pd-l1 inhibition as checkpoint immunotherapy
10 quality control and quality

This clinical research study will be monitored both internally by the PI and institutionally by the Duke Cancer Institute (DCI). In terms of internal review the PI will continuously monitor and tabulate adverse events. Appropriate reporting to the Duke University Medical Center IRB will be made. If an unexpected frequency of Grade III or IV events occur, depending on their nature, action appropriate to the nature and frequency of these adverse events will be taken. This may require a protocol amendment, dose de-escalation, or potentially closure of the study. The PI of this study will also continuously monitor the conduct, data, and safety of this study to ensure that:
- Interim analyses occur as scheduled; - Stopping rules for toxicity and/or response are met; - Risk/benefit ratio is not altered to the detriment of the subjects;
- Appropriate internal monitoring of AEs and outcomes is done;
- Over-accrual does not occur;
- Under-accrual is addressed with appropriate amendments or actions;
- Data are being appropriately collected in a reasonably timely manner.  
DCI review and monitoring of this protocol occurs in accordance with the NCI-approved Data and Safety Monitoring Plan. Briefly, protocol review begins with an initial review by the Cancer Protocol Committee
(CPC), which assesses the ethics and safety of the protocol. Documentation of these assessments will be maintained. Formal, independent monitoring will be conducted by the DCI Monitoring Team after the first 3 subjects are enrolled, followed by annual monitoring of 1-3 subjects until the study is closed to enrollment and subjects are no longer receiving study interventions that are more than minimal risk. DCI Monitoring Team reports and additional data/safety/toxicity reports submitted by the PI will be reviewed by the Safety Oversight Committee (SOC) on an annual basis. Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of serious and/or unexpected toxicities, or other concerns. Monitoring visits may also be initiated upon request by DUHS and DCI Leadership, CPC, SOC, the Duke Office of Audit, Risk and Compliance, a sponsor, an investigator, or the IRB. All study documents must be made available upon request to the DCI Monitoring Team and other authorized regulatory authorities, including but not limited to the National Institute of Health, National Cancer Institute, and the FDA. Every reasonable effort will be made to maintain confidentiality during study monitoring.
pd-l1 inhibition as checkpoint immunotherapy
10.2 data management and processing

Study documentation includes but is not limited to source documents, case report forms, monitoring logs, appointment schedules, study team correspondence with sponsors or regulatory bodies/committees, and regulatory documents that can be found in the DCI-mandated "Regulatory Binder", which includes but is not limited to signed protocol and amendments, approved and signed informed consent forms, FDA Form 1572, CAP and CLIA laboratory certifications, and clinical supplies receipts and distribution records. Source documents are original records that contain source data, which is all information in original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source documents include but are not limited to hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial. When possible, the original record should be retained as the source document. However, a photocopy is acceptable provided that it is a clear, legible, and an exact duplication of the original document.
pd-l1 inhibition as checkpoint immunotherapy
10.2.2 case report forms (crfs)

The electronic CRF will be the primary data collection document for the study. The CRFs will be updated in a timely manner following acquisition of new source data. Only the key personnel delegated on the delegation of authority log are permitted to make entries, changes, or corrections in the CRF. An audit trail will be maintained automatically by the electronic CRF management system. All users of this system will complete user training, as required or appropriate per regulations.
pd-l1 inhibition as checkpoint immunotherapy
10.2.3 data management procedures and

Users of the electronic CRF will have access based on their specific roles in the protocol. Completeness of entered data will be checked automatically by the eCRF system, and users will be alerted to the presence of data inconsistencies. Additionally, the data manager and project manager will cross-reference the data to verify accuracy. Missing or implausible data will be highlighted for the PI requiring appropriate responses (i.e. confirmation of data, correction of data, completion or confirmation that data is not available, etc.). The database will be reviewed and discussed prior to database closure, and will be closed only after resolution of all remaining queries. An audit trail will be kept of all subsequent changes to the data.
pd-l1 inhibition as checkpoint immunotherapy
10.2.4 study closure

