protocol umcc 2018.050 [ca209-8jj] impact
7.3 guidelines for evaluation of

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 at CT, MRI may be used instead of CT in selected instances. Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised. However, 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. 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.
protocol umcc 2018.050 [ca209-8jj] impact
7.4 response criteria 7.4.1 evaluation

Complete Response (CR): Disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions.  
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions (with a minimum absolute increase of 5 mm), taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR (taking as reference the baseline sum LD) nor sufficient increase to qualify for PD (taking as reference the smallest sum LD since the treatment started).  
For Cohort B only: After the first PD assessment per RECISTv1.1 (=irSD per irRECIST), patients will be evaluated for irPD at least 4 weeks apart according to the following definition: Immune-related Progressive Disease (irPD): At least a 20% increase in the sum of the LD of target lesions (with a minimum absolute increase of 5 mm), taking as reference the smallest sum LD recorded since the treatment started, or appearance of new lesions since the last evaluation.  
7.4.2 Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes should be non-pathological in size (<10 mm short axis).  
Incomplete Response/Stable Disease (SD): Persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limits.  
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.  
Although a clear progression on non-target lesions in absence of stable target lesions is exceptional, the opinion of the treating physician should prevail in such circumstances.
protocol umcc 2018.050 [ca209-8jj] impact
7.4.3 evaluation of best overall

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. Evaluation as per RECISTv1.1 and irRECIST.  
| Target                                    | Non-Target                                       | New                         | Overall                   |                     |                      |
|-------------------------------------------|--------------------------------------------------|-----------------------------|---------------------------|---------------------|----------------------|
| Lesions                                   | Lesions                                          | Lesions                     | Response  per RECIST  1.1 | Overall             |                      |
| Response  per  irRECIST  (Cohort B  only) | Best Response for  this Category Also  Requires: |                             |                           |                     |                      |
| CR                                        | CR                                               | No                          | CR                        | N/A                 | >4 wks. confirmation |
| CR                                        | CR                                               | No                          |                           |                     |                      |
| Non-CR/SD                                 | PR                                               | N/A                         | >4 wks. confirmation      |                     |                      |
| PR                                        | CR                                               | No                          |                           |                     |                      |
| Non-CR/PD                                 |                                                  |                             |                           |                     |                      |
| SD                                        | CR                                               | No                          | SD                        | documented at least |                      |
| Non-CR/PD                                 | N/A                                              | once >4 wks. from  baseline |                           |                     |                      |
| PD                                        | Any                                              | Any                         | PD                        | irSD                | >4 wks. from         |
| Any                                       | PD*                                              | Any                         | baseline;                 |                     |                      |
| Any                                       | Any                                              | Yes                         |                           |                     |                      |
| PD                                        | Any                                              | Any                         |                           |                     |                      |
| Any                                       | PD*                                              | Any                         | N/A                       | irPD                | No further           |
| Any                                       | Any                                              | Yes                         | confirmation required     |                     |                      |
|                                           |                                                  |                             |                           |                     |                      |  
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression.  
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as "*symptomatic deterioration*." Every effort should be made to document the objective progression even after discontinuation of treatment.
protocol umcc 2018.050 [ca209-8jj] impact
n/a=not applicable

Note: If subjects respond to treatment and are able to have their disease resected, the patient's response will be assessed prior to the surgery
protocol umcc 2018.050 [ca209-8jj] impact
7.5 duration of response -

Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started.
protocol umcc 2018.050 [ca209-8jj] impact
7.6 progression-free survival - non

Radiographic progression-free survival (PFS) is defined as the duration of time from start of treatment to time of radiographic progression as defined above in section 7.4 or death, the event that occurs first. Patients who have not experienced either event at the time of analysis will be censored at their last radiographic scan date. Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of radiographic or clinical progression or death, the event that occurs first. Patients who have not experienced either event at the time of analysis will be censored at the date of their last progression assessment.  
7.7 Safety/Tolerability Analyses will be performed for all patients having received at least one dose of study drug. The study will use the CTCAE version 4.03 for reporting of non-hematologic adverse events (http://ctep.cancer.gov/reporting/ctc.html)).
protocol umcc 2018.050 [ca209-8jj] impact
8.0 adverse events

8.1 Experimental Therapy For the most recent safety update, please refer to the current Investigator's Brochure or Study Agent Prescribing Information.
protocol umcc 2018.050 [ca209-8jj] impact
special warnings and precautions for

Subjects receiving nivolumab and/or ipilimumab are advised to use two acceptable (to treating investigator) methods of birth control (one of which must include a condom as a barrier method of contraception) starting at the time of informed consent and continuing throughout the course of treatment and for at least 5 months (for women) and 7 months
(for men) after nivolumab and/or ipilimumab immunotherapy is discontinued.
protocol umcc 2018.050 [ca209-8jj] impact
8.2 adverse event reporting requirements

Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in future studies using similar agents. Data on adverse events will be collected from the time of the initial study drug administration through 100 days after the last dose of study drug, that is nivolumab and/or ipilimumab. Any serious adverse event that occurs more than 100 days after the last study drug dose and is considered related to the study drug must also be reported. Serious Adverse Events (SAEs) will continue to be followed until:  
Resolution or the symptoms or signs that constitute the serious adverse event return to baseline; There is satisfactory explanation other than the study drug, nivolumab and/or ipilimumab, for the changes observed; or Death.
The investigator is responsible for the detection, documentation, grading and assignment of attribution of events meeting the criteria and definition of an AE or SAE. The definitions of AEs and SAEs are given below. It is the responsibility of the principal investigator to ensure that all staff involved in the trial is familiar with the content of this section. Any medical condition or laboratory abnormality with an onset date before initial study treatment administration is considered to be pre-existing in nature. Any known preexisting conditions that are ongoing at time of study entry should be considered medical history. All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.3, occurring from the initial study treatment administration through 100 days following the last dose of the study treatment must be recorded as an adverse event in the patient's source documents and on the CRF regardless of frequency, severity (grade) or assessed relationship to the study treatment. In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of a pre-existing condition that occurs after the patient begins study treatment is also considered an adverse event.
protocol umcc 2018.050 [ca209-8jj] impact
8.3 definitions adverse event

An adverse event (AE) is any untoward medical occurrence in a patient receiving study treatment and which does not necessarily have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an experimental intervention, whether or not related to the intervention.  
*Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) procedures* will not be reported as adverse events. However, the medical condition for which the procedure was performed must be reported if it meets the definition of an adverse event unless it is a pre-existing (prior to protocol treatment)
condition.  
Abnormal laboratory values or test results constitute adverse events if they induce clinical signs or symptoms or require therapy. They are to be captured under the signs, symptoms or diagnoses associated with them.
protocol umcc 2018.050 [ca209-8jj] impact
serious adverse event

An adverse event is considered "serious" if, in the view of either the investigator, it results in any of the following outcomes:  
Death If death results from (progression of) the disease, the disease should be reported as event (SAE) itself.  
A life-threatening adverse event An adverse even is considered 'life-threatening' if, in the view of either the investigator [or sponsor], its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event that, had it occurred in a more severe form, might have caused death.  
Inpatient hospitalization or prolongation of existing hospitalization for > 24 hours.  
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
A congenital anomaly/birth defect Important medical event Any event that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition of "Serious Adverse Event". Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home; convulsions that do not result in inpatient hospitalization or the development of drug dependency or drug abuse.  
Previously planned (prior to signing the informed consent form) surgeries should not be reported as SAEs unless the underlying medical condition has worsened during the course of the study. Preplanned hospitalizations or procedures for preexisting conditions that are already recorded in the patient's medical history at the time of study enrollment should not be considered SAEs. Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for example, for the administration of study therapy or other protocol-required procedure) should not be considered SAEs.  
However, if the preexisting condition worsened during the course of the study, it should be reported as an SAE.
protocol umcc 2018.050 [ca209-8jj] impact
expected adverse events

An adverse event (AE) is considered "expected" if:  
For approved and marketed drugs or devices, those adverse events are described in the approved Package Insert (Label).  
For investigational new drugs or devices, those adverse events are described in the FDA Investigator's Brochure.  
In clinical research studies, information on expected adverse events is also summarized in the protocol and in the consent document. See section 9.1 for the list of expected adverse events related to the drug under study.
protocol umcc 2018.050 [ca209-8jj] impact
unexpected adverse event

An adverse event (AE) is considered "unexpected" if it is not described in the Package Insert, Investigator's Brochure, in the protocol, or in the informed consent document.
protocol umcc 2018.050 [ca209-8jj] impact
8.4 adverse event characteristics 8.4.1

(AE description) and grade: The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.03. A copy of the CTCAE version 4.03 can be down loaded from the CTEP web site. (http://ctep.cancer.gov)
protocol umcc 2018.050 [ca209-8jj] impact
8.4.2 attribution of the ae

The investigator or co-investigator is responsible for assignment of attribution.  
Definite - The AE *is clearly related* to the study treatment.  
Probable - The AE *is likely related* to the study treatment.  
Possible - The AE *may be related* to the study treatment.  
Unlikely - The AE *is doubtfully related* to the study treatment. Unrelated - The AE *is clearly NOT related* to the study treatment.
protocol umcc 2018.050 [ca209-8jj] impact
8.5 serious adverse event reporting

All serious adverse events (SAEs) and unanticipated problems (UPs), regardless of causality to study drug, will be reported to the Principal Investigator and also to the Coordinating Center. All SAEs and UPs must be reported to the Coordinating Center within 24 hours of first awareness of the event. Events should be reported using the Coordinating Center SAE form as available in the study database. A copy of the Coordinating Center SAE form as available in the study database should be sent to the Coordinating Center via fax at 734-2320744 or via email to CTSU-Oncology-Multisite@med.umich.edu within 24 hours of the site's knowledge of the event.  
Follow-up information must also be reported within 24 hours of receipt of the information by the investigator.  
Participating sites should report all SAEs and UPs to their local IRB per current local institutional standards. The Coordinating Center will disseminate information regarding SAEs and UPs to the participating sites within 5 days of review of the information by the Coordinating Center's Principal Investigator (or designee in the event of extended absence) only in the case that the event(s) is believed to be related (i.e., possibly, probably, or definitely) to the study drug. The Coordinating Center will be responsible for reporting of events to the FDA and supporters, as appropriate (outlined below).
protocol umcc 2018.050 [ca209-8jj] impact
8.5.2 reporting procedures to bms

All Serious Adverse Events (SAEs) occurring from the initial study treatment administration through 100 days following the last dose of the study treatment will be reported by the Coordinating Center to BMS Worldwide safety. Any SAEs occurring after 100 days following the last dose of the study treatment that are believed to be related to study drug will also be reported to BMS Worldwide safety.  
The Coordinating Center will send the initial completed SAE Form within 24 hours of receipt via email to BMS Worldwide Safety (Worldwide.Safety@bms.com; Fax: 609-818-3804).  
If only limited information is initially available or an ongoing SAE changes in its intensity or relationship to the study drug, or if new information becomes available, a follow-up report will be generated and sent to BMS Worldwide Safety within 24 hours of receipt.
protocol umcc 2018.050 [ca209-8jj] impact
8.5.3 reporting procedures to fda

