table 6 evaluating adverse events
9.5 collection and shipping of

Shipping of Blood Specimen(s): Collect two 10 mL of venous blood at preregistration and then two 10 mL every 6 weeks in lavender top (EDTA anticoagulant)
vacutainer tube(s). The tubes should be inverted approximately 8-10 times to mix the EDTA. Refrigerate (please do not freeze) sample until shipping. The sample should be placed in a biohazard bag and shipped according to IATA guidelines within 2-3 hours of the blood being drawn on a cold pack (please do not use dry ice). For DFCI samples, call the MGH operator at 617-726-2000, ask to page 2-3389 and 2-1928, and leave a brief message indicating that the sample has been shipped. For any questions regarding samples, please contact Nathaniel Goss and/or Brian Shaw. When samples are shipped and for any concerns regarding shipments, please page Nathaniel Goss at 2-3389. Brastianos Lab Nathaniel Goss Simches Research Center 185 Cambridge Street Boston, MA 02114
table 6 evaluating adverse events
10. study calendar

Scans and x-rays must be done <3 weeks prior to the start of therapy. All eligibility labs are to be drawn within 14 days of day 1 (as stated in section 3.1.9). Assessments must be performed prior to administration of any study agent. Study assessments and agents should be administered within + 3 days of the protocol-specified date, unless otherwise noted.  
| Screening                                                                                                                                                                                      | End of           |                                     |            |                |     |     |     |     |        |            |           |           |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------|-------------------------------------|------------|----------------|-----|-----|-----|-----|--------|------------|-----------|-----------|
| Trial Period:                                                                                                                                                                                  | Phasea           | Treatment Cycles (21 day cycles)b,c | Treatmentd | Post-Treatment |     |     |     |     |        |            |           |           |
| To be repeated beyond  8 cyclesv                                                                                                                                                               |                  |                                     |            |                |     |     |     |     |        |            |           |           |
| Treatment  Cycle/Title:                                                                                                                                                                        | Study  Screening | Safety                              | Active     | Longterm       |     |     |     |     |        |            |           |           |
| (Visit 1)                                                                                                                                                                                      | 1                | 2                                   | 3          | 4              | 5   | 6   | 7   | 8   | Discon | Follow-upe | Followupf | Followupg |
| Scheduling Window                                                                                                                                                                              | At time of       | 30 days post  Every 6               | Every 3    |                |     |     |     |     |        |            |           |           |
| (Days):                                                                                                                                                                                        | -14 to 0         | ± 3                                 | ± 3        | ± 3            | ± 3 | ± 3 | ± 3 | ± 3 | Discon | discon     | weeks     | months    |
| Administrative Procedures Informed Consenth X Inclusion/Exclusion  Criteriai X Demographics and  Medical Historyj X Prior and  Concomitant  X Medication Reviewk Pembrolizumab  Administration | X                | X                                   | X          | X              | X   | X   | X   | X   |        |            |           |           |
| Post-study anticancer  therapy statusf                                                                                                                                                         | X                | X                                   | X          | X              |     |     |     |     |        |            |           |           |
| Survival Statusg                                                                                                                                                                               | X                | X                                   |            |                |     |     |     |     |        |            |           |           |
| Clinical Procedures/Assessments Review Adverse  Eventsl X                                                                                                                                      | X                | X                                   | X          | X              | X   | X   | X   | X   | X      | X          |           |           |
| Full Physical  Examinationm                                                                                                                                                                    | X                | X                                   | X          | X              | X   | X   | X   | X   | X      | X          | X         |           |
| Vital Signs and  Weightn                                                                                                                                                                       | X                | X                                   | X          | X              | X   | X   | X   | X   | X      | X          | X         |           |
| ECOG Performance  Statuso                                                                                                                                                                      | X                | X                                   | X          | X              | X   | X   | X   | X   | X      | X          | X         |           |
| Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory Pregnancy Test -  X Urine or Serum - HCGp PT/INR and aPTTq X                                                        | X                |                                     |            |                |     |     |     |     |        |            |           |           |
| CBC with  Differentialr                                                                                                                                                                        | X                | X                                   | X          | X              | X   | X   | X   | X   | X      | X          |           |           |
| Comprehensive  Serum Chemistry                                                                                                                                                                 | X                | X                                   | X          | X              | X   | X   | X   | X   | X      | X          |           |           |
| Panels TSHt                                                                                                                                                                                    | X                | X                                   | X          | X              | X   | X   | X   |     |        |            |           |           |
| Efficacy Measurements Tumor Imagingu X                                                                                                                                                         | X                | X                                   | X          | X              |     |     |     |     |        |            |           |           |
| Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood Archival Tissuew X44                                                                                                       |                  |                                     |            |                |     |     |     |     |        |            |           |           |  