Following completion of the studies, the PI will be responsible for ensuring the following activities:
- Data clarification and/or resolution
- Accounting, reconciliation, and destruction/return of used and unused study drugs - Review of site study records for completeness
- Shipment of all remaining laboratory samples to the designated laboratories
pd-l1 inhibition as checkpoint immunotherapy
11 statistical methods and data

All statistical analysis will be performed under the direction of the statistician designated in key personnel. Any data analysis carried out independently by the investigator must be approved by the statistician before publication or presentation.
pd-l1 inhibition as checkpoint immunotherapy
11.1 sample size estimation

This study will use the optimal two-stage design of Simon to test a hypothesis about response rate in subjects with NEPC treated with avelumab. Response will be defined as a complete (CR) or partial response (PR). Assuming that the response rate among subjects treated is 5%, the trial is designed to have 88% power with a one-sided type I error rate=5% to reject the null hypothesis of response rate of 5% when the true response rate was 20%. In the first stage, 18 subjects will be enrolled and if one or fewer responses are observed the trial will be terminated. However, if two or more responses are observed, an additional 26 subjects will be enrolled at the second stage for a total of 44 subjects. If five or more subjects respond, this new agent would be declared to have promising activity. This design has 88% power to conclude an agent is promising if its true objective response proportion is 20%; Type 1 error rate (one-sided) is 0.05 (this is the probability to conclude that a given agent is promising if its true objective response proportion is 5%).The probability of early termination under the null hypothesis is 0.77. These operating characteristics were selected to represent a reasonable compromise between high power, low false positive rates, and desire for small sample sizes, especially in the first stage. Allowing for 10% unevaluable rate, the target sample size is 49 subjects.
pd-l1 inhibition as checkpoint immunotherapy
11.2 analysis sets

This is a non-blinded single arm-arm phase II study of approximately 49 subjects, to assess the safety and efficacy of avelumab in patients with mCRPC
pd-l1 inhibition as checkpoint immunotherapy
11.3 patient demographics and other

Eligible men will have metastatic CRPC with NEPC phenotype with measureable disease at baseline.
pd-l1 inhibition as checkpoint immunotherapy
11.4 treatments

Avelumab with ADT (unless pure SCPC present) will start on cycle 1 day 1 and continue every 2 weeks until progression or unacceptable toxicity.
pd-l1 inhibition as checkpoint immunotherapy
11.5 primary objective

To estimate the overall response rate of men with NEPC treated with avelumab as determined by modified PCWG3 using iRECIST radiographic response.
pd-l1 inhibition as checkpoint immunotherapy
11.5.1 variable

Overall response rate (ORR) which is defined as either complete response (CR) or partial response
(PR).
pd-l1 inhibition as checkpoint immunotherapy
11.5.2 statistical hypothesis model method

The null hypothesis is that the ORR is less than 5%. The trial is designed to have 88% power with a one-sided type I error rate=5% to reject the null hypothesis when the true response rate was 20%.  
The objective response rate will be estimated with a standard error no greater than 10.7 percentage points.
pd-l1 inhibition as checkpoint immunotherapy
11.5.3 handling of missing values

Ineligible subjects and subjects who cancel registration before receiving any therapy will not be included in the analyses. We will follow each patient long enough to avoid censoring due to end of study. The binomial test assumes that other censoring than due to end of study is rare. The study results are just important reference and more studies are necessary for medical decision making.
pd-l1 inhibition as checkpoint immunotherapy
11.6 secondary objectives

1. To describe the efficacy of PD-L1 inhibition with avelumab as measured by PCWG3 using RECIST1.1 2. To describe the radiographic progression free survival (rPFS) of PD-L1 inhibition with avelumab using immune modified and PCWG3-modified RECIST 1.1 criteria in this setting.  
3. To describe the overall survival of PD-L1 inhibition in this setting.  
4. To described the toxicities and safety of PD-L1 inhibition with avelumab in men with metastatic neuroendocrine-like prostate cancer.
pd-l1 inhibition as checkpoint immunotherapy
11.6.1 key secondary objectives -

