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10.1.2 secondary endpoints

Secondary objectives include: determining safety and tolerability of olaparib in patients with mesothelioma; estimation of progression free-survival (PFS), identifying biomarkers of response to olaparib, and evaluating serum mesothelin and MPF as biomarkers of anti-tumor efficacy.  
| Objective                      | Endpoints                                                                                                                                                                                                 |                                                                                                                                                                                |
|--------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Assess safety and tolerability | x                                                                                                                                                                                                         | Numbers of DLTs identified by type and grade -  assessed approximately 21 days after enrollment of  last subject.                                                              |
| Assess PFS                     | x                                                                                                                                                                                                         | Kaplan Meier analysis of progression free survival in  all patients combined - assessed approximately 6  months after enrollment of last subject depending on  outcomes noted. |
| x                              | Comparison of responders vs. non-responders with  respect to biomarker baseline level changes over time -  assessed approximately 6 months after enrollment of  last subject depending on outcomes noted. |                                                                                                                                                                                |
| x                              | Preliminary evaluation of mesothelin and MPF with  respect to objective response - assessed approximately 6  months after enrollment of last subject depending on  outcomes noted.                        |                                                                                                                                                                                |
| Investigate                    | potential                                                                                                                                                                                                 | soluble                                                                                                                                                                        |
| mesothelin levels and MPF      |                                                                                                                                                                                                           |                                                                                                                                                                                |  
| Objective   | Endpoints  x Preliminary evaluation of mesothelin and MPF with  respect to progression free survival - assessed  approximately 6 months after enrollment of last  subject depending on outcomes noted.   |
|-------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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10.2 sample size determination

The primary objective of this pilot study is to obtain preliminary estimates of the overall response rates to olaparib in patients with malignant mesothelioma according to their individual comparison group:
x Comparison Group 1 - Patients with a germline mutation in DNA repair genes (estimated at 10-12% of all patients)  
x Comparison Group 2 - Patients with *BAP1* somatic mutations (estimated at 50-60% of all patients)
x Comparison Group 3 - Patients with neither germline DNA repair mutations nor BAP1 somatic mutations (estimated at 30-40% of all patients).
All patients will be enrolled without consideration of their mutation status, and then the results will be retrospectively categorized and evaluated by mutation type. These results will be used to determine if there are any further patients to be enrolled following an amendment taking into consideration the preliminary results obtained. It would be desirable if overall there was at least approximately a 20% response rate. The study will initially plan to enroll 30 evaluable patients in order to estimate the overall response rate with a maximum two-sided 90% confidence interval width of +/- 16%. If the observed response rate were 15-20%, the confidence interval width overall would be approximately +/-10-15%. Thus, 30 patients are adequate for an overall assessment of response. If during the initial 20 patients evaluated, there are 0-1 responses noted, then no further patients will be enrolled as soon as this can be determined since the upper one-sided 90% confidence interval bound on 1/20 is 18.1%, which is below the approximate response rate of interest. Because accrual is proceeding rapidly on the study and continued enrollment is desirable at this time, up to 25 total patients may be enrolled (5 additional patients) while awaiting the response evaluations among the first 20 patients. It is expected that 30 evaluable patients can be enrolled in approximately 12-18 months. As patient non-compliance with study drug dosing will prevent them from being evaluable, the accrual ceiling must be adjusted accordingly. Estimating an average of 3 cycles of study therapy and a noncompliance rate of 10% per cycle the accrual ceiling will be set at 40 patients.  
10.3 **POPULATIONS FOR ANALYSES** 10.3.1 Evaluable for Toxicity All patients will be evaluable for toxicity from the time of their first treatment with olaparib.  
Ph 2 Version Date: *02/24/20* 10.3.2 Evaluable for Objective Response, Progression Free Survival and Soluble Mesothelin Levels and PFS
Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, have taken at least 50% of the doses per given cycle, and have had their disease re-evaluated 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.)
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10.3.3 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, have taken at least 50% of the doses per given cycle, 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.
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10.4 statistical analyses 10.4.1 general

