Clinical trial NCT04377087
Conditions: Ovarian Cancer
Keywords: PARP-I BRCA mutation Epithelial ovarian cancer (EOC) Olaparib platinum sensitive recurrent ovarian carcinoma Poly ADP-Ribose Polymerase (PARP) inhibitor.
Sponsor: Sarah E Taylor
Start date: 2020-06-29; Completion date: 2023-05-31
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to test if delaying the start of the olaparib until there is a rise in a tumor marker called CA-125 will result in a longer time until the next or different treatment for the patient's cancer. The study will also evaluate how delaying the start of maintenance therapy will affect symptoms; physical functioning; quality of life; and impact on finances.

Detailed description:
This is a Phase II trial will investigate if waiting until the time of chemical recurrence, denoted by rising CA125, to start a PARP inhibitor will lead to an improved time to next therapy with improved quality of life and at a lower financial toxicity.

PARP-I have shown efficacy as both monotherapy and as maintenance therapy. This trial will explore whether patients with recurrent ovarian cancer could derive the same efficacy benefit from a delayed start of a PARP-I compared to immediate maintenance therapy. Delayed start would have the benefit of sparing the physical, psychological, and financial toxicity associated with prolonged treatment. This approach would be particularly relevant in a population of platinum-sensitive patients who can have prolonged treatment-free intervals.

With widespread use of PARP-I, regardless of timing, understanding, and overcoming PARP-I resistance is becoming a major clinical need.

Enrollment will start within 8 weeks of completion of platinum-based treatment. Monitored with CA 125 levels every 28 days. Olaparib will be started when CA 125 rises by two-fold of their nadir value. Olaparib will be dosed at 300 mg orally twice a day, 28 days of treatment will be a cycle. Follow-up will consist of CA125 drawn every 28 days and CT scans obtained at doubling of CA- 125 and then every 12 weeks\* to assess for recurrence or progression. Clinician- and patient-reported adverse events recorded every 28 days. Cancer-related worry and distress assessed every 28 days. Measures of quality of life and physical function, and financial toxicity assessed every 12 weeks.

Arms: arm 1: Olaparib dosed at 300mg orally twice daily, started when CA125 rises by two-fold of nadir value.
Interventions: intervention 1: Olaparib
Intervention descriptions: intervention 1: Olaparib is a potent oral poly (ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in BRCA1/2 deficient tumor cells through the formation of double-stranded DNA breaks which cannot be accurately repaired, which leads to disruption of cellular homeostasis and cell death.

Protocol documents:
Prot_SAP_000.pdf: 
Page 1  of 69
 
 
Local Protocol #: HCC#19-164 
ClinicalTrials.gov Identifier: 
TITLE: Phase IIA Trial of Delayed Initiation of Olaparib Maintenance Therapy in Platinum 
Sensitive Recurrent Ovarian Cancer 
 
 
 
Principal Investigator: 
Sarah E. Taylor, MD 
Assistant Professor 
Division of Gynecology Oncology 
Magee-Womens Hospital of UPMC 
300 Halket St, Suite 2130 
Pittsburgh, PA 15213 
Phone: 412-641-1153 
Fax: 412-641-5417 
E-mail: taylorse2@mail.magee.edu 


Page 2  of 69
 
 
Statistician: 
Study Coordinator: 
William Gooding 
UPCI Biostatistics Facility 
UPMC Cancer Pavilion 
Suite 325 Sterling Plaza 
5150 Centre Avenue, Suite 301 
201 North Craig Street 
Pittsburgh, PA 15232 
Pittsburgh, PA 15213 
Telephone: 
Telephone: 
Fax: 
Fax: 
Email: 
Email: 
 
Commercial Agent(s): olaparib (Lynparza®, NSC #) 
Protocol Type / Version # / Version Date: IIT / 1.1 / 12/13/2019 


Page 3  of 69
 
 
TABLE OF CONTENTS 
SCHEMA ................................................................................................................................... 5 
STUDY SYNOPSIS ................................................................................................................... 6 
1. 
OBJECTIVES AND ENDPOINTS .................................................................................... 9 
1.1 
Primary Objectives ................................................................................................... 9 
1.2 
Secondary Objectives ............................................................................................... 9 
1.3 
Exploratory Objectives ........................................................................................... 10 
2. 
BACKGROUND .............................................................................................................. 10 
2.1 
Maintenance Therapy in Ovarian Cancer ............................................................... 10 
2.2 
Poly ADP-Ribose Polymerase (PARP) inhibitors .................................................. 11 
2.3 
Exploratory Studies Background............................................................................ 13 
2.4 
Rationale ................................................................................................................ 13 
3. 
PATIENT SELECTION ................................................................................................... 13 
3.1 
Eligibility Criteria ................................................................................................... 13 
3.2 
Exclusion Criteria ................................................................................................... 14 
3.3 
Inclusion of Women and Minorities ....................................................................... 15 
4. 
SUBJECT SCREENING AND REGISTRATION PROCEDURES ............................... 15 
5. 
SURVEILLANCE MONITORING PLAN… .................................................................. 15 
6. 
TREATMENT PLAN ....................................................................................................... 15 
6.1 
Agent Administration ............................................................................................. 15 
6.2 
General Concomitant Medication and Supportive Care Guidelines ....................... 16 
6.3 
Duration of Therapy ............................................................................................... 17 
6.4 
Duration of Follow Up… ....................................................................................... 17 
6.5 
Criteria for Removal from Study… ....................................................................... 18 
6.6 
Duration of Study ................................................................................................... 18 
7. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................... 18 
7.1 
Hematologic Toxicity ............................................................................................. 18 
7.2 
Non-Hematologic Toxicity Attributable to olaparib .............................................. 20 
8. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ............................ 22 
8.1 
Adverse Events and Risk List for olaparib… ........................................................ 22 
8.2 
Adverse Event Characteristics ................................................................................ 23 
8.3 
Expedited Adverse Event Reporting ...................................................................... 23 
8.4 
Routine Adverse Event Reporting .......................................................................... 24 
8.5 
Secondary Malignancy ........................................................................................... 24 
9. 
PHARMACEUTICAL INFORMATION ......................................................................... 24 
10. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES........................................ 26 
10.1 
Integrated Laboratory Studies - Exploratory objective .......................................... 26 
11. STUDY CALENDAR ...................................................................................................... 27 
12. MEASUREMENT OF EFFECT ...................................................................................... 28 
12.1 
Antitumor Effect – Solid Tumors........................................................................... 29 
13. DATA REPORTING / REGULATORY REQUIREMENTS .......................................... 35 
13.1 
Study Oversight ...................................................................................................... 35 
13.2 
Data Reporting ....................................................................................................... 35 
14. STATISTICAL CONSIDERATIONS .............................................................................. 36 
14.1 
Study Design/Endpoints ......................................................................................... 36 
14.2 
Sample Size/Accrual Rate ...................................................................................... 38 
14.3 
Data Analysis ......................................................................................................... 38 
REFERENCES ......................................................................................................................... 40 


Page 4  of 69
 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ...................................................45 
APPENDIX B 
PATIENT DRUG DIARY: OLAPARIB .................................................. 46 
APPENDIX C 
Possible Interactions with Other Drugs and Herbal Supplements ............. 47 
APPENDIX D 
NCI PRO-CTCAE™ ITEMS .................................................................... 48 
APPENDIX E 
Assessment of Survivor Concerns (ASC) ................................................. 53 
APPENDIX F 
IMPACT OF EVENT SCALE- REVISED ............................................... 54 
APPENDIX G 
FACT-O (Version 4) ................................................................................. 55 
APPENDIX H 
PROMIS .................................................................................................... 57 
APPENDIX I 
Collection of Indirect and Nonmedical Direct Costs ................................. 61 
APPENDIX J 
Economic Hardship… ............................................................................... 64 
APPENDIX K 
COST (Comprehensive Score for financial Toxicity) Patient –Reported 
Outcome Measure ...................................................................................... 67 
APPENDIX L 
PHARMACOKINETICS SHEET DAY 28 – OLAPARIB ...................... 69 


Page 5  of 69
 
 
STUDY SCHEMA 
 
 
 
 
 
 
*CT scans can be obtained for rising CA125 or physician preference for patient symptoms 
 
 
 
Follow-up: 
• 
CA125 drawn every 28 days and CT scans obtained at doubling of CA- 
125 and then every 12 weeks* to assess for recurrence or progression 
• 
Clinician- and patient-reported adverse events recorded every 28 days 
• 
Cancer-related worry and distress assessed every 28 days 
• 
Measures of quality of life and physical function, and financial toxicity 
assessed every 12 weeks 
Olaparib dosed at 300mg orally twice a day 
28 days of treatment will be a cycle 
Olaparib started when CA125 rises by two-fold 
of their nadir value 
Monitored with CA125 levels every 28 days 
Enrollment within 8 weeks of completion of 
platinum-based treatment (N=75) 


Page 6  of 69
 
 
STUDY SYNOPSIS 
 
Title 
Phase IIA trial of delayed initiation of olaparib maintenance therapy in platinum 
sensitive recurrent ovarian cancer 
Phase 
Phase II 
Methodology 
Open-label study 
Study 
Duration 
42 months 
Study 
Center(s) 
Single center, University of Pittsburgh Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
Objectives 
Primary Objective(s): 
To estimate the time to next therapy, defined as time from completion of 
platinum-based therapy for treatment of recurrence until initiation of post- 
olaparib treatment, for delayed start olaparib in platinum sensitive recurrent 
epithelial ovarian cancer with a complete or partial response to last platinum 
therapy 
. 
Secondary Objective(s): 
To estimate the progression-free survival (PFS) for delayed start olaparib 
To estimate the overall survival (OS) for delayed start olaparib 
To determine the safety and tolerability for delayed start olaparib 
To determine the overall response rate of delayed start olaparib stratified by 
BRCA mutational status 
To evaluate the impact of delayed start olaparib on clinician and patient 
reported adverse events 
To evaluate the impact of delayed start olaparib on quality of life 
To evaluate the impact of delayed start olaparib on physical functioning 
To evaluate the impact of delayed start olaparib on worry and distress 
To evaluate the impact of delayed start olaparib on financial toxicity 
To explore exposure-response relationships between olaparib exposure and 
toxicity/efficacy 
Exploratory Objective: 
To evaluate PARP inhibitor resistance mechanisms 
Number of 
Subjects 
75 patients 


Page 7  of 69
 
 
Inclusion 
Criteria 
1. Patient has platinum-sensitive, recurrent ovarian, fallopian-tube or 
peritoneal cancer. Platinum sensitivity is defined as complete clinical 
remission after frontline chemotherapy lasting greater than 6 months 
2. Patient has completed at least 2 courses of platinum-based 
chemotherapy and in the most recent course of platinum therapy 
obtained a PR or CR as defined by the Response Evaluation Criteria 
in Solid Tumors (RECIST) v1.1 or a CA-125 response, according to 
Gynecological Cancer InterGroup (GCIG) criteria. 
3. BRCA testing required (results not needed for registration) 
4. Age ≥18 years old. 
5. ECOG performance status score of 0, 1, or 2. See Appendix A 
6. Life expectancy greater than 6 months. 
7. Normal organ and marrow function as defined below: 
9 
- Absolute neutrophil count (ANC) ≥ 1.5 x 10 /L 
9 
- Platelets ≥ 100 x 10 /L 
- Hemoglobin (Hgb) ≥ 8 g/dL (blood transfusions to reach this amount 
are allowed) 
- Serum creatinine ≤ 1.5 mg/dL 
- Total serum bilirubin ≤ 1.5 x ULN (in patients with known 
Gilbert Syndrome, a total bilirubin ≤ 3.0 x ULN, with direct 
bilirubin ≤ 1.5 x ULN) 
- AST and ALT ≤ 2.5 x ULN 
8. Able to take oral medication. 
9. Not pregnant and not breastfeeding. 
10. Able to understand and willingness to sign a written informed consent 
document. 
Exclusion 
Criteria 
1. Patient has had a prior invasive malignancy diagnosed within the last five years 
(except [1] non-melanoma skin cancer or [2] prior in situ carcinoma of the 
cervix or breast [3] has been without evidence of invasive disease for greater 
than 3 years) 
2. Patients receiving any other investigational agents 
3. History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to olaparib 
4. Uncontrolled intercurrent illness that could affect their participation in the 
study including, but not limited to, ongoing or active infection; symptomatic 
congestive heart failure; unstable angina pectoris; cardiac arrhythmia; 
known inadequately controlled hypertension; significant pulmonary disease 
including dyspnea at rest, patients requiring supplemental oxygen, or poor 
pulmonary reserve; or psychiatric illness/social situations that would limit 
compliance with study requirements 
5. Impairment of gastrointestinal function or disease that may 
significantly alter the absorption of olaparib 
6. Patients who have received prior treatment with a PARP inhibitor 
7. History of non-compliance to medical regimens 
 
Study 
Product(s), 
Dose, Route, 
Regimen 
Olaparib will be dosed at 300 mg orally twice a day. Twenty-eight days of 
treatment will be considered one cycle. 


Page 8  of 69
 
 
 
 
 
Duration of 
Administration 
Patients will be enrolled within 8 weeks of completing platinum-based therapy for 
recurrent disease. They will be monitored with CA125 levels every 28 days. 
Olaparib treatment will be started when CA125 rises by two-fold above their nadir 
value. Patients will continue treatment until disease progression, per RECIST v1.1 
or intolerable toxicity, defined as any grade 3 or 4 adverse event, per National 
Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0 or the Patient Reported Outcome CTCAE (PRO-CTCAE), that 
does not resolve completely or return to grade 1 within 28 days after onset. 
Reference 
Therapy 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical 
Methodology 
Primary endpoint The time from completion of platinum-based therapy for 
treatment of recurrence until initiation of post-olaparib treatment 
Secondary endpoints 
 
Progression-free survival (PFS) defined as time from enrollment until 
detected recurrence or progression of disease, via RECISTv1.1, or death 
from any cause. 
 
Overall survival (OS) as defined as the time from enrollment to death 
from any cause. 
 
Toxicity rates defined by the National Cancer Institute's Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 or Patient 
Reported Outcomes-Common Terminology Criteria for Adverse Events 
(PRO-CTCAE). 
 
Overall response rate as defined by RECIST or CA-125 and stratified by 
BRCA mutation status. 
 
Patient-reported adverse events using the NCI Patient Reported 
Outcomes-Common Terminology Criteria for Adverse Events (PRO- 
CTCAE) 
 
Health-related quality of life measured via The Functional Assessment of 
Cancer Therapy + Ovarian-specific scale (FACT-O) 
 
Physical function assessed through the PROMIS Physical Function-20a 
assesses self-reported performance of physical activities 
 
Worry and distress measured via Assessment of Survivor Concerns 
(ASC) Worry Subscale and Impact of Event Scale (IES-R). 
 
Financial toxicity measured through (a) monetary measure using the 
Modified Collection of Indirect and Nonmedical Direct Costs (COIN), (b) 
objective measure of financial burden assessed using Barrera et al’s 
Economic Hardship questionnaire, and (c) subjective measure of financial 
distress will be gauged using the Comprehensive Score for Financial 
Toxicity (COST Measure) 
 
Exposure as expressed by day 28 trough olaparib concentration measured 
by LC-MS/MS 
 


Page 9  of 69
 
 
1. STUDY OBJECTIVES and ENDPOINTS 
 
1.1. Primary Objective and Endpoint 
1.1.1. To determine the time to first subsequent therapy. 
 
1.1.1.1 Endpoint: The time from completion of platinum-based therapy for treatment of 
recurrence until initiation of post-olaparib treatment, for delayed start olaparib in platinum 
sensitive recurrent epithelial ovarian cancer with a complete or partial response to last 
platinum therapy 
 
1.2. Secondary Objectives and Endpoints 
1.2.1. To estimate the progression-free survival (PFS) for delayed start olaparib in 
platinum sensitive recurrent epithelial ovarian cancer with a complete or partial 
response to last platinum therapy 
 
1.2.1.1.  Endpoint: PFS defined as time from enrollment until detected recurrence or 
progression of disease, via RECISTv1.1, or death from any cause 
 
1.2.2. To estimate the overall survival (OS) for delayed start olaparib in platinum 
sensitive recurrent epithelial ovarian cancer with a complete or partial response to last 
platinum therapy 
 
1.2.2.1. 
Endpoint: OS defined as time from enrollment until death from any cause 
 
1.2.3. To determine the safety and tolerability for delayed start olaparib in platinum 
sensitive recurrent epithelial ovarian cancer with a complete or partial response to last 
platinum therapy 
 
1.2.3.1.  Endpoint: Toxicity rates defined by the National Cancer Institute's Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 
 
1.2.4. To determine the overall response rate of delayed start olaparib in platinum 
sensitive recurrent epithelial ovarian cancer with a partial response or complete 
response to last platinum therapy stratified by BRCA mutational status 
1.2.4.1. 
Endpoint: Overall response rate as defined by RECIST v1.1 
1.2.5. To evaluate the impact of delayed start olaparib in platinum sensitive recurrent 
epithelial ovarian cancer with a complete or partial response to last platinum therapy 
on patient reported adverse events 
 
1.2.5.1. Endpoint: Patient reported adverse events as reported by the NCI Patient 
Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO- 
CTCAE) 
 
1.2.6. To evaluate the impact of delayed start olaparib in platinum sensitive recurrent 
epithelial ovarian cancer with a complete or partial response to last platinum therapy 
on quality of life 


Page 10  of 
 
 
1.2.6.1. Endpoint: Health-related quality of life measured via The Functional 
Assessment of Cancer Therapy + Ovarian-specific scale (FACT-O) 
 
1.2.7. To evaluate the impact of delayed start olaparib in platinum sensitive recurrent 
epithelial ovarian cancer with a complete or partial response to last platinum therapy 
on physical functioning 
 
1.2.7.1. Endpoint: Physical function assessed through the PROMIS Physical 
Function-20a assesses self-reported performance of physical activities 
 
1.2.8. To evaluate the impact of delayed start olaparib in platinum sensitive recurrent 
epithelial ovarian caner with a complete or partial response to last platinum therapy on 
worry and distress 
 
1.2.8.1. Endpoint: Worry and distress measured via Assessment of Survivor 
Concerns (ASC) Worry Subscale and Impact of Event Scale (IES-R). 
 