The Kaplan-Meier method will be used to estimate both forms of progression-free survival as well as the overall survival distributions. Summary statistic will be computed for the duration of time on treatment distribution. The correlative science analyses will be considered exploratory and interpreted as such and reported using descriptive statistics and associations with clinical outcomes including response (radiographic) and progression free and overall survival.
pd-l1 inhibition as checkpoint immunotherapy
11.6.2 other secondary objectives -

In addition, descriptive statistics will be calculated for secondary endpoints of safety profile and quality-of-life (QOL) endpoints, the continuous safety and QOL endpoints will be summarized as the 60 of 71 CONFIDENTIAL
patient counts, mean, standard deviation, median, 25thand 75th percentiles, minimum and maximum. The categorical safety and QOL endpoints will be categorized using frequencies and percentages.
pd-l1 inhibition as checkpoint immunotherapy
11.7 exploratory objectives

1. To describe the impact of PD-L1 inhibition with avelumab on blood-based biomarker changes over time, including PSA, chromogranin-A, cell free DNA, LDH, and alkaline phosphatase.  
2. To determine if levels of circulating biomarkers secreted by neuroendocrine-like prostate cancers correlate with clinical and radiographic treatment response 3. To determine if the presence of different immunohistochemical markers on the pre-biopsy specimens prognosticates clinical and radiographic treatment response 4. To determine if the level of different circulating immune cells correlate with both progressive addition of immunotherapy as well as clinical and radiographic treatment response or disease progression 5. To determine if levels of cell free DNA correlate with clinical and radiographic treatment response 6. To isolate prostate neuroendocrine-like CTCs for ex vivo growth and culture and characterization studies.
pd-l1 inhibition as checkpoint immunotherapy
11.9 accrual and follow-up

The target sample size is 18 subjects in stage 1, and 49 subjects overall if stage 1 is successful. Accrual is expected to be completed within 12-18 months after study activation for each stage. Stage 2 would require expansion to additional sites (2-3 additional sites) for accrual. All subjects will be followed for disease progression and mortality from the date that the subjects were enrolled to the protocol.
pd-l1 inhibition as checkpoint immunotherapy
12 administrative and ethical consideration

This protocol was designed and will be conducted and reported in accordance with the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the Declaration of Helsinki, and applicable federal, state, and local regulations.
pd-l1 inhibition as checkpoint immunotherapy
12.2 duhs institutional review board

The protocol, informed consent form, advertising material, and additional protocol-related documents must be submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol Committee (CPC) for review. The study may be initiated only after the Principal Investigator has received written and dated approval from the CPC and IRB. The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol amendments and changes to the informed consent form. The CPC should be informed about any protocol amendments that potentially affect research design or data analysis (i.e. amendments affecting subject population, inclusion/exclusion criteria, agent administration, statistical analysis, etc.). The Principal Investigator must obtain protocol re-approval from the IRB within 1 year of the most recent IRB approval. The Principal Investigator must also obtain protocol re-approval from the CPC within 1 year of the most recent IRB approval, for as long as the protocol remains open to subject enrollment.
pd-l1 inhibition as checkpoint immunotherapy
12.3 informed consent

The informed consent form must be written in a manner that is understandable to the subject population. Prior to its use, the informed consent form must be approved by the IRB. The Principal Investigator or authorized key personnel will discuss with the potential subject the purpose of the research, methods, potential risks and benefits, subject concerns, and other studyrelated matters. This discussion will occur in a location that ensures subject privacy and in a manner that minimizes the possibility of coercion. Appropriate accommodations will be made available for potential subjects who cannot read or understand English or are visually impaired. Potential subjects will have the opportunity to contact the Principal investigator or authorized key personnel with questions, and will be given as much time as needed to make an informed decision about participation in the study.  
Before conducting any study-specific procedures, the Principal Investigator or designee must obtain written informed consent from the subject or a legally acceptable representative. The original informed consent form will be stored with the subject's study records, and a copy of the informed consent form will be provided to the subject.
pd-l1 inhibition as checkpoint immunotherapy
12.4 study documentation