In this trial, serious, unexpected adverse events believed to be definitely, probably or possibly related to the study treatment will be reported to the Food and Drug Administration via the MedWatch 3500A Form. The Michigan IND/IDE Assistance Program (MIAP) (University of Michigan) will assist the IND Sponsor in reporting SAEs to the FDA that meet the reporting requirements in 21 CFR
312.32. This reporting could include the initial report and follow-up reports when appropriate for the event.  
8.6 Routine Reporting All other adverse events- such as those that are expected, or are unlikely or definitely not related to the study participation- are to be reported annually as part of regular data submission.
protocol umcc 2018.050 [ca209-8jj] impact
8.7 reporting of unanticipated problems

There are types of incidents, experiences and outcomes that occur during the conduct of human subjects research that represent unanticipated problems but are not considered adverse events. For example, some unanticipated problems involve social or economic harm instead of the physical or psychological harm associated with adverse events. In other cases, unanticipated problems place subjects or others at increased risk of harm, but no harm occurs. Upon becoming aware of any incident, experience, or outcome (not related to an adverse event) that may represent an unanticipated problem, the investigator should assess whether the incident, experience, or outcome represents an unanticipated problem. The incident, experience or outcomes is considered unanticipated if it meets all of the following criteria:  
1. Unexpected (in terms of nature, severity, or frequency); 2. Related or possibly related to participation in the research; and 3. Suggests that the research places subjects or others at a greater risk of harm than was previously known or recognized.
If the investigator determines that the incident, experience, or outcome represents an unanticipated problem, the investigator must report it to the IRB within 7 calendar days of the study team becoming aware of the problem.
protocol umcc 2018.050 [ca209-8jj] impact
8.8 safety report reconciliation

The Sponsor will reconcile the clinical database SAE reports transmitted to BMS Global Pharmacovigilance (Worldwide.Safety@bms.com). Frequency of reconciliation should be every 3 months and prior to the database lock or final data summary. BMS GPV&E will email, upon request from the Investigator, the GPV&E reconciliation report. Requests for reconciliation should be sent to aepbusinessprocess@bms.com. The data elements listed on the GPV&E reconciliation report will be used for identification purposes. If the Investigator determines a report was not transmitted to BMS GPV&E, the report should be sent immediately to BMS.  
9.0 DRUG INFORMATION
9.1 Nivolumab Other names for the drug: Opdivo Description: Injection: 100 mg/10 mL solution in a single-dose vial. Classification - type of agent: Immunomodulatory; checkpoint inhibitor Mode of action:
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in enhanced T-cell function that is greater than the effects of either antibody alone, and results in improved anti-tumor responses in metastatic melanoma. In murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in increased anti-tumor activity.  
Pharmacokinetics:
Nivolumab pharmacokinetics (PK) were assessed using a population PK approach for both single-agent nivolumab and nivolumab with ipilimumab.  
nivolumab as a single agent: The PK of single-agent was studied in patients over a dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. Nivolumab clearance decreases over time, with a mean maximal reduction (% coefficient of variation [CV%]) from baseline values of approximately 24.5% (47.6%) resulting in a geometric mean steady state clearance (CLss) (CV%) of 8.2 mL/h (53.9%); the decrease in CLss is not considered clinically relevant. The geometric mean volume of distribution at steady state (Vss) (CV%) is 6.8 L (27.3%), and geometric mean elimination half-life (t1/2) is 25 days (77.5%).  
Steady-state concentrations of nivolumab were reached by approximately 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was approximately 3.7-fold. The exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. Nivolumab with ipilimumab: The geometric mean (CV%) CL, Vss, and terminal halflife of nivolumab were 10.0 mL/h (50.3%), 7.92 L (30.1%), and 24.8 days (94.3%), respectively. When administered in combination, the CL of nivolumab was increased by 24%, whereas there was no effect on the clearance of ipilimumab.  
Side effects:
Nivolumab as a single agent: fatigue, rash, musculoskeletal pain, pruritus, diarrhea,
nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, and pyrexia.  
Nivolumab with ipilimumab: fatigue, rash, diarrhea, nausea, pyrexia, vomiting, and dyspnea.  
Drug Interactions:
No formal pharmacokinetic drug-drug interaction studies have been conducted with nivolumab.  
Storage and stability:
The product does not contain a preservative. After preparation, store the nivolumab infusion either: - at room temperature for no more than 8 hours from the time of preparation. This includes room temperature storage of the infusion in the IV container and time for administration of the infusion or - under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of infusion preparation. Do not freeze.  
Preparation and Dispensing:
Visually inspect drug product solution for particulate matter and discoloration prior to administration. Nivolumab is a clear to opalescent, colorless to pale-yellow solution. Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do not shake the vial. - Withdraw the required volume of nivolumab and transfer into an intravenous container. - Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. - Mix diluted solution by gentle inversion. Do not shake. - Discard partially used vials or empty vials of nivolumab.  
Administration:
Administer the infusion over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer). Do not coadminister other drugs through the same intravenous line.  
Flush the intravenous line at end of infusion.  
When administered in combination with ipilimumab, infuse nivolumab first followed by ipilimumab on the same day. Use separate infusion bags and filters for each infusion.  
Availability: Provided by Bristol Myers Squibb, Inc. Return and Retention of Study Drug: Handling and disposal of nivolumab should be per institutional guidelines for the handling and disposal of biologic and cytotoxic agents
protocol umcc 2018.050 [ca209-8jj] impact
drug accountability