1.2.9. To evaluate the impact of delayed start olaparib in platinum sensitive recurrent 
epithelial ovarian cancer with a complete or partial response to last platinum therapy 
on financial toxicity 
 
1.2.9.1.  Endpoint: Financial toxicity measured through (a) monetary measure using 
the Modified Collection of Indirect and Nonmedical Direct Costs (COIN), (b) 
objective measure of financial burden assessed using Barrera et al’s Economic 
Hardship questionnaire51, and (c) subjective measure of financial distress will be 
gauged using the Comprehensive Score for Financial Toxicity (COST Measure). 
 
1.2.10. To explore exposure-response relationships between olaparib exposure and 
toxicity/efficacy. 
 
1.2.10.1. Endpoint: Exposure as expressed by day 28 trough olaparib concentration 
measured by LC-MS/MS. 
1.3. Exploratory Objective 
1.3.1. To evaluate PARP inhibitor resistance mechanisms 
1.3.1.1. 
Characterize genomic changes associated with olaparib resistance: For 
samples with limited tissue and therefore not amenable to patient derived 
xenograft (PDX) formation, we will use BROCA analysis on both pre and post- 
olaparib treatment samples to evaluate genes associated with homologous 
recombination (HR) defects. For samples for which PDX models are generated, 
we will perform whole genome sequencing (WGS) on the primary tissue, then 
compare WGS of primary tumors and PDX tumors. For specific genes in which 
we find molecular alterations, we will use knockdown and rescue assays in cell 
lines to validate olaparib resistance related to the identified target. 
1.3.1.2. 
Characterize transcriptome changes associated with olaparib resistance: For 
an unbiased evaluation of mRNA expression changes associated with olaparib 
resistance, we will perform RNASeq. RNASeq will be compared between pre 
and post-olaparib treatment samples. Candidate drivers of resistance will be 


Page 11  of 
 
 
compared with BROCA results and then validated with knockin/knockout studies 
as above. 
 
2. BACKGROUND 
2.1. 
Maintenance Therapy in Ovarian Cancer 
 
Epithelial ovarian cancer (EOC) encompasses cancers that originate in the ovary, fallopian tube 
and peritoneum, and is diagnosed in ~22,240 women annually in the United States1. More 
strikingly, 14,070 women will die from their disease in 2018, making EOC the 5th leading cause 
of cancer death in women1. Typically diagnosed at an advanced stage, the mainstay of treatment 
has been cytoreductive surgery followed by adjuvant chemotherapy2. Evolving data for the use 
of neoadjuvant chemotherapy has brought about a gradual practice change, which favors the use 
of neoadjuvant of chemotherapy for those patients with a low likelihood of primary cytoreduction 
to less than 1 cm of residual disease, including those with bulky disease and disease in locations 
not amenable to resection, and/or for patients with a high perioperative risk profile3. However, 
even with this change in practice over the last five years, platinum-containing chemotherapy 
regimens remain the mainstay of both neoadjuvant and frontline adjuvant therapy for EOC, 
fallopian tube (FTC) and primary peritoneal cancer (PPC), including after upfront cytoreduction 
and after interval cytoreduction. This is because these cancers are sensitive to frontline 
chemotherapy in approximately 75% of women. Unfortunately, most of these women will 
ultimately experience disease relapse2. Those women whose disease returns greater than 6 
months after the completion of primary therapy have platinum sensitive disease and are eligible 
for retreatment with a platinum-based therapy with an increasing response rate based on the 
amount of time since last treatment. However, there is little chance for a cure. 
Because most women with EOC will be in remission at the completion of primary therapy, but 
eventually experience recurrence, multiple clinical trials have investigated the utility of 
maintenance therapy in both primary and recurrent setting with the goal of improving survival. 
While many have shown an improvement in progression-free survival (PFS), none have improved 
overall survival (OS). Maintenance taxane therapy represents an important cautionary story; Initial 
results with one year of maintenance taxane therapy (vs. 3 months) showed a 7-month 
improvement in PFS. This finding led some clinicians to adopt maintenance taxane therapy as a 
standard of care. However, follow up studies demonstrated no OS advantage for maintenance taxol 
and significant increases in neuropathy3-4. Indeed, a Cochrane database meta-analysis of 
chemotherapy maintenance trials after frontline therapy were analysed and revealed a combined 
risk ratio of 1.03 [95% CI 0.96-1.10] for 5-year OS5. 
 
Improved PFS without improved OS remains a recurring theme for maintenance therapy in EOC. 
While controversy exists regarding bevacizumab, other anti-angiogenic agents6-9, pazopanib10, 
and nintedanib11, as well as other targeted agents such as erlotinib12 have all shown improved PFS 
without a statistically significant improvement in OS. Other investigators have examined immune 
targets, interferon-alfa13, oregovomab14, and abagovomab15, and all of the studies conducted, to 
date, have failed to show a survival advantage. 
2.2. 
Poly ADP-Ribose Polymerase (PARP) inhibitors (PARP-I) 
 
2.2.1 PARP-I Monotherapy 
PARP-I were developed as a potential therapy that creates synthetic lethality in cancer cells which 


Page 12  of 
 
 
harbor BRCA mutations. BRCA mutations create homologous recombination (HR) deficiency. HR 
defective cancer cells are unable to effectively repair double-strand DNA breaks and thus rely on 
single-strand DNA repair mechanisms. PARP is an instrumental enzyme for single-strand DNA 
repair via base excision repair (BER). When tumors harbor a BRCA mutation and are exposed to 
a PARP-I the cells can no longer repair DNA with high fidelity via either single- or double- 
stranded breaks, leading to synthetic lethality. Approximately 15% of women with EOC have a 
germline BRCA pathogenic variant and an additional 10% have a somatic mutation16-20. Mutations 
in other genes in the HR pathway, such as PALB2, ATM, BRIP1, CHEK2, and RAD51 may confer 
susceptibility to PARP inhibitors increasing the percentage of women with EOC who could 
potentially benefit from PARP-I treatment by about 20%21-24. Initial trials utilizing PARP 
inhibitors confirmed the concept and effectiveness of synthetic lethality25-28. While response rates 
were higher and more prolonged in BRCA mutant tumors, a study of rucaparib in all patients with 
platinum sensitive EOC showed that the PARP-I was active in ~50% of patients28. 
 
2.2.2 
PARP-I Maintenance Therapy for Recurrent Disease 
As PARP-I are more tolerable than chemotherapy for most patients, maintenance therapy studies 
were soon initiated. Four clinical trials, covering three agents, evaluated the use of PARP-I as 
maintenance therapy in platinum sensitive disease following either a partial (PR) or complete 
response (CR) to the most recent platinum-based treatment (Table 1-adapted from Gordon and 
Temkin)29-33. All the trials showed a statistically significant improvement in PFS compared to 
placebo and led to FDA approval of olaparib, rucaparib, and niraparib as maintenance therapies in 
recurrent platinum sensitive EOC. These approvals led to widespread practice acceptance for the 
use of PARP-I. However, despite FDA approval, maintenance therapy remains controversial33. 
This is because, parallel to the experience with other maintenance therapy approaches, to date, 
none of the PARP-I maintenance trials have demonstrated an OS advantage. Study 19, the only 
trial to report both PFS and OS data, did not observe an OS advantage for those treated with 
olaparib; for the entire population, median OS was 29.8‐months‐[95%‐CI‐26·9–35·7]‐in the 
olaparib arm vs 27.8 months‐[24·9–33·7] in the placebo arm. Additionally, 22% of patients in the 
olaparib group reported serious adverse events related to nausea, vomiting, fatigue, and anemia29. 
 
 
2.2.3 PARP-I and Financial Toxicity 


Page 13  of 
 
 
In addition to traditional measures of toxicity, the risk of financial toxicity in cancer therapy is 
gaining widespread attention. Financial toxicity is comprised of both objective financial burden of 
cancer treatment costs (e.g. drug costs, other direct costs, indirect costs from cancer treatment) and 
subjective financial distress driven by reductions in wealth (income, savings and assets) and 
cancer-related financial anxiety. Patients with EOC face financial hardships from the costs of 
initial surgery, multiple lines of therapy, travel for treatment, and lost time at work for patients 
and their caregivers. In light of the potential for side effects, need for more frequent monitoring, 
and the cost of treatment, the question then becomes whether or not there is a modification to the 
current maintenance regimen that could decrease side effects and financial toxicity, while not 
compromising efficacy. 
 
In September of 2017, the Institute for Clinical and Economic Review examined the effectiveness 
and value of PARP-I for ovarian cancer34. Of the FDA approved PARP inhibitors, olaparib costs 
$13,679/month. Rucaparib is $13,940/month, and Niraparib costs $14,965/ month. Olaparib 
maintenance was calculated to be $324,116/ quality-adjusted life year (QALY). Rucaparib 
maintenance was $369,175/QALY. Niraparib maintenance for those with a germline BRCA 
pathogenic variant was $291,454/QALY and for non-germline pathogenic variant carriers was 
notably $1,908,822/QALY. While there is no set standard within the US for what an acceptable 
threshold is, this report uses a value-based benchmark price for a drug defined as the price that 
would achieve incremental cost-effectiveness ratios of $100,000 and $150,000/ QALY gained. 
None of these drugs reach this benchmark at their current prices34. 
 
2.3 
Exploratory Studies Background 
 
With widespread use of PARP-I, regardless of timing, understanding, and overcoming PARP-I 
resistance is becoming a major clinical need. BRCA gene reversion36-37 and mutations in genes in 
the HR pathway such as RAD51C38 account for some of the potential etiologies of resistance, but 
many mechanisms remain unidentified. Evaluating the appropriate timing of PARP-I use represents 
an important opportunity to collect biospecimens to assess resistance mechanisms and to establish 
patient-derived xenograft (PDX) tumor models for future therapeutic development. 
 
2.4 
Rationale 
 
As noted previously, PARP-I have shown efficacy as both monotherapy and as maintenance 
therapy. For patients with recurrent EOC, a large phase III clinical trial demonstrated that delaying 
initiation of chemotherapy, as compared to early initiation of chemotherapy, which is considered 
the current standard of care, not only did not negatively impact patient OS, but also allowed patients 
to restart treatment 5 months later and reduce overall toxicities. This observation then begs the 
question as to whether patients with recurrent ovarian cancer could derive the same efficacy benefit 
from a delayed start of a PARP-I compared to immediate maintenance therapy. Delayed start would 
have the benefit of sparing the physical, psychological, and financial toxicity associated with 
prolonged treatment. This approach would be particularly relevant in a population of platinum- 
sensitive patients who can have prolonged treatment-free intervals. Accordingly, we hypothesize 
that waiting until the time of chemical recurrence, denoted by rising CA125, to start a PARP 
inhibitor will lead to an improved time to next therapy with improved quality of life and at a lower 
financial toxicity. CA-125, which is elevated in greater than 90% of patients with advanced stage 
ovarian cancer and remains a sensitive marker of recurrent disease, is known to be elevated 3-5 
months prior to clinically evident disease. By using this to guide start of olaparib treatment, women 
can initially remain off of treatment, but also start therapy prior to the start of symptoms associated 


Page 14  of 
 
 
with disease, striking a balance between drug toxicity and treatment to alleviate symptom burden 
from disease. Based on Study 19 data where progression free survival in the placebo arm was 4.8 
months and the progression free survival in olaparib treatment arm was 8.4 months, we estimated 
that by waiting to start olaparib until biochemical relapse will extend time to next treatment by 3 
months (8 to 11 months) beyond that reported in the olaparib arm of Study 19. 
If this treatment approach is superior or even non-inferior with regard to time to next therapy, it 
would be an important paradigm shift in the way we use these drugs, leading to similar efficacy 
outcomes, while decreasing the financial burden and improving overall quality of life. Moreover, 
by collecting tissue samples before and after treatment and evaluating for resistance mechanisms, 
PDX models developed from these samples can be used to test for combinations that may reverse 
the effects of the resistance and/or restore sensitivity to PARP-I, allowing for its use later on in a 
patient’s treatment course. 
 
3. PATIENT SELECTION 
 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria. Results of all baseline evaluations, which assure that all 
inclusion and exclusion criteria have been satisfied, must be reviewed by the Principal Investigator 
or his/her designee prior to enrollment of that patient. In addition, the patient must be thoroughly 
informed about all aspects of the study, including the study visit schedule and required evaluations 
and all regulatory requirements for informed consent. The written informed consent must be 
obtained from the patient prior to enrollment. The following criteria apply to all patients enrolled 
onto the study unless otherwise specified. 
 
3.1. 
Eligibility Criteria 
3.1.1. 
Patient has platinum-sensitive, recurrent ovarian, fallopian-tube or peritoneal 
cancer. Platinum sensitivity is defined as complete clinical remission after 
frontline chemotherapy lasting greater than 6 months 
3.1.2. 
Patient has completed at least 2 courses of platinum-based chemotherapy with a 
PR or CR as defined by the Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.139 or a CA-125 response, according to Gynecological Cancer 
InterGroup (GCIG) criteria40 
 
3.1.3. 
BRCA testing required (results not needed for registration) 
 
3.1.4. 
Age ≥18 years old 
3.1.5. 
ECOG performance status score of 0, 1, or 2 (See Appendix A) 
3.1.6. 
Life expectancy greater than 6 months 
 
3.1.7. 
Normal organ and marrow function as defined below: 
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
- Platelets ≥ 100 x 109/L 
- Hemoglobin (Hgb) ≥ 8 g/dL (blood transfusions to reach this amount are allowed) 


Page 15  of 
 
 
- Serum creatinine ≤ 1.5 mg/dL 
- Total serum bilirubin ≤ 1.5 x ULN 
-AST and ALT ≤ 2.5 x ULN 
3.1.8. 
Able to take oral medication 
3.1.9. 
Not pregnant and not breastfeeding 
 
3.1.10. Able to understand and willingness to sign a written informed consent document 
 
3.1.11. Patients must be enrolled within 8 weeks of completing last cycle of chemotherapy 
 
3.2 
Exclusion Criteria 
3.2.1 
Patient has had a prior invasive malignancy diagnosed within the last five years (except 
[1] non-melanoma skin cancer or [2] prior in situ carcinoma of the cervix or breast [3] 
has been without evidence of invasive disease for greater than 3 years) 
3.2.2 
Patients receiving any other investigational agents 
3.2.3 
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to olaparib 
3.2.4 
Uncontrolled intercurrent illness that could affect their participation in the study 
including, but not limited to, ongoing or active infection; symptomatic congestive 
heart failure; unstable angina pectoris; cardiac arrhythmia; known inadequately 
controlled hypertension; significant pulmonary disease including dyspnea at rest, 
patients requiring supplemental oxygen, or poor pulmonary reserve; or psychiatric 
illness/social situations that would limit compliance with study requirements 
 
3.2.5 
Impairment of gastrointestinal function or disease that may significantly alter 
the absorption of olaparib 
 
3.2.6 
Patients who have received prior treatment with a PARP inhibitor 
 
3.2.7 
History of noncompliance to medical regimens 
3.3 
Inclusion of Women and Minorities 
This clinical trial will not exclude potential subjects from participating in this or any study solely 
on the basis of ethnic origin or socioeconomic status. Every attempt will be made to enter all 
eligible patients in this protocol to address the study objectives in a population representative of 
the entire ovarian cancer population. (See Planned Enrollment Table in Section 13.2) 
 
4. SUBJECT SCREENING AND REGISTRATION PROCEDURES 
Subjects will be identified in the outpatient clinic. After informed consent is obtained, all patients 
satisfying the inclusion/exclusion criteria must have eligibility confirmed by the Clinical Trials 


Page 16  of 
 
 
Office. The patient will not be considered registered and enrolled in the study until all information 
is confirmed by the Clinical Trials Office of Research Staff. To enroll a patient, contact the 
Gyn/Onc Research group Monday through Friday, 8:00AM-4:00PM. 
 
