUE 
STUDY DRUG IF SCAR OR GRADE 3 
PEMPHIGOID IS CONFIRMED.


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Grade 1
No dose modifications.
For Grade 1
−
Consider symptomatic treatment, including 
oral antipruritics (e.g., diphenhydramine or 
hydroxyzine) and topical therapy 
(e.g., emolient, lotion, or institutional 
standard).
Grade 2
For persistent (>1 week) Grade 2 events, hold scheduled study 
drug/study regimen until resolution to Grade ≤1 or baseline.

If toxicity improves to Grade ≤1 or baseline, then resume 
drug/study regimen after completion of steroid taper (<10 
mg prednisone, or equivalent).
For Grade 2
−
Consider dermatology consult and skin 
biopsy, as indicated.
−
Consider symptomatic treatment, including 
oral antipruritics (e.g., diphenhydramine or 
hydroxyzine) and topical therapy 
−
Consider moderate-strength topical steroid.
−
If no improvement of rash/skin lesions 
occurs within 1 week or is worsening despite 
symptomatic treatment and/or use of 
moderate strength topical steroid, consider 
discussing with Clinical Study Lead, as 
needed, and promptly start systemic steroids 
such as prednisone 1 to 2 mg/kg/day PO or 
IV equivalent.
Grade 3
For Grade 3

Hold study drug/study regimen until resolution to Grade 
≤1 or baseline.

If toxicity improves to Grade ≤1 or baseline, then resume 
drug/study regimen after completion of steroid taper (<10 
mg prednisone, or equivalent).
 
For Grade 3
−
Reconsult dermatologist. Consider skin 
biopsy (preferably more than 1) as clinically 
feasible. 
−
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent.
−
Consider hospitalization.
−
Monitor the extent of rash [Rule of Nines].
−
Consider, as necessary, discussing with 
Clinical Study Lead.


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Grade 4
For Grade 4
Permanently discontinue study drug/study regimen.
For Grade 4
−
Reconsult a dermatologist. Consider skin 
biopsy (preferably more
−
than 1) as clinically feasible.
−
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent.
−
Consider hospitalization.
−
Monitor the extent of rash [Rule of Nines].
Consider, as necessary, discussing with Clinical Study 
Lead.
Endocrinopathy
(e.g., hyperthyroidism, 
thyroiditis, 
hypothyroidism, type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency)
Any Grade
(Depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression including brain 
metastases, or infections).
−
Consider consulting an endocrinologist for 
endocrine events.
−
Consider discussing with Clinical Study 
Lead, as needed.
−
Monitor patients for signs and symptoms of 
endocrinopathies. (Non-specific symptoms 
include headache, fatigue, behaviour 
changes, mental status changes, 
photophobia, visual field cuts, vertigo, 
abdominal pain, unusual bowel habits, 
polydipsia, polyuria, hypotension, and 
weakness.)
−
Depending on the suspected endocrinopathy, 
monitor and evaluate thyroid function tests: 
thyroid stimulating hormone (TSH), free T3 
and free T4 and other relevant endocrine and 
related labs (e.g., blood glucose and ketone 
levels, hemoglobin A1c (HgA1c)). 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 


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send a blood sample for appropriate 
autoimmune antibody testing.
−
Investigators should ask subjects with 
endocrinopathies who may require 
prolonged or continued hormonal 
replacement, to consult their primary care 
physicians or endocrinologists about further 
monitoring and treatment after completion of 
the study.
Grade 1
No dose modifications.
For Grade 1
−
Monitor patient with appropriate endocrine 
function tests.
−
For suspected hypophysitis/hypopituitarism, 
consider consulting an endocrinologist to 
guide assessment of early-morning 
adrenocorticotropin hormone (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 of range in 2 subsequent 
measurements, include free T4 at subsequent 
cycles as clinically indicated and consider 
consultation of an endocrinologist.
Grade 2, 3, or 4

For Grade 2-4 endocrinopathies other than hypothyroidism 
and type 1 diabetes mellitus (T1DM), consider holding 
study drug/study regimen dose until acute symptoms 
resolve.

Study drug/study regimen can be resumed once patient 
stabilizes and after completion of steroid taper (<10 mg 
prednisone, or equivalent).

Patients with endocrinopathies who may require prolonged 
or continued steroid replacement (e.g., adrenal 
insufficiency) can be retreated with study drug/study 
For Grade 2, 3, or 4 
−
Consult endocrinologist to guide evaluation 
of endocrine function and, as indicated by 
suspected endocrinopathy and as clinically 
indicated, consider pituitary scan.
−
For all patients with abnormal endocrine 
work up, except those with isolated 
hypothyroidism or T1DM, 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.
−
Isolated hypothyroidism may be treated 
with replacement therapy, without study 


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regimen if the patient is clinically stable as per investigator 
or treating physician’s clinical judgement.
drug/study regimen interruption, and 
without corticosteroids.
−
Isolated T1DM may be treated with 
appropriate diabetic therapy, and without 
corticosteroids. Only hold study 
drug/study regimen in setting of 
hyperglycemia when diagnostic workup is 
positive for diabetic ketoacidosis. 
−
For patients with normal endocrine workup 
(laboratory assessment or magnetic 
resonance imaging (MRI) scans), repeat 
laboratory assessments/MRI as clinically 
indicated.
Amylase/Lipase 
increased
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
Grade 1
No dose modifications.
Grade 2, 3, or 4
For Grade 2, 3, or 4
In consultation with relevant gastroenterology specialist, 
consider continuing study drug/study regimen if no 
clinical/radiologic evidence of pancreatitis ± improvement in 
amylase/lipase.
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g. disease 
progression, viral infection, concomitant 
medications, substance abuse).
−
For modest asymptomatic elevations in 
serum amylase and lipase, corticosteroid 
treatment is not indicated as long as there are 
no other signs or symptoms of pancreatic 
inflammation. 
−
Assess for signs/symptoms of pancreatitis 
−
Consider appropriate diagnostic testing (e.g., 
abdominal CT with contrast, MRCP if 
clinical suspicion of pancreatitis and no 
radiologic evidence on CT)
−
If isolated elevation of enzymes without 
evidence of pancreatitis, continue 
immunotherapy. Consider other causes of 
elevated amylase/lipase
−
If evidence of pancreatitis, manage 
according to pancreatitis recommendations 
Acute Pancreatitis
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology.
−
Consider Gastroenterology referral 


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defining the CTCAE 
grade/severity)
Grade 2
Consider holding study drug/regimen.
Grade 2
−
Consider IV hydration
−
Consider Gastroenterology referral
Grade 3, or 4
For Grade 3
Hold study drug/study regimen until resolution of elevated 
enzymes and no radiologic findings.
If no elevation in enzymes or return to baseline values, then 
resume study drug/study regimen after completion of steroid 
taper (<10 mg prednisone, or equivalent).
For Grade 4
Permanently discontinue study drug/study regimen.
For Grade 3, or 4
−
Promptly start systemic steroids 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent.
−
IV hydration
Nervous System Disorders
Aseptic Meningitis
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
−
Symptoms may include headache, photophobia, and 
neck stiffness, nausea/ vomiting which may resemble 
an infectious meningitis.
−
Patients may be febrile.
−
Mental status should be normal
For Any Grade
−
Consider neurology consult
−
Consider MRI brain with and without 
contrast with pituitary protocol and a lumbar 
puncture for diagnosis.
−
Exclude bacterial and viral infections. (ie 
HSV)
−
Consider antibiotic for bacterial coverage 
until cultures/panel results are back
−
Consider IV acyclovir until polymerase 
chain reactions are available
Any Grade
Permanently discontinue study drug/study regimen
For Any Grade
−
Consider neurology consult


