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11.1.3 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 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 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. FDG-PET. While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion. (b) No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD. (c) FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively described in the protocol and supported by disease-specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.  
Note: A 'positive' FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image. PET-CT. At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed. Cytology, Histology. These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases (*e.g.*, residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain). The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease.
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11.1.4 response criteria

11.1.4.1 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.  
11.1.4.2 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).  
11.1.4.3 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.  
11.1.4.4 Evaluation of Best Overall Response
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.
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for participants with measurable disease

| Lesions   | Lesions                                                                            | Lesions   | Response   | Confirmation is Required*                        |
|-----------|------------------------------------------------------------------------------------|-----------|------------|--------------------------------------------------|
| CR        | CR                                                                                 | No        | CR         | >4 wks Confirmation**                            |
| CR        | Non-CR/NonPD                                                                                    | No        | PR         | >4 wks Confirmation**                            |
| CR        | Not evaluated                                                                      | No        | PR         |                                                  |
| PR        | Non-CR/NonPD/not  evaluated                                                                                    | No        | PR         |                                                  |
| 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.  
| 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  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 |                    |
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11.1.5 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.
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11.1.6 progression-free survival

Overall Survival: Overall Survival (OS) is defined as the time from 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 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.
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11.2 antitumor effect - intracranial

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 4 weeks following initial documentation of objective response. Response and progression will be evaluated in this study using the modified RANO Response Criteria.
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11.2.1 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 in the CNS. 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.
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11.2.2 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 ≥10 mm with CT scan, MRI, or calipers by clinical exam. 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.
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11.2.3 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 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 is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. Conventional head CT and brain 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.
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11.2.4 response criteria

11.2.4.1 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.
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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:
- 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.  
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 Response  
Partial Response  
Stable Disease Progressive  
Disease  
T1-Gd+ None > 50%  
decrease  
<50% decrease- <25% increase  
New Lesion None None None Present*  
| Disease >25%  increase*   |
|---------------------------|  
| 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 |          |          |            |      |          |      |           |      |  
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
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11.2.4.2 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 measurable disease may only achieve SD or PD as their best "response."
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11.2.4.3 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.
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11.2.5 study continuation beyond initial

Immunotherapeutic agents such as ipilimumab and nivolumab 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 further progression after up to three months, 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 blockade17.  
Among patients on this study with initial radiographic PD, tumor assessment should be 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 criteria18 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).  
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 follow-up 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 response19. 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.
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11.3 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 RANO criteria outlined in Section 12.1.4. All non-CNS scans will be reviewed centrally by the DF/HCC Tumor Imaging Metrics Core (TIMC). Extracranial response will be assessed centrally using RECIST criteria.
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11.4 other response parameters

Cerebrospinal Fluid: Cerebrospinal fluid will collected as part of clinical care.  
| Response                             | Cytologic                                                           | Neurologic                                                              | Radiographic                                                                                             |         |                              |    |            |
|--------------------------------------|---------------------------------------------------------------------|-------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------|---------|------------------------------|----|------------|
| Complete                             | Reversion                                                           | to                                                                      | (-)                                                                                                      | CSF     | Disappearance of all disease |    |            |
| Response                             | cytology (or NA)                                                    | related                                                                 | symptoms                                                                                                 | present |                              |    |            |
| prior to therapy (or NA)             | Complete disappearance of  all detectable radiographic  EOD (or NA) |                                                                         |                                                                                                          |         |                              |    |            |
| Partial                              | >                                                                   | 50%                                                                     | decrease                                                                                                 | in      | Improvement                  | in | neurologic |
| Response                             | malignant CSF cytology                                              | symptoms or no worsening of  symptoms                                   | Improvement in radiographic  evidence of disease. No new  sites of measurable or  assessable CNS disease |         |                              |    |            |
| Stable                               | Not fulfilling the criteria                                         |                                                                         |                                                                                                          |         |                              |    |            |
| Disease                              | for CR or PR, but not  progressive disease                          | Not fulfilling the criteria for  CR or PR, but not progressive  disease | Not fulfilling the criteria for  CR, or PR but is not  progressive disease                               |         |                              |    |            |
| Progressive                          | >                                                                   | 50%                                                                     | increase                                                                                                 | in      | Development                  | of | new        |
| Disease                              | malignant CSF cytology                                              | neurologic symptoms related  to neoplastic meningitis                   | Increase                                                                                                 | in      | radiographic                 |    |            |
| evidence                             | of                                                                  | disease.                                                                |                                                                                                          |         |                              |    |            |
| Appearance of new sites of  disease. |                                                                     |                                                                         |                                                                                                          |         |                              |    |            |  
Leptomeningeal response will be defined as below:
Leptomeningeal response will be a secondary outcome. The immune related Response Criteria (irRC) will also be used in this study to support secondary efficacy endpoints for extracranial lesiona. Definitions of the immune-related Response Criteria (irRC) are below and are presented in Appendix B:
- Complete Response (CR): Disappearance of all lesions in two consecutive observations not less than 4 wk apart
- Partial Response (PR): ≥50% decrease in tumor burden compared with baseline in two observations at least 4 wk apart
- Stable Disease (SD): 50% decrease in tumor burden compared with baseline cannot be established nor 25% increase compared with nadir
- Progressive Disease (PD): At least 25% increase in tumor burden compared with nadir (at any single time point) in two consecutive observations at least 4 wk apart  
Index Lesion  
Non-Index Lesion  
New Measurable Lesions  
| New  Measurable  Lesions   | New  unmeasurable  lesions   | % change in   | Overall IR   |
|----------------------------|------------------------------|---------------|--------------|
| tumor burden               | Response  irSD               |               |              |
| <25%                       | irSD                         |               |              |
| <+25%                      |                              |               |              |  
CR CR No No -100% irCR PR Any Any Any > -50% irPR PR Any Any Any < -50% to  
<25%  
irSD  
PR Any Any Any > +25% irPD SD Any Any Any < -50% to  
<+25%  
irSD  
SD Any Any Any > +25% irPD PD Any Any Any > +25% irPD
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12. data reporting / regulatory