5. SURVEILLANCE MONITORING PLAN 
This is a single-arm, open-label phase II clinical trial evaluating delayed start olaparib 
maintenance therapy, based on a rise in CA125, for patients with epithelial ovarian cancer who 
have had a partial or complete response to platinum-based treatment. Patients will be enrolled 
within 8 weeks of completing platinum-based therapy for recurrent disease. At the time of 
enrollment, patients will be monitored with CA125 levels every 28 days. 
At the first evidence of a two-fold rise in CA125 from baseline, patients will undergo a CT scan 
to evaluate for any visible lesions, including new lesions for those with CR and new, persistent or 
progressive lesions for those with PR to most recent therapy, and then will be started on olaparib 
therapy. In the setting of new or progressive lesions, patients will be followed per protocol. 
Patients may undergo CT imaging prior to rise in CA-125 at the discretion of the treating 
physician for patient symptoms. Eighty-one patients will be enrolled through UPMC medical and 
gynecologic oncology offices. 
 
6. TREATMENT PLAN 
As noted above, at first evidence of two-fold rise in CA125, patients will undergo a CT scan to 
evaluate for any visible lesions and then will be started on olaparib therapy. 
 
The trial will involve the optional collection of tumor samples at enrollment (archival tissue) and 
at the time of recurrence or progression, if biopsies are obtained as part of standard of care, to 
understand the PARP-I resistance mechanisms. 
 
6.1. Agent Administration 
 
Olaparib treatment will be started when CA125 rises by two-fold of their nadir value. Olaparib 
will be dosed at 300 mg orally twice a day. Twenty-eight days of treatment will be considered one 
cycle. Patients will be required to maintain a medication diary (See Appendix B). 
 
Patients starting olaparib will continue treatment until disease progression, per RECIST v1.139 or 
intolerable toxicity, defined as any grade 3 or 4 adverse event, per National Cancer Institute's 
Common Terminology Criteria for Adverse Events (CTCAE) v5.0 or Patient Reported Outcomes- 
Common Terminology Criteria for Adverse Events (PRO-CTCAE), that does not resolve 
completely or to grade 1 within 28 days after onset. Patients removed from study for unacceptable 
adverse event(s) will be followed closely until resolution or stabilization of the adverse event (at 
least 30 days). 
 
Olaparib is FDA-approved for maintenance therapy for patients with platinum sensitive recurrent 
epithelial ovarian cancer with a complete or partial response to most recent platinum based 
chemotherapy. Therefore, drug will be covered by standard insurance. Additionally, after 
discussion with The UPMC Health Plan, they will approve treatment after 2 prior lines even with 
the delay in standard start time defined by the maintenance indication. 


Page 17  of 
 
 
Treatment will be administered on an outpatient basis. Appropriate dose modifications are 
described in Section 7. No other investigational or commercial agents or therapies may be 
administered with the intent to treat the patient's malignancy. 
 
Reported adverse events and potential risks are described in Section 7. 
 
6.2. 
General Concomitant Medication and Supportive Care Guidelines 
6.2.1. Concomitant Therapy: 
Patients must be instructed not to take any additional medications (including over-the-counter 
products) during the trial without prior consultation with the investigator. The investigator 
should instruct the patient to notify the study site about any new medications he/she takes after 
the start of study drug. All medications (other than study drug) and significant non-drug 
therapies (including physical therapy and blood transfusions) taken within 28 days of starting 
study treatment through the 30-day safety follow up visit should be reported on the Case Report 
Form. If concomitant therapy must be added or changed, the reason and name of the 
drug/therapy will be recorded. 
 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient are allowed, including drugs given prophylactically (e.g. antiemetics +/- steroids), 
with the following exceptions: 
 No other investigational therapy will be given to patients. 
 No anticancer agents other than the study medication administered as part of this study 
protocol should be given to patients. If such agents are required for a patient then the 
patient must first be withdrawn from the study. 
 Leukocyte growth factors (e.g., G-CSF and GM-CSF) are not to be administered 
systematically but may be prescribed by the investigator for severe neutropenia if this 
is thought to be appropriate. 
 No live vaccines will be administered to patient due to immunosuppressant potential of 
olaparib. 
Drugs or substances known to be inhibitors or inducers of the isoenzyme CYP3A should 
be avoided in association with olaparib as these can alter drug metabolism. Strong 
inhibitors or inducers of the isoenzyme CYP3A should not be administered as systemic 
therapy and should be avoided whenever possible (See Appendix C). Investigators should 
consult a frequently updated drug information reference for a list of strong inducers and 
inhibitors. 
o CYP3A inhibitors: Avoid concomitant use with moderate or strong CYP3A 
inhibitors (consider alternative agents with less CYP3A inhibition). If co- 
administration with a moderate CYP3A inhibitor cannot be avoided, reduce dose 
to 150 mg twice daily. If co-administration with a strong CYP3A inhibitor cannot 
be avoided, reduce dose to 100 mg twice daily. 
o CYP3A inducers: Avoid concomitant use with moderate or strong CYP3A4 
inducers; a potential for reduced olaparib efficacy exists if moderate CYP3A 
inducers cannot be avoided. 
6.2.2. Supportive care 


Page 18  of 
 
 
No routine prophylactic medications are indicated at the start of therapy. In general, the use of 
any concomitant medication/therapies deemed necessary for the care of the patient are allowed 
with the exceptions noted in 6.2.1 
 
6.3. 
Duration of Therapy 
Patients will be enrolled continuously to the study. Patients will continue evaluation and treatment 
until one of the following criteria applies: 
 
Disease progression per RECIST v1.139 
 Unacceptable adverse event(s) defined as any grade 3 or 4 adverse event, per National 
Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v5.0 or 
PRO-CTCAE, that does not resolve to grade < 1 within 28 days after onset. 
o Treatment will be interrupted for any grade 3 or 4 event related to treatment. If the 
toxicity resolves entirely or to grade 1, treatment will be restarted with a dose 
reduction. If the event does not resolve within 4 weeks or if two previous treatment 
interruptions with subsequent dose reductions occur, the patient will be withdrawn. 
 Patient withdraws consent. 
 Development of second malignancy (except for basal cell carcinoma or squamous cell 
carcinoma of the skin) that requires treatment, which would interfere with this study. 
 Intercurrent illness that prevents further administration of treatment 
 General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
6.4. 
Duration of Follow Up 
Patients will be followed until the initiation of the next therapy post olaparib treatment. Each 
patient, regardless of reason for removal from study, will have at least 18 months follow up relative 
to time of enrollment. Secondary efficacy endpoints will be tracked after official follow-up has 
been completed. 
Assessments in follow up: 
 Office visit or review of medical records every 3 months 
 Survival endpoints both progression free survival (PFS) and overall survival (OS) 
 
6.5. 
Criteria for Removal from Study 
Patients will be removed from treatment when any of the criteria listed in Section 6.3 apply or 
once they have completed follow-up as described in Section 6.4. The reasons for treatment 
discontinuation and study removal and the associated dates must be documented in the Case 
Report Form. 
Patients can be taken off study at any time at their own request, or they may be withdrawn at 
the discretion of the investigator for safety, behavioral, or administrative reasons. The reason(s) 
for discontinuation from study will be documented and may include: 
 Patient withdraws consent (termination of treatment and follow-up); 
 Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment; 
 Patient is unable to comply with protocol requirements; 


Page 19  of 
 
 
 Treating physician judges continuation on the study would not be in the patient’s best 
interest; 
 Patient becomes pregnant (pregnancy to be reported along same timelines as a serious 
adverse event); 
 Development of second malignancy (except for basal cell carcinoma or squamous cell 
carcinoma of the skin) that requires treatment, which would interfere with this study; 
 Lost to follow-up: if a research subject cannot be located to document PFS after 6 
months, the subject will be considered “lost to follow up” 
 Termination of the study by the University of Pittsburgh Medical Center 
 Patient completes protocol treatment and follow-up criteria. 
6.6. Duration of Study 
Patients are considered on study from the date of enrollment until initiation of post-olaparib 
therapy or for 30 days after removal from trial for any adverse event to allow for safety 
monitoring. Secondary efficacy endpoints will be tracked. 
 
7. DOSING DELAYS/DOSE MODIFICATIONS 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity. Toxicity will be assessed according 
to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5, and the 
NCI Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO- 
CTCAE). 
 
7.1. 
Hematologic Toxicity 
 
Toxicity/Grade 
Dose Adjustment and Management 
Recommendations 
Anemia (Hemoglobin)
Grade 1 (≥10.0 – LLN g/dL)
No dose adjustment required.
Grade 2 (≥8.0 – <10.0 g/dL)
No dose adjustment required.
Grade 3 (<8.0 g/dL) 
Dose interruption until recovery to grade ≤1. 
Monitor hemoglobin weekly until recovery. 
If resolves to grade ≤1 within 28 days, resume at reduced 
dose 250 mg PO BID. 
Dose may be reduced to 200 mg PO BID if recurs at 
reduced dose, but if recurs for a third time, treatment 
should be discontinued. 
Grade 4 Life-threatening 
consequences; urgent intervention 
indicated 
Dose interruption until recovery to grade <1. 
Monitor hemoglobin weekly until recovery. 
If resolves to grade ≤1 within 28 days, resume at reduced 
dose 250 mg PO BID. 
Dose may be reduced to 200 mg PO BID if recurs at 
reduced dose, but if recurs for a third time, treatment 
should be discontinued. 
Thrombocytopenia
Grade 1 (≥75 x 109/L)
No dose adjustment required.
Grade 2 (≥50 x 109/L – <75 x 109/L) 
Dose interruption until recovery to grade ≤1. 
Monitor platelets weekly until recovery. 
If resolves to grade ≤1 within 28 days, resume at reduced 
dose 250 mg PO BID. 


Page 20  of 
 
 
 
Dose may be reduced to 200 mg PO BID if recurs at 
reduced dose, but if recurs for a third time, treatment 
should be discontinued. 
Grade 3 (≥25 x 109/L - <50 x 109/L) 
Dose interruption until recovery to grade ≤1. 
Monitor platelets weekly until recovery. 
If resolves to grade ≤1 within 28 days, resume at reduced 
dose 250 mg PO BID. 
Dose may be reduced to 200 mg PO BID if recurs at 
reduced dose, but if recurs for a third time, treatment 
should be discontinued. 
Grade 4 (<25 x 109/L) 
Dose interruption until recovery to grade <1 
Monitor platelets weekly until recovery. 
If resolves to grade ≤1 within 28 days, resume at reduced 
dose 250 mg PO BID. 
Dose may be reduced to 200 mg PO BID if recurs at 
reduced dose, but if recurs for a third time, treatment 
should be discontinued. 
Absolute neutrophil count (ANC)
Grade 1 (≥1.5 x 109/L)
No dose adjustment required.
Grade 2 (≥1.0 - <1.5 x 109/L)
No dose adjustment required.
Grade 3 (≥0.5 - <1.0 x 109/L) 
Dose interruption until recovery to ≥1.0 x 109/L. If 
resolves to grade ≤1 within 28 days, resume at reduced 
dose 250 mg PO BID. 
Dose may be reduced to 200 mg PO BID if recurs at 
reduced dose, but if recurs for a third time, treatment 
should be discontinued. 
Grade 4 (<0.5 x 109/L) 
Dose interruption until recovery to ≥1.0 x 109/L. Re- 
initiate olaparib at 250 mg PO BID. If toxicity recurs at 
grade 4: temporary dose interruption until recovery to 
≥1.0 x 109/L and r 
Febrile neutropenia
Grade 3 ANC <1.0 x 109/L with a 
single temperature of >38.3 ºC (101 
ºF) or a sustained temperature of ≥38 
ºC (100.4 ºF) for more than one hour 
Dose interruption until improvement of ANC ≥1.0 x 109/L 
and no fever. Restart with dose reduction of 250 mg PO 
BID. If febrile neutropenia recurs, discontinue olaparib. 
Grade 4 Life-threatening 
consequences; urgent intervention 
indicated 
Discontinue olaparib 
 
Treatment-related anemia may be managed by transfusions without interruption of treatment 
Any hematologic AE that does not resolve to grade ≤1 within 28 days despite maximum 
supportive care remove from study. 
For severe hematologic toxicity or in cases where blood transfusion is still required despite dose 
reductions, interrupt olaparib and initiate appropriate hematologic investigation. If blood 
parameters remain clinically abnormal after 4 weeks of dose interruption, bone marrow biopsy 
and cytogenetic analysis should be considered. 
 
7.2. 
Non-Hematologic Toxicity Attributable to Olaparib 
General Olaparib Dose Adjustment and Management Recommendation of Non- 
Hematologic Toxicity 
 
Grade
Dose Adjustment and Management Recommendations


Page 21  of 
 
 
1 
No dose adjustment recommended. 
Initiate appropriate medical therapy and monitor. 
2 
Initiate appropriate medical therapy and monitor. 
If symptoms do not resolve or worsen while on medical therapy, dose 
interruption until recovery to grade ≤1. 
 
Re-initiate olaparib at the same dose. 
• If the same toxicity recurs at grade 2, interrupt olaparib until recovery to 
grade ≤1. Re-initiate olaparib at the next lower dose. (250 mg PO BID). 
3 
Dose interruption until recovery to grade ≤1. 
Initiate appropriate medical therapy and monitor. 
Re-initiate olaparib at the next lower dose level. 
• If toxicity recurs at grade 2: temporary dose interruption until recovery to 
grade ≤1 and reduce olaparib dose the next lower dose level. (250 mg PO 
BID). 
• If toxicity recurs at grade 3, discontinue olaparib. 
4 
Dose interruption until recovery to grade ≤1. 
Initiate appropriate medical therapy and monitor. 
 
Re-initiate olaparib at the next lower dose level. 
• If toxicity recurs at grade 2: temporary dose interruption until recovery to 
grade ≤1 and reduce olaparib dose the next lower dose level. (250 mg PO 
BID). 
• If toxicity recurs at grade 4, discontinue olaparib. 
 
7.2.1. Nausea/vomiting 
Prompt treatment of mild/moderate nausea/vomiting with antiemetics. 
If not controlled with medication, interrupt olaparib treatment; when symptoms are 
grade 1, restart olaparib treatment per protocol. 
 
7.2.2. Fatigue 
Evaluate for other possible causes of fatigue (eg anemia, insomnia, depression, 
hypothyroidism). 
Supportive care to cope with fatigue (e.g. strategies to conserve energy, scheduled 
nap, and exercise). 
If not controlled with supportive care, interrupt olaparib treatment; when 
symptoms are grade 1, restart olaparib treatment per protocol. 
 
7.2.3. Dysgeusia 
Supportive care to cope with dysgeusia (appropriate expectation counseling, 
modification food preparation). 
If not controlled with supportive care, interrupt olaparib treatment; when 
symptoms are grade 1, restart olaparib per protocol. 
 
7.2.4. Diarrhea 
Evaluate for other possible causes (eg infection, dietary, concomitant medications). 
If other sources are ruled out, initiate anti-motility agents for mild to moderate 
symptoms. 


Page 22  of 
 
 
If not controlled with medication, interrupt olaparib treatment; when symptoms are 
grade 1, restart olaparib treatment per protocol. 
 
7.2.5. Constipation 
Evaluate for other possible causes (eg bowel obstruction, dietary, concomitant 
medications). 
If other sources are ruled out, initiate stool softeners and/or laxatives for mild to 
moderate symptoms. 
If not controlled with medication, interrupt olaparib treatment; when symptoms are 
grade 1, restart olaparib treatment per protocol. 
 
7.2.6. Pneumonitis 
Interrupt olaparib and investigate patients with new or worsening respiratory 
symptoms, such as dyspnea, cough and fever, or a radiological abnormality 
consistent with pneumonitis. 
If pneumonitis confirmed, discontinue olaparib and treat appropriately 
(glucocorticoids). 
 
7.2.7. Renal Impairment 
CrCl 51 to 80 mL/minute: No dosage adjustment necessary; monitor closely for 
toxicity, as an increase in mean AUC has been observed in patients with mild 
impairment. 
CrCl 31 to 50 mL/minute: Reduce dose to 200 mg twice daily. 
CrCl ≤30 mL/minute: There are no dosage adjustments provided in the 
manufacturer's labeling (has not been studied). 
 