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−
Consider MRI brain with and without 
contrast with pituitary protocol and a lumbar 
puncture for diagnosis.
−
Exclude bacterial and viral infections. (ie 
HSV)
−
Consider IV acyclovir until polymerase 
chain reactions are available
−
Consider, as necessary, discussing with 
Clinical Study Lead.
−
Consider hospitalization.
−
Once infection has been ruled out promptly 
initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent.
Encephalitis
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
− Symptoms may include Confusion, altered behaviour, 
headaches, seizures, short-term memory loss, depressed level 
of consciousness, focal weakness, and speech abnormality.
For Any Grade 
−
Consider neurology consult
−
Consider testing including MRI of the brain 
with and without contrast, lumbar puncture, 
electroencephalogram (EEG) to evaluate for 
subclinical seizures, ESR, CRP, 
antineutrophil cytoplasmic antibody 
(ANCA) (if vasculitic process suspected), 
thyroid panel including TPO and 
thyroglobulin and additional autoantibodies 
to rule out paraneoplastic disorders.
−
Exclude bacterial and viral infections. (i.e.
−
HSV)Consider IV acyclovir until 
polymerase chain reactions are available.
Grade 2
For Grade 2
Permanently discontinue study drug/study regimen.
For Grade 2
−
Consider, as necessary, discussing with the 
Clinical Study Lead.
−
Once infection has been ruled out 
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−
For progressive symptoms or if oligoclonal 
bands are present consider 
methylprednisolone 1 g IV daily for 3–5 days 
plus IVIG or plasmapheresis
Grade 3 or 4
For Grade 3 or 4
Permanently discontinue study drug/study regimen.
For Grade 3 or 4
−
Consider, as necessary, discussing with 
Clinical Study Lead.
−
Consider hospitalization.
−
Once infection is ruled out, start 
methylprednisolone 1 g IV daily for 3–5 
days for progressive symptoms consider 
adding IVIG or plasmapheresis 
Demyelinating Disease 
(optic neuritis, 
transverse myelitis, 
acute demyelinating 
encephalomyelitis 
(ADEM))
Any Grade
General Guidance
−
Permanently discontinue 
immunotherapy
−
Consider MRI of the spine and brain
−
Once imaging is complete, consider lumbar 
puncture
Consider testing to rule out additional aetiologies: B12, 
copper, HIV, rapid plasma reagin (RPR), ANA, anti-
Ro/La antibodies, aquaporin-4 IgG, myelin 
oligodendrocyte glycoprotein (MOG) IgG, 
paraneoplastic panel
For Any Grade
−
Consider neurology consult
−
Inpatient care
−
Consider prompt 
initiation of high 
methylprednisolone 
pulse dosing
−
Strongly consider IVIG or plasmapheresis
Peripheral neuropathy
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade
−
Patients should be evaluated to rule out any 
alternative etiology for neuropathy (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 


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its treatments) throughout the neuraxis. 
Given the importance of prompt and 
accurate diagnosis, it is essential to have a 
low threshold to obtain a neurological 
consult.
−
Neurophysiologic diagnostic testing 
(e.g., electromyogram and nerve conduction 
investigations) are routinely indicated upon 
suspicion of such conditions and may be best 
facilitated by means of a neurology 
consultation.
Grade 1
No dose modifications.
For Grade 1
−
Consider discussing with the Clinical Study 
Lead, as needed.
−
Monitor symptoms for interference with 
ADLS, gait difficulties, imbalance, or 
autonomic dysfunction
Grade 2
Hold study drug/study regimen dose until resolution to Grade 
≤1.
For Grade 2
−
Consult a neurologist.
−
Consider EMG/NCS
−
Consider discussing with the Clinical Study 
Lead, as needed.
−
Observation for additional symptoms 
decompensation or consider initiating 
prednisone 0.5–1 mg/kg orally
−
− If progression, initiate methylprednisolone 
2–4 mg/kg/day and treat as GBS.
−
Sensory neuropathy/neuropathic pain may 
be managed by appropriate medications 
(e.g., gabapentin or duloxetine).
Grade 3 or 4
For Grade 3 or 4
Permanently discontinue study drug/study regimen.
For Grade 3 or 4 
−
Consider discussing with Clinical Study 
Lead, as needed.
−
Recommend hospitalization.


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−
Monitor symptoms and consult a 
neurologist.
−
Treat per Guillain-Barré Syndrome 
recommendations
Guillain-Barré 
Syndrome (GBS)
General Guidance
−
Recommend hospitalization
−
Obtain neurology consult
−
Obtain MRI of spine to rule out compression 
lesion
−
Obtain lumbar puncture
−
Antibody tests for GBS variants
−
Pulmonary function tests
−
Obtain electromyography (EMG) 
and nerve conduction studies
−
Frequently monitor pulmonary function 
tests and neurologic evaluations
−
Monitor for concurrent autonomic 
dysfunction
−
Initiate medication as needed for neuropathic 
pain
Grade 2-4
Grade 2-4
Permanently discontinue
Start IVIG or plasmapheresis in addition to 
methylprednisolone 1 gram daily for 5 days, then 
taper over 4 weeks.
Myasthenia gravis
General Guidance
−
Obtain neurology consult
−
Recommend hospitalization
−
Obtain pulmonary function tests
−
Obtain labs: ESR, CRP, creatine 
phosphokinase (CPK), aldolase and anti-
striational antibodies
−
Consider cardiac exam, ECG, troponin, 
transthoracic echocardiogram for possible 
concomitant myocarditis
−
Obtain electromyography (EMG) and nerve 
conduction studies
−
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CNS involvement by disease
−
Avoid medications that might exacerbate MG 
(e.g. beta blockers, some antibiotics, IV 
magnesium)
Grade 2
Permanently discontinue
−
Consider pyridostigmine 30mg three times 
daily and gradually increase based on 
symptoms (max dose 120mg four times 
daily)
−
Consider starting low dose prednisone 20mg 
daily and increase every 3-5 days. (Target 
dose 1mg/kg/day. Max dose 100mg daily)
Grade 3-4
Permanently discontinue
−
Start methylprednisolone 1-
2mg/kg/day. Taper steroids based on 
symptom improvement
−
Start plasmapheresis or IVIG
−
Consider rituximab if refractory to 
plasmapheresis or IVIG
−
Frequent PFT assessments
−
Daily neurologic evaluations
Myocarditis
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
Discontinue drug permanently if biopsy-proven immune-
mediated myocarditis.
For Any Grade
−
Initial work-up should include clinical 
evaluation, B-type natriuretic peptide (BNP), 
cardiac enzymes, electrocardiogram (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)
−
The prompt diagnosis of immune-mediated 
myocarditis is important, particularly in 
patients with baseline cardiopulmonary 
disease and reduced cardiac function. 
−
Consider discussing with the Clinical Study 
Lead, as needed.


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−
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). Consult a 
cardiologist early, to promptly assess 
whether and when to complete a cardiac 
biopsy, including any other diagnostic 
procedures.
−
as indicated. Spiral CT or cardiac MRI can 
complement ECHO to assess wall motion 
abnormalities when needed. 
Grade 2, 3 or 4

If Grade 2-4, permanently discontinue study 
drug/study regimen.
For Grade 2-4
−
Monitor symptoms daily, hospitalize.
−
Consider cardiology consultation and a 
prompt start of high-dose/pulse 
corticosteroid therapy
−
Supportive care (e.g., oxygen).
−
If no improvement consider additional 
immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab), IVIG or 
plasmapheresis or other therapies depending 
on the clinical condition of the patient, based 
on at the discretion of the treating specialist 
consultant or relevant practice guidelines. 
Caution: It is important to rule out sepsis 
and refer to infliximab label for general 
guidance before using infliximab. 
Infliximab is contraindicated for patients 
who have heart failure.
 Myositis/ Polymyositis 
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression, other medications, or 
infections).


