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untitled h2

Closure Effective Date: 04/18/2019 Reason: Study Closed - Study Accrual Goal Met No new subjects may be enrolled in the study- as described above.  
Any questions regarding this closure should be directed to the study's Principal Investigator NCT02939300 N/A
DF/HCC Protocol \#: [16-136] TITLE: Phase II Trial of Ipilimumab and Nivolumab in Leptomeningeal Metastases  
| Coordinating Center:          | Massachusetts General Hospital                                                                                                                                                                                                                                      |
|-------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| *Principal Investigator (PI): | 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                                                                                |
| Other Investigators:          | Daniel P. Cahill, MD, PhD  Massachusetts General Hospital Boston, MA  Elizabeth Gerstner, MD Massachusetts General Hospital Boston, MA  Kevin Oh, MD  Massachusetts General Hospital Boston, MA  Sandro Santagata, MD, PhD  Dana-Farber Cancer Institute Boston, MA |
| Statistician:                 | Study Coordinator:                                                                                                                                                                                                                                                  |
| Anita Giobbie-Hurder          | Panha Kosal                                                                                                                                                                                                                                                         |
| Department of Biostatistics   | Massachusetts General Hospital                                                                                                                                                                                                                                      |
| & Computational Biology       | Yawkey 9E, 55 Fruit Street                                                                                                                                                                                                                                          |
| Dana-Farber Cancer Institute  | Telephone: 617-643-6221  Fax: 617-643-7715  pkosal@mgh.harvard.edu                                                                                                                                                                                                  |  
Protocol Version Date: January 24, 2019 Responsible Research Nurse: **Responsible Data Manager:** Nicola Gribbin, RN Massachusetts General Hospital Yawkey 9E, 55 Fruit Street Telephone: 617-726-9579 Fax: 617-643-0572 NGRIBBIN@PARTNERS.ORG
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responsible data manager

Panha Kosal Massachusetts General Hospital Yawkey 9E, 55 Fruit Street Telephone: 617-643-6221 Fax: 617-643-7715 pkosal@mgh.harvard.edu Agents: ipilimumab and nivolumab Below, please describe the IND Status of this study by choosing IND \#/Sponsor OR Exemption from IND requirements, making sure to delete the inapplicable field(s).  
IND \#: *IND Exempt* IND Sponsor: Priscilla Brastianos, MD
Protocol Type / Version \# / Version Date:[Version 7.0 / Version Date: 24 January 2019 ]
2 SCHEMA  
  
  
| For NSCLC, head and neck cancer and              |
|--------------------------------------------------|
| induction phase of melanoma, renal cell,         |
| breast, small cell lung cancer, bladder and      |
| other solid tumors:                              |
| - Brain MRI q6wks                                |
| - Chest/abd/pelvis CT q6wks                      |
| For maintenance phase of melanoma, renal         |
| cell, breast, small cell lung cancer and bladder |
| and other solid tumors:                          |
| - Brain MRI q8wks                                |
| - Chest/abd/pelvis CT q8wks                      |  
| Clinical      |
|---------------|
| neurologic    |
| deterioration |
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table of contents

| SCHEMA                                                                                                              |                                                                                                                                                  |
|---------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|
| 1.                                                                                                                  | OBJECTIVES .                                                                                                                                     |
| 1.1                                                                                                                 | Study Design .                                                                                                                                   |
| 1.2                                                                                                                 | Primary Objectives                                                                                                                               |
| 1.3                                                                                                                 | Secondary Objectives                                                                                                                             |
| 1.4                                                                                                                 | Correlative Objectives ........................................................................................................................7 |
| 2.                                                                                                                  | BACKGROUND .                                                                                                                                     |
| 2.1                                                                                                                 | Study Disease(s)                                                                                                                                 |
| 2.2                                                                                                                 | IND Agents .                                                                                                                                     |
| 2.3                                                                                                                 | RATIONALE                                                                                                                                        |
| 2.4                                                                                                                 | Correlative Studies Background ........................................................................................16                        |
| 3.                                                                                                                  | PARTICIPANT SELECTION                                                                                                                            |
| 3.1                                                                                                                 | Eligibility Criteria .................................................................................................................17         |
| 3.2                                                                                                                 | Exclusion Criteria ..................................................................................................................19          |
| 3.3                                                                                                                 | Inclusion of Women and Minorities ................................................................................20                             |
| 4.                                                                                                                  | REGISTRATION PROCEDURES                                                                                                                          |
| 4.1                                                                                                                 | General Guidelines for DF/HCC Institutions .....................................................................21                               |
| 4.2                                                                                                                 | Registration Process for DF/HCC Institutions                                                                                                     |
| 4.3                                                                                                                 | General Guidelines for Other Investigative Sites ..........................................................21                                    |
| 4.4                                                                                                                 | Registration Process for Other Investigative Sites ...........................................................21                                 |
| 5.                                                                                                                  | TREATMENT PLAN .                                                                                                                                 |
| T Treatment Regimen                                                                                                 |                                                                                                                                                  |
| 5.1                                                                                                                 |                                                                                                                                                  |
| 5.2                                                                                                                 | Pre-Treatment Criteria ...........................................................................................................22             |
| 5.3                                                                                                                 | Agent Administration                                                                                                                             |
| 5.4                                                                                                                 | General Concomitant Medication and Supportive Care Guidelines......................24                                                            |
| 5.5                                                                                                                 | Criteria for Taking a Participant Off Protocol Therapy                                                                                           |
| 5.6                                                                                                                 | Duration of Follow Up                                                                                                                            |
| Criteria for Taking a Participant Off Study .....................................................................25 |                                                                                                                                                  |
| 5.7                                                                                                                 |                                                                                                                                                  |
| DOSING DELAYS/DOSE MODIFICATIONS ............................................................................25     |                                                                                                                                                  |
| 6.                                                                                                                  |                                                                                                                                                  |
| 7.                                                                                                                  | ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................30                                                                  |
| 7.1                                                                                                                 | Adverse Event Characteristics ......................................................................................30                           |
| 7.2                                                                                                                 | Expedited Adverse Event Reporting                                                                                                                |
| 7.3                                                                                                                 | Expedited Reporting to Hospital Risk Management ..................................................31                                             |
| 7.4                                                                                                                 | Routine Adverse Event Reporting ...................................................................................31                            |
| 7.5                                                                                                                 | Definitions                                                                                                                                      |
| Potential Drug Induced Liver Injury (DILI) ....................................................................33   |                                                                                                                                                  |
| 7.6                                                                                                                 |                                                                                                                                                  |  
Protocol Version Date: January 24, 2019  
| 7.7   | Pregnancy 33                                                                                                                                                                                                                                                              |
|-------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 7.8   | Overdose 34                                                                                                                                                                                                                                                               |
| 7.9   | Other Safety Considerations 34                                                                                                                                                                                                                                            |
| 7.10  | Adverse event reporting to BMS 34                                                                                                                                                                                                                                         |
| 8.    | PHARMACEUTICAL INFORMATION 36 8.1 Product Description of Ipilimumab and Nivolumab 36 Sponsor/Investigator drug destruction is allowed provided the following minimal  standards are met: 38 - On-site disposal practices must not expose humans to risks from the drug 38 |  
8. PHARMACEUTICAL INFORMATION ..........................................................................36 8.1 Product Description of Ipilimumab and Nivolumab ..............................................36 Sponsor/Investigator drug destruction is allowed provided the following minimal standards are met: ..................................................................................................38
- On-site disposal practices must not expose humans to risks from the drug. .........38 - On-site disposal practices and procedures are in agreement with applicable laws and regulations, including any special requirements for controlled or hazardous substances. ............................................................................................38
- Written procedures for on-site disposal are available and followed. The procedures must be filed with the Sponsor SOPs and a copy provided to BMS upon request..................................................................................................38
- Note vials and remaining IP are sent to destruction after dose preparation in the IV room as per site SOP. Whole vials are signed out on the accountability logs by the research pharmacy staff. ..............................................38
- Accountability and disposal records are complete, up-to-date, and available for BMS to review throughout the clinical trial period as per the study agreement. ....................................................................................................38 If conditions for destruction cannot be met, please contact BMS. ....................................38 It is the Sponsor Investigator's responsibility to arrange for disposal of all empty containers, provided that procedures for proper disposal have been established according to applicable federal, state, local, and institutional guidelines and procedures, and provided that appropriate records of disposal are kept. ....................................................................................................38 8.2 Nivolumab..............................................................................................................39 8.3 Ipilimumab .............................................................................................................40 9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................42 9.1 Background of exploratory biomarker studies:......................................................42 9.2 Methodology ..........................................................................................................42 9.3 Collection and Shipping of Tissue Specimen(s) ....................................................43 10. STUDY CALENDAR .......................................................................................................44  
| 11.   | MEASUREMENT OF EFFECT 50 11.1 Antitumor Effect - Extracranial lesion assessments 50 11.2 Antitumor Effect - Intracranial lesion assessments 56 11.3 Response Review 61 11.4 Other Response Parameters 61   |
|-------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 12.   | DATA REPORTING / REGULATORY REQUIREMENTS 63 12.1 Data Reporting 63                                                                                                                                         |  
| NCI Protocol #:                                                                                                                                      |                                                                                                                                       |
|------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------|
| DF/HCC Protocol #: 16-136                                                                                                                            |                                                                                                                                       |
| Protocol Version Date:  January 24, 2019                                                                                                             |                                                                                                                                       |
| 12.2                                                                                                                                                 | Data Safety Monitoring                                                                                                                |
| 12.3                                                                                                                                                 | Multicenter Guidelines                                                                                                                |
| 12.4                                                                                                                                                 | Collaborative Agreements Language                                                                                                     |
| 13.                                                                                                                                                  | STATISTICAL CONSIDERATIONS                                                                                                            |
| 13.1                                                                                                                                                 | Study Design/Endpoints....................................................................................................64          |
| 13.2                                                                                                                                                 | Sample Size, Accrual Rate and Study Duration .........................................................64                              |
| 13.3                                                                                                                                                 | Stratification Factors ............................................................................................................65 |
| 13.4                                                                                                                                                 | Interim Monitoring Plan ....................................................................................................65        |
| 13.5                                                                                                                                                 | Analysis of Primary Endpoints ........................................................................................65              |
| Analysis of Secondary Endpoints .....................................................................................65                              |                                                                                                                                       |
| 13.6                                                                                                                                                 |                                                                                                                                       |
| 13.7                                                                                                                                                 | Analysis of Exploratory Endpoints .................................................................................66                 |
| 13.8                                                                                                                                                 | Reporting and Exclusions .....................................................................................................66      |
| PUBLICATION PLAN .................................................................................................................................67 |                                                                                                                                       |
| 14.                                                                                                                                                  |                                                                                                                                       |
| REFERENCES .                                                                                                                                         |                                                                                                                                       |
| APPENDIX A                                                                                                                                           | PERFORMANCE STATUS CRITERIA ........................................................70                                                |
| APPENDIX B                                                                                                                                           | Tumor assessment per immune-related response criteria ...............................71                                               |
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1. objectives 1.1 study design

This is a Phase II trial of nivolumab and ipilimumab in leptomeningeal carcinomatosis. To estimate the overall survival of the combination of nivolumab and ipilimumab in leptomeningeal metastases 1. To describe the toxicity of nivolumab and ipilimumab in brain and leptomeningeal metastases.  
2. To estimate the central nervous system response rate (parenchymal brain metastases) of nivolumab and ipilimumab in patients with leptomeningeal disease 3. To estimate the systemic response rate of nivolumab and ipilimumab in patients with brain metastases 4. To estimate leptomeningeal disease response of nivolumab and ipilimumab in patients with leptomeningeal metastases.  
5. To estimate the systemic progression free-survival of patients receiving nivolumab and ipilumamb.  
6. To estimate the intracranial progression free-survival of patients receiving nivolumab and ipilimumab.  
1. To determine molecular biomarkers of response using next generation sequencing techniques.  
Approximately 5-8% of patients with cancer develop leptomeningeal carcinomatosis1. While virtually any malignancy can metastasize to the leptomeninges, this most commonly occurs with lung cancer, breast cancer and melanoma. Approximately 5-7% of patients with melanoma develop leptomeningeal carcinomatosis and there seems to be an association with the presence of parenchymal brain metastases and the development of leptomeningeal carcinomatosis2. As patients with cancer survive longer and diagnostic imaging techniques improve, leptomeningeal carcinomatosis is being diagnosed more frequently. Patients typically present with signs of increased intracranial pressure, cranial nerve palsies, seizures, stroke-like symptoms, encephalopathy, radiculopathies and cauda equina syndrome1. The median survival of patients with leptomeningeal metastases without treatment is approximately 4-6 weeks. Death usually results from rapid progressive neurologic deterioration. Treatment involves radiation to symptomatic sites of the neuraxis and to sites of bulk disease seen on imaging studies.  
Systemically administered chemotherapy has limited access to the CSF due to the blood-brain barrier. Intrathecal chemotherapy is designed to treat tumor cells floating in the cerebrospinal fluid (CSF), thereby preventing the development of new symptomatic sites of disease; however treatment-related toxicities of intrathecal chemotherapy are common, and include chemical meningitis, seizures and severe headaches3. Radiotherapy and intrathecal chemotherapy provide local control and may extend median survival of patients with leptomeningeal carcinomatosis to 3-6 months3,4. Novel therapies are needed to improve outcomes in patients with leptomeningeal carcinomatosis.
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2.2 ind agents 2.2.1 ipilimumab