7.2.8. Hepatic Impairment 
Child-Pugh classification A or B: No dose adjustment. 
Child-Pugh classification C: Use not recommended for use as safety and 
pharmacokinetics have not been studied in these patients. 
 
 
8. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. For this 
trial, routine and expedited reporting will begin at the start of study therapy. The following list 
of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine 
whether the event requires expedited reporting in addition to routine reporting. 
 
8.1. 
Adverse Events and Potential Risks List for Olaparib 
 
>10%: 
Cardiovascular: peripheral edema (14%) 
Central nervous system: fatigue (≤67%), headache (15% to 26%), dizziness (7% to 20%) 


Page 23  of 
 
 
Endocrine & metabolic: hypomagnesemia (5% to 14%) 
Gastrointestinal: nausea (58% to 77%), abdominal pain (45%), vomiting (30% to 43%), diarrhea 
(21% to 37%), constipation (16% to 28%), dysgeusia (9% to 27%), dyspepsia (8% to 25%), 
decreased appetite (16% to 22%), stomatitis (4% to 20%; grades 3/4: 1%) 
Genitourinary: urinary tract infection (13% to 14%) 
Hematologic & oncologic: increased MCV (57% to 89%), decrease in absolute neutrophil count 
(25% to 51%; grades 3/4: 7% to 11%), anemia (23% to 44%; grades 3/4: 7% to 21%), neutropenia 
(5% to 27%; grades 3/4: 6% to 9%), leukopenia (2% to 25%; grades 3/4: 3% to 5%), 
thrombocytopenia (4% to 14%; grades 3/4: 1%) 
Infection: influenza (≤36%) 
Neuromuscular & skeletal: asthenia (≤66%), arthralgia (≤30%), myalgia (≤30%), musculoskeletal 
pain (≤21%), back pain (14%) 
Renal: increased serum creatinine (3% to 45%) 
Respiratory: nasopharyngitis (≤36%), respiratory tract infection (≤36%), rhinitis (≤36%), sinusitis 
(≤36%), bronchitis (≤28%), cough (16% to 18%), dyspnea (13% to 15%) 
 
1% to 10%: 
Cardiovascular: edema (8% to 9%), pulmonary embolism (≤1%), venous thrombosis (≤1%) 
Central nervous system: peripheral neuropathy (5%), depression, insomnia 
Dermatologic: skin rash (5% to 6%), dermatitis (1%) 
Gastrointestinal: upper abdominal pain (7%) 
Hematologic & oncologic: lymphocytopenia (1% to 8%), myelodysplastic syndrome (acute 
myeloid leukemia; 1%) 
Hypersensitivity: hypersensitivity reaction (2%) 
Miscellaneous: fever (8% to 10%) 
 
<1%, postmarketing, and/or case reports: pneumonitis 
 
8.2 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. 
 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. 
 
8.3 Expedited Adverse Event Reporting 


Page 24  of 
 
 
8.3.1 Expedited Reporting Guidelines 
 
Use the protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note: A death on study requires both routine and expedited reporting, regardless of 
causality. Attribution to treatment or other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death 
2) A life-threatening adverse event 
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported within the timeframes 
detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
 
10 Calendar Days 
 
 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
 
Not required 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted 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. 
Serious 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 


Page 25  of 
 
 
8.4 Routine Adverse Event Reporting 
All Adverse Events must 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. 
 
8.5 
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. 
 
All secondary malignancies that occur following treatment with the trial agent should be 
reported expeditiously. Three options are available to describe the event: 
 
8.5.1 Leukemia secondary to oncology chemotherapy (e.g., acute myelogenous 
leukemia [AML]) 
8.5.2 Myelodysplastic syndrome (MDS) 
8.5.3 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. 
 
9. 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. 
 
9.1. 
Olaparib 
 
Chemical Name: 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4- 
fluorophenyl)methyl]phthalazin-1(2H)-one 
 
Other Names: Lynparza® 
 
Classification: Olaparib is a small molecule antineoplastic poly (ADP-ribose) polymerase (PARP) 
enzyme inhibitor, including PARP1, PARP2, and PARP3. 
 
Mechanism of Action: PARP enzymes are involved in DNA transcription, cell cycle regulation, 
and DNA repair. Olaparib is a potent oral PARP inhibitor that induces synthetic lethality in 
BRCA1/2 deficient tumor cells through the formation of double-stranded DNA breaks which 
cannot be accurately repaired, which leads to disruption of cellular homeostasis and cell death 
 
CAS Registry Number: 763113-22-0 


Page 26  of 
 
 
Molecular Formula: C24H23FN4O3 
M.W.: 434.46 
Approximate Solubility: Olaparib is a crystalline solid, is non-chiral and shows pH-independent 
low solubility across the physiological pH range. 
 
9.1.1. Olaparib Tablets 
 
How Supplied: Olaparib tablets are supplied by AstraZeneca Pharmaceuticals LP. Olaparib tablets 
for oral administration contain 100 mg or 150 mg of olaparib. Inactive ingredients in the tablet core 
are copovidone, mannitol, colloidal silicon dioxide and sodium stearyl fumarate. The tablet coating 
consists of hypromellose, polyethylene glycol 400, titanium dioxide, ferric oxide yellow and 
ferrosoferric oxide (150 mg tablet only). 
 
150 mg tablets: green to green/grey, oval, bi-convex, film-coated tablet, with debossment 
‘OP150’ on one side and plain on the reverse, are available in: 
 Bottles of 60 tablets (NDC 0310-0679-60) and 
 Bottles of 120 tablets (NDC 0310-0679-12). 
100 mg tablets: yellow to dark yellow, oval, bi-convex, film-coated tablet, with debossment 
‘OP100’on one side and plain on the reverse, are available in: 
 Bottles of 60 tablets (NDC 0310-0668-60) and 
 Bottles of 120 tablets (NDC 0310-0668-12). 
Storage: Store at 20ºC to 25ºC (68ºF to 77ºF), excursions permitted to 15ºC to 30ºC (59ºF to 86ºF). 
Store in original bottle to protect from moisture. 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. 
 
Stability: Stability data from three production scale batches stored in the proposed packaging under 
long term conditions for up to 36 months (25°C / 60% RH) and under accelerated conditions (40°C / 
75% RH) for 6 months according to the ICH guidelines has been provided. The 36 month data show 
no significant change with regards to the description, assay, organic impurities, polymorphic form, 
water content or particles size distribution for the samples stored at 25°C/60% RH, nor after 6 
months at 40°C/75% RH and 6 months at 50°C/ambient humidity. Based on the available stability 
data, the proposed retest period of 48 months for olaparib when stored in LDPE bags at or below 
30°C was considered acceptable. 
 
Route of Administration: Oral administration per the protocol treatment schedule. 
 
Method of Administration: Inform patients that olaparib should be taken twice daily with or 
without food. Instruct patients that if they miss a dose, they should take their next normal dose at 
the usual time. Swallow each tablet whole. Do not chew, crush, dissolve, or divide tablet. Do not 
take more than 4 tablets daily. Inform patients to avoid grapefruit, grapefruit juice, Seville oranges, 
Seville orange juice, pomelos, and starfruit while taking olaparib as these food products can alter 
the metabolism of olaparib. Inform patients not to substitute olaparib tablets (100 mg and 150 mg) 
with olaparib capsules (50 mg) on a milligram-to-milligram basis due to differences in the dosing 
and bioavailability of each formulation. 
 
10. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 


Page 27  of 
 
 
With the exception of patients who withdraw due to toxicity or withdraw consent, patients on this 
trial will ultimately develop PARP inhibitor resistant disease. This represents an important 
opportunity to collect biospecimens to evaluate resistance mechanisms and create patient derived 
xenograft tumor models for therapeutic development. 
 
10.1 Integrated Laboratory Studies – Exploratory Objective 
10.1.1 
Tissue collection is optional. If the patient consents, archival tissue will be obtained 
from previous surgical resection. If the patient undergoes biopsy at the time of disease 
progression at part of standard of care practice, tissue will be requested from this biopsy 
as well. 
10.1.2 
Specimen Collection: Pretreatment tumor samples will be obtained from archived 
formalin-fixed, paraffin embedded (FFPE) tissue from the Pitt Biospecimen Core 
(PBC). Subject samples will undergo pathologic review with to ensure accurate 
diagnosis and tissue quality, >50% tumor and >50% viable cells, for subsequent 
molecular analysis. Post-treatment samples will be obtained at the time of detected 
disease recurrence or progression. A portion of each biopsy will undergo pathologic 
review as above. 
10.1.3 
Research Specimens: All specimens will be de-identified and clinical information 
stored in a locked computer database system. Research samples will be processed in 
the Buckanovich lab. If tissue is limited, samples will be snap frozen in liquid nitrogen 
and stored at -80°C for DNA/RNA isolation (QIAGEN® AllPrep DNA/RNA kit). For 
larger specimens (laparoscopic biopsy/resection), a portion of each sample will be (1) 
snap-frozen for RNA and DNA isolation, (2) disaggregated into single cells 
suspensions and live cell suspensions frozen, and (3) immediately transferred in 
DMEM media to Champions Oncology for PDX development. 
10.1.4 
Characterize genomic changes associated with olaparib resistance: For samples with 
limited tissue and therefore not amenable to PDX formation, we will use BROCA 
analysis (http://tests.labmed.washington.edu/BROCA#BROCA_Gene_List) on both 
pre and post-olaparib treatment samples to evaluate 69 different genes associated with 
HR defects. A total of 1.4 Mb are sequenced and the average coverage ranges from 
320 to >1,000 sequencing reads per bp. Genomic regions are captured using 
biotinylated RNA oliognucleotides (SureSelect), prepared in paired-end libraries with 
~200 bp insert size, and sequenced on an Illumina HiSeq2000. For samples for which 
PDX models are generated, we will perform whole genome sequencing (WGS) on the 
primary tissue, then compare WGS of primary tumors and PDX tumors. For specific 
genes in which we find molecular alterations, we will use knockdown and rescue 
assays in cell lines to validate olaparib resistance related to the identified target. 
10.1.5 
Characterize transcriptome changes associated with olaparib resistance: For an 
unbiased evaluation of mRNA expression changes associated with olaparib resistance, 
we will perform RNASeq (Novogene, utilizing Illumina’s NovaSeq platform) with a 
random-primed cDNA synthesis non-strand-specific protocol. RNASeq will be 
compared between pre and post-olaparib treatment samples. Candidate drivers of 
resistance will be compared with BROCA results and then validated with 
knockin/knockout studies as above. Resistance mechanisms identified in the above 
studies can then be used in future work with the PDX models to test novel therapeutics 
to overcome PARP-I resistance. 
10.1.6 
Pharmacokinetics: To explore exposure-response relationships between olaparib 


Page 28  of 
 
 
exposure and toxicity/efficacy. A steady-state trough sample will be obtained around 
day 28. Trough concentrations (if need be corrected for time since dosing) will be 
compared between patients with/without response and patients with/without toxicity. 
This assay will be performed at the UPMC Hillman Cancer Center Cancer 
Pharmacokineitc and Pharmacodynamics Facility. (CPPF). The published olaparib 
assay has successfully been implemented and is available (Nijenhuis et al. Journal of 
Chromatography B, 940 (2013) 121– 125). Note: plan the patient’s day 28 visit such 
that their blood can be drawn at about the time they would otherwise take their dose, 
but BEFORE they take it. Ask patients to take bring their olaparib so they can take 
their dose after their PK blood draw. See appendix D for practical details. 
11. STUDY CALENDAR 
Baseline evaluations are to be conducted within 14 days prior to start of trial. Imaging CT 
scans and x-rays must be done <4 weeks prior to the start of therapy. 
 
 
Procedure/Test 
 
Pre- Study
Surveillance 
every 4 weeks 
Day 1 of 
each cycle 
Every 12 
weeks 
30 day 
follow- up* 
Every 3 
months 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Concurrent medications 
X 
X 
X 
 
X 
 
Medical history 
X 
 
 
 
 
 
Physical exam A 
X 
X 
X 
 
X 
 
Vital signs A 
X 
X 
X 
 
X 
 
Height and Weight A 
X 
X 
X 
 
X 
 
Performance status A 
X 
X 
X 
 
X 
 
CBC w/diff, platelets A 
X 
 
X 
 
X 
 
Serum chemistry A,B 
X 
 
X 
 
X 
 
CA125 A 
X 
X 
X 
 
X 
 
PTT/PT/INR C 
X 
 
 
 
 
 
EKG C 
X 
 
 
 
 
 
Tumor Measurements D 
X 
 
 
X 
 
 
Baseline signs & symptoms 
X 
 
 
 
 
 
Adverse event evaluationE 
X 
X 
X 
 
X 
 
Worry and Distress MeasuresF 
X 
X 
X 
 
X 
 
Quality of Life and Physical 
Function MeasuresG 
 
X 
 
 
X 
X 
 
Financial Toxicity MeasuresH 
X 
 
 
X 
X 
 
Urine or serum B-HCG 
for WOCBP I 
 
X 
 
 
 
 
 
Tissue CollectionJ 
X 
 
 
 
X 
 
PK plasma sampleK 
 
 
XK 
 
 
 


Page 29  of 
 
 
BRCA testingL 
X 
 
 
 
 
 
Survival Follow-upM 
 
 
 
 
 
X 
 
 
*Patients should be seen 30 days after completion of treatment to assess for resolution of toxicity 
A. These procedures do not need to be repeated in cycle 1 if done pre-study within 7 days prior to 
start of protocol therapy. 
B. Albumin, alkaline phosphatase, total bilirubin, direct bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, magnesium, 
phosphorus 
C. Required pre-study, then as clinically indicated 
D. Prior to olaparib initiation, imaging will only be done for doubling of nadir CA125 or per physician 
discretion for patient symptoms. Following initiation of olaparib, CT scans will be obtained every 12 
weeks as part of surveillance. CT scans can be obtained for rising CA125 or physician preference for 
patient symptoms before scheduled routine surveillance. 
E. Adverse event evaluation will include both the CTCAE and the PRO-CTCAE (See Appendix D). 
F. Worry and distress measured via Assessment of Survivor Concerns (ASC) (See Appendix E) worry 
subscale and Impact of Event Scale (IES-R) (See Appendix F). 
G. Health-related quality of life will be measured via The Functional Assessment of Cancer Therapy + 
Ovarian-specific scale (FACT-O) (See Appendix G) and physical function assessed through the 
PROMIS Physical Function-20a assesses self-reported performance of physical activities (See 
Appendix H). 
H. Financial toxicity will be measured through a) monetary measure using the Modified Collection of 
Indirect and Nonmedical Direct Costs (COIN) (See Appendix I), b) objective measure of financial 
burden assessed using Barrera et al.’s Economic Hardship questionnaire (See Appendix J), and c) 
subjective measure of financial distress will be gauged using the Comprehensive Score for Financial 
Toxicity (COST Measure) (See Appendix K). 
I. 
Pregnancy test for women of childbearing potential (WOCBP) must be done within 24 hours prior to 
initiation of olaparib. 
J. 
Tissue collection is not mandatory. If permission granted, tissue prior to initiation on olaparib will be 
obtained from archival stores. If patient undergoes biopsy at the time of progression as part of standard 
of care, tissue will be collected after routine processing. 
K. A mandatory trough plasma sample will be obtained only once at approximately 28 days after initiation 
of treatment (See Appendix L). 
L. BRCA testing required (Results not needed for registration 
M. Chart review or office visit every 3 months for 18 months from time of enrollment 
 
 
12. MEASUREMENT OF EFFECT 
Although not all patients will have measurable disease, patients with partial response to the 
previous platinum-based therapy are eligible for this study, and they will be carefully monitored 
for tumor response and symptom relief in addition to safety and tolerability. Patients will be 
assessed by standard criteria. For this study, patients will undergo a clinical assessment every 4 
weeks while receiving olaparib. Tumor response will be evaluated at 12 week intervals. 
 
12.1. Antitumor Effect – Solid Tumors 
 
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 


Page 30  of 
 
 
nodes are used in the RECIST criteria. 
 
12.1.1. 
Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with olaparib. 
 
Evaluable for objective response by RECIST. Patients who have received at least 1 cycle 
of therapy and have had their disease re-evaluated with a 3-month post treatment CT will 
be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable for objective response by CA-125. Patients who have received at least 1 cycle 
of therapy, have a CA-125 before treatment below the upper limit of the normal (for 
values above this limit, any increase in a second sample has to be <15% increase) and 
have had their disease re-evaluated with monthly CA125, will be considered evaluable 
for response. These patients will have their response classified according to the 
definitions stated below. (Note: Patients who exhibit objective disease progression prior 
to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-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. 
 