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defining the CTCAE 
grade/severity)
−
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, 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 
Clinical Study Lead.
−
Consider that patients may present with or 
progress to rhabdomyolysis. Treat signs and 
symptoms as per institutional protocol or 
local clinical practice.
−
Initial work-up should include clinical 
evaluation, creatine kinase, aldolase, lactate 
dehydrogenase (LDH), blood urea nitrogen 
(BUN)/creatinine, erythrocyte sedimentation 
rate or C-reactive protein (CRP) 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 


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conduction studies, MRI of the muscles, 
and/or a muscle biopsy. Consider Barium 
swallow for evaluation of dysphagia or 
dysphonia.
Grade 1

No dose modifications.
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 
Clinical Study Lead.
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.
For Grade 2
−
Monitor symptoms daily and consider 
hospitalization.
−
Consider Rheumatology or Neurology 
consult, and initiate evaluation.
−
Consider, as necessary, discussing with the 
Clinical Study Lead.
−
If clinical course is rapidly progressive 
(particularly if difficulty breathing and/or 
trouble swallowing), promptly 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 2 to 3 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 days, consider additional 
immunosuppressive therapy such as a TNF 
inhibitor (e.g., infliximab ) IVIG or 
plasmapheresis, or other therapies based on 
the discretion of the specialist consultant or 
relevant practice guideline. Caution: It is 
important to rule out sepsis and refer to 


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infliximab label for general guidance 
before using infliximab.
Grade 3 
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 3 
−
Monitor symptoms closely; recommend 
hospitalization.
−
Consider Rheumatology or Neurology 
consult
−
Consider discussing with the Clinical Study 
Lead, as needed.
−
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 improvement within 
2 to 3 days, consider starting another 
immunosuppressive therapy such as a TNF 
inhibitor (e.g., infliximab at 5 mg/kg IV, 
may be repeated at 2 and 6 weeks after 
initial dose at the discretion of the treating 
provider or relevant practice guidelines). 
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.
Grade 4
For Grade 4
Permanently discontinue study drug/study regimen.
Grade 4
−
Monitor symptoms closely; recommend 
hospitalization.
−
Consider Rheumatology and/or Neurology 
consult
−
Consider discussing with the Clinical Study 
Lead, as needed.
−
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 
improvement within 2 to 3 days, 
consider starting another 


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1 SCAR terms include Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Erythema Multiforme, Acute Generalized Exanthematous Pustulosis, Drug Reaction 
with Eosinophilia and Systemic Symptoms (DRESS) and Drug-induced hypersensitivity syndrome.
immunosuppressive therapy such as a 
TNF inhibitor (e.g., infliximab at 5 
mg/kg IV, may be repeated at 2 and 6 
weeks after initial dose at the discretion 
of the treating provider or relevant 
practice guidelines). Caution: It is 
important to rule out sepsis and refer 
to infliximab label for general guidance 
before using infliximab.


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Other–Immune-Mediated Reactions
Severity Grade of the Event 
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTCAE 
grade/severity)
Dose Modifications
Toxicity Management
Any Grade
Note: It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all 
organs, some of them are not noted specifically in these 
guidelines (e.g. immune thrombocytopenia, haemolytic 
anaemia, uveitis, vasculitis).
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections). 
−
The Clinical Study Lead may be contacted for immune-
mediated reactions not listed in the “specific immune-
mediated reactions” section
−
Consultation with relevant specialist
−
Treat accordingly, as per institutional standard.
Grade 1
No dose modifications.
Monitor as clinically indicated
Grade 2

Hold study drug/study regimen until resolution to 
≤Grade 1 or baseline.

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.

Consider whether study drug/study regimen should be 
permanently discontinued in Grade 2 events with high 
likelihood for morbidity and/or mortality when they 
do not rapidly improve to Grade <1 upon treatment 
with systemic steroids and following full taper
Grade 3
Hold study drug/study regimen until resolution to Grade 
<1 or baseline 
Grade 4
Permanently discontinue study drug/study regimen 
For Grade 2, 3, or 4
Treat accordingly, as per institutional standard, appropriate 
clinical practice guidelines, and society guidelines. (See 
page 4).
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 Clinical Study Lead.”


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Infusion-Related Reactions
Severity Grade of the Event 
(Refer to NCI CTCAE 
applicable version in study 
protocol for defining the 
CTCAE grade/severity)
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 or study protocol 
prior to subsequent doses.
−
Consider steroids for patients who have previously experienced 
infusion reaction; use of steroid premedication may be permitted in 
these situations.
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 standard, 
appropriate clinical practice guidelines, and society guidelines. 


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Non-Immune-Mediated Reactions
Severity Grade of the Event 
(Refer to NCI CTCAE 
applicable version in study 
protocol for defining the 
CTCAE grade/severity)
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 2-3
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline.
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 Clinical Study Lead.”

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/11/2024
Page 1 of 24
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: Anish Thomas, M.D.
STUDY TITLE:
Phase II Trial of Olaparib (LYNPARZA) plus Durvalumab 
(IMFINZI) 
in 
EGFR-Mutated 
Adenocarcinomas 
that 
Transform to Small Cell Lung Cancer (SCLC) and Other 
Neuroendocrine Tumors
STUDY SITE: 
NIH Clinical Center
Cohort: 
Affected patient
Consent Version:
03/11/2024
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Anish Thomas, MD, by phone at 240-760-6241 or email anish.thomas@nih.gov
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study. 
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. Additional information that may help you make 
a decision can be found in other sections of the document. Taking part in research at the NIH is 
your choice.
You are being asked to take part in this study because you had EGFR-mutated non-small-cell 
lung carcinoma (NSCLC) that was treated and now transformed to small cell lung carcinoma or 
another neuroendocrine tumor.
The purpose of this study is to see if combination of durvalumab and olaparib will cause your 
tumors to shrink. 
The use of durvalumab and olaparib in this study is considered investigational which means this 
combination has not been approved by the U.S. Food and Drug Administration (FDA) to treat 
small cell lung carcinoma or other neuroendocrine tumors. However, the FDA has given us 
permission to use durvalumab and olaparib in this study. 
Durvalumab has been approved by FDA to treat non-small cell lung cancer (NSCLC) and other 
cancers. Durvalumab is designed to boost the body’s immune system by targeting a protein on 
tumor cells called PD-L1. PD-L1 usually helps the immune system work properly. In cancer, 
PD-L1 helps tumors avoid being seen and destroyed by the immune system. Durvalumab may 
increase the immune system’s ability to find and destroy cancer cells. 
Olaparib has been approved by FDA to treat other cancers besides the one that we are studying. 
Olaparib belongs to group of drugs called PARP inhibitors that target and block several 
pathways needed for cancer cells to grow and cause cancer cells to die.
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/11/2024
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
There are other standard of care drugs and/or procedures that may be used to treat your disease, 
and these can be given to you by your regular cancer doctor if you are not in this study. For 
example: there is chemotherapy and radiation therapy. You can also participate in another 
clinical trial using drugs called immune checkpoint inhibitors (such as cabozantinib or 
pembrolizumab). The treatment given in this study and the known possible side effects may or 
may not be significantly different than if you were to receive standard care or taking part in 
another clinical trial. For example: chemotherapy and radiation therapy cause fatigue, hair loss, 
bruising and bleeding, infection, low blood cell counts. Immune checkpoint inhibitors may cause 
inflammation of the lung, intestines or liver, and kidney, heart, or problems of the nervous 
system. Any of these treatments can cause nausea, vomiting, diarrhea and rash.
The study drug durvalumab is a checkpoint inhibitor and has similar side effects to those listed 
above. The most common side effects of the other study drug, olaparib, include low blood cell 
counts, fatigue, nausea, vomiting, diarrhea, and infections.
If you decide to join this study, here are some of the most important things that you should know 
that will happen:

First, we will perform tests to find out if you fit the study requirements. We will do 
standard blood and urine tests and scans to test your health and see the status of your 
disease. These tests may be done under a separate protocol or on the study. We may also 
collect records from your outside physicians. 

