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eci reporting procedure

Immediately upon awareness of an ECI, the Investigator (or designee) completes the DCI SAE Report Form and will submit the form within 2 business days of knowledge of the event to the funding companies. External sites should submit the form within 24 hours to the Duke study team via the REDCap SAE reporting tool.  
Note: It is imperative that initial ECI reports are submitted as soon as possible (within 2 business days of knowledge of the event) with available information to the funding companies. Missing and/or clarified event information may be provided in a follow-up report.  
Follow-up information including severity, action taken, concomitant medications, and outcome should be communicated to the funding companies as soon as possible using the same forms mentioned above. The Lead PI will review the report form with accompanying source document, sign page 5and the PI or designee will then promptly submit it to the funding companies. Within two business days of receipt, the study team will submit the SAE report form and other relevant safety information to the following supporting companies:
Merck Global Safety ATTN: Worldwide Product Safety Ipsen Safety ATTN: Ipsen Call Center
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10.4 other safety considerations

The Investigator must also report in the same timelines as SAEs any incidence of medication error, occupational exposure, abuse or misuse that is associated with or result in an adverse event. All related fatal outcomes must also be reported in the same timeline as a SAE.  
Refer to SAE reporting procedures in Section 10.2.
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10.4.1 pregnancy and lactation

Although pregnancy and lactation are not considered adverse events, it is the responsibility of Investigators or their designees to report any pregnancy or lactation in a subject (spontaneously reported to them) that occurs during the trial. Pregnancies and lactations that occur after the consent form is signed but before treatment allocation/randomization must be reported by the Investigator if they cause the subject to be excluded from the trial, or are the result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.  
Pregnancies and lactations that occur from the time of treatment allocation/randomization through 120 days following cessation of funding companies' product, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported by the Investigator.  
All reported pregnancies must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events (Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) must also be reported.  
Such events must be reported according to SAE reporting procedures (refer to Section 10.2).
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11.0 administrative responsibilities 11.1 institutional

Before study initiation, the Investigator must have written and dated approval/favorable opinion from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the protocol, consent form, subject recruitment materials/process (e.g., advertisements), and any other written information to be provided to subjects. The Investigator should provide the IRB/IEC with reports, updates, and other information (e.g., Safety Updates, Amendment IRB/IECs, and Administrative Letters) according to regulatory requirements and institution procedures. Copies of all IRB/IEC approvals, as well as annual re-approvals and approved/stamped informed consent forms must be submitted to Duke GI Oncology Clinical Trials Office.
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11.2 protocol and protocol revisions

All revisions to the protocol will be provided to the supporting companies by the Lead PI or designee(s) at the Duke GI Oncology Clinical Trials Office. The Lead PI must have written and dated approval/favorable opinion from the Duke University Health System (DUHS) IRB of revised protocol prior to distribution to Investigators at external participating sites.  
Investigators must obtain written and dated and approval/favorable opinion from the IRB/IEC before conducting any updated protocol version. Study must be conducted as described in the approved protocol. The Investigator must not implement changes of the approved protocol without prior written agreement by the Lead PI and prior review and documented approval/favorable agreement by the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to study subjects, or when the changes involve only logistical or administrative aspects of the study (e.g., changes in research personnel or change in phone numbers). Documentation of approval(s) from the IRB/IEC must be sent to Duke GI Oncology Clinical Trials Office.
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11.3 protocol deviations and violations

A protocol deviation is non-adherence to protocol specific study procedures or schedules that does not involve inclusion/exclusion criteria, primary objective evaluation criteria, and/or Good Clinical Practice
(GCP) guidelines.  
A protocol violation is any significant divergence from the protocol such as non-adherence on the part of the subject, the Investigator, or the sponsor to protocol specific inclusion/exclusion criteria, primary objective evaluation criteria, and/or GCP guidelines.  
As a matter of policy, the Lead PI (ie. sponsor) will not grant exceptions to protocol specific entry criteria to allow subjects to enter a study. If it is found that a subject who did not meet protocol eligibility criteria was entered in a study (a protocol violation), the Lead PI and/or designee(s) at the Duke GI Oncology Clinical Trials Office must be informed immediately. Such subjects will be discontinued from the study, except in an exceptional instance following review and written approval by the Lead PI and the responsible IRB/IEC.  
Protocol deviations and violations must be documented and reported to the Lead PI and/or designee(s)
at the Duke GI Oncology Clinical Trials Office. In accordance with applicable regulations, Investigators must report protocol deviations and violations to their local IRB/IEC according to their institutional guidelines.
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11.4 informed consent