Ipilimumab (BMS-734016, MDX010, MDX-CTLA4) is a fully human monoclonal immunoglobulin (Ig) G1κ specific for human cytotoxic T lymphocyte antigen 4 (CTLA-4, CD152), which is expressed on a subset of activated T cells. CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the antitumor response. Yervoy (ipilimumab) has been approved for use in over 47 countries including the United States (US, Mar-2011), the European Union (EU, Jul-2011), and Australia (Jul-2011).
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nonclinical studies

Ipilimumab has specificity and a high affinity for human CTLA-4. The calculated dissociation constant value from an average of several studies was 5.25 nM. Binding of ipilimumab to purified, recombinant human CTLA-4 antigen was also demonstrated by enzyme-linked immunosorbent assay with half-maximal binding at 15 ng/mL, whereas saturation was observed at approximately 0.1 µg/mL. No cross-reactivity was observed against human CD28. Ipilimumab completely blocked binding of B7.1 and B7.2 to human CTLA-4 at concentrations higher than 6 µg/mL and 1 µg/mL, respectively.
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effects in humans

Bristol-Myers Squibb (BMS) and Medarex, Inc. (MDX, acquired by BMS in Sep-2009) have cosponsored an extensive clinical development program for ipilimumab, encompassing more than 19,500 subjects (total number of subjects enrolled in ipilimumab studies) in several cancer types in completed and ongoing studies, as well as a compassionate use program. The focus of the clinical program is in melanoma, prostate cancer, and lung cancer, with advanced melanoma being the most comprehensively studied indication. Ipilimumab is being investigated both as monotherapy and in combination with other modalities such as chemotherapy, radiation therapy, and other immunotherapies. Phase 3 programs are ongoing in melanoma, prostate cancer, and lung cancer. In melanoma, 2 completed Phase 3 studies (MDX010-20 and CA184024) have demonstrated a clinically meaningful and statistically significant survival benefit in pretreated advanced melanoma and previously untreated advanced melanoma, respectively. The safety profile of ipilimumab is generally consistent across these trials with a) the majority adverse events (AEs) being inflammatory in nature consistent with the proposed mechanism of action of ipilimumab, b) the same types of such immune-mediated events in the gastrointestinal (GI) tract, skin, liver, and endocrine system being reported, and c) most of these events being manageable with immune suppressive therapies. In melanoma, 2 BMS-sponsored Phase 3 studies are ongoing in subjects with high-risk Stage III melanoma (CA184029, with adjuvant immunotherapy) and pretreated and treatment-naïve advanced melanoma (CA184169, 3 mg/kg versus 10 mg/kg ipilimumab). The completed Phase 3 study CA184043 evaluated ipilimumab in subjects with metastatic castration-resistant prostate cancer (mCRPC) who had progressed during or following docetaxel. Eligible subjects were randomized to a single dose of bone-directed radiotherapy (RT), followed by either ipilimumab 10 mg/kg or placebo (799 randomized: 399 ipilimumab, 400 placebo). This study did not meet its primary endpoint of overall survival (OS). The hazard ratio (HR) of 0.85 (95% confidence interval [CI]: 0.72 to 1.00) for survival favored ipilimumab but did not reach statistical significance with a P-value of 0.053. Planned sensitivity analyses favored ipilimumab, where the greatest benefit appeared to be in subgroups defined by good prognostic features and low burden of disease. Additional evidence of ipilimumab activity observed in the study included a reduced risk of disease progression relative to placebo (HR = 0.70) and superior clinical outcomes compared to placebo in tumor regression and declines in prostate specific antigen (PSA). The safety profile in this study was consistent with the previously defined AE profile at the same dose. A second Phase 3 study CA184095 evaluating ipilimumab 10 mg/kg versus placebo in men with asymptomatic or minimally symptomatic, chemotherapy-naïve mCRPC with no visceral metastases has completed enrollment and is currently in follow-up. In addition, a completed large Phase 2 study (CA184041) has investigated the addition of ipilimumab to carboplatin and paclitaxel using 2 different schedules (concurrent and phased) in subjects with non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC, a secondary endpoint). Ipilimumab, given in combination with paclitaxel/carboplatin in a phased schedule improved irPFS compared to the control treatment, but no improvement was seen when ipilimumab was given in a concurrent schedule. Phased ipilimumab also improved PFS according to mWHO criteria and showed a trend for improved OS. The efficacy and safety of ipilimumab in a phased schedule with carboplatin/paclitaxel is also being investigated in an ongoing Phase 3 study in subjects with advanced squamous NSCLC (CA184104). The efficacy and safety of ipilimumab in a phased schedule with etoposide/platinum in subjects with extensive stage disease SCLC is being investigated in an ongoing Phase 3 study (CA184156). The unique immune-based mechanism of action is reflected in the clinical patterns of anti-cancer activity in some patients. Ipilimumab induces an immunologic response, and measurable clinical effects emerge after the immunological effects. Tumor infiltration with lymphocytes and the associated inflammation (documented by biopsy in some subjects) is likely the cornerstone of the effect of ipilimumab and can manifest in various patterns of clinical activity leading to tumor control. In some cases, inflammation may not be noted by radiological examination and objective response is observed with the first tumor assessment in a manner seen in patients receiving other types of anti-cancer treatments. In other cases, response may be preceded by an apparent increase in initial tumor volume and/or the appearance of new lesions, which may be mistaken for tumor progression on radiological evaluations. Therefore, in patients who are not experiencing rapid clinical deterioration, confirmation of progression is recommended, at the investigator's discretion, to better understand the prognosis as well as to avoid unnecessarily initiating potentially toxic alternative therapies in subjects who might be benefiting from treatment. Immune-related response criteria were developed based on these observations to systematically categorize novel patterns of clinical activity and are currently being prospectively evaluated in clinical studies. In metastatic diseases, stabilization is more common than response, and in some instances is associated with a slow, steady decline in tumor burden over many months, sometimes improving to partial and/or complete responses. Thus, the immune-based mechanism of action of ipilimumab results in durable disease control, sometimes with novel patterns of response, which contribute to its unique improvement in OS. The unique immune-based mechanism of action is also reflected in the safety profile. The most common treatment-related AEs are inflammatory in nature, consistent with the mechanism of action of the drug and generally medically manageable with topical and/or systemic immunosuppressants. Such immunological safety events are described as immune-related adverse events (irAEs) or immune-mediated adverse reactions (imARs). The irAEs are described as AEs of unknown etiology, which were consistent with an immune phenomenon and were considered causally related to drug exposure by investigators. The irAEs primarily involve the GI tract and skin. Immune-related AEs in the liver were also observed, particularly in subjects receiving 10 mg/kg. Endocrinopathy and neuropathy were important irAEs observed less frequently. The imARs were adjudicated in a blinded fashion based on sponsor-physician data review to exclude noninflammatory etiologies, such as infection or tumor progression, and to consider available evidence of inflammation, such as tumor biopsies or responsiveness to steroids, in an effort to determine whether specific AEs or abnormal hepatic laboratory values were likely to be immune mediated and associated with ipilimumab treatment. The early diagnosis of inflammatory events is important to initiate therapy and minimize complications.  
Inflammatory events are generally manageable using symptomatic or immuno-suppressive therapy as recommended through detailed diagnosis and management guidelines. A program-wide independent Data Monitoring Committee (DMC) reviews data from the ipilimumab studies, allowing for an ongoing safety and benefit/risk assessment in subjects receiving ipilimumab. The DMC charter includes explicit stopping rules for some studies, allowing the DMC to recommend discontinuing further treatment across the ipilimumab program, if necessary. In summary, ipilimumab offers clinically meaningful and statistically significant survival benefit to patients with pretreated advanced melanoma (as 3 mg/kg monotherapy compared to the melanoma peptide vaccine gp100) and previously untreated advanced melanoma (at 10 mg/kg in combination with dacarbazine [DTIC] compared to DTIC alone), and evidence of clinical activity in randomized studies in other tumor types. These findings, together with evidence of a safety profile that is manageable with careful monitoring and appropriate intervention for treatment of immune-related toxicities, suggest an acceptable benefit to risk ratio.
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2.2.2 nivolumab

Nivolumab (also referred to as BMS-936558 or MDX1106) is a fully human monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1
(PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative regulatory molecule expressed by activated T and B lymphocytes. Binding of PD-1 to its ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes immune responses and antigen-specific T-cell responses to both foreign antigens as well as selfantigens. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced using standard mammalian cell cultivation and chromatographic purification technologies. The clinical study product is a sterile solution for parenteral administration (Nivolumab Investigator Brochure).
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nonclinical studies

Nivolumab has been shown to bind specifically to the human PD-1 receptor and not to related members of the CD28 family, such as CD28 inducible co-stimulator (ICOS), cytotoxic T lymphocyte antigen-4 (CTLA-4), and B and T lymphocyte attenuator (BTLA). Nivolumab inhibits the interaction of PD-1 with its ligands, PD-L1 and PD-L2, resulting in enhanced T-cell proliferation and interferon-gamma (IFN-γ) release in vitro. Fluorescent-activated cell sorter
(FACS) analysis confirmed that nivolumab binds to transfected CHO and activated human Tcells expressing cell surface PD-1 and to cynomolgus monkey PD-1, but not to rat or rabbit PD-1 molecules. Nivolumab has also been shown to bind to PD-1 on virus-specific CD8+ T-cells from chronically infected hepatitis C virus patients. PD-1 inhibition in a mixed lymphocyte reaction
(MLR) resulted in a reproducible concentration-dependent enhancement of IFN-γ release in the MLR up to 50 g/mL. No effect was observed with a human IgG4 isotype control or CD4+ T cells and dendritic cell (DC) controls. In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab was well tolerated at doses up to 50 mg/kg, administered weekly for 5 weeks, and at doses up to 50 mg/kg, administered twice weekly for 27 doses. Nivolumab-related findings were limited to a reversible decrease of 28% in triiodothyronine (T3) among the females administered 27 doses of 50 mg/kg. No corresponding changes in the level of thyroxin (T4), thyroid-stimulating hormone (TSH), or histologic changes in the thyroid were observed. While nivolumab alone was well tolerated in cynomolgus monkeys, combination studies have highlighted the potential for enhanced toxicity when combined with other immunostimulatory agents.  
Ipilimumab (BMS-734016), an anti-CTLA-4 monoclonal antibody (mAb) that blocks the downregulation of T-cell activation, was used in combination with nivolumab to investigate the effects of concurrent inhibition of the PD-1 and CTLA-4 receptors in nonhuman primates. Although gastrointestinal (GI) toxicity has not been observed in cynomolgus monkeys treated with nivolumab alone, dose-dependent GI toxicity was evident in cynomolgus monkeys treated weekly for 4 weeks with a combination of nivolumab + ipilimumab at combinations of 10 and 3 mg/kg and 50 and 10 mg/kg, respectively. GI effects have also been observed at a low incidence after ipilimumab administration.13 Two 4-week toxicity studies in cynomolgus monkeys were conducted with 2 anti-lymphocyte-activation gene 3 (LAG-3) mAbs that inhibit the function of LAG-3 on the surface of activated CD4+ and CD8+ T cells. The combination of nivolumab + MDX1408 was clinically well tolerated up to 50 mg/kg MDX1408 and 50 mg/kg nivolumab with findings limited to nonadverse and pharmacologically-mediated changes in the peripheral blood and lymphoid tissues, including increases in CD4+ T lymphocytes expressing CD25.  
However, the combination of 50 mg/kg nivolumab + 100mg/kg BMS-986016, administered once weekly, was associated with moribundity (1 of 10 animals) attributed to central nervous system (CNS) vasculitis. Findings in surviving monkeys administered nivolumab alone or in combination with BMS-986016 were limited to minimal inflammation of the choroid plexus or vasculature of the brain parenchyma (1 male in the combination group), without evidence of other degenerative changes. These findings, which were observed at nivolumab exposures that were approximately 13× greater than those observed in humans at 3 mg/kg, every 2 weeks
(Q2W), are consistent with an expected immunostimulatory pharmacologic effect of nivolumab and highlight the potential synergistic roles of PD-1 and LAG-3 in maintaining self-tolerance. In addition, an enhanced pre- and postnatal development (ePPND) study in pregnant cynomolgus monkeys with nivolumab was conducted. Administration of nivolumab at up to 50 mg/kg 2QW was well tolerated by pregnant monkeys; however, nivolumab was determined to be a selective developmental toxicant when administered from the period of organogenesis to parturition at ≥
10 mg/kg (area under the concentration-time curve [AUC] from time zero to 168 hours [AUC(0168 h)] 117,000 µg•h/mL). Specifically, increased developmental mortality (including late gestational fetal losses and extreme prematurity with associated neonatal mortality) was noted in the absence of overt maternal toxicity. There were no nivolumab-related changes in surviving infants tested throughout the 6-month postnatal period. Although the cause of these pregnancy failures was undetermined, nivolumab-related effects on pregnancy maintenance are consistent with the established role of PD-L1 in maintaining fetomaternal tolerance in mice.
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effects in humans