If you fit the study requirements and decide to take part, you will start your treatment 
with durvalumab and olaparib. We will then send you home with a supply of olaparib 
that you will need to take. We will need to see you at the Clinical Center every 4 weeks 
while you are receiving treatment. There is one additional visit after 2 first weeks on 
treatment. You will not need to stay in the hospital for this study. Each visit should last 
no more than 8 hours.

As described above and later in more detail in this consent form, you may have side 
effects if you take part in this study. Some can be mild or very serious, temporary, long-
lasting, or permanent, and may include death. You will be seen regularly during the 
study. You will have clinical, laboratory, and imaging tests to see how you are doing and 
see how your disease is responding. We will also collect samples from you (such as: 
blood and tumor tissues) for both clinical and research purposes. Some of the samples 
are required and some are optional.

After the study treatment has ended we would like to see you in the Clinical Center 
approximately one month later to check on your health. After that we are planning to 
contact you by phone or e-mail to learn about your health status, and to see how you are 
doing, for the rest of your life or until the study is stopped. If you stop treatment for 
reasons other than worsening of your disease, we will continue to invite you for imaging 
studies approximately every 8 weeks until worsening of your disease. You can have 
these studies at home institution and send us the results.
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/11/2024
Page 3 of 24
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
This study may benefit you by shrinking your tumor or lessening your symptoms, such as pain, 
that are caused by the cancer. Even if you do not benefit from this study, the results from our 
research will help others in the future.
You are free to stop taking part in the trial at any time. If you decide to stop, the study doctor 
may ask you to agree to certain tests to make sure it is safe for you to stop.
The remaining document will now describe more about the research study. This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information described in this document. Some people have personal, religious, or ethical 
beliefs that may limit the kinds of medical or research treatments they would want to receive (such 
as blood transfusions). Take the time needed to ask any questions and discuss this study with NIH 
staff, and with your family, friends, and personal health care providers.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research. 
WHY IS THIS STUDY BEING DONE?
This is a research study. The purpose of this study is to see if combination of durvalumab and 
olaparib will cause your tumors to shrink.
We are asking you to join this research study because you had EGFR-mutated non-small-cell lung 
carcinoma (NSCLC) that was treated and now transformed to small cell lung carcinoma or another 
neuroendocrine tumor.
The use of durvalumab and olaparib in this study is considered investigational which means this 
combination has not been approved by the U.S. Food and Drug Administration (FDA) to treat 
small cell lung carcinoma or other neuroendocrine tumors. However, the FDA has given us 
permission to use durvalumab and olaparib in this study. 
Durvalumab has been approved by FDA to treat non-small cell lung cancer (NSCLC) and other 
cancers. Durvalumab is designed to boost the body’s immune system by targeting a protein on 
tumor cells called PD-L1. PD-L1 usually helps the immune system work properly. In cancer, PD-
L1 helps tumors avoid being seen and destroyed by the immune system. Durvalumab may increase 
the immune system’s ability to find and destroy cancer cells. 
Olaparib has been approved by the FDA to treat other cancers besides the one that we are studying. 
Olaparib belongs to group of drugs called PARP inhibitors that target and block several pathways 
needed for cancer cells to grow and cause cancer cells to die.
WHAT WILL HAPPEN DURING THE STUDY?
Durvalumab will be administered to you by IV (through an intravenous catheter, a small plastic 
tube that is put into a vein, usually in your arm) on Day 1 of each cycle (1 Cycle = 28 days).
You will take olaparib by mouth every day of every cycle. 
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/11/2024
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Olaparib should be taken 2 times a day. Try to space your doses out evenly throughout the day, so 
ideally, take a dose at 8 am and 8 pm with approximately 1 cup (240 mL) of water. You may take 
the tablets with a light meal/snack (i.e. 2 pieces of toast or a couple of crackers). If you need to 
take your olaparib earlier than scheduled or you missed a dose, you can take it in the time period 
of +/- 2 hours of the scheduled time. If you vomit after taking olaparib, please, do not immediately 
take another tablet unless the tablet is visible. You should simply proceed with next dose as 
scheduled.
If you have nausea or vomiting caused by olaparib, we will give you ondansetron to prevent or 
decrease the nausea and vomiting. You will need to take ondansetron by mouth with small meal 
or snack approximately 30 minutes prior to each dose of olaparib.
You will be given a Medication Diary to complete for each cycle. In the diary, you will be asked 
to record the date and time of each dose of olaparib. You will also be asked to record missed doses. 
Please bring the diary with you to every study visit.
At each visit, please also bring all empty bottles and any unused medication you may have.
If your doctor is convinced that you have unacceptable side effects caused by one of treatment 
drugs, this drug will be stopped, and you may continue treatment with the other drug if your study 
doctor finds that it is in your interest. Treatment will continue until you have unacceptable side 
effects (both drugs) or you are no longer benefiting from the study therapy.
Treatment and all study related procedures will be done during outpatient visits without planned 
hospitalization. However, we might still choose to keep your overnight if needed for biopsy and 
other situations that arise.
Before you begin the study
Before you begin this study, you will need to have standard clinical exams and tests to make sure 
you are eligible for this study. These tests may be done under a separate protocol or on the study. 
We may also collect records from your outside physicians. 
These following tests and exams will need to be performed:

Physical exam and medical history to check on your overall health 

We will check your heart through 3 electrocardiograms also called ECGs (a test that looks 
at electrical activity of your heart through electrodes/small stickers placed on your chest, 
arms, and legs).

Routine clinical blood and urine tests to further check on your health status. 

As part of this study, we will do blood tests to check for infections with HIV (the virus that 
causes AIDS), Hepatitis B and C (viruses that infect the liver). If you are infected with any 
of these viruses, you will be able to take part in this study if you are getting treatment for 
these diseases and if the virus cannot be found through blood tests. We will tell you what 
the results of blood tests mean, how to find care, how to avoid infecting others, how we 
report these infections, and the importance of informing your partners at possible risk 
because of your HIV or hepatitis infection.
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/11/2024
Page 5 of 24
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

If your doctor suspects it is needed, we may test you for tuberculosis a disease caused by 
germs that are spread from person to person through the air. A small amount of substance 
called purified protein derivative (PPD) is injected under your skin. If you have a red raised 
bump at the injection site, you may have been exposed to tuberculosis germs.

Computer tomography (CT) or Magnetic Resonance Imaging (MRI) scan to see your 
cancer. A CT produces a series of x-ray images of different parts of your body. An MRI 
makes pictures of the inside of your body using strong magnets instead of x-ray energy. 
Either scan may take about 30 minutes.

We will collect and review prior biopsy samples of your tumor and reports to confirm your 
diagnosis. 

We will check all the medications that you are currently taking. 

Pregnancy test (by blood or urine) if you are a woman who can have children.
You will be removed from the study if the results of the reviews/tests show that you are not eligible 
to participate.
You will be asked to provide documentation to confirm your diagnosis. If documentation is not 
available, we will perform a biopsy (collect a sample of your tumor) to confirm your diagnosis.
During the study
Ongoing procedures before treatment and with every cycle: 

Physical examination, including weight and vital signs.

Review of your symptoms, medications and your ability to perform your normal activities.

Discussion of any symptoms you might be having

Routine blood and urine tests to find out if you are anemic, have low blood counts, and if 
your liver, kidneys, thyroid, clotting system and other organs are working well. 

Electrocardiogram (EKG – a record of your heartbeat) to evaluate your heart.

Pregnancy test if you are a woman who can have children.
On Day 15 of cycle 1: 

Physical examination, including weight and vital signs.