12.1.2. 
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. If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
 
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 


Page 31  of 
 
 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non- 
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non- 
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters. If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum. The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
12.1.3. 
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. 


Page 32  of 
 
 
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). 
 
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: 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 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 


Page 33  of 
 
 
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 
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 that is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.1.4. 
Response Criteria 
 
12.1.4.1. 
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 


Page 34  of 
 
 
baseline sum if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (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. 
 
12.1.4.2 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). 
12.1.4.3 Evaluation Based on CA125 
 
Complete Response (CR): Normalization of CA-125 levels. The response must be 
confirmed and maintained for at least 28 days. No new or progressive disease on 
imaging. 
 
Partial Response (PR): At least a 50% reduction in CA-125 levels from a 
pretreatment sample but not reaching normalization. The response must be 
confirmed and maintained for at least 28 days. No new or progressive disease on 
imaging. 
 
Progressive Disease (PD):  
 
 Patients with elevated CA-125 pretreatment and normalization of CA-125 must 
show evidence of CA-125 greater than, or equal to, 2 times the upper limit of 
the reference range on 2 occasions at least 1 week apart or 
 Patients with elevated CA-125 before treatment, which never normalizes, must 
show evidence of CA-125 greater than, or equal to, 2 times the nadir value on 2 
occasions at least 1 week apart or 


Page 35  of 
 
 
 Patients with CA-125 in the reference range before treatment must show 
evidence of CA-125 greater than, or equal to, 2 times the upper limit of the 
reference range on 2 occasions at least 1 week apart 
 Response determined via measurable disease (measurement of target and non- 
target lesions) takes precedence over CA-125 criteria 
Stable Disease (SD): CA-125 fluctuations not fitting above criteria 
 
 
12.1.5 
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. 
 
12.1.5.1 Evaluation of Overall Response 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target Lesions
New Lesions*
Overall Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR 
Non-CR/Non-PD/not 
evaluated
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated
No 
SD 
PD
Any
Yes or No
PD
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. 
**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


Page 36  of 
 
 
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 
 
13. 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). 
 
13.1. Study Oversight 
 
This protocol is monitored at several levels, as described in this section. The Protocol Principal 
Investigator is responsible for monitoring the overall 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). 
 
All studies are also reviewed in accordance with the UPMC Hillman Cancer Center data safety 
monitoring plan (DSMP). 
 
13.2. Data Reporting 
 
13.2.1. 
Responsibility for Data Submission 
 
Investigator/Sub-investigators, regulatory, CRS management, clinical research coordinators, 
clinical research associates, data managers, and clinic staff meet monthly in the UPMC Hillman 
Cancer Center Data Safety Monitoring Board (DSMB) to review and discuss study data to include, 
but not limited to, the following: 
 serious adverse events 
 subject safety issues 
 recruitment issues 
 accrual 
 protocol deviations 
 breaches of confidentiality 
All toxicities encountered during the study will be evaluated on an ongoing basis according to the 
NCI Common Toxicity Criteria version 5.0 or Patient Reported Outcomes-Common Terminology 
Criteria for Adverse Events (PRO-CTCAE). All study treatment associated adverse events that are 
both serious and unexpected will be reported to the IRB. Any modifications necessary to ensure 
subject safety and decisions to continue, or close, the trial to accrual are also discussed during these 
meetings. If any literature becomes available which changes the risk/benefit ratio or suggests that 
conducting the trial is no longer ethical, the IRB will be notified in the form of an Unanticipated 
Problem submission and the study may be terminated. 


Page 37  of 
 
 
All study data reviewed and discussed during these meetings will be kept confidential. Any breach 
in subject confidentiality will be reported to the IRB in the form of an Unanticipated Problem 
submission. The summaries of these meetings are forwarded to the UPMC Hillman Cancer Center 
DSMC, which also meets monthly following a designated format. 
 
For all research protocols, there will be a commitment to comply with the IRB’s policies for 
reporting unanticipated problems involving risk to subjects or others (including adverse events). 
DSMC progress reports, to include a summary of all serious adverse events and modifications, and 
approval will be submitted to the IRB at the time of renewal. 
Both the UPMC Hillman Cancer Center DSMC as well as the individual disease center DSMB have 
the authority to suspend accrual or further investigate treatment on any trial based on information 
discussed at these meetings. 
 
14. STATISTICAL CONSIDERATIONS 
 
14.1 
Study Design/Endpoints 
 
Primary endpoint is defined as the time to next therapy from completion of platinum-based 
therapy for treatment of recurrence until initiation of post-olaparib treatment. Based on Ledermann 
et al,29 the expected median time to progression on olaparib following platinum response is 8.4 
months for a cohort with 22% BRCA mutation prevalence. 
 
Secondary endpoints 
Progression-free survival is defined as the time from enrollment until detected recurrence or 
progression of disease, via RECISTv1.1, or death from any cause. 
 Overall survival as defined as the time from enrollment to death from any cause. 
 Toxicity rates defined by the National Cancer Institute's Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0. 
 Response rate as defined by RECIST or CA-125 and stratified by BRCA mutation status. 
 Patient-reported adverse events using the NCI Patient Reported Outcomes-Common 
Terminology Criteria for Adverse Events (PRO-CTCAE) (See Appendix 
 Health-related quality of life measured via The Functional Assessment of Cancer Therapy + 
Ovarian-specific scale (FACT-O) 
 Physical function assessed through the PROMIS Physical Function-20a assesses self-reported 
performance of physical activities 
 Worry and distress measured via Assessment of Survivor Concerns (ASC) Worry Subscale and 
Impact of Event Scale (IES-R) 
 Financial toxicity measured through 
a) monetary measure using the Modified Collection of Indirect and Nonmedical Direct Costs 
(COIN), 
b) objective measure of financial burden assessed using Barrera et al.’s Economic Hardship 
questionnaire51, and 
c) subjective measure of financial distress will be gauged using the Comprehensive Score for 
Financial Toxicity (COST Measure). 
 Exposure measured through quantitating olaparib by LC-MS/MS in a trough sample. 
PLANNED ENROLLMENT REPORT 


Page 38  of 
 
 
Racial Categories 
Ethnic Categorie s 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female
Female
 
American Indian/ 
Alaska Native 
 
0 
 
0 
 
0 
 
 
Racial Categories 
Ethnic Categories 
 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female
Female
 
 
Asian 
 
3 
 
0 
 
3 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
 
0 
Black or 
African 
American 
7 
0 
 
7 
 
White 
65 
0 
 
65 
 
More Than One Race 
0 
0 
 
0 
 
Total 
 
75 
 
0 
 
75 
 
13.2 
SAMPLE SIZE/ACCRUAL RATE 
Study 19 is the only PARP inhibitor maintenance trial in the platinum sensitive recurrent 
setting to report both PFS and OS data. Median progression-free survival was 8.4 months 
in the olaparib group versus 4.8 months in the placebo group (hazard ratio for progression 
or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). The secondary end 
point of time to progression according to the RECIST guidelines or CA-125 level, 
whichever showed earlier progression, was also significantly longer in the olaparib group 
than in the placebo group (median, 8.3 months vs. 3.7 months; hazard ratio for progression, 
0.35; 95% CI, 0.25 to 0.47; P<0.001). There was no statistically significant OS advantage 
noted for those treated with olaparib; for the entire population median OS was 29.8‐months‐ 
[95%‐CI‐26·9–35·7]‐in the olaparib arm vs 27.8 months‐[24·9–33·7] in the placebo arm. 
For those patients evaluable for response (n=61), there were 16 (26.2%) either PR or CR by 
RECIST and 1 (1.6%) by CA12529. 
Using the reported data from Study 19, we will assess whether delaying olaparib until 
biochemical relapse will increase the median time to next treatment by ~3 months (from 8 
to 11 months). We assume 3-4 patients can be accrued/month and that the BRCA mutation 


Page 39  of 
 
 
prevalence will be ~20% and thereby be comparable to the historical control group. With 2 
years of accrual and 18 months of additional follow up, we will require 75 eligible patients. 
This will allow 90% power for a level 0.10 one-sided one sample exponential test to detect 
an improvement in median time to next treatment from 8 to 11 months. Due to the 
possibility of lost to long-term follow-up, we plan to accrue an additional 10% of the 
targeted accrual. Therefore, the sample size for this study will be approximately 83 patients 
in order to successfully accrue 75 evaluable patients. 
 
13.3 
DATA ANALYSIS 
13.3.1 
Analysis Sets 
Evaluable patients: patients who meet all of the protocol inclusion/exclusion criteria and 
begin treatment with the protocol regimen. 
Safety set: data from all evaluable patients who receive initial treatment of the study 
treatment will be used in the analysis of safety. 
Efficacy set: data from all evaluable patients who receive initial treatment of the study 
treatment will be used in the analysis of efficacy endpoints. 
 
Exploratory set: the data from all study-eligible patients (i.e. those meeting all of the 
protocol inclusion/exclusion criteria) who begin the study treatment and have tissue 
samples taken will be used in the analyses to address the correlative biomarker aims. 
 
13.3.2 
Analysis of Baseline Demographic Variables 
 
Baseline descriptive statistics on all evaluable patients will be provided for demographic 
variables (age, BMI, race/ethnicity), ECOG performance status, disease stage and status at 
the time of enrollment (stable disease, progressive disease), and treatment regimens 
previously used. 
 
13.3.3 
Analysis of Safety Endpoints 
 
The NCI common terminology criteria for adverse events (CTCAE 5.0) will be used to 
evaluate toxicity; we will consider a toxicity to be an adverse event that is possibly, 
probably or definitely related to treatment. The maximum grade of toxicity for each 
category of interest will be recorded for each patient and the summary results will be 
tabulated by category and grade. Statistics on the number of cycles received by patients 
and any dose reductions will also be tabulated. 
 
13.3.4 
Analysis of Efficacy Endpoints 
 
Allowing 18 months of follow-up following the last patient accrual, time to next treatment 
will be estimated by the Kaplan-Meier method. Median time to next treatment will be 
estimated with 90% confidence intervals. The maximum likelihood estimate of the hazard 
rate (hazard of next treatment) will be calculated and used to conduct a one-tailed 


Page 40  of 
 
 
exponential test at level alpha = .10. This will test the hypothesis that time to next treatment 
is increased over that expected for olaparib without delay (this assumes the data follow an 
exponential distribution, otherwise, an alternate parametric test or a one sample log rank 
test will be used). Toxicities will be summarized by grade, frequency and attribution to 
olaparib. Median progression-free survival (PFS) and overall survival (OS) will be 
estimated using the Kaplan Meir method. The Kaplan-Meier method with a log rank test 
will be applied to test differential response by mutation status. We will estimate the 
response rate utilizing RECIST and/or GCIG criteria. For those patients with measurable 
disease and elevated CA125, both RECIST and GCIG criteria will be utilized. For those 
without measurable disease, GCIG criteria alone will be used to record response. Overall 
response will be defined as the number of patients with best overall response of CR and 
PR. The effect of treatment will be reported with its supporting 90% confidence interval. 
 
13.3.5 Analysis of Patient Reported Outcomes, Quality of Life and Financial Toxicity Endpoints 
 
Additional Secondary Endpoints include a series of quality of life instruments and 
financial toxicity measures. These instruments will be administered starting at onset of trial 
enrollment and periodically thereafter. Patient reported adverse events, worry and distress 
(3 instruments measured every 4 weeks), health related quality of life, physical functioning 
and financial toxicity (5 instruments measured every 12 weeks) will provide data for 
longitudinal analysis with mixed effects linear models. We will focus on change over time 
particularly between the two treatment periods, pre and post olaparib. Our linear mixed 
effects models will emphasize random coefficients that allow non-linear profiles, typically 
polynomial regression, restricted cubic splines or piecewise linear splines with a knot to 
represent the time of starting olaparib. These models will permit us to estimate whether 
quality of life and financial toxicity change over the course of the clinical trial and, in 
particular, whether the observed change suggests a shift that is consistent with the start of 
olaparib therapy. 
 
For drug exposure measured through quantitating olaparib by LC-MS/MS in a trough 
sample, trough concentrations between groups will be compared with non-parametric 
Wilcoxon signed rank test with significance set at P<0.05. If significant, we may explore 
ROC analyses. 
 
13.3.6 Analysis of Exploratory Endpoints 
 
DNA: BROCA or whole genome sequencing for mutational changes will be assessed in 
pre and post- olaparib treatment. Variant changes over time will be reported descriptively. 
These will be assessed against reference genome to determine pathogenic variants. 
 
RNA: RNA-Seq analysis will be performed per a recent comparative and guideline 
paper55, sequencing reads will be examined for data quality by FastQC, and aligned, 
assembled and annotated (gene-based and isoform-based) using HISAT2, StringTie and 
Ballgown56. Differential expression analysis based on count data will be performed by 
DESeq257. Low expressed genes will be filtered (25% of genes with smallest sum of counts 
across all samples). Assuming significance level at 0.05, n=40 samples (20 each pre/post 
therapy) standard deviation at 0.1, we will have >99%. statistical power to detect a 
difference for a given gene with effect size=0.8. When we account for multiple testing for 
10,000 genes, we still have 70% statistical power to detect a difference of effect size 3 at 


Page 41  of 
 
 
Family-Wise Error Rate (FWER) of 0.05. Using False Discovery Rate (FDR) for multiple 
testing control (e.g. using Benjamini-Hochberg procedure) can only increase the power. 
 
REFERENCES 
1. Noone AM, Howlader N, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto 
A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975- 
2015, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2015/, based 
on November 2017 SEER data submission, posted to the SEER web site, April 2018. 
2. Jayson GC, Kohn EC, Kitchener HC, et al. Ovarian cancer. Lancet. 2014 Oct 
11;384(9951):1376-88. 
3. Markman M, Liu PY, Moon J, Monk BJ, Copeland L, Wilczynski S, Alberts D. Impact on 
survival of 12 versus 3 monthly cycles of paclitaxel (175 mg/m2) administered to patients with 
advanced ovarian cancer who attained a complete response to primary platinum-paclitaxel: 
Follow-up of a Southwest Oncology Group and Gynecologic Oncology Group phase 3 trial. 
Gynecol Oncol 114: 195-8, 2009. 
4. Copeland JC, Brady MF, Burger RA, Rodgers WH, Huang H, Cella D, Fowler JM, Walker LJ, 
Krishnansu ST, Bender DP, Morris RT, Lowery WJ, Miller DS, Dewdney SB, Spirtos NM, 
Lele SB, Guntupalli SR, Ueland FR, Glasser GE, Mannel RS, DiSaia PJ. A phase III trial of 
maintenance therapy in women with advanced ovarian/Fallopian tube/peritoneal cancer 
(O/PC/FT) after a complete clinical response (CCR) to first-line therapy – an nrg oncology 
study. Scientific Plenary VI. Presented at the 2017 Annual Meeting for Women's Cancers. 
March 14, 2017, National Harbor, Washington DC. 
5. Chen H, Fang F, Liu GJ, Xie HY, Zou J, Feng D. Maintenance chemotherapy for ovarian cancer 
(Review). Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD007414 
6. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley 
HD, Fowler J, Greer BE, Boente M, Birrer MJ, Liang SX, Gynecologic Oncology Group. 
Incorporation of bevacizumab in the primary treatment of ovarian cancer.N Engl J Med. 2011 
Dec;365(26):2473-83. 
7. Oza AM, Cook AD, Pfisterer J, Embleton A, Ledermann JA, Pujade-Lauraine E, Kristensen G, 
Carey MS, Beale P, Cervantes A, Park-Simon TW, Rustin G, Joly F, Mirza MR, Plante M, 
Quinn M, Poveda A, Jayson GC, Stark D, Swart AM, Farrelly L, Kaplan R, Parmar MK, Perren 
TJ, ICON7 trial investigators. Standard chemotherapy with or without bevacizumab for women 
with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised 
trial. Lancet Oncol. 2015 Aug;16(8):928-36. Epub 2015 Jun 23. 
8. Aghajanian C, Goff B, Nycum LR, Wang YV, Husain A, Blank SV. Final overall survival and 
safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in 
patients with platinum-sensitive recurrent ovarian cancer. Gynecol Oncol. 2015 Oct;139(1):10- 
6. 
9. Coleman RL, Brady MF, Herzog TJ, et al. A phase III randomized controlled clinical trial of 
carboplatin and paclitaxel alone or in combination with bevacizumab followed by bevacizumab 
and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian, peritoneal 
primary and fallopian tube cancer (Gynecologic Oncology Group 0213). Scientific Plenary #3 
Presented at the 2015 Annual Meeting for Women's Cancers. March 28, 2015. Chicago, IL. 
10. Incorporation of pazopanib in maintenance therapy of ovarian cancer. du Bois A, Floquet A, 
Kim JW, Rau J, Del Campo JM, Friedlander M, Pignata S, Fujiwara K, Vergote I, Colombo N, 
Mirza MR, Monk BJ, Kimmig R, Ray-Coquard I, Zang R, Diaz-Padilla I, Baumann KH, 
Mouret-Reynier MA, Kim JH, Kurzeder C, Lesoin A, Vasey P, Marth C, Canzler U, Scambia 
G, Shimada M, Calvert P, Pujade-Lauraine E, Kim BG, Herzog TJ, Mitrica I, Schade-Brittinger 
C, Wang Q, Crescenzo R, Harter P Incorporation of pazopanib in maintenance therapy of 