The Investigator must ensure that subjects or their legally acceptable representatives are clearly and fully informed about the purpose, potential risks and other critical issues regarding clinical trials in which they volunteer to participate. Preparation of the consent form is the responsibility of the Investigator and must include all elements required by CFR 21 Part 50.25 and their IRB. A copy of the proposed informed consent document must be submitted to the Lead PI or designee(s) at the Duke GI Oncology Clinical Trials Office for review and comment prior to submission to the local IRB/IEC.  
Informed consent must be obtained prior to performing any study-related procedures that are not part of normal subject care, including screening and changes in medications. A copy of the signed informed consent form must be given to the study subject.
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11.5 source and study documentation

Source documents include all original recordings of observations or notations of clinical activities and all reports and records necessary for the evaluation and reconstruction of the clinical study.  
Accordingly, source documents include, but are not limited to, laboratory reports (including normal and abnormal results), radiology reports, subject diaries, biopsy reports, ultrasound photographs, subject progress notes, hospital charts or pharmacy records and any other similar reports or records of any procedure performed in accordance with the protocol. Whenever possible, the original recording of an observation should be retained as the source document; however, a photocopy is acceptable provided that it is a clear, legible, and exact duplication of the original certified document. When clinical observations are entered directly into an electronic medical record system (i.e. in lieu of original hardcopy records), the electronic record can serve as the source document if the system has must be validated to meet the FDA requirements for electronic records and signatures (i.e. meets 21 CFR Part 11 compliant).  
Regulations require that Investigators maintain information in the study subject's medical records which corroborate data recorded on the CRF. In order to comply with these regulatory requirements, the following information will be maintained and made available as required by the Lead PI or designee(s), monitors, and/or regulatory inspectors:  
Medical history/physical condition of the study subject prior to involvement in the study sufficient to verify protocol entry criteria.  
Dated note that informed consent was obtained for the subject's participation in the study.  
Dated and signed notes for each subject visit including results of examinations. Notations on abnormal lab results and their resolution.  
Dated reports of special assessments (e.g., ECG reports). Dated and signed notes regarding adverse events (includng event description, severity, onset date, duration, relation to study treatment, outcome and treatment for adverse event).  
Dated notes regarding concomitant medications taken during the study (including start and stop dates).  
Subject condition upon completion of or withdrawal from the study.
Study documentation includes all CRFs, data correction forms, source documents, monitoring logs and appointment schedules, sponsor-investigator correspondence and regulatory documents (e.g., protocol and amendments, IRB/IEC correspondence and approvals, approved and signed subject consent forms, Statement of Investigator form, and clinical study supplies receipts and distribution records). The Investigator will prepare and maintain complete and accurate study documentation in compliance with GCP guidelines and applicable federal, state, and local laws, rules and regulations; and, for each subject participating in the study, promptly complete all CRFs and such other reports as required by this protocol following completion or termination of the clinical study or as otherwise required pursuant to any agreement with the Lead PI and Duke Cancer Institute (DCI). The Investigator acknowledges that, within legal and regulatory restrictions and institutional and ethical considerations, study documentation will be promptly and fully disclosed to Lead PI or designee(s) by the Investigator upon request and also shall be made available at the Investigator's site upon request for inspection, copying, review and audit at reasonable times by representatives of the Lead PI and DCI or responsible government agencies as required by law. The Investigator agrees to promptly take any reasonable steps that are requested by the Lead PI or designee(s) as a result of an audit to cure deficiencies in the study documentation and case report forms.
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11.6 case report forms

Subject data will be entered (ie. CRFs completed) into an electronic data capture (EDC) system called Medidata RAVE. This database is maintained on a secure Duke University server and is accessible via internet with login and password. CRFs should be completed by trained study personnel according to guidelines provided by the Lead PI or designee(s) at the Duke GI Oncology Clinical Trials Office. The Investigator or qualified designee is responsible for recording and verifying the accuracy of subject data. The Investigator acknowledges that his/her electronic signature is the legally binding equivalent of a written signature. By entering his/her electronic signature, the Investigator confirms that all recorded data have been verified as accurate. In the event of discrepant data, the study monitor or study designee will request data clarification from the Investigator or designee for which may be resolved electronically in the EDC system. Accurate and reliable data collection will be ensured through verification and crosscheck of the CRFs against the Investigator's study records (source document verification) by the study monitor or study designee.
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11.7 monitoring and audits/inspections