Response rates will be determined in all patients and in the three comparison groups, based on all evaluable patients, and reported along with appropriate confidence intervals. 10.4.2 Analysis of the Primary Endpoints After enrollment, when the mutation determination is possible, the response rates will be assessed according to each of the three categories of mutation and the results reported accordingly. The proportions responding in each category will be presented along with 95% confidence intervals. The results obtained will be used to determine if there are any further patients to be enrolled following an amendment taking into consideration the preliminary results obtained. 10.4.3 Analysis of the Secondary Endpoint(s) The secondary objectives will be assessed using the following measures. Descriptive tabulations of toxicity will be provided. Kaplan-Meier analysis of PFS will be performed, including reporting PFS at relevant time points, along with 95% confidence intervals. Responders vs. non-responders will be compared with respect to serum mesothelin and MPF baseline levels or changes over time (see section 5.1 for biomarkers to be reported), with results compared between response categories using two-tailed Wilcoxon rank sum tests. Serum mesothelin and MPF at baseline will be categorized into two groups of approximately equal size and tested for their association with PFS using Kaplan-Meier curves and two-tailed log-rank tests. Changes in serum mesothelin and MPF will be determined up until the end of treatment, and landmark analyses will be used to assess their association with PFS.
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10.4.4 safety analyses

Safety of the agent will be assessed by reporting the grade of adverse events noted in each patient and reporting the proportion with grade 3 and grade 4 adverse events. Safety data will be presented Ph 2 Version Date: *02/24/20* in individual listings. Summaries will also be prepared. The safety data will consist of the reporting of all adverse events, vital signs, physical examination data, and appropriate laboratory safety data. 10.4.5 Baseline Descriptive Statistics Limited demographic and clinical characteristics of all patients will be reported. 10.4.6 Planned Interim Analyses If during the initial 20 patients evaluated, there are 0-1 responses noted, then no further patients will be enrolled as soon as this can be determined. since the upper one-sided 90% confidence interval bound on 1/20 is 18.1%, which is below the approximate response rate of interest. Because accrual is proceeding rapidly on the study and continued enrollment is desirable at this time, up to 25 total patients may be enrolled (5 additional patients) while awaiting the response evaluations among the first 20 patients. . 10.4.7 Sub-Group Analyses None will be performed. 10.4.8 Tabulation of Individual Participant Data Toxicity data may be reported on a per-patient basis if adequate events are noted, or may be summarized. 10.4.9 Exploratory Analyses No exploratory analyses are planned.
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11 collaborative agreements 11.1 collaborative

The study agent, olaparib, will be provided under a CRADA (\# 02299) between NCI and the manufacturer, AstraZeneca.
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11.2 intramural material transfer agreement

Rather than amending the above mentioned CRADA to include the current study, an internal MTA (\#43420-27) was executed to make the study agent supplied under the CRADA available for the current study.
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11.3 quality agreement

As a supplement to address items required by the sponsor that were not addressed in the CRADA or the MTA, a quality agreement was executed between the Raffit Hassan, M.D. and AstraZeneca to establish the obligations and the responsibilities of each party relating to the quality assurance requirements of the manufacture, analysis, packing and/or release by AstraZeneca of products and the supply to the investigator.
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12 human subjects protections 12.1

This study will be open to all individuals with malignant mesothelioma regardless of gender, ethnicity, or race provided that the aforementioned inclusion and exclusion criteria are met. The selection criteria reflect all available nonclinical and clinical safety experience with olaparib. Further, the selection criteria address the potential pharmacokinetics issues that may confound the reliable assessment of the study objective related to the pharmacokinetic drug-drug interaction. The treatment of men as well as women is justified because of the severity of the underlying neoplastic disease. Men and women who use appropriate contraception or women who are not of child-bearing potential will be enrolled into this study. The proportion of men and women enrolled into the dose-escalation cohorts of this study depends only on the availability of subjects at the NIH Clinical Center.
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12.2 participation of children