Review of your symptoms, medications and your ability to perform your normal activities.

Discussion of any symptoms you might be having

Routine blood and urine tests to find out if you are anemic, have low blood counts, and if 
your liver, kidneys, thyroid, clotting system and other organs are working well. 
Ongoing procedures before treatment and every 2 cycles:

Imaging assessments/scans – either a CT scan or MRI of chest, abdomen and pelvis. 
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Magnetic resonance imaging (MRI) uses a strong magnetic field and radio waves to take pictures 
of your body. The MRI scanner is a metal cylinder surrounded by a strong magnetic field. During 
the MRI, you will lie on a table that can slide in and out of the cylinder. We will place soft padding 
or a coil around your head. You will be in the scanner about 30 minutes. You may be asked to lie 
still for up to 30 minutes at a time. While in the scanner you will hear loud knocking noises, and 
you will be fitted with earplugs or earmuffs to muffle the sound. You will be able to communicate 
with the MRI staff at all times during your scan, and you may ask to be moved out of the machine 
at any time. 
Additional research testing
In addition to the tests that we will conduct to determine whether you are having side effects or if 
you are responding to the study therapy, we will also collect samples from you for purposes of 
research only. The samples are being done to look at the effects of therapy on your immune system 
and markers of tumor activity. This will include collecting and testing tumor cells. 

Blood samples will be collected before treatment, on day 1 of every cycle and day 15 of 
cycle 1. Samples will be used to study how well your tumor responds to treatment, and to 
look at all of your genes and how well they are working. 

We will ask you to provide samples of your tumors from previous surgeries or biopsies if 
available. We also may perform three optional tumor biopsies: One before treatment, one 
on day 15 of cycle 1 and one if your disease gets worse. Please see Risks from Biopsy for 
the possible risks of biopsy. You will be asked to sign a separate consent each time you 
agree to have an optional biopsy. You can participate in the study even if you decide not 
to undergo the biopsy procedures. Samples will be used to study all of your tumor genes 
and how well they are working. 
Tumor and blood samples collected for research purposes on this study may be used to look for 
specific changes in the DNA in tumors that could be used to develop new ways of diagnosing and 
treating cancer. DNA (also called deoxyribonucleic acid) in the cells carries genetic information 
and passes it from one generation of cells to the next – like an instruction manual. Normal tissue 
contains the DNA (instructions) that you were born with, DNA in tumor cells has changed – or 
mutated – and we think that change in the DNA is what causes tumors to form and to grow. RNA 
(also called ribonucleic acid) carries the instructions from the DNA to the parts of your cells that 
make proteins. 
To look at your DNA and RNA, we may use do what is called “DNA or RNA sequencing.” This 
is where we will do special tests in the lab to look at the sequence, or order, of how your DNA or 
RNA are put together. This is what makes you unique. 
To determine which parts of the DNA or RNA have mutated, we will compare the DNA or RNA 
in your tumor cells to DNA or RNA from normal cells. We will then analyze the results from 
similar tumors to see if there are any changes in the DNA or RNA that are common to a particular 
type of tumor.
However, you should know that the analyses that we perform in our laboratory are for research 
purposes only; they are not nearly as sensitive as the tests that are performed in a laboratory that 
is certified to perform genetic testing or testing for routine clinical care. For these reasons, we will 
not give you the results of the research tests done on your research samples in most cases. There 
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
may be exceptions to what we share with you and this is described later in this consent form in the 
section for “Return of research results”.
When you are finished taking the drugs (treatment)
Approximately 30 days after you have finished taking the study drug, you will be asked to return 
to Clinical Center for a safety follow up visit. At this visit, you will be asked questions about your 
health, get a physical exam and undergo blood tests. 
If you have been taken off treatment for reasons other than worsening of your disease, you will 
continue to have imaging studies approximately every 8 weeks until worsening of your disease. 
You can have these studies at home institution and send us results.
If you are unable to return for these visits, we will obtain the information from you by telephone 
or e-mail.
Once you stop coming to Clinical Center for safety visits and your scans, we will call or e-mail 
you every 6 months to ask you about your general well-being.
HOW LONG WILL THE STUDY TAKE?
You will come for study treatments every 28 days until your disease gets worse or you have 
unacceptable side effects at which time we will stop treatment.
Visits will range from 4-8 hours in length.
After stopping treatment, we would like to see you in the NIH Clinical Center one month later and 
follow you after that for the rest of your life by telephone or e-mail. 
If you stop treatment for reasons other than worsening of your disease, we would like to invite you 
for imaging studies approximately every 8 weeks until worsening of your disease. 
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
About 14 people will take the study drugs at the NIH.
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
The drugs used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if 
changes occur that may affect your health.
Here are important points about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last longer.

Some side effects may be serious and may even result in death.
Here are important points about how you and the study doctor can make side effects less of a 
problem:

Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect.

The study doctor may be able to treat some side effects.
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/11/2024
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

The study doctor may adjust the study drugs to try to reduce side effects.
Durvalumab
Most of the possible side effects listed below are mild to moderate. However, some side effects 
can be very serious and life-threatening and may even result in death. Some side effects do not 
need treatment while others generally get better with treatment. Some patients may need to delay 
doses of durvalumab to allow the side effects to get better. The most important possible side 
effects, which are listed below, may occur because of the way durvalumab works on the immune 
system and they have been seen in patients treated with durvalumab in clinical studies. Side effects 
like these have also been seen in clinical studies with other drugs that are very similar to 
durvalumab. Management of these side effects may require the administration of drugs such as 
steroids or other agents that can affect your immune system and reduce inflammation.
Very common, some may be serious 
In 100 people receiving durvalumab, more than 10 may have:

Diarrhea,

Rash/dry itchy skin

Feeling tired 

Nausea 

Vomiting 

Abdominal pain

Upper respiratory tract infections

Decreased appetite 

Shortness of breath 

Cough with or without mucus

Fever
Common, some may be serious
In 100 people receiving durvalumab, from 1 to 10 may have:

Liver problems: Increases in the blood level of substances called enzymes found within 
your liver cells. The enzyme changes are unlikely to make you feel unwell, however, if 
these blood enzyme levels become very high, your study doctor may need to stop the 
study medication. You may develop inflammation of the liver called hepatitis; however, 
this is uncommon. In some cases, this could be caused by your immune system attacking 
your liver. Signs and symptoms of this include yellowing of the skin or whites of the 
eyes, dark urine, severe nausea and vomiting, pain in the upper right side of your 
abdomen, skin itchiness, not feeling hungry and bleeding or bruising more easily than 
normal.

Inflammation in the lungs (pneumonitis): symptoms may include but are not limited to 
a new or worsening cough, shortness of breath possibly with fever. In some cases, this 
could be caused by your immune system attacking your lungs. Preliminary data 
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


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Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
suggested that there may be the tendency of higher frequency and severity in Japanese 
patients compared with non-Japanese patients: tell your study doctor right away if you 
have any of these symptoms as it may need to be treated urgently.

Low thyroid (Hypothyroidism): this is when the thyroid gland produces less thyroid 
hormone than it should which causes the metabolism to run too slow. Symptoms may 
include but are not limited to fatigue, increased sensitivity to cold, constipation, dry skin, 
unexplained weight gain, puffy face, muscle weakness, slow heart rate, thinning hair, 
impaired memory. The condition can be treated with replacement thyroid hormone.

High thyroid (Hyperthyroidism): this is when the thyroid gland produces too much 
thyroid hormone. Symptoms include anxiety or nervousness, weight loss, frequent and 
loose bowel movements, breathlessness, feeling hot and possibly having heart 
palpitations. Depending on the severity of the symptoms, treatment may include just 
monitoring the symptoms, treating the symptoms themselves and/or giving medicine to 
block the thyroid hormone.