Page 42  of 
 
 
ovarian cancer. J Clin Oncol. 2014;32(30):3374. 
11. DuBois A, Kristensen G, Ray-Coquard I, et al. AGO-OVAR 12: A randomized placebo- 
controlled GCIG/ENGOT intergroup phase III trial of standard frontline chemotherapy +/- 
nintedanib for advanced ovarian cancer. Int J Gynecol Oncol 2013; 23 (suppl 1). Oral abstract. 
12. Despierre E, Vergote I, Anderson R, Coens C, Katsaros D, Hirsch FR, Boeckx B, Varella- 
Garcia M, Ferrero A, Ray-Coquard I, Berns EM, Casado A, Lambrechts D, Jimeno A; European 
Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC- 
GCG); Groupe d’Investigateurs Nationaux pour les Etudes des Cancers de l’Ovaire (GINECO); 
Austrian Arbeitsgemeinschaft für Gynäkologische Onkologie (A-AGO); National Cancer 
Research Institute (NCRI); Australia New Zealand Gynaecological Oncology Group 
(ANZGOG); Mario Negri Gynecologic Oncology group (MaNGO). Epidermal Growth Factor 
Receptor (EGFR) Pathway Biomarkers in the Randomized Phase III Trial of Erlotinib Versus 
Observation in Ovarian Cancer Patients with No Evidence of Disease Progression after First- 
Line Platinum-Based Chemotherapy. Target Oncol. 2015 Dec;10(4):583-96. 
13. GD Hall, JM Brown, RE Coleman , et al : Maintenance treatment with interferon for advanced 
ovarian cancer: Results of the Northern and Yorkshire Gynaecology Group randomised phase 
III study Br J Cancer 91: 621– 626, 2004 
14. J Berek, P Taylor, W McGuire , etal : Oregovomab maintenance monoimmunotherapy does not 
improve outcomes in advanced ovarian cancer J Clin Oncol 27: 418– 425, 2009 
15. Sabbatini P, Harter P, Scambia G, Sehouli J, Meier W, Wimberger P, Baumann KH, Kurzeder 
C, Schmalfeldt B, Cibula D, Bidzinski M, Casado A, Martoni A, Colombo N, Holloway RW, 
Selvaggi L, Li A, del Campo J, Cwiertka K, Pinter T, Vermorken JB, Pujade-Lauraine E, 
Scartoni S, Bertolotti M, Simonelli C, Capriati A, Maggi CA, Berek JS, Pfisterer J. 
Abagovomab as maintenance therapy in patients with epithelial ovarian cancer: a phase III trial 
of the AGO OVAR, COGI, GINECO, and GEICO--the MIMOSA study. 2013 Apr 
20;31(12):1554-61 
16. Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, et al. BRCA mutation 
frequency and patterns of treatment response in BRCA mutation-positive women with ovarian 
cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol 
2012;30(21):2654e63. 
17.  Zhang S, Royer R, Li S, McLaughlin JR, Rosen B, Risch HA, et al. Frequencies of BRCA1 
and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol 
Oncol  2011;121(2):353e7.   
18. Janavicius R, Rudaitis V, Mickys U, Elsakov P, Griskevicius L. Comprehensive BRCA1 and 
BRCA2 mutational profile in Lithuania. Cancer Genet 2014;207(5):195e205.  
19. Song H, Cicek MS, Dicks E, Harrington P, Ramus SJ, Cunningham JM, et al. The contribution 
of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian 
cancer in the population. Hum Mol Genet 2014;23(17): 4703e9. 
20. Vicus D, Finch A, Cass I, Rosen B, Murphy J, Fan I, et al. Prevalence of BRCA1 and BRCA2 
germ line mutations among women with carcinoma of the fallopian tube. Gynecol Oncol 
2010;118(3):299e302. 
21. Aguilar-Quesada, R., Munoz-Gamez, J.A., Martin-Oliva, D., Peralta, A., Valenzuela, M.T., 
Matinez-Romero, R. et al. Interaction between ATM and PARP-1 in response to DNA damage 
and sensitization of ATM deficient cells through PARP inhibition. BMC Mol. Biol. 2007; 8: 29 
22. Buisson, R., Dion-Cote, A.M., Coulombe, Y., Launay, H., Cai, H., Stasiak, A.Z. et 
al. Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating 
homologous recombination. Nat. Struct. Mol. Biol. 2010; 17: 1247–1254 
23. Rafnar, T., Gudbjartsson, D.F., Sulem, P., Jonasdottir, A., Sigurdsson, A., Jonasdottir, A. et 
al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat. Genet. 2011; 43: 1104–1107 


Page 43  of 
 
 
24. Walsh, T., Casadei, S., Lee, M.K., Pennil, C.C., Nord, A.S., Thornton, A.M. et al. Mutations in 
12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively 
parallel sequencing. Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 18032–18037 
25. Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, Amnon A, Bell-McGuinn 
KM, Chen LM, Friedlander M, Safra T, Vergote I, Wickens M, Lowe ES, Carmichael 
J, Kaufman B. Phase II, open-label, randomized, multicenter study comparing the efficacy and 
safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal 
doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin 
Oncol. 2012 Feb 1;30(4):372-9. 
26. Kaufman, B., Shapira-Frommer, R., Schmutzler, R.K., Audeh, M.W., Friedlander, M., 
Balmana, J. et al. Olaparib monotherapy in patients with advanced cancer and a germline 
BRCA1/2 mutation. J. Clin. Oncol. 2015; 33: 244–250 
27. Kristeleit R, Shapiro GI, Burris HA, Oza AM, LoRusso P, Patel MR, et al. A Phase I-II study 
of the oral PARP inhibitor rucaparib in patients with germline BRCA1/2 -mutated ovarian 
carcinoma or other solid tumors. Clin Cancer Res 2017; 23(15): 4095-106. 
28. Swisher, E.M., Lin, K.K., Oza, A.M., Scott, C.L., Giordano, H., Sun, J. et al. Rucaparib in 
relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, 
multicentre, open-label, phase 2 trial. Lancet Oncol. 2017; 18: 75–87 
29. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier 
W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis 
U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J 
Med. 2012 Apr 12;366(15):1382-92. 
30. Pujade-Lauraine, E., Ledermann, J.A., Selle, F., Gebski, V., Penson, R.T., Oza, A.M. et 
al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian 
cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, 
placebo-controlled, phase 3 trial. Lancet Oncol. 2017; 18: 1274–1284 
31. Coleman, R.L., Oza, A.M., Lorusso, D., Aghajanian, C., Oaknin, A., Dean, A. et al. Rucaparib 
maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy 
(ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. (pii: S0140- 
6736(17)32440-6)Lancet. 2017; 
32. Mirza, M.R., Monk, B.J., Herrstedt, J., Oza, A.M., Mahner, S., Redondo, A. et al. Niraparib 
maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N. Engl. J. 
Med. 2016; 375: 2154–2164. 
33. Gordon SW and Temkin SM. Is There a Role for Maintenance PARP for Patients With 
Platinum-Sensitive Ovarian Cancer? Current Controversies in Oncology. ASCO Connection. 
Published 
Apr 
25, 
2018. 
https://connection.asco.org/magazine/current-controversies- 
oncology/there-role-maintenance-parp-patients-platinum-sensitive. 
34. Poly ADP-Ribose Polymerase (PARP) Inhibitors for Ovarian Cancer: Effectiveness and Value 
Final Evidence Report September 28, 2017. Prepared for CEPAC. ©Institute for Clinical and 
Economic 
Review, 
2017 
https://icer-review.org/wp- 
content/uploads/2017/02/MWCEPAC_OVARIAN_FINAL_EVIDENCE_REPORT_1011201 
7.pdf 
35. Rustin GJ, van der Burg ME, Griffin CL, Guthrie D, Lamont A, Jayson GC, Kristensen G, 
Mediola C, Coens C, Qian W, Parmar MK, Swart AM; MRC OV05; EORTC 55955 
investigators. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 
55955): a randomised trial. Lancet. 2010 Oct 2;376(9747):1155-63. 
36. Norquist, B., Wurz, K.A., Pennil, C.C., Garcia, R., Gross, J., Sakai, W. et al. Secondary somatic 
mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian 
carcinomas. J. Clin. Oncol. 2011; 29: 3008–3015 


Page 44  of 
 
 
37. Barber, L.J., Sandhu, S., Chen, L., Campbell, J., Kozarewa, I., Fenwick, K. et al. Secondary 
mutations in BRCA2 associated with clinical resistance to a PARP inhibitor. J. 
Pathol. 2013; 229: 422–429 
38. Kondrashova O, Nguyen M, Shield-Artin K, Tinker AV, Teng NNH, Harrell MI, et al. 
Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired 
Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer Discov. 
2017 Sep;7(9):984-998. 
39. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: Revised RECIST guidelines (version 1.1). European 
Journal of Cancer 45(2009) 228-247. 
40. Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, du Bois A, 
Kristensen G, Jakobsen A, Sagae S, Greven K, Parmar M, Friedlander M, Cervantes A, 
Vermorken J. Definitions for response and progression in ovarian cancer clinical trials 
incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup 
(GCIG).Int J Gynecol Cancer 2011;21:419-23. 
41. National Institutes of Health, National Cancer Institute. Patient-Reported Outcomes version of 
the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Rockville (MD): NCI 
Available from: https://healthcaredelivery.cancer.gov/pro-ctcae/. 
42. Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman M, Yellen 
SB, Winicour P, Brannon J, et al. The Functional Assessment of Cancer Therapy scale: 
development and validation of the general measure. J Clin Oncol. 1993 Mar;11(3):570-9. 
43. Basen-Engquist K, Bodurka-Bevers D, Fitzgerald MA, Webster K, Cella D, Hu S, Gershenson 
DM. Reliability and validity of the functional assessment of cancer therapy-ovarian. J Clin 
Oncol. 2001 Mar 15;19(6):1809-17. 
44. Rose M, Bjorner JB, Gandek B, Bruce B, Fries JF, Ware JE. The PROMIS Physical Function 
Item Bank Was Calibrated to a Standardized Metric and Shown to Improve Measurement 
Efficiency. J Clin Epidemiol. 2014 May; 67(5): 516–526. 
45. Gotay CC, Pagano IS. Assessment of Survivor Concerns (ASC): A newly proposed brief 
questionnaire. Health Qual Life Outcomes. 2007; 5: 15. 
46. Hershman DL1, Greenlee H, Awad D, Kalinsky K, Maurer M, Kranwinkel G, Brafman 
L, Jayasena R, Tsai WY, Neugut AI, Crew KD. Randomized controlled trial of a clinic-based 
survivorship intervention following adjuvant therapy in breast cancer survivors. Breast Cancer 
Res Treat. 2013 Apr;138(3):795-806. 
47. Thewes, B., Butow, P., Bell, M. L., Beith, J., Stuart-Harris, R., Grossi, M.,Dailey, D. (2012). 
Fear of cancer recurrence in young women with a history of early-stage breast cancer: A cross- 
sectional study of prevalence and association with health behaviours. Supportive Care in 
Cancer, 20, 2651-2659. 
48. John M. Salsman,1,2,* Benjamin D. Schalet,1 Michael A. Andrykowski,3 and David Cella1,2 The 
impact of events scale: a comparison of frequency versus severity approaches to measuring 
cancer-specific distress. Psychooncology. 2015 Dec; 24(12): 1738–1745. 
49. Andrea Vodermaier, Wolfgang Linden, and Christopher Siu Screening for Emotional Distress 
in Cancer Patients: A Systematic Review of Assessment Instruments J Natl Cancer Inst. 2009 
Nov 4; 101(21): 1464–1488. 
50. Sherman EJ1, Pfister DG, Ruchlin HS, Rubin DM, Radzyner MH, Kelleher GH, Slovin 
SF, Kelly WK, Scher HI. The Collection of Indirect and Nonmedical Direct Costs (COIN) 
form: a new tool for collecting the invisible costs of androgen independent prostate carcinoma. 
Cancer. 2001 Feb 15;91(4):841-53. 


Page 45  of 
 
 
51. Barrera M Jr1, Caples H, Tein JY. The psychological sense of economic hardship: measurement 
models, validity, and cross-ethnic equivalence for urban families. Am J Community 
Psychol. 2001 Jun;29(3):493-517. 
52. de Souza JA1, Yap BJ, Hlubocky FJ, Wroblewski K, Ratain MJ, Cella D, Daugherty CK. The 
development of a financial toxicity patient-reported outcome in cancer: The COST measure. 
Cancer. 2014 Oct 15;120(20):3245-53. 
53. de Souza JA, Yap BJ, Wroblewski K, Blinder V, Araújo FS, Hlubocky FJ, Nicholas 
LH, O'Connor  JM, Brockstein  B, Ratain  MJ, Daugherty  CK, Cella  D. 
Measuring financial toxicity as a clinically relevant patient-reported outcome: The validation 
of the COmprehensive Score for financial Toxicity (COST). Cancer. 2017 Feb 1;123(3):476- 
484. 
54. Silva, I.A., et al., Aldehyde dehydrogenase in combination with CD133 defines angiogenic 
ovarian cancer stem cells that portend poor patient survival. Cancer Res, 2011. 71(11): p. 3991- 
4001. 
55. Sahraeian, S.M.E., et al., Gaining comprehensive biological insight into the transcriptome by 
performing a broad-spectrum RNA-seq analysis. Nat Commun, 2017. 8(1): p. 59. 
56. Pertea, M., et al., Transcript-level expression analysis of RNA-seq experiments with HISAT, 
StringTie and Ballgown. Nat Protoc, 2016. 11(9): p. 1650-67. 
57. Love, M.I., W. Huber, and S. Anders, Moderated estimation of fold change and dispersion for 
RNA-seq data with DESeq2. Genome Biol, 2014. 15(12): p. 550. 


Page 46  of 
 
 
APPENDIX A: 
PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
Grade
Descriptions
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
 
 
1 
 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5
Dead.


Page 47  of 
 
 
APPENDIX B: PATIENT DRUG DIARY: OLAPARIB 
 
Today’s Date  
 Cycle #  
 
Patient Name 
 Patient Study ID 
1. Complete one form for each cycle (28 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. 
6. The first row in the table below is an EXAMPLE ROW for how to complete this diary. 
OLAPARIB
Take 
(number) 
mg and 
(number) 
mg tablets twice a day 12 hours apart. 
Day
Date
100mg
150mg
AM
PM
1
9/1/2019
0
2
8:00
8:00
1
 
 
 
 
 
2
 
 
 
 
 
3
 
 
 
 
 
4
 
 
 
 
 
5
 
 
 
 
 
6
 
 
 
 
 
7
 
 
 
 
 
8
 
 
 
 
 
9
 
 
 
 
 
10
 
 
 
 
 
11
 
 
 
 
 
12
 
 
 
 
 
13
 
 
 
 
 
14
 
 
 
 
 
15
 
 
 
 
 
16
 
 
 
 
 
17
 
 
 
 
 
18
 
 
 
 
 
19
 
 
 
 
 
20
 
 
 
 
 
21
 
 
 
 
 
22
 
 
 
 
 
23
 
 
 
 
 
24
 
 
 
 
 
25
 
 
 
 
 
26
 
 
 
 
 
27
 
 
 
 
 
28
 
 
 
 
 
Patient’s Signature:  
 Date:  
 
 
Physician/Nurse/Data Manager’s Signature  
 
 
Date 


Page 48  of 
 
 
APPENDIX C: Possible Interactions with Other Drugs and Herbal Supplements 
CYP3A4 Inhibitors 
Strong Inhibitors 
(prohibited) 
Moderate Inhibitors 
(use with caution avoid if 
possible) 
Weak Inhibitors 
(use with caution avoid if 
possible) 
Amprenavir1 
Atazanavir1 
Clarithromycin 
Conivaptan1 
Delavirdine1 
Fosamprenavir1 
Fospropofol1 
Imatinib1 
Indinavir 
Isoniazid1 
Itraconazole 
Ketoconazole 
Miconazole1 
Nefazodone 
Nelfinavir 
Nicardipine1 Posaconazole1 
Propofol1 
Quinidine1 
Ritonavir 
Saquinavir2 
Telithromycin
Amiodarone1 
Aprepitant 
Cimetidine1 
Clotrimazole1 
Cyclosporine1 
Desipramine1 Doxycycline1 
Efavirenz1 
Erythromycin 
Fluconazole 
Fosaprepitant1 
Grapefruit juice 
Haloperidol1 
Lidocaine1 
Metronidazole1 
Norfloxacin1 
Sertraline1 
Tetracycline1 
Verapamil 
Voriconazole1 
Chloramphenicol2 
Ciprofloxacin2 
Diethyldithiocarbamate2 
Fluvoxamine2 
Gestodene2 
Mibefradil2 
Mifepristone 
Norfluoxetine2 
Star fruit2 
Troleandomycin2 
1 Cited in Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong LL, 
Goldman MP, Lance LL, eds. Drug Information Handbook 20th ed. Hudson, OH; LexiComp Inc. 2011- 
2012: 1810-1818 
2 Cited in Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University 
School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/table.asp. Accessed Nov 2011. Note: 
Drugs without a superscript are cited in both the Lacy and Flockhart references. 
CYP3A4 Inducers 
Armodafenil1 
Barbiturates2 
Bosentan1 
Carbamazepine 
Dexamethasone1 
Efavirenz
Fosphenytoin1 
Glucocorticoids2 (see 
note) 
Modafinil2 
Nafcillin1 
Nevirapine
Oxcarbazepine 
Pentobarbital1 
Phenobarbital 
Phenytoin 
Pioglitazone2 
Primidone1 
Rifabutin 
Rifampin 
Rifapentine1 
St. John’s wort2 
Troglitazone3 
Note: Topical steroids are permitted. Systemic steroids may be acceptable after discussion with PI. 
1 Cited in Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong LL, 
Goldman MP, Lance LL, eds. Drug Information Handbook 20th ed. Hudson, OH; LexiComp Inc. 2011- 
2012: 1810-1818 
2 Cited in Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University 
School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/table.asp. Accessed Nov 2011. 
3 Weak inhibitor per Lacy et al. May be used with caution. Note: Drugs without a superscript are cited in 
both the Lacy and Flockhart references. 