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: List and Reporting Requirements).
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12.1 data reporting

12.1.1 Method
The ODQ will collect, manage, and perform quality checks on the data for this study.  
12.1.2 Responsibility for Data Submission Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data forms to the ODQ according to the schedule set by the ODQ.  
| Form                         | Submission Timeline                                                             |    |      |    |    |
|------------------------------|---------------------------------------------------------------------------------|----|------|----|----|
| Eligibility Checklist        | Complete prior to registration with ODQ                                         |    |      |    |    |
| On Study Form                | Within 14 days of registration                                                  |    |      |    |    |
| Baseline Assessment Form     | Within 14 days of registration                                                  |    |      |    |    |
| Treatment Form               | Within 10 days of treatment administration                                      |    |      |    |    |
| Adverse Event Report Form    | Within                                                                          | 10 | days | of | AE |
| assessment/notification      |                                                                                 |    |      |    |    |
| Response Assessment Form     | Within 10 days of response assessment                                           |    |      |    |    |
| Off Treatment/Off Study Form | Within 14 days of completing treatment or  being taken off study for any reason |    |      |    |    |
| Follow up/Survival Form      | Within 14 days of the protocol defined  follow up visit date or call            |    |      |    |    |  
12.2 **Data Safety Monitoring**
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual data from this study. The committee is composed of clinical specialists with experience in oncology and who have no direct relationship with the study. Information that raises any questions about participant safety will be addressed with the Overall PI and study team. The DSMC will review each protocol up to four times a year or more often if required to review toxicity and accrual data. Information to be provided to the committee may include: up-to-date participant accrual; current dose level information; DLT information; all grade 2 or higher unexpected adverse events that have been reported; summary of all deaths occurring with 30 days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths while being treated and during active follow-up; any response information; audit results, and a summary provided by the study team. Other information (e.g. scans, laboratory values) will be provided upon request. 12.3 **Multicenter Guidelines** N/A 12.4 **Collaborative Agreements Language** N/A
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13. statistical considerations

This is a single arm phase II trial to investigate the therapeutic effect of ipilimumab and nivolumab in leptomeningeal carcinomatosis.
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13.1 study design/endpoints

Primary endpoint: Rate of overall survival at 3 months Secondary Endpoints: 1. Toxicity by CTCAE criteria (grade 3 or higher hematologic toxicity; grade 3 or higher neurologic toxicity) 2. Intracranial response in patients with leptomeningeal metastases 3. Extracranial response as determined by RECIST and irRC 4. Leptomeningeal disease response as defined in section 11.4 5. Time to the first occurrence of extracranial disease progression, or death from any cause 6. Time to the first occurrence of intracranial disease progression, or death from any cause
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exploratory endpoints genetic alterations 13.2

Accrual of up to 20 patients may be required to achieve 18 evaluable patients. The primary endpoint is the rate of overall survival at 3 months (OS3). Any patient whose vital status at 3 months cannot be determined will be counted as having died. A Simon two-stage design will be used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Nine patients will be enrolled in the first stage. If 0 or 1 patients are alive at 3 months, the trial will be stopped early. If 2 or more patients are alive at 3 months, we will enroll an additional 9 patients. If at least 6 patients among the total of 18 patients are alive at 3 months, then the treatment would be promising in the cohort. This design has a type-I error of 8% (target 10%) and power of 86% (target 85%). If the null hypothesis is true, then the probability is 0.50 of stopping at the end of the first stage. In addition, we will assess for the primary outcome of any histologic, molecular subtype (e.g., ER/PR-positive, HER2-positive breast cancer, EGFR mutant lung cancer) with 6 patients enrolled for that particular subtype. If no patient within a particular histologic subtype has achieved the primary outcome, then patients with that histology will no longer be eligible to enroll in the trial. Under the alternative hypothesis (i.e., OS3 = 43%), the probability is 0.03 of observing no patients with OS3 among 6 patients.  
The accrual rate is based on our institutional patient volume of 3-4 patients per month with leptomeningeal carcinomatosis seen in our multidisciplinary brain metastasis clinic. We estimate that 1-2 patients per month will be eligible for this protocol. Therefore, 20 patients will be accrued within 10-20 months. Based on six months of follow-up (median survival of patients is approximately 2-4 months), total study duration will be 24 months.
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13.5 analysis of primary endpoints

The primary endpoint is the rate of overall survival at 3 months (OS3). Any patient whose vital status is unknown due to loss of follow-up will be classified as having died for purposes of estimating the primary endpoint. The proportion of patients alive at 3 months will be summarized with a 90% confidence interval estimated using the method of Atkinson and Brown, which allows for the two-stage design. Based on a sample of 18 patients, the confidence interval will be no wider than 0.42.
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13.6 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 ipilimumab and nivolumab. The data for each cohort will be summarized separately, although safety data may be combined, if appropriate. 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. Intracranial/Extracranial Response: The proportion of patients with intracranial response of intraparenchymal brain metastases (CR or PR by RANO) will be presented with a two-sided, 90% exact binomial confidence interval. For a sample of 18 patients, the confidence interval will have maximum width of 0.42. Extracranial response rates (CR or PR) according to RECIST and irRC will be summarized. Rates will be accompanied by two-sided 90% exact binomial confidence intervals. Cases where RECIST and irRC responses do not agree will be documented.  
Leptomeningeal Disease Response: The proportion of patients with leptomeningeal disease response (CR or PR) will be presented with a two-sided, 90% exact binomial confidence interval. For a sample of 18 patients, the confidence interval will have maximum width of 0.42. Extracranial PFS and Intracranial PFS: Extracranial PFS (EPFS) is defined as the time from first dose of study drug to documented extracranial progression (per RECIST or irRC) or death, whichever occurs first. Intracranial PFS (IPFS) is defined as the time from first dose of ipilimumab and nivolumab to documented intracranial progression (RANO) or death, whichever occurs first. For both endpoints, the follow-up of patients who have neither died nor progressed at the time of analysis will be censored at the date of last adequate disease assessment. Each cohort will be presented separately. Median EPFS and IPFS will be presented and accompanied by 90% confidence intervals estimated using log(-log(survival)) methodology. Point estimates at 3 and 6 months will also be presented with confidence intervals.
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13.7 analysis of exploratory endpoints