The investigator, or a responsible party designated by the investigator, must maintain a careful record of the inventory and disposition of nivolumab. The drug accountability records will capture drug receipt, drug dispensing, drug return and final disposition.  
9.2 Ipilimumab Other names for the drug: Yervoy Description:  
Injection: 200 mg/40 mL (5 mg/mL) (3)
Classification - type of agent: Immunomodulatory; checkpoint inhibitor Mode of action: human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody Pharmacokinetics:
The pharmacokinetics (PK) of ipilimumab was studied in 785 patients with unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg once every 3 weeks for 4 doses. The PK of ipilimumab is linear in the dose range of 0.3 to 10 mg/kg. Following administration of ipilimumab every 3 weeks, the systemic accumulation was 1.5-fold or less. Steady-state concentrations of ipilimumab were reached by the third dose; the mean Cmin at steady state was 19.4 mcg/mL at 3 mg/kg and 58.1 mcg/mL at 10 mg/kg every 3 weeks. The mean value (percent coefficient of variation) based on population PK analysis for the terminal half-life (t1/2) was 15.4 days (34%) and for clearance (CL) was 16.8 mL/h (38%). Specific Populations The effects of various covariates on the PK of ipilimumab were assessed in population PK analyses. The CL of ipilimumab increased with increasing body weight supporting the recommended body weight (mg/kg) based dosing. The following factors had no clinically important effect on the CL of ipilimumab: age (range: 23 to 88 years), sex, performance status, renal impairment, mild hepatic impairment, previous cancer therapy, and baseline lactate dehydrogenase (LDH)
levels. The effect of race was not examined due to limited data available in nonCaucasian ethnic groups.  
Renal Impairment: No clinically important differences in the CL of ipilimumab were found between patients with renal impairment and patients with normal renal function.  
Hepatic Impairment: The effect of hepatic impairment on the CL of ipilimumab was evaluated in patients with mild hepatic impairment (n=76) compared to patients with normal hepatic function (n=708) in the population PK analyses, and no clinically important differences in the CL of ipilimumab were found. Ipilimumab has not been studied in patients with moderate or severe hepatic impairment.  
Side effects: Ipilimumab can result in severe and fatal immune-mediated reactions.  
Drug Interactions: No formal pharmacokinetic drug interaction studies have been conducted with ipilimumab.  
Storage and stability:
- Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C, 36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F).
protocol umcc 2018.050 [ca209-8jj] impact
preparation and dispensing

- Do not shake product. - Inspect parenteral drug products visually for particulate matter and discoloration prior to administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution may have pale-yellow color), or there is foreign particulate matter other than translucent-to-white, amorphous particles. - Allow the vials to stand at room temperature for approximately 5 minutes prior to preparation of infusion.  
- Withdraw the required volume of ipilimumab and transfer into an intravenous bag.  
- Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2 mg/mL. Mix diluted solution by gentle inversion.  
- Discard partially used vials or empty vials of ipilimumab.  
Administration:
- Do not mix ipilimumab with, or administer as an infusion with, other medicinal products. - Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5%
Dextrose Injection, USP after each dose.  
- Administer diluted solution over 90 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein-binding in-line filter.  
Availability: Provided by Bristol Myers Squibb, Inc.  
Return and Retention of Study Drug:Handling and disposal of ipilimumab should be per institutional guidelines for the handling and disposal of biologic and cytotoxic agents Drug Accountability:The investigator, or a responsible party designated by the investigator, must maintain a careful record of the inventory and disposition of ipilimumab. The drug accountability records will capture drug receipt, drug dispensing, drug return and final disposition.
protocol umcc 2018.050 [ca209-8jj] impact
10.0 correlatives/special studies

Specimens will be collected for banking and archival purposes. Submission of samples for correlative studies is expected of all subjects at baseline and optional tumor biopsy will be performed for those who consent to it.
protocol umcc 2018.050 [ca209-8jj] impact
10.1 sample collection guidelines

Prior to study enrollment, patients must have documented CDK12 loss on a prior biopsy (or cell-free DNA or other is allowed) of primary or metastatic tissue. Metastatic tissue is strongly preferred.  
Willingness to provide archival tissue submission is mandatory. If archival tissue, contains inadequate tissue for NGS (i.e., less than 30% tumor content) or patient does not consent to fresh tissue biopsy, or fresh biopsy is not feasible, then patient may enroll in study if all other eligibility criteria are met. In general, visceral metastases are prioritized over soft tissue or lymph node, and least preferable are bone metastases.  
Refer to Section 6.0 for tumor tissue and blood collection time points and Lab Manual for collection and processing details.  
10.2 Specimen Banking Patient samples (tissue and blood) collected for this study will be retained at the University of Michigan. Specimens will be stored indefinitely or until they are used up. If future use is denied or withdrawn by the patient, best efforts will be made to stop any additional studies and to destroy the specimens.  
Specimens being stored long-term for potential use not outlined in the protocol are subject to University Policy Governing Tissue Sample Collection, Ownership, Usage, and Disposition within all UMMS Research Repositories https://research.medicine.umich.edu/office-research/biorepository/governance-policies.
protocol umcc 2018.050 [ca209-8jj] impact
11.0 statistical considerations