Study documentation includes but is not limited to source documents, case report forms (CRFs), monitoring logs, appointment schedules, study team correspondence with sponsors or regulatory bodies/committees, and regulatory documents that can be found in the DCI-mandated "Regulatory Binder", which includes but is not limited to signed protocol and amendments, approved and signed informed consent forms, FDA Form 1572, CAP and CLIA laboratory certifications, and clinical supplies receipts and distribution records. Source documents are original records that contain source data, which is all information in original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source documents include but are not limited to hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial. When possible, the original record should be retained as the source document. However, a photocopy is acceptable provided that it is a clear, legible, and an exact duplication of the original document.  
A case report form (CRF) (please indicate whether a paper or electronic CRF will be used) will be the primary data collection document for the study. Only the key personnel delegated on the delegation of authority log are permitted to make entries, changes, or corrections in the CRF. For electronic CRFs, an audit trail will be maintained by the electronic CRF management system.
pd-l1 inhibition as checkpoint immunotherapy
12.5 privacy confidentiality and data

The Principal Investigator will ensure that subject privacy and confidentiality of the subject's data will be maintained.  
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during the course of the study. All research related interactions with the participant will be conducted by qualified research staff who are directly involved in the conduct of the research study. To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock and key accessible only by the research staff. Electronic records of subject data will be maintained using a dedicated web-access secure database , which is housed in an encrypted and passwordprotected server behind the Duke firewall. Access to electronic databases will be limited to delegated personnel. The security and viability of the IT infrastructure will be managed by the DCI and/or Duke Medicine.  
Upon completion of the study, research records will be archived and handled per institutional policy.  
Subject names or identifiers will not be used in reports, presentations at scientific meetings, or publications in scientific journals
pd-l1 inhibition as checkpoint immunotherapy
12.6 data and safety monitoring

Data and Safety Monitoring will be performed in accordance with the external site Data and Safety Monitoring Plan, provided under separate cover.
pd-l1 inhibition as checkpoint immunotherapy
12.7 protocol amendments

All protocol amendments must be initiated by the Principal Investigator and approved by the IRB prior to implementation. IRB approval is not required for protocol changes that occur to protect the safety of a subject from an immediate hazard. However, the Principal Investigator must inform the IRB and all other applicable regulatory agencies of such action immediately.  
Though not yet required, the CPC should be informed about any protocol amendments that potentially affect research design or data analysis (i.e. amendments affecting subject population, inclusion/exclusion criteria, agent administration, etc.).
pd-l1 inhibition as checkpoint immunotherapy
12.8 records retention

The Principal Investigator will maintain study-related records for a period of at least six years after study completion per Duke policy.
pd-l1 inhibition as checkpoint immunotherapy
12.9 conflict of interest

The Principal Investigator and Sub-Investigators must comply with applicable federal, state, and local regulations regarding reporting and disclosure of conflict of interest. Conflicts of interest may arise from situations in which financial or other personal considerations have the potential to compromise or bias professional judgment and objectivity. Conflicts of interest include but are not limited to royalty or consulting fees, speaking honoraria, advisory board appointments, publicly-traded or privately-held equities, stock options, intellectual property, and gifts.  
The Duke University School of Medicine's Research Integrity Office (RIO) reviews and manages research-related conflicts of interest. The Principal Investigator and Sub-Investigators must report conflicts of interest annually and within 10 days of a change in status, and when applicable, must have a documented management plan that is developed in conjunction with the Duke RIO and approved by the IRB/IEC.
pd-l1 inhibition as checkpoint immunotherapy
13 references