Biomarkers of blood and tissue: Analyses of blood 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.
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13.8 reporting and exclusions 13.8.1

All participants who have received at least one dose of nivolumab and ipilimumab will be evaluable for toxicity from the time of their first treatment.
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13.8.2 evaluation of the primary

To be included in the assessment of the primary objective, patients need to receive at least one cycle.
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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.
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references

1. Brastianos PK, Brastianos H, Eichler AF. Leptomeningeal Carcinomatosis. In: Palmieri D, ed. Central Nervous System Metastasis, the Biological Basis and Clinical Consideraiton. New York: Springer; 2013:187-201. 2. Raizer JJ, Hwu WJ, Panageas KS, et al. Brain and leptomeningeal metastases from cutaneous melanoma: survival outcomes based on clinical features. Neuro-oncology 2008;10:199-207. 3. Glantz MJ, Jaeckle KA, Chamberlain MC, et al. A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 1999;5:3394-402. 4. Grossman SA, Finkelstein DM, Ruckdeschel JC, Trump DL, Moynihan T, Ettinger DS. Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. Eastern Cooperative Oncology Group. J Clin Oncol 1993;11:561-9. 5. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16. 6. Flaherty KT, Robert C, Hersey P, et al. Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma. N Engl J Med 2012. 7. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012;380:35865. 8. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23. 9. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dosecomparison cohort of a phase 1 trial. Lancet 2014;384:1109-17.  
10. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:2517-26. 11. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med 2013. 12. Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, openlabel, phase 2 trial. Lancet Oncol 2012.  
13. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012;13:459-65. 14. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012;13:459-65. 15. Ahmed KA, Stallworth DG, Kim Y, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol 2016;27:434-41. 16. Bot I, Blank CU, Brandsma D. Clinical and radiological response of leptomeningeal melanoma after whole brain radiotherapy and ipilimumab. J Neurol 2012;259:1976-8. 17. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-65. 18. Macdonald DR, Cascino TL, Schold SC, Jr., Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8:1277-80. 19. Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412-20.  
| ECOG Performance Status Scale                                                                                                                                                              | Karnofsky Performance Scale                                   |                                                                           |                                                                        |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|---------------------------------------------------------------------------|------------------------------------------------------------------------|
| Grade                                                                                                                                                                                      | Descriptions                                                  | Percent                                                                   | Description                                                            |
| 100                                                                                                                                                                                        | Normal, no complaints, no evidence  of disease.               |                                                                           |                                                                        |
| Normal activity. Fully active, able                                                                                                                                                        |                                                               |                                                                           |                                                                        |
| 0                                                                                                                                                                                          | to carry on all pre-disease  performance without restriction. | 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  sedentary nature (e.g., light  housework, office work). | 80                                                            | Normal activity with effort; some  signs or symptoms of disease.          |                                                                        |
| 1                                                                                                                                                                                          | 70                                                            | Cares for self, unable to carry on  normal activity or to do active work. |                                                                        |
| 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.                             | Requires occasional assistance, but                           |                                                                           |                                                                        |
| 60                                                                                                                                                                                         | is able to care for most of his/her  needs.                   |                                                                           |                                                                        |
| 2                                                                                                                                                                                          | 50                                                            | Requires considerable assistance and  frequent medical care.              |                                                                        |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                                                     | 40                                                            | Disabled, requires special care and  assistance.                          |                                                                        |
| 3                                                                                                                                                                                          | 30                                                            | Severely disabled, hospitalization  indicated. Death not imminent.        |                                                                        |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                   | 20                                                            | Very sick, hospitalization indicated.  Death not imminent.                |                                                                        |
| 4                                                                                                                                                                                          | 10                                                            | Moribund, fatal processes  progressing rapidly.                           |                                                                        |
| 5                                                                                                                                                                                          | Dead.                                                         | 0                                                                         | Dead.                                                                  |
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appendix b tumor assessment per

Immune-related Response Criteria (irRC) are derived from modified World Health Organization (mWHO) conventions. Assessments of lymph nodes are derived from current RECIST guidelines.
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definitions of measurable/non-measurable lesions

All measurable and non-measurable lesions should be assessed at Screening and at the defined tumor assessment time points. Additional assessments may be performed, as clinically indicated for suspicion of progression.
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measurable lesions

Measurable lesions are lesions that can be accurately measured in 2 perpendicular diameters, with at least 1 diameter > 20 mm and the other dimension > 10 mm (10 mm x 10 mm for spiral CT with cuts of 5 mm). The area will be defined as the product of the largest diameter with its perpendicular. Lymph nodes may also be considered measurable. To be considered pathologically enlarged and measurable, a lymph node must be at least 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).
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non-measurable lesions