| Screening                                                                                                                                                                                                                                            | End of           |                                     |            |                |     |     |     |     |        |            |           |           |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------|-------------------------------------|------------|----------------|-----|-----|-----|-----|--------|------------|-----------|-----------|
| Trial Period:                                                                                                                                                                                                                                        | Phasea           | Treatment Cycles (21 day cycles)b,c | Treatmentd | Post-Treatment |     |     |     |     |        |            |           |           |
| To be repeated beyond  8 cyclesv                                                                                                                                                                                                                     |                  |                                     |            |                |     |     |     |     |        |            |           |           |
| Treatment  Cycle/Title:                                                                                                                                                                                                                              | Study  Screening | Safety                              | Active     | Longterm       |     |     |     |     |        |            |           |           |
| (Visit 1)                                                                                                                                                                                                                                            | 1                | 2                                   | 3          | 4              | 5   | 6   | 7   | 8   | Discon | Follow-upe | Followupf | Followupg |
| Scheduling Window                                                                                                                                                                                                                                    | At time of       | 30 days post  Every 6               | Every 3    |                |     |     |     |     |        |            |           |           |
| (Days):                                                                                                                                                                                                                                              | -14 to 0         | ± 3                                 | ± 3        | ± 3            | ± 3 | ± 3 | ± 3 | ± 3 | Discon | discon     | weeks     | months    |
| Research Bloodx                                                                                                                                                                                                                                      | X                | X                                   | X          | X              | X   | X   |     |     |        |            |           |           |
| aAll screening procedures to be performed within 14 days of start of study treatment, except scans which can be obtained within 21 days of starting  study treatment, and informed consent may occur up to 28 days prior to start of study treatment |                  |                                     |            |                |     |     |     |     |        |            |           |           |  
Research Bloodx X X X X X X aAll screening procedures to be performed within 14 days of start of study treatment, except scans which can be obtained within 21 days of starting study treatment, and informed consent may occur up to 28 days prior to start of study treatment bC1D1 and Day 1 of subsequent cycles: For C1D1 screening assessments may serve as day 1 assessments if performed within 7 days before start of study treatment, except serum pregnancy (within 72 hours of drug) and except in the event that there are any indications that the participant's condition is deteriorating for which laboratory evaluations should be repeated within 48 hours prior to initiation. C1D1 labs must meet eligibility criteria. For all subsequent cycles, required assessments should be performed within 3 days of scheduled cycle day 1.  
cStudy drug therapy administration windows include + 3 days for each agent. dEnd of Tx: End of treatment assessments to be performed within 7 days after last day drug administration or within 7 days after decision to end treatment. Assessments may continue for ongoing reportable adverse events.  
e30-Day Post Drug: A contact/visit is to be performed at 30 days (+/-5 days) after the last study drug is given. This may be performed via documented phone conversation with a study nurse or clinician or a clinic visit. All participants will be followed until resolution or stabilization of any serious or reportable adverse events occurring during treatment or starting within 30 days of last study drug.  
fActive Follow Up: In participants who discontinue study treatment without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic imaging every 6 weeks (+/- 7 days) until (1) the start of new anti-cancer treatment, (2) documented disease progression, or (3) death whichever occurs first.  
gLong Term Follow Up: participants will be followed every 3 months (+/- 1 month) via contact or medical record review until death for posttreatment therapies, reason for stopping those therapies and survival.  
hInformed Consent: Informed Consent may be obtained within 28 days of start of study treatment iInclusion/Exclusion Criteria: source documentation providing investigator's confirmation that the participant had met all eligibility criteria must be available prior to registration.  
jDemographics and Medical History: to include review of treatment history for cancer, any ongoing medical conditions and medical history pertaining to eligibility on study and involvement during study.  
kConcomitant medications and reason for administration should be documented in the case history from within 28 days before starting study treatment up to the 30-Day Post Drug Visit.  
lAdverse event assessment: adverse events experienced by participants will be collected and recorded from the first dose of study treatment up to the 30-Day Post Drug Visit of the last dose of study medication (+/- 5 days depending on when 30-Day Post Drug visit/contact occurs) and all SAEs (related and unrelated to trial treatment) / ECIs up to 90 days after the last dose of trial mFull Physical Exam (including neurologic exam): to be completed by the investigator or qualified designee at screening, C1D1 and start of all subsequent cycles.  
nVital signs: weight, heart rate, blood pressure, respiration rate, temperature. Vital signs must be performed prior to administration of treatment on treatment days. Height required only at screening.  
oPerformance Status: See Appendix A for ECOG scale. pPregnancy Test: For women of child bearing potential, a urine pregnancy test should be performed within 72 hours of first dose of study treatment.  
If urine pregnancy results are positive or cannot be confirmed as negative, a serum pregnancy test will be required.  
qCoagulation - PT/INR, PTT required at screening only.  
rHematology: erythrocytes (RBC), hemoglobin, hematocrit, platelets, total WBC plus differential (neutrophils/ANC, lymphocytes, monocytes, eosinophils, basophils).  
sSerum Chemistry: albumin, alkaline phosphatase (ALP), bicarbonate (HCO3 ), BUN, calcium, chloride, creatinine, glucose, lactate dehydrogenase
(LDH) magnesium, phosphorous, potassium, SGOT (AST), SGPT (ALT), sodium, total protein, total bilirubin (if total bilirubin is greater than the upper limit of normal, direct should be performed), and uric acid.  
tTSH will be performed at baseline, week 1, beginning of cycle 2 and then every 2 cycles. TSH results do not need to be back prior to dosing uBrain MRI will be performed every 2 cycles. In the rare circumstance where patients have extracranial metastases, chest/abd/pelvis CT will also be obtained every 2 cycles. If pembrolizumab is held or interrupted, the scan schedule should be maintained at every 2 cycles.  
vAs per section 5.12, completed 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of study medication, whichever is later wTissue collected as part of clinical care (e.g. from prior biopsy, craniotomy) will be collected. Tissue needs to be submitted within 30 days after patient enrollment. See Section 9 for specimen collection requirements xBlood will be collected at screening every 2 cycles (two 10 mL EDTA/lavender top tube) and at the end of treatment
table 6 evaluating adverse events
11. measurement of effect 11.1