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: a cancer journal for clinicians 2016;66:730.  
2. Marcus DM, Goodman M, Jani AB, Osunkoya AO, Rossi PJ. A comprehensive review of incidence and survival in patients with rare histological variants of prostate cancer in the United States from 1973 to 2008. Prostate cancer and prostatic diseases 2012;15:283-8. 3. Wang HT, Yao YH, Li BG, Tang Y, Chang JW, Zhang J. Neuroendocrine Prostate Cancer (NEPC) progressing from conventional prostatic adenocarcinoma: factors associated with time to development of NEPC and survival from NEPC diagnosis-a systematic review and pooled analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2014;32:3383-90. 4. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. The New England journal of medicine 2004;351:1502-12.  
5. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010;376:1147-54. 6. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. The New England journal of medicine 2011;364:1995-2005.  
7. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. The New England journal of medicine 2013;368:138-48. 8. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. The New England journal of medicine 2014;371:424-33. 9. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. The New England journal of medicine 2012;367:1187-97.  
10. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. The New England journal of medicine 2013;369:213-23. 11. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. The New England journal of medicine 2010;363:411-22.  
12. Aggarwal R, Zhang T, Small EJ, Armstrong AJ. Neuroendocrine prostate cancer: subtypes, biology, and clinical outcomes. Journal of the National Comprehensive Cancer Network : JNCCN 2014;12:719-26. 13. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015;161:1215-28.  
14. Aparicio AM, Harzstark AL, Corn PG, et al. Platinum-based chemotherapy for variant castrateresistant prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2013;19:3621-30.  
15. Beltran H, Prandi D, Mosquera JM, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nature medicine 2016;22:298-305. 16. Spiess PE, Pettaway CA, Vakar-Lopez F, et al. Treatment outcomes of small cell carcinoma of the prostate: a single-center study. Cancer 2007;110:1729-37. 17. Steineck G, Reuter V, Kelly WK, Frank R, Schwartz L, Scher HI. Cytotoxic treatment of aggressive prostate tumors with or without neuroendocrine elements. Acta oncologica 2002;41:668-74. 18. Nadal R, Schweizer M, Kryvenko ON, Epstein JI, Eisenberger MA. Small cell carcinoma of the prostate. Nature reviews Urology 2014;11:213-9. 19. Hager S, Ackermann CJ, Joerger M, Gillessen S, Omlin A. Anti-tumour activity of platinum compounds in advanced prostate cancer-a systematic literature review. Annals of oncology : official journal of the European Society for Medical Oncology 2016;27:975-84. 20. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. The New England journal of medicine 2016;375:443-53. 21. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. The New England journal of medicine 2015;373:1697-708.  
22. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF
mutation. The New England journal of medicine 2015;372:320-30.  
23. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. The New England journal of medicine 2010;363:711-23. 24. Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. The Lancet Oncology 2016;17:883-95.  
25. Gulley JL, Spigel D, Kelly K, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in advanced NSCLC patients: A phase 1b, open-label expansion trial in patients progressing after platinum-based chemotherapy. Journal of Clinical Oncology 2015;33.  
26. Disis ML, Patel MR, Pant S, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, recurrent or refractory ovarian cancer: A phase Ib, open-label expansion trial. Journal of Clinical Oncology 2015;33. 27. Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. The Lancet Oncology 2016.  
28. Bishop JL, Sio A, Angeles A, et al. PD-L1 is highly expressed in Enzalutamide resistant prostate cancer. Oncotarget 2015;6:234-42. 29. Beltran H, Rickman DS, Park K, et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer discovery 2011;1:487-95.  
30. Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2016;34:140218.  
31. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours:
revised RECIST guideline (version 1.1). European journal of cancer 2009;45:228-47. 32. Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. The Lancet Oncology 2017;18:e143-e52.  
33. Beltran H, Jendrisak A, Landers M, et al. The Initial Detection and Partial Characterization of Circulating Tumor Cells in Neuroendocrine Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2016;22:1510-9. 34. Corn PG, Tu SM, Zurita AJ, et al. A multi-institutional randomized phase II study (NCT01505868)
of cabazitaxel (CAB) plus or minus carboplatin (CARB) in men with metastatic castration-resistant prostate cancer (mCRPC). Journal of Clinical Oncology 2015;33. 35. Lee JL, Ahn JH, Choi MK, et al. Gemcitabine-oxaliplatin plus prednisolone is active in patients with castration-resistant prostate cancer for whom docetaxel-based chemotherapy failed. British journal of cancer 2014;110:2472-8. 36. Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. The Lancet Oncology 2015;16:375-84. 37. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. The New England journal of medicine 2015;372:2006-17.  
38. Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. The Lancet Oncology 2014;15:70012.  
39. Graff JN, Alumkal JJ, Drake CG, et al. Early evidence of anti-PD-1 activity in enzalutamideresistant prostate cancer. Oncotarget 2016.  
40. Hoos A, Eggermont AM, Janetzki S, et al. Improved endpoints for cancer immunotherapy trials.  
Journal of the National Cancer Institute 2010;102:1388-97.
pd-l1 inhibition as checkpoint immunotherapy
14 appendix a performance status