11.1 Study Design/Study Endpoints This is a multi-center, prospective, one arm, 3 cohort study to evaluate the efficacy of immunotherapy in patients with metastatic cancers and CDK12 loss. Patients with metastatic castration resistant prostate cancer (mCRPC) will be enrolled in Cohort A until 25 evaluable patients are identified. Once Cohort A is full, mCRPC patients will enroll in Cohort C. Patients with other metastatic subtypes will be enrolled in Cohort B.  
An Mini-Max Simon Two-Stage design will be used to assess ORR defined as a 50%
decline in PSA from baseline in CDK12 loss of function metastatic CRPC patients. It is assumed that an ORR of 30% or more would be interesting for further study compared to a reference ORR of 10% based on the KEYNOTE-199 trial [35]. Accrual of 25 objective PSA response evaluable patients will provide 80% power to detect this difference in ORR with a type I error of 5%. Interim analysis will be completed after 15 objective PSA
response evaluable patients (Cohort A only). If 2 or more patients have a PSA response, then the 2nd stage will open and accrue 10 more patients. If 6 or more patients out of 25 have a PSA response, then the treatment will be recommended for further study in this population.  
Cohort B will accrue 15 patients with non-prostate histology. A reference ORR of 5% is assumed in patients with non-prostate histology. With 15 patients, we have 76% power to detect an ORR of 25% with a one-sided type I error of 5%. If 3 or more responses are seen in cohort B then we will conclude that there is preliminary evidence of activity. Cohort C will accrue 25 mCRPC patients. A reference ORR of 10% is assumed, allowing 80% power to detect an ORR of 30% or more with a one-sided type I error of 5%. If 6 or more patients out of 25 have a PSA response, then the treatment will be recommended for further study in this population.
protocol umcc 2018.050 [ca209-8jj] impact
11.2 sample size and accrual

The trial is expected to accrue the total study population of 65 patients harboring CDK12 loss, including 50 objective PSA response evaluable metastatic prostate cancer patients and 15 objective response evaluable patients with non-prostate tumor histology over 2 years.
protocol umcc 2018.050 [ca209-8jj] impact
11.3 data analyses plans

Primary Endpoint Analysis: The primary endpoint for Cohort A and Cohort C is overall response rate using PSA
criteria. The primary analysis will include the response count and proportion with the associated exact 95% binomial confidence interval in the mCRPC cohort. If stage 2 is initiated, then the efficacy analysis methods for the reported response confidence interval will be as described by Koyama and Chen [33].  
Secondary Endpoint Analysis:
Efficacy in Cohort B will be described using overall response rate (CR/PR) using RECIST 1.1 criteria. The response count and proportion will be reported with the associated 95%
exact binomial confidence interval.  
Safety and tolerability of, nivolumab and ipilimumab combination therapy followed by nivolumab monotherapy, or nivolumab monotherapy only, will be described by the frequency and severity of adverse events by CTCAE criteria. The proportion of patients removed from treatment due to AEs will be reported. The number and proportion of patients with dose reductions and/or holds will be reported separately and overall. Each measure will be reported for the entire trial and separately by cohort.  
Secondary efficacy time-to-event endpoints including radiographic progression-free survival (rPFS), progression-free survival (PFS), duration of response (DOR) among responders, duration of therapy (DOT), time to progression (TTP) and overall survival (OS) will be reported using Kaplan-Meier methods. The median, if reached, and the 52week event-free proportion with the associated 95% greenwood formula confidence interval will be reported for each endpoint. For subjects with metastatic CRPC, PSA
progression-free survival and time to PSA progression by PCWG3 criteria will also be described for Cohort A using the same the Kaplan-Meier measures described previously. Objective tumor response in patients with measurable disease by RECIST 1.1 criteria will reported separately by location using PCWG3 recommendations and will include waterfall plots and counts with proportions and the associated 95% confidence intervals. Each endpoint will be reported for all patients if applicable and separately for each cohort.  
Quality of Life (QoL) in subjects treated on protocol therapy will be described using EORTC-QLQ-C30 and BPI-SF measures. Baseline will be described using means or medians with an associated variance statistic. Change from baseline will be reported at each time point thereafter with similar descriptive statistics. Each measure will be reported for the overall population and separately by cohort. Each QoL change from baseline will be analyzed using a general linear model with repeated measures for an association with response.  
Exploratory Endpoint Analysis Tumor genome profiling by integrated DNA and RNA sequencing at baseline and optionally at progression will be described using figures representing the profiled patients.  
These figures will order patients by degree of response (PSA response for Cohort A and Cohort C; and RECIST response for Cohort B). A logistic model with response as the outcome may be used with specific markers as independent covariates to estimate an effect size if a profound pattern is seen. Differences seen in paired samples (baseline and progression) will be described individually and labeled as a responder/nonresponder. Immune infiltration in tumor biopsies will be described using figures.  
Associations of the profiles with the response will be described using counts and proportions.  
12.0 DATA AND SAFETY MONITORING
This study will be monitored in accordance with the NCI approved University of Michigan Rogel Cancer Center Data and Safety Monitoring Plan, with oversight by the Rogel Cancer Center Data and Safety Monitoring Committee (DSMC). The Sponsor-Investigator (S-I)/Study Principal Investigator will provide ongoing monitoring of data and patient safety in this trial and conduct regular data review with participating sites The Sponsor-Investigator (S-I)/Study Principal Investigator and/or the Project Manager/Delegate will review data and patient safety issues with participating sites per a defined quarterly meeting cadence. Depending on the protocol activity, the meeting cadence may be more frequent. This data review meeting may be achieved via a teleconference or another similar mechanism to discuss matters related to:  
Enrollment rate relative to expectations, characteristics of participants Safety of study participants (Serious Adverse Event & Adverse Event reporting) Adherence to protocol (protocol deviations)
Completeness, validity and integrity of study data Retention of study participants
Participating sites are required to ensure all pertinent data for the review period are available in the database at the time of the discussion. Participating sites unable to participate in the data review meeting are required to provide written confirmation that their site has reviewed the relevant data and patient safety issues for the review period and their site's data are in alignment with the data reported in the database. Written confirmation is to be provided to the Project Manager/Delegate within the timeline requested to retain compliance with monitoring timelines. Documentation of the teleconference or alternate mechanism utilized to review items above is to be retained in the Trial Master File. The Project Manager/Delegate is responsible for collating the data from all participating sites and completing the Protocol Specific Data and Safety Monitoring Report (DSMR) form to document the data review meeting discussion. The DSMR will be signed by the Sponsor-Investigator (S-I)/Study Principal Investigator or designated Co-Investigator and submitted to the DSMC on a quarterly basis for independent review.  
13.0 DATA MANAGEMENT
All information will be recorded locally and entered into Case Report Forms (CRFs) on the webbased electronic data capture (EDC) system of the University of Michigan. Online access will be provided to each site by the Coordinating Center. CRFs will be reviewed and source verified by the MSC during annual monitoring visits and prior to and between visits. Discrepant, unusual and incomplete data will be queried by the MSC. The investigator or study coordinator will be responsible for providing resolutions to the data queries, as appropriate. The investigator must ensure that all data queries are dealt with promptly.  
The data submission schedule is as follows:
After subject enrollment o Subject Status o Demographics During study participation o All data should be entered online within 10 business days of data acquisition.  
Information on Serious Adverse Events must be entered within the reporting timeframe specified in Section 8 of the protocol. All study information should be recorded in an appropriate source document (e.g. clinic chart).
protocol umcc 2018.050 [ca209-8jj] impact
14.0 quality assurance and audits