For the purposes of this study, participants should be re-evaluated for intracranial response every 6 weeks. In addition to a baseline scan, confirmatory scans should also be obtained at 6 weeks following initial documentation of objective response. Response and progression will be evaluated in this study using the modified RANO Response Criteria.
table 6 evaluating adverse events
11.2 definitions

Evaluable for objective response. Only those participants who have measurable CNS
disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for target disease response. These participants will have their response classified according to the definitions stated below. (Note: Participants who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Evaluable non-measurable evaluable disease. Participants who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
table 6 evaluating adverse events
11.2.1 disease parameters

Measurable disease. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥10 mm with MRI. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). For multifocal intracranial disease, no more than 5 target measurable lesions (each ≥10mm in diameter in both dimensions) should be selected for measurement. Target lesions should be selected on the basis of their size (lesions with longest diameter), be representative of other lesions and lend themselves to reproducible repeated measurements.  
Non-measurable disease. Unidimensionally measurable lesions, masses with margins not clearly defined, lesions with maximal diameter < 1cm.
table 6 evaluating adverse events
11.2.2 methods for evaluation of

All measurements should be taken and recorded in metric notation using a ruler, calipers, or a digital measurement tool. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 3 weeks before the beginning of the treatment.  
The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam.
table 6 evaluating adverse events
11.3 response criteria

11.3.1.1 Evaluation of Intracranial Lesions Complete Response (CR): Requires all of the following:
complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks no new lesions stable or decreasing corticosteroids (the steroid dose at the time of the scan evaluation should be no greater than the dose at time of baseline scan)
stable or improved clinically Participants with non-measurable disease cannot have a complete response. The best possible response is stable disease.
table 6 evaluating adverse events
partial response (pr) all of

Greater than or equal to 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this scan will be considered only stable disease.  
no progression of non-measurable disease.  
no new lesions stable or reduced corticosteroid dose (the steroid dose at the time of the scan evaluation should be no greater than the dose at time of baseline scan)
stable or improved clinically Progressive Disease (PD): At least one of the following must be true:
>25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline clear worsening of any nonmeasurable disease* appearance of any new enhancing lesion/site clear clinical worsening (unless clearly unrelated to this cancer, e.g. seizures, medication side effects, complications of therapy, cerebrovascular events, infecion)
failure to return for evaluation due to death or deteriorating condition
* Progression of non-measurable CNS lesions is defined as follows:
47 a lesion initially at baseline ≤ 5mm in diameter that increases to ≥ 10mm in diameter, or a lesion initially at baseline 6-9 mm in diameter that increases by at least 5 mm in diameter.  
a lesion that is smaller than 10mm that is too complex or has poorly defined margins, that is now unequivocally progressing by more than 25%
Stable Disease (SD): All of the following criteria must be met:
Does not qualify for CR, PR or progression All measurable and non-measurable sites must be assessed using the same techniques as baseline Stable clinically.  
A summary of the response criteria is in the below:  
| Complete                                                                                                                                                                                                                                      | Partial                 | Stable Disease   | Progressive   |          |        |    |           |    |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|------------------|---------------|----------|--------|----|-----------|----|
| Response                                                                                                                                                                                                                                      | Response                | Disease          |               |          |        |    |           |    |
| T1-Gd+                                                                                                                                                                                                                                        | None                    | >                | 50%           | <50%     |        |    |           |    |
| decrease                                                                                                                                                                                                                                      | decrease- <25% increase | >25%  increase*  |               |          |        |    |           |    |
| New Lesion                                                                                                                                                                                                                                    | None                    | None             | None          | Present* |        |    |           |    |
| Corticosteroids                                                                                                                                                                                                                               | Stable                  | or               | Stable        | or       | Stable | or | Stable    | or |
| decrease                                                                                                                                                                                                                                      | decrease                | decrease         | increasing    |          |        |    |           |    |
| Clinical Status                                                                                                                                                                                                                               | Stable                  | or               | Stable        | or       | Stable | or | Decrease* |    |
| improved                                                                                                                                                                                                                                      | improved                | improved         |               |          |        |    |           |    |
| Requirement for                                                                                                                                                                                                                               | All                     | All              | All           | Any*     |        |    |           |    |
| Response NA=not applicable #: Progression occurs when any of the criteria with * is present Increase in corticosteroids alone will not be taken into account in determining  progression in the absence of persistent clinical deterioriation |                         |                  |               |          |        |    |           |    |
table 6 evaluating adverse events
11.3.1.2 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. If a response recorded at one scheduled MRI does not persist at the next regular scheduled MRI, the response will still be recorded based on the prior scan, but will be designated as a non-sustained response. If the response is sustained, i.e. still present on the subsequent MRI at least four weeks later, it will be recorded as a sustained response, lasting until the time of tumor progression. Participants without 48 measurable disease may only achieve SD or PD as their best "response."
table 6 evaluating adverse events
11.3.2 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, or death due to any cause. Participants without events reported are censored at the last disease evaluation). Duration of overall complete response: The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented, or death due to any cause. Participants without events reported are censored at the last disease evaluation. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.
table 6 evaluating adverse events
11.3.3 study continuation beyond initial

Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific immune responses which may manifest as initial worsening of enhancement and edema on MRI or CT scans (i.e. pseudo-progression). In addition, the response patterns seen with immunotherapeutics may extend beyond the typical time course of responses seen with cytotoxic agents, and can manifest a clinical response after an initial increase in tumor burden or even the appearance of new lesions. For these reasons, the immune- related response criteria (irRC) have endorsed continuation of study therapy beyond initial radiographic evidence of progression for clinically stable patients undergoing immune based therapies. Therefore, the following adaptations will be used to assess response for patients treated on this study: Potential Pseudo-progression: If radiologic imaging shows initial PD, subjects who are not experiencing significant clinical decline, may be allowed to continue study treatment for up to three months. Patients who have radiographic evidence of progression after up to three months (as defined by progression as in 11.3.1.1), or who decline significantly at anytime, will be classified as progressive with the date of disease progression back-dated to the first date that the subject met criteria for progression and such subjects will be discontinued from study therapy. Three months is the most common timeframe for pseudo-progression observed among patients with advanced melanoma or other solid tumors treated with PD-1/PD-L1 immune checkpoint blockade40.  
Among patients on this study with initial radiographic PD, tumor assessment should be 49 repeated regularly in order to confirm PD with the option of continuing treatment as described below while awaiting radiologic confirmation of progression. If repeat imaging shows a stabilization or reduction in the tumor burden compared to the initial scan demonstrating PD, treatment may be continued / resumed. If repeat imaging after up to three months confirms progressive disease, then the date of disease progression will be the first date the subject met criteria for progression and subjects will be discontinued from study therapy. Subjects who have confirmed disease progression will discontinue study medication and enter the follow up/survival phase of the study. In determining whether or not the tumor burden has increased or decreased, investigators should consider all target lesions as well as non-target lesions. Tumor Enhancement to Define Progression: RANO expanded the previously utilized Macdonald criteria41 to include the development of "significantly" increased T2 or FLAIR abnormality in the definition of progressive disease because such changes can be a major component defining radiographic progression following therapeutic use of VEGF/VEGFR-targeting therapeutics which are known to elicit potent anti-permeability changes that limit contrast uptake. However, immune based therapies are expected to be associated with inflammatory changes that may include edema. Therefore, our study will define radiographic progressive disease by assessment of enhancing tumor burden only and will not include assessment of T2 or FLAIR changes as outlined in RANO because:
There is no expectation that immunotherapy agents including PD-1 inhibitors will falsely diminish enhancing tumor burden as has been noted with anti-angiogenic therapies; and Immune based therapies are expected to induce inflammatory responses which may be associated with increased edema and T2/FLAIR changes. Such radiographic finding may inaccurately be interpreted to represent tumor progression (i.e. pseudoprogression).  
Treatment beyond evidence of radiographic PD: In subjects who have initial evidence of radiographic PD, it is at the discretion of the treating physician whether to continue a subject on study treatment for up to three months pending confirmation of PD on followup imaging. This clinical judgment decision should be based on the subject's overall clinical condition, including performance status, clinical symptoms, and laboratory data. Subjects may receive study treatment while waiting for confirmation of PD if they are not experiencing significant clinical decline and if:
The subject is believed to demonstrate clinical benefit from the study regimen as determined by the treating physician; The subject is adequately tolerating study therapy.  
When feasible, study therapy should not be discontinued until radiographic progression is confirmed. This allowance to continue treatment despite initial radiologic progression takes into account the observation that some subjects can have a transient tumor flare in the first few months after the start of immunotherapy, but with subsequent disease response42. Subjects that are exhibiting significant neurologic decline are not required to have repeat imaging for confirmation of progressive disease. Participants with progressive radiographic findings are encouraged to undergo surgical intervention in order to delineate pseudo-progression due to inflammation associated with PD-1 blockade from true tumor progression. Participants with histopathologic findings of significant immune infiltrate and evolving gliosis will be allowed to continue study therapy. In contrast, those with clear evidence of progressive tumor by histopathologic evaluation will be defined as progressive and discontinued from study therapy. For such patients, the date of tumor progression will be the first date the participant met radiographic criteria for PD.
table 6 evaluating adverse events
11.3.4 response review