Non-measurable (evaluable) lesions are all other lesions, including unidimensional measurable disease and small lesions (lesions without at least 1 diameter > 20 mm, or pathological lymph nodes with short axis  15 mm), and any of the following: lesions occurring in a previously irradiated area (unless they are documented as new lesions since the completion of radiation therapy), bone lesions, leptomeningeal disease, ascites, pleural or pericardial effusion, lymphangitis cutis/pulmonis, abdominal masses that are not pathologically/cytologically confirmed and followed by imaging techniques and cystic lesions. Lymph nodes that have a short axis < 10 mm are considered non-pathological and should not be recorded or followed.
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definitions of index/non-index lesions index

Measurable lesions, up to a maximum of 5 lesions per organ and ten lesions in total, must be identified as index lesions to be measured at Screening. The index lesions should be representative of all involved organs. In addition, index lesions must be selected based on their size (eg, lesions with the longest diameters), their suitability for accurate repeat assessment by imaging techniques, and how representative they are of the subject's tumor burden. At Screening, a Sum of the Product Diameters (SPD) for all index lesions will be calculated and considered the baseline SPD. The baseline sum will be used as the reference point to determine the objective tumor response of the index lesions at tumor assessment.
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non index lesions

Measurable lesions, other than index lesions, and all sites of non-measurable disease, will be identified as non-index lesions. Non-index lesions will be evaluated at the same assessment time points as the index lesions. In subsequent assessments, changes in non-index lesions will contribute only in the assessment of complete response.
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calculation of sum of product

Sum of Product of Diameters is an estimate of tumor burden. The 2 greatest perpendicular diameters are used to estimate the size of each tumor lesion. The SPD is calculated as the sum of the product of the diameters for index tumor lesions. Several variations of the SPD are identified for the purpose of classification of tumor responses. SPD at Baseline: The sum of the product of the diameters for all index lesions identified at baseline prior to treatment on Day 1. SPD at tumor assessment: For every on-study tumor assessment collected per protocol or as clinically indicated, the SPD at tumor assessment will be calculated using tumor imaging scans. All index lesions and all new measurable lesions that have emerged after baseline will contribute to the SPD at tumor assessment (irSPD). SPD at NADIR: For tumors that are assessed more than 1 time after baseline, the lowest value of the SPD (SPD Baseline or SPD at tumor assessment) is used to classify subsequent tumor assessments for each subject. The SPD at tumor assessment using the irRC for progressive disease incorporates the contribution of new measurable lesions. Each net percentage change in tumor burden per assessment using irRC accounts for the size and growth kinetics of both old and new lesions as they appear. In this study the irRC as defined by the Investigator will serve as the basis of key endpoints for efficacy analyses and guide clinical care.
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definition of index lesion response

Immune-related Complete Response (irCR), which is defined as complete disappearance of all index lesions. Lymph nodes that shrink to < 10 mm short axis are considered normal. Immune-related Partial Response (irPR), which is defined as a decrease, relative to baseline, of 50% or greater in the sum of the products of the 2 largest perpendicular diameters of all index and all new measurable lesions (ie, Percentage Change in Tumor Burden), in the absence of irCR. Note: the appearance of new measurable lesions is factored into the overall tumor burden, but does not automatically qualify as progressive disease until the SPD increases by > 25% when compared to SPD at nadir Immune-related Stable Disease (irSD), which is defined as not meeting the criteria for irCR or irPR, in the absence of immune-related progressive disease (irPD) Immune-related Progressive Disease (irPD), which is defined as at least a 25% increase in Tumor Burden (ie, taking sum of the products of all index lesions and any new measurable lesions) when compared to SPD at nadir.
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definition of non-index lesion response

Immune-related Complete Response (irCR), which is defined as complete disappearance of all non-index lesions. Lymph nodes that shrink to < 10 mm short axis are considered normal.  
Immune-related Partial Response (irPR), non-index lesion(s) are not considered in the definition of PR, this term does not apply. Immune-related Stable Disease (irSD), non-index lesion(s) are not considered in the definition of SD, this term does not apply. Immune-related Progressive Disease (irPD), increases in number or size of non-index lesion(s) does not constitute progressive disease unless/until Tumor Burden increases by 25% (ie, the SPD at nadir of index lesions and any new measurable lesions increases by the required amount).
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impact of new lesions on

New lesions alone do not qualify as progressive disease. However their contribution to total tumor burden is included in the SPD which in turn feeds into the irRC for tumor response. Therefore, new non-measurable lesions will not discontinue any subject from the study. Definition of Overall Response Using irRC Will Be Based on the Following Criteria:
- Immune-related Complete Response (irCR): Complete disappearance of all tumor lesions
(index and non-index), together with no new measurable or unmeasurable lesions, for at least 4 weeks from the date of documentation of irCR. All lymph nodes short axes must be < 10 mm.  
- Immune-related Partial Response (irPR): The sum of the products of the 2 largest perpendicular diameters of all index lesions is measured and captured as the SPD baseline. At each subsequent tumor assessment, the sum of the products of the 2 largest perpendicular diameters of all index lesions and of new measurable lesions are added together to provide the Immune Response Sum of the Product of the Diameters (irSPD). A decrease, relative to baseline of the irSPD of 50% or greater is considered an irPR, in the absence of irCR. Must be confirmed no less than 4 weeks from the first irPR.  
- Immune-related Stable Disease (irSD): irSD is defined as the failure to meet criteria for immune complete response or immune partial response, in the absence of progressive disease.  
- Immune-related Progressive Disease (irPD): It is recommended in difficult cases (eg, increase in SPD or irSPD accompanied with significant individual lesion regression, "mixed response", or in presence of stable or improving performance status/clinical condition) to confirm PD at the following tumor assessment. Any of the following will constitute progressive disease:
- At least 25% increase in the SPD of all index lesions over nadir SPD calculated for these lesions
- At least a 25% increase in the SPD of all index lesions and new measurable lesions
- (irSPD) over the nadir SPD calculated for the index lesions.
protocol number nci tbd bmsca209-405
impact of new lesions on