The study will be monitored both internally by the Lead PI and externally by the Duke Cancer Institute (DCI) Monitoring Team in accordance with their NCI-approved "Institutional Protocol Monitoring Procedures and Guidelines for NIH-sponsored Research Involving Human Subjects".  
In terms of internal review, the Lead PI and/or designee(s) will continuously monitor and tabulate adverse events. Appropriate reporting to the DUHS IRB will be made. If an unexpected frequency of Grade 3 or 4 adverse events occurs, 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 deescalation, or potentially closure of the study. The Lead PI of this study will also continuously monitor the conduct, data, and safety of this study to ensure that:
Interim analyses occur as scheduled (if applicable);  
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 adverse events and outcomes is done;  
Over-accrual does not occur; Under-accrual is addressed with appropriate amendments or actions; Data are being appropriately recorded on the CRF in a reasonably timely manner.
The Duke Cancer Institute (DCI) Monitoring Team will conduct monitoring visits to ensure subject safety and to ensure that the protocol is conducted, recorded, and reported in accordance with the protocol, standard operating procedures, GCP, and applicable regulatory requirements. As specified in the DCI Data and Safety Monitoring Plan, the DCI Monitoring Team will conduct routine monitoring after the third subject is 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. An external site monitoring plan addendum describes monitoring at participating sites. Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of serious and/or unexpected toxicities, or other concerns and may be initiated upon request of DUHS and DCI leadership, the DCI Cancer Protocol Committee, the Safety Oversight Committee (SOC), the sponsor, the Principal 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.  
The DCI Safety Oversight Committee (SOC) will perform annual reviews on findings from the DCI Monitoring Team visit and additional safety and toxicity data submitted by the Principal Investigator. DCI Quality Assurance personnel, or designee, may conduct audits at sites. Audits will include, but not be limited to: audit trail of data handling and processes, SOPs, drug supply, presence of required documents, the informed consent process, and comparison of case report forms/database with source documents. The Investigator agrees to accommodate and participate in audits conducted at a reasonable time in a reasonable manner, as needed. Regulatory authorities may also audit an Investigator during or after the study. The Investigator should contact the Lead PI and designee(s) at the Duke GI Oncology Clinical Trials Office as well as their local IRB, immediately if this occurs, and must fully cooperate with governmental (e.g., FDA) audits conducted at a reasonable time in a reasonable manner. The Duke University Compliance Program - Human Subject Research Compliance (HSRC) section may conduct confidential audits to evaluate compliance with the protocol and the principles of GCP. The Lead PI agrees to allow the HSRC auditor(s) direct access to all relevant documents and to allocate his/her time and the time of the study team at the Duke GI Oncology Clinical Trials Office to the CTQA auditor(s) in order to discuss findings and any relevant issues.
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11.8 study closeout

Upon completion of the study (defined as all subjects have completed all follow-up visits, all CRFs are complete, and all queries have been resolved) the Lead PI or designee(s) at the Duke GI Oncology Clinical Trials Office will notify the Investigator of closeout and a study closeout visit will be performed.  
The study monitor or study designee will ensure that the Investigator's regulatory files are up to date and complete, and that any outstanding issues from previous visits have been resolved. Other issues to be reviewed at the closeout visit include: retention of study files, possibility of site audits, publication policy, and study closure with local IRB.
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11.9 records retention

The Investigator will maintain the records of study drug disposition, worksheets and all other studyspecific documentation (e.g., study files, source documentation) until notified by the Lead PI or designee(s) at the Duke GI Oncology Clinical Trials Office that records may be destroyed. If the application is not filed or is withdrawn, the Investigator will maintain the records for at least two (2) years after the formal discontinuation of the clinical development program for this product(s). To avoid error, the Investigator will contact the Lead PI or designee(s) at the Duke GI Oncology Clinical Trials Office before the destruction of any records pertaining to the study to ensure they no longer need to be retained. In addition, the Lead PI or designee(s) will be contacted if the Investigator plans to leave the institution so that arrangements can be made for the transfer of records.
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12.0 references