All brain MRI scans will be reviewed centrally by the DF/HCC Tumor Imaging Metrics Core (TIMC). CNS response will be assessed centrally using the criteria outlined in Section 11.0.
table 6 evaluating adverse events
11.4 antitumor effect - extracranial

For patients that have metastatic meningioma, participants should be re-evaluated for extracranial response every 6 weeks. In addition to a baseline scan, confirmatory scans should also be obtained 6 weeks following initial documentation of objective response. Response and progression will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [*Eur J Ca* 45:228-247, 2009]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.
table 6 evaluating adverse events
11.4.1 definitions

Evaluable for Target Disease response. Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for target disease response. These participants will have their response classified according to the definitions stated below. (Note: Participants who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Evaluable Non-Target Disease Response. Participants who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
table 6 evaluating adverse events
11.4.2 disease parameters

Measurable disease. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).  
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm 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. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis),
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all considered non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if noncystic lesions are present in the same participant, these are preferred for selection as target lesions. Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target** lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow up.
table 6 evaluating adverse events
11.4.3 methods for evaluation of

All measurements should be taken and recorded in metric notation using a ruler, calipers, or a digital measurement tool. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 3 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam.  
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial (*e.g.*, skin nodules and palpable lymph nodes) and ≥10 mm in diameter as assessed using calipers (*e.g.*, skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung; however, CT is preferable. Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size of a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (*e.g.* for body scans). Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible.
table 6 evaluating adverse events
11.4.4 response criteria

11.4.4.1 Evaluation of Target Lesions Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.  
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the 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 progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.  
11.4.4.2 Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. *Unequivocal progression* should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator).  
11.4.4.3 Evaluation of New Lesions The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning technique, 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). However, a lesion identified on a follow-up scan in an anatomical location that was not scanned at baseline is considered new and will indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up evaluation will clarify if it truly represents new disease and if PD is confirmed, progression should be declared using the date of the initial scan on which the lesion was discovered.  
54
table 6 evaluating adverse events
11.4.4.4 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.
table 6 evaluating adverse events
for participants with measurable disease

| Target   | Non-Target                                                                         | New       | Overall   | Best Overall Response when                       |
|----------|------------------------------------------------------------------------------------|-----------|-----------|--------------------------------------------------|
| Lesions  | Lesions                                                                            | Lesions   | Response  | Confirmation is Required*                        |
| CR       | CR                                                                                 | No        | CR        | >4 wks Confirmation**                            |
| CR       | Non-CR/NonPD                                                                                    | No        | PR        |                                                  |
| CR       | Not evaluated                                                                      | No        | PR        |                                                  |
| PR       | Non-CR/NonPD/not  evaluated                                                                                    | No        | PR        | >4 wks Confirmation**                            |
| SD       | Non-CR/NonPD/not  evaluated                                                                                    | No        | SD        | Documented at least once >4  wks from baseline** |
| PD       | Any                                                                                | Yes or No | PD        |                                                  |
| Any      | PD***                                                                              | Yes or No | PD        | no prior SD, PR or CR                            |
| Any      | Any                                                                                | Yes       | PD        |                                                  |
|         | See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. |           |           |                                                  |
| **       | Only for non-randomized trials with response as primary endpoint.                  |           |           |                                                  |
| ***      | In exceptional circumstances, unequivocal progression in non-target lesions may be |           |           |                                                  |
|          | accepted as disease progression.                                                   |           |           |                                                  |  
Note: Participants 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.
table 6 evaluating adverse events
for participants with non-measurable disease

| Non-Target Lesions   | New Lesions                                                                              | Overall Response   |
|----------------------|------------------------------------------------------------------------------------------|--------------------|
| CR                   | No                                                                                       | CR                 |
| Non-CR/non-PD        | No                                                                                       | Non-CR/non-PD*     |
| Not all evaluated    | No                                                                                       | not evaluated      |
| Unequivocal PD       | Yes or No                                                                                | PD                 |
| Any                  | Yes                                                                                      | PD                 |
|                     | 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is 55 |                    |  
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised
table 6 evaluating adverse events
11.4.5 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, or death due to any cause. Participants without events reported are censored at the last disease evaluation).  
Duration of overall complete response: The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented, or death due to any cause. Participants without events reported are censored at the last disease evaluation. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.
table 6 evaluating adverse events
11.4.6 progression-free survival

Overall Survival: Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation. Time to Progression: Time to Progression (TTP) is defined as the time from randomization (or registration) to progression, or censored at date of last disease evaluation for those without progression reported.
table 6 evaluating adverse events
11.4.7 response review

All non-CNS scans will be reviewed centrally by the DF/HCC Tumor Imaging Metrics Core (TIMC).
table 6 evaluating adverse events
12. end of treatment/intervention 12.1

Patients who are in CR, PR or SD will continue on therapy until progression of disease, excessive toxicity requiring the patient to come off of treatment, or the patient withdraws from treatment. After treatment is discontinued, patients will be followed per the study calendar in section 10.0.
table 6 evaluating adverse events
12.1.2 disease progression

