A Phase 1/2 Study of Olaparib in Combination With Ramucirumab in Metastatic Gastric and Gastroesophageal Junction Adenocarcinoma (10017760)
Phase: PHASE1
Conditions: Metastatic Esophageal Carcinoma, Metastatic Gastric Carcinoma, Metastatic Gastroesophageal Junction Adenocarcinoma, Recurrent Esophageal Carcinoma, Recurrent Gastric Carcinoma, Recurrent Gastroesophageal Junction Adenocarcinoma, Stage III Esophageal Cancer AJCC v7, Stage III Gastric Cancer AJCC v7, Stage IV Esophageal Cancer AJCC v7, Stage IV Gastric Cancer AJCC v7, Unresectable Esophageal Carcinoma, Unresectable Gastric Carcinoma, Unresectable Gastroesophageal Junction Adenocarcinoma
Sponsor: National Cancer Institute (NCI)

i 
SUMMARY OF CHANGES – Protocol 
 
For Protocol Amendment # to: A Phase 1 / 2 Study of Olaparib in Combination with 
Ramucirumab in Metastatic Gastric and Gastroesophageal Junction Adenocarcinoma (10017760) 
 
NCI Protocol #: # 10066 
Local Protocol #: 200021407 
 
NCI Version Date: 
Protocol Date: 6/2/2022 
 
 
I. Protocol Changes Requested by CTEP:  
# 
Section 
Comments 
1. 
Title 
Page 
The study coordinator, data manager and research coordinator were updated 
to Christina Wiess.  
2. 
Title 
Page 
The protocol amendment dates were updated on the title page.  
3. 
All 
The protocol version date was updated in the header. 
4. 
Schema Reinserted text regarding including chest, abdomen, and pelvis imaging and 
reducing imaging intervals to 12 week (+/- 7 day) intervals for patients that 
remain on study for > 6 months. Correct schema picture also reinserted.  
5. 
10 
Reinserted row for adverse event evaluation in the study calendar. 
6. 
10 
Reinserted text and footnotes regarding tumor measurements and radiologic 
evaluations. 
7. 
Title 
page 
Reinserted Clinicaltrials.gov identifier.  
8. 
TOC 
Updated table of contents. 
9. 
9.3.6 
The correlative study section as updated to include language for shipping 
plasma from Yale University to the NCLN Genomics Laboratory for 
circulating tumor DNA analysis.  
10. Appendix 
D 
The wallet card was updated per CTEP recommendations.  

1 
 
NCI Protocol #: 
10066 
 
Local Protocol #: 
2000021407 
 
ClinicalTrials.gov Identifier:  NCT030008278 
 
TITLE: A Phase 1 / 2 Study of Olaparib in Combination with Ramucirumab in Metastatic 
Gastric and Gastroesophageal Junction Adenocarcinoma (10017760)  
 
Corresponding Organization: LAO-CT018 / Yale University Cancer Center LAO 
 
Principal Investigator: 
Michael Cecchini  MD 
Yale Cancer Center 
333 Cedar Street 
New Haven, CT 06520 
PO Box 208028 
Office: (203) 494-8566 
Fax (203) 785 - 3788 
michael.cecchini@yale.edu 
 
Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
Co-investigator: 
Patricia LoRusso 
Yale Cancer Center 
333 Cedar St WWW211 
PO Box 208028 
New Haven CT 06520 
Phone (203) 785-3333 
Fax (203) 785-3788 

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Version Date: 6/2/2022 
 
 
2
Patricia.lorusso@yale.edu 
 
Co-investigator: 
Jill Lacy MD 
Yale Cancer Center 
333 Cedar Street 
New Haven, CT 06520 
PO Box 208028 
Office: (203) 737-1600 
Fax (203) 785 - 3788 
Jill.lacy@yale.edu 
 
Statistician: 
 
Study Coordinator: 
 
Yu Shyr 
Christina Wiess 
 
Center for Quantitative Sciences 
300 George St 
 
571 Preston Building 
New Haven CT 06511 
 
Nashville, TN 37232-6848 
 
Phone: (615) 636-2572 
Telephone (203) 785-2836 
 
Fax: (615) 936-2602 
Fax (203) 785-5792 
 
Yu.shyr@vanderbilt.edu 
Christina.wiess@yale.edu 
 
Responsible Research Coordinator: 
Responsible Data Manager: 
 
Christina Wiess 
Name Christina Wiess 
 
Address 20 York St 
Address 300 George St 
 
Address New Haven CT 06250 
Address New Haven CT 06511 
 
Telephone (203) 785-2836 
Telephone 
 
Fax (203) 785-5792 
Fax 
 
christina.wiess@yale.edu 
christina.wiess@yale.edu 
 
NCI-Supplied Agent(s):  Olaparib, NSC 747856 
Other Agent(s):  Ramucirumab, NSC 749128 commercially available through Eli Lilly 
 
IND #:  #
 
IND Sponsor: DCTD, NCI  
 
Protocol Type / Version # / Version Date: 
Original / Version 1 / Version Date 7/25/16 
 
 
 
 
Revision / Version 2 / Version Date 2/15/17 
 
 
 
 
Revision / Version 3 / Version Date 3/31/17 
 
 
 
 
Revision / Version 4 / Version Date 6/26/17 
 
 
 
 
Revision / Version 5 / Version Date 9/12/17 
 
 
 
 
Amendment / Version 6 / Version Date 1/29/18 
 
 
 
 
Amendment / Version 7 / Version Date 4/30/18 
 
 
 
 
Amendment / Version 8 / Version Date 7/25/18 
 
 
 
 
Amendment / Version 9 / Version Date 1/31/19 
Amendment / Version 10 / Version Date 3/25/19 
(Withdrawn by CTEP) 

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3
 
 
 
 
Amendment / Version 11 / Version Date 5/29/19 
 
 
 
        Amendment / Version 12 / Version Date 6/2/2022  
 
 
SCHEMA 
 
This study begins with a phase 1 dose escalation lead-in with olaparib and ramucirumab for 
eligible patients with metastatic gastric or gastroesophageal junction adenocarcinoma who have 
previously received at least one line of chemotherapy in the metastatic setting. A 3+3 dose 
escalation design will be done for olaparib at doses of 200mg BID and 300mg BID (tablet 
formulation) with standard ramucirumab dosing of 8 mg/kg every 2 weeks. After the 
recommended phase 2 dose is determined, the phase 2 part of the study will begin. In phase 2, 
patients will be enrolled and treated with olaparib twice daily and ramucirumab 8 mg/kg every 2 
weeks. Response assessment scans will be done every 6 weeks (imaging should include the 
chest, abdomen and pelvis), and treatment will continue until disease progression or 
unacceptable toxicity. Patients that remain on treatment for > 6 months may decrease the 
response assessment scan interval to every 12 weeks (+/- 7 days) at the discretion of the 
investigator. All patients will undergo a biopsy prior to treatment, which will be used for 
integrated biomarker analysis with the BROCA-HR panel to assess for the presence of mutations 
in homologous repair genes. The patients in phase 2 will also undergo an optional repeat biopsy 
at 16 weeks for correlative analysis including development of a post treatment PDX. Within the 
BROCA-HR panel we estimate the 17 genes characteristic of homologous repair deficiency 
(HRD) to be present in 30-40% of our study population. Deleterious mutations in the following 
genes will be considered a positive result for the BROCA-HR biomarker: ATM, ATR, BARD1, 
BLM, BRCA1, BRCA2, BRIP1, CHEK2, MRE11A, NBN, PALB2, RAD51, RAD51C, 
RAD51D, RBBP8, SLX4, XRCC2, CDK12. Because we do not know the true distribution of our 
biomarker, we will proceed with this 40 patient pilot study to help plan a larger study based on 
both our observed biomarker prevalence and our response rates. If response rates are observed 
regardless of biomarker status the subsequent study may not be biomarker driven. Based on 
published data in the COSMIC and TCGA databases we expect the BROCA-HR biomarker to be 
positive in approximately 35% of cases and we will enroll to 40 patients in phase 2 and proceed 
as follows:  
 
1. If there are 6 or more BROCA-HR+ patients (34 or less BROCA-HR- patients): 
If there are no responses in BROCA-HR+ patients and no response in BROCA-
HR- patients, then it is unlikely we will proceed to a larger study with this 
combination.  
• For BROCA-HR+ patients: the probability of ≥ 1 responses is > 80% if the 
true response rate ≥ 25%  
• For BROCA-HR- patients: The probability of ≥ 1 response is > 99% if the 
true response rate is ≥ 20% and the probability of ≥ 1 response of 80% if the 
true response rate is ≥ 5%. 
 
2. If there are 6 or more BROCA-HR+ patients (34 or fewer BROCA-HR-): For 
BROCA-HR- patients, the study will require at least 4 responses for success if 
we have at least 26 BROCA-HR- patients (65% incidence rate). The probability 

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of 4 responses is 80% if the true response rate is 20%. The study will require at 
least 3 responses for success if we have at least 20 BROCA-HR- patients (50% 
incidence rate) the probability of ≥ 3 responses = 80% if the true response rate = 
20%. It is very unlikely the incidence rate of BROCA-HR- will be less than 50%. 
 
3. If there are less than 6 BROCA-HR+ patients (35 or more BROCA-HR- 
patients): If no responses are observed in either cohort, then it is unlikely we will 
proceed to a larger study with this combination. The probability of ≥ 6 BROCA-
HR+ patients is > 85% if the true incidence of BROCA-HR+ is ≥ 20%. The 
probability of ≥ 6 BROCA-HR+ patients is > 99% if the true incidence rate of 
BROCA-HR+ is ≥ 35%. 
 
Based upon the results in the above scenarios we will discuss with CTEP on the plan to proceed 
to a larger study. 
 
 
 
Dose Escalation Schedule 
Dose Level 
Dose* 
Olaparib  
Ramucirumab 
N/A 

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5
(mg) 
(mg/kg) 
-2 
100 mg, twice daily 
8 mg/kg every 2 
weeks, intravenous 
 
-1 
150 mg, twice daily 
8 mg/kg every 2 
weeks, intravenous 
 
1 (starting dose) 
200 mg twice daily, 
orally 
8mg/kg every 2 
weeks, intravenous 
 
2 
300 mg twice daily, 
orally 
8mg/kg every 2 
weeks, intravenous 
 
 

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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objectives ...................................................................................................8 
1.2 
Secondary Objectives ...............................................................................................8 
2. 
BACKGROUND .................................................................................................................8 
2.1 
Gastric and Gastroesophageal Adenocarcinoma .....................................................8 
2.2 
CTEP IND Agent(s) ...............................................................................................10 
2.3 
Other Agent: Ramucirumab (Cryamza) .................................................................16 
2.4 
Rationale for the Combination of Olaparib and Ramucirumab .............................22 
2.5 
Correlative Studies Background ............................................................................23 
3. 
PATIENT SELECTION ....................................................................................................28 
3.1 
Inclusion Criteria ...................................................................................................29 
3.2 
Exclusion Criteria ..................................................................................................32 
3.3 
Inclusion of Women and Minorities ......................................................................34 
4. 
REGISTRATION PROCEDURES ...................................................................................34 
4.1 
Investigator and Research Associate Registration with CTEP ..............................34 
4.2 
Site Registration .....................................................................................................35 
4.3 
Patient Registration ................................................................................................37 
4.4 
General Guidelines .................................................................................................38 
5. 
TREATMENT PLAN ........................................................................................................38 
5.1 
Agent Administration .............................................................................................38 
5.2 
Dose Escalation ......................................................................................................41 
5.3 
Dose Expansion: ....................................................................................................43 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................43 
5.5 
Safety Monitoring ..................................................................................................44 
5.6 
Duration of Therapy ...............................................................................................45 
5.7 
Duration of Follow Up ...........................................................................................46 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................47 
6.1 
Olaparib and Ramucirumab Dose Modification Tables ........................................47 
6.2 
General Management of Adverse Events for Phase 1 and 2 ..................................47 
6.3 
Management of Specific Adverse Events for Phase 1 and 2: ................................49 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................58 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................58 
7.2 
Adverse Event Characteristics ...............................................................................62 
7.3 
Expedited Adverse Event Reporting ......................................................................62 
7.4 
Routine Adverse Event Reporting .........................................................................64 
7.5 
Secondary Malignancy ...........................................................................................64 

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7.6 
Second Malignancy ................................................................................................65 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................65 
8.1 
CTEP IND Agent(s) ...............................................................................................65 
8.2 
Commercial Agent .................................................................................................68 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................70 
9.1 
Integral Laboratory or Imaging Studies .................................................................70 
9.2 
Integrated Correlative Studies ................................................................................70 
9.3 
Exploratory/Ancillary Correlative Studies ............................................................71 
10. 
STUDY CALENDAR .......................................................................................................81 
11. 
MEASUREMENT OF EFFECT........................................................................................82 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................82 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................89 
12.1 
Study Oversight .....................................................................................................89 
12.2 
Data Reporting .......................................................................................................90 
12.3 
CTEP Multicenter Guidelines ................................................................................91 
12.4 
Collaborative Agreements Language .....................................................................92 
12.5 
Genomic Data Sharing Plan ...................................................................................93 
13. 
STATISTICAL CONSIDERATIONS...............................................................................93 
13.1 
Study Design/Endpoints.........................................................................................93 
13.2 
Sample Size/Accrual Rate ......................................................................................95 
13.3 
Stratification Factors ..............................................................................................96 
13.4 
Analysis of Secondary Endpoints ..........................................................................96 
13.5 
Reporting and Exclusions ......................................................................................97 
REFERENCES ..............................................................................................................................99 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................104 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATIONS .........................105 
AppendiX C 
PILL DIARY FOR OLAPARIB ..............................................................106 
APPENDIX D 
PATIENT DRUG INFORMATION HANDOUT AND 
WALLET CARD .............................................................................................................107 
APPENDIX E 
DIARRHEA MANAGEMENT ...............................................................110 
 
 
 

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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.12     Phase 1 Primary Objective: 
 
To determine the safe dose of olaparib with ramucirumab, but not to exceed olaparib dose of 
300mg twice daily (tablet formulation). 
 
1.13 Phase 2 Primary Objective:  
To determine the efficacy of olaparib plus ramucirumab as measured by the objective response 
rates (ORR) stratified by BROCA-HR biomarker status. 
 
 
1.2 
Secondary Objectives 
• To estimate median progression-free survival (PFS) stratified by BROCA-HR biomarker 
status. 
• To estimate median overall survival (OS) stratified by BROCA-HR biomarker status.  
• To measure the prevalence of the BROCA-HR biomarker in our study population. 
• To determine toxicity of olaparib and ramucirumab combination. 
 
1.3       Exploratory Objectives 
• To assess the correlation between the signature 3 status and mutations in BROCA-HR 
panel.  
• To evaluate the association between findings from BROCA-HR panel with response to 
therapy. 
• To evaluate the association between findings from BROCA-HR panel and signature 3 
results with response to therapy.  
• To determine results of immunoassay for poly-ADP-ribosylated (PAR) substrates in 
tumor tissue.  
• 
To create a PDX model to study DNA repair in gastric tumors treated with PARP 
inhibitors (PARPi) from both pre-treatment biopsy and repeat biopsy after 16 weeks of 
treatment. 
• 
Development of a novel genomic assay for BRCAness 
• 
Defining T cell receptor diversity of gastric cancer patients  +/- BRCAness 
• 
Biobank additional tumor tissue for future genomic analysis. 
• 
Biobank peripheral blood for future genomic analysis and assessment of circulating 
tumor DNA. 
 
2. BACKGROUND 
 
2.1 
Gastric and Gastroesophageal Adenocarcinoma  
 
Despite decreased incidence, gastric cancer remains a significant public health problem in the 
state of Connecticut, US, and globally. Moreover, the incidence of GEJ-centered 
adenocarcinomas has increased dramatically in Western countries over the past four decades. It 
is estimated that were will be 26,370 new cases of gastric cancer, and 16,910 new cases of 

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esophageal cancer, the majority of which are GEJ–centered adenocarcinomas, in the United Stats 
in 2016 [1]. Global gastric cancer incidence has declined with improved sanitation, food 
preparation and infection control, but the most recent global incidence remains high with 
951,600 cases in 2012 [2]. The five-year survival rate of gastroesophageal adenocarcinoma is 
<30% for all stages and < 4% for metastatic disease [3, 4].  It’s estimated that were will be 310 
deaths attributed to gastroesophageal cancer for Connecticut in 2016 [5]. Thus, gastric and GEJ 
adenocarcinomas remain highly lethal with early propensity for metastatic spread, and despite 
new therapies, improvement in survival has been modest [4].  
 
National Comprehensive Cancer Network (NCCN) guidelines for metastatic gastroesophageal 
adenocarcinoma recommend a platinum containing doublet or triplet in the first line setting, but 
median survival is less than 1 year [6]. Approved second-line regimens include ramucirumab as 
single agent or in combination with paclitaxel [7, 8]. Targeted therapy for HER2 positive disease 
with trastuzumab has been effective [9], but the role for other targeted agents remains unclear. 
Olaparib in combination with paclitaxel has shown mixed results in gastric cancers expressing 
low levels of the ataxia telangiectasia (ATM) protein and further study is ongoing [10]. Low 
levels of ATM protein are thought to be a sign of defective double stranded DNA repair 
mechanisms through interaction with BRCA [10]. Gastric cancer cell lines have demonstrated 
sensitivity to olaparib, which is even more pronounced with low levels of ATM expression [11]. 
 
Defective DNA repair is a widely known mechanism for cancer development. BRCA mutations 
result in defective DNA repair by causing defects within error-free homology-directed double 
strand break repair. Cells must then rely on the more error prone non-homologous DNA repair, 
which results in increased mutational burden within cells and predisposes to breast, ovarian, and 
pancreatic cancer. While the association between BRCA mutation and gastric cancer is weaker 
than the association with breast and ovarian cancer, recent data reveals that evidence of 
homologous recombination deficiency (HRD) may be present in up to 12% of non-BRCA 
mutated gastric cancers as determined by a molecular signature for HRD. This observation is 
discussed further in Correlative Studies Background, section 2.5.2 [12].  
 
Additional evidence supporting defective homologous repair in the pathogenesis of gastric 
cancer relates to mutations in reported in the DNA repair gene ATM. Mutations in ATM have 
been reported in 11% of gastric cancers, and found to be expressed at low levels in 14% of 
patients in a prospective study [10, 13, 14]. The BROCA-HR mutation panel developed by Dr. 
Swisher at the University of Washington is a gene panel that has been validated and is available 
to assess for the presence of mutations in 84 DNA repair genes. This panel contains 17 DNA 
repair genes with actionable mutations, including ATM and BRCA. Mutations within the 
BROCA-HR panel have been reported in more than 40% of gastric cancers reported in the 
cosmic database, and details regarding the panel are discussed further in the Correlative Studies 
Background, section 2.5.1 [15, 16]. The use of the BROCA-HR panel and the use of mutational 
signatures both present opportunities as biomarkers to identify tumors with defective 
homologous repair that may be more susceptible to the combination of ramucirumab and 
olaparib. The rationale for this combination is further described in section 2.4. A separate test, 
the Myriad HRD assay, measures homologous recombination in tumor cells. Homologous repair 
is measured by three components: loss of herozygosity, large-scale state transitions, and 
telomeric allelic imbalance [17]. The Myriad assay is currently under review for validation for 

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ovarian and breast cancer, but also presents an opportunity for use as a biomarker for defective 
homologous repair in gastric patients [17, 18]. 
 
2.2 
CTEP IND Agent(s) 
 
2.2.1 Olaparib (AZD 2281) 
 
Olaparib (AZD2281, KU-0059436) is a potent oral inhibitor of polyadenosine 5’diphosphoribose 
polymerase (PARP). PARP inhibition is a novel approach to targeting tumors that have 
homologous recombination DNA repair pathway deficiencies. In HRD tumors, single agent 
treatment with olaparib can lead to tumor regression by a process known as synthetic lethality- a 
result of the accumulation of un-repaired DNA double-strand breaks and an unsupportable 
increase in genomic instability. In synthetic lethality, neither the deficiency in homologous repair 
nor PARP inhibition is cytotoxic by itself, but the combination of both leads to cell death. 
 
Olaparib is the first PARP inhibitor approved by regulatory agencies for clinical indication. In 
the US, the FDA has approved olaparib as monotherapy for patients with deleterious or 
suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) in patients 
with advanced ovarian cancer who have been treated with three or more prior lines of 
chemotherapy. Additionally, the European Medicines Agency (EMA) approved olaparib as 
monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed 
BRCA-mutated (germline and/or somatic) high grade serous epithelial ovarian, fallopian tube, or 
primary peritoneal cancer who are in response (complete response or partial response) to 
platinum-based chemotherapy. 
 
The majority of completed studies were performed with the capsule formulation of olaparib. 
However since 2012/2013 most new studies, including the phase III registration studies, are 
being performed with the tablet formulation which was designed to deliver the therapeutic dose 
of olaparib in fewer dose units than the capsule.  
 
Mechanism of Action  
The mechanism of action for olaparib activity has been proposed to involve the trapping of 
inactivated PARP onto the single-strand breaks preventing their repair and generating a potential 
block for cellular DNA replication [19, 20]. An important consequence of this is that processing 
of trapped PARP-DNA complexes and/or the stalling of replication forks, or collapsing of 
replication forks leads to the generation of more serious DNA double stranded breaks [19, 20]. 
Under normal circumstances these double stranded breaks would be repaired by processes that 
involve ATM and additional homologous recombination DNA repair proteins such as RAD51, 
BRCA1, and BRCA2 (Olaparib IB v. 14). However, when homologous repair is not functioning 
cells must rely on the more error prone base-excision repair system, which requires PARP 
function. Homologous repair dysfunction sensitizes cells to PARP inhibition leading to further 
chromosomal instability, cell cycle arrest and apoptosis [21]. In cases where DNA repair defects 
may not result in the same level of sensitivity as BRCA mutations single agent olaparib may not 
be sufficient to induce cell kill through synthetic lethality. However, it may still be possible to 
induce tumor cell death through combinations with ionizing radiation or chemotherapies that 
either increases DNA damage accumulation or mitotic stress. Pre-clinical studies support these 

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findings, showing that other BRCA mutant, but not wild-type, human cell lines are highly 
sensitive to olaparib [22].   
 
Nonclinical Pharmacology and Efficacy  
Olaparib was developed as a PARP inhibitor from a targeted screening program of 
pharmacophores with the aim of enhancing killing actions of certain existing cancer 
chemotherapies such as topoisomerase I inhibitors and alkylating agents. Olaparib is an agent 
that has potential both as monotherapy as well as in combination with other cancer treatments 
[22].  
  
Multiple tumor cell lines have been investigated using colony formation assays for sensitivity to 
PARP inhibition with olaparib as a single agent. These cell lines have shown wide-ranging 
cellular activity from low nM to 10μM. The effective concentration for inhibiting cellular PARP 
activity in cancer cells by >90% is approximately 30 nM to 100 nM olaparib in several human 
tumor cell lines including ovarian A2780, breast MCF-7, and colorectal SW620. These 
concentrations led to significant ablation of PARP activity (based on the inhibition of PAR 
formation), with maximal PARP-1 inhibition occurring at around 100 nM. Consistent with this, 
maximal potentiation of an appropriate DNA SSB-inducing chemotoxic agent (MMS) was also 
seen in vitro at 100 nM, which equates to 43.4 ng/mL. 
 
Following single oral doses, absorption was rapid (maximum plasma concentration Cmax <2 
hours in mice, rats and dogs) while bioavailability was <60% in male and female mice, <20% in 
male and female rats and ~79% in male dogs (Olaparib IB v. 14). Low oral bioavailability in rats 
may have been due to poor absorption or rapid first pass metabolism. Distribution of olaparib is 
in the gastrointestinal tract and in tissues associated with the metabolism and elimination of 
foreign compounds. Further investigations are still ongoing. Excretion is primarily via the feces 
(65% to 75%) and, to a lesser extent, the urine (20% to 30%).  
 