TITLE: Phase II Trial of Ipilimumab and Nivolumab in Leptomeningeal Metastases from Melanoma PHARMACY **MANUAL**
Version 2.0 May 14, 2018  
  
Bristol-Myers Squibb Research and Development Pharmacy Services P.O. Box 4000 Princeton, NJ 08543
protocol number nci tbd bmsca209-405
document history

| Document     | Date of Issue   | Summary of Change                                              |
|--------------|-----------------|----------------------------------------------------------------|
| Manual V 1.0 | May 19, 2016    | Version 1.0                                                    |
| Manual V 2.0 | May 14, 2018    | Nivolumab and Ipilimumab infusion times reduced to 30 minutes. |  
| DOCUMENT HISTORY 2 TABLE OF CONTENTS 3 1 OBJECTIVE 3 2 SPONSOR CONTACTS 4 3 STUDY TREATMENT 5 3.1 Nivolumab (BMS-936558) 5 3.1.1 Product Description 3.1.2 Handling and Dose Preparation 3.1.3 Product storage and stability 3.2 Ipilimumab 7 3.2.1 Product Description 3.2.2 Handling and Dose Preparation 3.2.3 Product storage and stability 4 SITE TEMPERATURE EXCURSIONS 10 5 PRODUCT RECEIPT, ACCOUTABILITY, AND  DESTRUCTION 10 6 DATA COLLECTION 11 APPENDIX 1 TEMPERATURE EXCURSION RESPONSE   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
APPENDIX 1 TEMPERATURE EXCURSION RESPONSE  
FORM .................................................................. 12  
TABLE OF CONTENTS  
| APPENDIX 2   | SAMPLE CALCULATION FORM 13   |
|--------------|------------------------------|
protocol number nci tbd bmsca209-405
1 objective

The objective of this procedure manual is to provide the study site with clear and detailed information for the storage, handling, preparation and administration of clinical products used in the Bristol-Myers Squibb CA209-405. The information within this procedure manual is intended to supplement Section 8 of the CA209-405 clinical protocol.
protocol number nci tbd bmsca209-405
2 sponsor contacts

If concerns regarding the quality or appearance of the study drug, or questions regarding administration arise, do not dispense the study drug and contact the Bristol-Myers Squibb immediately:
Questions with regard to drug preparation and manual content: Peter Trimboli, RPh Pharmacy Services, Drug Supply Management Bristol-Myers Squibb Research and Development Telephone: 609-252-4862 Email: peter.trimboli@bms.com Medical lead contacts:
Priscilla Brastianos Massachusetts General Hospital 55 Fruit Street, Yawkey 9E pbrastianos@partners.org Ryan Sullivan, MD MGH Cancer Center Boston, MA RSULLIVAN7@mgh.harvard.edu
protocol number nci tbd bmsca209-405
3.0 study treatment

Diluents for drug Dilution (Dextrose 5%, 0.9% NaCl), syringes, tubing for intravenous administration, and filters will be provided for by the clinical site *by Bristol-Myers Squibb.* Refer to appropriate section of the clinical protocol (Study Drug) for dosing for Nivolumab and Ipilimumab.
protocol number nci tbd bmsca209-405
3.1 nivolumab injection 3.1.1 description

| Product Name                       | Nivolumab Injection (or BMS 936558), 100 mg/vial (10  mg/mL) Packaging: Vials assembled into white dispensing boxes  containing 5 - 10 x 100 mg vials each.                         |
|------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Product description  and Packaging | Vials: 10 cc Type I glass vial. 20 mm stopper and seal,  respectively.  Appearance: Clear to opalescent, colorless to pale yellow  liquid, light (few) particulates may be present. |
| Product Ingredients                | Each vial contains 100 mg Nivolumab                                                                                                                                                 |
protocol number nci tbd bmsca209-405
3.1.2 handling and dose preparation

As with all injectable drugs, care should be taken when handling and preparing Nivolumab. Whenever possible, Nivolumab infusions should be prepared in a laminar flow hood, glovebox, or safety cabinet using standard procedures for the safe handling of intravenous agents applying aseptic techniques. Gloves are required. If nivolumab solution comes in contact with the skin or mucosa, immediately and thoroughly wash with soap and water.
protocol number nci tbd bmsca209-405
dose preparation and administration

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.
protocol number nci tbd bmsca209-405
preparation

- 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 (see example below)
- Mix diluted solution by gentle inversion. Do not shake.  
- Discard partially used vials or empty vials of Nivolumab.
protocol number nci tbd bmsca209-405
storage of infusion

The product does not contain a preservative. After preparation, store the Nivolumab infusion either:
- at room temperature for no more than 4 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.
protocol number nci tbd bmsca209-405
do not freeze. administration

Administer the infusion over 30 (+/- 6 minutes) 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 **with appropriate amount**
of diluent (e.g. 15-20 ml) to ensure that the total dose is administered. Total infusion and flush time should equal to 30 (+/-) 6 **minutes.** Dose selection for Nivolumab should be assigned per subject as outlined in the study drug dosing section of the clinical protocol. When Nivolumab is administered in combination with Ipilimumab, the Nivolumab will be infused first, followed by the ipilimumab to start approximately 30 minutes after the Nivolumab infusion completion. Preparation examples are listed below assuming at 77.2 kg patient weight. Example 1: 1 mg/kg dose (rounding to nearest mg dose) Nivolumab 77 mg (7.7 ml Nivolumab 10mg/ml solution, local rounding rules applicable) may be mixed with 52.3 ml NS or D5W to a total volume *= 60 ml (concentration = 1.3* mg/ml) which can be infused over 30 minutes (+/- 6 min) at 1ml/min followed by flush Example 2: 3 mg/kg dose (rounding to the nearest mg dose)
Nivolumab 232 mg (23.2 ml *Nivolumab 10mg/ml solution, local rounding rules applicable)* may be mixed with 36.8 ml NS or D5W to a total volume *= 60 ml(concentration = 3.9* mg/ml) which can be infused over 30 minutes (+/- 6 min) at 1 ml/min *followed by flush.*
protocol number nci tbd bmsca209-405
3.1.3 product storage and stability