Remove from protocol therapy any patient with disease progression. Document details, including tumor measurements, on data forms. After disease progression, patients should be followed for survival per the study calendar (Section 10.0).
table 6 evaluating adverse events
12.1.3 discontinuation of study agent

If the patient discontinues study agent, patients should be followed for disease progression and survival per the study calendar (Section 10.0).
table 6 evaluating adverse events
12.2 definitions and follow-up requirements

Definition of ineligible patients: A study participant who is registered to the trial but does not meet all of the eligibility criteria is deemed to be ineligible. Patients who are deemed ineligible may continue protocol treatment, provided the treating physician, study chair, and executive officer agree there are no safety concerns if the patient were to continue protocol treatment. Notification of the local IRB may be necessary per local IRB policies. Definition of clinical follow-up: The follow-up period where the study participant is no longer receiving treatment, but is still following the study calendar for tests, exams, and correlative endpoints (e.g., specimen collection, quality of life, disease assessments as required by the study).  
Definition of survival only follow-up: The follow-up period where the study participant is monitored for long-term endpoints, is no longer receiving study treatment, and is not required to follow the study calendar for tests, exams, and correlative endpoints (e.g. specimen collection, quality of life, disease assessments as required by the study). In this follow-up period, there is a schedule in which case report forms should be submitted, but the physician visits are based on the standard of care.
table 6 evaluating adverse events
12.2.1 follow-up for ineligible patients

Study participants who are registered to the trial but deemed ineligible must complete follow-up requirements as specified below. Baseline, on-study and off-treatment notice data submission required. 12.2.2 Follow-up for Patients Never Receiving Protocol Intervention Study participants who are registered to the trial but who never go on to receive study intervention must still complete follow-up requirements as specified below. Baseline, on-study and off-treatment notice data submission required.
table 6 evaluating adverse events
12.3 extraordinary medical circumstances

If, at any time the constraints of this protocol are detrimental to the patient's health and/or the patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In this event: Document the reason(s) for discontinuation of therapy on data forms. Follow the patient for protocol endpoints as required by the Study Calendar.
table 6 evaluating adverse events
13.0 statistical considerations 13.1 study

There will be a single phase 2 arm in this study. Patients with recurrent or residual meningioma will be eligible for this trial. There is no planned interim analysis.
table 6 evaluating adverse events
13.2 endpoints primary endpoints

The primary endpoint is progression-free survival at 6 months (PFS6). PFS6 is defined as not having progressive disease or death within six months of the first day of treatment. Contrastenhanced cranial magnetic resonance imaging (MRI) will be performed every 6 weeks. Standard response criteria will be used (see Section 11.0). All patients meeting the eligibility criteria that have signed the consent form and have begun treatment will be considered evaluable for the analysis of primary endpoint.
table 6 evaluating adverse events
secondary endpoints

1. Toxicity by CTCAE criteria (grade 3 or higher hematologic toxicity; grade 3 or higher neurologic toxicity)
2. Overall survival 3. Intracranial response as defined by RANO criteria
table 6 evaluating adverse events
exploratory endpoints 1. genetic alterations

The total accrual for this phase II trial will be 26 patients in order to achieve 24 evaluable patients. The estimated accrual rate will be approximately 1 patients per month for this protocol. Twenty-six patients will be accrued within 24-28 months. Based on 6 months of follow-up, the total study duration will be 36 months. Both men and women of all races and ethnic groups are eligible for this trial. Every effort will be made to include patients from minority populations.
table 6 evaluating adverse events
13.6 analysis of primary endpoints

The goal will be to enroll 24 patients. The primary endpoint is the rate of 6 month PFS. The trial will distinguish between 6 month PFS rates of 26% vs. 52%. The historical control of 6 month PFS is based on a recent meta-analysis showing a PFS-6 of 26% in recurrent Grade II/III
meningiomas43 and other studies in this patient population44-46. If at least 10 patients demonstrate 6 month PFS, among the 24 evaluable patients, the agent will be considered worthy of further study, yielding at least 88% power to detect a true 6 month PFS rate of at least 52%, using an exact binomial test with a one-sided significance level of 0.1, against the null hypothesis of 26% 6-month PFS.
table 6 evaluating adverse events
13.7 analysis of secondary endpoints

Safety and Tolerability: All adverse events recorded during the trial will be summarized for all patients having received one or more doses of pembrolizumab. The proportions of patients with grade-3 or higher hematologic toxicities or grade-3 or higher neurologic toxicities will be presented with 90% exact binomial confidence intervals. The incidence of events that are new or worsening from the time of first dose of treatment will be summarized according to system organ class and/or preferred term, severity (based on CTCAE grade), type of adverse event, and relation to study treatment. Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and tabulated by primary system organ class, and type of adverse event. Overall Survival: The distributions of overall survival will be summarized using the method of Kaplan-Meier. The follow-up of patients who are alive at the time of analysis will be censored at the date of last assessment of vital status. Median OS will be presented and accompanied by 90% confidence intervals estimated using log(-log(survival)) methodology. Survival point estimates at 3 and 6 months will also be presented with confidence intervals. Intracranial/Extracranial Response: Contrast-enhanced cranial magnetic resonance imaging (MRI) will be performed every 6 weeks. The proportion of patients with intracranial response (CR, PR or SD by RANO) will be presented with a two-sided, 90% exact binomial confidence interval.
table 6 evaluating adverse events
13.8 analysis of exploratory endpoints