Kidney problems: you may have an increase of creatinine levels in a blood test 
(creatinine is a protein marker that measures kidney function) but not have any 
symptoms or feel unwell. Uncommonly a patient may experience nephritis which is an 
inflammation of the kidneys that stops the kidneys from working properly. 

Nervous system problems: symptoms can include unusual weakness of legs, arms, or 
face, Numbness or tingling in hands or feet. In rare situations there is the potential for 
the inflammation of the nervous system to be severe and cause damage to the nerve cells 
or breakdown in the communication between nerves and muscles: tell your study doctor 
right away if you have problems swallowing, if you start to feel weak very quickly and 
you are having trouble breathing.

Infusion Related Reactions: reactions may occur during or after the infusion of study 
medication. The reaction may cause fever or chills and a change in blood pressure or 
difficulty in breathing which might be serious. Tell your study doctor right away if you 
experience any of these symptoms even if it has been several days after the infusion has 
been completed. 

Inflammation of the intestine (colitis). It may cause abdominal pain and diarrhea with or 
without blood. Fever may be present. It may require you to receive additional fluids. If 
left untreated, in rare occasions this may lead to a tear in the wall of the intestine which 
can be serious and life threatening. Tell your study doctor right away if you have any of 
these symptoms. 

A hoarse voice

Painful urination

Night sweats

Pneumonia

Oral thrush

Dental and oral soft tissue infection

Pain in muscles and joints

Influenza
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

Accumulation of fluid causing swelling, especially in your hands and feet
Uncommon, some may be serious
In 100 people receiving durvalumab, 1 or fewer may have:

Inflammation of the pancreas (pancreatitis). Pancreatitis usually causes symptoms of 
persistent upper abdominal pain (sometimes made worse by eating and drinking), 
nausea, vomiting and general weakness. Pancreatitis usually settles with simple 
measures but it can be a serious condition and can be fatal. You should immediately tell 
your study doctor if you develop any of these symptoms. You may get an increase of 
lipase and amylase levels in a blood test (related to the pancreas) but not have any 
symptoms or feel unwell. Lipase and amylase are enzymes or protein markers that 
measure the function of your pancreas. Uncommonly these increases may be associated 
with pancreatitis.

Inflammation of the thyroid

Allergic reactions: These can cause swelling of the face, lips and throat, breathing 
difficulties along with hives or nettle like rash. You should immediately tell your study 
doctor if you develop any of these symptoms. 

Problems with your adrenal glands (Adrenal Insufficiency): may cause stomach pains, 
vomiting, muscle weakness and fatigue, depression, low blood pressure, weight loss, 
kidney problems, and changes in mood and personality. These complications may be 
permanent and may require hormone replacement 

Problems with the pituitary gland (hypopituitarism): Hypopituitarism refers to decreased 
output of hormones from the pituitary gland in the brain and may be caused by 
inflammation of the pituitary gland (hypophysitis). Symptoms may include headaches, 
thirstiness, and trouble seeing or double vision, leakage of breast milk or irregular 
periods in women. These complications may be permanent and may require hormone 
replacement.

Inflammation of the muscles or associated tissues, such as blood vessels that supply the 
muscles (Myositis/polymyositis). Symptoms can include muscle weakness and aches, 
tired feeling when standing or walking, muscle pain and soreness that does not resolve 
after a few weeks.

Inflammation or sores in the lining of the small rectum that may be painful, bloody bowel 
movements, rectal bleeding or mucoid discharge
Rare side effects, some may be serious 
In 1,000 people receiving durvalumab, 1 or fewer may have:

Type 1 Diabetes mellitus which may cause increased blood glucose levels (called 
‘hyperglycemia’): symptoms may include weight loss, increased urination, increased 
thirst, and increased hunger. Type 1 diabetes will require replacement of insulin through 
injection. Tell your study doctor right away if you have any of these symptoms. 

A disorder affecting how the body regulates salt and water which can result in intense 
thirst and heavy urination (diabetes insipidus).
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


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
Problems with the pituitary gland (hypopituitarism): hypopituitarism refers to decreased 
output of hormones from the pituitary gland in the brain and may be caused by 
inflammation of the pituitary gland (hypophysitis). Symptoms may include headaches, 
thirstiness, and trouble seeing or double vision, leakage of breast milk or irregular 
periods in women. These complications may be permanent and may require hormone 
replacement.

Inflammation of the heart muscle (myocarditis). Symptoms can include chest pain, rapid 
or abnormal heartbeat, shortness of breath and swelling of your legs. Tell your study 
doctor right away if you experience any of these symptoms.

Inflammation of the membrane surrounding the heart

Growths of tiny collections of inflammatory cells in different parts of the body

Inflammation of the middle layer of the eye and other events involving the eye (e.g. 
inflammation of the cornea and optic nerves)

Inflammation of the brain or the membranes that cover the brain and spinal cord

Hardening and tightening of the skin and connective tissues and loss of skin color

Pemphigoid (a rare autoimmune blistering of the skin and mucus membranes)

Other hematological events (e.g., abnormal breakdown of the red blood cells and low 
levels of platelets, in some cases by your immune system)

Inflammation of the blood vessels and rheumatological events (inflammatory disorder 
causing muscle pain and stiffness and autoimmune arthritis)

Myasthenia Gravis which results in weakness and rapid fatigue of any of the muscles 
under your voluntary control.

Inflammation of the bile duct system (cholangitis) that leads to scarring (sclerosis) and 
narrowing of the ducts. The bile duct system carries bile from your liver and gallbladder 
into the first part of your small intestine

Inflammation of the bladder (cystitis)
In addition to the possible risks identified in patients treated with durvalumab, other immune-
mediated side effects are possible that have not been observed and can result in inflammatory side 
effects in any organ or tissue.
Olaparib
Very common, some may be serious 
In 100 people receiving olaparib, more than 10 and up to 100 may have:

Low red blood cell count (anemia) which may cause you to feel tired, weak, or have 
shortness of breath. In some instance, this decrease in red blood cell count may be 
serious and require blood transfusions (when you are given new blood or blood 
products from a donor).
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


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
A decrease in white blood cells (specific type called neutrophils) with or without fever. 
In some cases, this decrease can be serious and lead to infection requiring antibiotic 
treatment and possibly hospitalization (neutropenia).

A decrease in white blood cells in blood (leukopenia) which may be serious in rare 
cases.

Dizziness

Headache

Changes in taste

Cough

Shortness of breath

Constipation

Heartburn

Diarrhea, nausea, vomiting

Tiredness (including weakness)

Loss of appetite
Common, some may be serious
In 100 people receiving olaparib, from 1 to 10 may have: 

Bruising, bleeding which may be caused by a reduction in platelets (blood cells that 
help the blood to clot), and can lead to bleeding requiring platelet transfusions 
(thrombocytopenia).

Lymphocyte count decreased (type of white blood cell that is part of the immune 
system) which may lead to an infection.

Inflamed and sore mouth 

Upper abdominal pain

Rash

Blood creatinine increased (creatinine is a measure that tells us how well your kidneys 
are working). This may mean that your kidneys are not working well.

A blood clot that starts in a vein (venous thromboembolism). These clots can also 
develop in deep veins in the arm, lower leg, thigh or pelvis and can in serious cases 
travel to the lungs.
Uncommon, some may be serious
In 1,000 people receiving olaparib, more than 1 but less than 10 may have:

Irreversible abnormal blood counts and bone marrow damage, which may lead to 
leukemia (myelodysplasia).