The Data and Safety Monitoring Committee can request a 'for cause' quality assurance audit of the trial if the committee identifies a need for a more rigorous evaluation of study-related issues. A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its conduct or even after its completion. If an inspection has been requested by a regulatory authority, the site investigator must immediately inform the Coordinating Center that such a request has been made.
protocol umcc 2018.050 [ca209-8jj] impact
15.0 clinical trial monitoring

Clinical studies coordinated by The University of Michigan Rogel Cancer Center must be conducted in accordance with the ethical principles that are consistent with Good Clinical Practices (GCP) and in compliance with other applicable regulatory requirements. This study will be monitored by a representative of the Coordinating Center of the Rogel Cancer Center. Monitoring visits will be made during the conduct of the study and at study close-out. Prior to subject recruitment, a participating site will undergo a site initiation meeting to be conducted by the Coordinating Center. This will be done as an actual site visit; teleconference, videoconference, or web-based meeting after the site has been given access to the study database and assembled a study reference binder. The site's principal investigator and his/her study staff should make every effort in attending the site initiation meeting. Study–related questions or issues identified during the site initiation meeting will be followed-up by the appropriate Coordinating Center personnel until they have been answered and resolved. Monitoring of this study can include both 'Centralized Monitoring', the review of source documents at the Coordinating Center and 'On-site Monitoring', an actual site visit. The first 'Centralized' visit should occur after the first subject enrolled completes the first treatment cycle. The study site will send the de-identified source documents to the Coordinating Center for monitoring. 'Centralized' monitoring may be requested by the Coordinating Center if an amendment requires changes to the protocol procedures. The site will send in pertinent de-identified source documents, as defined by the Coordinating Center for monitoring.  
The first annual 'On-site' monitoring visit should occur after the first five study participants are enrolled or twelve months after a study opens, whichever occurs first. The annual visit may be conducted as a 'Centralized' visit if less than three subjects have enrolled at the study site. The type of visit is at the discretion of the Coordinating Center. At a minimum, a routine monitoring visit will be done at least once a year, or once during the course of the study if the study duration is less than 12 months. The purpose of these visits is to verify:  
Adherence to the protocol Completeness and accuracy of study data and samples collected Proper storage, dispensing and inventory of study medication Compliance with regulations
During a monitoring visit to a site, access to relevant hospital and clinical records must be given by the site investigator to the Coordinating Center representative conducting the monitoring visit to verify consistency of data collected on the CRFs with the original source data. While most patient cases will be selected from patients accrued since the previous monitoring visit, any patient case has the potential for review. At least one or more unannounced cases will be reviewed, if the total accruals warrant selection of unannounced cases. The Coordinating Center expects the relevant investigational staff to be available to facilitate the conduct of the visit, that source documents are available at the time of the visit, and that a suitable environment will be provided for review of study-related documents. Any issues identified during these visits will be communicated to the site and are expected to be resolved by the site in a timely manner. For review of study-related documents at the Coordinating Center, the site will be required to ship or fax documents to be reviewed.  
Participating site will also undergo a site close-out upon completion, termination or cancellation of a study to ensure fulfillment of study obligations during the conduct of the study, and that the site Investigator is aware of his/her ongoing responsibilities. In general, a site close-out is conducted during a site visit; however, site close-out can occur without a site visit.
protocol umcc 2018.050 [ca209-8jj] impact
16.0 references