Investigations in human in vitro systems indicated metabolism of olaparib was CYP mediated 
and that CYP3A4 and 3A5 were the dominant metabolic enzymes (Olaparib IB v. 14). Similar 
studies indicated flavin mono-oxygenase-3 was not able to metabolize olaparib. For in vitro 
direct inhibition assays, olaparib (0.1 to 500 μM) was a weak inhibitor of CYP3A (IC50 119 μM). 
Olaparib (0.1 to 100 μM) was also tested against CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 
and 2E1. At <100 μM olaparib, no significant direct inhibitor effect on CYPs 1A2, 2A6, 2B6, 
2C8, 2D6 or 2E1 was observed although more limited inhibition of CYP2C9 (22%) and 
CYP2C19 (26%) was observed. Regulatory guidance suggested clinically meaningful drug 
interaction due to olaparib directly inhibiting hepatic and GI tract CYP3A4/5 cannot be 
excluded. In time dependent inhibition assays, olaparib had only very minor effects against 
CYP3A and no effect against other CYPs.  
 
In studies using Madin-Darby Canine Kidney (MDCK) II cells transfected with multidrug 
resistance 1 (MDR1; Pgp), BCRP or MRP-2 drug efflux transporters, olaparib was shown to be a 
substrate of MDR1 but not BCRP or MRP-2 (Olaparib IB v. 14). Olaparib’s ability to inhibit 
MDR1, BCRP, and MRP-2 was also investigated. MDR1 and BCRP were expressed in MDCK 
II cells while MRP-2 was prepared in isolated membrane vesicles. Olaparib was shown to inhibit 
MDR1 (IC50 76 μM) and very weakly inhibit BCRP. Olaparib did not inhibit MRP-2. The 

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possibility for inhibition of hepatic uptake transporters OATP1B1, OATP1B3, OCT1 or NTCP 
was investigated. Olaparib was an inhibitor of OTAp1B1 and the IC50 (20.3 μM and 27.1 μM) 
was dependent on the substrate used. Olaparib was an inhibitor of OCT1 (IC50 37.9 μM), it 
caused no significant inhibition of OATP1B3 and was a very weak inhibitor of NTCP (IC50 >100 
μM) (Olaparib Investigator’s Brochure, 2015). 
 
Nonclinical Toxicology  
Non-clinical safety evaluation studies conducted with olaparib include single dose oral and iv 
studies in mice and rats, repeat dosing oral studies of up to 1 months duration in mice, pivotal 
repeat dosing studies of up to 6 months duration in rats and dogs, a battery of in vitro and in vivo 
genetic toxicity studies and reproductive toxicology studies in rats, which are summarized in 
section 4.3 (toxicology) of the Olaparib IB v. 14. There were no noted effects on the 
cardiovascular or respiratory parameters of an anesthesized dog or any behavioral, autonomic, or 
motor effects in the rat. Toxicology studies indicate that the target organ of toxicity is the bone 
marrow. Ex vivo work has confirmed that olaparib is also active against human marrow. The 
cytotoxic effect becomes evident at a higher concentration than required to fully ablate PARP 
activity. 28-day dog and rat studies demonstrate a reversible myelotoxic effect that is mild to 
moderate. Platelets are first affected, followed by white blood cells. In 26-week repeat-dose 
studies in rats, doses were well tolerated in male rats, with hematological effects and increased 
spleen weights observed at all dosages. In female rats, doses of 15 mg/kg/day resulted in 
significant reduction in body weight. Hematological effects and increased spleen weights were 
again observed at all dosages. The difference between sexes was considered to be due to the fact 
that females had greater plasma exposure levels than males. In 26-week repeat-dose studies in 
dogs, olaparib was well tolerated. Hematological changes were observed, characterized by 
pancytopenia.  
 
Clinical Pharmacology – Single-dose Tablet Data (Olaparib IB v. 14)  
Following administration of single oral doses of the tablet formulation at doses of 25, 50 and 250 
mg (n=6 per cohort), absorption was rapid and slightly more rapid than the capsule dose. The 
peak plasma concentration was typically achieved at 1.5 hours. Following the peak, plasma 
concentrations declined in a biphasic manner with an average terminal elimination t1/2 of 12.2 
hours (Sd 5.31 hours) and 13.02 hours (Sd 4.16 hours). The Gmean apparent oral plasma 
clearance was approximately 7.95 L/h and 6.36 L/h. The volume of distribution was greater than 
total body water indicating that olaparib was distributed into the tissues, 146.2 L and 112.1 L. 
The observed variability in exposure was moderate to high, the Gmean %CV for AUC and Cmax 
following 300 mg single dose olaparib ranged from 24.3% to 67.4%. 
 
The relative bioavailabilities of the tablet formulation (compared to capsule) at the 3 dose levels 
studied are shown in Table 10 in the Olaparib Investigator’s Brochure, 2015. At the 2 lower 
tablet doses (25 and 50 mg), following normalization for dose, although the Cmax achieved after 
dosing with the tablet formulation tended to be higher than that with the capsule, the AUC values 
for the 2 formulations were actually very similar. However, at the highest tablet dose (250 mg), 
the exposure delivered by the tablet formulation (both dose-normalized Cmax and AUC) was 
higher than that delivered by the capsule. The tablet and the capsule formulations cannot 
therefore be considered to be bioequivalent. 
 

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Safety Profile: As of 15 December 2016, approximately 6558 patients are estimated to have 
received olaparib in the clinical programme including AstraZeneca-sponsored studies (3923 
patients), a MAP (676 patients), ISSs and collaborative group studies (1959 patients). An 
estimated 4475 patients with ovarian, breast, pancreatic, gastric and a variety of other solid 
tumors are estimated to have received treatment with olaparib in AstraZeneca-sponsored, 
interventional studies (3799 patients) and the MAP (676 patients). Since 2012/2013, most new 
clinical studies have utilized the tablet formulation which was designed to deliver the therapeutic 
dose of olaparib in fewer dose units than the capsule. Of the 4475 patients, 2109 received the 
capsule formulation, 2341 received the tablet formulation, and 25 received both capsule and 
tablet. In the AstraZeneca-sponsored, interventional studies, olaparib was given either as 
monotherapy (2618 patients) or in combination with chemotherapy or other anti-cancer agents, 
including studies where patients received monotherapy and combination therapy sequentially 
(n=1181).  
 
Data from the available pre-clinical studies and subsequent clinical development programme 
demonstrate that olaparib appears to be active and generally well tolerated in patients with solid 
tumours including those with BRCA mutated cancers. In ovarian cancer, responses have been 
seen in all patient groups, including platinum resistant and refractory cancer.  
 
From the available data to date in patients with advanced cancer, there is no evidence of any 
unexpected toxicity following long-term olaparib (capsule) monotherapy exposure.  
 
Adverse laboratory findings and/or clinical diagnoses considered to be associated with 
administration of olaparib monotherapy include hematological effects (anemia, neutropenia, 
lymphopenia, thrombocytopenia, MCV elevation and increase in blood creatinine), nausea and 
vomiting, decreased appetite, diarrhea, dyspepsia, stomatitis, upper abdominal pain, dysguesia, 
fatigue (including asthenia), headache and dizziness. Most of these events were generally mild or 
moderate in intensity.  
 
In a relatively small number of patients, pneumonitis, MDS/AML and new primary malignancies 
have been observed. Evidence from across the development programme for olaparib does not 
support a conclusion that there is a causal relationship between olaparib and these events. There 
are important potential risks for olaparib and are being kept under close surveillance.  
 
 
Data from studies of olaparib in combination with various chemotherapy agents indicate an 
increase in bone marrow toxicity (anemia, neutropenia, thrombocytopenia) greater than expected 
if the agents had been administered alone. The effects are generally transient but treatment 
delays are common and alternative administration schedules/toxicity management processes are 
currently being evaluated within some of these studies. When this type of toxicity has occurred it 
has been managed by routine clinical practice including dose delays, dose reductions, 
intermittent dosing and/or the use of supportive care measures, including G-CSF. Currently, all 
ongoing olaparib combination studies are being closely monitored for myelotoxicity. Results of a 
Phase II study in combination with carboplatin/paclitaxel (Study D0810C0041) showed that 
addition of olaparib to carboplatin AUC 4 + paclitaxel in the chemotherapy phase had a 
generally similar tolerability profile to carboplatin AUC 6 + paclitaxel. The regimen of olaparib 

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capsule 200 mg bd for 10 days out of 21, with carboplatin AUC 4 + paclitaxel had an acceptable 
and manageable tolerability profile in patients with recurrent serous ovarian cancer. Olaparib 
tolerability during the monotherapy maintenance phase was consistent with the previously 
known safety and tolerability profile. In Study D0810C00039 and Study 081BC00004, olaparib 
100 mg tablet bd in combination with weekly paclitaxel 80 mg/m2 was well tolerated, with no 
new unexpected safety findings. In both studies, the incidence of neutropenia was higher for the 
olaparib combination arm and this contributed to higher rates of dose modifications for patients 
on olaparib compared to placebo. In Study D081BC00004, there was also a higher incidence of 
anemia on the olaparib + paclitaxel combination arm than the placebo + paclitaxel arm and more 
dose interruptions, reductions and discontinuations. 
 
Important potential risks  
Myelodysplastic syndrome/acute myeloid leukemia: 
The incidence of MDS/AML in patients treated in clinical trials with olaparib monotherapy, 
including long-term survival follow-up, was <1.5% and the majority of events had a fatal 
outcome. 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 germline BRCA mutation carriers 
and some of the patients had a history of previous cancer 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. 
 
New Primary Malignancies other than MDS/AML: 
New primary malignancies have been reported in <1% 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. 
 
Pneumonitis: 
Pneumonitis has been reported in <1.0% patients treated with olaparib monotherapy in clinical 
studies. Reports of pneumonitis had no consistent clinical pattern and were confounded by a 
number of pre-disposing factors (cancer and/or metastases in lungs, underlying pulmonary 
disease, smoking history, and/or previous chemotherapy and radiotherapy). When olaparib was 
used in clinical studies in combination with other therapies there have been events with a fatal 
outcome. If patients present with new or worsening respiratory symptoms such as dyspnea, 
cough and fever, or an abnormal chest radiologic finding is observed, olaparib treatment should 
be interrupted and prompt investigation initiated. If pneumonitis is confirmed, olaparib treatment 
should be discontinued and the patient treated appropriately. 
 
Laboratory toxicities:  
From the completed studies, there are no safety concerns noted for the renal or hepatic 
parameters measured and no clinically significant changes of concern relating to coagulation 
parameters. Changes observed in the hematological parameters (decreased hemoglobin, 
neutrophils, thrombocytes and lymphocytes) are known to be associated with olaparib 
monotherapy and/or can be explained by co-existing conditions/previous chemotherapy. Mean 

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corpuscular volume increases have also been observed with olaparib. The clinical significance of 
this laboratory finding is unknown. Data from Phase 1 and Phase 2 studies of olaparib in 
combination with various chemotherapy agents indicate an increase in neutropenia, 
thrombocytopenia, and anemia compared to giving these agents alone. These findings are 
consistent with pre-clinical findings and are reflected in the more severe hematological events 
i.e., CTCAE Grade 4 neutropenia, febrile neutropenia and thrombocytopenia being reported as 
SAEs.  
 
Mild elevations in creatinine with no apparent sequelae have been observed in the absence of an 
elevation in urea or blood urea nitrogen or a reported abnormality on urinalysis. The clinical 
significance of these mild elevations in creatinine is unknown but inhibition of organic cation-
transporter-2 by olaparib is considered a plausible mechanistic explanation.  
 
Clinical Efficacy:  
 
The regulatory approvals of olaparib were based on study D0810C00019. This was a Phase 2, 
randomized, double-blind, multicenter study to assess the efficacy of olaparib (capsule 
formulation) in the treatment of patients with platinum sensitive serous ovarian cancer, following 
treatment with 2 or more platinum containing regimens [23]. Patients that responded to platinum 
based chemotherapy were randomly assigned to maintenance therapy with either placebo or 
olaparib at a dose of 400mg twice daily. The primary endpoint was PFS according to the 
RECIST guidelines. Of the 265 patients randomized into the study, all olaparib (136) and 
128/129 placebo patients received study treatment. PFS was significantly longer with olaparib 
than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of 
chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 
0.49; P<0.001). Subgroup analyses of PFS showed that, regardless of subgroup, patients in the 
olaparib group had a lower risk of progression. The investigators concluded that olaparib as 
maintenance treatment significantly improved PFS among patients with platinum-sensitive, 
relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. 
The toxicity profile of olaparib in this population was consistent with that in previous studies.  
 
Fong et al reported the result of a phase 1 study in a study population enriched in carriers of a 
BRCA1 or BRCA2 mutation [24].The investigators enrolled and treated 60 patients; 22 were 
carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA-associated 
cancer but declined to undergo mutational testing. The olaparib dose and schedule were 
increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously. 
Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice daily 
(grade 3 mood alteration and fatigue) and two of five patients receiving 600 mg twice daily 
(grade 4 thrombocytopenia and grade 3 somnolence). This led to enrollment of another cohort, 
consisting only of carriers of a BRCA1 or BRCA2 mutation, to receive olaparib at a dose of 200 
mg twice daily. Other adverse effects included mild gastrointestinal symptoms. There was no 
obvious increase in adverse effects seen in the mutation carriers. Pharmacokinetic data indicated 
rapid absorption and elimination; pharmacodynamic studies confirmed PARP inhibition in 
surrogate samples (of peripheral-blood mononuclear cells and plucked eyebrow-hair follicles) 
and tumor tissue. Objective antitumor activity was reported only in mutation carriers, all of 
whom had ovarian, breast, or prostate cancer and had received multiple treatment regimens.  

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In an expansion phase in BRCA-deficient ovarian cancer at a dose of olaparib 200 mg BID, fifty 
patients were treated, including 48 with BRCA-deficient germline mutations and two patients of 
unknown status or significance. Twenty (40%) patients achieved complete response (CR) or 
partial response (PR) by RECIST and/or GCIG-CA125 criteria. An additional three patients 
experienced stable disease (SD) for more than four cycles [25]. A multicenter phase 2 study 
enrolled two sequential cohorts of women with known germline BRCA1 or BRCA2 mutations 
and recurrent advanced ovarian cancer to receive olaparib continuously at a dose of 400 mg BID 
(Cohort 1) or 100 mg BID (Cohort 2) [26]. Responses were observed in 33% (11 of 33) patients 
enrolled in the 400mg BID cohort and 13% (3 of 24) patients enrolled in the 100 mg BID cohort. 
A phase 2 study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer 
showed ORR of 41% in ovarian patients with BRCA1 or BRCA2 mutations and 24% without 
mutations and no confirmed responses in patients with breast cancer [27]. 
 
Kaufman et al reported the results from the phase 2 study of olaparib monotherapy in patients 
with advanced solid cancer and germline BRCA1/2 mutation [28]. Olaparib was given 400mg 
twice a day and the primary endpoint was tumor response rate. A total of 298 patients received 
treatment and were evaluable. The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 
31.6) overall and 31.1% (60 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 
23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in 
ovarian, breast, pancreatic, and prostate cancers, respectively. Stable disease ≥ 8 weeks was 
observed in 42% of patients (95% CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% 
(95% CI, 34.0 to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with 
ovarian, breast, pancreatic, or prostate cancer, respectively.  
 
Lee and Kohn and colleagues have examined olaparib with carboplatin in two schedules in 
BRCA1/2 mutation carriers with breast and/or ovarian cancer and women with high grade serous 
ovarian cancers[29]. They also observed clinical activity with over 80% of ovarian cancer 
patients attaining either SD or PR lasting up to 18+ months. Additional phase 1 and 2 trials in 
both BRCA-deficient and BRCA-competent ovarian cancer are currently ongoing. 
 
 
2.3 
Other Agent: Ramucirumab (Cryamza) 
 
Pathways that mediate angiogenesis are considered important targets in cancer drug development 
and drugs that target this pathway have been correlated with multiple outcomes. Vascular 
endothelial growth factors (VEGFs; including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and 
placental growth factor) have emerged as key regulators of angiogenesis and the expression of 
VEGFs has been correlated with poor prognosis in several solid tumor types, including gastric 
adenocarcinoma. 
 
A comprehensive clinical development program to assess ramucirumab in the treatment of solid 
tumor malignancies was initiated following Phase 1 studies evaluating dose, schedule, and 
toxicity. The clinical development has focused on tumors where VEGF ligands (including 
VEGF-A) and VEGF-R2 are overexpressed and where the unmet medical need is high [30, 31]. 
 
 

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Mechanism of Action 
 
Ramucirumab is a human receptor-targeted antibody that specifically binds VEGF Receptor 2 
(VEGF-R2). The binding of ramucirumab to VEGF-R2 prevents its interaction with activating 
ligands, VEGF-A, VEGF-C, and VEGF-D [31, 32]. As a result, ramucirumab inhibits ligand-
stimulated activation of VEGF-R2, thereby inhibiting ligand-induced proliferation, downstream 
signaling components including Erk1/Erk2, and migration of human endothelial cells [33, 34]. 
Preclinical data for DC101, a neutralizing rat anti-mouse mAB specific for murine VEGF-R2, 
demonstrate antitumor activity in multiple tumor models. 
 
Nonclinical Pharmacology, Efficacy and Toxicology (Ramucirumab Investigator’s 
Brochure 2014) 
 
The pharmacokinetics (PK) and toxicokinetics (TK) of ramucirumab were determined in 
cynomolgus monkeys. The PK behavior of ramucirumab in monkeys was typical of a 
monoclonal antibody. The PK was nonlinear and showed antibody accumulation with repeated 
doses. The formation of antidrug antibodies (ADA) was assessed in all primate studies, and 
generally indicated the presence of ADA in individual animals; however, the predictive value of 
this finding for the occurrence of immunogenicity in humans is unclear. Formal studies to 
characterize the disposition, excretion, and metabolism of ramucirumab have not been 
conducted. As a monoclonal antibody, ramucirumab will be largely confined to the extracellular 
space and elimination is primarily by catabolism of the antibody.  
 
PK and TK of ramucirumab in cynomolgus monkeys was obtained in 5 and 39 week repeat-dose 
toxicology studies. Animals were administered IV doses of 0, 4, 12, or 40 mg/kg ramucirumab 
DP weekly and blood samples for ramucirumab concentration analysis in serum were obtained 
after the first dose.  
 
Non-compartmental analysis of the contentration-vs-time data from the monkey toxicology 
studies indicated that the PK behavior of ramucirumab was non-linear over the 4-50 mg/kg dose 
range. Ramucirumab half-life increased and clearance decreased with increasing dose. The 
steady-state volume of distribution was approximately equal to the vascular space at each dose 
level. Mean ramucirumab AUC in the 50mg/kg group increased between the first and 39th doses, 
indicating that drug accumulation occurred. Antibodies against ramucirumab were detected in 
the 4, 12, and 40 mg/kg dose groups in the 5 week study and in the 5, 16 mg/kg dose groups in 
the 39 week study. The PK behavior of ramucirumab in monkeys is thus nonlinear and typical of 
a monoclonal antibody. 
 
The toxicity of IV ramucirumab was evaluated in monkeys that received 4 doses over 5 weeks, 
or weekly doses for up to 39 weeks. The effect of ramucirumab was also assessed in an 
incisional model of wound healing after a single IV dose, and no impairment in wound healing 
was observed. Focal muscle fiber degeneration and mononuclear cell infiltration were seen in 
skeletal muscle in ramucirumab treated animals only, but were concluded to not be treatment 
related due to the focal nature of lesions and low incidence in females. No ramucirumab related 
adverse events were evident in the routine toxicological assessments. Treatment of monkeys with 
ramucirumab for 39 weeks resulted in renal toxicity at doses of 16 and 50 mg/kg and thickening 

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and osteochondropathy of the epiphyseal growth plate noted at 5 mg/kg and above. Thus a no 
observable adverse effect level for ramucirumab was not established when administered to 
monkeys once a week for 39 weeks.  
 
Nonclinical in vitro pharmacodynamics studies demonstrated that ramucirumab possesses high 
affinity for VEGF receptor 2 and that picomolar concentrations of the antibody can inhibit 
binding of VEGF in vitro. Thus ramucirumab potently inhibits VEGF-mediated VEFR2 
activating, signaling, and biologic effects in endothelial cells. These responses include cell 
migration, proliferation, and survival. Pharmacological proof-of principle experiments that 
validated targeting VEGFR2 as an antiangiogenic strategy depended on the use of a surrogate 
antibody, DC101.  
 
The preclinical pharmacodynamics data demonstrated that ramucirumab binds specifically and 
with high affinity to human VEGFR2, and not to murine VEGFR2 or the related human VEGF 
receptors, VEGF receptor 1 and VEGF Receptor 3. Additionally, ramucirumab is capable of 
inhibiting the relevant in vitro biological consequences of VEGF stimulated activation of 
VEGFR2. The antiangiogenic and antitumor effects observed in mice treated with DC101 
provide the basis to anticipate potent antiangiogenic effects of ramucirumab in human cancers.   
 
Clinical Pharmacology 
 
Serum ramucirumab concentrations were determined using either an original bioanalytical assay 
or a modified bioanalytical assay. The original PK assay was modified and validated to meet the 
industry bioanalytical assay standards. Only data using the modified assay are considered the 
primary source for ramucirumab PK characterization and are presented.  
 
For gastric cancer, trough concentrations (or minimum concentrations) were collected in both the  
Phase 2 and 3 studies for the REGARD and RAINBOW clinical trials. Using the dosing regimen 
of ramucirumab 8 mg/kg every 2 weeks the observed minimum concentration values were 
similar between both REGARD and RAINBOW. The mean observed trough values were 
approximately 50 μg/mL and approximately 60 to 70 μg/mL before the fourth and seventh doses, 
respectively.  
 
In a pooled analysis of 11 studies involving 1639 patients across multiple cancers revealed the 
volume of distribution at steady state (Vm) and terminal half life were 0.0147 L/h (30.0%) and 
5.4L (15.0%) and 14 days (20.0%) respectively. Results from this pooled analysis indicate that 
the PK of ramucirumab following 8 and 10 mg/kg dose administrations were linear and time 
independent. Covariate analysis indicate that ramucirumab is not affected by body weight, sex, 
age, serum albumin, race, hepatic status, and renal function. 
 
Two dedicated studies were conduced to assess the effect of concomitant ramucirumab 
administration on the PK of paclitaxel and docetaxel. In study 14T-IE-JVCA was demonstrated 
that concomitant administration of ramucirumab had no effect on the dose normalized AUC and 
Cmax of paclitaxel. Similarly in study 14T-IE-JVCB dose normalized AUC and Cmax of 
irinotecan and SN-38 in cycle 2 were similar to those when FOLFIRI was administered alone in 
cycle 1, which suggests that concominant administration of ramucirumab is unlikely to impact 

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the PK of irinotecan and its active metabolite SN-39. In study 14T-IE-JVCC the dose-normalized 
AUC and Cmax of docetaxel were similar whether docetaxel was administered with or without 
ramucirumab, which suggests that concominant administration of ramucirumab is unlikely to 
impact the PK of docetaxel.  
 
Safety Profile 
 
Weekly doses of ramucirumab ranging from 2 to 16mg/kg were evaluated in the Phase 1 study 
JVBM. An MTD for weekly dosing was identified as 13 mg/kg. Every-2-week (6 to 10 mg/kg) 
and every-3-week (15 to 20mg/kg) dose regimens were evaluated in an additional dose ranging 
study (Study JVBN). All dose regimens in study JVBN were well tolerated and no MTD was 
identified in this study. 
 