Children will not participate in this study for the reasons indicated in the eligibility criteria.
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12.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (section 12.4.4), all subjects will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment of whether an individual has the capacity to provide consent; assistance in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint a surrogate. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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12.4 evaluation of benefits and

Potential risks of the study include the possible occurrence of any of a range of side effects as listed in section 13.1.3 and the consent document. The procedure for protecting against or minimizing risks will be to medically evaluate patients on a regular basis, provide premedications and supportive therapies as described earlier. 12.4.1.2 Research Blood Collection Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 12.4.2 Image Guided Biopsy Collection The risks of the research biopsy collected at baseline include pain, bleeding and infection at the biopsy site. In addition, as the biopsy may be collected under CT guidance, subjects in this study may be exposed to approximately 0.80 rem. This amount is below the guideline of 5 rem per year allowed for adult research subjects by the NIH Radiation Safety Committee. 12.4.3 Non-Physical Risks of Genetic Research These risks are noted in the consent document. 12.4.4 Benefits The potential benefit to a patient (including those who have lost the capacity to consent) participating in the study is a reduction in the bulk of his/her tumor, which may or may not have a favorable impact on symptoms and/or survival.
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12.5 risk benefit assessment

Patients with advanced and/or metastatic mesothelioma, are in continuous need of improved therapy options. This is especially true for patients who have progressed on standard therapy such as the patient population that will be eligible for this trial. Pre-clinical and clinical data (see sections 1.2.2 and 1.2.3) suggest that olaparib may improve outcomes in patients with mesothelioma, particularly in those with mismatch repair defects. A number of clinically appropriate strategies to minimize risk to patients have been built into the protocol through the means of inclusion/exclusion criteria, monitoring strategies, and management guidelines. Overall, the potential benefits of olaparib for mesothelioma patients retaining the ability to consent and those who lose capacity to consent during the course of the trial outweigh the risks associated with the proposed entry-into-human trial with olaparib.
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12.6 consent process and documentation

The procedures and tests involved in this study and the associated risks, discomforts and benefits of these processes including the disclosure of genetic results (see section 5.3.1), will be carefully explained to the patient, and a signed informed consent document will be obtained prior to entry onto the study. 12.6.1 Telephone Re-consent Reconsent by telephone is permitted on this study. Telephone consent will be obtained per OHSRP/IRBO and CCR policies and procedures..
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13 pharmaceutical information

There will be no IND obtained for the use of the commercial agent (olaparib) used in this study. This study meets the criteria for exemption for an IND as this investigation is not intended to support a new indication for use or any other significant change to the labeling; the drug is already approved and marketed and the investigation is not intended to support a significant change in advertising; and the investigation does not involve a route of administration or dosage level in use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.
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13.1 olaparib) 13.1.1 source

The olaparib tablets used in this study will be supplied under a collaborative agreement with the manufacturer, AstraZeneca.
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13.1.2 mode of action

Olaparib is an inhibitor of subclasses 1, 2, and 3 of polyadenosine 5' diphosphoribose polymerase (PARP-1, PARP-2, and PARP-3). In tumors that are deficient in the homologous recombination DNA repair pathway (example, BRCA mutants), inhibition of PARP by olaparib causes accumulation of DNA double-strand breaks and genomic instability. Olaparib may also enhance the effects of DNA damage caused by ionizing radiation and chemotherapy.
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13.1.3 toxicity 13.1.3.1 serious adverse