1. Vinik AI. Advances in Diagnosis and Treatment of Pancreatic Neuroendocrine Tumors (PNETS).  
Endocr Pract. 2014 Oct 8:1-23. [Epub ahead of print] PubMed PMID: 25297671.  
2. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN,
Rashid A, Evans DB. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008 Jun 20;26(18):3063-72.  
3. Strosberg JR. Systemic treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETS):
current approaches and future options. Endocr Pract. 2014 Feb;20(2):167-75.  
4. Sun L, Coy DH. Somatostatin and its Analogs. Curr Drug Targets. 2014 Dec 5.[Epub ahead of print]
5. Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B,
Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebocontrolled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63.  
6. Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators.  
Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33.  
7. Vikman S, Sommaggio R, De La Torre M, Oberg K, Essand M, Giandomenico V, Loskog A,
Totterman TH. Midgut carcinoid patients display increased numbers of regulatory T cells in peripheral blood with infiltration into tumor tissue. Acta Oncol. 2009;48(3):391-400.  
8. Bhathena SJ, Louie J, Schechter GP et al. Identification of human mononuclear leukocytes bearing receptors for somatostatin and glucagon. Diabetes 1981; 30: 127–131.  
9. Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B;
International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96.  
10. Schultheis AM, Scheel AH, Ozretić L, George J, Thomas RK, Hagemann T, Zander T, Wolf J,
Buettner R. PD-L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer. 2015 Jan 9. pii: S0959-8049(14)01166-6.  
11. Martín-Richard M, Massutí B, Pineda E, Alonso V, Marmol M, Castellano D, Fonseca E, Galán A,
Llanos M, Sala MA, Pericay C, Rivera F, Sastre J, Segura A, Quindós M, Maisonobe P; TTD (Tumores del Tracto Digestivo) Study Group. Antiproliferative effects of lanreotide autogel in patients with progressive, well-differentiated neuroendocrine tumours: a Spanish, multicentre, openlabel, single arm phase II study. BMC Cancer. 2013 Sep 20;13:427.  
12. Spranger S, et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013; 5:200ra116.10.1126/scitranslmed.3006504 13. Carbognin L, Pilotto S, Milella M, Vaccaro V, Brunelli M, Caliò A, Cuppone F, Sperduti I, Giannarelli D, Chilosi M, Bronte V, Scarpa A, Bria E, Tortora G. Differential Activity of Nivolumab, Pembrolizumab and MPDL3280A according to the Tumor Expression of Programmed DeathLigand-1 (PD-L1): Sensitivity Analysis of Trials in Melanoma, Lung and Genitourinary Cancers.  
PLoS One. 2015;10(6):e0130142.
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appendix a. recist 1.1

RECIST version 1.1* will be used in this study for assessment of tumor response. While either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study.  
*E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M.  
Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
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definitions

Response and progression will be evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1). Changes in only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the RECIST criteria. Note: Lesions are either measurable or non-measurable using the criteria provided below. The term "evaluable" in reference to measurability will not be used because it does not provide additional meaning or accuracy. Measurable Disease Tumor lesions : Must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:  
.  
.  
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10mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice thickness and a minimum of 10mm)
10mm caliper measurement by clinical exam (when superficial)
2mm by chest X-ray (if clearly defined and surrounded by aerated lung)
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be ≥15mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed.
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non-measurable disease

All other lesions (or sites of disease), including small lesions (longest diameter ≥10 to <15 mm with conventional techniques or <10 mm using spiral CT scan), are considered non-measurable disease. Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques are all nonmeasurable.  
Bone lesions:  
Bone scan, PET scan or plain films are not considered adequate imaging techniques to
•
measure bone lesions. However, these techniques can be used to confirm the presence or disappearance of bone lesions.  
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that
.  
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered as measurable lesions if the soft tissue component meets the definition of measurability described above.
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Blastic bone lesions are non-measurable.
Cystic lesions:  
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 noncystic lesions are present in the same patient, these are preferred for selection as target lesions.
Lesions with prior local treatment:
Tumor lesions situated in a previously irradiated area, or in an area subjected to other locoregional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion. Study protocols should detail the conditions under which such lesions would be considered measurable.
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target lesions