REGARD demonstrated a well-tolerated safety profile in the gastric cancer monotherapy setting. 
Due to the low incidence of hypertension and neutropenia, no safety-exposure relationship was 
identified. 
 
In RAINBOW, the overall safety profile was also considered management, although increasing 
ramucirumab exposure was correlated with increased incidence of Grade 3 or greater 
hypertension, neutropenia, and leukopenia. Of note, there were no Grade 4 or 5 hypertension 
events in RAINBOW. Hypertension was managed primarily by the use of standard 
antihypertensive medication, and the association of neutropenia with ramicurmab exposure does 
not appear to translate to an increased risk of febrile neutropenia with higher ramucirmab 
exposure. 
 
Laboratory Toxicities 
 
In study 14T-MC-JVBT(ramucirumab and FOLFOX) the overall safety profile for ramucirumab 
revealed the most common Grade ≥3 AE reported regardless of causality was: 
a. Neutropenia 22 patients (26.8%) in ramucirumab arm vs 29 patients (36.3%) in placebo 
arm 
b. Fatigue 15 patients (18.3%) in ramucirumab arm vs 12 patients (15.0%) in placebo arm 
c. Neuropathy 7 patients (8.5%) in ramucirumab arm vs 9 patients (11.3%) in placebo arm 
22 patients (26.8%) in ramucirumab arm vs 29 patients (36.3%) in placebo arm 
 
In study 14T-IE-JVBD (REGARD) the most common Grade ≥3 was: 
d. Hypertension 7.6% in ramucirumab arm vs 2.6% in placebo arm 
 
In study 14T-IE-JVBE (RAINBOW) the most common Grade ≥3 was: 
e. Fatigue  11.9% in ramucirumab arm vs 5.5% in placebo arm 
f. Neutropenia 40.7% in ramucirumab arm vs 18.8% in placebo arm 
g. Leukopenia 17.4%% in ramucirumab arm vs  6.7% in placebo arm 
h. Hypertension 14.1% in ramucirumab arm vs 2.4% in placebo arm 
 
Clinical Efficacy 
 

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Several factors provided rationale for further clinical development of ramucirumab in gastric 
cancer; these include contribution of angiogenesis to cancer pathogenesis, and preclinical 
evaluations of the rat antibody to murine VEGF-R2, DC101. Ramucirumab does not cross react 
with the murine VEGF-R2, and for this reason DC101 was used in murine models, and 
preliminary evidence of potential activity of other antiangiogenic agents in gastric cancer [35, 
36].  
 
Clinical activity was seen early in the development of ramucirumab. In Phase 1 studies, 
ramucirumab was generally well tolerated and exhibited preliminary evidence of anti-tumor 
activity in patients with solid tumors. The maximum tolerated dose (MTD) of ramucirumab was 
identified to be 13 mg/kg when given once weekly in the phase 1 dose-escalation study, Study 
14T-IE-JVBM (JVBM). Preliminary activity was observed across a range of doses, including the 
2-mg/kg weekly dose. Every-2-week (6 to 10 mg/kg) and every-3-week (15 to 20 mg/kg) dose 
regimens were evaluated in an additional dose-ranging study, 14T-IE-JVBN (JVBN). No MTD 
was identified for every-2-week or every-3-week dosing; all dose regimens were well tolerated, 
and preliminary evidence of clinical efficacy was observed across a range of dose/schedule 
cohorts [7].  
 
Two dose regiments, 8 mg/kg every 2 weeks and 10 mg/kg were selected in the subsequent 
phase 2 and phase 3 studies. The ramucirumab dose of 8 mg/kg every 2 weeks has demonstrated 
a statistically significant and clinically meaningful benefit in OS in the phase 3 REGARD study: 
ramucirumab plus BSC vs placebo plus BSC with advanced gastric cancer. Median OS was 5.2 
months in the ramucirumab arm versus 3.8 months in the placebo arm (Hazard ratio = 0.776, 
95% confidence interval [CI]: 0.603, 0.998; p=0.47). Ramucirumab was well tolerated in this 
patient population with similar rates for most adverse events (AEs) between the ramucirumab 
and placebo arms. Rates of hypertension were higher in the ramucirumab arm than in the placebo 
arm (38 [16%] vs 9 [8%]), whereas rates of other AEs were mostly similar between arms (223 
[94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab arm and 2 (2%) in the placebo arm 
were considered to be related to study drug. Based on this benefit, ramucirumab monotherapy 
was approved as a second line treatment for metastatic gastric cancer.   
 
The approval of ramucirumab in combination with paclitaxel in patients with advanced gastric or 
GEJ cancer whose disease has progressed after prior platinum/fluoropyrimidine-based 
chemotherapy was based on the randomized RAINBOW Phase 3 study [8]. The primary 
endpoint of OS was met; median OS was 9.63 months on the ramucirumab plus paclitaxel arm 
compared with 7.36 on the placebo plus paclitaxel arm (HR=0.807, 95% CI: 0.678, 0.962; 
p=.0169). Grade ≥ 3 AEs occurring in >5% of patients on the ramucirumab plus paclitaxel arm 
were: neutropenia (40.7% ramucirumab plus paclitaxel arm; 18.8% placebo plus paclitaxel arm), 
leukopenia (17.4% vs 6.7%), hypertension (14.1% vs 2.4%), anemia (9.2% vs 10.3%), fatigue 
(7.0% vs 4.0%), abdominal pain (5.5% vs 3.3%), and asthenia (5.5% vs 3.3%). Febrile 
neutropenia was reported in 3.1% in the ramucirumab plus paclitaxel arm and 2.4% placebo plus 
paclitaxel arm.  
 
A placebo-controlled, double-blind phase 2 study, 14T-MC-JVBT (JVBT), of ramucirumab in 
combination with mFOLFOX-6 as first line therapy for advanced adenocarcinoma of the 
esophagus, GEJ or stomach (N=168) showed no improvement in the primary endpoint of 

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progression-free survival. Median PFS was 6.4 months for the ramucirumab arm vs 6.7 months 
for the placebo arm; stratified HR=0.98, 95% CI: 0.69, 1.37; p=0.886), or the secondary OS 
endpoint (median OS was 11.7 months vs 11.5 months; stratified HR=1.08, 95% CI: 0.73, 1.58; 
p=.712), but did lead to improved PFS rate at 3 months (89.0% versus 75.3%) and an improved 
disease control rate (DCR)(84.5% vs 66.7%; p=0.008). The majority of patients had a primary 
tumor location involving the GEJ/cardia/esophagus (76.8%), with nearly half of the patients 
(47.6%) with a primary tumor location of esophagus. Progression-free survival was similar for 
all subgroups pairings with the exception of primary tumor location. In a preplanned subgroup 
analysis, an improvement in PFS (as assessed by HR) was observed for ramucirumab in patients 
with a primary tumor location of gastric/GEJ/cardia (median PFS was 8.7 months for the 
ramucirumab arm vs 7.1 months in the placebo arm; HR=0.77) compared to patients with a 
primary tumor location of esophagus (median PFS was 5.6 months vs 6.1 months; HR=1.30). A 
higher rate of discontinuation from study treatment for reasons other than progressive disease 
(PD) in the ramucirumab arm compared with the placebo arm was observed (50% vs 19%), 
which led to lower study drug exposure in the experimental arm. These observations may have 
had a negative impact on the results of the PFS assessment of the entire study population. 
Overall, the safety profile for ramucirumab in this study was consistent with the known safety 
profile of ramucirumab. The most common ≥ 3 AE (by consolidated AE) reported was 
neutropenia (26.8% ramucirumab arm vs 36.3% placebo arm). Fatigue (18.3% in the 
ramucirumab arm vs 15.0% in the placebo arm) and neuropathy (8.5% vs 11.3%) were the most 
common Grade ≥ 3 AEs (by consolidated term) reported at a similar frequency in each arm. The 
following treatment-emergent adverse events (TEAEs) (by consolidated term) were reported 
more frequently (≥ 5% greater) in the ramucirumab arm than in the placebo arm for 
thrombocytopenia (56.1% vs 38.8%), headache (23.2% vs 15.0%), hypokalemia (19.5% vs 
8.8%), hypocalcaemia (9.8% vs 2.5%), and hypophosphatemia (7.3% vs 1.3%). Grade ≥ 3 
adverse events of special interest (AESIs) were uncommon with the exception of hypertension 
(15.9% vs 3.8%).  
 
More information about the known and expected benefits, risks, and reasonably anticipated AEs 
of ramucirumab are found in the Investigator’s Brochure (IB). Information on AEs expected to 
be related to ramucirumab may be found in Section 7 (Development Core Safety Information) of 
the IB.  
 
Ramucirumab has been approved by the US FDA as a single agent and in combination with 
paclitaxel for the treatment of patients with advanced or metastatic, gastric or GEJ 
adenocarcinoma after fluoropyrimidine- or platinum-containing chemotherapy (CYRAMZA 
package insert [PI]. 
 
The approval of ramucirumab as a single agent was based on clinical efficacy and safety 
demonstrated in the randomized Phase 3 study, REGARD, which compared ramucirumab 
monotherapy with best supportive care in patients with advanced gastric or GEJ adenocarcinoma 
whose disease had progressed after prior chemotherapy [7].   
 
In both the REGARD and RAINBOW trials, which were conducted in the second-line setting, 
ramucirumab was administered at a dose of 8mg/kg every 2 weeks (REGARD), and 8mg/kg on 
Day 1 and Day 15 using a 28-day schedule (RAINBOW). In summary, the dosing regimen of 

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8mg/kg every 2 weeks is anticipated to produce an acceptable benefit-risk profile in patients with 
metastatic gastric or GEJ adenocarcinoma as second-line treatment.  
 
2.4 
Rationale for the Combination of Olaparib and Ramucirumab 
 
The process of DNA damage repair is complex, and additional alterations beyond BRCA 1 and 2 
play a role in sensitivity to PARP inhibition. This has led to the concept of “BRCAness,” and we 
propose that the BROCA-HR panel can help identify patients with the BRCAness phenotype in 
addition the more typical BRCA mutations. Preclinical work has shown that hypoxia may induce 
BRCAness, which can potentially be taken advantage of through the combined effects of 
VEGF/VEGF receptor (VEGFR) and PARP inhibition.  
 
Hypoxia has been shown to down regulate BRCA 1 expression through promoter modification 
by E2F4 complexes, which results in decreased homologous repair in human cancer cell lines 
[37-39]. Subsequent work has shown that gene silencing of BRCA 1 can occur through 
epigenetic modification by H3K9 methylation of the BRCA 1 promoter, which is potentiated 
under hypoxic conditions [38]. These modifications result in genetic instability, as cells then 
must rely on non-homologous DNA repair, which is more error prone. Similar findings have has 
also been reported for RAD51, another gene involved in the homologous repair pathway [38, 40-
42].  
 
As expected the exact opposite changes were seen in VEGF expression under hypoxic 
conditions, which further supports the potential synergy for PARP and VEGF/VEGFR inhibition 
[38]. Data also exists that PARP inhibitors themselves likely inhibit tumor angiogenesis [43]. 
The argument for synergy was strengthened by evidence in cancer cell lines that revealed 
increased lethality with PARP inhibitors in hypoxic conditions as compared to normoxic 
conditions [44]. Subsequently, VEGFR3 inhibition in ovarian cell lines has also been shown to 
result in reduced BRCA expression [45].  
 
Based on these pre-clinical observations, a phase 2 trial comparing olaparib and cediranib to 
olaparib alone for metastatic ovarian cancer was recently completed. Significant improvement in 
progression-free survival was seen with the combination of cediranib and olaparib, and the 
benefit was observed for both BRCA mutated and non-BRCA mutated individuals [46]. A phase 
3 study is currently ongoing to confirm these findings.  
 
These pre-clinical and clinical observations of synergy between PARP and angiogenesis 
inhibition in BRCA-deficient tumors provide rationale for combining olaparib with ramucirumab 
in tumors characterized by defective homologous DNA repair pathway. Ramucirumab is a fully 
humanized IgG1 monoclonal antibody that binds to VEGFR-2 and blocks VEGF-A, VEGF-C, 
and VEGF-D binding and receptor-mediated pathway activation. Ramucirumab is approved for 
second-line therapy in gastroesophageal adenocarcinoma.  In this setting ramucirumab is well 
tolerated and has been shown to significantly extend progression-free survival compared to best 
supportive care.  
 
As noted above, the olaparib and cediranib combination resulted in high response rates 
regardless of the presence of BRCA mutations. Based on this we anticipate responses in both 

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biomarker positive and negative cohorts given the proposed synergy with this combination 
therapy. Thus, we propose an open-label single arm study of olaparib in combination with 
ramucirumab for metastatic gastric adenocarcinomas with the use of the BROCA-HR integrated 
biomarker, which is described in further detail below in section 2.5.1. 
 
2.5 
 Correlative Studies Background 
 
2.5.1 BROCA-HR Panel 
Aim: To determine whether mutations in HRD genes confer sensitivity to ramucirumab and 
olaparib. 
 
BRCA1 and BRCA2 (BRCA1/2) are tumor suppressor genes, in which inherited loss-of-function 
mutations confer a high lifetime risk of breast and ovarian carcinoma. BRCA1/2 are key 
components of the BRCA-Fanconi anemia (FA) pathway, which is critical to homologous 
combination-mediated DNA repair. Other genes in this pathway (BRIP1/FANCJ, 
PALB2/FANCN, RAD51C/FANCO, RAD51D) also contribute to hereditary breast and ovarian 
cancer [47-51], and as our sequencing efforts have increased mutations in these same genes have 
been recognized in other cancers, including gastric cancer. The Cancer Genome Atlas Network 
(TCGA) suggested that up to half of serous ovarian carcinomas have homologous recombination 
defects (HRD), but that estimate was based on a variety of molecular findings, many with 
uncertain impact on DNA repair function[52]. PARP inhibitors (PARPi) demonstrate synthetic 
lethality in cells with HRD, including cells deficient in BRCA1/2 [21, 53]. Recurrent ovarian 
carcinomas in BRCA1/2 mutation carriers have an approximate 40% response rate to PARPi and 
also have an increased response to platinum-based chemotherapy [54]. Importantly, 
approximately 25% of serous ovarian cancers that are wildtype for BRCA1/2 also respond to 
PARPi [27]. 
 
Germline BRCA1/2 mutations are the prototype molecular alterations that confer HRD [21, 53]. 
BRCA1 and BRCA2 somatic mutation occur in approximately 6% of ovarian cancer cases and 
also appear to confer sensitivity to PARPi [55]. Of note, PARPi also selectively kill cells in vitro 
that are deficient in other homologous recombination (HR) genes including RAD51D, NBN, 
ATM, and CHEK2 [47, 56].  Germline and somatic mutations in BRCA1/2 and other BRCA-FA 
genes in ovarian carcinomas are associated with improved response to primary platinum therapy 
and longer overall survival [57]. Germline and somatic BRCA-FA mutations are not limited to 
high-grade serous ovarian carcinomas, but can be found in all histological sub-types with the 
exception of mucinous carcinomas [57].  
 
In order to respond to a PARPi, cancer cells need to be deficient in HR but also proficient in the 
alternative error prone non-homologous end joining (NHEJ) DNA repair pathway [58, 59]. Thus, 
loss of HR is not, by itself, sufficient for PARPi sensitivity, and an accurate predictor of PARPi 
responsiveness could require assessment of many components of both the HR and NHEJ 
pathways. A more efficient assay, which would not require a prior knowledge of the critical 
elements in these DNA repair pathways, would instead measure DNA repair capacity. Recent 
evidence suggests that BRCA1/2 deficient cancers exhibit global DNA alterations termed 
“genomic scarring” that are consistent with their reliance on the NHEJ pathway [60-62]. This 
genomic scar could serve as a downstream functional output to measure DNA repair capacity, 

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indicative of both HR deficiency and NHEJ proficiency. Therefore, mutations in NHEJ and other 
pathways that could affect HR as well as genomic scarring will also be evaluated as exploratory 
biomarkers.   
 
Relevance 
 
The marked susceptibility of patients with BRCA-mutated cancers has validated germline BRCA 
mutations as a predictive biomarker for PARPi response [63]. Other mechanisms of HRD may 
be a functional biomarker for response to DNA damaging agents and PARPi. Thus, it is 
important to identify the subset of patients have germline or somatic mutations in HRD genes 
and to examine their potential as predictive biomarkers. Additional exploratory biomarkers for 
HRD will include BRCA1 methylation, BRCA1 protein expression, and genomic scarring. We 
hypothesize that the BROCA-HR test will identify subsets of gastric cancer patients with HRD, 
and may yield biomarkers with potential to guide administration of this combination regimen. 
Preliminary Data 
BROCA-HR and genomic scarring 
BROCA is a targeted capture and massively parallel sequencing assay that is capable of 
identifying all classes of mutations including gene rearrangements [51, 64]. Using BROCA, 
Walsh et al demonstrated that nearly one-fourth of women with ovarian carcinoma have 
germline loss of function mutations in at least 12 genes [51]. Furthermore, most of these genes 
are in the BRCA-FA pathway. After BRCA1/2, the most common genes mutated in women with 
ovarian cancer are BRIP1 (FANCJ), RAD51D, RAD51C (FANCO), and PALB2 (FANCN) [51, 
65].  Pennington et al applied BROCA to detect somatic mutations in tumor DNA from 363 
women with ovarian carcinoma. Combining germline and somatic mutations increased the 
fraction of cases identified with HRD to 31%, including 23% with germline and 9% with somatic 
mutations in FA/HR genes (and 1% with both somatic and germline mutations). The presence of 
either a germline or somatic FA/HR mutation is highly predictive of an improved primary 
response to platinum chemotherapy (p<0.0005) and longer overall survival (p=.001, Pennington, 
Swisher et al manuscript in progress). Germline and somatic loss of function mutations were 
identified in all of the 13 FA/HR genes evaluated.  
Dr. Swisher’s laboratory has developed a new version of BROCA (BROCA-HR) that includes 
many additional DNA repair genes (84 total genes), and 3000 single nucleotide polymorphisms 
(SNPs). Similar sequencing accuracy and sensitivity sequencing DNA is obtained from formalin 
fixed paraffin embedded (FFPE), fresh blood and flash frozen specimens. BROCA-HR includes 
genes that are targets of both somatic and germline mutations. The BROCA-HR includes genes 
that regulate HR or NHEJ that, if mutated, could mediate resistance to PARPi such as 
TP53BP1[66-68] . The BROCA design is flexible and can be altered to include any genes of 
research interest. The current design for BROCA-HR includes the following genes: 
 
BROCA-HR gene list (n=84) 
a. FA-BRCA HR pathway: ATM, ATR, BABAM1, BAP1, BARD1, BLM, BRCA1, BRCA2 
(FANCD1), BRIP1 (FANCJ), BRCC3, BRE, CHEK1, CHEK2, C11ORF30 (Emsy), ERCC1, 
ERCC4 (FANCQ), FAM175A (abraxas), FANCA, FANCB, FANCC, FANCD2,  FANCE, 
FANCF, FANCG (XRCCC9), FANCI, FANCL, FAMCM, GEN1, MRE11A, NBN, PALB2 

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(FANCO), RAD50, RAD51, RAD51C (FANCO), RAD51D, RBBP8 (CtIP), SLX4 (FANCP), 
UIMC1 (RAP80), XRCC2  
b. DNA mismatch repair MLH1, MSH2 (and EPCAM), MSH6, PMS2  
c. Other DNA repair, surveillance genes, or modifier genes : CDK12, CDH4, HELQ, NEIL1, 
PPM1D, POLD1, POLE, POLQ, RIF1,TP53, ID4, PARP1, PAXIP1, POLQ, RINT1, TP53BP1, 
USP28, WRN, XRCC3  
d. NER genes: ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, DDB1, XPA, XPC  
e. NHEJ genes: DCLRE1C, LIG4, PRKDC, TOBP1, XRCC4, XRCC5, XRCC6  
f. PI3K pathway: PTEN, PI3KCA 
 
2.5.2 Signature 3 
Aim: To determine whether a mutational signature characteristic of HRD confers sensitivity to 
ramucirumab and olaparib. 
 
Evidence of defective homologous repair has been reported in up to 12% of Gastric Tumors 
based on mutational signature analysis. Alexandrov et al. utilized whole genome sequencing, 
followed by frequency of single base substitutions to describe 21 distinct mutational signatures 
across 30 cancer types [69]. Cancer genomes generally carry a large number of somatic 
mutations, which for the most part are passenger mutations [70]. However the frequency and 
distribution of these single base somatic mutations creates an imprint on the cancer genome, 
which can provide insight into the pathogenesis of a particular tumor [71]. For example, previous 
work has shown that C:G > A:T substitutions occur at higher frequencies for smoking-associated 
lung cancers [72]. Alexandrov’s work has taken this a step further by analyzing the frequencies 
of the 6 classes of base substitutions (C:G > A:T, C:G > G:C, C:G > T:A, T:A > A:T, T:A > 
C:G, T:A >G:C), which including the 5’ and 3’ bases yields 96 possible combinations [69]. 
Whole exome sequencing data from more than 7000 tumors across 30 different cancer types 
were analyzed, which resulted in approximately 5 million somatic substitutions as well as 
insertions and deletions.  
 
After analyzing the frequency for the 96 possible combinations of base substitution it was noted 
that the number of somatic mutations was variable amongst the different cancer classes. This 
sequencing data allowed for the identification of 21 distinct mutational signatures across the 30 
cancer types through the application of validated mathematical algorithms [61, 69, 71]. This 
same mathematical modeling allows for the quantification of each signature in a particular 
cancer genome as multiple signatures may contribute to a different proportion of the mutations 
detected in a specific tumor [70, 71]. Helleday et al. uses the analogy of a human face to help 
explain; the aggregate of all the somatic substitutions would represent the face, while the facial 
features such as the eyes, nose, and mouth would represent the extracted individual mutational 
signatures [71]. Some signatures were notable for a very specific base substitution, and others 
had a more homogenous distribution of the 96 possible combinations. While an individual 
signature can be seen across multiple cancers, several signatures were discovered to have strong 
associations to specific cancers and known driver mutations [70]. In addition to the distribution 
of the 96 somatic substitutions large insertions and deletions were found to have a strong 
association with signature 3, which was strongly associated with BRCA1 and BRCA2 mutations 
[12, 69].  
 
Signature 3 was observed in BRCA-mutated ovarian, breast, and pancreatic cancers and was 

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characterized by a homogenous distribution of base substitutions [69]. Additionally, increased 
numbers of indels with overlapping microhomologies at break points were identified in signature 
3 tumors [12, 69]. These findings strongly suggest that signature 3 is characteristic of a defective 
homologous DNA repair pathway. Subsequently, signature 3 has been described in 7-12% of 
gastric cancers with the majority being non-BRCA mutated, which indicates a separate defect in 
the homologous DNA repair pathway or additional mechanisms of BRCA silencing [12]. This 
offers a novel biomarker to identify tumors with defects in the homologous double-stranded 
DNA repair pathway that may benefit from agents targeting DNA repair pathways, specifically 
PARP inhibitors. 
 
2.5.3 Immunoassay for poly-ADP-ribosylated (PAR) products:  
 
Aim: To assess the effectiveness for olaparib and ramucirumab to inhibit DNA repair in gastric 
carcinoma.  
 