A review of the AstraZeneca Patient Safety database (which includes AstraZeneca-sponsored, investigator-sponsored/collaborative group monotherapy studies and Managed Access Program reports) as of 15 June 2016 identified a total of 1413 SAEs (1093 unblinded, 320 blinded) received IURPSDWLHQWVLQRODSDULEPRQRWKHUDS\VWXGLHV6$(UHSRUWVRISDWLHQWVWUHDWHGZLWK olaparib/placebo monotherapy) were anemia (n=143), abdominal pain (n=40), vomiting (n=47), nausea (n=42) and dyspnea (n=41). The most commonly reported SAEs from these monotherapy studies were similar for the tablet and capsule formulation. 13.1.3.2 Frequent Adverse Events
- Most common adverse reactions and laboratory abnormalities in clinical trials were anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash, abdominal pain/discomfort, increase in creatinine, mean corpuscular volume elevation, decrease in hemoglobin, decrease in lymphocytes, decrease in absolute neutrophil count, and decrease in platelets.  
- The following adverse reactions and laboratory abnormalitLHVKDYHEHHQLGHQWLILHGLQWR
<20% of the 223 patients receiving olaparib: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash.  
- The following adverse reactions and laboratory abQRUPDOLWLHV KDYH EHHQLGHQWLILHGLQWR
<10% of the 223 patients receiving olaparib and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/ eczema, pruritus, hypertension, venous thrombosis (including pulmonary embolism), and hot flush.  
13.1.3.3 Warnings and Precautions
- Myelodysplastic syndrome/Acute Myeloid Leukemia: (MDS/AML) occurred in patients exposed to olaparib, and some cases were fatal. Monitor patients for hematological toxicity at baseline and monthly thereafter. Discontinue if MDS/AML is confirmed.  
- Pneumonitis: occurred in patients exposed to olaparib, and some cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed.  
Ph 2 Version Date: *02/24/20*
- Embryo-Fetal toxicity: olaparib can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to avoid pregnancy.  
13.1.4 Formulation and preparation Olaparib tablets are supplied as green, film-coated tablets in 100 mg and 150 mg strengths. The 100 mg strength is also available as a yellow, film-coated tablet.  
x 100 mg tablets are 14.5 mm x 7.25 mm oval-shaped x 150 mg are 14.5 mm x 7.25 mm oval-shaped
Olaparib tablets will be packed in high-density polyethylene (HDPE) bottles with child-resistant closures. Each dosing container will contain 32 tablets. Olaparib sufficient for 1 21-day cycle + 3 additional days in case of vomiting will be dispensed to patients on Day 1 at the beginning of each subsequent cycle until the patient completes the study, withdraws from the study or closure of the study. Tablet core components include active drug substance, copovidone, colloidal silicon dioxide, mannitol and sodium stearyl fumarate. Film coating contains hydroxypropyl methylcellulose (hypromellose), macrogol 400 (polyethylene glycol 400), titanium dioxide, iron oxide yellow and iron oxide black. The yellow tablet film coating only differs from the green film coating with the omission of iron oxide black.
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13.1.5 stability and storage

All study drugs should be kept in a secure place under appropriate storage conditions. Store in a secure location below 30° C (86° F). Sites are not permitted to re-package tablets. Once the bottle is opened, olaparib tablets must be used within 3 months of the opening date; unused tablets should be discarded. Instruct patients not to open a bottle until they are ready to use it. 13.1.6 Administration Procedures Please refer to section 3.2. 13.1.7 Incompatibilities CYP3A Inhibitors: Avoid concomitant use of strong and moderate CYP3A inhibitors. If the inhibitor cannot be avoided, the dose may be reduced as allowed by protocol. CYP3A Inducers: Avoid concomitant use of strong and moderate CYP3A inducers. If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy.
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13.2 clinomics platform (nsr device)

The platform was developed in house by the Center for Cancer Research and is available for use by investigators at the NCI. Testing will be performed in the NCI Laboratory of Pathology (CLIA\#21D0716664) and/or ClinOmics (CLIA\# 21D2125203)
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13.2.2 toxicity

None. However, participants may experience non-physical risks of genetic research as described in section 12.4.3.
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14 references