All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 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 organ, but in addition should be those that lend themselves to reproducible repeated measurements.  
Lymph nodes merit special mention since they are normal anatomical structures which may be visible by imaging even if not involved by tumor. Pathological nodes which are defined as measurable and may be identified as target lesions must meet the criterion of a short axis of
≥15mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter normally used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition may be axial, saggital or coronal). The smaller of these measures is the short axis. For example, an abdominal node which is reported as being 20mm x 30mm has a short axis of 20mm and qualifies as a malignant, measurable node. In this example, 20mm should be recorded as the node measurement. All other pathological nodes (those with short axis ≥10mm but <15 mm) should be considered non-target lesions. Nodes that have a short axis <10mm are considered nonpathological and should not be recorded or followed.  
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 as noted above, only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease.
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non-target lesions

All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-target lesions and should also be recorded at baseline. Measurements are not required and these lesions should be followed as 'present', 'absent', or in rare cases 'unequivocal progression' (more details to follow). In addition, it is possible to record multiple non-target lesions involving the same organ as a single item on the case record form (e.g. 'multiple enlarged pelvic lymph nodes' or 'multiple liver metastases').
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guidelines for evaluation of measurable

All measurements should be recorded in metric notation, using calipers if clinically assessed. All baseline evaluations should be performed as close as possible to the treatment start 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 should always be done rather than 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 and
>10mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by color photography including a ruler to estimate the size of the lesion is suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be undertaken since it is more objective and may also be reviewed at the end of the study.  
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung. CT, MRI: CT is the best currently available and reproducible method to measure lesions selected for response assessment. This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5mm or less. When CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). 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 from 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, they can be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response or surgical resection is an endpoint.  
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If markers are initially above the upper normal limit, however, they must normalize for a patient to be considered in complete response. Because tumor markers are disease specific, instructions for their measurement should be incorporated into protocols on a disease specific basis. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer), have been published. In addition, the Gynecologic Cancer Intergroup has developed CA125 progression criteria which are to be integrated with objective tumor assessment for use in first-line trials in ovarian cancer. Cytology, histology: These techniques can be used to differentiate between PR and CR in rare cases if required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where known residual benign tumors can remain). When effusions are known to be a potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can be considered if the measurable tumor has met criteria for response or stable disease in order to differentiate between response (or stable disease) and progressive disease.
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response criteria

Evaluation of Target Lesions
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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.  
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Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.  
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Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).  
.  
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.
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis measurement recorded (measured in the same anatomical plane as the baseline examination),
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, the 'sum' of lesions may not be zero even if complete response criteria are met, since a normal lymph node is defined as having a short axis of <10 mm. Case report forms or other data collection methods may therefore be designed to have target nodal lesions recorded in a separate section where, in order to qualify for CR, each node must achieve a short axis <10 mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.  
Target lesions that become 'too small to measure'. While on study, all lesions (nodal and nonnodal) recorded at baseline should have their actual measurements recorded at each subsequent evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable assigning an exact measure and may report them as being 'too small to measure'.  
When this occurs it is important that a value be recorded on the case report form.  If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement should be recorded as 0mm. If the lesion is believed to be present and is faintly seen but too small to measure, a default value of 5mm should be assigned (Note: It is less likely that this rule will be used for lymph nodes since they usually have a definable size when normal and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned in this circumstance as well). This default value is derived from the 5 mm CT slice thickness (but should not be changed with varying CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore providing this default value will prevent false responses or progressions based upon measurement error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be recorded, even if it is below 5 mm.  
Lesions that split or coalesce on treatment. When non-nodal lesions 'fragment', the longest diameters of the fragmented portions should be added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such that they are no longer separable, the vector of the longest diameter in this instance should be the maximal longest diameter for the 'coalesced lesion'. Evaluation of Non-target Lesions While some non-target lesions may actually be measurable, they need not be measured and instead should be assessed only qualitatively at the time points specified in the protocol.  
Complete Response (CR): Disappearance of all non-target lesions and normalization of
•
tumor marker level. All lymph nodes must be non-pathological in size (<10mm short axis).  
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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): Unequivocal progression (see comments below) of existing nontarget lesions. (Note: the appearance of one or more new lesions is also considered progression).
When the patient also has measurable disease. In this setting, to achieve 'unequivocal progression' on the basis of the non-target disease, there must be an overall level of substantial worsening in non-target disease such that, even in presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 'increase' in the size of one or more non-target lesions is usually not sufficient to quality for unequivocal progression status. The designation of overall progression solely on the basis of change in non-target disease in the face of SD or PR of target disease will therefore be extremely rare.  
When the patient has only non-measurable disease. This circumstance arises in some phase III
trials when it is not a criterion of study entry to have measurable disease. The same general concept apply here as noted above, however, in this instance there is no measurable disease assessment to factor into the interpretation of an increase in non-measurable disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for unequivocal progression is to consider if the increase in overall disease burden based on the change in nonmeasurable disease is comparable in magnitude to the increase that would be required to declare PD for measurable disease: i.e. an increase in tumor burden representing an additional 73% increase in 'volume' (which is equivalent to a 20% increase diameter in a measurable lesion). Examples include an increase in a pleural effusion from 'trace' to 'large', an increase in lymphangitic disease from localized to widespread, or may be described in protocols as 'sufficient to require a change in therapy'. If 'unequivocal progression' is seen, the patient should be considered to have had overall PD at that point. While it would be ideal to have objective criteria to apply to nonmeasurable disease, the very nature of that disease makes it impossible to do so, therefore the increase must be substantial.
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new lesions