Page 49  of 
 
 
APPENDIX D: NCI PRO-CTCAE™ ITEMS 
Item Library Version 1.0 
English 
Form created on 6 August 2019 
 
As individuals go through treatment for their cancer they sometimes experience 
different symptoms and side effects. For each question, please check or mark an 
in the one box that best describes your experiences over the past 7 days… 
1. In the last 7 days, what was the SEVERITY of your DRY MOUTH at its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
 
2. In the last 7 days, what was the SEVERITY of your MOUTH OR THROAT SORES at their 
WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did MOUTH OR THROAT SORES INTERFERE with your usual 
or daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
3. In the last 7 days, what was the SEVERITY of your PROBLEMS WITH TASTING FOOD 
OR DRINK at their WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
 
4. In the last 7 days, what was the SEVERITY of your DECREASED APPETITE at its 
WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did DECREASED APPETITE INTERFERE with your usual or 
daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
5. In the last 7 days, how OFTEN did you have NAUSEA? 
○ Never ○ Rarely ○ Occasionally ○ Frequently ○ Almost constantly 
In the last 7 days, what was the SEVERITY of your NAUSEA at its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
6. In the last 7 days, how OFTEN did you have VOMITING? 
○ Never ○ Rarely ○ Occasionally ○ Frequently ○ Almost constantly 
In the last 7 days, what was the SEVERITY of your VOMITING at its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
 
7. In the last 7 days, how OFTEN did you have HEARTBURN? 
○ Never ○ Rarely ○ Occasionally ○ Frequently ○ Almost constantly 
In the last 7 days, what was the SEVERITY of your HEARTBURN at its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
 
8. In the last 7 days, how OFTEN did you have BLOATING OF THE ABDOMEN (BELLY)? 
○ Never ○ Rarely ○ Occasionally ○ Frequently ○ Almost constantly 


Page 50  of 
 
 
In the last 7 days, what was the SEVERITY of your BLOATING OF THE ABDOMEN 
(BELLY) at its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
 
9. In the last 7 days, what was the SEVERITY of your CONSTIPATION at its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
 
10. In the last 7 days, how OFTEN did you have LOOSE OR WATERY STOOLS 
(DIARRHEA/DIARRHOEA)? 
○ Never ○ Rarely ○ Occasionally ○ Frequently ○ Almost constantly 
 
11. In the last 7 days, how OFTEN did you have PAIN IN THE ABDOMEN (BELLY AREA)? 
○ Never ○ Rarely ○ Occasionally ○ Frequently ○ Almost constantly 
In the last 7 days, what was the SEVERITY of your PAIN IN THE ABDOMEN (BELLY 
AREA) at its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did PAIN IN THE ABDOMEN (BELLY AREA) INTERFERE 
with your usual or daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
12. In the last 7 days, what was the SEVERITY of your SHORTNESS OF BREATH at its 
WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did your SHORTNESS OF BREATH INTERFERE with your 
usual or daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
13. In the last 7 days, what was the SEVERITY of your COUGH at its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did COUGH INTERFERE with your usual or daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
14. In the last 7 days, how OFTEN did you have ARM OR LEG SWELLING? 
○ Never ○ Rarely ○ Occasionally ○ Frequently ○ Almost constantly 
In the last 7 days, what was the SEVERITY of your ARM OR LEG SWELLING at its 
WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did ARM OR LEG SWELLING INTERFERE with your usual or 
daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
15. In the last 7 days, did you have any RASH? 
○ Yes ○ No 
 
16. In the last 7 days, what was the SEVERITY of your ITCHY SKIN at its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 


Page 51  of 
 
 
17. In the last 7 days, what was the SEVERITY of your NUMBNESS OR TINGLING IN 
YOUR HANDS OR FEET at its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did NUMBNESS OR TINGLING IN YOUR HANDS OR FEET 
INTERFERE with your usual or daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
18. In the last 7 days, what was the SEVERITY of your DIZZINESS at its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did DIZZINESS INTERFERE with your usual or daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
19. In the last 7 days, what was the SEVERITY of your PROBLEMS WITH 
CONCENTRATION at their WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did PROBLEMS WITH CONCENTRATION INTERFERE with 
your usual or daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
20. In the last 7 days, what was the SEVERITY of your PROBLEMS WITH MEMORY at their 
WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did PROBLEMS WITH MEMORY INTERFERE with your usual 
or daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
21. In the last 7 days, how OFTEN did you have a HEADACHE? 
○ Never ○ Rarely ○ Occasionally ○ Frequently ○ Almost constantly 
In the last 7 days, what was the SEVERITY of your HEADACHE at its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did your HEADACHE INTERFERE with your usual or daily 
activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
22. In the last 7 days, how OFTEN did you have ACHING MUSCLES? 
○ Never ○ Rarely ○ Occasionally ○ Frequently ○ Almost constantly 
In the last 7 days, what was the SEVERITY of your ACHING MUSCLES at their WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did ACHING MUSCLES INTERFERE with your usual or daily 
activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
23. In the last 7 days, how OFTEN did you have ACHING JOINTS (SUCH AS ELBOWS, 
KNEES, SHOULDERS)? 
○ Never ○ Rarely ○ Occasionally ○ Frequently ○ Almost constantly 
In the last 7 days, what was the SEVERITY of your ACHING JOINTS (SUCH AS ELBOWS, 
KNEES, SHOULDERS) at their WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 


Page 52  of 
 
 
In the last 7 days, how much did ACHING JOINTS (SUCH AS ELBOWS, KNEES, 
SHOULDERS) INTERFERE with your usual or daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
24. In the last 7 days, what was the SEVERITY of your INSOMNIA (INCLUDING 
DIFFICULTY FALLING ASLEEP, STAYING ASLEEP, OR WAKING UP EARLY) at its 
WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did INSOMNIA (INCLUDING DIFFICULTY FALLING 
ASLEEP, STAYING ASLEEP, OR WAKING UP EARLY) INTERFERE with your usual or 
daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
25. In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR LACK 
OF ENERGY at its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did FATIGUE, TIREDNESS, OR LACK OF ENERGY 
INTERFERE with your usual or daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
26. In the last 7 days, how OFTEN did you feel ANXIETY? 
○ Never ○ Rarely ○ Occasionally ○ Frequently ○ Almost constantly 
In the last 7 days, what was the SEVERITY of your ANXIETY at its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did ANXIETY INTERFERE with your usual or daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
27. In the last 7 days, how OFTEN did you have SAD OR UNHAPPY FEELINGS? 
○ Never ○ Rarely ○ Occasionally ○ Frequently ○ Almost constantly 
In the last 7 days, what was the SEVERITY of your SAD OR UNHAPPY FEELINGS at their 
WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
In the last 7 days, how much did SAD OR UNHAPPY FEELINGS INTERFERE with your 
usual or daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
28. In the last 7 days, what was the SEVERITY of your PAIN OR BURNING WITH 
URINATION at its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
 
29. In the last 7 days, how OFTEN did you feel an URGE TO URINATE ALL OF A 
SUDDEN? 
○ Never ○ Rarely ○ Occasionally ○ Frequently ○ Almost constantly 
In the last 7 days, how much did SUDDEN URGES TO URINATE INTERFERE with your 
usual or daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
30. In the last 7 days, were there times when you had to URINATE FREQUENTLY? 


Page 53  of 
 
 
○ Never ○ Rarely ○ Occasionally ○ Frequently ○ Almost constantly 
In the last 7 days, how much did FREQUENT URINATION INTERFERE with your usual or 
daily activities? 
○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much 
 
31. In the last 7 days, what was the SEVERITY of your DECREASED SEXUAL INTEREST at 
its WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
○ Not sexually active 
○ Prefer not to answer 
 
Do you have any other symptoms that you wish to report? 
○ Yes ○ No 
Please list any other symptoms: 
1. In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
2. In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
3. In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
4. In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
5. In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
○ None ○ Mild ○ Moderate ○ Severe ○ Very severe 
 
The PRO-CTCAE™ items and information herein were developed by the NATIONAL CANCER 
INSTITUTE at the NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the 
PRO-CTCAE™ is subject to NCI's Terms of Use. 


Page 54  of 
 
 
APPENDIX E: Assessment of Survivor Concerns (ASC) 
Below is a list of worries people sometimes have after a diagnosis of cancer. Please indicate 
how much worry you experience with each of the following topics. 
 
I worry about… 
Not at all 
1 
A little bit 
2 
Somewhat 
3 
Very much 
4 
1.  Future diagnostic tests 




2.  Another type of cancer 




3.  My cancer coming back 






Page 55  of 
 
 
APPENDIX F: IMPACT OF EVENT SCALE- REVISED 
 
INSTRUCTIONS: Below is a list of difficulties people sometimes have after stressful life 
events. Please read each item, and then indicate how distressing each difficulty has been for you 
 
DURING THE PAST SEVEN DAYS with respect to  
, 
which occurred on  
. How much were you distressed or bothered 
by these difficulties? 
 
Not at all = 0
A little bit = 1
Moderately = 2
Quite a bit = 3
Extremely = 4
 
1.
Any reminder brought back feelings about it.
2.
I had trouble staying asleep.
3.
Other things kept making me think about it.
4.
I felt irritable and angry.
5.
I avoided letting myself get upset when I thought about it or was reminded of it.
6.
I thought about it when I didn't mean to.
7.
I felt as if it hadn’t happened or wasn’t real.
8.
I stayed away from reminders of it.
9.
Pictures about it popped into my mind.
10.
I was jumpy and easily startled.
11.
I tried not to think about it.
12.
I was aware that I still had a lot of feelings about it, but I didn't deal with them.
13.
My feelings about it were kind of numb.
14.
I found myself acting or feeling like I was back at that time.
15.
I had trouble falling asleep.
16.
I had waves of strong feelings about it.
17.
I tried to remove it from my memory.
18.
I had trouble concentrating.
19. Reminders of it caused me to have physical reactions, such as sweating, trouble 
breathing, nausea, or a pounding heart. 
20.
I had dreams about it.
21.
I felt watchful and on-guard.
22.
I tried not to talk about it.
 
The Intrusion subscale is the MEAN item response of items 1, 2, 3, 6, 9, 14, 16, 20. Thus, 
scores can range from 0 through 4. 
 
The Avoidance subscale is the MEAN item response of items 5, 7, 8, 11, 12, 13, 17, 22. Thus, 
scores can range from 0 through 4. 
The Hyperarousal subscale is the MEAN item response of items 4, 10, 15, 18, 19, 21. Thus, 
scores can range from 0 through 4. 
 
Citations: Weiss, D.S. & Marmar, C.R. (1997). The Impact of Event Scale-Revised. In J.P. Wilson, & T. M. Keane 
(Eds.), Assessing Psychological Trauma and PTSD: A Practitioner's Handbook. (pp. 399-411). New York: 
Guilford. 
Weiss, D. S. (2004). The Impact of Event Scale-Revised. In J. P. Wilson, & T. M. Keane (Eds.), Assessing 
psychological trauma and PTSD: A practitioner's handbook (2nd ed., pp. 168-189). New York: Guilford Press. 


Page 56  of 
 
 
APPENDIX G: FACT-O (Version 4) 
English (Universal) 16 November 2007 
Copyright 1987, 1997 Page 1 of 3 
 
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
PHYSICAL WELL-BEING 
Not at all A little bit  Somewhat  Quite a bit  Very much 
GP1 I have a lack of energy............................................... 0
1
2  
3
4
GP2 I have nausea...............................................................0
GP3 Because of my physical condition, I have trouble 
meeting the needs of my family ..................................... 0 
1
 
1 
2
 
2 
 
3
 
3 
4
 
4
GP4 I have pain...................................................................0
1
2  
3
4
GP5 I am bothered by side effects of treatment..................0
1
2  
3
4
GP6 I feel ill........................................................................0
1
2  
3
4
GP7 I am forced to spend time in bed ................................. 0 
1 
2  
3 
4
SOCIAL/FAMILY WELL-BEING 
GS1 I feel close to my friends ............................................. 0 
 
1 
 
2 
 
 
3 
 
4
GS2 I get emotional support from my family.................... 0
1
2  
3
4
GS3 I get support from my friends .................................... 0
1
2  
3
4
GS4 My family has accepted my illness .............................0 
GS5 I am satisfied with family communication about my 
illness ............................................................................. 0 
1 
1 
2
2
 
3 
3 
4
4
GS6 I feel close to my partner (or the person who is my 
Main support) .................................................................. 0 
1 
2
 
3 
4
Q1 Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box and go to the next section. 
GS7 I am satisfied with my sex life .................................... 0 
 
 
1 
 
 
2
 
 
 
3 
 
 
4
EMOTIONAL WELL-BEING Not 
GE1 I feel sad ......................................................................... 0 
 
1 
 
 
2 
 
3 
 
4
GE2 I am satisfied with how I am coping with my illness .... 0
1
 
2
3
4
GE3 I am losing hope in the fight against my illness ............0
1
 
2
3
4
GE4 I feel nervous .................................................................0
1
 
2
3
4
GE5 I worry about dying .......................................................0
1
 
2
3
4
GE6 I worry that my condition will get worse ....................... 0 
1 
 
2 
3 
4
FUNCTIONAL WELL-BEING 
GF1 I am able to work (include work at home) ......................0 
 
1 
 
 
2 
 
3 
 
4
GF2 My work (include work at home) is fulfilling.................0
1
 
2
3
4
GF3 I am able to enjoy life ..................................................... 0
1
 
2
3
4
GF4 I have accepted my illness ..............................................0
1
 
2
3
4
GF5 I am sleeping well........................................................... 0
1
 
2
3
4


Page 57  of 
 
 
 
GF6 I am enjoying the things I usually do for fun...................0
1
2
3
4
GF7 I am content with the quality of my life right now .......... 0 
1 
2 
3 
4
ADDITIONAL CONCERNS 
O1 I have swelling in my stomach area .................................. 0 
 
1 
 
2 
 
3 
 
4
C2 I am losing weight..............................................................0
1
2
3
4
C3 I have control of my bowels...............................................0
1
2
3
4
O2 I have been vomiting..........................................................0
1
2
3
4
B5 I am bothered by hair loss.................................................. 0
1
2
3
4
C6 I have a good appetite ........................................................0
1
2
3
4
C7 I like the appearance of my body....................................... 0
1
2
3
4
BMT5 I am able to get around by myself....................................0
1
2
3
4
B9 I am able to feel like a woman ........................................... 0
1
2
3
4
O3 I have cramps in my stomach area..................................... 0
1
2
3
4
BL4 I am interested in sex. ........................................................ 0
1
2
3
4
BMT7 I have concerns about my ability to have children...........0
1
2
3
4


Page 58  of 
 
 
APPENDIX H: PROMIS 
PROMIS Item Bank v2.0 - Ability to Participate in Social Roles and Activities – Short Form 6a 
 
Ability to Participate in Social Roles and Activities – Short Form 6a 
Please respond to 
each item by 
marking one box 
per row. Never 
Rarely
 
Sometimes
Usually
Always
SRPPER11_CaPS
I have trouble 
doing all of 

5 

4 

3 

2 

1 
 
my regular
 
 
 
 
 
 
leisure
 
 
 
 
 
 
activities with
 
 
 
 
 
 
others
 
 
 
 
 
 
.....................
 