1. Robinson BW, Lake RA: **Advances in malignant mesothelioma**. *N Engl J Med* 2005, 353(15):1591-1603.  
2. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C *et al*: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. *Journal of clinical oncology : official journal of the American Society of* Clinical Oncology 2003, 21(14):2636-2644.  
3. Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, Cox NJ, Dogan AU, Pass HI,
Trusa S *et al*: **Germline BAP1 mutations predispose to malignant mesothelioma**. *Nat* Genet 2011, 43(10):1022-1025.  
4. Bott M, Brevet M, Taylor BS, Shimizu S, Ito T, Wang L, Creaney J, Lake RA, Zakowski MF, Reva B *et al*: **The nuclear deubiquitinase BAP1 is commonly inactivated by** somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. *Nat Genet* 2011, 43(7):668-672.  
5. Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, Douglas-Jones A,
Smith GC, Martin NM, O'Connor M *et al*: Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin. *Cancer Res* 2009, 69(9):38503855.  
6. Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA,
Derksen PW, de Bruin M, Zevenhoven J, Lau A *et al*: **High sensitivity of BRCA1-** GHILFLHQWPDPPDU\WXPRUVWRWKH3$53LQKLELWRU$='DORQHDQGLQ combination with platinum drugs. *Proc Natl Acad Sci U S A* 2008, 105(44):1707917084.  
7. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ *et al*: **Inhibition of poly(ADP-ribose) polymerase in tumors** from BRCA mutation carriers. *N Engl J Med* 2009, 361(2):123-134.  
8. Helleday T: **The underlying mechanism for the PARP and BRCA synthetic lethality:**
clearing up the misunderstandings. *Mol Oncol* 2011, 5(4):387-393.  
9. Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S,
Pommier Y: **Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors**. *Cancer* Res 2012, 72(21):5588-5599.  
10. Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, Hirte H,
Huntsman D, Clemons M, Gilks B *et al*: Olaparib in patients with recurrent highgrade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. *Lancet Oncol* 2011, 12(9):852-861.  
Ph 2 Version Date: *02/24/20* 11. Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A *et al*: **Olaparib for Metastatic Breast Cancer in Patients with a** Germline BRCA Mutation. *N Engl J Med* 2017, 377(6):523-533.  
12. Oza AM, Cibula D, Benzaquen AO, Poole C, Mathijssen RH, Sonke GS, Colombo N,
Spacek J, Vuylsteke P, Hirte H *et al*: **Olaparib combined with chemotherapy for** recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol 2015, 16(1):87-97.  
13. Lee JM, Hays JL, Annunziata CM, Noonan AM, Minasian L, Zujewski JA, Yu M,
Gordon N, Ji J, Sissung TM *et al*: **Phase I/Ib study of olaparib and carboplatin in** BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. *J Natl Cancer Inst* 2014, 106(6):dju089.  
14. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M,
Dillon KJ, Hickson I, Knights C *et al*: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. *Nature* 2005, 434(7035):917-921.  
15. McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S, Giavara S, O'Connor MJ, Tutt AN, Zdzienicka MZ *et al*: **Deficiency in the repair of DNA damage by** homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. *Cancer Res* 2006, 66(16):8109-8115.  
16. Menear KA, Adcock C, Alonso FC, Blackburn K, Copsey L, Drzewiecki J, Fundo A, Le Gall A, Gomez S, Javaid H *et al*: **Novel alkoxybenzamide inhibitors of poly(ADPribose) polymerase**. *Bioorg Med Chem Lett* 2008, (14):3942-3945.  
17. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J,
Arbuck S, Gwyther S, Mooney M *et al*: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). *European journal of cancer* 2009, 45(2):228-247.  
18. Byrne MJ, Nowak AK: **Modified RECIST criteria for assessment of response in**
malignant pleural mesothelioma. *Annals of oncology : official journal of the European* Society for Medical Oncology / ESMO 2004, 15(2):257-260.  
19. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA,
Higano C, Bubley GJ, Dreicer R *et al*: Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008, 26(7):1148-1159.  
20. Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, Eisenhauer E, Sagae S, Greven K, Vergote I *et al*: Re: New guidelines to evaluate the response to treatment in solid tumors (ovarian cancer). *Journal of the National Cancer Institute* 2004, 96(6):487-488.  
21. Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD,
Freidlin B, Halabi S, Hudes G *et al*: Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1999, 17(11):3461-3467.  
22. Vergote I, Rustin GJ, Eisenhauer EA, Kristensen GB, Pujade-Lauraine E, Parmar MK,
Friedlander M, Jakobsen A, Vermorken JB: Re: new guidelines to evaluate the response to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer Intergroup. *Journal of the National Cancer Institute* 2000, 92(18):1534-1535.
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15 appendices