1. Robinson, D., et al., *Integrative clinical genomics of advanced prostate cancer.* Cell, 2015. 161(5): p. 1215-28.  
2. Robinson, D.R., et al., *Integrative clinical genomics of metastatic cancer.* Nature, 2017.  
548(7667): p. 297-303.  
3. Chila, R., F. Guffanti, and G. Damia, Role and therapeutic potential of CDK12 in human cancers. Cancer Treat Rev, 2016. 50: p. 83-88.  
4. Teply, B.A. and E.S. Antonarakis, *Treatment strategies for DNA repair-deficient prostate* cancer. Expert Rev Clin Pharmacol, 2017. 10(8): p. 889-898.  
5. Joshi, P.M., et al., Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors. J Biol Chem, 2014. 289(13): p. 9247-53.  
6. Popova, T., et al., Ovarian Cancers Harboring Inactivating Mutations in CDK12 Display a Distinct Genomic Instability Pattern Characterized by Large Tandem Duplications. Cancer Res, 2016. 76(7): p. 1882-91.  
7. Ekumi, K.M., et al., Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex. Nucleic Acids Res, 2015. 43(5): p. 2575-89.  
8. Snyder, A., et al., *Genetic basis for clinical response to CTLA-4 blockade in melanoma.*
N Engl J Med, 2014. 371(23): p. 2189-2199.  
9. Yaghmour, G., et al., *Role of Genomic Instability in Immunotherapy with Checkpoint* Inhibitors. Anticancer Res, 2016. 36(8): p. 4033-8.  
10. Brahmer, J.R., et al., *Phase I study of single-agent anti-programmed death-1 (MDX1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and* immunologic correlates. J Clin Oncol, 2010. 28(19): p. 3167-75.  
11. Beer, T.M., et al., *Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus* Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer. J Clin Oncol, 2017. 35(1): p. 40-47.  
12. Graff, J.N., et al., *Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate* cancer. Oncotarget, 2016. 7(33): p. 52810-52817.  
13. Basnet, A., et al., A Case of Locally Advanced Castration-resistant Prostate Cancer With Remarkable Response to Nivolumab. Clin Genitourin Cancer, 2017.  
14. Postow, M.A., et al., *Nivolumab and ipilimumab versus ipilimumab in untreated* melanoma. N Engl J Med, 2015. 372(21): p. 2006-17.  
15. Antonia, S.J., et al., *Nivolumab alone and nivolumab plus ipilimumab in recurrent smallcell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.* Lancet Oncol, 2016. 17(7): p. 883-895.  
33. Koyama, T. and H. Chen, Proper inference from Simon's two-stage designs. Stat Med, 2008. 27(16): p. 3145-54.  
34. Eisenhauer, P., et al., New response evaluation criteria in solid tumours: Revised RECIST
guideline (version 1.1). European Journal of Cancer, 2009. 45 (2): p. 228-247.  
35. De Bono, J.S.e.a., KEYNOTE-199: Pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC). . Journal of Clinical Oncology, 2018. 36.  
16. Wu, Y., et al., *The clinical value of combination of immune checkpoint inhibitors in* cancer patients: A meta-analysis of efficacy and safety. Int J Cancer, 2017.  
17. Alexandrov, L.B., et al., *Mutational signatures associated with tobacco smoking in* human cancer. Science, 2016. 354(6312): p. 618-622.  
18. Rizvi, N.A., et al., *Cancer immunology. Mutational landscape determines sensitivity to* PD-1 blockade in non-small cell lung cancer. Science, 2015. 348(6230): p. 124-8.  
19. Roychowdhury, S., et al., *Personalized Oncology Through Integrative High-Throughput* Sequencing: A Pilot Study. Science Translational Medicine, 2011. 3(111).  
20. Cieslik, M., et al., *The use of exome capture RNA-seq for highly degraded RNA with* application to clinical cancer sequencing. Genome Research, 2015. 25(9): p. 1372-1381.  
21. Robinson, D., et al., *Integrative Clinical Genomics of Advanced Prostate Cancer.* Cell, 2015. 161(5): p. 1215-1228.  
22. Mehra, R., et al., *Biallelic Alteration and Dysregulation of the Hippo Pathway in* Mucinous Tubular and Spindle Cell Carcinoma of the Kidney. Cancer Discov, 2016. 6(11): p. 1258-1266.  
23. Cieslik, M., et al., The use of exome capture RNA-seq for highly degraded RNA with application to clinical cancer sequencing. Genome Res, 2015. 25(9): p. 1372-81.  
24. Koboldt, D.C., et al., VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res, 2012. 22(3): p. 568-76.  
25. Ye, K., et al., Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads. Bioinformatics, 2009. 25(21): p. 2865-71.  
26. Lonigro, R.J., et al., Detection of somatic copy number alterations in cancer using targeted exome capture sequencing. Neoplasia, 2011. 13(11): p. 1019-25.  
27. Dobin, A., et al., *STAR: ultrafast universal RNA-seq aligner.* Bioinformatics, 2013.  
29(1): p. 15-21.  
28. Liao, Y., G.K. Smyth, and W. Shi, *The Subread aligner: fast, accurate and scalable read* mapping by seed-and-vote. Nucleic Acids Res, 2013. 41(10): p. e108.  
29. Ritchie, M.E., et al., *limma powers differential expression analyses for RNA-sequencing* and microarray studies. Nucleic Acids Res, 2015. 43(7): p. e47.  
30. Smyth, G.K., Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol, 2004. 3: p. Article3.  
31. Law, C.W., et al., *voom: Precision weights unlock linear model analysis tools for RNAseq read counts.* Genome Biol, 2014. 15(2): p. R29.  
32. Newman, A.M., et al., *Robust enumeration of cell subsets from tissue expression profiles.*
Nat Methods, 2015. 12(5): p. 453-7.
protocol umcc 2018.050 [ca209-8jj] impact
appendices appendix a