Nivolumab 100 mg vials for injection should be refrigerated at 2°C to 8°C (36°F to 46°F).  
Protected from light and **should not be frozen**. Do not use beyond the expiration date on the vial. Protect the vials from light by storing in the original package until time of use. Vials do not contain preservative and thus are intended for single use only and should be discarded after use and product reconciliation. Nivolumab should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of Nivolumab with other agents.
protocol number nci tbd bmsca209-405
3.2 ipilimumab injection 3.2.1 description

| Product Name                       | Ipilimumab Injection, 200 mg/vial (5 mg/mL), 40 ml.  Packaging: Vials assembled into cartons containing 4 vial(s)  each.            |
|------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------|
| Product description  and Packaging | Vials: 50 cc Type I glass vial. 20 mm stopper and seal.  Appearance: Clear, colorless liquid. Light (few) particles may  be present |
| Product Ingredients                | Each vial contains 200 mg (40 ml) Ipilimumab for injection                                                                          |
protocol number nci tbd bmsca209-405
3.2.2 handling and dose preparation

As with all injectable drugs, care should be taken when handling and preparing ipilimumab. Whenever possible, ipilimumab infusions should be prepared in a laminar flow hood, glovebox, or safety cabinet using standard procedures for the safe handling of intravenous agents applying aseptic techniques. Gloves are required. If ipilimumab solution comes in contact with the skin or mucosa, immediately and thoroughly wash with soap and water.
protocol number nci tbd bmsca209-405
dose preparation and administration

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. DO NOT SHAKE THE VIAL.
protocol number nci tbd bmsca209-405
preparation

- 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 **and stored in PVC, non-PVC or glass containers.** Mix diluted solution by gentle inversion. Discard partially used vials or empty vials of Ipilimumab as outlined in section 4.8 of the clinical protocol.
protocol number nci tbd bmsca209-405
administration

- Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after each dose. - Administer diluted solution over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein-binding in-line filter.
Ipilimumab should be dosed per patient or subject as outlined in the clinical protocol, study drug dosing section or as otherwise indicted by the principle investigator. When Ipilimumab is administered in combination with Nivolumab, the Nivolumab will be infused first, followed by the ipilimumab to start approximately 30 minutes after the Nivolumab infusion completion.
protocol number nci tbd bmsca209-405
example

For ease of practical administration a total volume of 150 ml has been selected. Other infusion volumes may be used however it is recommended to keep concentration range of 1 - 2 mg/ml. 3 mg/kg in a 77 kg patient Ipilimumab 231 mg (46.2 *ml ipilimumab 5mg/ml solution) may be mixed with 103.8* ml (local rounding rules exception) NS or D5W to a total volume of 150 ml which can be infused over 90 minutes at 1.7 ml/min (concentration = 1.5 *mg/ml).*
protocol number nci tbd bmsca209-405
3.2.3 product storage and stability

Ipilimumab 200 mg vials for injection should be refrigerated at 2°C to 8°C (36°F to 46°F).  
Protected from light and **should not be frozen**. Do not use beyond the expiration date on the vial. Protect the vials from light by storing in the original package until time of use. Vials do not contain preservative and thus are intended for single use only and should be discarded as outlined in section 4.8 of the clinical protocol. 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) including preparation time, transit time and administration time. Ipilimumab should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of ipilimumab with other agents.
protocol number nci tbd bmsca209-405
4 site temperature excursions and

Drug must be stored under the proper conditions as listed on the clinical supply label and outlined in the respective drug supply sections of the clinical protocol. If any temperature excursions are encountered during on site storage, please report these to BMS for assessment as outlined in the Bristol-Myers Squibb, "Investigational Medicinal Product ( IMP) handling at Investigational Sites: Shipment, Receipt, Storage, Use Date Extension and Return/Destruction" guideline using the Temperature Excursion Response Form. See Appendix 1 Proper storage conditions must be maintained during movement of inventory within an investigational site. Storage conditions for medications requiring storage at 2ºC to 8ºC
(36ºF-46ºF) must be maintained throughout the transport with documentation maintained within the site files. Where controlled storage conditions (for example, temperature, relative humidity, light, etc.) are required during transit, the necessary environmental controls must be in place to ensure that the drug product remains within the acceptable temperature range. Temperature monitoring devices such as min max device must be implemented during transit.
protocol number nci tbd bmsca209-405
5 product receipt accoutability and

1. Open box **immediately** upon receipt.  
2. Carefully inspect kits ensuring all of the supplies were received in good condition, correct quantity received, and all of the container ID \#s were received as noted on packing slip.  
3. Sign and date (date of receipt) packing slip and file with study-specific documents. 4. Log in all supplies in each shipment on the appropriate Clinical Supplies Inventory Form (provided separately)
protocol number nci tbd bmsca209-405
accountability