| Karnofsky Performance Scale   |                                                                         |
|-------------------------------|-------------------------------------------------------------------------|
| %                             | Description                                                             |
| 100                           | Normal, no complaints, no evidence of disease                           |
| 90                            | Able to carry on normal activity, minor signs or symptoms of disease    |
| 80                            | Normal activity with effort, some signs or symptoms of disease          |
| 70                            | Cares for self, unable to carry on normal activity or to do active work |
| 60                            | Requires occasional assistance but is able to care for most needs       |
| 50                            | Requires considerable assistance and frequent medical care              |
| 40                            | Disabled, requires special care and assistance                          |
| 30                            | Severely disabled, hospitalization indicated. Death not imminent.       |
| 20                            | Very sick, hospitalization indicated. Death not imminent.               |
| 10                            | Moribund, fatal processes progressing rapidly                           |
| 0                             | Dead                                                                    |
pd-l1 inhibition as checkpoint immunotherapy
15 appendix b fact-p (version

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.  
| past 7 days.  PHYSICAL WELL-BEING   | Not                                                                                                                                                                           | A little   | Somewhat      | Quite   | Very   |    |
|-------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|------|---------|--------|----|
| at all                              | bit                                                                                                                                                                           | a bit      | much |         |        |    |
| GP1                                 | I have a lack of energy                                                                                                                                                       | 0          | 1    | 2       | 3      | 4  |
| GP2                                 | I have nausea                                                                                                                                                                 | 0          | 1    | 2       | 3      | 4  |
| GP3                                 | Because of my physical condition, I have trouble  meeting the needs of my family                                                                                              | 0          | 1    | 2       | 3      | 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            | Not                                                                                                                                                                           | A little   | Somewhat      | Quite   | Very   |    |
| at all                              | bit                                                                                                                                                                           | a bit      | much |         |        |    |
| 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          | 1    | 2       | 3      | 4  |
| GS5                                 | I am satisfied with family communication about my  illness                                                                                                                    | 0          | 1    | 2       | 3      | 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  |  
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
EMOTIONAL WELL-BEING Not  
at all  
A little  
bit  
Somewhat**Quite**  
a bit  
Very  
much  
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 **Not**  
at all  
A little  
bit  
SomewhatQuite  
a bit  
Very  
much  
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  
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  
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
| ADDITIONAL CONCERNS   | Not at                                                  | A little   | Somewhat      | Quite   | Very   |    |
|-----------------------|---------------------------------------------------------|------------|------|---------|--------|----|
| all                   | bit                                                     | a bit      | much |         |        |    |
| C2                    | I am losing weight                                      | 0          | 1    | 2       | 3      | 4  |
| C6                    | I have a good appetite                                  | 0          | 1    | 2       | 3      | 4  |
| P1                    | I have aches and pains that bother me                   | 0          | 1    | 2       | 3      | 4  |
| P2                    | I have certain parts of my body where I experience pain | 0          | 1    | 2       | 3      | 4  |
| P3                    | My pain keeps me from doing things I want to do         | 0          | 1    | 2       | 3      | 4  |
| P4                    | I am satisfied with my present comfort level            | 0          | 1    | 2       | 3      | 4  |
| P5                    | I am able to feel like a man                            | 0          | 1    | 2       | 3      | 4  |
| P6                    | I have trouble moving my bowels                         | 0          | 1    | 2       | 3      | 4  |
| P7                    | I have difficulty urinating                             | 0          | 1    | 2       | 3      | 4  |
| BL2                   | I urinate more frequently than usual                    | 0          | 1    | 2       | 3      | 4  |
| P8                    | My problems with urinating limit my activities          | 0          | 1    | 2       | 3      | 4  |
| BL5                   | I am able to have and maintain an erection              | 0          | 1    | 2       | 3      | 4  |