Because the product of the PARP enzyme is poly-ADP-ribosylated (PAR) molecules, an 
immunoassay to quantify the amount of cellular PAR was developed as a clinical biomarker of 
PARP inhibition. Abbott Laboratories and the NCI-Frederick laboratories developed and cross-
validated a quantitative immunoassay for PAR [73].  The validated assay is a sandwich enzyme 
chemiluminescence immunoassay employing commercially obtained antibodies to PAR, and 
pure PAR as a standard. Assay dynamic range is 31 to 2000 pg/ml PAR, with a lower limit of 
quantitation of approximately 15 pg/ml PAR. The standard curve is linear throughout the range 
(with an adjusted R2 typically better than 0.98). The assay uses high, midrange, and low controls 
produced from the human melanoma line Colo829. Specimen handling was optimized for both 
PBMCs and tumor needle biopsies (18 ga), and harmonized for use with the same standards and 
controls. Specimens could be subjected to at least 3 freeze-thaw cycles without a detectable loss 
of antigen binding. Assay precision was determined at both Abbott and the NCI-Frederick, to be 
better than 80% (estimated total imprecision at Abbott, 7% or less). Accuracy, as assessed by 
spike recovery of pure PAR into PBMC lysates, was 100% +/- 20%. Assay dilution linearity was 
established for the Colo829 controls and tumor lysates, although deviations from linearity are 
observed in some tumor homogenates, and assay conditions are controlled to compensate for that 
lack of linearity. The validated assay was used to measure PAR levels in PBMCs of healthy 
donors, in animal models after administration of a single and multiple dosing of ABT-888, and 
will be used to measure PAR in PBMCs and tumor biopsies in the proposed protocol.  
2.5.4 Novel Genomic assay for “BRCAness” 
Aim: To build a genomic assay for identifying BRCAness in clinical samples to identify 
genomically-driven mechanisms of sensitivity to PARP inhibition. 
 
Homologous recombination pathways have been described in great detail, both in model 
organisms as well as in human cancer. However, despite the growing list of gene products 
responsible for or involved in homologous recombination-based repair, assays that reliably detect 
homologous recombination repair deficiency are still lacking. Therefore we will develop and 
perfect a sensitive DNA sequencing-based diagnostic of HR defects. Towards this goal, we will 
obtain whole-exome sequencing (WES) in various cancer that harbor mutations (germline or 
bialleleic somatic) in key DNA-repair genes.  

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Samples will be obtained as part of this clinical trial with the PARP inhibitor olaparib in 
gastroesophageal cancers. Exome wide patterns of break and repair in HR-deficiency cancers 
will be defined and then we will attempt to package this in a compact targeted footprint, ideally 
less than 100kb, so that it can be adapted to multiplexed and cell free applications in the clinic. 
2.5.5 Factors demonstrating synthetic lethality with PARP inhibitors in gastric cancers. 
Aim 1: Investigate the role of key signal transduction pathways in regulating the DNA damage 
response pathway in gastric cancer cell line models. 
Aim 2: Unbiased identification of modifiers of responsiveness to PARP inhibitors.  
Aim 3: Test effects of PARP inhibitors alone or in combination with other agents (based on 
results of Aims 1 and 2) in patient-derived xenograft models. 
 
It has become clear that signaling through oncogenic pathways result in activation of DNA 
damage checkpoint response pathways. For example, acute expression of oncogenic RAS results 
in activation of DNA damage response (DDR) pathways, which is mediated by the ATR protein 
kinase and checkpoint kinases, CHK 1/2 [74, 75]. In agreement with this, inhibition of CK1 
activation results in enhanced sensitivity to DNA-damaging cytotoxic agents [76]. Emerging 
evidence demonstrates that components of the DNA damage checkpoint response are regulated 
through RAS effector pathways. In particular the PI3 kinase pathway has been demonstrated to 
regulate ATM activity. This effect was enhanced by dual-inhibition of MEK and PI3 kinase in a 
melanoma model [77]. A possible role of the RAF-MEK-ERK pathway in regulating DDR is 
further supported by our findings demonstrating regulation of ATM protein expression by MEK 
as determined by Reverse-Phase Protein Analysis. In contrast to other cancers of the GI system, 
RAS oncogenes are rarely mutated in gastric cancers and the role and regulation of specific DDR 
components through oncogenic signal transduction processes in this disease is poorly understood 
[14]. Therefore, in Aim 1, we will investigate the role of key signal transduction pathways in 
regulating the DNA damage response pathway in gastric cancer cell line models. We will further 
seek to identify new markers of sensitivity to PARP inhibition in gastric cancer in an unbiased 
fashion. Previous work performed by Dr. Ashworth and colleagues identified such markers 
(including NBS1, TDG, XPA, and MK2) in breast cancer models using a multi-dimensional set of 
genomic and RNA expression data [78]. Since this correlative approach is limited in its ability to 
predict causality, we will focus in Aim 2 on identifying so far unknown mediators of 
responsiveness to PARP inhibitors in gastric cancer using a CRISPRi screening approach. In aim 
3 we will test the effects of PARP inhibitors alone or in combination with other agents in PDX 
models. These models overcome limitation of cell line derived in vivo models (loss of 
characteristics of the parent tumor, lack of clinical annotation, and the limited representation of 
genotypes and subtypes) and closely resemble conditions in human tumors. As part of an 
ongoing effort, Dr. Janjigian’s group at Memorial Sloan Kettering Cancer Center (MSKCC) has 
been able to implant 131 tumor samples from patients with esophagogastric cancers in mice were 
so far, with 32 resulting in established PDX tumors. Engraftment rates were 46% (orthotopic) 
and 26% (subcutaneous). Both normal and tumor patient DNA from patients and PDX tumor 
DNA are being analyzed by next generation DNA sequencing. Data so far demonstrate 
consistently that primary and PDX tumors exhibit similar histology, mutational profile, and copy 
number plots, suggesting that PDXs represent the tumors from which they are derived. To date, 
10 of the 32 PDXs have been analyzed with tumors clustering with the CIN subtype, 1 with the 
MSI subtype and 2 were genomically stable. We are planning on obtaining fresh tumor biopsies 

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from selected patients with olaparib and ramucirumab to generate additional PDX models 
representing BRCAness genotypes. 
 
2.5.6 T Cell receptor diversity. 
Aim: To define the T cell receptor diversity of gastric cancer patients with and without 
BRCAness.  
Humans generate T cells with a circulating diversity of > 100 x 106. Persistence of antigen-
specific T cells is dependent on the presence of the specific antigens. If BRCAness is associated 
with a greater number of neoantigens, then the repertoire of T cells within these patients should 
reflect this increased antigenic diversity. We therefore hypothesize that patients with the 
BRCAness phenotype will have a higher diversity of T cell clonotypes. Moreover, if PARPi 
induced tumor cell lysis, this will lead to release of antigens, which could in turn be associated 
with treatment induced T cell repertoire diversification. To test this hypothesis, we will perform 
next-generation T-cell receptor sequencing on both fresh tumor samples and blood from patients 
with gastric cancer to assess both of these compartments. T cells see antigen through their TCR, 
which is comprised of two subunits, α and a β. Each is generated by a VDJ recombination event 
resulting in a broad range of T cell clones with different specificities. The β subunit has greater 
clonal diversity. We have used next-generation sequencing of the T cell receptor β chain (TCRβ) 
to define the diversity and frequency of T cell clones in the blood of cancer patients. The Fong 
lab has demonstrated that CTLA-4 blockade induces global remodeling of the T cell repertoire 
[79]. We found that anti-CTLA-4 administration promotes active turnover in the T cell 
repertoire, which increases with sequential treatments, and a net result of increased repertoire 
diversity overall. These changes occurred both in naïve and non-naïve T cells, the latter of which 
includes the antigen-experienced effector T cell population. Interestingly, maintenance of high-
frequency clonotypes (greater than 1 in 1000) was associated with clinical response and 
improved overall survival following ipilimumab. We have since sequenced blood from patients 
with localized prostate cancer, metastatic castration resistant prostate cancer, or age-matched 
healthy men without cancer. We find that men with prostate cancer have a significantly more 
diverse T cell repertoire (i.e. lower clonality index). This finding would indicate that cancer can 
induce the diversification of the pool of circulating T cell clones in these patients. In this study, 
TCR diversity will be measured by the number of unique TCR, the distribution of TCR 
frequency, and the Shannon’s diversity index [79]. We will also determine through these studies 
whether the circulating T cell repertoire is reflective of the T cells within the tumor 
microenvironment. 
 
3. PATIENT SELECTION 
 

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3.1 
Inclusion Criteria 
3.1.1 The patient must have histologically confirmed, gastric carcinoma, including GEJ 
adenocarcinoma (patients with adenocarcinoma of the distal esophagus are eligible if the 
primary tumor involves the GEJ). 
3.1.2 The patient has metastatic disease or locally recurrent, unresectable disease.  
3.1.3 The patient must have measurable disease by RECIST v1.1. Please see Section 11 for the 
definition of measurable disease. 
3.1.4 The patient must have experienced disease progression during or within 4 months after 
the last dose of chemotherapy for metastatic disease, during or within 6 months after the 
last dose of adjuvant chemotherapy, or have been intolerant of previous chemotherapy. 
3.1.5 The patient must have experienced disease progression or intolerance as outlined above 
after treatment with 1 or more prior chemotherapies. 
3.1.6 All previous treatments are acceptable as long as they did not contain bevacizumab, 
ramucirumab or PARP inhibitors. 
3.1.7 Elevation in tumor markers without radiographic evidence of disease progression is not 
satisfactory for progression on previous treatment. 
3.1.8 The patient is ≥ 18 years of age. 
3.1.9 The patient has a life expectancy of ≥ 16 weeks. 
3.1.10 ECOG performance status score of 0-1 (Karnofsky ≥60%). 
3.1.11 Patients must have normal organ and marrow function within 28 days prior to 
administration of study treatment as defined below: 
 
− 
Hemoglobin ≥10 g/dL with no blood transfusions (packed red blood cells and 
platelet transfusions) in the past 28 days. 
 
− 
White blood cells (WBC) > 3 x 109/L 
 
− 
Absolute neutrophil count (ANC) ≥ 1.5 109/L 
 
− 
Platelet count ≥ 100 X 109/L 
 
− 
No features suggestive of MDS/AML on peripheral blood smear or bone marrow 
biopsy, if clinically indicated. 
 
− 
Total bilirubin ≤1.5 x the institutional upper limit of normal (ULN) 
 
− 
AST (SGOT) / ALT (SGPT) ≤ 2.5 × institutional ULN unless liver metastases are 
present in which case they must be ≤ 5 x ULN 
 
− 
Calculated serum creatinine clearance ≥ 60 mL/min/1.73 m2  
 
− 
Proteinuria with urinary protein ≤ 1+ on dipstick or routine urinalysis, or a 24-
hour urine collection for protein < 1000 mg of protein in 24 hours. 
 
− 
Coagulation parameters (INR, aPTT) ≤1.25 x institutional limits, except where a 
lupus anti-coagulant has been confirmed or the patient is on warfarin. Patients on 

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full dose anticoaugulation must be on a stable dose for at least 14 days. If 
receiving warfarin, the patient must have an INR ≤ 3.0 without any evidence of 
active bleeding within 14 days prior to first dose of study treatment or a 
pathologic condition that carries a high risk of bleeding (tumor involvement with 
major blood vessels or varicies).  
 
3.1.12 Postmenopausal or evidence of non-childbearing status for women of childbearing 
potential a negative urine or serum pregnancy test within 28 days of study treatment and 
confirmed prior to treatment on day 1. Postmenopausal is 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 > 1 year interval since last menses. 
 
Surgical sterilization (bilateral oophorectomy or hysterectomy). 
3.1.13 The effects of olaparib and ramucirumab on the developing fetus are unknown. For this 
reason, women of child-bearing potential and men must agree to use adequate 
contraception including hormonal, barrier, or abstinence. Contraception must be started 
prior to study enrollment. Female patients of childbearing potential must have a negative 
serum pregnancy test within 7 days prior to 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. Both men and women treated or 
enrolled on this protocol must also agree to use adequate contraception prior to the study, 
for the duration of the study participation, and for 3 months after completion of olaparib 
and ramucirumab administration. Male patients and their partners, who are sexually 
active and of childbearing potential, must agree to the use of two highly effective forms 
of contraception in combination, throughout the period of taking study treatment and 
for 3 months after last dose of study drug(s) to prevent pregnancy in a partner. 
3.1.14 Ability to understand and the willingness to sign a written informed consent document. 
3.1.15 The patient must be willing to undergo a biopsy prior to treatment, an on treatment 
biopsy at week 16 is optional if felt to be safe in the opinion of the investigator.   
3.1.16 For inclusion into optional exploratory genetic and biomarker research, patients must 
fulfill the following criteria: 
• Provision of informed consent for genetic research 
• Provision of informed consent for biomarker research 
If a patient declines to participate in the optional exploratory genetic research or the 
optional biomarker research, there will be no penalty or loss of benefit to the patient. The 
patient will not be excluded from other parts of the study.  

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3.1.17 Patients must be able to tolerate oral medications by mouth, and not have a 
gastrointestinal illness that would preclude absorption of olaparib. 
3.1.18 Adequately controlled blood pressure (BP) <140 mmHg (systolic) and <90 mmHg 
(diastolic) taken in the clinic setting by a medical professional within 2 weeks prior to 
starting study. Patients with hypertension may be managed with up to a maximum of 3 
antihypertensive medications. A cardiologist or blood pressure specialist must evaluate 
patients who are on 3 antihypertensive medications within 4 weeks of enrollment. 
3.1.19 Patients who have the following risk factors are considered to be at increased risk for 
cardiac toxicity and must have documented LVEF by Echocardiogram greater than 
institution’s lower limit of normal (or 55% if threshold for normal not otherwise specified 
by institutional guidelines) obtained within 3 months. 
• Prior treatment with anthracyclines 
• Prior treatment with trastuzumab 
• A New York Heart Association (NYHA) classification of II controlled with 
treatment (See Appendix B) 
• Prior central thoracic radiation therapy (RT), including RT to the heart. 
• History of myocardial infarction within 12 months (patients with history of 
myocardial infarction within 6 months are excluded) 
 

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3.2 
Exclusion Criteria 
3.2.1 Patients with untreated brain metastases are excluded from this clinical trial because of 
their poor prognosis and because they often develop progressive neurologic dysfunction 
that would confound the evaluation of neurologic and other adverse events. A scan to 
confirm the absence of brain metastases is not required. The patient can receive a stable 
dose of corticosteroids before and during the study as long as these were started at least 4 
weeks prior to treatment. Patients with spinal cord compression are also excluded unless 
considered to have received definitive treatment for this and evidence of clinically stable 
disease for 28 days. 
3.2.2 Patients who have not recovered from adverse events due to prior anti-cancer therapy 
(i.e., have residual toxicities > CTCAE Grade 1 or baseline, with the exception of 
alopecia). 
3.2.3 Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication. 
3.2.4 The patient has experienced any grade 3-4 gastrointestinal bleeding within 3 months prior 
to randomization. 
3.2.5 The patient has experienced any arterial thrombotic events, including but not limited to 
myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable 
angina, within 6 months prior to enrollment. 
3.2.6 The patient has an ongoing or active infection, symptomatic congestive heart failure, 
unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, 
uncontrolled thrombotic or hemorrhagic disorder, or any other serious uncontrolled 
medical disorder in the opinion of the investigator. 
3.2.7 The patient has an ongoing or active psychiatric illness or social situation that would 
limited compliance with study requirements. 
3.2.8 Clinically significant peripheral vascular disease or vascular disease (abdominal aortic 
aneurysm >5cm) or aortic dissection). If known history of abdominal aortic aneurysm 
with ≥ 4cm in diameter, all of the following must be met. 
• An ultrasound within the last 6 months required to document that it is ≤5cm 
• Patient must be asymptomatic from the aneurysm 
• Blood pressure must be well controlled as defined in this protocol (see section 6). 
3.2.9 The patient has uncontrolled or poorly controlled hypertension despite standard medical 
management as defined in this protocol (see section 6). 
3.2.10 NYHA classification of III or IV. 
3.2.11 A resting EKG with a QTC ≥ 470 msec detected on 2 or more time points within a 2 hour 
period or family history of long QT syndrome. If the EKG demonstrates QTC ≥ 470 
msec, the patient will only be eligible if a repeat EKG demonstrates QTC ≤ 470 msec. 
3.2.12 History of hypertensive crisis or hypertensive encephalopathy within 3 years. 
3.2.13 Major surgery within 28 days of starting study treatment and patients must have 
recovered from any effects of any major surgery. 
3.2.14 An open biopsy, non-healing wound, ulcer or significant traumatic injury within 28 days 
prior to starting treatment (percutaneous, endobronchial, and endoscopic biopsies are 
allowed). 
3.2.15 The patient has received chemotherapy, radiotherapy (except for palliative reasons), 
immunotherapy, or targeted therapy for gastric cancer within 3 weeks of study treatment. 
3.2.16 The patient has received any investigational therapy within 4 weeks of enrollment. 

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33
3.2.17 The patient has received prior therapy with bevacizumab, ramucirumab or any PARP 
inhibitor, including olaparib. 
3.2.18 Patients must not have evidence of coagulopathy or bleeding diathesis. Therapeutic 
anticoagulation for prior thromboembolic events is permitted. The clinical indication for 
therapeutic anticoagulation must be clearly documented prior to enrollment and must be 
discussed with the PI. Due to risk of serious bleeding with ramucirumab, patients on 
greater than or equal to 2 anti-thrombotic agents, including but not limited to anti-platelet 
agents (NSAIDS/aspirin, clopidogrel), heparin, low molecular weight heparin, warfarin 
and a direct thrombin inhibitor will be excluded. 
3.2.19 The patient has elective or planned major surgery to be performed during the course of 
the clinical trial. 
3.2.20 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to olaparib and ramucirumab.  
3.2.21 Patients with a known hypersensitivity to olaparib or any of the excipients of the product. 
3.2.22 Patients with a known hypersensitivity to the combination/comparator agent. 
3.2.23 Pregnant or breast feeding women are excluded from this study because olaparib and 
ramucirumab have the potential for teratogenic or abortifacient effects.  
3.2.24 Immunocompromised patients, this includes HIV-positive patients, because of the 
potential for interaction with antiretroviral therapy and ramucirumab and/or olaparib. In 
addition, these patients are at increased risk of lethal infections when treated with 
marrow-suppressive therapy. 
3.2.25 Patients with a known history of Hepatitis B (defined as Hepatitis B surface antigen 
[HBsAg] reactive) or known active Hepatitis C virus (defined as detectable HCV RNA) 
infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by 
local health authority.  
3.2.26 The patient has known and active alcohol or drug dependency. 
3.2.27 The patient has a concurrent active malignancy other than treated non-melanoma skin 
cancers or in situ neoplasm. A patient with a prior history of malignancy is eligible, 
provided that they have been free of disease for ≥ 5 years. 
3.2.28 Patients may not have features suggestive of myelodysplastic syndrome (MDS) or acute 
myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if 
clinically indicated. 
3.2.29 Patients may not have had a prior allogeneic bone marrow transplant or double umbilical 
cord blood transplantation (dUCBT).  
3.2.30 Patients may not have current signs and/or symptoms of bowel obstruction within 1 
month prior to starting study drugs, except if it was a temporary incident (improved 
within <24 hr with medical management). 
3.2.31 History of hemoptysis within the last 1 month. 
3.2.32 History of abdominal fistula, intra-abdominal abscess, or gastrointestinal perforation 
within the last 3 months. 
3.2.33 Dependency on IV hydration > 1 day per week within the screening period. 
3.2.34 Participants receiving any medications or substances that are strong inhibitors or inducers 
of CYP3A4/5 are ineligible. The required washout period prior to starting treatment is 2 
weeks for CYP3A inhibitors, 3 weeks for CYP3A inducers, and 5 weeks for 
enzalutamide. Dihydropyridine calcium-channel blockers are permitted for management 
of hypertension.  

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36
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 10066 protocol page located on the 
CTSU Web site.  Permission to view and download this protocol is restricted and is based 
on person and site roster data housed in the CTSU RSS.  To participate, Investigators and 
Associates must be associated with the Corresponding or Participating protocol 
organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO-CT 018, 
and protocol #10066. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 Requirements For 10066 Site Registration: 
 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted) 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered 
and tracked in the CTSU RSS.   
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab →Regulatory 

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Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU 
website.   
 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment 
initiation to check slot availability.  Registration staff should ensure that a slot is 
available and secured for the patient before completing an enrollment. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  

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4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. Registrars must 
hold a minimum of an AP registration type. 
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.   
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is available on the Theradex websitehttp://www.theradex.com/clinicalTechnologies/?National-
Cancer-Institute-NCI-11. This link to the Theradex website is also on the CTSU website 
OPEN tab. For questions about the use of IWRS for slot reservations, contact the 
Theradex Helpdesk at 609-619-7802 or Theradex main number 609-799-7580; 
CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 10 days. Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 

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39
 
Dose Escalation Schedule 
Dose Level 
Dose* 
Olaparib 
(mg) 
Ramucirumab 
(mg/kg) 
N/A 
-2 
100 mg twice daily, 
orally (tablet) 
8 mg/kg every 2 
weeks, intravenous 
 
-1 
150 mg twice daily, 
orally (tablet) 
8 mg/kg every 2 
weeks, intravenous 
 
1 (starting dose) 
200 mg twice daily, 
orally (tablet) 
8 mg/kg every 2 
weeks, intravenous 
 
2 
300 mg twice daily, 
orally (tablet) 
8 mg/kg every 2 
weeks, intravenous 
 
 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Olaparib 
Swallow whole, do 
not chew or crush. 
Take AM and PM 
dose 12 hours apart, 
doses can be taken 
with or without food. 
The patient will be 
requested to maintain 
a medication diary of 
each dose 
medication. This 
medication diary will 
be returned to clinic 
staff at the end of 
each course 
(Appendix C). 
 
Up to 300mg 
(tablet 
formulation) 
Oral 
Twice 
daily 
14 days  
(2 weeks) 
 
 
 
Ramucirumab  
Intravenous 
antihistamine (H1 
receptor antagonist); 
for grade 1-2 
infusion reactions 
dexamethasone and 
acetaminophen are 
added. 
8mg/kg 
Through 
intraveno
us line 
Day 1 
every 2 
weeks  
 

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5.1.1 CTEP IND Agent(s) 
 
5.1.2 Olaparib 
 
For the phase 1 dose escalation, olaparib dosing will be increased in a 3+3 dose 
escalation with doses of 200mg and 300mg twice daily (See 6.0). In phase 2, after biopsy 
for the BROCA-HR panel patients will receive olaparib dose TBD within 14 days of 
biopsy. The olaparib will be given at the appropriate dose level orally continuously twice 
daily, with doses taken at the same times each day 12 hours apart. The olaparib tablets 
can be taken with or without food and should be swallowed whole with water and never 
chewed, crushed, dissolved or divided. The olaparib will be dispensed at the start of each 
cycle. Patients will be provided with a pill diary. Patients will be advised to avoid 
grapefruit juice while on study due to P450 interactions.  
 
If difficulty tolerating oral medications and vomiting occurs the vomited dose should not 
be made up. Should an enrolled patient miss a scheduled dose the patient will be allowed 
to take the dose up to a maximum of 2 hours after that normally scheduled dose time, but 
if greater than 2 hours the patient should wait until their next allotted dose time. 
 
 
Dose Reductions 
For guidance on dose reductions for management of AEs refer to section 6.  
 
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 (≥ 60 ml/min/1.73 m2), retesting should be 
performed promptly. In the instances where the CrCl falls to between 31 and 50 
ml/min/1.73 m2 the olaparib dose will be reduced by one dose level (see section 6).  
 
5.1.3 Ramucirumab 
 
For both the phase 1 dose escalation and the phase 2, ramucirumab will be dosed at 8 
mg/kg on day 1 of each 2-week cycle. Ramucirumab at the appropriate dose level will be 
delivered intravenously over 60 minutes (+/- 15 minutes) through either a peripheral IV 
or central line. (Please refer to the ramucirumab package insert). 
 