The PK, clinical activity, and safety of nivolumab have been assessed in completed Phase 1 and ongoing Phase 2 and 3 studies sponsored by Bristol-Myers Squibb Company (BMS) in subjects with non-small cell lung cancer (NSCLC), melanoma, and clear-cell renal cell carcinoma (RCC) in addition to other tumor types. The current Phase 3 clinical program focuses on squamous and nonsquamous NSCLC, malignant melanoma, and RCC. Clinical activity and safety information presented in this Investigator Brochure (IB) focuses primarily on that obtained from CA209063 (Phase 2 study in refractory squamous NSCLC), CA209037 (Phase 3 study in melanoma), MDX1106-03 (also known as CA209003; Phase 1 study in metastatic NSCLC, colorectal cancer (CRC), melanoma, RCC, or metastatic castrate-resistant prostate cancer [mCRPC]), CA209010 (Phase 2 study in advanced/metastatic clear-cell RCC). Data are also provided from Phase 1 studies CA209004 (also known as MDX1106-04), CA209012, CA209016, CA209038, and CA209039. Nivolumab is being investigated both as monotherapy and in combination with chemotherapy, targeted therapies, and other immunotherapies. The single-dose pharmacokinetics (PK) of nivolumab was linear and dose-proportional in the range of 0.3 mg/kg to 10 mg/kg. The multiple-dose PK of nivolumab was linear with doseproportional increases in maximum serum concentration (Cmax) and area under the concentration-time curve over the dosing interval (AUC[TAU]) in the range of 0.1 mg/kg to 10 mg/kg. Both elimination and distribution of nivolumab in the dose range studied appear to be independent of dose in the dose-ranging studies, while the end of infusion and minimum serum concentration (Cmin) after the first dose were approximately dose proportional. Based on population PK (PPK) results (preliminary data), clearance of nivolumab is independent of dose in the dose range (0.1 mg/kg to 10 mg/kg) and tumor types studied. Body weight normalized dosing showed approximately constant trough concentrations over a wide range of body weights and, therefore, is appropriate for future clinical trials with nivolumab. Nivolumab has demonstrated clinical activity as monotherapy and as combination therapy with ipilimumab in several tumor types, including RCC, melanoma, NSCLC, and some lymphomas. The majority of responses were durable and exceeded 6 months. The overall safety experience with nivolumab, as a monotherapy or in combination with other therapeutics, is based on experience in approximately 4,000 subjects treated to date. For monotherapy, the safety profile is similar across tumor types. The only exception is pulmonary inflammation adverse events (AEs), which may be numerically greater in subjects with NSCLC, because in some cases, it can be difficult to distinguish between nivolumab-related and unrelated causes of pulmonary symptoms and radiographic changes. There is no pattern in the incidence, severity, or causality of AEs to nivolumab dose level. In several ongoing clinical trials, the safety of nivolumab in combination with other therapeutics such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted therapies is being explored. Most studies are ongoing and, as such, the safety profile of nivolumab combinations continues to evolve. The most advanced combination under development is nivolumab + ipilimumab in subjects with melanoma. Thus far, the combination of both agents results in a safety profile with similar types of AEs as either agent alone, but in some cases with a greater frequency.
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2.2.3 nivolumab combined with ipilimumab

Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may improve antitumor activity. In vitro combinations of nivolumab plus ipilimumab increase IFN-γ production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. Increased antitumor activity of the combination was also observed in 3 of 5 syngeneic murine cancer models. In a murine melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodies increased the proportion of CTLA-4 and PD-1-expressing CD4/CD8 tumor infiltrating T effector cells and dual blockade increased tumor infiltration of T effector cells and decreased intratumoral T regulatory cells, as compared to either agent alone. Preclinically, a 4-week toxicity study of nivolumab in combination with ipilimumab conducted in cynomolgus monkeys demonstrated that the combination of nivolumab and ipilimuma resulted in dose-dependent gastrointestinal (GI) toxicity. Histologic findings included inflammatory changes in the large intestine, which increased in incidence and severity in a dosedependent manner. GI toxicity/colitis was not observed in cynomolgus monkeys administered nivolumab alone, but was observed in monkeys receiving ipilimumab. Nivolumab in combination with ipilimumab was also associated with lymphoid hypocellularity of the cortex and/or medulla of the thymus and with acinar cell degranulation in the pancreas. Additional findings included interstitial mononuclear cell infiltrates in the kidneys, portal mononuclear cell infiltrates in the liver and myeloid hypercellularity in the bone marrow. Nivolumab in combination with ipilimumab at the high-dose level (ie, 50 mg/kg and 10 mg/kg, respectively) was associated with the death of 1 animal, attributed to acute gastric dilatation without histopathological evidence of colitis upon pathology evaluation of the GI tract.
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clinical data

In the Phase 1 study CA209004, ascending doses of nivolumab have been studied concomitantly with ascending doses of ipilimumab in subjects with unresectable or metastatic melanoma. In each arm in this multi-arm study, ipilimumab was administered once every 3 weeks for 4 doses with nivolumab administered once every 3 weeks for 8 doses. Starting at week 24, ipilimumab and nivolumab were administered once every 12 weeks for 8 doses. The three initial dose escalation cohorts consisted of Cohort 1 (nivolumab 0.3 mg/kg plus ipilimumab 3 mg/kg; n = 14), Cohort 2 (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; n = 17) and Cohort 3 (nivolumab 3 mg/kg plus ipilimumab 3 mg/kg; n = 6). Later, the study was amended to include Cohort 2a which evaluated nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (n = 16) and Cohort 8 that represents an additional cohort of patients treated with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg The maintenance regimen for Cohorts 1-3 consisted of nivolumab q3 weeks x 4 then nivolumab plus ipilimumab q12 weeks x 8, while the maintenance regimen for Cohort 8 consisted of nivolumab 3 mg/kg q2 weeks until progression. The following dose limiting toxicities (DLTs) were observed in Cohort 1 - Grade 3 elevated AST/ALT (1 subject); in Cohort 2 - Grade 3 uveitis (1 subject) and Grade 3 elevated AST/ALT (1 subject) and in Cohort 3 Grade 4 elevated lipase (2 subjects) and Grade 3 elevated lipase (1 subject). Based on these data, Cohort 2 was identified as the maximum tolerated dose (MTD) and Cohort 3 exceeded the MTD. Among the 53 patients in the concurrent-regimen group, adverse events of any grade, regardless of whether they were attributed to the therapy, were observed in 98% of patients. Treatment-related adverse events of any grade were reported in 96.2% of patients, in pooled Cohorts 1-3 and 95.1% of Cohort 8. The drug-related skin select AE category was the most frequently reported category in all cohorts; rash and pruritus were the most frequently reported drug-related AEs in all cohorts. The most frequently reported drug-related AEs of any grade were rash (62.3%, Cohorts 1-3; 58.5%, Cohort 8), pruritus (56.6%, Cohorts 1-3; 46.3% Cohort 8), diarrhea (41.5%, Cohorts 1-3; 31.7%, Cohort 8), fatigue (41.5%, Cohorts 1-3; 41.5%, Cohort 8), lipase increased (26.4%, Cohorts 1-3; 14.6%, Cohort 8), AST increased (24.5%, Cohorts 1-3; 9.8%, Cohort 8), ALT increased (22.6%, Cohorts 1-3; 12.2%, Cohort 8), nausea (22.6%, Cohorts 1-3; 24.4%, Cohort 8), pyrexia (22.6%, Cohorts 1-3; 22.0%, Cohort 8), amylase increased (20.8%, Cohorts 1-3; 12.2%, Cohort 8). The only reported drug-related AE belonging to the pulmonary select AE category was pneumonitis; 3 (5.7%) subjects in Cohorts 1 to 3 and 1 (2.4%) subject in Cohort 8. Grade 3-4 events were reported in 1 subject each in Cohort 2a and Cohort 8. Treatment-related SAEs of any grade were reported in 58.5% of patients on pooled Cohorts 1-3 and 41.5 % of Cohort 8. The most frequently reported SAE in ≥ 5% subjects included: ALT increased, AST increased, lipase increased, colitis, diarrhea, amylase increased, pneumonitis, and pyrexia. A total of 13 subjects (24.5%) in Cohorts 1-3 and 9 subjects (22.0%) in Cohort 8 discontinued therapy due to treatment-related adverse events. The majority of the deaths were due to disease progression in CA209004. One subject died due to drug-related enterocolitis. The only CNS treatment related AE reported in >10% of subjects was headache [11.3% Cohorts 1-3 (Grade 1-2); 12.2% Cohort 8 with 1 Grade 3-4 event (2.4%)]. A single case of radiation necrosis was observed in a subject who received SRT for progression in the brain while on nivolumab monotherapy maintenance dosing. The subject had completed 4 doses of induction with combination ipilimumab and nivolumab, and 3 doses of nivolumab monotherapy maintenance. He received SRT for progression between dose \#3 and dose \#4 of nivolumab maintenance. He subsequently received a single dose of combination maintenance.  
Approximately 5-6 weeks after the dose of combination maintenance, radionecrosis was diagnosed. Attribution was assessed as related to SRT and unrelated to study drug. Three subjects experienced drug-related CNS adverse events that led to discontinuation - one subject with blurred vision (Grade 1) and headache (Grade 2), one subject with presyncope (Grade 3) and one subject with ageusia (Grade 1). A single subject experienced CNS adverse events assessed as not related, that led to discontinuation: muscular weakness (Grade 3), dizziness (Grade 2), headache (Grade 2), confusion (Grade 2). None of these subjects had received prior brain radiotherapy. Of the 11 subjects who did receive prior radiotherapy to the brain, only 1 subject experienced a CNS adverse event which was the case of radiation necrosis described above. Because of the potential for clinically meaningful nivolumab or ipilimumab related AEs requiring early recognition and prompt intervention, management algorithms have been developed for suspected pulmonary toxicity, GI, hepatotoxicity, endocrinopathy, skin toxicity, neurological toxicity and renal toxicity. Prompt interventions are recommended according to the management algorithms. In order to standardize the management, for the overlapping adverse event management algorithms present in both the nivolumab and ipilimumab IB (GI, hepatic, and endocrine algorithms), the recommendations are to follow the BMS-936558 (nivolumab) IB adverse event algorithms and not the ipilimumab IB algorithms. The algorithms recommended for utilization in CA209204 are contained in the nivolumab (BMS-936558) IB. As of August, 2014, 3 subjects out of approximately 4000 patients on nivolumab clinical trials have developed opportunistic infections (2 cases of Aspergillus pneumonia, and 1 case of Pneumocystis jiroveci pneumonia) after receiving prolonged treatment with high dose steroids for nivolumab-related adverse events. Details of these cases are available in the Investigator Brochure.
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2.3 rationale

The treatment of patients with many types of cancers has been revolutionized over the past decade with the development of immune checkpoint inhibitors targeting cytotoxic T-lymphocyte antigen 4 (CTLA4) and the programmed death 1 (PD1) receptor-ligand (PDL1, PDL2) interaction, as well as the development of small molecule inhibitors. These advances have led to the regulatory approval of ipilimumab, nivolumab, and pembrolizumab5-10. More recently, the combination of the anti-CTLA4 antibody ipilimumab and the anti-PD1 antibody nivolumab has been associated with deep responses in half of treated patients11. In addition to these advances, previously "untreatable" patient cohorts, such as those with brain metastases, have been evaluated in dedicated clinical trials. In fact, both ipilimumab and dabrafenib have demonstrated single-agent central nervous system (CNS) effects, leading to a remarkable loosening of eligibility criteria for melanoma clinical trials that just 5 years ago typically required 3 and up to 12 month stability of CNS metastasis12,13. A Phase II study of ipilimumab in patients with asymptomatic melanoma brain metastases showed disease activity in 18% of patients14.  
Although a clinical trial of nivolumab in brain metastases has not yet been published, a retrospective study demonstrated that patients with brain metastases receiving the combination of nivolumab and stereotactic radiation had improved survival compared to surgery and/or radiation alone15. An ongoing study by Goldberg and Kluger et al.13,14 showed that pembrolizumab is well tolerated and has promising activity in patients with asymptomatic brain metastases from melanoma and non-small cell lung cancer (NSCLC). Of 12 evaluable patients with melanoma brain metastases, partial responses were observed in 3 patients and stable disease in 2 patients14.  
Of 9 evaluable patients with brain metastases from nonsmall cell lung cancer (NSCLC), partial responses were observed in 4 patients13. Now, early phase trials often allow patients with asymptomatic and untreated metastases to enroll, and nearly all therapies deemed promising in melanoma are being tested in dedicated phase II trials for patients with untreated brain metastases. As astounding as these developments are, there remains one group of patients who remain ineligible for virtually every therapeutic trial, those with leptomeningeal disease (LMD). While any malignancy can metastasize to the leptomeninges, this most commonly occurs with lung cancer, breast cancer and melanoma. Approximately 5-8% of patients with cancer develop leptomeningeal carcinomatosis1. As visceral metastatic disease is better controlled and patients are surviving longer, LMD is being diagnosed more frequently. The median survival of patients with LMD without treatment is dismal, typically 4-6 weeks. Novel therapies are needed to improve outcomes in patients with LMD. The absence of effective therapies, and more importantly, access to treatment as part of clinical trials is a great unmet need in cancer. A recent study demonstrated that ipilimumab has activity in patients with brain metastases; however and not surprisingly, patients with LMD were excluded from this study. In our experience at Massachusetts General Hospital (MGH) Cancer Center, we have observed 2 clinical responses in the approximately 10 patients with melanoma and LMD who have received ipilimumab. Moreover there was one published report of describing a patient with leptomeningeal disease from melanoma having a complete response after receiving ipilimimab16.  
Furthermore, in a separate PI-initiated trial (DF/HCC \#16-153), an interim analysis of 18 patients with LMD treated with pembrolizumab showed that primary endpoint has been met, and more than 8 patients survived more than 3 months. The role of immunotherapy has not been systematically explored in this patient population, and based on our limited but encouraging experience with our patients, we have proposed a Phase II trial of ipilimumab plus nivolumab in patients with LMD, using a dose schedule that has demonstrated efficacy in other tumors. This trial offers a unique opportunity to systematically study LMD at the genomic and immune microenvironmental levels before and during therapy.
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2.4 correlative studies background