Biomarkers of blood and tissue: Analyses of blood, imaging, and tissue biomarkers will be based on descriptive statistics, as appropriate for the biomarker. To examine response according to pre-treatment levels of biomarkers, the study sample will be divided retrospectively according to the primary endpoint of response or non-response. Pretreatment biomarker levels will be summarized descriptively for the two response groups and compared using Wilcoxon rank-sum tests for markers measured on a continuous scale, or Fisher's exact tests for those measured on a categorical scale. Where appropriate, visualization of the relationship between baseline marker levels and the distributions of PFS or OS will employ Kaplan-Meier estimates stratified by biomarker levels. Medians of the time-to-event endpoints will be shown with two-sided 90% confidence intervals; the distributions of PFS and OS will be compared across biomarker strata using the log-rank test. Changes in biomarkers between pretreatment and progression or treatment discontinuation will be calculated (post-pre) for each patient and summarized descriptively. In addition, the correlation of changes in tissue biomarkers with changes in measures of peripheral blood markers will be explored graphically, or by appropriate statistical methods based on data availability, to assess associations.
table 6 evaluating adverse events
13.9 reporting and exclusions 13.9.1

All participants who have received at least one dose of study medication will be evaluable for toxicity from the time of their first treatment.
table 6 evaluating adverse events
13.9.2 evaluation of the primary

To be included in the assessment of the primary objective, patients need to receive at least one cycle. If systemic progression occurs prior to the 6 week CNS response timepoint, patient will still be included in the analysis of primary objective.
table 6 evaluating adverse events
14 publication plan

The results should be made public within 24 months of reaching the end of the study. The end of the study is the time point at which the last data items are to be reported, or after the outcome data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. A full report of the outcomes should be made public no later than three (3) years after the end of the study.
table 6 evaluating adverse events
references