5.1.4 Premedication for Ramucirumab 
 
Premedication is required for all patients prior to each infusion of ramucirumab. The 
recommended agents are histamine (H1) antagonists, such as diphenhydramine chloride. 
Additional premedication may be given at the investigator’s discretion (please refer to 
ramucirumab package insert). All premedication administered must be documented in the 
case report forms. 
 

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41
5.1.5 Other Modality or Procedures 
 
N/A 
 
5.2 
 Dose Escalation 
 
A 3+3 dose escalation scheme will be used for olaparib in phase 1 with a plan to only escalate by 
one dose level. A definition of adverse events is included at the bottom of this section. 
Management and dose modifications associated with adverse events are outlined further in 
Section 6. With a 3+3 dose escalation design if no dose-limiting toxicity (DLT) is observed a 
total of 9 patients would be enrolled. However, if DLTs are observed during dose escalation 9-12 
patients could be enrolled depending on whether DLTs were seen at one or both dose levels. If 2 
or more DLTs are observed in the first cohort the study would de-escalate the dose. There are 2 
dose levels below the starting dose (dose level -1 and dose level -2), and this could take a 
maximum of 18 patients if DLTs were seen at all dose levels. A schema for the 3+3 design is 
provided below, and the starting dose of olaparib is 200 mg twice daily as outlined in Section 6. 
The maximum dose of olaparib tested in this study will be an increase of one dose level to 
olaparib 300 mg twice daily, which is the maximum tolerated dose per the olaparib IB. Even if 
no DLTs are observed, the dose of olaparib will not be increased beyond 300 mg twice daily 
(dose level 2) in this study.  
 
The DLT evaluation period is 28 days and dose escalation will proceed according to the 
following scheme and DLT definitions are defined below. A patient is evaluable for DLT if 
he/she receives 2 doses (100%) of ramucirumab and 45 doses (80%) of olaparib within the first 
28 days OR he/she experiences a DLT. If this minimum amount of treatment is not reached due 
to treatment related AEs, this is considered a DLT. However, patients who fail to achieve this 
minimum amount of treatment due to reasons that are clearly unrelated to treatment (e.g. error on 
part of patient or outside physician) would be replaced. 
 
Due to the non-overlapping toxicity profiles of olaparib and ramucirumab the likelihood for DLT 
is estimated at 15 to 25%. The doses of olaparib and ramucirumab will not be increased beyond 
the previously established maximally tolerated doses as described in the respective investigator 
brochures. In the REGARD study, which evaluated ramucirumab monotherapy in gastric cancer, 
it was well tolerated with no increase in  ≥ grade 3 AEs as compared to placebo. Similarly in 
Study 19, which evaluated olaparib monotherapy in ovarian cancer it was well tolerated with ≥ 
grade 3 AEs 15% higher than the placebo group. 
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. The dose of 
olaparib will not be increased beyond dose level 2. If 0 
out of 3 DLTs are observed at dose level 2 an additional 
3 patients will be enrolled at this dose level. 
≥2 
Dose escalation will be stopped.  This dose level will be 

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42
declared the maximally administered dose1 (highest 
dose administered).  Three (3) additional patients will be 
entered at the next lowest dose level if 3 or fewer 
patients were treated previously at that dose.  
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose1. Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose. 
≤1 out of 6 at dose level 2 or at the 
highest dose level below the 
maximally administered dose  
This is generally the recommended phase 2 dose2. At 
least 6 patients must be entered at the recommended 
phase 2 dose. The olaparib dose will not be escalated 
beyond dose level 2. If 0 out of 3 DLTs are observed at 
dose level 2, an additional 3 patients will be enrolled. 
1 Maximum administered dose: The highest dose level of olaparib that 2 or more patients 
suffers a DLT (or 300 mg twice daily of olaparib if no DLTs are observed). 
2 Recommended phase 2 dose: The highest dose level of olaparib that ≤1 out of 6 patients 
suffers a DLT. 
 
Definition of Dose Limiting Toxicities 
 
Non-Hematologic: 
Any grade 3-4 non-hematologic toxicity at least “possibly related” to the combination of olaparib 
and ramucirumab occurring from cycle 1 day 1 through cycle 2 day 2 during phase 1 will be 
considered a DLT with the following exceptions:  
1. Grade 3 toxicity that lasts ≤ 2 days for nausea, vomiting, fatigue, diarrhea, constipation or 
anorexia will not be considered a DLT.  
2. Grade 3 hypertension will not be considered a DLT unless it persists for ≥ 14 days 
despite optimal medical management. 
3. Transient (≤ 7 days) Grade ≥ 3 elevations in AST and/or ALT without other evidence of 
hepatic injury will not be considered a DLT.  
4. A subject did not receive at least 45 doses (80%) of olaparib or 2 doses (100%) of 
ramucirumab up to and including cycle 2 day 1 (i.e., other AEs not attributed as DLTs 
and/or dosing lab eligibility not met) will be considered a DLT. 
 
Hematologic:  
Any grade 4 hematologic toxicity (except lymphopenia) that lasts ≥ 7 days at least “possibly 
related” to the combination of olaparib and ramucirumab occurring from cycle 1 day 1 through 
cycle 2 day 2 during phase 1 will be considered a DLT with the following exceptions: 
1. Thrombocytopenia grade ≥ 3 with clinically significant bleeding will be considered a 

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43
DLT.  
2. Febrile neutropenia (a single temperature of 38.3°C (101°F) or more orally) or 38.0°C 
(100.4°F) or more over one hour and ANC < 1.0 x 109 / L will be considered a DLT. 
3. Grade 3 neutropenia that lasts ≥ 14 days will be considered a DLT. 
 
 
5.3 
Dose Expansion: 
 
After completion of the phase 1 portion of the study the maximum safe dose of olaparib will be 
used for phase 2. An additional 40 patients will be enrolled for phase 2 for treatment with 
combined olaparib (dose TBD) and ramucirumab 8 mg/kg. During phase 2 patients will continue 
to be monitored for occurrence of DLT.  If ≥ 2 of the first 6 patients or ≥ 2 of patients 7-12 
experience a DLT, the Principal Investigator will discuss with all study investigators and with 
CTEP whether further addition of patients is needed to re-assess the recommended phase 2 dose. 
Monitoring of all safety and toxicity data is done by the Principal Investigator and the 
corresponding organization on a real-time basis as data are entered into Medidata Rave using the 
Web Reporting Module. The adverse event CRF is used for routine AE reporting in Rave. All 
participating sites are expected to notify the Principal Investigator when a DLT has occurred. 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of olaparib and ramucirumab with other 
concomitantly administered drugs, the case report form must capture the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies. The Principal Investigator 
should be alerted if the patient is taking any agent known to affect or with the potential for drug 
interactions. In vitro studies demonstrate that olaparib is primarily metabolized by CYP 3A4/5 
enzymes. Potent inhibitors or inducers of CYP 3A4/5 are prohibited. The study team should 
check a frequently-updated medical reference for a list of drugs to avoid or minimize use of.  
Appendix D (Patient Drug Information Handout and Wallet Card) should be provided to patients 
if available. 
 
Patients who are taking warfarin may participate in this trial; however, it is recommended that 
international normalized 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.  
 
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 

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44
denosumab for bone disease and corticosteroids for the symptomatic control of brain metastases 
provided the dose is stable before and during the study and they were started at least 4 weeks 
prior to beginning study treatment.  
 
Subsequent therapies for cancer  
Details of first and subsequent therapies for cancer and/or details of surgery for the treatment of 
the cancer, after discontinuation of treatment, will be collected.  Reasons for starting subsequent 
anti-cancer therapies including access to other PARP inhibitors or investigational drugs will be 
collected and included in the exploratory assessments of OS. 
 
Medications that may NOT be administered 
No other chemotherapy, immunotherapy, hormonal therapy or other novel agent is to be 
permitted while the patient is receiving study medication. 
 
 
5.5 
Safety Monitoring 
 
• Laboratory safety assessment:  Full hematology assessments for safety (hemoglobin, red 
blood cells [RBC], placelets, mean cell volume [MCV], mean cell hemoglobin 
concentration [MCHC], mean cell hemoglobin [MCH], white blood cells [WBC], 
absolute differential white cell count (neutrophils, lymphocytes, monocytes, eosinophils 
and basophils) and absolute neutrophil count or segmented neutrophil count and Band 
forms should be performed at each treatment visit and when clinically indicated. If 
absolute differentials are not available, please provide % differentials. Coagulation 
[activated partial thromboplastin time {APTT} and international normalized ratio {INR}] 
will be performed at baseline and if clinically indicated unless the patient is receiving 
warfarin. Patient taking warfarin may participate in this study; however, it is 
recommended that prothrombin time (INR and APTT) be monitored carefully at least 
once per week for the first month, then monthly if the INR is stable. 
 
• Biochemistry assessment for safety (sodium, potassium, calcium, magnesium, glucose, 
creatinine, total bilirubin, gamma glutamyltransferase [GGT], alkaline phosphatase 
[ALP], aspartate transaminase [AST], alanine transaminase [ALT], urea or blood urea 
nitrogen [BUN], total protein, albumin and lactic dehydrogenase [LDH]). All should be 
performed at each treatment visit.  
 
• Urinalysis by dipstick should be performed at baseline. A urine dipstick for protein 
should be performed for on treatment visits or full urinalysis may be obtained if clinically 
indicated. Microscopic analysis should be performed by the hospital’s local laboratory if 
required.  
 
• Bone marrow or blood cytogenetic samples should be collected for patients with 
prolonged hematologic toxicities. 
 
These tests will be performed by the hospital’s local laboratory. Additional analyses may be 
performed if clinically indicated. Any clinical significant abnormal laboratory values should 

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45
be repeated as clinically indicated.  
 
• In case a subject shows an  AST or ALT please refer to section 6 for management 
considerations.  
 
• Resting 12-lead EKG: 
 
EKGs are required within 7 days prior to starting study treatment and when clinically 
indicated. 
 
Twelve-lead EKGs will be obtained after the patient has been rested in a supine position for 
at least 5 minutes in each case. The investigator or designated physician will review the paper 
copies of each of the timed 12-lead EKGs on each of the study days when they are collected. 
 
EKGs will be recorded at 25 mm/sec. All EKGs should be assessed by the investigator as to 
whether they are clinically significantly abnormal / not clinically significantly abnormal. If 
there is a clinically significant abnormal finding, the Investigator will record it as an AE. The 
original EKGs must be stored in the patient medical record as source data. 
 
• Serum or urine pregnancy test: 
 
Two pregnancy tests on blood or urine samples will be performed for pre-menopausal 
women of childbearing potential, one within 28 days prior to the start of study treatment, and 
the other on Day 1 of the study prior to commencing treatment. Tests will be performed by 
the hospital’s local laboratory. If results are positive the patient is ineligible/must be 
discontinued from the study. In the event of a suspected pregnancy during the study, the test 
should be repeated.  
 
• Bone marrow or blood cytogenetic analysis: 
 
Bone marrow or blood cytogenetic analysis may be performed according to standard 
hematological practice for patients with prolonged hematological toxicities. Bone marrow 
analysis should include an aspirate for cellular morphology, cytogenetic analysis and flow 
cytometry, and a score 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. If findings are consistent with MDS/AML, 
study drug should be discontinued and a full description of findings should be submitted with 
an SAE report. Presence or absence of blood  cytogenetic abnormalities and flow cytometry 
will be documented on the clinical database. 
 
• Thyroid Function: 
 
Thyroid function should be monitored per the ramucirumab (CYRAMZA) package insert.  
 
5.6 
Duration of Therapy 
 

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In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
• 
Disease progression 
 
• 
Concurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 
 
• 
Patient decides to withdraw from the study 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 
• 
Pregnancy 
 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
• 
Termination of the study by sponsor 
 
• 
The drug manufacturer can no longer provide the study agent 
 
• 
Severe non-compliance with the study protocol. 
 
• 
Bone marrow findings consistent with myelodysplastic syndrome (MDS) / acute 
myeloid leukemia (AML). 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
 
5.7 
Duration of Follow Up 
• Patients who are off study treatment due to disease progression will be seen at 4 
weeks for a post treatment visit, and will continue to be followed for survival. 
• Patients who discontinue the study treatment for reasons other than disease 
progression will be seen at 4 weeks after discontinuing study treatment and 
continue to undergo radiographic tumor assessment until radiographic 
documentation of disease progression every 6 weeks, or earlier if clinically 
indicated, or until overall study completion, whichever comes first.  

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• Patients who discontinue the study treatment for unacceptable adverse event(s) 
will be followed until resolution or stabilization of the adverse event or until 
radiographic documentation of disease progression as noted above.  
• Patients who are discontinued from study drugs will be followed for survival 
every 3 months. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
The dose levels and general approach to dose modification of olaparib and ramucirumab 
combination is described in the tables below. Ramucirumab will be maintained at standard dose 
of 8 mg/kg, and olaparib will be decreased in the event of AEs. The recommended phase 2 dose 
for olaparib is TBD based on phase 1 of the study. 
 
6.1 
Olaparib and Ramucirumab Dose Modification Tables 
 
Olaparib Dosing for Phase 1 and Phase 2: 
Dose Level 
Olaparib Dose 
Dose Reduction 1 
Dose Reduction 2 
-2 
100 mg, twice daily 
Off study treatment 
-- 
-1 
150 mg, twice daily 
100 mg, twice daily 
Off study treatment 
 1 
200 mg, twice daily 
150 mg, twice daily 
100 mg, twice daily 
 2 
300 mg, twice daily 
200 mg, twice daily 
150 mg, twice daily 
 
 
Ramucirumab Dosing for Phase 1 and Phase 2: 
Dose Level 
Ramucirumab Dose 
1 (starting dose for both phase 1 and phase 2) 8 mg/kg, every 2 weeks 
 
General Management of Adverse Events: 
 
Patients experiencing ongoing clinical benefit who experience a related AE where continuation 
of one of the drugs is considered, in the judgment of the treating investigator AND study PI, to 
be potentially life-threatening or with the potential for long-term harm to the patient, may be 
allowed to continue on the unrelated drug after discussion with the study PI. 
 
 
 
6.2 
General Management of Adverse Events for Phase 1 and 2  
 
The DLT definitions are provided in section 5.2 and the DLT period for phase 1 is specified 
to be 28 days. Patients that miss > 11 doses of olaparib in the 28 day DLT period for drug 
related AEs despite appropriate supportive care and causality investigation will be 
permanently discontinued from olaparib and ramucirumab therapy. 
 
Patients experiencing ongoing clinical benefit who experience a related AE that would 
necessitate stopping study treatment may be allowed to continue on the unrelated drug if felt to 
be in the best interest of the patient by the treating investigator after discussion with the study PI 

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General Management of Non Hematologic Adverse Events (see below for specific AE 
management tables for select toxicities). 
 
Observation  
Action  
Grade 1 AE resolves promptly with 
supportive care 
No change in dose 
Any grade 2 non-hematologic AE related to 
olaparib or ramucirumab that resolves within 
5 days with appropriate supportive care 
(excluding hypertension or other AEs with 
specific management instructions outlined 
below, or easily correctable asymptomatic 
grade 2 abnormalities).  
Hold study drugs1 until toxicity resolves to ≤ 
grade 1. Treatment may be restarted at the 
same dose without dose reduction. 
Any grade 2 non-hematologic AE related to 
olaparib or ramucirumab that persists more 
than 5 days despite appropriate supportive 
care (excluding hypertension or other AEs 
with specific management instructions 
outlined below, or easily correctable 
asymptomatic grade 2 abnormalities). 
Hold study drugs1 for up to 14 days until 
toxicity resolves to ≤ grade 1. Treatment may 
be restarted at one dose level lower for 
olaparib as per dose reduction levels above2. 
The overall PI of the study should be 
informed regarding all dose modifications. 
Patients whose toxicity has not resolved after 
14 days will be permanently discontinued 
from olaparib and ramucirumab therapy. 
 
Patients experiencing persistent grade 2 
fatigue that is felt to be acceptable by both 
patient and treating investigator may continue 
on study drug without dose hold or reduction 
at the treating investigator’s discretion. 
Any ≥ grade 3 non-hematologic AE 
(excluding grade 3 hypertension or easily 
correctable grade 3 abnormalities for ≤ 2 days 
as outlined in section 5.2). Refer to section 
5.2 for DLT criteria. 
Hold study drugs1 for up to 14 days until 
toxicity resolves to ≤ grade 1. Treatment may 
be restarted at one dose level lower for 
olaparib, as per the dose reduction levels 
above2. The overall PI of the study should be 
informed regarding all dose modifications.   
• Grade 3 or 4 non-hematologic AE 
related to olaparib or ramucirumab 
lasting >14 days despite maximum 
supportive care and treatment being 
held 3. Refer to section 5.2 for DLT 
lcriteria. 
• Grade 3 or 4 non-hematologic AE 
related to olaparib and ramucirumab 
that occurs at the lowest reduced dose 
level. 
The patient will be permanently discontinued 
from olaparib and ramucirumab therapy4.  
1At the discretion of the investigator, the study drugs may be held or dose modified 

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independently if the observed toxicity is attributed to only one of the drugs, while the patient 
continues to receive the drug not associated with the observed toxicity. The time a given drug 
is held should not exceed 14 days. 
2Patients who are at the lowest dose reduced level may have their drug resumed at that dose 
level after discussion with overall PI. 
3Excluding hypertension. For thromboembolic events, treatment may be resumed at the 
discretion of the investigator once patient is asymptomatic.  
4At the discretion of the investigator the patient may continue to receive the drug not 
associated with the observed toxicity as monotherapy after a discussion with the overall PI. 
 
6.3 
Management of Specific Adverse Events for Phase 1 and 2: 
 
Please refer to section 5.2 for a definition of DLTs in the 28 day DLT period for phase 1. 
 
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 (ie 2 pieces of toast or a couple of biscuits). 
 
Events of nausea and vomiting are known to be associated with olaparib treatment. In study 
D0810C00019 nausea was reported in 71% of the olaparib treated patients and 36% in the 
placebo treated patients and vomiting was reported in 34% of the olaparib treated patients and 
14% in the placebo treated patients. 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. 
 
As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), generally a 
single agent antiemetic should be considered. 
 
Nausea  
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab 
≤ Grade 1 
No change in dose. 
No change in dose 
Grade 2 
If it lasts ≤ 5 days, hold until ≤ 
grade 1 and resume at same dose 
level. If it lasts ≥ 6 days hold* up 
to 14 days until ≤ grade 1 and 
treatment may be restarted at one 
dose level lower. 
No change in dose** 
Grade 3 
Hold* until ≤ Grade 1.  Resume at 
one dose level lower. 
No change in dose** 
 
Grade 4 
N/A 
N/A 
*Patients requiring a delay of >2 weeks should be permanently discontinued from olaparib. 
**At the discretion of the investigator the patient may continue to receive ramucirumab if it is 
not associated with the observed toxicity. 

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Nausea  
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab 
Recommended management:  Daily serotonin (5-HT3) antagonists are recommended for 
nausea management with break through treatment options including prochlorperazine, 
benzodiazepines, steroids, cannabinoids, and atypical antipsychotics. 
 
 
Vomiting  
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucriumab 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
If it lasts ≤ 5 days, hold until ≤ 
grade 1 and resume at same dose 
level. If it lasts ≥ 6 days hold* up 
to 14 days until ≤ grade 1 and 
treatment may be restarted at one 
dose level lower. 
No change in dose** 
Grade 3 
Hold* until ≤ grade 1. Resume at 
one dose level lower. 
No change in dose** 
Grade 4 
Hold* until ≤ grade 1.  Resume at 
one dose level lower. 
No change in dose** 
*Patients requiring a delay of >2 weeks should be permanently discontinued from olaparib. 
**At the discretion of the investigator the patient may continue to receive ramucirumab if it is 
not associated with the observed toxicity. 
Recommended management:  antiemetics. 
 
 
Diarrhea  
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab 
≤ Grade 1 
No change in dose. 
No change in dose 
Grade 2 
If it lasts ≤ 5 days, hold until ≤ 
grade 1 and resume at same dose 
level. If it lasts ≥ 6 days hold* up 
to 14 days until ≤ grade 1 and 
treatment may be restarted at one 
dose level lower. 
No change in dose** 
Grade 3 
Hold* until ≤ grade 1.  Resume at 
one dose level lower. 
No change in dose** 
Grade 4 
Hold* until ≤ grade 1.  Resume at 
one dose level lower. 
No change in dose** 
*Patients requiring a delay of >2 weeks should be permanently discontinued from olaparib. 
**At the discretion of the investigator the patient may continue to receive ramucirumab if it is 
not associated with the observed toxicity. 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-
free for 12 hours (maximum dosage:  16 mg/24 hours) 

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Diarrhea  
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
Appendix E includes instructions for diarrhea management for the patient, and should be 
provided to the patient. 
 
 
Leukopenia  
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab  
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose** 
Grade 3 
Hold* until ≤ grade 2.  Resume at 
one dose level lower. 
No change in dose** 
Grade 4 
Hold* until ≤ grade 2.  Resume at 
one dose level lower. 
No change in dose** 
*Patients requiring a delay of >2 weeks despite appropriate supportive care and causality 
investigation should permanently discontinue olaparib. 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 should be 
discontinued permanently if blood counts do not recover to CTC grade 1 or better within 4 
weeks of dose interruption. 
**At the discretion of the investigator the patient may continue to receive ramucirumab if it is 
not associated with the observed toxicity. 
Insert any recommended management guidelines, if appropriate. 
 
 
Neutropenia ( 
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab  
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose** 
Grade 3 
Hold* until ≤ grade 2.  Resume at 
one dose level lower. 
No change in dose** 
Grade 4 
Hold* until ≤ grade 2.  Resume at 
one dose level lower. 
No change in dose** 
*Patients requiring a delay of >2 weeks despite appropriate supportive care and causality 
investigation should be discontinued from olaparib. 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 should be 
discontinued permanently if blood counts do not recover to CTC grade 1 or better within 4 
weeks of dose interruption. 
**At the discretion of the investigator the patient may continue to receive ramucirumab if it is 

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Neutropenia ( 
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab  
not associated with the observed toxicity. 
Insert any recommended management guidelines, if appropriate. 
 
Febrile Neutropenia  Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab  
≤ Grade 1 
N/A 
N/A 
Grade 2 
N/A 
N/A 
Grade 3 
Off protocol therapy. 
No change in dose** 
Grade 4 
Off protocol therapy. 
No change in dose** 
*Patients requiring a delay of >2 weeks should be permanently discontinued from olaparib. 
**At the discretion of the investigator the patient may continue to receive ramucirumab if it is 
not associated with the observed toxicity. 
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. 
 
 
Anemia  
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab  
Hemoglobin ≥ 10 
 
No change in dose 
No change in dose 
Hemoglobin < 10 but 
≥ 8 g/dl (CTCAE 
Grade 2) 
First occurrence: 
Give appropriate supportive 
treatment and investigate causality. 
 
Investigator judgment to continue 
olaparib with supportive treatment 
(e.g. transfusion) or interrupt dose 
for a maximum of 4 weeks. Study 
treatment can be restarted if 
hemoglobin has recovered to > 9 
g/dl. 
 
Subsequent occurrences:* 
If hemoglobin < 10 but ≥ 9 g/dl 
investigator judgment to continue 
olaparib with supportive treatment 
(e.g. transfusion) or dose interrupt 
(for a maximum of 4 weeks) and 
upon recovery dose reduction may 
be considered by 1 dose level as a 
No change in dose** 

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Anemia  
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab  
first step and 2 dose levels as a 
second step. 
 
If Hemoglobin < 9 but ≥ 8 g/dl 
dose interrupt (for max of 4 weeks) 
and continue with supportive 
treatment (e.g. transfusion) until 
hemoglobin ≥ 9 and upon recovery 
dose reduction may be considered 
by 1 dose level as a first step and 2 
dose levels as a second step. 
Hemoglobin < 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 
hemoglobin ≥ 9 g/dl. 
 