Genetic heterogeneity is a major limitation to the identification of predictors of response to nonCNS and CNS metastases, as well as LMD. We propose to evaluate recurrent clinically relevant mutations and genetic heterogeneity in non-CNS metastases and LMD. We will collect primary (when possible) and non-CNS metastatic tumors, and CSF cytology specimens as part of this clinical trial and perform whole exome and transcriptome sequencing of these samples. Of note, patients with LMD have Ommaya/VP shunts, thus allowing for frequent sampling of CSF. We will create phylogenetic trees to understand the evolutionary patterns in the metastatic process to the leptomeninges. In cases where we have primary tumors, we will compare mutational profiles between different sites. To date we have demonstrated our ability to perform these assays through next generation sequencing of 101 CNS metastases matched with primary tumors and other distal metastatic sites. We will use these same techniques to understand the genomic evolution of LMD, and to identify genomic biomarkers of response to immunotherapy. The tumor microenvironment is a complex system that includes tumor cells, stromal elements, infiltrating immune cells, and host tissue (e.g. liver in hepatic metastases), all interacting in ways that influence the effectiveness of any therapy, especially immunotherapy. Our groups have performed studies of the immune characteristics of the tumor microenvironment before and after checkpoint blockade. To date, there have been no descriptions of the CSF/LM tumor microenvironment in LMD, either unperturbed or after immunotherapy. We will be collecting CSF from every patient in this study. Lumbar punctures are part of standard of care in patients with leptomeningeal carcinomatosis. Serial CSF samples will give us the opportunity to study tumor evolution over the course of treatment with ipilimumab and nivolumab. Here we will perform unbiased transcriptome sequencing of purified CD4+ and CD8+ T cells and CD11b+ myeloid cells from the CSF to define the effects of immunotherapy on LMD in the patients described above. We will also evaluate expression of cytokines and other proteins in the CSF to further examine how checkpoint blockade alters the CSF/LM microenvironment. In parallel, we will purify the same immune cell types from paired PBMC samples for comparative transcriptomic analyses and collect sera for comparative cytokine/proteomic analyses with CSF. These comparative analyses should identify if there are alterations in the blood that reflect the biology of the CSF/LM microenvironment and can serve as biomarkers.
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3. participant selection 3.1 eligibility

3.1.1 Participants must have histologically or cytologically confirmed disease from any solid tumor.  
3.1.2 Age >18 years.
3.1.3 ECOG performance status ≤ 2 (Karnofsky ≥60%, see Appendix A)  
3.1.4 Life expectancy of greater than 3 weeks 3.1.5 Participants must have normal organ and marrow function as defined in Table 1, all screening labs should be performed within 14 days of treatment initiation.
Table 1 Adequate Organ Function Laboratory Values  
| System                                         | Laboratory Value   |
|------------------------------------------------|--------------------|
| Hematological Absolute neutrophil count  (ANC) | ≥1500 /mcL         |  
| Protocol Version Date: January 24, 2019                                                                                 |                                                                                                                                                                                                                                                                                                    |                                                             |
|-------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|
| Platelets                                                                                                               | ≥100,000 / mcL                                                                                                                                                                                                                                                                                     |                                                             |
| Hemoglobin                                                                                                              | ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency  (within 7 days of assessment)                                                                                                                                                                                                        |                                                             |
| Renal                                                                                                                   | ≤                                                                                                                                                                                                                                                                                                  | Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) |
| ≥ 40 mL/min (if using the Cockcroft-Gault formula below):                                                               |                                                                                                                                                                                                                                                                                                    |                                                             |
| Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used in place  of creatinine or CrCl) | Female CrCl = (140 - age in years) x weight in kg x 0.85   72 x serum creatinine in mg/dL  Male CrCl = (140 - age in years) x weight in kg x 1.00   72 x serum creatinine in mg/dL                                                                                                                 |                                                             |
| Hepatic Serum total bilirubin                                                                                           | ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5  ULN                                                                                                                                                                                                          |                                                             |
| AST (SGOT) and ALT (SGPT)                                                                                               | ≤ 3 ULN OR ≤ 5 X ULN for subjects with liver metastases                                                                                                                                                                                                                                            |                                                             |
| Albumin                                                                                                                 | >2.5 mg/dL                                                                                                                                                                                                                                                                                         |                                                             |
| Coagulation International Normalized Ratio  (INR) or Prothrombin Time  (PT)                                             | ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of  anticoagulants  ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of  anticoagulants |                                                             |
| a Creatinine clearance should be calculated per institutional standard. Activated Partial  Thromboplastin Time (aPTT)   |                                                                                                                                                                                                                                                                                                    |                                                             |  
3.1.6 Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug.  
3.1.7. Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of nivolumab.  
3.1.8. Women must not be breastfeeding. 3.1.9. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing
potential, ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception 3.1.7 Ability to understand and the willingness to sign a written informed consent document.  
3.1.8 Stable dose of dexamethasone 2 mg or less for 7 days prior to initiation of treatment  
3.1.9 Carcinomatous meningitis, as defined by positive cytology or biopsy. If CSF cytology is negative, but imaging is consistent with carcinomatous meningitis, patient is eligible.
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3.2 exclusion criteria

3.2.1 Participants who have had chemotherapy, targeted small molecule therapy or study therapy within 5 days of protocol treatment, or those who have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 2 weeks earlier. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.  
3.2.2 Participants who are receiving any other investigational agents. 3.2.3 Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger 3.2.4 Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Subjects are permitted to use topical, ocular, intraarticular, intranasal, and inhalational corticosteroids (with minimal systemic absorption).  
Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.  
3.2.5 As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen.
3.2.6 Patients should be excluded if they have had prior systemic treatment with a combination of anti-CTLA4 antibody and anti-PD1/PDL1 antibody. Prior treatment with single agent anti-CTLA4, anti-PD1 or anti-PDL1 antibody is allowed.  
3.2.7 Has a known history of active TB (Bacillus Tuberculosis) 3.2.8 Patients should be excluded if they are positive test for hepatitis B virus surface antigen
(HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection 3.2.9 Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).  
These participants are at increased risk of lethal infections when treated with marrowsuppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.  
3.2.10 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.  
3.2.11 Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.  
3.2.12 Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.  
3.2.13 Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.  
3.2.14 Has known history of, or any evidence of active, non-infectious pneumonitis.  
3.2.15 Has an active infection requiring systemic therapy. 3.2.16 Has received a live vaccine within 30 days of planned start of study therapy. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.  
3.2.17 History of allergy to study drug components 3.2.18 History of severe hypersensitivity reaction to any monoclonal antibody
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3.3 inclusion of women and

Both men and women of all races and ethnic groups are eligible for this trial.
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4. registration procedures 4.1 general

Institutions will register eligible participants in the Clinical Trials Management System (CTMS) OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not registered to the protocol before protocol therapy begins will be considered ineligible and registration will be denied. An investigator will confirm eligibility criteria and a member of the study team will complete the protocol-specific eligibility checklist.  
Following registration, participants may begin protocol therapy. Issues that would cause treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant does not receive protocol therapy following registration, the participant's registration on the study must be canceled. Registration cancellations must be made in OnCore as soon as possible.
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4.2 registration process for df/hcc

DF/HCC Standard Operating Procedure for Human Subject Research Titled *Subject Protocol* Registration (SOP \#: REGIST-101) must be followed.  
4.3 General Guidelines for Other Investigative **Sites** N/A 4.4 Registration Process for Other Investigative **Sites** N/A
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5. treatment plan 5.1 treatment

For melanoma: patients will be treated with the combination regimen of nivolumab 1 mg/kg combined with ipilimumab 3mg/kg Q3W (4 doses), followed by nivolumab monotherapy (480 mg Q4W) until progression or unacceptable toxicity. For nonsmall cell lung cancer and head and neck cancer: patients will be treated with nivolumab 3mg/kg Q2W + ipilimumab 1mg/kg Q6W For small cell lung cancer, breast cancer, and bladder cancer: patients will be treated with nivolumab 1mg/kg + ipilimumab 3mg/kg Q3W x 4 doses, followed by nivolumab 240 mg Q2W For renal cell carcinoma and other solid tumors (not listed above): patients will be treated with nivolumab 3mg/kg + ipilimumab 1mg/kg Q3W x 4 doses, followed by nivolumab 480 mg Q4W Each treatment cycle will be 6 weeks, with the exception of the nivolumab maintenance monotherapy phase in melanoma, renal cell carcinoma and other solid tumors, when each cycle will be 8 weeks. Treatment will be administered on an outpatient basis. Reported adverse events and potential risks are described in Section 7. Appropriate dose modifications are described in Section 6. No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the participant's malignancy.
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5.2 pre-treatment criteria 5.2.1 cycle

| System                                                                                                                  | Laboratory Value                                                                                                                                                                   |                                                             |
|-------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|
| Hematological Absolute neutrophil count  (ANC)                                                                          | ≥1500 /mcL                                                                                                                                                                         |                                                             |
| Platelets                                                                                                               | ≥100,000 / mcL                                                                                                                                                                     |                                                             |
| Hemoglobin                                                                                                              | ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency  (within 7 days of assessment)                                                                                        |                                                             |
| Renal                                                                                                                   | ≤                                                                                                                                                                                  | Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) |
| ≥ 40 mL/min (if using the Cockcroft-Gault formula below):                                                               |                                                                                                                                                                                    |                                                             |
| Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used in place  of creatinine or CrCl) | Female CrCl = (140 - age in years) x weight in kg x 0.85   72 x serum creatinine in mg/dL  Male CrCl = (140 - age in years) x weight in kg x 1.00   72 x serum creatinine in mg/dL |                                                             |
| Hepatic Serum total bilirubin                                                                                           | ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5  ULN                                                                                          |                                                             |
| AST (SGOT) and ALT (SGPT)                                                                                               | ≤ 3 ULN OR ≤ 5 X ULN for subjects with liver metastases                                                                                                                            |                                                             |
| Albumin                                                                                                                 | >2.5 mg/dL                                                                                                                                                                         |                                                             |
| Coagulation International Normalized Ratio                                                                              | ≤1.5 X ULN unless subject is receiving anticoagulant therapy                                                                                                                       |                                                             |  
A serum or urine pregnancy testing is required within 72 hrs of study enrollment. Cycle 1, Day 1 labs will be used to confirm eligilibity.  
| (INR) or Prothrombin Time  (PT)                                                                                       | as long as PT or PTT is within therapeutic range of intended use of  anticoagulants  ≤1.5 X ULN unless subject is receiving anticoagulant therapy  as long as PT or PTT is within therapeutic range of intended use of  anticoagulants   |
|-----------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| a Creatinine clearance should be calculated per institutional standard. Activated Partial  Thromboplastin Time (aPTT) |                                                                                                                                                                                                                                          |
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5.2.2 subsequent cycles