 
 
 
 
SRPPER18_CaPS
I have trouble 
doing all of 

5 

4 

3 

2 

1 
 
the family
 
 
 
 
 
 
activities that I  
 
 
 
 
 
want to
 
 
 
 
 
 
do...................
 
 
 
 
 
 
......
 
 
 
 
 
SRPPER23_CaPS
I have trouble 
doing all of 

5 

4 

3 

2 

1 
 
my usual work  
 
 
 
 
 
(include work
 
 
 
 
 
 
at home)
 
 
 
 
 
 
.......................
 
 
 
 
 
 
......
 
 
 
 
 
SRPPER46_CaPS
I have trouble 
doing all of 

5 

4 

3 

2 

1 
 
the activities
 
 
 
 
 
 
with friends
 
 
 
 
 
 
that I want to
 
 
 
 
 
 
do
 
 
 
 
 
 
...................
 
 
 
 
 
SRPPER15_CaPS
I have to limit 
the things I do 

5 

4 

3 

2 

1 
 
for fun with
 
 
 
 
 
 
others..............
 
 
 
 
 
 
.......................
 
 
 
 
 
 
............
 
 
 
 
 
SRPPER28r1
I have to limit 
my regular 

5 

4 

3 

2 

1 
 
activities with
 
 
 
 
 
 
friends
 
 
 
 
 
 
.......................
 
 
 
 
 
 
.......................
 
 
 
 
 
 
......
 
 
 
 
 


Page 59  of 
 
 
PROMIS Item Bank v2.0 - Satisfaction with Social Roles and Activities – Short Form 6a 
 
Satisfaction with Social Roles and Activities – Short Form 6a 
Please respond to 
each item by 
marking one box 
per row. Not at all 
A little bit 
Somewhat
Quite a bit  
Very much
SRPSAT06r1
I am satisfied 
with my 

1 

2 

3 

4 

5 
 
ability to do
 
 
 
 
 
 
things for my
 
 
 
 
 
 
family
 
 
 
 
 
 
........................
 
 
 
 
 
 
........
 
 
 
 
 
SRPSAT33_CaPS
I am satisfied 
with my 

1 

2 

3 

4 

5 
 
ability to do
 
 
 
 
 
 
things for fun
 
 
 
 
 
 
with
 
 
 
 
 
 
others..............
 
 
 
 
 
 
..........
 
 
 
 
 
SRPSAT34r1
I feel good 
about my 

1 

2 

3 

4 

5 
 
ability to do
 
 
 
 
 
 
things for my
 
 
 
 
 
 
friends............
 
 
 
 
 
 
........................
 
 
 
 
 
 
......
 
 
 
 
 
SRPSAT49r1
I am satisfied 
with my 

1 

2 

3 

4 

5 
 
ability to
 
 
 
 
 
 
perform my
 
 
 
 
 
 
daily routines
 
 
 
 
 
 
........................
 
 
 
 
 
 
............
 
 
 
 
 
SRPSAT33r1
I am satisfied 
with my 

1 

2 

3 

4 

5 
 
ability to do
 
 
 
 
 
 
things for fun
 
 
 
 
 
 
outside my
 
 
 
 
 
 
home ..............
 
 
 
 
 
SRPSAT46_CaPS
I am satisfied 
with my 

1 

2 

3 

4 

5 
 
ability to meet
 
 
 
 
 
 
the needs of
 
 
 
 
 
 
my
 
 
 
 
 
 
friends............
 
 
 
 
 
 
.....................
 
 
 
 
 


Page 60  of 
 
 
PROMIS® Item Bank v2.0 – Physical Function – Short Form 10a 
Physical Function – Short Form 10a 
Please respond to 
each question or 
statement by 
marking one box 
per row. Not at all 
Very little 
Somewhat
Quite a lot  
Cannot do
PFA1
Does your 
health now 

5 

4 

3 

2 

1 
 
limit you in
 
 
 
 
 
 
doing
 
 
 
 
 
 
vigorous
 
 
 
 
 
 
activities,
 
 
 
 
 
 
such as
 
 
 
 
 
 
running,
 
 
 
 
 
 
lifting heavy
 
 
 
 
 
 
objects,
 
 
 
 
 
 
participating
 
 
 
 
 
 
in strenuous
 
 
 
 
 
 
sports?
 
 
 
 
 
 
.......................
 
 
 
 
 
 
.......................
 
 
 
 
 
 
..........
 
 
 
 
 
PFC36r1
Does your 
health now 

5 

4 

3 

2 

1 
 
limit you in
 
 
 
 
 
 
walking more
 
 
 
 
 
 
than a mile
 
 
 
 
 
 
(1.6 km)?
 
 
 
 
 
PFC37
Does your 
health now 

5 

4 

3 

2 

1 
 
limit you in
 
 
 
 
 
 
climbing one
 
 
 
 
 
 
flight of
 
 
 
 
 
 
stairs?
 
 
 
 
 
 
......................
 
 
 
 
 
PFA5
Does your 
health now 

5 

4 

3 

2 

1 
 
limit you in
 
 
 
 
 
 
lifting or
 
 
 
 
 
 
carrying
 
 
 
 
 
 
groceries?
 
 
 
 
 
 
.......................
 
 
 
 
 
 
..........
 
 
 
 
 
PFA3
Does your 
health now 

5 

4 

3 

2 

1 
 
limit you in
 
 
 
 
 
 
bending,
 
 
 
 
 
 
kneeling, or
 
 
 
 
 


Page 61  of 
 
 
 
 
stooping?
................. 
 
 
 
 
 
Without any
difficulty 
With a little difficulty
With some difficulty
With much difficulty
Cannot do
PFA11
Are you able 
to do chores 
such as 
vacuuming or 
yard work? 
....................... 
.... 

5 

4 

3 

2 

1 
PFA16r1
Are you able 
to dress 
yourself, 
including 
tying 
shoelaces and 
buttoning 
your clothes? 
....................... 
....................... 
......... 

5 

4 

3 

2 

1 
PFB26
Are you able 
to shampoo 
your hair? 
.......... 

5 

4 

3 

2 

1 
PFA55
Are you able 
to wash and 
dry your 
body? .. 

5 

4 

3 

2 

1 
PFC45r1
Are you able 
to sit on and 
get up from 
the toilet? 
....................... 
....................... 
............ 

5 

4 

3 

2 

1 


Page 62  of 
 
 
APPENDIX I: Collection of Indirect and Nonmedical Direct Costs (Modified COIN) 
Subject ID: 
 
Date Completed: 
 
 
PRELIMINARY INFORMATION 
1. What was your employment status at the time your cancer was diagnosed? 
o Working full time 
o Working part time 
o Homemaker 
o Disabled 
o Unemployed and seeking work 
o Retired 
o Student 
o Other; specify:  
 
2. What best describes your occupation at the time of your cancer diagnosis? If you were not 
employed, which category best describes your last job? 
o Professional, technical (e.g., teacher, lawyer, physician, engineer) 
o Manager, administrator or proprietor (e.g., manager, real estate agent, postmasters) 
o Clerical and related (e.g., secretary, clerk, mail carrier) 
o Sales occupations (e.g., sales person, demonstrator, agent or broker) 
o Service occupations (police, cook, hairdresser) 
o Skilled crafts, repair work (e.g., carpenter, telephone line worker) 
o Equipment or vehicle operator (e.g., driver, brakeman) 
o Laborer (e.g., helper, longshoreman, warehouse worker) 
o Farmer (owners, managers, operators, tenants) 
o Military 
o Homemaker 
o Not working 
o Other; specify: 
 
3. Which category best describes your gross/before taxes earnings at the time 


Page 63  of 
 
 
Your cancer was diagnosed? (your average income from your job, as opposed to income from 
interest on investments) 
o Less than $10,000 
o $10,000--‐$19,000 
o $20,000--‐$39,000 
o $40,000--‐$59,000 
o $60,000--‐$79,000 
o $80,000--‐$99,000 
o $100,000--‐$150,000 
o Over $150,000 
4. What type of health insurance did you have at the time of your cancer diagnosis? 
o Medicaid 
o Medicare 
o Disability insurance 
o HMO 
o Individual health insurance 
o Group health insurance 
o National health insurance 
o VA/military sponsored 
o No insurance (self pay) 
o No insurance, no means of payment 
5. What is your current employment status? 
o Currently working full time 
o Currently working part time 
o Homemaker 
o Disabled 
o Unemployed and seeking work 
o Retired 
o Student 


Page 64  of 
 
 
o Other; specify:  
 
6. If you are not working, when did you stop?  
/ 
/ 
 
N/A (Not Applicable); presently working 
 
OUT--‐OF--‐POCKET COSTS 
Please indicate the number of times the following services were used OVER THE LAST 
MONTH related to your cancer care, whether it was covered all or in part by your insurance, 
and the out of pocket costs to you (including co--‐payments). 
Service used 
# of times 
Insurance coverage 
Out--‐of--‐pocket costs 
All Part None 
7. Visiting nursing care 
$ 
8. Home health care 
$ 
9. Physical/occupational therapy 
$ 
10. Transportation (for medical purposes only) 
$ 
11. Parking (for medical purposes only) 
$ 
12. Prescriptive medication 
$ 
13. Over--‐the--‐counter medication 
$ 
14. Hospital bills 
$ 
15. Physician bills 
$ 
16. Special food or food supplements 
$ 
17. Supplies (e.g., urinary pads, dressings) 
$ 
18. Equipment (e.g., wheelchair, oxygen) 
$ 
19. Mental health counselors 
$ 
20. Any others? 
o Yes, please specify: 
$ 
1 
 
2 
3 
4 
5 
o No 


Page 65  of 
 
 
APPENDIX J: Economic Hardship 
ID: 
 
Date 
Completed: 
 
Please circle or check one answer that best applies to you. 
 
Financial Strain
Almost 
Never 
Once in a 
While 
Sometimes 
A lot of the time 
(frequently) 
Almost 
Always
In the next three months,
how often do you think 
that you and your family 
will experience bad times 
such as poor housing or 
not having enough food?
1
2
3
4
5
In the next three months, 
how often do you expect 
that you will have to do 
without the basic things 
that your family needs? 
1 
2 
3 
4 
5 
Inability to Make Ends Meet 
A great 
Quite a bit 
Some 
A little 
No 
deal of 
of difficulty 
difficulty 
difficulty 
difficulty 
difficulty 
 
 
 
 at all 
Think back over the past 
1 
2 
3 
4 
5 
3 months and tell us how 
much difficulty you had 
paying your bills. Would 
you say you had... 
More than Some money Just enough Somewhat Very short 
enough 
left 
money left short of of money 
money 
 
 
money 
left 
Think again over the past 3 
1 
2 
3 
4 
5 
months. Generally, at the 
end of each month did you 
end up with... 
Not Enough Money for Necessities 
Please think about how you 
Felt about your family’s 


Page 66  of 
 
 
 
economic situation over thee
past 3 months. Indicate how 
much you would agree or 
disagree with each statement. 
 
 
Strongly 
 
 
Agree
 
 
Neutral/mixed 
 
 
Disagree
 
 
Strongly 
My family had enough money 
agree
1 
2 
3 
4 
disagree
5 
to afford the kind of home
we should have. 
 
 
 
 
 
We had enough money to 
afford the kind of clothing 
ae should have. 
1 
2 
3 
4 
5 
We had enough money to 
afford the kind of furniture 
or household appliances we 
should have. 
1 
2 
3 
4 
5 
We had enough money to 
afford the kind of car we need.
1 
2 
3 
4 
5 
We had enough money to 
1 
2
3 
4 
5 
afford the kind of food we
should have. 
 
 
 
 
 
We had enough money to 
afford the kind of medical 
care we should have. 
1 
2
3 
4 
5 
My family had enough money 
to afford leisure and 
recreational activities. 
1 
2
3 
4 
5 
 
Economic Adjustments/Cutbacks 
In the last 3 months, has your family 
 
 
Yes 
 
 
 
No 
made any of the following adjustments
 
1
2
because of financial need?
 
 
 
Changed food shopping or eating habits 
a lot to save money 
 
 
 
Shut down the heat or air conditioning 
to save money even though it made 
the house uncomfortable 
 
 
 


Page 67  of 
 
 
Didn’t go to see the doctor or 
Dentist when you needed to 
Because you had to save money 
Fell far behind in paying bills 


Page 68  of 
 
 
APPENDIX K: COST (Comprehensive Score for financial Toxicity) Patient –Reported 
Outcome Measure 
 
Not at all
A little bit
Somewhat
Quite a bit Very much
1 I know that I have enough money 
in savings, retirement, or assets 
to cover the costs of my treatment. 
0 
1 
2 
3 
4 
2 My out--‐of--‐pocket medical 
expenses are more than I thought 
they would be. 
0 
1 
2 
3 
4 
3 I worry about the financial problems 
I will have in the future as a result of 
my illness or treatment. 
0 
1 
2 
3 
4 
4 I feel I have no choice about the 
amount of money I spend on care. 
0 
1 
2 
3 
4 
5 I am frustrated that I cannot work 
or contribute as much as I usually do. 
0 
1 
2 
3 
4 
6 I am satisfied with my current 
financial situation. 
0 
1 
2 
3 
4 
7 I am able to meet my monthly 
expenses. 
0 
1 
2 
3 
4 
8 I feel financially stressed. 
0 
1 
2 
3 
4 
9 I am concerned about keeping 
my job and income, including 
work at home. 
0 
1 
2 
3 
4 
10 My cancer or treatment has 
reduced my satisfaction with 
my present financial situation. 
0 
1 
2 
3 
4 
11 I feel in control of my financial 
situation. 
0 
1 
2 
3 
4 
Supplementary Table 3. Final 11--‐item COST measure. Items 1, 6, 7 and 11 should be reversed scored, 
as higher scores indicate higher distress. 
COST - Financial Toxicity scoring template 28th March 2014 
 
Instructions:* 
1. Record answers in "item response" column. If missing, mark with an X 
2. Perform reversals as indicated, and sum individual items to obtain a score. 
3. Multiply the sum of the item scores by the number of items in the scale, then divide by the number of 
items answered. This produces the final score. 
4. The higher the score, the higher the financial toxicity. 
 
Item Code
Reverse code
 
Item response
 
Item Score
1
4
‐
=


Page 69  of 
 
 
 
2
0
+
=
3
0
+
=
4
0
+
=
5
0
+
=
6
4
‐
=
7
4
‐
=
8
0
+
=
9
0
+
=
10
0
+
=
11
4
‐
=
 
 
Sum individual item scores: 
 
Multiple by 11: 
 
Divide by number of items answered: 
= COST score 
 
 
*For guidelines on handling missing data and scoring options, please refer to the Administration and Scoring 
Guidelines in the manual or on--‐line at www.facit.org. 


Page 70  of 
 
 
APPENDIX L: PHARMACOKINETICS SHEET DAY 28 - OLAPARIB 
 
Phase IIA trial of delayed initiation of olaparib maintenance therapy in platinum sensitive recurrent ovarian cancer 
Study Sample Collection Log
 
 
 
 
 
 
 
Subject Initials: 
(First_Middle_Last) 
Subject ID: 
Date: 
BSA: 
(m2) 
Site Name: 
Pharmacokinetic (PK) Sample Collection
 
 
 
 
 
 
At approximately Day 28, right before the patient would otherwise take their dose, ~3-4 mL of peripheral blood will be collected in a purple top tube (e.g. BD vacutainer 
367861 plastic 13 x 75 4 mL tube); Invert tube to mix; centrifuge for 10 min at ~1000 x g; aspirate plasma and place into appropriately-labeled microcentrifuge tubes. After 
processing, store plasma at -70°C or below. At the time of sample transfer, a copy of this completed PK form must be transferred also. 
Note the times administering of oral dose, in this form; speciifcally the time of previous dose, and the time of the dose immediately after the blood draw. 
Olaparib 
Protocol Sample and Time 
Point 
Projected Sample Due Time
(24 hr clock) 
Actual Time 
(24 hr clock) 
Comments 
Day ~28 
Administer the olaparib after taking the blood sample 
 
Olaparib Dose (mg): 
 twice daily 
Time of previous olaparib 
dose 
 
 
commonly the night prior 
pre/trough blood sample 
 
 
 
Time of olaparib dose 
immediately after sample