| 15.1                                                                                                                                                            | APPENDIX A - PERFORMANCE STATUS CRITERIA                                |                                                                    |                 |           |             |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------|--------------------------------------------------------------------|-----------------|-----------|-------------|
| ECOG Performance Status Scale                                                                                                                                   | Karnofsky Performance Scale                                             |                                                                    |                 |           |             |
| Grade                                                                                                                                                           | Descriptions                                                            | Percent                                                            | Description     |           |             |
| 100                                                                                                                                                             | Normal,                                                                 | no                                                                 | complaints,     | no        |             |
| evidence of disease.                                                                                                                                            |                                                                         |                                                                    |                 |           |             |
| Normal activity. Fully active, able                                                                                                                             |                                                                         |                                                                    |                 |           |             |
| 0                                                                                                                                                               | to                                                                      | carry                                                              | on              | all       | pre-disease |
| performance without restriction.                                                                                                                                | Able to carry on normal activity;                                       |                                                                    |                 |           |             |
| 90                                                                                                                                                              | minor                                                                   | signs                                                              | or              | symptoms  | of          |
| disease.                                                                                                                                                        |                                                                         |                                                                    |                 |           |             |
| Symptoms,                                                                                                                                                       | but                                                                     | ambulatory.                                                        |                 |           |             |
| Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work). | 80                                                                      | Normal activity with effort; some  signs or symptoms of disease.   |                 |           |             |
| 1                                                                                                                                                               | Cares for self, unable to carry on                                      |                                                                    |                 |           |             |
| 70                                                                                                                                                              | normal activity or to do active  work.  Requires occasional assistance, |                                                                    |                 |           |             |
| 60                                                                                                                                                              | but is able to care for most of  his/her needs.                         |                                                                    |                 |           |             |
| 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.                            |                                                                         |                                                                    |                 |           |             |
| 2                                                                                                                                                               | 50                                                                      | Requires considerable assistance  and frequent medical care.       |                 |           |             |
| 40                                                                                                                                                              | Disabled, requires special care  and assistance.                        |                                                                    |                 |           |             |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                          |                                                                         |                                                                    |                 |           |             |
| 3                                                                                                                                                               | 30                                                                      | Severely disabled, hospitalization  indicated. Death not imminent. |                 |           |             |
| 20                                                                                                                                                              | Very                                                                    | sick,                                                              | hospitalization |           |             |
| indicated. Death not imminent.                                                                                                                                  |                                                                         |                                                                    |                 |           |             |
| 100%                                                                                                                                                            | bedridden.                                                              | Completely                                                         |                 |           |             |
| disabled. Cannot carry on any selfcare. Totally confined to bed or  chair.                                                                                                                                                                 |                                                                         |                                                                    |                 |           |             |
| 4                                                                                                                                                               | 10                                                                      | Moribund,                                                          | fatal           | processes |             |
| progressing rapidly.                                                                                                                                            |                                                                         |                                                                    |                 |           |             |
| 5                                                                                                                                                               | Dead.                                                                   | 0                                                                  | Dead.           |           |             |  
Ph 2 Version Date: *02/24/20* 15.2 APPENDIX B **-COCKCROFT-GAULT FORMULA**
Creatine Clearance (mL/min) = (140 - age) x weight in kg (x 0.85 for females)
(serum creatinine [mg/dL] x 72)
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instructions to the patient