Undesirable reactions produced by the normal immune system (hypersensitivity)

Swelling that occurs just beneath the surface of the skin (angioedema)
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


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
Skin irritation or inflammation (dermatitis)

Increased blood cell size and volume 

Cancer of the blood and bone marrow (the soft inner part of certain bones, where 
new blood cells are made) which may at time be serious (acute myeloid leukemia)

Blockage of an artery, typically by a clot of blood (embolism)

Blockage in one of the pulmonary arteries in your lungs (pulmonary embolism) 

Inflammation of the lung tissue (pneumonitis), which may cause new or worsening 
symptoms of shortness of breath. This may be serious or life threatening.
Rare, and may be serious
In 10,000 people receiving olaparib, more than 1 but less than 10 may have:

Red blood cells that are larger than normal 

Flat, firm, hot, red, and painful lumps that usually appear on the shins (erythema 
nodosum)
Getting medical treatment right away may keep these problems from becoming more serious. Let 
your study doctor know of any questions you have about possible side effects. You can ask the 
study doctor questions about side effects at any time.
Risks from Biopsy 
This procedure usually causes only brief discomfort at the site from which the biopsy is taken. 
Risks of biopsy may include bleeding, injury to internal organs, and infection. Rarely, these 
complications from biopsy could result in hospitalization and require additional medical care. 
Risks of sedation will be described at the time of procedure. 
Risks from Blood Collection 
Side effects of blood draws include pain and bruising in the area where the needle was placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop. About 22 tablespoons of blood may be collected at each visit 
with a maximum of 99 tablespoons in an 8-week period.
Risks from Urine Collection
There are no risks related to urine collection.
Risks from CT contrast
Itching, hives or headaches are possible risks associated with contrast agents that may be used 
during CT imaging. Symptoms of a more serious allergic reaction include shortness of breath and 
swelling of the throat or other parts of the body. Very rarely, the contrast agents used in CT can 
cause kidney problems for certain participants, such as those with impaired kidney function.
Risks from Electrocardiograms
Other than possibly experiencing some minor skin irritation from the electrodes, there are no 
anticipated risks related to complete the electrocardiogram and/or the echocardiogram.
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


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What are the risks related to pregnancy? 
If you are capable of becoming pregnant, we will ask you to have a pregnancy test before beginning 
this study. You will need to use one highly effective birth control method and your partner will 
need to use a male condom or practice total/true abstinence throughout the study treatment and for 
at least 6 months after last dose of study drugs. Your study team will provide additional details on 
what methods may be used. If you become pregnant during this time, there may be unknown risks 
to the fetus or unborn child, or risks that we did not anticipate. There may be long-term effects of 
the treatment being studied that could increase the risk of harm to a fetus. You must tell the study 
doctor if your birth control method fails while you are in the study. If you think or know you have 
become pregnant during the restricted period, please contact the research team member identified 
at the top of this document as soon as possible. If you plan to become pregnant in the future, please 
discuss with the research team how long you need to wait before becoming pregnant after 
completing the course of this study drug or procedures on this study.
You may not participate in this study if you are pregnant. If you are capable of becoming pregnant, 
we will perform a pregnancy test before exposing you to radiation. You must tell us if you may 
have become pregnant within the previous 14 days because the pregnancy test is unreliable during 
that time.
If you are a sexually active person with a partner capable of becoming pregnant, you will need to 
use a condom or total/true abstinence throughout the study and for at least 3 months after the last 
dose of study drugs. There may be unknown risks to a fetus or risks we did not anticipate. You and 
your partner must both agree to use birth control if you want to take part in this study. If you think 
your partner has become pregnant during the restricted time period, please contact the research 
team member identified at the top of this document as soon as possible. If you and your partner 
plan for your partner to become pregnant after the restricted time period, please discuss this with 
the study team.
What are the risks of radiation from being in the study? 
During your participation in this research study, you will be exposed to radiation from 3 CT guided 
biopsies and CTs every 8 weeks. The amount of radiation exposure you will receive from these 
procedures is equal to approximately 9 rem. A rem is a unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them. The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources. This type of radiation is called “background radiation.” 
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CTs that you get in this study will expose you to the roughly the same amount of radiation as 
27.3 years’ worth of background radiation. Being exposed to too much radiation can cause harmful 
side effects such as an increase in the risk of cancer. The risk depends on how much radiation you 
are exposed to. Please be aware that about 40 out of 100 people (40%) will get cancer during their 
lifetime, and 20 out of 100 (20%) will die from cancer. The risk of getting cancer from the radiation 
exposure in this study is 0.9 out of 100 (0.9%) and of getting a fatal cancer is 0.5 out of 100 (0.5%).
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


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Risks from MRI
You might be at risk for injury from the MRI magnet if you have some kinds of metal in your 
body. It may be unsafe for you to have an MRI scan if you have:

pacemakers or other implanted electrical devices, 

brain stimulators, 

some types of dental implants, 

aneurysm clips (metal clips on the wall of a large artery), 

metal prostheses (including metal pins and rods, heart valves, and cochlear implants), 

permanent eyeliner, 

tattoos, 

an implanted delivery pump, 

or shrapnel fragments. Welders and metal workers may have small metal fragments in the 
eye. 
You will be screened for these conditions before having any MRI scan. If you have a question 
about metal in your body, you should tell us. You will be asked to fill out an MRI screening form 
before each MRI scan you have. 
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be removed 
before you enter the MRI scan room.
If you are afraid of confined (small, cramped) spaces, you may get anxious during an MRI. If you 
have back problems, you may have back pain or discomfort from lying in the scanner. 
The noise from the scanner is loud enough to damage your hearing, especially if you already have 
hearing loss. We will give you hearing protection. If the hearing protection comes loose during the 
scan, you should let us know right away.
There are no known long-term risks of MRI scans.
Risks from MRI Contrast (Gadolinium)
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein. These 
could cause pain and swelling. 
Mild symptoms from gadolinium happen in less than 1% of people who get it. Symptoms usually 
go away quickly. Mild symptoms may include:

your arm being cold during the injection, 

a metallic taste, 

headache, and 

nausea. 
More severe symptoms have been reported in an extremely small number of people (fewer than 1 
in 300,000 people). These symptoms include: 

shortness of breath, 

wheezing, 

hives, and 
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


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
lowering of blood pressure. 
You should not get gadolinium if you ever had an allergic reaction to it. We will ask you about 
any allergic reactions before giving you gadolinium. 
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis (NSF).” NSF always involves the skin and can also involve the 
muscles, joints, and internal organs. NSF has resulted in a very small number of deaths. We may 
do a blood test of your kidney function within 30 days before an MRI scan with gadolinium 
contrast. You will not get gadolinium for a research MRI scan if your kidney function is below the 
safe level. 
Most of the gadolinium contrast will leave your body in the urine. However, the FDA has issued 
a safety alert that says small amounts of gadolinium may stay in your body for months or years. 
The long-term effects of the gadolinium that stays in your body are unknown. Some types of 
gadolinium are less likely to remain in the body than others. In this study, we will use the 
gadolinium that is less likely to stay in your body. We will also give you additional information 
called a “Medication Guide.” If you ask, we will also give you individual information about any 
remaining gadolinium we see on your scans.
Privacy Risks Associated with Genetic Testing
It may be possible that genetic information from you could be used by law enforcement agencies 
or other entities to identify you or your blood relatives
Psychological or Social Risks Associated with Return of Incidental or Secondary Findings
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might create 
a need to make challenging decisions about how to respond. 
Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them. 
Protections against misuse of genetic information 
This study involves genetic testing on samples. Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your employers 
or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law that prohibits 
plans and health insurers from requesting genetic information or using genetic information. It also 
prohibits employment discrimination based on your health information. However, GINA does not 
address discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
condition or disease that has a genetic component.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You might not benefit from being in this study. 
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However, the potential benefit to you might include shrinking of your tumor or lessening of your 
symptoms, such as pain, that are caused by the cancer.
Are there any potential benefits to others that might result from the study?
In the future, other people might benefit from this study because what we learn in this study may 
eventually be used to treat others with your disease. 
WHAT OTHER OPTIONS ARE THERE FOR YOU?
Before you decide whether to be in this study, we will discuss the other options that are available 
to you. Instead of being in this study, you could:

choose to be treated with surgery, radiation or with drugs already approved by the FDA for 
your disease

choose to take part in a different study, if one is available

choose not to be treated for cancer but you may want to receive comfort care to relieve 
symptoms.
You should discuss with your doctor your other choices and their risks and benefits.
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
When we are examining your DNA, it is possible that we could identify possible changes in other 
parts of your DNA that are not related to this research. These are known as “incidental medical 
findings”. 
These include: 

Changes in genes that are related to diseases other than cancer. 