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11. Chamberlain MC. Hydroxyurea for recurrent surgery and radiation refractory highgrade meningioma. J Neurooncol 2012;107:315-21.  
12. Chamberlain MC, Glantz MJ. Interferon-alpha for recurrent World Health Organization grade 1 intracranial meningiomas. Cancer 2008;113:2146-51. 13. Norden AD, Raizer JJ, Abrey LE, et al. Phase II trials of erlotinib or gefitinib in patients with recurrent meningioma. Journal of neuro-oncology 2010;96:211-7.  
14. Brastianos PK, Horowitz PM, Santagata S, et al. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet 2013;45:285-9. 15. Clark VE, Erson-Omay EZ, Serin A, et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science 2013;339:1077-80. 16. Du Z, Abedalthagafi M, Aizer AA, et al. Increased expression of the immune modulatory molecule PD-L1 (CD274) in anaplastic meningioma. Oncotarget 2014. 17. Furtner J, Schopf V, Seystahl K, et al. Kinetics of tumor size and peritumoral brain edema before, during, and after systemic therapy in recurrent WHO grade II or III meningioma. Neuro-oncology 2015. 18. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122-33. 19. Brastianos PK, Taylor-Weiner A, Manley PE, et al. Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nat Genet 2014;46:161-5. 20. Brastianos PK, Carter SL, Santagata S, et al. Genomic Characterization of Brain 61 Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov 2015. 21. Brastianos PK, Carter SL, Santagata S, Taylor-Weiner A. Abstract: Genomic characterization of 101 brain metastases and paired primary tumors reveals patterns of clonal evolution and selection of driver mutations. AACR 2014.  
22. Brastianos PK, Taylor-Weiner A, Manley PE, et al. Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nat Genet 2014. 23. Shankar GM, Taylor-Weiner A, Lelic N, et al. Sporadic hemangioblastomas are characterized by cryptic VHL inactivation. Acta neuropathologica communications 2014;2:2. 24. Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 2013;29:15-21. 25. Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC bioinformatics 2011;12:323.  
26. DeLuca DS, Levin JZ, Sivachenko A, et al. RNA-SeQC: RNA-seq metrics for quality control and process optimization. Bioinformatics 2012;28:1530-2. 27. Brooks AN, Yang L, Duff MO, et al. Conservation of an RNA regulatory map between Drosophila and mammals. Genome research 2011;21:193-202. 28. Abedalthagafi MS, Bi WL, Merrill PH, et al. ARID1A and TERT promoter mutations in dedifferentiated meningioma. Cancer genetics 2015;208:345-50. 29. Abedalthagafi MS, Merrill PH, Bi WL, et al. Angiomatous meningiomas have a distinct genetic profile with multiple chromosomal polysomies including polysomy of chromosome 5. Oncotarget 2014;5:10596-606. 30. Lamszus K LU, Schmidt NO, Stavrou D, Ergun S, Westphal M. Vascular endothelial growth factor, hepatocyte growth factor/scatter factor, basic fibroblast growth factor, and placenta growth factor in human meningiomas and their relation to angiogenesis and malignancy. Neurosurgery 2000;46:938-47 31. Zhu XP LK, Kamaly-Asl ID, et al. Quantification of endothelial permeability, leakage space, and blood volume in brain tumors using combined T1 and T2* contrast-enhanced dynamic MR imaging. J Magn Reson Imaging 2000;11:575-85. 32. Sorensen AG BT, Zhang WT, et al. A "vascular normalization index" as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res 2009;69:5296-300.  
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35. Yang S LM, Zagzag D, et al. Dynamic contrast-enhanced perfusion MR imaging measurements of endothelial permeability: differentiation between atypical and typical meningiomas. AJNR Am J Neuroradiol 2003;24:1554-9. 36. Batchelor TT SA, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11:83-95. 37. Sorensen AG EK, Polaskova P, et al. Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res 2012;72:402-7. 38. Gerstner ER CP, Wen PY, Jain RK, Batchelor TT, Sorensen G. Infiltrative patterns of 62 glioblastoma spread detected via diffusion MRI after treatment with cediranib. Neuro Oncol 2010;12:466-72. 39. Batchelor TT GE, Emblem KE, et al. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation.  
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43. Kaley T, Barani I, Chamberlain M, et al. Historical benchmarks for medical therapy trials in surgery- and radiation-refractory meningioma: a RANO review. Neuro Oncol 2014;16:829-40. 44. Norden AD, Ligon KL, Hammond SN, et al. Phase II study of monthly pasireotide LAR (SOM230C) for recurrent or progressive meningioma. Neurology 2015;84:280-6. 45. Wen PY, Yung WK, Lamborn KR, et al. Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01-08). Neuro Oncol 2009;11:853-60. 46. Norden AD, Raizer JJ, Abrey LE, et al. Phase II trials of erlotinib or gefitinib in patients with recurrent meningioma. J Neurooncol 2010;96:211-7.  
| ECOG Performance Status Scale                                                                                                           | Karnofsky Performance Scale                                                             |                                                                        |                                                            |                                       |             |
|-----------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------|------------------------------------------------------------------------|------------------------------------------------------------|---------------------------------------|-------------|
| Grade                                                                                                                                   | Descriptions                                                                            | Percent                                                                | Description                                                |                                       |             |
| 100                                                                                                                                     | Normal, no complaints, no evidence                                                      |                                                                        |                                                            |                                       |             |
| Normal activity. Fully active, able                                                                                                     | of disease.                                                                             |                                                                        |                                                            |                                       |             |
| 0                                                                                                                                       | to                                                                                      | carry                                                                  | on                                                         | all                                   | pre-disease |
| performance without restriction.                                                                                                        | 90                                                                                      | Able to carry on normal activity;  minor signs or symptoms of disease. |                                                            |                                       |             |
| Symptoms,                                                                                                                               | but                                                                                     | ambulatory.                                                            |                                                            |                                       |             |
| Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  70                              | Cares for self, unable to carry on                                                      |                                                                        |                                                            |                                       |             |
| sedentary                                                                                                                               | nature                                                                                  | (e.g.,                                                                 | light                                                      | normal activity or to do active work. |             |
| housework, office work).                                                                                                                | 80                                                                                      | Normal activity with effort; some  signs or symptoms of disease.       |                                                            |                                       |             |
| 1                                                                                                                                       | Requires occasional assistance, but                                                     |                                                                        |                                                            |                                       |             |
| 60                                                                                                                                      | is able to care for most of his/her                                                     |                                                                        |                                                            |                                       |             |
| 2                                                                                                                                       | needs.                                                                                  |                                                                        |                                                            |                                       |             |
| In                                                                                                                                      | bed                                                                                     | <50%                                                                   | of                                                         | the                                   | time.       |
| Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours. 50 | Requires considerable assistance and  frequent medical care.                            |                                                                        |                                                            |                                       |             |
| In bed >50% of the time. Capable  40                                                                                                    | Disabled, requires special care and  assistance.                                        |                                                                        |                                                            |                                       |             |
| 3                                                                                                                                       | of only limited self-care, confined  to bed or chair more than 50% of  waking hours. 30 | Severely                                                               | disabled,                                                  | hospitalization                       |             |
| indicated. Death not imminent.                                                                                                          |                                                                                         |                                                                        |                                                            |                                       |             |
| 100%                                                                                                                                    | bedridden.                                                                              | Completely  20                                                         | Very sick, hospitalization indicated.  Death not imminent. |                                       |             |
| 4                                                                                                                                       | disabled.                                                                               | Cannot carry on any                                                    |                                                            |                                       |             |
| self-care. Totally confined to bed  or chair. 10                                                                                        | Moribund,                                                                               | fatal                                                                  | processes                                                  |                                       |             |
| progressing rapidly.                                                                                                                    |                                                                                         |                                                                        |                                                            |                                       |             |
| 5                                                                                                                                       | Dead.                                                                                   | 0                                                                      | Dead.                                                      |                                       |             |  
APPENDIX B Event of clinical interest guidance document