Pregnancy Test: Every 6 weeks. After discontinuation from nivolumab these should be repeated at approximately 30 days and approximately 70 days. Laboratory testing prior to each dose: Within 72 hrs prior to re-dosing to include CBC w/ differential, LFTs, BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, Glucose, amylase, lipase, TSH (with reflexive Free T4 and Free T3)  
| System                                                                                                                  | Laboratory Value                                                                                                                                                                   |                                                             |
|-------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|
| Hematological Absolute neutrophil count  (ANC)                                                                          | ≥1500 /mcL                                                                                                                                                                         |                                                             |
| Platelets                                                                                                               | ≥100,000 / mcL                                                                                                                                                                     |                                                             |
| Hemoglobin                                                                                                              | ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency  (within 7 days of assessment)                                                                                        |                                                             |
| Renal                                                                                                                   | ≤                                                                                                                                                                                  | Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) |
| ≥ 40 mL/min (if using the Cockcroft-Gault formula below):                                                               |                                                                                                                                                                                    |                                                             |
| Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used in place  of creatinine or CrCl) | Female CrCl = (140 - age in years) x weight in kg x 0.85   72 x serum creatinine in mg/dL  Male CrCl = (140 - age in years) x weight in kg x 1.00   72 x serum creatinine in mg/dL |                                                             |
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5.3 agent administration

For treatment schedule, see section 5.1 When study drugs (ipilimumab or nivolumab) are to be administered on the same day, separate infusion bags and filters must be used for each infusion. It is recommended that nivolumab be administered first. The second infusion will always be ipilimumab, and will start approximately 30 minutes after completion of the nivolumab infusion. 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 study drugs Nivolumab & Ipilimumab.  
BMS-936558 (nivolumab) is to be administered as a 30 minute IV infusion. Ipilimumab should be administered as a 30 minute infusion following. Ipilimumab and nivolumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose solution. 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. All doses should be rounded up or to the nearest milligram per institutional standard. For the q3 week schedule, patients may be dosed no less than 18 days from the previous dose of drug; and dosed up to 3 days after the scheduled date if necessary. For the q4 week schedule, patients may be dosed no less than 24 days from the previous dose of drug; and dosed up to 3 days after the scheduled date if necessary. There will be no dose modifications permitted. Dose reductions or dose escalations are not permitted.
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5.4 general concomitant medication and

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. Note: Radiation therapy to a symptomatic single extracranial site and/or one intracranial site may be allowed at the investigator's discretion, as long as ipilimumab is held during radiation and at least 3 weeks after completion of radiation.
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5.5 criteria for taking a

Duration of therapy will depend on individual response, evidence of disease progression and tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for until one of the following criteria applies:
- Disease progression - Intercurrent illness that prevents further administration of treatment  
- Unacceptable adverse event(s) - Participant demonstrates an inability or unwillingness to comply with the oral medication regimen and/or documentation requirements
- Participant decides to withdraw from the protocol therapy
- General or specific changes in the participant's condition render the participant unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply. The reason for removal from protocol therapy, and the date the participant was removed, must be documented in the case report form (CRF). Alternative care options will be discussed with the participant. A Office of Data Quality (ODQ) Treatment Ended/Off Study Form will be filled out when a participant is removed from protocol therapy. This form can be found on the ODQ website or obtained from the ODQ registration staff. In the event of unusual or life-threatening complications, treating investigators must immediately notify the Overall PI, Priscilla Brastianos at 617-724-8563.
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5.6 duration of follow up

Patients will have a followup visit 30 days from the last dose +/- 7 days or coincide with the date of discontinuation (+/- 7 days) if date of discontinuation is greater than 37 days after last dose. Follow-up visit 2 will be 8-10 weeks (+/- 7 days) from follow-up visit 1. After 2 followup visits, patients will be followed with a phone call every 10-12 weeks for survival information for 2 years after removal from protocol therapy or until death, whichever occurs first. Participants removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.
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5.7 criteria for taking a

Participants will be removed from study when any of the following criteria apply:
- Lost to follow-up
- Withdrawal of consent for data submission
- Death The reason for taking a participant off study, and the date the participant was removed, must be documented in the case report form (CRF). An ODQ Treatment Ended/Off Study Form will be filled out when a participant comes off study. This form can be found on the ODQ website or obtained from the ODQ registration staff.
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6. dosing delays/dose modifications

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A copy of the CTCAE version 4.0 can be downloaded from the CTEP website http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
There will be no dose modifications permitted. Dose reductions or dose escalations are not permitted.
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management algorithms for immuno-oncology agents

Immuno-oncology (I-O) agents are associated with adverse events that can differ in severity and duration than adverse events caused by other therapeutic classes. Nivolumab and ipilimumab are considered immuno-oncology agents in this protocol. Management algorithms have been developed to assist investigators in assessing and managing the following groups of adverse events: Gastrointestinal, Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, and Neurological. Early recognition and intervention are recommended according to the management algorithms; and in addition include ophthalmologic evaluations for any visual symptoms in order to evaluate for nivolumab or ipilimumab related uveitis. The recommendations are to follow the algorithms in the nivolumab investigator brochure for immune related events; while the ipilimumab investigator brochure contains similar algorithms, the algorithms in the nivolumab brochure have been aligned to accommodate combinations as well as nivolumab monotherapy. For subjects expected who require more than 4 weeks of corticosteroids or other immunosuppressants to manage an adverse event, consider the following recommendations
- Antimicrobial/antifungal prophylaxis per institutional guidelines to prevent opportunistic infections such as Pneumocystis jiroveci and fungal infections.  
- Early consultation with an infectious disease specialist should be considered. Depending on the presentation, consultation with a pulmonologist for bronchoscopy or a gastroenterologist for endoscopy may also be appropriate.  
- In patients who develop recurrent adverse events in the setting of ongoing or prior immunosuppressant use, an opportunistic infection should be considered in the differential diagnosis.  
Additional details on the safety of nivolumab and ipilimumab , including results from clinical studies, are available in the IB.
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dose delay criteria

Because of the potential for clinically meaningful nivolumab-related AEs requiring early recognition and prompt intervention, management algorithms have been developed for suspected AEs of selected categories. [see current Investigator Brochure for citation examples] Dose delay criteria apply for all drug-related adverse events (regardless of whether or not the event is attributed to nivolumab, ipilimumab or both). All study drugs must be delayed until treatment can resume. Nivolumab and ipilimumab administration should be delayed for the following:
- Any Grade ≥ 2 non-skin, drug-related adverse event, with the following exceptions:  
o Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay
- Any Grade 3 skin, drug-related adverse event
- Any Grade 3 drug-related laboratory abnormality, with the following exceptions for asymptomatic amylase or lipase, AST, ALT, or total bilirubin:
o Grade 3 amylase or lipase abnormalities that are not associated with symptoms or clinical manifestations of pancreatitis do not require a dose delay. It is recommended to consult with the principle investigator for Grade 3 amylase or lipase abnormalities.  
o If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, delay dosing for drug-related Grade ≥ 2 toxicity o If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, delay dosing for drug-related Grade ≥ 3 toxicity
- Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the investigator, warrants delaying the dose of study medication.
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criteria to resume treatment

Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade ≤1 or baseline value, with the following exceptions:
- Subjects may resume treatment in the presence of Grade 2 fatigue  
- Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in the presence of Grade 2 skin toxicity
- Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the presence of Grade 2 AST/ALT OR total bilirubin
- Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting discontinuation parameters should have treatment permanently discontinued
- Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline before treatment is resumed
- Drug-related endocrinopathies adequately controlled with only physiologic hormone replacement may resume treatment
If the criteria to resume treatment are met, the subject should restart treatment at the next scheduled timepoint per protocol. However, if the treatment is delayed past the next scheduled timepoint per protocol, the next scheduled timepoint will be delayed until dosing resumes. If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study therapy, except as specified in discontinuation section.
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discontinuation criteria

Treatment should be permanently discontinued for the following:  
- Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within the re-treatment period OR requires systemic treatment
- Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic adverse event, hypersensitivity reactions, and infusion reactions o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, colitis, neurologic adverse event, hypersensitivity reaction, or infusion reaction of any duration requires discontinuation o Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation except those noted below
- Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires discontinuation
- Any drug-related liver function test (LFT) abnormality that meets the following criteria require discontinuation: - AST or ALT > 8 x ULN - Total bilirubin > 5 x ULN - Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
- Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following events which do not require discontinuation:  
- Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 within 1 week of onset.  
- Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical sequelae and are corrected with supplementation/appropriate management within 72 hours of their onset
- Any dosing interruption lasting > 6 weeks with the following exceptions:
- Dosing interruptions to allow for prolonged steroid tapers to manage drug-related adverse events are allowed. Prior to re-initiating treatment in a subject with a dosing interruption lasting > 6 weeks, the Investigator must be consulted. Tumor assessments should continue as per protocol even if dosing is interrupted  
- Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be allowed if approved by the Investigator. Prior to re-initiating treatment in a subject with a dosing interruption lasting > 6 weeks, the Investigator must be consulted. Tumor assessments should continue as per protocol even if dosing is interrupted
- Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the Investigator, presents a substantial clinical risk to the subject with continued nivolumab or ipilimumab dosing
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treatment of nivolumab or ipilimumab

Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, it is unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. Infusion reactions should be graded according to NCI CTCAE 4.0 guidelines. Treatment recommendations are provided below and may be modified based on local treatment standards and guidelines as appropriate:
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not indicated) Remain at bedside and monitor subject until recovery from symptoms. The following prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before additional nivolumab administrations.  
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 24 hours). Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat the subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen); remain at bedside and monitor subject until resolution of symptoms. Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of the original infusion rate when symptoms resolve; if no further complications ensue after 30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur then no further nivolumab or ipilimumab will be administered at that visit. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until resolution of symptoms. The amount of study drug infused must be recorded on the electronic case report form (eCRF). The following prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) should be administered at least 30 minutes before additional nivolumab or ipilimumab administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be used.  
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following initial improvement; hospitalization indicated for other clinical sequelae [eg, renal impairment, pulmonary infiltrates]). Grade 4: (life threatening; pressor or ventilatory support indicated). Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of normal saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until the investigator is comfortable that the symptoms will not recur. Nivolumab or ipilimumab will be permanently discontinued. Investigators should follow their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized pruritis within 1 week after treatment), symptomatic treatment may be given (eg, oral antihistamine, or corticosteroids).
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7. adverse events list and

Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of reported and/or potential AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine whether the event requires expedited reporting in addition to routine reporting.
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7.1 adverse event characteristics

- **CTCAE term (AE description) and grade:** The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
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- for expedited reporting purposes

- AEs for the agent(s) that are listed above should be reported only if the adverse event varies in nature, intensity or frequency from the expected toxicity information which is provided.  
- Other AEs for the protocol that do not require expedited reporting are outlined in the next section (Expedited Adverse Event Reporting) under the sub-heading of ProtocolSpecific Expedited Adverse Event Reporting Exclusions.  
- **Attribution** of the AE:
- Definite - The AE *is clearly related* to the study treatment. - Probable - The AE *is likely related* to the study treatment. - Possible - The AE *may be related* to the study treatment.  
- Unlikely - The AE *is doubtfully related* to the study treatment. - Unrelated - The AE *is clearly NOT related* to the study treatment.
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7.2 expedited adverse event reporting

7.2.1 Investigators **must** report to the Overall PI any serious adverse event (SAE) that occurs after the initial dose of study treatment, during treatment, or within 30 days of the last dose of treatment on the local institutional SAE form.
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7.2.2 df/hcc expedited reporting guidelines

Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human Research Studies (OHRS) per the DFCI IRB reporting policy.
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7.3 expedited reporting to hospital

Participating investigators will report to their local Risk Management office any participant safety reports or sentinel events that require reporting according to institutional policy.
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7.4 routine adverse event reporting

All Adverse Events **must** be reported in routine study data submissions to the Overall PI on the toxicity case report forms. **AEs reported through expedited processes (e.g., reported to the**
IRB, FDA, etc.) must also be reported in routine study data submissions.
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7.5 definitions

7.5.1 An **Adverse Event (AE)** is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product. The causal relationship to study drug is determined by a physician and should be used to assess all adverse events (AE).  
7.5.2 A S*erious Adverse Event (SAE)* is any untoward medical occurrence that at any dose:
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- results in death

- is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe)
- requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE below)
- results in persistent or significant disability/incapacity
- is a congenital anomaly/birth defect - is an important medical event (defined as a medical event(s) that may not be immediately life-threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the subject or may require intervention [eg, medical, surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples of such events include, but are not limited to, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.)
- Potential drug induced liver injury (DILI) is also considered an important medical event.  
- Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug is an SAE.  
- Although pregnancy, overdose, and cancer are not always serious by regulatory definition, these events must be handled as SAEs.
The following hospitalizations are not considered SAEs:
− a visit to the emergency room or other hospital department < 24 hours, that does not result in admission (unless considered an important medical or life-threatening event)
− elective surgery, planned prior to signing consent − admissions as per protocol for a planned medical/surgical procedure − routine health assessment requiring admission for baseline/trending of health status
(eg, routine colonoscopy)
− Medical/surgical admission other than to remedy ill health and planned prior to entry into the study. Appropriate documentation is required in these cases  
− Admission encountered for another life circumstance that carries no bearing on health status and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, caregiver respite, family circumstances, administrative reason).  
7.5.3 Nonserious Adverse Events
- A *nonserious adverse event* is an AE not classified as serious.  
- Nonserious Adverse Events are to be provided to BMS in aggregate via interim or final study reports as specified in the agreement or, if a regulatory requirement [e.g. IND US trial] as part of an annual reporting requirement.  
- Nonserious AE information should also be collected from the start of a placebo lead-in period or other observational period intended to establish a baseline status for the subjects.
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7.6 potential drug induced liver

Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs. Potential drug induced liver injury is defined as:
1) ALT or AST elevation > 3 times upper limit of normal (ULN)
AND
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase) AND
3) No other immediately apparent possible causes of AST/ALT elevation and hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the administration of other drug(s) known to be hepatotoxic.
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7.7 pregnancy

If, following initiation of the investigational product, it is subsequently discovered that a study subject is pregnant or may have been pregnant at the time of investigational product exposure, including during at least 6 half lives after product administration, the investigational product will be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject safety). The investigator must immediately notify Worldwide Safety @BMS of this event via the Pregnancy Surveillance Form in accordance with SAE reporting procedures. Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome and, where applicable, offspring information must be reported on the Pregnancy Surveillance Form [provided upon request from BMS] Any pregnancy that occurs in a female partner of a male study participant should be reported to BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 7.8 **Overdose** An overdose is defined as the accidental or intentional administration of any dose of a product that is considered both excessive and medically important. All occurrences of overdose must be reported as an SAE.
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7.9 other safety considerations

Any significant worsening noted during interim or final physical examinations, electrocardiograms, x-rays, and any other potential safety assessments, whether or not these procedures are required by the protocol, should also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
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7.10 adverse event reporting to

- All Serious Adverse Events (SAEs) that occur following the subject's written consent to participate in the study through 100 days of discontinuation of dosing must be reported to BMS Worldwide Safety.  
- The BMS SAE form should be used to report SAEs. If the BMS form cannot be used, another acceptable form (i.e CIOMS or Medwatch) must be reviewed and approved by BMS. The BMS protocol ID number must be included on whatever form is submitted by the Sponsor/Investigator.  
- Following the subject's written consent to participate in the study, all SAEs, whether related or not related to study drug, are collected, including those thought to be associated with protocol-specified procedures. The investigator should report any SAE occurring after these time periods that is believed to be related to study drug or protocol-specified procedure.  
- In accordance with local regulations, BMS will notify investigators of all reported SAEs that are suspected (related to the investigational product) and unexpected (i.e., not previously described in the IB). In the European Union (EU), an event meeting these criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). Investigator notification of these events will be in the form of an expedited safety report (ESR).
o Other important findings which may be reported by the as an ESR include:
increased frequency of a clinically significant expected SAE, an SAE considered associated with study procedures that could modify the conduct of the study, lack of efficacy that poses significant hazard to study subjects, clinically significant safety finding from a nonclinical (eg, animal) study, important safety recommendations from a study data monitoring committee, or sponsor decision to end or temporarily halt a clinical study for safety reasons.  
o Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the IB. Where required by local regulations or when there is a central IRB/IEC for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will determine if the informed consent requires revision. The investigator should also comply with the IRB/IEC procedures for reporting any other safety information.  
o In addition, suspected serious adverse reactions (whether expected or unexpected)
shall be reported by BMS to the relevant competent health authorities in all concerned countries according to local regulations (either as expedited and/or in aggregate reports).  
- Following the subject's written consent to participate in the study, all SAEs, whether related or not related to study drug, must be collected, including those thought to be associated with protocol-specified procedures. All SAEs must be collected that occur within 100 days of discontinuation of dosing.  
- All SAEs must be collected that occur during the screening period. If applicable, SAEs must be collected that relate to any protocol-specified procedure (eg, a follow-up skin biopsy). The investigator should report any SAE that occurs after these time periods that is believed to be related to study drug or protocol-specified procedure.  
- SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies on a Pregnancy Surveillance Form.
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- sae email address worldwide.safety@bms.com

- If only limited information is initially available, follow-up reports are required. (Note:
Follow-up SAE reports should include the same investigator term(s) initially reported.)
- If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or designee) using the same procedure used for transmitting the initial SAE report.  
- All SAEs should be followed to resolution or stabilization. - The Sponsor/Investigator will ensure that all SAEs in the clinical database are reported to BMS and any applicable health authority during the conduct of the study. This reconciliation will occur at least quarterly and be initiated by the sponsor/investigator. Sponsor/investigator will request a reconciliation report from: aepbusinessprocess@bms.com. During reconciliation, any events found to not be reported previously to BMS must be sent to Worldwide.Safety@BMS.com.  
- An SAE report should be completed for any event where doubt exists regarding its seriousness.  
- If the investigator believes that an SAE is not related to study drug, but is potentially related to the conditions of the study (such as withdrawal of previous therapy or a complication of a study procedure), the relationship should be specified in the narrative section of the SAE Report Form.  
- If only limited information is initially available, follow-up reports are required. (Note:
Follow-up SAE reports should include the same investigator term(s) initially reported.)
- If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes available, a follow-up SAE report should be sent within 24 hours to BMS using the same procedure used for transmitting the initial SAE report. All SAEs should be followed to resolution or stabilization. All SAEs should be followed to resolution or stabilization.
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8. pharmaceutical information

| Table                | Product Description                                                           |                                             |                                                                  |            |         |            |         |
|----------------------|-------------------------------------------------------------------------------|---------------------------------------------|------------------------------------------------------------------|------------|---------|------------|---------|
| Product  Description | and                                                                           |                                             |                                                                  |            |         |            |         |
| Dosage Form          | Potency                                                                       | Primary  Packagin g  (Volume)/  Label  Type | Secondary  Packaging (Qty) /Label  Type                          | Appearance | Storage | Conditions |         |
| (per label)          |                                                                               |                                             |                                                                  |            |         |            |         |
| Nivolumab            | BMS                                                                               |                                             |                                                                  |            |         |            |         |
| 936558-01  Solution  | for                                                                           |                                             |                                                                  |            |         |            |         |
| Injectiona           | 100 mg (10                                                                    | 10                                          | mL                                                               | 5          | vials   | per        |         |
| mg/mL)               | viall                                                                         | carton/                                     | Open                                                                  |            |         |            |         |
| label                | Clear to opalescent  colorless to pale  yellow liquid. May  contain particles | 2                                           | to                                                               | 8°C.       | Protect |            |         |
| from                 | light                                                                         | and                                         |                                                                  |            |         |            |         |
| freezing.            |                                                                               |                                             |                                                                  |            |         |            |         |
| Ipilimumab  Solution | for                                                                           |                                             |                                                                  |            |         |            |         |
| Injection            | 200 mg (5                                                                     | 40                                          | mL                                                               | 4          | vials   | per        |         |
| mg/mL)               | vial                                                                          | carton/Openlabel                                             | Clear, colorless to  pale yellow liquid.  May contain  particles | 2          | to      | 8°C.       | Protect |
| from                 | light                                                                         | and                                         |                                                                  |            |         |            |         |
| freezing.            |                                                                               |                                             |                                                                  |            |         |            |         |
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8.1 product description of ipilimumab

If stored in a glass front refrigerator, vials should be stored in the carton. Recommended safety measures for preparation and handling of Nivolumab and Ipilimumab include laboratory coats and gloves. For additional details on prepared drug storage and use time of Nivolumab or Ipilimumab under room temperature/light and refrigeration, please refer to the BMS-936558 (Nivolumab) and Ipilimumab Investigator Brochure section for "Recommended Storage and Use Conditions"
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8.1.2 handling

The investigator should ensure that the study drug is stored in accordance with the environmental conditions (temperature, light, and humidity) as per product information and the Investigator Brochure and per local regulations. It is the responsibility of the investigator to ensure that investigational product is only dispensed to study subjects. The investigational product must be dispensed only from official study sites by authorized personnel according to local regulations. If concerns regarding the quality or appearance of the study drug arise, the study drug should not be dispensed and contact BMS immediately. Please refer to the current version of the Investigator Brochure and/or shipment reference sheets for additional information on storage, handling, dispensing, and infusion information for Nivolumab.  
8.1.3 **Preparation**
See Section 8.2 for Nivolumab instructions and 8.3 for Ipilimumab instructions.
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8.1.4 administration

See Section 8.2 for Nivolumab instructions and 8.3 for Ipilimumab instructions.
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8.1.5 accountability

The investigator is responsible for ensuring that the investigational product is stored under the appropriate environmental conditions (temperature, light, and humidity)
- If concerns regarding the quality or appearance of the investigational product arise, do not dispense the investigational product, and contact BMS immediately. If commercial investigational product is used, it should be stored in accordance with the appropriate local labeling
- If the study drug(s) are to be destroyed on site, it is the investigator's responsibility to ensure that arrangements have been made for disposal, and that procedures for proper disposal have been established according to applicable regulations, guidelines, and institutional procedures
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8.1.6 destruction and return

Sponsor/Investigator drug destruction is allowed provided the following minimal standards are met: - On-site disposal practices must not expose humans to risks from the drug.  
- On-site disposal practices and procedures are in agreement with applicable laws and regulations, including any special requirements for controlled or hazardous substances.  
- Written procedures for on-site disposal are available and followed. The procedures must be filed with the Sponsor SOPs and a copy provided to BMS upon request.  
- Note vials and remaining IP are sent to destruction after dose preparation in the IV room as per site SOP. Whole vials are signed out on the accountability logs by the research pharmacy staff.  
- Accountability and disposal records are complete, up-to-date, and available for BMS to review throughout the clinical trial period as per the study agreement.
If conditions for destruction cannot be met, please contact BMS. It is the Sponsor Investigator's responsibility to arrange for disposal of all empty containers, provided that procedures for proper disposal have been established according to applicable federal, state, local, and institutional guidelines and procedures, and provided that appropriate records of disposal are kept.
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8.1.7 ordering initial orders

- Following submission and approval of the required regulatory documents, a supply of Nivolumab and Ipilimumab may be ordered from by completing a Drug Request Form provided by BMS for this specific trial.  
- The initial order should be limited to the amount needed for two doses. Allow 5 business days for shipment of drug from BMS receipt of the Drug Request Form. Drug is protocol specific, but not patient specific. All drug products will be shipped by courier in a temperature-controlled container. It is possible that sites may have more than one Nivolumab clinical study ongoing at the same time. It is imperative that only drug product designated for this protocol number be used for this study.  
- Pharmacy supplies not provided by BMS: Empty IV bags/containers, approved diluents, Inline filters and infusion tubing
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re-supply

- Drug re-supply request form should be submitted electronically at least 7 business days before the expected delivery date. Deliveries will be made Tuesday through Friday.  
- When assessing need for resupply, institutions should keep in mind the number of vials used per treatment dose, and that shipments may take 14 business days from receipt of request.
Drug is not patient-specific. Be sure to check with your pharmacy regarding existing investigational stock to assure optimal use of drug on hand.
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drug excursions

- Drug excursions should be reported immediately to BMS on the form provided with the study-specific drug order form
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8.2 nivolumab

As this is provided for guidance only, please see investigator brochure for additional information regarding preparation and administration Nivolumab has a concentration of 10mg/mL and is provided in a 10mL vial. Ten or five vials are provided in a carton.  
Storage Conditions & Handling:
- Store at 2-8°C (36-46°F), protect from light, freezing, and shaking.  
- If any temperature excursions are encountered during storage, please report these to BMS for assessment via the Temperature Excursion Response Form.  
- As with all injectable drugs, care should be taken when handling and preparing Nivolumab.  
Whenever possible, Nivolumab should be prepared in a laminar flow hood or safety cabinet using standard precautions for the safe handling of intravenous agents applying aseptic technique.  
- Partially used vials should be disposed at the site following procedures for the disposal of anticancer drugs.
After final drug reconciliation, unused Nivolumab vials should be disposed at the site following procedures for the disposal of anticancer drugs. For further information, please either discuss with your BMS CSR&O protocol manager or refer to your site IP Destruction policies and procedures Use Time/Stability: Please refer to the appropriate section of the current Investigator Brochure.  
Due to parameters surrounding the use time of Nivolumab and Ipilimumab, the time of preparation should be noted in the Pharmacy Source documents [accountability logs] or in study files as required for investigator sponsored research [FDA and GCP] The administration of BMS-936558-01 injection prepared for dosing Nivolumab infusion must be completed within 24 hours of preparation. If not used immediately, the infusion solution may be stored up to 20 hours in a refrigerator at under refrigeration conditions (2°-°-8°C (, 36°-46°F) and used within 24 hours, and a maximum of 4 hours of the total 24 hours can be at room temperature (20°-25°C, 68°-77°F) and under room light. The maximum 4-hour period under room temperature and room light conditions for undiluted and diluted solutions of BMS-93655801 injection in the IV bag includes the product administration period. Nivolumab infusions are 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 protocolspecified doses. It is not to be administered as an IV push or bolus injection.
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preparation and administration