As per the clinical protocol it is the responsibility of the investigator to ensure that a current disposition record of investigational product accountability and reconciliation is maintained at each study site where study drug is inventoried and dispensed. In addition, records or logs must comply with applicable country/local regulations and guidelines and should include:
- Amount received and placed in storage area - Amount currently in storage area Confidential Bristol-Myers Squibb 10
- Label ID number or batch number - Amount dispensed to and returned by subject, including unique subject identifiers
- Amount transferred to another area/site for dispensing or storage
- Non-study disposition (e.g. lost, wasted)
- Amount destroyed at study site, if applicable - Amount returned to the Sponsor, if applicable - Dates and initials of person responsible for Investigational Product (IP)
- Dispensing/accountability, as per the Site Signature and Delegation Log.
protocol number nci tbd bmsca209-405
study drug destruction

Study drugs (those supplied by BMS or sourced by the site/investigator) can be destroyed on site if local policies allow to do so. It is the Investigator's responsibility to ensure that arrangements have been made for the disposal, procedures for proper disposal have been established according to applicable regulations, guidelines and institutional procedures, and appropriate records of the disposal have been documented. All drug destruction whether performed on or off site should be documented according to local policies and procedures and should be documented accordingly.
appendix 1 bristol-myers squibb
6 irt and data collection

Temperature Excursion Response Form for Investigational Medicinal Products Section A. To be completed by the site at the time of Site Storage Temperature Excursion:
Protocol Number: Site Number/Investigator Name/Country:  
| Description of Drug Products involved in Excursion: Batch number (s) printed on label:                                | Container numbers:    |                        |
|-----------------------------------------------------------------------------------------------------------------------|-----------------------|------------------------|
| Description of Excursion (temperature highs/lows and duration): Below label storage lower limit …...°C Duration:…………. | Low extreme t°: …..°C |                        |
| Above label storage upper limit ….. °C                                                                                | Duration:………...       | High extreme t°: …..°C |
| Reason for excursion:                                                                                                 |                       |                        |  
Has the issue been resolved?  
| Have these specific containers been involved in a previous excursion?        | NO                 | YES                                 |
|------------------------------------------------------------------------------|--------------------|-------------------------------------|
| If yes, please provide: Batch number (s):                                    | Container numbers: | Temperature highs/lows and duration |
| When is the next planned patient visit when these supplies may be dispensed? |                    |                                     |  
Excursion information submitted by: _________________________________________ Date: ____________
*Print/Signature/Title of site staff* Section B. Usage Decision to be made by Bristol-Myers Squibb:
Temperature excursion details for the products listed above have been evaluated. Usage decision is based on the temperature data that were made available by the investigational site.  
Conclusion (and comments):
All **products are suitable for continued use**
______________________________________________________________________________________ ______________________________________________________________________________________
All products are NOT suitable for further dispensation. Please remove supplies from available inventory and work with your Site Manager/Site Monitor to have supplies destroyed and **IVRS updated if applicable.** ______________________________________________________________________________________ ______________________________________________________________________________________
Assessment completed by:_______________________________________________ Date ___________
Print/Signature/Title
appendix 1 bristol-myers squibb
appendix 2

Templates as provided via separate attachment or below may serve as a sample for dosage calculations and may be printed out and used to document any calculations and infusion times as required by the clinical study team. *Content in this attachment may be added or omitted.*  
| Drug Dose and Volume Calculator  for IV Infusion                                                                                                                                                                                         |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Drug Product : Protocol number Patient name or ID:                                                                                                                                                                                       |
| Preparation date and time:                                                                                                                                                                                                               |
| Drug Strength (mg/mL) Subject body weight (kg) 1Dose in mg Volume of Drug (mL) Total Volume of infusion (mL) Volume of Diluent (mL) NS or D5W Infusion duration (min) Infusion Rate (mL/min) Infusion hang time Infusion completion time |  
Note: If required, flush line with separate volume of same diluent (15-20 ml) as outlined in the study pharmacy manual 1Reference protocol appendix section 4 (Study Drug) for patient dose per tier or cohort  
| DANA-FARBER CANCER INSTITUTE Nursing Protocol Education Sheet                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                        |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------|
| Protocol Number:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | 16-136                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                        |
| Protocol Name:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | A Phase II Trial of Ipilumumab and Nivolumab in Leptomenigeal Metastases                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                        |
| DFCI Site PI:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | David Reardon, MD                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                        |
| DFCI Research Nurse:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Debra LaFrankie, Sandra Ruland, Lisa Doherty, Jennifer Stefanik, Caroline Kane, Brittney Fontana                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                        |
| Page the DFCI research nurse or DFCI site PI if there are any questions/concerns about the protocol.  Please also refer to ONC 15: Oncology Nursing Protocol Education Policy *** Remember to check the ALERT PAGE***  SPECIAL NURSING CONSIDERATIONS UNIQUE TO THIS PROTOCOL                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                        |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Ipilimumab is a fully human monoclonal immunoglobulin (Ig) specific for human cytotoxic T lymphocyte antigen  4, which is expressed on a subset of activated T cells (Section 2.2.1)                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                        |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Nivolumab is a fully human monoclonal antibody that targets the PD-1 CD279 cell surface membrane receptor  (Section 2.2.2)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                        |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | A cycle is defined as six weeks, with the exception of the nivolumab maintenance monotherapy phase in  melanoma and renal cell carcinoma a cycle when each cycle will be 8 weeks (Section 5.1)                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                        |
| Study Design                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Nivolumab will be dosed as mg /kg      |
| Dose  Calc.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Ipilumumab will be dosed as mg /kg     |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | The dosing calculations should be based on the body weight. If the subject's weight on the day of dosing differs  by > 5% from the weight used to calculate the dose, the dose must be recalculated (Section 5.3)                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                        |
| Agent Administration Guidelines are found in Section 5.3 - For treatment schedule by histology, see Section 5.1. When study drugs are to be administered on the same  day, separate infusion bags and filters must be used for each infusion. - Nivolumab will be administered first. - Ipilumumab will be administered approximately 30 minutes after completion of Nivolumab. The Ipilimumab  infusion will start no sooner than 30 minutes after completion of Nivolumab infusion. - An infusion window of +/- 10 minutes is allowed for both Nivolumab and Ipilimumab  - The criteria to treat is outlined in Table 1, and in section 5.2. - Nivolumab is to be administered as a 30 minute IV infusion. - Ipilumumab is to be administered as a 30 minute IV infusion. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                        |
| Administration                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                        |
| Study Drug                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Criteria to Treat, Dose Modifications/Dosing Delays for Toxicity are outlined in Sections 5.2 and 6 - There will be no dose modifications permitted. Dose reductions or dose escalations are not permitted (Section 5.3 and 6) - This protocol uses NCI CTCAE criteria, version 4.0                                                                                                                                                                                                                                                                                                                                                                          |                                        |
| Mods &  Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                        |
| Dose                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Concomitant Therapy Guidelines are in Section 5.4 - Antiemetic premedications should not be routinely administered prior to dosing of drugs. See Section 6 for  premedication recommendations following a nivolumab or ipilimumab related infusion reaction                                                                                                                                                                                                                                                                                                                                                                                                  |                                        |
| Con Meds                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | The study calendars are in Section 10. |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Vital signs: The time points are in Section 10.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                        |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | ECGs are obtained at screening, and then as clinically indicated.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                        |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Biomarkers: The time points are in Section 10                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                        |
| Required  Data                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | All study drugs require documentation of exact administration time. Please be sure to DOCUMENT study medication actual UP/DOWN times in medical record (e.g. LMR, eMAR,  nursing notes). Edit eMAR as needed to match the exact time given.  If there is a discrepancy in the infusion time, delay in administration, or the infusion takes longer than is  permitted by the guidelines of the protocol, please document the reason for the discrepancy in the medical  record.  Please be sure to also DOCUMENT any required observation periods, any additional vital signs, routes of  administration, injection sites, and exact time of PK collections. |                                        |
| Charting Tips                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                        |  
  