Changes in genes that are not known to cause any disease. These are known as normal 
variations. 

Changes in genes that are new and of uncertain clinical importance. This means that we do not 
know if they could cause or contribute to a disease or if they are normal variations. 
Some of your samples may be tested in a laboratory that is certified to perform genetic testing. 
If this happens, we will offer to share the results for these tests.
Some of the analyses will be performed in our laboratory and will be nearly as sensitive as the 
tests that are performed in a laboratory that is certified to perform genetic testing. This means 
the genetic changes that we find may or may not be valid. Therefore, we do not plan to inform 
you of all of the genetic results of testing on your tissue and blood that is performed in our 
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research lab. However, in the unlikely event that we discover a finding believed to be clinically 
important based on medical standards at the time we first analyze your results, we will contact 
you. This could be many years in the future. We will ask you to provide a sample to verify the 
findings we have seen in our lab. If the results are verified, you will be re-contacted and offered 
a referral to a genetic healthcare provider to discuss the results.
EARLY WITHDRAWAL FROM THE STUDY 
Your doctor may decide to stop your therapy for the following reasons:

if your disease worsens or comes back during treatment

if you become pregnant

if you have side effects from the treatment that your doctor thinks are too severe

if the durvalumab and olaparib become unavailable

if new information shows that another treatment would be better for you

if the study is stopped for any reason

if you permanently lose the capacity to consent
In this case, you will be informed of the reason therapy is being stopped.
After the therapy is stopped, we would like to see you for a safety visit approximately one month 
after stopping therapy.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you.
STORAGE, SHARING AND FUTURE RESEARCH USING YOUR SPECIMENS AND 
DATA
Will Your Specimens or Data Be Saved for Use in Other Research Studies?
As part of this study, we are obtaining specimens and data from you. We will remove all the 
identifiers, such as your name, date of birth, address, or medical record number and label your 
specimens and data with a code so that you cannot easily be identified. However, the code will 
be linked through a key to information that can identify you. We plan to store and use these 
specimens and data for studies other than the ones described in this consent form that are going 
on right now, as well as studies that may be conducted in the future. These studies may provide 
additional information that will be helpful in understanding small cell lung carcinoma or another 
neuroendocrine cancer, or other diseases or conditions. This could include studies to develop 
other research tests, treatments, drugs, or devices, that may lead to development of a commercial 
product by the NIH and/or its research or commercial partners. There are no plans to provide 
financial compensation to you if this happens. Also, it is unlikely that we will learn anything 
from these studies that may directly benefit you.
I give permission for my coded specimens and data to be stored and used for future research as 
described above.
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


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_____ Yes
_____ No
Initials
Initials
Will Your Specimens or Data Be Shared for Use in Other Research Studies?
We may share your coded specimens and data with other researchers. If we do, while we will 
maintain the code key, we will not share it, so the other researchers will not be able to identify 
you. They may be doing research in areas similar to this research or in other unrelated areas. 
These researchers may be at NIH, other research centers and institutions, or commercial entities. 
I give permission for my coded specimens and data to be shared with other researchers and used 
by these researchers for future research as described above.
_____ Yes 
_____ No
Initials
Initials
If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your specimens and data. For example, if some research with your specimens and 
data has already been completed, the information from that research may still be used. Also, for 
example, if the specimens and data have been shared already with other researchers, it might not 
be possible to withdraw them. 
In addition to the planned use and sharing described above, we might remove all identifiers and 
codes from your specimens and data and use or share them with other researchers for future 
research at the NIH or other places. When we or the other researchers access your anonymized 
data, there will be no way to link the specimens or data back to you. We will not contact you to 
ask your permission or otherwise inform you before we do this. We might do this even if you 
answered "no" to the above questions. If we do this, we would not be able to remove your 
specimens or data to prevent their use in future research studies, even if you asked, because we 
will not be able to tell which are your specimens or data.
NIH policies require that your clinical and other study data be placed in an internal NIH database 
that is accessible to other NIH researchers for future research. These researchers will not have 
access to any of your identifiers, such as your name, date of birth, address, or medical record 
number; and your data will be labeled with only a code. We cannot offer you a choice of whether 
your data to be placed in this database or not. If you do not wish to have your data placed in this 
database, you should not enroll in this study.
Will Your Genomic Data Be Shared Outside of This Study?
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
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ethnicity, and sex. If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that researchers and 
non-researchers will be able to access summary information about all the participants included 
in the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we 
cannot offer you a choice of whether your data will be shared. If you do not wish to have your 
data placed in a repository, you should not enroll in this study.
How Long Will Your Specimens and Data be Stored by the NIH?
Your specimens and data may be stored by the NIH indefinitely.
Risks of Storage and Sharing of Specimens and Data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your specimens 
and data.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount of 
compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses. Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid. The amount and form 
of these payments are determined by the NCI Travel and Lodging Reimbursement Policy. You 
will be given a summary of the policy which provides more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/11/2024
Page 21 of 24
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

If some tests and procedures are performed outside the NIH Clinical Center, 
you may have to pay for these costs if they are not covered by your insurance 
company.

Medicines that are not part of the study treatment will not be provided or paid 
for by the NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
CONFLICT OF INTEREST (COI)
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a COI Guide. You may ask your research team for a copy of 
the COI Guide or for more information. Members of the research team who do not work for NIH 
are expected to follow these guidelines or the guidelines of their home institution, but they do not 
need to report their personal finances to the NIH.
AstraZeneca is providing Olaparib and Durvalumab for this study to NIH without charge. No NIH 
investigator involved in this study receives payments or other benefits from any company whose 
drug, product or device is being tested. However, there are some research partners not associated 
with the NIH working on this study who may receive payments or benefits, limited by the rules of 
their workplace. 
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY 
Will your medical information be kept private?
We will do our best to make sure that the personal information in your medical record will be kept 
private. However, we cannot guarantee total privacy. Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor, Center for Cancer Research of National Cancer Institute.

Qualified representatives from AstraZeneca, the pharmaceutical company who provides 
durvalumab and olaparib.
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible. However, there is always a chance that, 
despite our best efforts, your identity and/or information about your participation in this research 
may be inadvertently released or improperly accessed by unauthorized persons.
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/11/2024
Page 22 of 24
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission. However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act.
Certificate of Confidentiality 
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances. 
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.
The Certificate does not protect your information when it: 
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that we collect under the authority of the Public Health Service Act. In some cases, the Privacy 
Act protections differ from the Certificate of Confidentiality. For example, sometimes the Privacy 
Act allows release of information from your record without your permission, for example, if it is 
requested by Congress. Information may also be released for certain research purposes with due 
consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit. However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES 
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/11/2024
Page 23 of 24
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Anish Thomas, 
M.D., anish.thomas@nih.gov, 240-760-6241. You may also call the NIH Clinical Center Patient 
Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you 
have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/11/2024
Page 24 of 24
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness should sign below if either:
1. A short form consent process has been used to enroll a non-English speaking subject or
2. An oral presentation of the full consent has been used to enroll a blind or illiterate subject
Signature of Witness
Print Name of Witness
Date
NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 20C0149
IRB EFFECTIVE DATE: 5/9/2024