The appearance of new malignant lesions denotes disease progression; therefore, some comments on detection of new lesions are important. There are no specific criteria for the identification of new radiographic lesions; however, the finding of a new lesion should be unequivocal: i.e. not attributable to differences in scanning technique, change in imaging modality or findings thought to represent something other than tumor (for example, some 'new' bone lesions may be simply healing or flare of pre-existing lesions). This is particularly important when the patient's baseline lesions show partial or complete response. For example, necrosis of a liver lesion may be reported on a CT scan report as a 'new' cystic lesion, which it is not.  
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is considered a new lesion and will indicate disease progression. An example of this is the patient who has visceral disease at baseline and while on study has a CT or MRI brain ordered which reveals metastases. The patient's brain metastases are considered to be evidence of PD even if he/she did not have brain imaging at baseline.  
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new lesion, then progression should be declared using the date of the initial scan.  
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:  
.  
.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion.  
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.  
Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation. On occasion a response may not be documented until after the end of therapy so protocols should be clear if post-treatment assessments are to be considered in determination of best overall response. Protocols must specify how any new therapy introduced before progression will affect best response designation. The patient's best overall response assignment will depend on the findings of both target and non-target disease and will also take into consideration the appearance of new lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may also require confirmatory measurement. Specifically, in non-randomised trials where response is the primary endpoint, confirmation of PR or CR is needed to deem either one the "best overall response."
The best overall response is determined once all the data for the patient is known. Best response determination in trials where confirmation of complete or partial response IS NOT required: Best response in these trials is defined as the best response across all time points (for example, a patient who has SD at first assessment, PR at second assessment, and PD on last assessment has a best overall response of PR). When SD is believed to be best response, it must also meet the protocol specified minimum time from baseline. If the minimum time is not met when SD is otherwise the best time point response, the patient's best response depends on the subsequent assessments. For example, a patient who has SD at first assessment, PD at second and does not meet minimum duration for SD, will have a best response of PD. The same patient lost to follow-up after the first SD assessment would be considered inevaluable.
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appendix b. immune-related response criteria

The immune related response criteria* (irRC) has been developed to adequately characterize additional patterns of response and progression specific to patients treated with immunotherapy, that cannot be captured by the conventional criteria such as such as Response Evaluation Criteria in Solid Tumors (RECIST).  
*Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R,
Hodi FS. et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.  
Clin Cancer Res. 2009;15(23):7412–7420.
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antitumor response based on total

For the irRC, only index and measurable new lesions are taken into account (in contrast to conventional WHO criteria, which do not require the measurement of new lesions, nor do they include new lesion measurements in the characterization of evolving tumor burden). At the baseline tumor assessment, the sum of the products of the two largest perpendicular diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions and five cutaneous index lesions) is calculated. At each subsequent tumor assessment, the SPD of the index lesions and of new, measurable lesions (≥5 × 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral lesions) are added together to provide the total tumor burden:
Tumor Burden = SPDindex lesions + SPDnew, measurable lesions
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time-point response assessment using irrc.