Oncology Clinical Research 3401 Princeton Pike, Lawrenceville, NJ 08648
Administrative Letter Date: 24-Sep-2018 IND Number: 125,872 Site Number: All Re: Protocol CA209568: A Study of Nivolumab in Combination with Ipilimumab (part 1); and Nivolumab plus Ipilimumab in Combination with Chemotherapy (part 2) as First Line Therapy in Stage IV Non-Small Cell Lung Cancer (NSCLC) CheckMate 568, CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 568) Dear Investigator: The Purpose of this Administrative Letter is to change the contact details of the Study Director. This is an administrative protocol change and does not significantly affect the safety of subjects, study scope, or scientific quality of a Phase II or III protocol. Accordingly, it may be implemented immediately. The changes made to the protocol are as follows:
appendix 1 bristol-myers squibb
1. page section title page

Study Director/Medical Monitor Xuemei Li, MD
Bristol-Myers Squibb 3401 Princeton Pike Lawrenceville, NJ 08648 Telephone (office): 609-302-4597 Fax: 609-302-6804
appendix 1 bristol-myers squibb
study director

Ravi Kasinathan, PhD
Bristol-Myers Squibb 3401 Princeton Pike Lawrenceville, NJ 08648 Telephone (office): 609-302-5742 Telephone (cell): (267) 516-7837 Fax: 609-302-6804 Medical Monitor Xuemei Li, MD
Bristol-Myers Squibb 3401 Princeton Pike Lawrenceville, NJ 08648 Telephone (office): 609-302-4597 Fax: 609-302-6804 Please maintain a copy of this administrative letter with your protocol. Please provide a copy to your Investigational Review Board / Ethics Committee, unless agreed otherwise with BMS.  
 Study Director
2
memorandum
study director

Bristol-Myers Squibb Company  
  
  
Clinical Supply Operations Pharmacy Services Telephone:
(609)-252-4862 Fax:
(609)-252-7856 To:   All Study Pharmacists From:  Peter Trimboli, PharmD, R.Ph.  
Date: September 21, 2018 Subject: Preparation for infusions containing Nivolumab, IB 17 update C:   Dan Crosby, Thomas Haby, Donna Turchi, Doug Baylis, Debbie Clarkson Dear Pharmacist(s);
Please note the latest Investigator Brochure for Nivolumab (Version 17; June 27, 2018)
includes the following information that may be added to existing pharmacy instructions and/or pharmacy manuals which outline the instructions for preparation for infusions containing Nivolumab:
memorandum
drug product preparation

Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2micron pore size, low-protein binding (polyethersulfone membrane) in-line filter at the protocol-specified doses and infusion times. It is not to be administered as an IV push or bolus injection. When the dose is based on patient weight (ie, mg/kg), nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to protein concentrations as low as 0.35 mg/mL. When the dose is fixed (eg, 240 mg, 360 mg, or 480 mg flat dose), nivolumab injection can be infused undiluted or diluted so as not to exceed a total infusion volume of 160 mL. For patients weighing less than 40 kilograms (kg), the total volume of infusion must not exceed 4 mL per kg of patient weight.  
Recommended storage and use conditions Nivolumab Injection Vials of nivolumab injection must be stored at 2ºC to 8ºC (36ºF to 46ºF) and protected from light and freezing. The unopened vials can be stored at room temperature (up to 25ºC, 77ºF) and room light for up to 48 hours. Excursions up to 25°C beyond 48 hours must be reported using the appropriate Temperature Excursion Report Form as outlined in the BMS IMP (Investigative Medicinal Product) handling document.  
Fuither questions may be sent to our Pharmacy Services Team:
pharmacyservices@bms.com  
  
Karishma Patel, R.Ph Pharmacy Services Bristol-Myers Squibb Phone 609-252-4862 email: pharmacyservices@bms.com