Upon recovery dose reduce by one 
dose level as a first step and 2 dose 
levels as a second step. 
No change in dose** 
*Patients requiring a delay of > 4 weeks and/or red blood cell transfusion dependence despite 
appropriate supportive care and causality investigation should be permanently discontinued 
from olaparib. 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.  
**At the discretion of the investigator the patient may continue to receive ramucirumab if it is 
not associated with the observed toxicity. 
Packed red blood cell transfusions, if indicated, should be done according to local hospital 
guidelines. 
 
Thrombocytopenia  Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
No change in dose** 
Grade 3 
Hold* until ≤ grade 1.  Resume at 
one dose level lower. 
No change in dose** 
Grade 4 
Hold* until ≤ grade 1.  Resume at 
one dose level lower. 
No change in dose** 
*Patients requiring a delay of >2 weeks and/or platelet transfusion dependence despite 

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Thrombocytopenia  Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab 
appropriate supportive care and causality investigation should be permanently discontinued 
from olaparib. 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 should be discontinued permanently if blood 
counts do not recover to CTC gr 1 or better within 4 weeks of dose interruption. 
**At the discretion of the investigator the patient may continue to receive ramucirumab if it is 
not associated with the observed toxicity. 
Platelet transfusions, if indicated, should be done according to local hospital guidelines. 
 
Hypertension: 
 
Only modifications in ramucirumab will be modified for hypertension, and olaparib doses will 
not be reduced unless other toxicities are experienced.  
 
Hypertension  
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
No change in dose** 
No change in dose, but if persists ≥ 
14 days after initiation of optimal 
medical management, hold* until ≤ 
grade 1. If ramucirumab 
discontinued the treating physician 
and study PI will discuss 
continuing olaparib monotherapy.   
Grade 4 
No change in dose** 
Discontinue ramucirumab and 
discussion between treating 
physician and PI continuing on 
olaparib monotherapy. 
*Patients requiring a delay of >4 weeks should discontinue ramucirumab. 
**At the discretion of the investigator the patient may continue to receive olaparib if it is not 
associated with the observed toxicity after discussion with the overall study PI. 
If hypertension grade 2: Initiate blood pressure (BP) medication for first-line treatment. 
Escalate dose of medication in stepwise fashion until BP is controlled or at a maximum dose. If 
BP is not controlled to <140/90 mmHg with one drug regimen, then add a second agent.  
If hypertension grade 3: Maximize 2 drug regimen. Suggestions: ACE inhibitor plus beta 
blocker. Escalate doses of existing medication until BP is controlled or at a maximum dose. If 
BP is not controlled to <140/90 with two drug regimen then add a third agent. Additional BP 
meds up to 4 may be maximized to control BP. 
If hypertension grade 4: Initiate treatment as inpatient hospital admission for ICU management, 
IV therapy as necessary. 
 

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Proteinuria  
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab 
1+ Proteinuria 
No change in dose 
No change in dose 
≥ 2+ Proteinuria 
No change in dose 
Continue as scheduled, and 
conduct a 24-hour urine collection 
prior to subsequent treatment. If <2 
g/24 hours continue without dose 
interruption, if 2-3 g/24 hours hold 
until proteinuria ≤ 1+ or < 2 g/24 
hours..  Resume at same dose 
level.** 
Grade 4 
N/A 
N/A 
*Patients requiring a delay of >2 weeks should discontinue ramucirumab. 
**For patients with 2+ proteinuria on urine dipstick a 24 hour urine collection will be 
conducted. If the protein level is < 2 g/24 hours the patient will continue on the same dose 
without interruption. If the protein level is 2-3 g/24 hours, ramucirumab will be held for up to 2 
weeks and a 24 hour urine protein will be repeated. The patient will be discontinued 
permanently from ramucirumab if the 24 hour urine protein level is > 3 g/24 hours. 
If proteinuria grade ≥ 2: consider consultation with nephrologist. 
 
 
Decrease in LVEF: 
Patients who have any of the following should undergo an echocardiogram (ECHO) at baseline 
and every 4 cycles while on study: 
• Prior treatment with anthracyclines 
• Prior treatment with trastuzumab 
• NYHA classification of II controlled with treatment (see Appendix B) 
• Prior central thoracic radiation 
• History of myocardial infarction within the prior 12 months 
• Prior history of impaired cardiac function 
 
The decision to continue to hold olaparib/ramucirumab is based on the LVEF compared to the 
institutional lower limit of normal and change in ejection fraction from screening, according to 
the following table. If the institution’s lower limit of normal is not specified, an LVEF of 55% 
should be considered the threshold. 
 
Decreased Left 
Ventricular 
Ejection Fraction  
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab 
<10% from 
screening* 
No change in dose. 
No change in dose. 
10-19% from 
screening* 
No change in dose. 
No change in dose and repeat 
echocardiogram after 2 additional 
cycles.  

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Decreased Left 
Ventricular 
Ejection Fraction  
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab 
≥ 20% from 
screening* 
No change in dose. 
Hold treatment and repeat 
echocardiogram  in 10-14 days. If 
decrease in EF remains ≥ 20% 
from screening, discontinue 
ramucirumab and discussion 
between treating physician and PI 
about continuing olaparib 
monotherapy.** 
*If no screening ECHO the change should be calculated from prior patient ECHO or if not 
available, the institutional lower limit of normal. 
**Repeating ECHO will be at discretion of the treating physician. 
If baseline cardiac dysfunction or decreased ejection fraction: Hold treatment as outlined and 
consider consultation with a cardiologist.  
 
 
Decrease in Creatinine Clearance  
 
Creatinine 
Clearance  
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab 
CrCl ≤ 30 
Hold* until CrCl > 30 
Hold* until CrCl > 30 
CrCl 31-50 
Decrease by one dose level 
Continue at same dose level 
CrCl 51-59 
No change in dose. 
No change in dose. 
CrCl ≥ 60 
No change in dose. 
No change in dose. 
*Patients requiring a delay of >2 weeks should be discontinued from both olaparib and 
ramucirumab. 
 
Infusion Reaction 
 
Infusion Reaction  
Management/Next Dose for 
Olaparib 
Management/Next Dose for 
Ramucirumab 
Grade 1-2 
No change in dose 
Reduce the infusion rate of 
ramucirumab by 50%. 
Grade 3-4 
No change in dose. 
Permanently discontinue 
ramucirumab.  
*Patients requiring a delay of >2 weeks should be discontinued from ramucirumab. 
 
Gastrointestinal Perforation. 
 
Gastrointestinal perforations have been observed in patients receiving ramucirumab, most 
commonly related to the primary tumor. Ramucirumab should be permanently discontinued in 
those patients who experience a gastrointestinal perforation or fistula. 
 

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Hemorrhage and arterial thromboembolic events (ATEs) 
Hemorrhage and arterial thromboembolic events have been observed with ramucirumab. 
Ramucirumab will be permanently discontinued in patients who experience these types of 
events. 
 
Management of new or worsening pulmonary symptoms  
 
If new or worsening pulmonary symptoms (e.g., dyspnoea) 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. If 
significant pulmonary abnormalities are identified, these need to be discussed with the Study 
Physician.” 
 
Olaparib adverse events of special interest 
 
Adverse events of special interested [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 CTEP to AstraZeneca. An AESI may be serious or non-serious. Adverse 
Events of Special Interest for olaparib are the Important Potential Risks of MDS/AML, new 
primary malignancy (other than MDS/AML) and pneumonitis.  
 
ANY event of MDS/AML, new primary malignancy, or pneumonitis should be report to CTEP 
whether it is concered a non-serious AE [eg non-melanoma skin cancer] or SAE, and regardless 
of investigator’s assessment of causality or knowledge of the treatment arm. 
 
A questionnaire may be sent to any investigator reporting an AESI, as an aid to provide further 
detailed information on the event. During the study there may be other events identified as 
AESIs that require the use of a questionnaire to help characterize the event and gain a better 
understanding regarding the relationship between the event and study treatment. 
 
There are currently no identified OAEs for olaparib.  
 
Overdose of olaparib 
 
There is currently no specific treatment in the event of overdose with olaparib and possible 
symptoms of overdose are not established. 
 
Olaparib must only be used in accordance with the dosing recommendations in this protocol. 
Any dose or frequency of dosing that exceeds the dosing regimen specified in this protocol 
should be reported as an overdose. Adverse reactions associated with overdose should be treated 
symptomatically and should be managed appropriately. An overdose with associated AEs should 
be recorded.  
 

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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 started study treatment within 4 weeks for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be discussed 
with the principal investigator and CTEP. 
 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded. 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. 
 
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.  
 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Sections 7.2 and 
7.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs)  
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset of AEs, 
the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text.  The SPEER is a list of events that are protocol-
specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/adverse effects.htm for further clarification.  
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the 
SPEER.  Report ONLY AEs higher than this grade expeditiously.  If this CAEPR is part of a 

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Adverse events reported on olaparib (AZD2281) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that olaparib (AZD2281) caused the adverse 
event: 
 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (nodal rhythm); Chest pain - cardiac; 
Sinus bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Hypothyroidism 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Colonic obstruction; Dry mouth; Dysphagia; 
Enterocolitis; Esophageal stenosis; Flatulence; Gastroesophageal reflux disease; Gastrointestinal 
disorders - Other (gastrointestinal hemorrhage); Gastrointestinal disorders - Other (intestinal obstruction); 
Gastrointestinal disorders - Other (intestinal perforation); Ileus; Jejunal perforation; Obstruction gastric; 
Pancreatitis; Periodontal disease; Rectal hemorrhage; Small intestinal obstruction; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Fever; Malaise; 
Non-cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (systemic inflammatory response 
syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Dermatitis radiation; Fracture; 
Gastrointestinal anastomotic leak; Injury, poisoning and procedural complications - Other (vena cava 
injury); Wound dehiscence 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood 
bilirubin increased; GGT increased; Hemoglobin increased; Lipase increased; Lymphocyte count 
decreased; Serum amylase increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hypermagnesemia; 
Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Avascular necrosis; Bone pain; 
Generalized muscle weakness; Muscle weakness lower limb; Muscle weakness upper limb; Neck pain; 
Rotator cuff injury; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Treatment 
related secondary malignancy; Tumor pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Ataxia; Cognitive disturbance; Concentration impairment; 
Encephalopathy; Intracranial hemorrhage; Peripheral sensory neuropathy; Reversible posterior 
leukoencephalopathy syndrome; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Hallucinations; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other 
(decreased glomerular filtration rate); Renal and urinary disorders - Other (hydronephrosis); Urinary tract 
obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Hypoxia; Oropharyngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal 
disorders - Other (chronic obstructive pulmonary disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Pruritus 
VASCULAR DISORDERS - Arterial thromboembolism; Flushing; Hot flashes; Hypertension; Hypotension; 
Peripheral ischemia; Thromboembolic event 
 
 
 
 
Note: Olaparib (AZD2281) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
 
 

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7.1.1.2 
Please see the October 2016 FDA-approved package insert for ramucirumab for a list 
of the associated AEs. 
 
 
7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade: 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 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined below. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm
).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 

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NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  

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7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
8. PHARMACEUTICAL INFORMATION  
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
8.1 
CTEP IND Agent(s) 
 
8.1.1 CTEP IND Olaparib (NSC 747856) 
 
Chemical Name:  4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-
fluorophenyl)methyl]phthalazin-1(2H)-one 
 
Other Names: AZD2281; KU-0059436; CO-CE 42 
 
Classification: PARP inhibitor 
 
CAS Registry Number: 763113-22-0 
 
Molecular Formula:  C24H23FN4O3 
 
M.W.: 434.46 
 
Approximate Solubility: 0.1 mg/mL pH independent solubility across physiologic range 
 
Mode of Action: Olaparib is an inhibitor of subclasses 1, 2, and 3 of polyadenosine 5’ 
diphosphoribose polymerase (PARP-1, PARP-2, and PARP-3). In tumors that are deficient in the 
homologous recombination DNA repair pathway (example, BRCA mutants), inhibition of PARP by 
olaparib causes accumulation of DNA double-strand breaks and genomic instability. Olaparib may 
also enhance the effects of DNA damage caused by ionizing radiation and chemotherapy.  
 
Description: crystalline solid 
 
How Supplied: AstraZeneca supplies and the CTEP, DCTD distributes olaparib as green, film-
coated tablets in 100 mg and 150 mg strengths.  
 
• 100 mg tablets are 14.5 mm x 7.25 mm oval-shaped 
• 150 mg are 14.5 mm x 7.25 mm oval-shaped 
 
Tablets are packaged in induction-sealed high-density polyethylene (HDPE) bottles with child-
resistant closures. Each bottle contains 32 tablets with desiccant.  

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Tablet core components include active drug substance, copovidone, colloidal silicon dioxide, 
mannitol and sodium stearyl fumarate. Film coating contains hydroxypropyl methylcellulose 
(hypromellose), macrogol 400 (polyethylene glycol 400), titanium dioxide, iron oxide yellow and 
iron oxide black. 
 
Storage: Store in a secure location below 30° C (86° F).  
 
If a storage temperature excursion is identified, promptly return olaparib (AZD2281) to room 
temperature and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:  Shelf-life studies are ongoing. Sites are not permitted to re-package tablets. Sites are 
not permitted to re-package tablets. Once the bottle is opened, olaparib tablets must be used 
within 3 months of the opening date; unused tablets should be discarded. Instruct patients not to 
open a bottle until they are ready to use it. 
 
Route and Method of Administration:  Oral. Take tablets without regard to meals.  
 
Potential Drug Interactions:  In vivo data indicate that CYP3A4/5 is important for olaparib 
metabolism and clearance in humans. For this reason, avoid concomitant administration of strong 
and moderate CYP 3A4/5 inducers and inhibitors.  Consult the protocol document or study 
investigator prior to making any dose adjustments related to potential drug-drug interactions. 
 
In vitro data shows olaparib is a substrate for P-glycoprotein (P-gp), but not for organic anion-
transporting polypeptides (OATP1B1 and OATP1B3), organic cation transporter 1 (OCT1), multi-
drug resistance protein 2 (MRP-2) efflux transporter or breast cancer resistance protein (BCRP). 
Administration of strong P-gp inhibitors and inducers should be avoided with concurrent olaparib.   
 
Based on in vitro data, olaparib inhibits CYP 3A4 and UGT1A1 enzyme systems and induces CYP 
1A2, 2B6, and 3A4 and potentially induces CYP 2C9, 2C19 and P-gp. Therefore, avoid 
concomitant administration of sensitive substrates, particularly those with narrow therapeutic 
ranges.   
 
Olaparib is also an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, multi-drug and toxin 
extrusion proteins (MATE1 and MATE2K) and a weak inhibitor of BRCP, but not an inhibitor of 
OATP1B3 or MRP-2. In vitro studies suggest that olaparib may increase exposure of substrates of 
these transport systems, although the clinical relevance is not clear. The manufacturer recommends 
that statins, in particular, should be administered with caution when given concomitantly with 
olaparib. 
 
Live virus and live bacterial vaccines should not be administered whilst 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. The efficacy of hormonal 

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contraceptives may be reduced if co administered with olaparib. 
 
Patient Care Implications: Pre-clinical data indicate that olaparib adversely affects embryofetal 
survival and development. Therefore, women of child-bearing potential and their partners should 
agree to use two (2) highly effective forms of contraception throughout study participation and for 
at least one (1) month after the last dose of olaparib.  It is not known whether olaparib is found in 
seminal fluid, so as a precaution, male study participants must use a condom during treatment and 
for three (3) months after the last dose and should avoid fathering a child or donating sperm during 
this same time period. The study investigator should discuss the most appropriate forms of highly 
effective contraceptive methods for each patient.  
 
Lactation is a protocol exclusion criterion and not advised since there is potential for serious adverse 
reactions in breastfed infants. Advise lactating women to not breastfeed during study treatment and 
for one (1) month after receiving the last dose of olaparib.  
 
Because the adverse events related to olaparib may include asthenia, fatigue and dizziness, 
patients should be advised to use caution while driving or using machinery. 
 
There are no data on the effect of olaparib on wound healing, therefore as a precaution, 
olaparib treatment should be stopped at least 3 days prior to planned surgery. After surgery 
olaparib can be restarted when the wound has healed. No stoppage of olaparib is required for any 
needle biopsy procedure. 
 
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
therapeutic or palliative radiation treatment. Study treatment should be restarted within 4 weeks 
as long as any bone marrow toxicity has recovered. 
 
8.1.2 CTEP IND Olaparib (NSC 747856) 
 
 
8.1.3 Agent Ordering and Agent Accountability 
 
8.1.3.1 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where 
the patient is to be treated.  PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained).  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational agents.  
The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution. 
 
Sites may order olaparib supplies when a patient is enrolled onto the study. 

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Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent 
Order Processing (OAOP) application.  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account and the maintenance of 
an “active” account status and a “current” password.  For questions about drug orders, 
transfers, returns, or accountability, call or email PMB any time.  Refer to the PMB’s 
website for specific policies and guidelines related to agent management.   
 
8.1.3.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.1.3.3 
Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators 
and research staff through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status and a “current” password. Questions above IB access may be directed to the 
PMB IB coordinator via email. 
 
8.1.3.4 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent management.htm  
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/index.jsp 
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
• IB Coordinator: IBCoordinator@mail.nih.gov 
 
8.2 
Commercial Agent  
 
Ramucirumab (CYRAMZA®) is commercially available and will be dosed at 8 mg/kg every 2 
weeks as described above, please see the October 2016 FDA-approved package insert for 
additional details.  

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Product description:  Ramucirumab is a recombinant human IgG1 monoclonal antibody that 
specifically binds to vascular endothelial growth factor receptor 2. Ramucirumab has an 
approximate molecular weight of 147 kDa. Ramucirumab is produced in genetically engineered 
mammalian NS0 cells. Ramucirumab is a sterile, preservative-free, clear to slightly opalescent 
and colorless to slightly yellow solution for intravenous infusion following dilution and 
preparation.  
 
How supplied: Ramucirumab is supplied at a concentration of 10 mg/mL in either 100 mg (10 
mL) or 500 mg (50 mL) single-dose vials. Ramucirumab is formulated in glycine (9.98 mg/mL), 
histidine (0.65 mg/mL), histidine monohydrochloride (1.22 mg/mL), polysorbate 80 (0.1 
mg/mL), sodium chloride (4.383 mg/mL), and Water for Injection, USP, pH 6.0. 
 
Storage and handling: Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of 
use. Keep the vial in the outer carton in order to protect from light. DO NOT FREEZE OR 
SHAKE the vial.  
 
Solution preparation (how the dose is to be prepared):  
Inspect vial contents for particulate matter and discoloration prior to dilution. Discard the vial, if 
particulate matter or discolorations are identified. Store vials in a refrigerator at 2°C to 8°C (36°F 
to 46°F) until time of use. Keep the vial in the outer carton in order to protect from light.  
• Calculate the dose and the required volume of ramucirumab needed to prepare the infusion 
solution. Vials contain either 100 mg/10 mL or 500 mg/50 mL at a concentration of 10 mg/mL 
solution of ramucirumab.  
• Withdraw the required volume of ramucirumab and further dilute with only 0.9% Sodium 
Chloride Injection in an intravenous infusion container to a final volume of 250 mL. Do not use 
dextrose containing solutions.  
• Gently invert the container to ensure adequate mixing.  
• DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or 
co-infuse with other electrolytes or medications.  
• Store diluted infusion for no more than 24 hours at 2°C to 8°C (36°F to 46°F) or 4 hours at 
room temperature (below 25°C [77°F]).  
• Discard vial with any unused portion of ramucirumab. 
 
Route of administration: Visually inspect the diluted solution for particulate matter and 
discoloration prior to administration. If particulate matter or discolorations are identified, discard 
the solution. Administer diluted ramucirumab infusion via infusion pump over 60 minutes (+/- 
15 minutes) through a separate infusion line. Use of a protein sparing 0.22 micron filter is 
recommended. Flush the line with sterile sodium chloride (0.9%) solution for injection at the end 
of the infusion. 
 
Prior to each ramucirumab infusion, premedicate all patients with an intravenous histamine H1 
antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 
or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and 
acetaminophen prior to each ramucirumab infusion. 
 

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Agent Ordering:  Commercially available through Eli Lilly and Company. 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Integral Laboratory or Imaging Studies 
Not applicable  
 
9.2 
Integrated Correlative Studies 
 
9.2.1 BROCA-HR  (Integrated Biomarker) 
To assess correlation of response and effect of homologous recombination deficiency (HRD) 
status, the BROCA-HR assay, established by the Swisher laboratory will be applied. In addition 
to testing the tumors, a blood sample will be obtained at baseline for germline BROCA-HR 
testing. Somatic BROCA-HR testing will be done using the baseline tumor biopsy tissue on all 
pre-treatment biopsy specimens. The prevalence of biomarkers and correlation with response 
will be used to plan subsequent study as described in section 13. 
 
One hypothesis for response to a PARP inhibitor is that cancer cells need to be deficient in 
homologous repair, but also proficient in the alternative error prone non-homologous end joining 
DNA repair pathway. Thus, loss of HR is not by itself, sufficient for sensitivity to a PARP 
inhibitor, and an accurate predictor of responsiveness could require assessment of many 
components of both the HR and non-homologous end joining pathways. A more efficient assay, 
which would not require a prior knowledge of the critical elements of these DNA repair 
pathways, would instead measure DNA repair capacity. Recent evidence suggests that 
BRCA1/BRCA2 deficient cancers exhibit global DNA alterations termed “genomic scarring” 
that are consistent with their reliance on non-homologous end joining. This genome scar could 
serve as a downstream functional output to measure DNA repair capacity, indicative of both HR 
deficiency and non-homologous end joining proficiency. The BROCA-HR panel will be applied 
to the tumor samples as an integrated biomarker to evaluate if “genomic scarring” is present in 
the tumor samples. Additional detail is provided in 2.4.1. 
 
DNA will be extracted from peripheral blood mononuclear cells and FFPE archived tumor tissue 
containing at least 30% tumor nuclei. A targeted capture and massively parallel sequencing 
approach called BROCA-HR will be applied to samples. For the proposed study, the most recent 
version of BROCA-HR panel with 84 genes that serves as a single assay for germline and 
somatic mutations that influence response to therapy will be utilized. Library preparation has 
been fully automated to increase sample turnaround and lower cost. Paired-end libraries with 
350bp inserts will be prepared from 1 μg of constitutional or neoplastic DNA and hybridize to a 
custom pool of oligonucleotides targeting genomic regions as previously described using the 
SureSelectXT enrichment system on a Bravo liquid-handling instrument (Agilent). Following 
capture, samples will be barcoded with 48 different indexed primers. The pooled samples are 
sequenced on a single lane of a HiSeq flowcell (Illumina) with 2x101bp paired end reads and a 
7bp index read to allow for de-multiplexing and binning of individual samples. Single agent 
variants and insertions and deletions will be detected as previously described with some updates 
in the bioinformatics pipeline. Deletions and duplications of exons will be detected by a 
combination of depth of coverage and split read analysis as previously described, supplemented 

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with additional alignments generated by SLOPE. All germline loss of function mutations in 
cancer susceptibility genes will be confirmed with PCR amplification and Sanger sequencing. 
Cases will be identified as HR proficient or deficient based on sequencing data of known 
Fanconi anemia (FA)-BRCA genes and then correlate HR proficiency with response to PARPi 
on the trial. 
 
9.2.1.1 
Collection, handling, and shipping of specimens. Details for specimen collection, 
preparation, and shipping will be outlined in a lab manual that will be provided to the 
sites. In short, tumor samples will be collected at each study site. Tissue will be 
formalin-fixed and paraffin embedded. The samples will then be shipped to the Yale 
STS laboratory for further processing. Slides with cut tumor sections will be shipped 
from Yale to Dr. Swisher’s lab at University of Washington for the analysis described 
above. In addition, 7ml of blood is required for germline sequencing, which will be 
shipped to Dr. Swisher’s laboratory directly. 
 