1. Complete one form for each cycle (21 days). 2. You will take ___ olaparib tablets twice a day ~**12 hours apart** on every day of the cycle. You must take the tablets with a large glass of water. A light snack (biscuits/ toast) is also recommended to help reduce nausea.  
3. The olaparib tablets should be swallowed whole and not chewed, crushed, dissolved or divided. 4. You should avoid drinking grapefruit juice while on study. 5. If you miss a scheduled dose, you may take the scheduled dose up to 2 hours after the scheduled dose time.  
If it is more than 2 hours after the scheduled dose time, do not take the missed dose. You should then take the next dose at the scheduled time.  
6. If you miss more than half of the doses (21 tablets) in any cycle, we will have to remove you from the study. 7. Record the date, the number of tablets you took, and when you took them.  
8. If you have any comments or notice any side effects, please record them in the Comments column. 9. Please bring your pill bottle and this form to your physician when you go for your next appointment.  
| DAY   | DATE                     | # Tablets and When Taken   | COMMENTS (side effects or missed doses)   |
|-------|--------------------------|----------------------------|-------------------------------------------|
| 1     | _________AM  _________PM |                            |                                           |
| 2     | _________AM  _________PM |                            |                                           |
| 3     | _________AM  _________PM |                            |                                           |
| 4     | _________AM  _________PM |                            |                                           |
| 5     | _________AM  _________PM |                            |                                           |
| 6     | _________AM  _________PM |                            |                                           |  
| Version Date: 02/24/20  DAY DATE   | # Tablets and When Taken   | COMMENTS (side effects or missed doses)   |
|------------------------------------|----------------------------|-------------------------------------------|
| 7                                  | _________AM  _________PM   |                                           |
| 8                                  | _________AM  _________PM   |                                           |
| 9                                  | _________AM  _________PM   |                                           |
| 10                                 | _________AM  _________PM   |                                           |
| 11                                 | _________AM  _________PM   |                                           |
| 12                                 | _________AM  _________PM   |                                           |
| 13                                 | _________AM  _________PM   |                                           |
| 14                                 | _________AM  _________PM   |                                           |
| 15                                 | _________AM  _________PM   |                                           |
| 16                                 | _________AM  _________PM   |                                           |
| 17                                 | _________AM  _________PM   |                                           |
| 18                                 | _________AM  _________PM   |                                           |
| 19                                 | _________AM  _________PM   |                                           |  
65 Ph 2 Version Date: *02/24/20*  
| DAY   | DATE                     | # Tablets and When Taken   | COMMENTS (side effects or missed doses)   |
|-------|--------------------------|----------------------------|-------------------------------------------|
| 20    | _________AM  _________PM |                            |                                           |
| 21    | _________AM  _________PM |                            |                                           |  
Patient's Signature: ________________________________________ Date: _________________________
The Study Team will complete this section:
1. Date patient started protocol treatment______________
2. Date patient was removed from study therapy _____________
3. Total number of pills taken this cycle (Days 1-21)___________
Physician/Nurse Signature ____________________________________________________________________
Ph 2 Version Date: *02/24/20*
untitled h1
15.4 appendix d - actions

This Appendix describes the process to be followed in order to identify and appropriately report cases of Hy's Law. It is not intended to be a comprehensive guide to the management of elevated liver biochemistries. During the course of the study the Investigator will remain vigilant for increases in liver biochemistry. The investigator is responsible for determining whether a patient meets potential Hy's Law (PHL) criteria at any point during the study. The Investigator participates in review and assessment of cases meeting PHL criteria to agree whether Hy's Law (HL) criteria are met. HL criteria are met if there is no alternative explanation for the elevations in liver biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational Medicinal Product (IMP). The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review and assessment in line with standard safety reporting processes.
untitled h1
15.4.2 definitions

15.4.2.1 Potential Hy's Law (PHL) $VSDUWDWH$PLQRWUDQVIHUDVH$67RU$ODQLQH$PLQRWUDQVIHUDVH$/7[8SSHU/LPLWRI Normal (ULN) **together with** 7RWDO%LOLUXELQ7%/[8/1DWDQ\SRLQWGXULQJWKHVWXG\ following the start of study medication irrespective of an increase in Alkaline Phosphatase (ALP).
untitled h1
15.4.2.2 hy's law (hl)