| ECOG Performance Status Scale                                |                                                           |
|--------------------------------------------------------------|-----------------------------------------------------------|
| Grade                                                        | Description                                               |
| 0                                                            | Normal activity.  Fully active, able to carry on all pre- |
| disease performance without restriction.                     |                                                           |
| Symptoms but ambulatory.  Restricted in physically           |                                                           |
| 1                                                            | strenuous activity, but ambulatory and able to carry out  |
| work of a light or sedentary nature ( e.g., light housework, |                                                           |
| office work).                                                |                                                           |
| 2                                                            | In bed <50% of the time.  Ambulatory and capable of all   |
| self-care, but unable to carry out any work activities.  Up  |                                                           |
| and about more than 50% of waking hours.                     |                                                           |
| 3                                                            | In bed >50% of the time.  Capable of only limited self-   |
| care, confined to bed or chair more than 50% of waking       |                                                           |
| hours.                                                       |                                                           |
| 4                                                            | 100% bedridden.  Completely disabled.  Cannot carry on    |
| any self-care.  Totally confined to bed or chair.            |                                                           |
| Dead.                                                        |                                                           |
| S                                                            |                                                           |
protocol umcc 2018.050 [ca209-8jj] impact
appendix c eortc qlq-c30 (version

We are interested in some things about you and your health. Please answer all of the questions yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will remain strictly confidential. Please fill in your initials:
Your birthdate (Day, Month, Year):
Today's date (Day, Month, Year):  
|                                                                                                            | Not at   | A      | Quite      | Very   |
|------------------------------------------------------------------------------------------------------------|----------|--------|------------|--------|
| All                                                                                                        | Little   | a Bit  | Much       |        |
| 1. Do you have any trouble doing strenuous activities,   like carrying a heavy shopping bag or a suitcase? | 1        | 2      | 3          | 4      |
| 2. Do you have any trouble taking a long walk?                                                             | 1        | 2      | 3          | 4      |
| 3. Do you have any trouble taking a short walk outside of the house?                                       | 1        | 2      | 3          | 4      |
| 4. Do you need to stay in bed or a chair during the day?                                                   | 1        | 2      | 3          | 4      |
| 5. Do you need help with eating, dressing, washing   yourself or using the toilet?                         | 1        | 2      | 3          | 4      |
| During the past week:                                                                                      | Not at   | A      | Quite      | Very   |
|                                                                                                            | All      | Little | a Bit Much |        |
| 6. Were you limited in doing either your work or other daily activities?                                   | 1        | 2      | 3          | 4      |
| 7. Were you limited in pursuing your hobbies or other leisure time   activities?                           | 1        | 2      | 3          | 4      |
| 8. Were you short of breath?                                                                               | 1        | 2      | 3          | 4      |
| 9. Have you had pain?                                                                                      | 1        | 2      | 3          | 4      |
| 10. Did you need to rest?                                                                                  | 1        | 2      | 3          | 4      |
| 11. Have you had trouble sleeping?                                                                         | 1        | 2      | 3          | 4      |
| 12. Have you felt weak?                                                                                    | 1        | 2      | 3          | 4      |
| 13. Have you lacked appetite?                                                                              | 1        | 2      | 3          | 4      |
| 14. Have you felt nauseated?                                                                               | 1        | 2      | 3          | 4      |
| 15. Have you vomited?                                                                                      | 1        | 2      | 3          | 4      |
| 16. Have you been constipated?                                                                             | 1        | 2      | 3          | 4      |  
| During the past week:                                                                                     | Not at   | A      | Quite Very   |    |
|-----------------------------------------------------------------------------------------------------------|----------|--------|--------------|----|
|                                                                                                           | All      | Little | a Bit Much   |    |
| 17. Have you had diarrhea?                                                                                | 1        | 2      | 3            | 4  |
| 18. Were you tired?                                                                                       | 1        | 2      | 3            | 4  |
| 19. Did pain interfere with your daily activities?                                                        | 1        | 2      | 3            | 4  |
| 20. Have you had difficulty in concentrating on things,  like reading a newspaper or watching television? | 1        | 2      | 3            | 4  |
| 21. Did you feel tense?                                                                                   | 1        | 2      | 3            | 4  |
| 22. Did you worry?                                                                                        | 1        | 2      | 3            | 4  |
| 23. Did you feel irritable?                                                                               | 1        | 2      | 3            | 4  |
| 24. Did you feel depressed?                                                                               | 1        | 2      | 3            | 4  |
| 25. Have you had difficulty remembering things?                                                           | 1        | 2      | 3            | 4  |
| 26. Has your physical condition or medical treatment  interfered with your family life?                   | 1        | 2      | 3            | 4  |
| 27. Has your physical condition or medical treatment  interfered with your social activities?             | 1        | 2      | 3            | 4  |
| 28. Has your physical condition or medical treatment  caused you financial difficulties?                  | 1        | 2      | 3            | 4  |
protocol umcc 2018.050 [ca209-8jj] impact
for the following questions please

29. How would you rate your overall health during the past week?  
1 2 3 4 5 6 7 Very poor Excellent 30. How would you rate your overall quality of life during the past week?  
| 1         | 2         | 3   | 4   | 5   | 6   | 7   |
|-----------|-----------|-----|-----|-----|-----|-----|
| Very poor | Excellent |     |     |     |     |     |