Percentage changes in tumor burden per assessment time point describe the size and growth kinetics of both conventional and new, measurable lesions as they appear. At each tumor assessment, the response in index and new, measurable lesions is defined based on the change in tumor burden (after ruling out irPD). Decreases in tumor burden must be assessed relative to baseline measurements (i.e., the SPD of all index lesions at screening).
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overall response using the irrc.

The overall response according to the irRC is derived from time-point response assessments
(based on tumor burden) as follows:
.  
irCR, complete disappearance of all lesions (whether measurable or not, and no new lesions)
confirmation by a repeat, consecutive assessment no less than 4 wk from the date first documented
•
irPR, decrease in tumor burden ≥50%relative to baseline confirmed by a consecutive assessment at least 4 wk after first documentation
•
irSD, not meeting criteria for irCR or irPR, in absence of irPD
.  
irPD, increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden)
confirmation by a repeat, consecutive assessment no less than 4 wk from the date first documented
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appendix c. ecog performance status

The ECOG Scale of Performance Status, developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group Chair*, describes a patient's level of functioning in terms of their ability to care for themself, daily activity, and physical ability (walking, working, etc.).  
*Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.  
| Grade                                                                | Description                                                         |
|----------------------------------------------------------------------|---------------------------------------------------------------------|
| Normal activity. Fully active, able to carry on all pre-disease      |                                                                     |
| 0                                                                    | performance without restriction.                                    |
| Symptoms, but ambulatory. Restricted in physically strenuous         |                                                                     |
| 1                                                                    | activity, but ambulatory and able to carry out work of a light or   |
| sedentary nature (e.g., light housework, office work).               |                                                                     |
| In bed <50% of the time. Ambulatory and capable of all self-care,    |                                                                     |
| 2                                                                    | but unable to carry out any work activities. Up and about more than |
| 50% of waking hours.                                                 |                                                                     |
| In bed >50% of the time. Capable of only limited self-care, confined |                                                                     |
| 3                                                                    | to bed or chair more than 50% of waking hours.                      |
| 100% bedridden. Completely disabled. Cannot carry on any self-       |                                                                     |
| 4                                                                    | care. Totally confined to bed or chair.                             |
| 5                                                                    | Dead.                                                               |
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appendix d. study calendar