$67RU$/7[ULN together **with** 7%/[8/1ZKHUHQRRWKHUUHDVRn, other than the IMP, can be found to explain the combination of increases, e.g., elevated ALP indicating cholestasis, viral hepatitis, another drug. For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the same day) the elevation in TBL, but there is no specified timeframe within which the elevations in transaminases and TBL must occur. 15.4.3 Identification of Potential Hy's Law Cases In order to identify cases of PHL it is important to perform a comprehensive review of laboratory data for any patient who meets any of the following identification criteria in isolation or in combination:
x $/7[8/1 x $67[8/1 x 7%/[8/1 The Investigator will without delay review each new laboratory report and if the identification criteria are met will:
x Determine whether the patient meets PHL criteria (see Definitions within this Appendix for definition) by reviewing laboratory reports from all previous visits x Promptly enter the laboratory data into the laboratory CRF
15.4.4 Follow-up 15.4.4.1 Potential Hy's Law Criteria not met If the patient does not meet PHL criteria the Investigator will:
x Perform follow-up on subsequent laboratory results according to the guidance provided in the Clinical Study Protocol.  
15.4.4.2 Potential Hy's Law Criteria met If the patient does meet PHL criteria the Investigator will:
x Monitor the patient until liver biochemistry parameters and appropriate clinical symptoms and signs return to normal or baseline levels, or as long as medically indicated x Investigate the etiology of the event and perform diagnostic investigations. x Complete the three Liver CRF Modules as information becomes available x If at any time the PHL case meets serious criteria, report it as an SAE using standard reporting procedures 15.4.4.3 Review and Assessment of Potential Hy's Law Cases The instructions in this Section should be followed for all cases where PHL criteria are met. No later than 3 weeks after the biochemistry abnormality was initially detected, the Investigator will follow the instructions below. If there is an alternative explanation for the ALT or AST and TBL elevations, a determination of whether the alternative explanation is an AE will be made and subsequently whether the AE meets the criteria for a SAE:
x If the alternative explanation is not an AE, record the alternative explanation on the appropriate CRF
x If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly and follow the AZ standard processes If there is no explanation that would explain the ALT or AST and TBL elevations other than the IMP:
x Report an SAE (report term 'Hy's Law') according to AstraZeneca standard processes.  
The 'Medically Important' serious criterion should be used if no other serious criteria apply
Ph 2 Version Date: *02/24/20* As there is no alternative explanation for the HL case, a causality assessment of
'related' should be assigned.  
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to assess whether or not the case meets the criteria for HL, then it is assumed that there is no alternative explanation until such time as an informed decision can be made:
x Report an SAE (report term 'Potential Hy's Law') applying serious criteria and causality assessment as per above x Continue follow-up and review according to agreed plan. Once the necessary supplementary information is obtained, repeat the review and assessment to determine whether HL criteria are met. Update the SAE report according to the outcome of the review 15.4.5 Actions Required for Repeat Episodes of Potential Hy's Law This section is applicable when a patient meets PHL criteria on study treatment and has already met PHL criteria at a previous on study treatment visit. The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL is based on the nature of the alternative cause identified for the previous occurrence. The investigator should determine the cause for the previous occurrence of PHL criteria being met and answer the following question:
x Was the alternative cause for the previous occurrence of PHL criteria being met found to be the disease under study e.g. chronic or progressing malignant disease, severe infection or liver disease?  
If No: follow the process described in Potential Hy's Law Criteria met of this Appendix If Yes:
Determine if there has been a significant change in the patient's condition\# compared with when PHL criteria were previously met x If there is no significant change no action is required x If there is a significant change, follow the process described in Section 15.4.4.2 of this Appendix
\# A 'significant' change in the patient's condition refers to a clinically relevant change in any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in combination, or a clinically relevant change in associated symptoms. The determination of whether there has been a significant change will be at the discretion of the Investigator; this may be in consultation with the Study Physician if there is any uncertainty.