9.1.1.2 
Site(s) Performing Correlative Study:  
Dr. Elizabeth M. Swisher, MD  
University of Washington  
1959 NE Pacific St  
Health Sciences Building K154  
Seattle, Washington 98195-6460  
Phone: 206-543-3669  
swishere@uw.edu 
 
9.3 
Exploratory/Ancillary Correlative Studies 
 
9.3.1 Immunoassay for Poly-ADP-Ribosylated (PAR) Substrates 
 
The immunoassay for PAR substrates will be performed on all 16 week post treatment biopsy 
specimens. The PARP enzyme creates poly-ADP-ribosylated (PAR) molecules, thus an 
immunoassay was developed to measure PAR as a surrogate for PARP inhibition. Abbot 
Laboratoies and the NCI-Frederick developed a cross-validated quantitative immunoassay for 
poly-ADP-ribosylated (PAR) substrate. The assay dynamic range is 31-2000 pg/ml PAR with a 
lower limit of quantitation of 15 pg/ml PAR. The assay uses high, midrange, and low controls 
produced from the human melanoma line Colo829. Specimen handling was optimized for both 
PBMCs and tumor needle biopies (18 gauge), and harmonized for use with the same standard 
and controls. Specimens could be subjected to at least 3 freeze-thaw cycles without a detectable 
loss of antigen binding. Assay precision was determined at both Abbott and the NCI-Frederick to 
be better than 80%. Accuracy, as assessed by spike recovery of pure PAR into peripheral blood 
mononuclear cell lysates was 100% +/- 20%. Assay dilution linearity was established for the 
Colo829 controls and tumor lysates, although deviations from linearity are observed in some 
tumor homogenates, and assay conditions are controlled to compensate for the lack of linearity. 
The validated assay has been used to measure PAR levels in peripheral blood mononuclear cells 
in healthy donors, and will be used to measure PAR in peripheral blood mononuclear cells and 
tumor biopsies in the proposed protocol.  
 

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9.3.1.1 
Collection of Specimen(s) 
9.3.1.2 
Handling of Specimens(s) 
9.3.1.3 
Shipping of Specimen(s) 
9.3.1.4 
Site Performing Correlative Study:  
Dr. Joann Sweasy Laboratory 
 
15 York Street 
 
Hunter Building 308 
 
New Haven, CT 06520 
 
 
Joann.sweasy@yale.edu 
 
 
203-785-2981 
 
9.3.2 Signature 3 
Collection, Handling, and Shipping of Specimens: 
 
Signature 3 testing will be done on all pre-treatment biopsies for analysis as a potential 
biomarker. The results of signature 3 testing will be correlated with ORR, and other potential 
biomarkers including the BROCA-HR panel and signature 3 testing The following description of 
the biomarker testing for this was prepared at the recommendation of Drs. James Tricoli and 
Tracy Lively at the NCI, who were consulted about the form this part of the protocol should take.  
Because much of the DNA-Based Mutation Assay Template does not fit next generation 
sequencing (NGS) of tumor DNA, they suggested that a separate, full description of the proposed 
testing be submitted along with a copy of the DNA-Based Mutation Assay Template competed to 
the extent possible for a study involving NGS. 
 
Whole exome screening of DNA from gastric tumors for the signature 3 mutational pattern will 
be performed in the Yale Clinical Molecular Pathology Laboratory (YCMP Lab) on tissue 
microdissected from histologic sections of gastric tumor specimens. These sections will be cut 
from formalin-fixed, paraffin-embedded (FFPE) blocks and mounted unstained on glass 
microscope slides.  One of the sections adjacent to those cut for microdissection will be stained 
with hematoxylin and eosin and examined by a pathologist (Dr. Sklar) to assess tumor content, 
location of the tumor cells within the section, and the extent, if present, of necrosis, hemorrhage, 
or any other potentially interfering features or conditions.  The areas containing concentrated 
tumor cell populations in the stained slide will be circled and the corresponding regions in the 
unstained slides manually microdissected with a sterile scalpel blade.  In cases for which manual 
microdissection is not adequate, for instance, due to small clusters of tumor cells distributed 
within stroma or other non-malignant tissue, laser-capture microdissection will be carried out.  
The goal for this pre-analytic part of the testing is to obtain, either by manual or laser-capture 
microdissection, starting material that is enriched for tumor cells to the level of at least 70% 
tumor.  Enrichment of tumor prior to sequencing increases the sensitivity of the sequencing, 
which will be important because of the reduced read depth inherent in whole exome sequencing 
(WES). 
 
DNA will be extracted from these tissues using the Qiagen FFPE DNA Tissue Kit.  Additionally, 
normal DNA from the patient will be obtained from buccal swabs or from histologically normal 
tissue, free of tumor.  WES of tumor and normal DNA will be conducted in parallel using the Ion 
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by highly multiplexed PCR of tumor and normal DNA using AmpliSeq Exome primers.  
Libraries for tumor and normal DNA will be built separately incorporating short oligonucleotide 
sequences at the end of the fragments to “barcode” the DNA fragments from the two sources.  
(Since the libraries generated from tumor and normal DNA will be mixed and sequenced 
together, barcoding is necessary to disambiguate the results for tumor and normal DNA when the 
sequence results are analyzed.)  Input for the initial amplification during library building (18 
cycles of PCR) will be 60 ng of genomic tumor DNA and 20 ng of normal DNA (lower for 
normal DNA because of less need for read depth and analytic sensitivity), distributed among 12 
primer pools in 12 different tubes. Amplicons from the library builds will be reamplified and 
attached to sequencing microbeads in aqueous droplets within water-oil emulsions (all performed 
using the Ion Chef instrument), such that the great majority of beads are decorated with a pure, 
clonal population of amplicons.  Sequencing of the DNA amplicons on beads will be carried out 
with P1 v3 sequencing chips (each containing >165 million sensor wells each capable of 
sequencing amplicons attached to a single bead) on a Proton sequencer, or with Ion 540 chips on 
a S5 XL sequencer.  Both instruments are available in the lab for this project; however, the 
greater likelihood is that the P1/Proton system will be used because it is cheaper.  With highly 
efficient sequencing chip loading that achieved in the YCMP Lab (occupation of ~90% of wells 
in the P1 chip), the mean read depth is expected to exceed 200x for the tumor DNA and 
proportionately lower for the normal control.  Using the newer HiQ chemistry, average fragment 
lengths should be about 250 nucleotides for about 3.2 megabases of total DNA, covering about 
98% of the exome.   
 
The raw sequencing results will be aligned to the hg19 reference genome and variants called 
using Torrent Suite, Ion Reporter, and custom software developed at Yale.  Those variants 
deemed somatic by virtue of their absence from the matched normal DNA of the patient, will be 
evaluated for signature 3 sequences, using an algorithm designed in house, specifically for this 
purpose.  Mutations in critical genes and a sampling of signature 3 mutations (a sampling only 
because of the high volume of such mutations expected per case) will be manually checked as a 
quality control, in addition to review of overall quality metrics produced by Ion Torrent software 
for each sequencing run.  
 
The Ion Platform system affords a particular advantage relative to Illumina sequencing for the 
research proposed in this LOI. Ion Torrent has pioneered the use of highly multiplex PCR to 
select regions of genomic DNA for targeted sequencing (for instance, ~24,,000 amplicons per 
primer pool to cover the entire exome).  This approach generally means that smaller amounts of 
starting DNA are needed for sequencing, including for WES—a critical consideration when 
dealing with clinical samples, which often consist of core needle biopsy or aspiration specimens 
that must also be utilized for a variety of diagnostic tests and analyses.  The theoretical 
disadvantage of Ion Torrent is lower throughput.  To increase read depth and horizontal coverage 
across the exome, an entire sequencing chip will be used for each case (tumor plus paired normal 
control from the same patient).  Illumina flow cells accommodate more cases per run, but this 
difference is negated by the fact that cases for the proposed trial will come in one at a time and 
batching will not be possible, to achieve a turnaround time for returning sequencing results 
within 10 days of receipt of the specimen in the YCMP Lab, which is the intent for biomarker 
analysis in this trial.  Both Illumina and Ion Torrent sequencing are associated with systematic 
sequencing errors—Illumina related to CG-rich regions and Ion Torrent related to 

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74
homopolymeric regions of sequence.  The YCMP Lab has extensive experience with the 
bioinformatics to interpret Ion Torrent sequencing and the identification of artifacts, both through 
the development out of the Yale Tumor Profiling Lab (see below), from which the YCMP Lab 
was spun off, and through the NCI-MATCH trial for which the YCMP Lab is one of the four 
national sequencing centers.  Furthermore, the parallel sequencing of normal paired DNA permits 
discrimination and elimination of many of these artifacts encountered with Ion Torrent 
sequencing. 
 
Validation for feasibility, clinical sensitivity, specificity, limit of detection, reproducibility, and 
fit for purpose will be carried out using control samples that are available to the YCMP Lab from 
the Yale Tumor Profiling Lab, which was founded by Dr. Sklar six years ago, and performs 
routine clinical NGS of tumor DNA using a variety of gene panels, including a 409-gene panel 
that contains analyzes most known cancer-related genes. Among the cases that have been 
sequenced and are available as controls, are a sizable number that contain verified BRCA1/2 
mutations or lack mutations in BRCA1/2 and other genes in the homologous repair pathway.  
DNA samples from cases that have been previously analyzed by WES are also available, as are 
DNA from cell lines that have been previously subjected to WES. 
 
Feasibiilty testing will carried out on six cases of FFPE tissue with known sequences.  The 
primary purpose of this activity will be to insure that the coverage and depth of sequencing 
described above can be achieved on a routine basis.   
 
Following feasibility testing, validation for clinical sensitivity will be performed on 20 DNA 
samples.  The vast number of potential variants that are possible within the human genome 
presents a problem for validation of biomarker detection by NGS, compared, for instance, to 
validation of a single variant or small set of variants located within one or two genes.  We will 
take two approaches to this problem.  One will be to sequence the DNA from 12 FFPE samples 
(preferably gastric carcinomas), the DNA of which has either been large gene panel sequenced or 
undergone WES.  We will select these cases to contain a variety of different types of mutations: 
single nucleotide variants (SNVs), small insertions and deletions (indels, ≤4 basepairs), larger 
indels (>4 basepairs), and gene amplifications.  However, for this validation and trial, the most 
relevant variants will be SNVs because signature 3 mutations represent a subset of SNVs.  
Additionally, six of the FFPE cases will be ones that contain mutations of BRCA1 or 2, both to 
confirm that mutations in these genes can be detected in FFPE tissues and that the signature 3 
pattern of mutation normally associated with mutations of BRCA1/2 can be accurately discerned. 
 
The second approach will be to perform WES on DNA of eight from established HAPmap cell 
lines in which all single nucleotide polymorphisms (SNPs) have been determined previously and 
are available from commercial and other sources.  Some of them have been used in the NCI-
MATCH sequencing validations and are already in the lab.  These cells lines will be prepared as 
cell pellets, fixed in 10% buffered formalin, and embedded in paraffin, to simulate FFPE tissue.  
The rationale for using HAPmap cell lines is to evaluate the sequencing system being utilized as 
efficiently and thoroughly as possible for its ability to detect variants throughout the exome. 
 
Validation for specificity will be combined with sensitivity testing to show that false negative 
variants are detected at a minimum in the 20 samples studied for clinical sensitivity by WES.  A 

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sampling of apparent false negative variants that cannot be eliminated by adjusting 
bioinformatics filters used in variant calling will be analyzed by Sanger sequencing to resolve the 
ambiguity and help to establish the true rate of false negative results. 
 
Limit of detection will be performed by performing WES on serially diluting four FFPE DNA 
samples into HAPmap DNA (e.g., 50%, 25%, 12.5%, 6.25%, and 3.12%) to determine the lowest 
concentration at which confirmed variants within the FFPE DNA can still be detected.  The 
expected level is 5-10%, given the mean average read depth of 200x. 
 
Validation of reproducibility will be conducted by performing WES three times each on DNA 
four FFPE samples to determine whether each sequence analysis produces the same results.  
These three repetitions will be performed on different days, which is required due to the capacity 
of the Proton sequencer, but also serves as a truer test of reproducibility.  Additionally, over the 
course of the trial, DNA from the same HAPmap sample will be analyzed after every twentieth 
case to check for continued reproducibility.  
 
Fit for purpose validation of the entire biomarker workflow will be carried out by having two 
centers other than Yale mail samples to the YCMP lab and performing WES to insure that 
samples can be processed efficiently within the 10-day window.  Optimally, we will try to have 
this performed on samples that have been extensively sequenced elsewhere.  Alternatively, we 
can mail to ourselves samples from which the DNA has previously been sequenced at Yale. 
 
Please also see the NCI template for “DNA-based Mutation Assays” and the “Standard Operating 
Procedures” for WES by the Yale Clinical Molecular Pathology Laboratory, which are provided 
as separate documents.  
 
Site Performing Correlative Study: 
Dr. Jeffrey Sklar in the Yale Molecular Pathology Lab 
PO Box 208023 
310 Cedar St. LH 215 
New Haven CT 06520 
203-785 4492 
 
9.3.3 Genomic assay for “BRCAness” 
 
Through our involvement in the PanCancer genomics project, we have direct access to the 
combined germline and somatic data form 3,299 TCGA tumors from 12 cancer types [80] [81] . 
These are exome data derived from TCGA. Approximately 150 of these exomes are form 
germline carriers of mutant BRCA 1/2 alleles. Since our goal is to build a diagnostic test that can 
identify not only germline variants in BRCA family genes, but to also identify genomic scarring 
based on LOH/HRD we need a test with sufficient coverage to do both. We will run three 
algorithms on the TCGA germline BRCA 1/2 deficient and disease-matched controls: The 
number of telomeric allelic imbalances (NtAI), large scale transition (LST), and homologous 
recombination deficiency score (HRD-LOH) [82-84]. 
 
We will run all three assays on SNP data from the aforementioned 300 case / control sets and 

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76
assess diagnostic sensitivity, specificity and accuracy, using germline BRCA status as the gold 
standard. AUC curves will be calculated and the top performing test(s) will then be brought 
forward first to the down sampling set, described below. 
 
The most ideal scenario would be if we had enough sequence data in the panels that we use for 
allocation to clinical trials, such as that conduced herein. This trial will use the BROCA-HR 
panel, and whole exome sequencing data will be available for the signature 3 correlative 
analysis. We will then rerun the NTAI, LST, and HRD-LOH assays described above using the 
down sampled exome data as the input. 
 
AUC curves will be calculated and the top performing test(s) will then be validated by analyzing 
archival cases of gastric cancer available through the UCSF HDFCCC Tissue Core. DNA 
extracted from tissue samples will be analyzed for the HR defect signature identified through the 
work described above and mutations in the BRCAness-associated genes identified by us 
(BRCA1, BRCA2, ATM, ATR, PTEN, PARP1, MRE11A, PALB2, CDK12, BAP1, PRKDC, 
BARD1, BACH1, FANCD2, FANCE, CHEK1, CHEK2, PMS2, FANCA, FANCC, FANCF, 
XPA, NBN, BLM, BRIP1, RAD51B, RAD51C, RAD51D, and RAD50) by next generation 
DNA sequence analysis using a capture approach and the Illumina Myseq instrument (available 
at the UCSF Gladstone Genomics Core). Subsequently, the signature will be applied in a 
systematic manner to the data produced in the clinical trial with one of these assays. The 
validation studies will be performed in Dr. Ashworth’ laboratory at UCSF. Prior work in gastric 
cancer estimates that around 20% of samples will score in the upper quartile of all three of these 
assays [85]. These estimates will then be available for further analysis such as supervised 
analytics looking at response to PARP, platinum, and other clinically observed characteristics. 
 
Expected results: This aim will determine the applicability of clinically deployed sub-exome 
sequencing panels for the assessment of BRCAness using genomic measurements. 
 
Pitfalls/alternative approaches: It is possible that the DNA footprint generated by the commercial 
assays fails to reliably detect BRCANess in TCGA exomes. In particular, the NtAI may not 
perform well because it requires telomeric sequences, which are not well captured on sub-exome 
panels. If this were the case, and further funding were obtained we could begin work on building 
a targeted addition to these tests, but that would increase costs and not be ideal for large 
population screening at major cancer centers.  
 
Site(s) Performing Correlative Study:  
Dr. Michael Korn (UCSF) 
Box 1705, UCSF 
San Francisco, CA 94143-1705 
Michael.Korn@ucsf.edu 
 
 
9.3.4 Factors demonstrating synthetic lethality with PARP inhibitors in gastric cancers.  
 
Aim 1. Elucidating the role of key signal transduction processes in mediating responsiveness to 
PARP inhibitors in gastric cancer. We will expand our panel of gastric cancer cell lines to a total 

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of 20 cell lines. These lines that are genomically well characterized as part of the Cancer Cell 
Line Encyclopedia (Broad Institute). Cell lines will be selected harboring mutations conferring 
BRCAness and to represent chromosomally instable and mismatch repair deficient subtypes of 
gastric cancer. We will profile cell lines for their responsiveness to DNA damaging agents and 
PARP inhibitors, either alone or in combination. These include bleomycin (a direct inducer of 
DNA double-strand breaks) and cisplatin as well as temozolomide (both indirect inducers of 
DNA double-strand breaks). Cell lines will be treated with bleomycin (100 μg/ml), cisplatin (5 
μM) or temozolomide (200 μg/ml) or PARP inhibitors (olaparib, talazoparib or rucaparib; all 
compounds are available at the Ashworth and Korn labs from commercial sources) for up to 5 
days and analyzed for cell viability (Cell TiterGlo assay), alterations in cell cycle distribution, 
and apoptosis (fluorescence activated cell sorting, FACS). To assess the extent of DNA damage 
we will measure intra-nuclear γH2AX focus formation by confocal microscopy. Cells will be 
grown and treated on cover-slips in 6-well dishes and, after fixation, stained using a rabbit anti- 
γH2AX antibody. The number of foci in at least 100 cells per cover slip will be determined. To 
assess PARP activity, poly-ADOP-ribolyzation will be determined using a chemiluminescence 
detection approach (Universal Chemiluminescent PARP Assay Kit, Trevigen). Based on the 
results of this initial screen, a subset of cells with low and high DNA repair response to DNA 
damaging agents as well as low and high sensitivity to PARP inhibitors will be selected.  Cells 
will be treated with increasing doses of inhibitors of key oncogenic pathways, including PI3K 
(BKM120, BYL719), RAF-MEK-ERK (GSK1120212, PD-0325901), TGFβ (LY2157299), 
WNT (PRI-724), Notch (LY-3039478), Hedghog (vismodegib), JAK-STAT (ruxolitinib). Based 
on these results of this initial screening, drug combinations will be tested. For example ,if we 
reproduce down-regulation of DNA repair activity by PI3 kinase inhibitors, we will assess 
efficacy of these inhibitors in combination with PARP inhibitors +/- DNA damaging agents.  
 
Aim 2. Unbiased identification of modifiers of responsiveness to PARP inhibitors. We will 
utilize a pooled shRNA library (DECIPHER, Cellecta) to identify potential modifiers of response 
to PARP inhibitors. The library contains 27,500 sHRNAs targeting 5,046 signaling components. 
We will select gastric cancer cell lines with intermediate sensitivity to the highly potent and 
selective PARP inhibitor talazoparib based on the results obtained in Aim 2A. Cells will be 
infected with lentiviruses expressing the sHRNA library and subjected to selection. 
Subsequently, cells will be treated with talazoparib or with vehicle control. Abundance of each 
barcoded hairpin will be quantified to identify shRNAs that were selectively depleted during 
treatment with talazoparib, but not vehicle. TO assess the total population of transduced shRNAs 
for control purposes, genomic DNA will also be isolated and shRNAs identified from cells just 
after transduction but before drug treatment. Analysis of abundance shRNA species, next-
generation DNA sequencing will be utilized in collaboration with the UCSF Genome Analysis 
Core. Hits will be validated experimentally using multiple shRNA species or specific inhibitors 
if available. 
 
Aim 3. Establishment of PDX tumors from patient samples and assessment of target inhibition 
and efficacy of novel drug combinations involving PARP inhibitors. Fresh biopsies will be 
obtained from selected patients, and on repeat biopsy at 16 weeks for eligible patients. We will 
aim at capturing tumors harboring a diverse spectrum of mutations conferring BRCAness. We 
will rest target inhibition and efficacy of novel combination therapies in these PDX models. 
Based on our preliminary data, we expect that this will include a combination of MEK and 

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PARP inhibitors. Before testing this combination or new combination resulting from the work in 
aims 1 and 2, in mice harboring xenograft tumors, we will assess treatment toxicity in NOD scid 
mice. Groups of three mice will be treated with solvent (DMSO), single inhibitors (e.g. 
talazoparib or PD0325901), or the combination of both at three different dose levels. In the case 
of talazoparib and PD0325901, mice will be treated at dose levels 0.1, 0.22, and 0.33 mg/kg of 
talazoparib and 5, 7.5, and 10 mg/kg of PD0325901 resulting in a 4 x 4 matrix requiring 32 mice 
per study. The maximum doses of both inhibitors that can be administered without occurrence of 
severe toxicity will be chosen for subsequent studies. We will then proceed with 
pharmacodynamics studies to validate target inhibition by the PARP and MEK inhibitor 
combination in the PDX models. Per individual tumor model, subcutaneous tumors will be 
generated in 6 mice and allowed to grow to a volume of 300 mm3. Animals will be dosed with 
the compounds (for example talazoparib and PD0325901) or vehicle control buffer for three days 
at doses that were found to be safe in the toxicity studies. Animals will be sacrificed for hours 
following the last drug administration. Tumors and adjacent normal tissue will be harvested and 
snap-frozen in liquid nitrogen or fixed in buffered formalin. Proteins will be extracted from 
frozen tissues using protocols established at our laboratory. Phosphorylation of effector proteins, 
including pERK, pAKT, and pPRAS40 will be determined by quantitative Western blot analysis 
using fluorescence based imaging system (Odyssey, Licor). PARP inhibition will be assessed 
using the PARP in vivo PD Assay II kit (Trevigen). If no evidence of target inhibition is 
observed in any model for a given inhibitor, the respective experiment will be repeated at a 
modified dose based on the toxicity study. Otherwise, apoptosis induction will be evaluated by 
TUNEL assay. A Student t-test will be used to determine statistical significance of differences 
between treated and control groups. Efficacy studies in primary PDA xenograft tumors will also 
be conducted. Having established optimal doses for efficient target inhibition, we plan efficacy 
studies in the selected PDX models. Endpoints for these studies will be tumor response rate and 
overall survival. Tumor size will be calculated with biweekly caliper measurements. Compounds 
will be administered daily by oral lavage. Experiments will be terminated on day 28 or when any 
tumor exceeds 1,500 mm3 in greatest dimension. Relative tumor growth inhibition (TGI) will be 
calculated by relative tumor growth of treated mice (T) divided by relative tumor growth of 
control mice I or (T/C). We will use the following definitions: Response = 0-20% TGI; Stable 
disease = 21% to 50% TGI; Tumor progression ≥50% TGI. Per study, there will be four cohorts 
treated with control (i.e. DMSO), single agents (for example talazoparib and PD0235901), and 
drug combination. We will enroll 8 tumor bearing mice per treatment group. With this sample 
size and using a 1-sided t-test, we can detect a 33% or greater growth inhibition with 80% power 
at a 5% level of significance. Experiments will be repeated once. Differences in response rates 
will be determined using Satterwaite’s t-test (unequal variances) with 1-sided 5% Type I error. 
Kaplan-Meier survival data will be analyzed using a log rank test. 
 