| Screening Period 1                                                                                                            | Treatment Period 2               | Follow-up Period 3               |           |      |
|-------------------------------------------------------------------------------------------------------------------------------|----------------------------------|----------------------------------|-----------|------|
| Study Procedures                                                                                                              | Day 1                            | Every 12                         | 30 ( ± 7) | Long |
| Days -28 to -1                                                                                                                | (±7days)                         | Weeks 19                         | Days 20   | Term |
| Informed Consent                                                                                                              | X4                               |                                  |           |      |
| Demographics                                                                                                                  | x                                |                                  |           |      |
| Medical and Cancer History                                                                                                    | x                                |                                  |           |      |
| Concomitant Medications                                                                                                       | X --- (throughout study) 5 --- X |                                  |           |      |
| x                                                                                                                             |                                  |                                  |           |      |
| Physical Examination                                                                                                          | x                                | x                                | x         |      |
| Height                                                                                                                        | x                                |                                  |           |      |
| Vital Signs and Weight®                                                                                                       | x                                | x                                | x         |      |
| ECOG Performance Status'                                                                                                      | x                                |                                  |           |      |
| x                                                                                                                             | x                                |                                  |           |      |
| CBC with Differential                                                                                                         | X                                | X9                               | x         |      |
| X®                                                                                                                            | X9                               |                                  |           |      |
| Chemistries including LFTs                                                                                                    | x                                |                                  |           |      |
| Urinalysis                                                                                                                    | X8                               | Xa                               | x         |      |
| Thyroid Function Tests                                                                                                        | x                                | x                                | X10       |      |
| Serum Pregnancy Test                                                                                                          | X®                               | x                                | x         |      |
| Pembrolizumab 11                                                                                                              | x                                |                                  |           |      |
| Lanreotide Depot¹²                                                                                                            | x                                |                                  |           |      |
| Adverse Event Assessment                                                                                                      | x                                | X --- (throughout study) 5 --- X | X21       |      |
| Tumor Assessment 13                                                                                                           | x                                | x                                |           |      |
| Chromogranin A                                                                                                                | x                                | x                                | X21       |      |
| Tumor Tissue                                                                                                                  | X14                              |                                  |           |      |
| Circulating Immune Cells 15                                                                                                   | X16                              | X17                              | x         |      |
| X16                                                                                                                           |                                  |                                  |           |      |
| Protein Multiplex Arrays 18                                                                                                   | x                                | x                                |           |      |
| Survival                                                                                                                      | x                                |                                  |           |      |
| 2                                                                                                                             | Refer to Section 5.1             |                                  |           |      |
| Collection is 21 days. For C2 and all subsequent cycles, a window of +/-7 days is allowed for D1 visits. Refer to Section 5.2 |                                  |                                  |           |      |  
3 4.  
5. 6.  
7. 8. 9.  
10.  
1.  
12. 13.  
14 15. 16. 17 18.  
19.  
20. 21.  
Must perform within 7 days prior to Cycle 1 Day 1.  If completed within 7 days of Cycle 1 Day 1, no need to repeat.  If repeated on Cycle 1 Day 1, must wait for results to confirm eligibility prior to starting study drug.  
After Cycle 1, may perform up to 3 days prior to treatment visit During follow up period, only performed if clinically indicated.  
Refer to Section 6.2 Refer to Section 6.3 .  
Radiographic assessments (restaging scans) include CT and/or MRI of chest, abdomen and pelvis every 12 weeks (ie. after every 4 cycles).  Same method for tumor assessment should be employed at every assessment.  
Archived or fresh tumor tissue if available. Refer to Section 8.1 and Study Manual.  
Peripheral blood.  Refer to Section 8.2 and Study Manual Baseline time point may be obtained on Cycle 1 Day 1 prior to the first dose of study drug.  
First restaging only (ie. after Cycle 4 only).  
Peripheral blood.  Refer to Section 8.3 and Study Manual.  
Study procedures for restaging may be completed 12 (±1) weeks.  
Refer to Section 5.3 . May be completed more than 28 days prior to Cycle 1 Day 1.  
Collect this data throughout study when changes or events occur.  
Temperature (°C), blood pressure, heart rate, and weight (kg).  
Refer to Appendix C
After the last dose of study drug.  
Subjects discontinued from study treatment with no documented disease progression and no subsequent anti-cancer treatment should have disease status and chromogranin A followed per standard of care schedule until disease progression is documented.
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appendix e. laboratory tests

| CC with differential                         |                                                     |                           |    |                 |
|----------------------------------------------|-----------------------------------------------------|---------------------------|----|-----------------|
| hematocrit                                   | WBC (total and differential)                        | absolute neutrophil count |    |                 |
| .                                            | .                                                   | .                         |    |                 |
| hemoglobin                                   | red blood cell (RBC) count                          | absolute lymphocyte count |    |                 |
| .                                            | .                                                   | .                         |    |                 |
| platelet count                               |                                                     |                           |    |                 |
| .                                            |                                                     |                           |    |                 |
| Chemistries with liver function tests (LFTs) |                                                     |                           |    |                 |
| .                                            | albumin                                             | blood urea nitrogen (BUN) | .  | potassium       |
| .                                            |                                                     |                           |    |                 |
| alkaline phosphatase (ALP)                   | chloride                                            | sodium                    |    |                 |
| .                                            | .                                                   | .                         |    |                 |
| .                                            | ALT                                                 | creatinine                | .  | total bilirubin |
| .                                            |                                                     |                           |    |                 |
| .                                            | AST                                                 | glucose                   | .  | total protein   |
| .                                            |                                                     |                           |    |                 |
| .                                            | bicarbonate                                         | calcium                   |    |                 |
| .                                            |                                                     |                           |    |                 |
| Urinalysis                                   |                                                     |                           |    |                 |
| .                                            | including blood, glucose, protein, specific gravity |                           |    |                 |  
.  
including blood, glucose, protein, specific gravity Thyroid Function Tests  
| Thyroid Function Tests      |                              |                    |
|-----------------------------|------------------------------|--------------------|
| thyroid stimulating hormone | total thriiodothyronine (T3) | free tyroxine (T4) |
| .                           | .                            | .                  |
| (TSH)                       |                              |                    |
| Pregnancy Test              |                              |                    |
| serum β-HCG pregnancy test  |                              |                    |
| .                           |                              |                    |