Pitfalls/alterative approaches: The proposed experiments are likely to reveal new mechanisms 
involved in DNA homologous recombination repair that can be exploited therapeutically. Our 
findings related to the interaction of the RAF-MEK-ERK pathway and PARP inhibitors 
sensitivity are an example of successful application of the candidate pathway approach. 
However, the pathways of interest are highly interconnected. Based on the findings of the 
experiments described, we might expand mechanistic analysis to be able to interpret findings. In 
such case we will utilize Reverse Phase Protein Lysate Array technology as we have done 
before. We expect that CRISPR analysis will be technically feasible and reveal new regulators of 

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HR repair. The technology is established in the Ashworth lab. If technical challenges are 
encountered, we will collarboarte with Drs. Kampmann and Weissman at UCSF who invented 
the technology. The team at Memorial Sloan Kettering Cancer Center has extensive experience 
with establishing PDX models and we don’t expect any problems with this part of the aim.  
 
Sites Performing Correlative Study:  
Dr. Michael Korn (UCSF) and Dr. Yelena Janjigian (Memorial Sloan Kettering) 
Box 1705, UCSF 
San Francisco, CA 94143-1705 
Michael.Korn@ucsf.edu 
 
9.3.5 T Cell Receptor Diversity. 
 
By using next generation sequencing of TCRβ repertoire, Dr. Fong’s lab has demonstrated that 
maintenance of pre-existing high-frequency clonotypes is associated with clinical response and 
improved overall survival following ipilimumab [79]. Using these established methods, we will 
determine the T cell clonotypes in blood of clinical trial patients obtained pre- and post-
treatment. Repertoire diversity will be measured using Shannon’s and clonality [86, 87]. 
Repertoire change between serial timepoints will be measured using Morisita’s distance, which 
is not significantly influence by sample size [88, 89]. Numbers will be reported as distances with 
1 indicating maximal dissimilarity. Paired t test will be applied to each diversity metric 
comparing pre-and post-treatment to test if there is a significant treatment effect. Two-sample 
Wilcoxon rank sum test will be utilized to compare the clonality index at each time point 
between patients with and without BRCAness. All analyses will be done by statistical software. 
Statistical significance will be declared at an alpha level of 0.05, and no adjustment will be made 
for multiple comparisons unless noted. Identification of differentially abundant clonotypes pre 
and post-treatment for each sample will be performed using a DESeq R package modified to 
account for normal variation in the repertoire over time and to compensate for the lack of 
replicates in the experimental design. Multiple testing adjustments will be accomplished by 
controlling FDR for each sample. Downstream analysis will be applied to those significant clone 
to see if multiple T cell clonotypes with different nucleotide sequences may converge upon the 
same amino acid sequence, which would be consistent with antigen selection.  
 
Where available, comparisons of TCR transcript frequency and repertoire diversity (Shannon’s 
and clonality indices) will be made between pre- and post-treatment biopsies by paired Wilcoxon 
rank sum test. At an alpha level of 0.05, 20 samples would ensure 80% power to detect effect 
size of 0.66 in repertoire diversity to declare that there is a significant difference in TCR 
frequency between pre- and post-treatment biopsies. We also plan to compare biopsies from 
patients with and without BRCAness. 
 
We routinely test PBMC processed in our laboratory for HLA-A2 expression. For patients who 
possess this HLA allele (approximately 40% of UCSF patients) and are known to have HPV+ 
tumors, we use MHC-peptide tetramers, specific for HPV derived epitopes (Beckman Coulter, 
Brea, CA) to FACS sort HPV reactive CD8 T cells. These sorted T cells will also be subjected to 
TCR sequencing. We will then use the clone-specific sequences to track these antigen-reactive T 
cells in both the blood and tissue with established methodologies [79]. 

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Pitfalls/alternative approaches: As we have seen in pancreatic adenocarcinoma, BRCA2 carreirs 
can possess a higher number of neoepitopes. We anticipate that patients with the highest 
neoepitope burden (e.g. with BRCAness phenotype) will have a lower clonality indices (i.e. 
greater TCR diversity) in both the blood and the tumors. The tetramer sorting experiments will 
allow us to determine the relative contribution of virus-specific T cells to the modulated immune 
responses with PARPi. However, the circulating T cell repertoire may not reflect what is going 
on in the tumors. Our approach will allow us to determine whether the TCR repertoire in the 
blood can serve as a surrogate for the TCR repertoire in the tumor. We may find that a high 
neoantigen burden could actually lead to increased clonality (i.e. decreased diversity) in tumors 
due to focusing of the immune response to these immunodominant epitopes. Nevertheless our 
approach will be able to assess for this alternative hypothesis. We do not anticipate any 
difficulties in performing these assays. These results would lay rationale for combinations with 
immunotherapy in the future.  
 
Site(s) Performing Correlative Study:  
Dr. Michael Korn (UCSF) 
Box 1705, UCSF 
San Francisco, CA 94143-1705 
Michael.Korn@ucsf.edu 
 
9.3.6 Circulating Tumor DNA (Exploratory Correlative). 
Peripheral blood will be placed in a biorepository for assessment of circulating tumor DNA and 
molecular profiling at a later date. 
 
9.3.6.1 
Specimen Receipt and Processing at the EET Biobank  
Plasma specimens will be transferred to the EET Biobank for extraction of cfDNA. 
 
9.3.6.2 
Site Performing Correlative Study 
Circulating Tumor DNA will be performed by the NCLN Genomics Laboratory under the 
direction of Mickey Williams, Ph. D.  
 
9.3.6.3 
Shipment of specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
NCLN Genomics Laboratory at The University of Texas MD Anderson Cancer 
Center 
6565 MD Anderson Blvd 
Suite 3.4019 
Houston, TX 77030 
Attn: CTO, NCLN Lab, Jincy Veliyathu or Khushali Rajendra Patel 
 
9.3.6.4 
Contact Information for Notification of Specimen Shipment 
Thomas Forbes, NCLNGenomicsReceiving@nih.gov 
  
 

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81
 
10. STUDY CALENDAR 
 
Phase 1 and Phase 2: 
Baseline evaluations are to be conducted within the 28-day screening period. CT scans and x-
rays must be done <4 weeks prior to the start of therapy.  In the event that the patient’s condition 
is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of 
the next cycle of therapy. 
 
 
Pre- 
Study11 
Cycle 1  
(±2 days)  
Cycle 2 
(±2 days) 
Cycle 3 
(±2 days) 
Cycle 4 
(±2 days) 
Cycles 5 – 7  
(±2 days) 
Cycle 8 and 
later 
(±2 days) 
Follow up5 
Day 
 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
 
Olaparib 
 
A-----------------------------------------------------------------------------------------------→ 
 
Ramucirumab13 
 
B 
 
B 
 
B 
 
B 
 
B 
 
B 
 
 
Informed consent 
X11 
 
 
 
 
 
 
 
 
 
 
 
 
 
BROCA-HR Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-treatment Biopsy1 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
On-treatment Biopsy2 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
 
Research blood for biobank  
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event Evaluation 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Physical exam 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Performance status 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
INR and PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/diff, plts 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum chemistry3 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Buccal swab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH10 
X 
 
 
 
 
 
 
 
 
X10 
 
 
 
 
Urinalysis8 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
EKG 9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor measurements12,14 
X 
Tumor measurements are repeated every 6-weeks ± 7 days14. Documentation 
(radiologic) must be provided for patients removed from study for progressive 
disease. Imaging should include chest, abdomen, and pelvis. 
X7 
Radiologic evaluation12,14 
X 
Radiologic measurements should be performed every 6-weeks ± 7 days14 for the 
duration of enrollment. Imaging should include chest, abdomen, and pelvis. 
X7 
B-HCG 
X4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO (if indicated) 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 

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82
A: 
Olaparib:  Dose as assigned; administration schedule 
B: 
Ramucirumab:  Dose as assigned; administration schedule 
1:      Mandatory for all patients in both phases of study between 3 – 28  days before day 1 of treatment. 
2:      Optional for all patients if felt to be safe in the opinion of the investigator. The on treatment biopsy should be obtained between days 3 – 
11  of cycle 8 (week 16).  
3: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [50], sodium, magnesium, and GGT. 
4: 
Serum pregnancy test (women of childbearing potential) one test 28 days prior to starting treatment. Day 1 serum pregnancy test should 
be prior to starting treatment.  
5: 
Off-study evaluation: 4 weeks after coming off study. Patients will continue to be evaluated for survival every 3 months. 
6:      Prior treatment with anthracyclines, prior treatment with trastuzumab, NYHA classification of II controlled with treatment (see Appendix   
B), prior central thoracic radiation, history of myocardial infarction within the prior 12 months, prior history of impaired cardiac function. 
7:     For patients who discontinue the study treatment for reasons other than disease progression will continue to undergo restaging scans every 
6 weeks ± 7 days or earlier if clinically indicated, until the documentation of disease progression (see section 5.6 for duration of follow 
up). 
8:    Full urinalysis at screening, a urine dipstick protein level may substitute for a full urinalysis for on treatment visits although a full 
urinalysis may be done if clinically indicated. 
9:    Within 7 days prior to starting treatment and when clinically indicated. 
10: TSH monitoring should be done every 12 weeks or as indicated. 
11. The screening period is 28 days and patients must start day 1 of treatment within 28 days of signing consent. 
12 Radiologic evaluations should include the chest, abdomen, and pelvis. When appropriate, additional sites of imaging may be applicable 
depending on disease extent. 
13. Ramucirumab should be run over 60 minutes (+/- 15 minutes). 
14. Patients that remain on treatment for > 6 months may decrease the response assessment scan interval to every 12 weeks (+/- 7 days) at the 
discretion of the investigator.  
 
 
11. MEASUREMENT OF EFFECT 
 
Although the clinical benefit of these drugs has not yet been established, the intent of offering 
this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability. Patients 
with measurable disease will be assessed by standard criteria.  For the purposes of this study, 
patients should be re-evaluated every week for the first 3 weeks, then every 2 weeks thereafter.  
In addition to a baseline scan, confirmatory scans will also be obtained ever 6 weeks following 
initial documentation of an objective response. Patients on treatment for > 6 months may 
decrease the response assessment interval to every 12 weeks (+/- 7 days) at the discretion of the 
investigator. 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every ever 6 weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained 6 weeks following 
initial documentation of objective response. Patients on treatment for > 6 months may decrease 
the response assessment interval to every 12 weeks (+/- 7 days) at the discretion of the 
investigator. 
 
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) [Eur J Ca 45:228-247, 2009].  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. 
 
11.1.1 Definitions 
 

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Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with olaparib and ramucirumab. 
 
Evaluable for objective response.  All patients who receive treatment will be counted for 
response rate evaluation.  These patients will have their response classified according to 
the definitions stated below.  (Note:  Patients who exhibit objective disease progression 
prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  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 [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 

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Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during 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 (≥1 cm) 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 (0.5 cm) or less.  If CT 
scans have slice thickness greater than 5 mm (0.5 cm), 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).   

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85
 
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. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  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 biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 

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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. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
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 (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 

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20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
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 
[<1 cm] 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). 
 
11.1.4.3 
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 recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions* 
Overall 
Response 
Best Overall Response when 
Confirmation is Required** 
CR 
CR 
No 
CR 
≥4 wks. Confirmation 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
No 
PR 

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PD/not 
evaluated 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Confirmation will be obtained at the regularly scheduled interval of every 6 weeks for 
study patients and for patients who come off study for reasons other than disease 
progression. 
***  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 
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 
 
11.1.5 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.  

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11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first.  
 
11.1.7 Response Review 
 
Radiology assessments for Yale site will be provided by the Yale tumor metric core. 
Assessment for other participating sites should be performed per the site’s own tumor 
metric core.  
 
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least monthly, 
or more frequently, conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and adverse events and unanticipated problems.   
 
During the Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and pharmacovigilance.  Decisions to proceed to the 
second stage of a Phase 2 trial will require sign-off by the Protocol Principal Investigator and the 
Protocol Statistician. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 

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plan. 
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (https://eapps-ctep.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Read-Only, CRA, Lab Admin, SLA, or Site Investigator) on 
either the LPO or Participating Organization roster at the enrolling site. To hold the Rave CRA 
role or CRA Lab Admin role, the user must hold a minimum of an AP registration type. To hold 
the Rave Site Investigator role, the individual must be registered as an NPIVR or IVR. 
Associates can hold read only roles in Rave.  
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at 
http://theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted three times annually (one annual site visit and two data audits).  
For CTMS monitored studies, after users have activated their accounts, please contact the 
Theradex Help Desk at (609) 799-7580 or by email at CTMSSupport@theradex.com for 
additional support with Rave and completion of CRFs. 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 

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91
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm
)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the 
recommended phase 2 dose (RP2D), and a description of any dose-limiting toxicities 
(DLTs).  CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry 
and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
12.3 
CTEP Multicenter Guidelines 
 
N/A 
 

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12.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 

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93
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information.  
 
12.5 
Genomic Data Sharing Plan 
 
Investigators will submit large-scale human genomic data and relevant associated tissue to an 
NIH-designated data repository in a timely manner. Investigators will also submit any 
information necessary to interpret the submitted genomic data, such as study protocols, data 
instruments, and survey tools. The NIH will release data submitted to NIH-designated data 
repositories no later than 6 months after the initial data submission begins, or at the time of 
acceptance of the first publication, whichever comes first. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is a phase 1 and 2 open-label single arm clinical trial with no randomization of olaparib 
with ramucirumab for patients with metastatic gastric and gastroesophageal junction 
adenocarcinoma who have failed at least one prior line of chemotherapy. The study has a phase 1 
dose escalation lead in phase for olaparib with standard dose ramucirumab. The primary 
objective of phase 1 is to determine the safe dose of olaparib with ramucirumab. Olaparib will be 

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increased up to 300 mg twice daily in tablet dosing. Based on published toxicity profiles for 
olaparib and ramucirumab outlined in section 5.2 the probability of DLT is in the range of 0.15 
to 0.25. The primary objective of phase 2 is to measure the efficacy for olaparib plus 
ramucirumab by objective response rate (ORR). In phase 2, 40 patients will be enrolled as a pilot 
study to help determine the foundation for a biomarker stratification design in a larger study. 
Incidence rates for the BROCA-HR biomarker will be measured in all enrolled patients for both 
stages. If the incidence rate of the BROCA-HR biomarker is too low (<10%) or efficacy is seen 
it is unlikely we would not proceed to a larger study. The historical control for ramucirumab 
monotherapy is an ORR of 3%, and we will assume a null hypothesis of 5%.  
 
Primary Endpoints: 
Phase 1: Dose limiting toxicity for olaparib in combination with ramucirumab and the maximum 
tolerated dose (or the maximum safe dose). 
Phase 2: Objective response rate by RECIST v1.1 criteria for combined therapy with olaparib 
and ramucirumab. 
 
Analytic Plan for Primary Endpoints: 
Phase 1: A 3+3 dose escalating approach will be used to determine what dose is the safe dose 
and should be used in the Phase 2 portion of the study. 
 
Phase 2:  Because we do not know the true distribution of our biomarker we will proceed with 
this 40 patient pilot study to help plan a larger study based on both our observed biomarker 
prevalence and our response rates. If response rates are observed regardless of biomarker status 
the subsequent study may not be biomarker driven or an alternative biomarker may be used. 
Based on published data in the COSMIC and TCGA databases we expect the genes characteristic 
for HRD in the BROCA-HR biomarker to be positive in approximately 35% of cases. These 
genes are: ATM, ATR, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, MRE11A, NBN, 
PALB2, RAD51, RAD51C, RAD51D, RBBP8, SLX4, XRCC2, CDK12. Based on the proposed 
prevalence of these genes we will enroll to 40 patients and proceed as follows: 
 
Sample Size Justification: 
 
1. If there are 6 or more BROCA-HR+ patients (34 or less BROCA-HR- patients): If 
there are no responses in BROCA-HR+ patients and no response in BROCA-HR- 
patients, then it is unlikely we will proceed to a larger study with this 
combination.  
• For BROCA-HR+ patients: the probability of ≥ 1 responses is > 80% if 
the true response rate ≥ 25%  
• For BROCA-HR- patients: The probability of ≥ 1 response is > 99% if the 
true response rate is ≥ 20% and the probability of ≥ 1 response of 80% if 
the true response rate is ≥ 5%. 
 
2. If there are 6 or more BROCA-HR+ patients (34 or fewer BROCA-HR-): For 
BROCA-HR- patients, the study will require at least 4 responses for success if we 
have at least 26 BROCA-HR- patients (65% incidence rate). The probability of 4 
responses is 80% if the true response rate is 20%. The study will require at least 3 

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responses for success if we have at least 20 BROCA-HR- patients (50% incidence 
rate) the probability of ≥ 3 responses = 80% if the true response rate = 20%. It is 
very unlikely the incidence rate of BROCA-HR- will be less than 50%. 
 
3. If there are less than 6 BROCA-HR+ patients (35 or more BROCA-HR- patients): 
If no responses are observed in either cohort, then it is unlikely we will proceed to 
a larger study with this combination. The probability of ≥ 6 BROCA-HR+ 
patients is > 85% if the true incidence of BROCA-HR+ is ≥ 20%. The probability 
of ≥ 6 BROCA-HR+ patients is > 99% if the true incidence rate of BROCA-HR+ 
is ≥ 35%. 
 
Based upon the results in the above scenarios we will discuss with CTEP on the plan to proceed 
to a larger study. 
 
Analysis Plan: 
 
The objective response is defined as a complete or partial response, as determined by 
investigator assessment using RECIST v 1.1 and confirmed by repeated assessment > 4 weeks 
after initial documentation. Patients with missing or no response assessments are classified as 
non-responders. The ORR will be estimated using the 95% confidence interval (CI) based on 
Wilson’s method. A 5% 2-sided alpha will be used. 
 
The Wilcoxon rank sum test and Fisher’s exact test will be applied to study the association 
between the response status and the continuous and categorical variables, respectively. The 
generalized non-linear model and logistic regression will be applied for multivariable data 
analysis. The adjusted p-value and 95% CI of the odds ration (OR) will be reported. 
 
For the PAR assay and PDX generation involving biopsy samples, the findings will be primarily 
hypothesis generating and will use descriptive statistics. In addition, with the proposed sample 
size of 20, the half-width of the 90% CI will be less than 20% with respect to the binary 
endpoint. It has at least 85% power to detect a correlation coefficient > 0.5 with one-side type I 
error = 10% with respect to the continuous endpoint.  
 
 
 
13.2 
Sample Size/Accrual Rate 
 
Planned sample size Phase I: 6 patients 
Planned sample size Phase II: 40 patients 
Accrual Rate: 10/month 
 
 
PLANNED ENROLLMENT REPORT 

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• Toxicity rates will be tabulated by type and grade and compared to established rates for 
ramucirumab monotherapy. Ninety-five percent confidence intervals will be calculated 
for each of these. 
 
Analytic Plan for Exploratory Endpoints: 
• The association of BROCA HR assay with Signature 3 will be assessed using a series of 
contingency table analyses. For instance, we can examine the association of the presence 
of an individual mutation from the BROCA HR panel with the signature 3 (yes/no) using 
Fisher’s exact test. Next, using a Cochran Mantel Haenzel test we can examine the 
relationship across the measures. Finally, we wish to examine the relationship of each of 
these measures with response. To do this multiple logistic regression models can be fit 
with the response (CR/PR vs SD/PD) considered as the outcome variable and the 3 assay 
measures can be used predictors. This model can include interactions among the assays. 
Additional covariates including patient level characteristics (age, gender) and group can 
be included in these models. These analyses are exploratory therefore no formal 
adjustment for multiple comparisons will be performed, however it is understood that 
these tests will be considered hypothesis generating primarily.  
 
• Tumor cells for PDX model, and biobanked tumor tissue and peripheral blood will be 
used for future studies. 
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
olaparib and ramucirumab.  
 
13.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be 

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performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided.  
 
 
 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 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. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATIONS 
 
 
 
Clinical Evaluation of Functional Capacity of Patients with Heart Disease in Relation to 
Ordinary Physical Activity 
 
Class 
Cardiac 
Symptoms 
Limitations 
Need for 
Additional Rest* 
Physical Ability 
to Work** 
I 
None 
None 
None 
Full Time 
II 
Only Moderate 
Slight 
Usually only 
slight or 
occasional 
Usually full time 
III 
Defined with 
less than 
ordinary activity 
Marked 
Usually 
moderate  
Usually part 
time 
IV 
May be present 
even at rest, and 
any activity 
increases 
discomfort 
Extreme 
Marked 
Unable to work 
 
* To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician 
** At accustomed occupation or usual tasks  
 

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APPENDIX C 
PILL DIARY FOR OLAPARIB  
Today’s Date _______________________   Cycle # _______________________ 
Patient Name _______________________   Patient Study ID _______________________ 
 
1. Complete one form for each cycle (14 days). 
2. Record the date, the number of tablets you took, and when you took them. 
3. Bring your pill bottles (including empty bottles) and this form to every appointment. 
4. Do not chew, dissolve, or crush medications. DO NOT make up vomited doses. 
5. If you miss a dose, you have up to 2 hours to make this dose up. Otherwise, write 
“missed” where you would normally write the time of your dose. 
The first row in the table below is an EXAMPLE ROW for how to complete this diary. 
OLAPARIB 
Take _____ (number) _____ mg tablets twice a day 12 hours apart with or without food. You 
should avoid grapefruit, grapefruit juice, and Seville oranges while on study because of their 
affects on the metabolism of olaparib. 
Day 
Date 
100 mg 
150 mg 
AM 
PM 
Comments 
 
1 
1/1/17 
2 
0 
8:00 
8:00 
 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX D 
PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, olaparib. This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for others 
who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
Olaparib interacts with certain specific enzymes in the liver and can effect the ability to process 
other medications, and other medications can affect the ability of your body to process olaparib. 
 
Olaparib interacts with a certain specific enzyme in your liver called CYP 3A4 isoenzymes. The 
drug itself induces the CYP3A4 isozymes, and olaparib is broken down by this enzyme and will 
be affected by other drugs that inhibit or induce this enzyme. 
 
Olaparib may also interact with P-glycoprotein, organic anion-transporting polypeptide 
(OATPB1), organic cation transporter 1 and 2 (OCT1 and OCT2), OAT3, multi-drug and toxin 
extrusion proteins (MATE1 and MATE2K), and BRCP. Administration of strong inhibitors and 
inducers of these proteins should be avoided while on olaparib. The manufacturer recommends 
that statins, in particular, should be administered with caution when given concomitantly with 
olaparib. 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Olaparib may interact with other drugs which can cause side effects. For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial.  It is also very important to tell your doctors if you stop taking any regular 
medicines, or if you start taking a new medicine while you take part in this study.  When you talk 
about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort. 
Avoid ingesting grapefruit, grapefruit juice, Seville oranges, and Seville orange juice while 
taking olaparib. It is helpful to bring your medication bottles or an updated medication list with 
you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
These are the things that you and they need to know:  
 

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Olaparib must be used very carefully with other medicines that use liver enzymes.  Before you 
enroll onto the clinical trial, your study doctor will work with your regular health care providers 
to review any medicines and herbal supplements that are considered strong inducers/inhibitors or 
substrates of CYP 3A4 isoenzyme. 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is _____________________________________ 
and he or she can be contacted at _____________________________________. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX E 
DIARRHEA MANAGEMENT 
 
 
Information for patients and caregivers for the management of diarrhea: 
 
• You should take Imodium 4 mg at the onset of diarrhea. 
• If diarrhea persists, you should then take 2 mg every 2 hours with each 
additional bowel movement. No more than 16 mg of Imodium should be 
consumed in a 24-hour period.  
• If you develop more than 4 episodes of diarrhea in 24 hours you should 
call your study doctor.