1. Visually inspect the drug product solution for particulate matter and discoloration prior to administration. Discard if solution is cloudy, if there is pronounced discoloration (solution may have a pale-yellow color), or if there is foreign particulate matter other than a few translucent-to-white, amorphous particles. Note: Mix by gently *inverting several times. Do* not shake.  
2. Aseptically withdraw the required volume of Nivolumab solution into a syringe, and dispense into an IV. bag. If multiple vials are needed for a subject, it is important to use a separate sterile syringe and needle for each vial to prevent problems such as dulling of needle tip, stopper coring, repeated friction of plunger against syringe barrel wall. **Do not** enter into each vial more than once. **Do not** administer study drug as an IV push or bolus injection 3. Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% Dextrose Injection solution. It is acceptable to add Nivolumab solution from the vials into an appropriate pre-filled bag of diluent.  
4. Note: Nivolumab infusion concentration must be at or above *the minimum allowable* concentration of 0.35 mg/mL [IBV13 Addendum Section 3.2.2]
5. Note: It is not recommended that so-called "channel" or tube systems are used to transport prepared infusions of Nivolumab.  
6. Attach the IV bag containing the Nivolumab solution to the infusion set and filter. 7. At the end of the infusion period, flush the line with a sufficient quantity of approved diluents.
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8.3 ipilimumab

Ipilimumab vials (40 mL) are shipped in quantities of four. Ipilimumab (BMS-734016) Injection (5 mg/ml) must be stored refrigerated (2-8°C, 36-46°F) with protection from light and from freezing. Ipilimumab may be stored in IV infusion bags (PVC, non-PVC/non-DEHP) or glass infusion containers for up to 24 hours at room temperature (20-25°C, 68-77°F) or refrigerated (28°C, 36-46°F). This would include any time in transit and the total time for infusion. Drug must be completely delivered within 24 hours of preparation.
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storage conditions & handling

Ipilimumab injection may be stored undiluted, 200 mg/vial (5 mg/mL), or following dilution to concentrations between 1 mg/mL and 4 mg/mL in 0.9% Sodium Chloride Injection (USP), or 5% Dextrose Injection (USP) in PVC, non-PVC/ or glass containers for up to 24 hours in the refrigerator (2°C to 8°C) or at room temperature/room light. For longer storage, Ipilimumab should be kept refrigerated (2°C to 8°C) with protection from light.  
Ipilimumab injection must not be frozen. Partially used vials or empty vials of Ipilimumab Injection should be discarded at the site according to appropriate drug disposal procedures.
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preparation and administration as this

1. As Ipilimumab is stored long term at refrigerated temperatures (2-8ºC) and protected from light and freezing, allow the appropriate number of vials of Ipilimumab to stand at room temperature for approximately five minutes.  
2. Ensure that the Ipilimumab solution is clear colorless, essentially free from particulate matter on visual inspection. If multiple vials are needed for a subject, it is important to use a separate sterile syringe and needle for each vial to prevent problems such as dulling of needle tip, stopper coring, repeated friction of plunger against syringe barrel wall, etc.  
3. Aseptically transfer the required volume of Ipilimumab solution into a syringe. [Note: A
sufficient excess of Ipilimumab is incorporated into each vial to account for withdrawal losses].  
4. Do not draw into each vial more than once. Discard partially used vials or empty vials. 5. Ipilimumab solution should be added to an appropriate size infusion container to accommodate the calculated final volume. Total dose should be calculated using the most recent subject weight; if weight on dosing day differs by 5% from prior weight used to calculate dosing, the dose should be recalculated and study drug adjusted accordingly. Mix by GENTLY inverting several times. DO NOT shake. Ipilimumab injection may be diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.  
6. Visually inspect the final solution. If the initial diluted solution or final solution for infusion is not clear or contents appear to contain precipitate, the solution should be discarded.  
7. Immediately after the infusion is complete, flush with an adequate amount of 0.9%
Sodium Chloride injection (USP) or 5% Dextrose injection (USP) to completely flush the residual fluid (dead space) in your administration set (approximately 30-50mL); this will ensure that all active drug is delivered to the study participant 8. Safely discard any unused portion of the infusion solution. Do not store for reuse.  
Ipilimumab should be administered under the supervision of a physician experienced in the use of intravenous (IV) agents. Ipilimumab is administered as an IV infusion only Ipilimumab infusions are 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 protocolspecified doses. It is not to be administered as an IV push or bolus injection.  
It is possible that sites may have more than one Ipilimumab clinical study ongoing at the same time. It is imperative that only product designated for this protocol be used for this study. 9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
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9.1 background of exploratory biomarker

The objectives of our exploratory biomarkers are to define the genomic characteristics and the immune microenvironment of leptomeningeal disease in the setting of immune checkpoint inhibitors. Whole-exome sequencing and transcriptome data from non-CNS and CNS metastases and LMD will enable the identification of mutations, insertion/deletion events, and copy-number changes. We also expect to identify genetic signatures that predict response to immunotherapy. Based on our preliminary data across 104 brain metastases, we anticipate that we will identify novel drivers in LMD. We expect to observe changes in RNA/protein expression profiles and identify gene pathways that are consistently and differentially enriched in CSF T cells and myeloid cells by checkpoint blockade. Correlation of clinical outcome with these transcriptomic analyses may lead to predictive signatures of response to immunotherapy. Moreover, we may find evidence of immunosuppression by other pathways, which may suggest new therapeutic strategies for LMD for future investigations. In addition, we may find gene pathways that are enriched in T cells and/or myeloid cells in both the peripheral blood and CSF, which may provide a strategy for immune monitoring of patients on immunotherapy in a more accessible manner. Likewise, we may find changes in cytokines and the proteome in the CSF in response to immunotherapy. If similar cytokines/proteins are altered in the CSF and blood, then such proteins have the potential to serve as biomarkers for responsiveness to immunotherapy.
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9.2 methodology

Whole-exome sequencing: Whole-exome sequencing from tumor and cell-free DNA from CSF and blood will be performed using pipelines that have been tested on several thousand samples at the Broad Institute and described in our recent publications. DNA will be subjected to solutionphase hybrid capture followed by Illumina sequencing to >150x mean coverage. Mutations and allele-specific copy-number changes will be determined within the Firehose pipeline environment at the Broad Institute using a suite of existing tools. The significance of copynumber changes and mutations will be determined using GISTIC and MutSig, respectively, and compared to rates of alterations in the same genes in published large sequencing efforts of unmatched samples. To understand inter- and intratumoral heterogeneity, we will perform an integrative analysis of somatic single nucleotide variants and somatic copy-number alterations. This analysis will allow us to estimate the clonal architecture of the primary and metastatic samples from each patient, and to reconstruct phylogenetic trees relating all of the subclones. For each recurrent mutation, the frequency with which these mutations are present in all or only fractions of cancer cells will be determined. Transcriptome sequencing and analysis: RNA will be extracted with QIAGEN kits. Non-strand specific RNA sequencing performed at the Broad Institute uses a large-scale, automated variant of the Illumina Tru Seq™ RNA Sample Preparation. This method uses oligo dT beads to select mRNA from the total RNA sample. The selected RNA is heat fragmented and randomly primed before cDNA synthesis from the RNA template. The resultant cDNA then goes through Illumina library prep (end repair, base 'A' addition, adapter ligation, and enrichment) using Broad designed indexed adapters for multiplexing. After enrichment, the samples will be qPCR
quantified and equimolar pooled before proceeding to Illumina sequencing, which is done on the Illumina HiSeq 2000. RNA-seq analysis will be carried out using PRADA (Pipeline for RNASequencing Data Analysis). Somatic variant, small deletions and insertion calling will be performed within the Firehose environment at the Broad Institute with the published caller algorithms. Cell Purification by Flow Cytometry: CSF will be sorted on CD45 to separate tumor (CD45-)
and immune (CD45+) cells for genomic and transcriptomic analyses. CD4+ and CD8+ T cells and myeloid cells (CD11b+) will be purified from the CSF and PBMC by flow cytometry and processed for transcriptome sequencing. We will systematically assess differentially expressed transcripts in pre- and on- treatment samples to determine if there is enrichment within particular gene pathways (such as exhaustion, anergy, senescence) through GeneSet Enrichment Analysis (GSEA) and gene co-expression network analysis. Cytokine and Proteomic Analyses: We will analyze cytokines in CSF and serum using cytokine bead arrays. High-resolution mass spectrometers and isobaric tandem mass tags will be used to quantify proteins from CSF and serum samples. The tandem mass tag technology allows for the analysis of 6-10 samples within a single experiment. For example, protein expression can be profiled after nine treatment conditions and compared to an untreated sample across >6,000 proteins. All mass spectrometry data will be analyzed in partnership with the Thermo Fisher Scientific Center for Multiplexed Proteomics at Harvard Medical School.
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9.3 collection and shipping of

Collection, Processing and Handling of CSF: One 3 to 10 mL sample of CSF in a clear CSF tube should be collected as per section 10 every three weeks and couriered to the Brastianos laboratory at the address below within 1 hour of obtaining the sample. Label each tube with (1) sample collection date and time, (2) patient study ID and medical record number, (3) protocol study number, and (4) sample type (e.g., CSF). When a sample is shipped, please page the Brastianos lab by calling 617-726-2000 and ask to page Nathaniel Goss at 2-3389 and Brian Shaw at 2-1928.. For any questions or concerns regarding research sample collection or shipment, please contact Nathaniel Goss or Brian Shaw.  
Brastianos Lab 185 Cambridge Street CPZN 3700 Boston, MA 02114 Collection, Processing and Handling of Archived Specimens: If available, for each resection or prior biopsy 1 FFPE block should be clearly labeled and forwarded to Dr. Brastianos' laboratory (at the address below) at Massachusetts General Hospital for molecular testing within 30 days of registration, or surgery happens during trial, within 30 days of surgery or biopsy. If an institution is unable to provide a tissue block, cut 15 unstained slides five-micron sections and mount on charged glass slides. Slides need to be cut with a new blade and using a fresh water bath to avoid contamination. Label the slides with patient ID number, accession number, and order of sections (include thickness of section if applicable). For samples containing less than 1 square cm of tumor tissue, multiple sections should be mounted onto each slide to ensure that the appropriate amount of tumor tissue is available. Do not bake or place covers slips on the slide. Shipping of Tissue Specimen(s): Shipment on Monday through Thursday by overnight service to assure receipt is encouraged. Do not ship specimens on Fridays or Saturdays.
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brittany bent

Massachusetts General Hospital Cancer Center 55 Fruit Street, Yawkey 9E Boston, MA 02114 Shipping of Blood Specimen(s): Collect 20 mL of venous blood at pre-registration, 20 mL every 3-4 weeks as per the calendar in section 10. All blood samples should be collected in EDTA anticoagulant vacutainer tubes. The tubes should be inverted approximately 8-10 times to mix the EDTA. Refrigerate (please do not freeze) sample until shipping. The sample should be placed in a biohazard bag and couriered to the Brastianos laboratory at the address below within 1 hour of obtaining the sample. Label each tube with (1) sample collection date and time, (2) patient study ID and medical record number, (3) protocol study number, and (4) sample type (e.g., blood). When a sample is shipped, please page the receiving lab by calling 617-726-2000 and ask to page Nathaniel Goss at 2-3389 and Brian Shaw at 2-1928.For any questions or concerns regarding research sample collection or shipment, please contact Nathaniel Goss or Brian Shaw.
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10. study calendar

Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy, with the exception of CSF with positive cytology, which must be done ≤ 6 weeks prior to initiation of study treatment. Also, if patients received other chemotherapy or targeted therapy within 14 days prior to start of protocol therapy, CBC and serum chemistry (including LFTs and creatinine) should be done within 5 days prior to start of protocol therapy. Scans and x-rays must be done ≤ 4 weeks prior to the start of therapy. In the event that the participant's condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy.  
Protocol Version Date: January 24, 2019 Assessments must be performed prior to administration of any study agent. Study assessments and agents should be administered within + 3 days of the protocol-specified date, unless otherwise noted.  
| Bladder Cancer, Renal Cancer and Other Solid Tumors  Wk Wk Wk Wk Wk Wk   | Wk                                                                                                                                                                                                                                                                                    | Wk                                                                                                                                                         | Wk   | Wk   | Wk   | Wk   | Off Studyh   | Follow-up   |    |    |    |    |         |    |    |
|--------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|------|------|------|------|--------------|-------------|----|----|----|----|---------|----|----|
| Study                                                                    | 1                                                                                                                                                                                                                                                                                     | 2                                                                                                                                                          | 3    | 4    | 5    | 6    | 7            | 8           | 9  | 10 | 11 | 12 | visitsi |    |    |
| Ipilimumab                                                               | A                                                                                                                                                                                                                                                                                     | A                                                                                                                                                          | A    | A    |      |      |              |             |    |    |    |    |         |    |    |
| Nivolumab                                                                | B                                                                                                                                                                                                                                                                                     | B                                                                                                                                                          | B    | B    |      |      |              |             |    |    |    |    |         |    |    |
| Informed consenta                                                        | X                                                                                                                                                                                                                                                                                     |                                                                                                                                                            |      |      |      |      |              |             |    |    |    |    |         |    |    |
| Demographicsa                                                            | X                                                                                                                                                                                                                                                                                     |                                                                                                                                                            |      |      |      |      |              |             |    |    |    |    |         |    |    |
| Medical historya                                                         | X                                                                                                                                                                                                                                                                                     |                                                                                                                                                            |      |      |      |      |              |             |    |    |    |    |         |    |    |
| Concurrent meds                                                          | X                                                                                                                                                                                                                                                                                     | X---------------------------------------------------------------------------------------------X                                                            |      |      |      |      |              |             |    |    |    |    |         |    |    |
| Physical examb                                                           | X                                                                                                                                                                                                                                                                                     | X                                                                                                                                                          | X    | X    | X    | X    | X            | X           | X  | X  | X  | X  | X       | X  | X  |
| Vital signs                                                              | X                                                                                                                                                                                                                                                                                     | X                                                                                                                                                          | X    | X    | X    | X    | X            | X           | X  | X  | X  | X  | X       | X  | X  |
| Height                                                                   | X                                                                                                                                                                                                                                                                                     |                                                                                                                                                            |      |      |      |      |              |             |    |    |    |    |         |    |    |
| Weight                                                                   | X                                                                                                                                                                                                                                                                                     | X                                                                                                                                                          | X    | X    | X    | X    | X            |             |    |    |    |    |         |    |    |
| Performance status                                                       | X                                                                                                                                                                                                                                                                                     | X                                                                                                                                                          | X    | X    | X    | X    | X            |             |    |    |    |    |         |    |    |
| CBC w/diff, plts                                                         | X                                                                                                                                                                                                                                                                                     | X                                                                                                                                                          | X    | X    | X    | X    | X            |             |    |    |    |    |         |    |    |
| Serum chemistryc                                                         | X                                                                                                                                                                                                                                                                                     | X                                                                                                                                                          | X    | X    | X    | X    | X            |             |    |    |    |    |         |    |    |
| EKG (as indicated)d                                                      | X                                                                                                                                                                                                                                                                                     |                                                                                                                                                            |      |      |      |      |              |             |    |    |    |    |         |    |    |
| Adverse event evaluation                                                 | X---------------------------------------------------------------------------------------------X                                                                                                                                                                                       | X                                                                                                                                                          | X    |      |      |      |              |             |    |    |    |    |         |    |    |
| Tumor measurements                                                       | X                                                                                                                                                                                                                                                                                     | Tumor measurements are repeated every 6 weeks. Documentation (radiologic) must  be provided for participants removed from study for progressive disease. X |      |      |      |      |              |             |    |    |    |    |         |    |    |
| Pre                                                                          |                                                                                                                                                                                                                                                                                       |                                                                                                                                                            |      |      |      |      |              |             |    |    |    |    |         |    |    |
| Radiologic evaluation                                                    | X                                                                                                                                                                                                                                                                                     | Radiologic measurements should be performed every 6 weeks (Brain MRI and CT Chest/Abd/Pelvis)                                                              | X    | X    |      |      |              |             |    |    |    |    |         |    |    |
| B-HCG                                                                    | Xe                                                                                                                                                                                                                                                                                    | X                                                                                                                                                          | X    |      |      |      |              |             |    |    |    |    |         |    |    |
| Cerebrospinal fluid                                                      | Xf                                                                                                                                                                                                                                                                                    | X                                                                                                                                                          | X    | X    | X    |      |              |             |    |    |    |    |         |    |    |
| Bloodj                                                                   | X                                                                                                                                                                                                                                                                                     | X                                                                                                                                                          | X    | X    | X    | X    | X            |             |    |    |    |    |         |    |    |
| Archival tissueg                                                         | X                                                                                                                                                                                                                                                                                     | X                                                                                                                                                          | X    |      |      |      |              |             |    |    |    |    |         |    |    |
| A:                                                                       | For melanoma, small cell lung cancer, breast cancer, bladder cancer and other solid tumors (except NSCLC and head and neck cancers): Ipilimumab  3mg/kg every 3 weeks x 4 doses during induction.. For renal cell cancer: Ipilimumab 1mg/kg every 3 weeks x 4 doses during induction. |                                                                                                                                                            |      |      |      |      |              |             |    |    |    |    |         |    |    |
| B:                                                                       | For melanoma, small cell lung cancer, breast cancer, bladder cancer and other solid tumors (except NSCLC and head and neck cancers): Nivolumab                                                                                                                                        |                                                                                                                                                            |      |      |      |      |              |             |    |    |    |    |         |    |    |  
Archival tissueg X X X
A: For melanoma, small cell lung cancer, breast cancer, bladder cancer and other solid tumors (except NSCLC and head and neck cancers): Ipilimumab 3mg/kg every 3 weeks x 4 doses during induction.. For renal cell cancer: Ipilimumab 1mg/kg every 3 weeks x 4 doses during induction.  
B: For melanoma, small cell lung cancer, breast cancer, bladder cancer and other solid tumors (except NSCLC and head and neck cancers): Nivolumab 1mg/kg every 3 weeks for 4 doses during induction. For renal cell cancer: nivolumab 3mg/kg every 3 weeks x 4 doses during induction. aAll screening procedures to be performed within 14 days of start of study treatment, with the exception of CSF with positive cytology, which can be 6 weeks prior to initiation of study treatment. C1D1 and Day 1 of subsequent cycles: For C1D1 only, screening assessments may serve as day 1 assessments, except serum pregnancy (within 72 hours of drug) and except in the event that there are any indications that the participant's condition is deteriorating for which laboratory evaluations should be repeated within 48 hours prior to initiation. For all subsequent cycles, required assessments should be performed within 3 days of scheduled cycle day 1.  
bPhysical examination must include neurologic assessment. cSerum chemistries: Serum chemistry tests include albumin, amylase, lipase, BUN, creatinine, ALT, AST, LDH, serum alkaline phosphatase, direct and total bilirubin, glucose, total protein, sodium, potassium, chloride, HCO3, calcium, uric acid and TSH. A reflexive free T4 and free T3 will be performed reflexively for out of range TSH values. Patients should also be tested for Hepatitis B virus surface antigens (HBV sAg) and hepatitis C virus ribonucleic acid
(HCV antibodies) at screening only. dEKG should be obtained at baseline for screening and then as clinically indicated eSerum pregnancy test (women of childbearing potential) is required within 72 hours of C1D1 dose. Pregnancy will be performed every 6 weeks while on treatment, and at 30 days and 70 days post last dose of Niolumab fCerebrospinal fluid will be collected every 3 weeks during the induction phase and every 4weeks during the maintenance phase to assess disease status (will be sent for cell count, protein, glucose, cytology) and 10cc will be saved for correlative studies as described in Section 9.0 gTissue collected as part of clinical care (e.g. from prior biopsy, craniotomy) will be collected. See Section 9 for specimen collection h: Off-study evaluation: End of treatment assessments to be performed within 7 days after last day drug administration or within 7 days after decision to end treatment. Assessments may continue for ongoing reportable adverse events. In participants who discontinue study treatment without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic imaging every 6 weeks (+/- 7 days) until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death or (4) the end of the study, whichever occurs first i: Follow-up visit 1 = 30 days from the last dose +/- 7 days or coincide with the date of discontinuation (+/- 7 days) if date of discontinuation is greater than 37 days after last dose, Follow-up visit 2 (FU2) = 8-10 weeks (+/- 7 days) from follow-up visit 1. After 2 followup visits, patients will be followed with a phone call every 10-12 weeks for survival information.  
jBlood will be collected at screening, Day 1, then every 3 weeks during the induction phase and every 4 weeks during the maintenance phase (two 10 mL
EDTA/lavender top tube) and at the end of treatment Calendar During Maintenance Phase for Melanoma, Small Cell Lung Cancer, Breast Cancer, Bladder Cancer, Renal Cancer and other Solid Tumors  
| Wk                                                                                                                                                      | Wk                                                                                                                   | Wk                                 | Wk   |                  |    |    |    |    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------|------------------------------------|------|------------------|----|----|----|----|
| 21                                                                                                                                                      | 22                                                                                                                   | 23                                 | 24   | Off  Treatment h | Followup visitsi    |    |    |    |
| To be repeated beyond 24  weeks until patient goes off  study                                                                                           |                                                                                                                      |                                    |      |                  |    |    |    |    |
| Nivolumab                                                                                                                                               | (for melanoma                                                                                                        |                                    |      |                  |    |    |    |    |
| and renal cell carcinoma)                                                                                                                               | B                                                                                                                    | B                                  | B    |                  |    |    |    |    |
| Wk                                                                                                                                                      | Wk                                                                                                                   | Wk                                 | Wk   | Wk               | Wk | Wk | Wk |    |
| 13                                                                                                                                                      | 14                                                                                                                   | 15                                 | 16   | 17               | 18 | 19 | 20 |    |
| Nivolumab (for small cell  lung cancer, breast cancer and  C                                                                                            | C                                                                                                                    | C                                  | C    | C                | C  |    |    |    |
| bladder cancer) Concurrent meds                                                                                                                         | X---------------------------------------------------------------------------------------------------------X          |                                    |      |                  |    |    |    |    |
| Physical examb                                                                                                                                          | X                                                                                                                    | X                                  | X    | X                | X  | X  | X  | X  |
| Vital signs                                                                                                                                             | X                                                                                                                    | X                                  | X    | X                | X  | X  | X  | X  |
| Height Weight                                                                                                                                           | X                                                                                                                    | X                                  | X    | X                | X  | X  | X  | X  |
| Performance status                                                                                                                                      | X                                                                                                                    | X                                  | X    | X                | X  | X  | X  | X  |
| CBC w/diff, plts                                                                                                                                        | X                                                                                                                    | X                                  | X    | X                | X  | X  | X  | X  |
| Serum chemistryc                                                                                                                                        | X                                                                                                                    | X                                  | X    | X                | X  | X  | X  | X  |
| EKG (as indicated)d Adverse event evaluation                                                                                                            | X---------------------------------------------------------------------------------------------------------X          | X                                  | X    |                  |    |    |    |    |
| Tumor measurements                                                                                                                                      | Tumor measurements are repeated every 8 weeks.                                                                       | Documentation (radiologic) must be |      |                  |    |    |    |    |
| provided for participants removed from study for progressive disease.                                                                                   | X                                                                                                                    |                                    |      |                  |    |    |    |    |
| Radiologic evaluation                                                                                                                                   | Radiologic measurements should be performed every 8 weeks (Brain MRI and CT  Chest/Abd/Pelvis) X                     | X                                  |      |                  |    |    |    |    |
| B-HCG                                                                                                                                                   | X                                                                                                                    | X                                  | X    |                  |    |    |    |    |
| Cerebrospinal fluid                                                                                                                                     | X                                                                                                                    | X                                  | X    |                  |    |    |    |    |
| Bloodj                                                                                                                                                  | X                                                                                                                    | X                                  | X    | X                | X  |    |    |    |
| Archival tissueg                                                                                                                                        | X                                                                                                                    | X                                  |      |                  |    |    |    |    |
| B:                                                                                                                                                      | For melanoma, renal cell carcinoma and other solid tumors: Nivolumab 480 mg Q4 weeks during maintenance phase        |                                    |      |                  |    |    |    |    |
| C:                                                                                                                                                      | For small cell lung cancer, breast cancer and bladder cancer: nivolumab 240mg every 2 weeks during maintenance phase |                                    |      |                  |    |    |    |    |
| a All screening procedures to be performed within 14 days of start of study treatment, with the exception of CSF with positive cytology, which can be 6 |                                                                                                                      |                                    |      |                  |    |    |    |    |  
Archival tissueg X X
B: For melanoma, renal cell carcinoma and other solid tumors: Nivolumab 480 mg Q4 weeks during maintenance phase C: For small cell lung cancer, breast cancer and bladder cancer: nivolumab 240mg every 2 weeks during maintenance phase aAll screening procedures to be performed within 14 days of start of study treatment, with the exception of CSF with positive cytology, which can be 6 weeks prior to initiation of study treatment. C1D1 and Day 1 of subsequent cycles: For C1D1 only, screening assessments may serve as day 1 assessments, except serum pregnancy (within 72 hours of drug) and except in the event that there are any indications that the participant's condition is deteriorating for which laboratory evaluations should be repeated within 48 hours prior to initiation. For all subsequent cycles, required assessments should be performed within 3 days of scheduled cycle day 1.  
bPhysical examination must include neurologic assessment.  
cSerum chemistries: Serum chemistry tests include albumin, amylase, lipase, BUN, creatinine, ALT, AST, LDH, serum alkaline phosphatase, direct and total bilirubin, glucose, total protein, sodium, potassium, chloride, HCO3, calcium, uric acid and TSH. A reflexive free T4 and free T3 will be performed reflexively for out of range TSH values. Patients should also be tested for Hepatitis B virus surface antigens (HBV sAg) and hepatitis C virus ribonucleic acid (HCV antibodies) at screening only. dEKG should be obtained at baseline for screening and then as clinically indicated eSerum pregnancy test (women of childbearing potential) is required within 72 hours of C1D1 dose. Pregnancy will be performed every 6 weeks while on treatment, and at 30 days and 70 days post last dose of Nivolumab. fCerebrospinal fluid will be collected every 4 weeks during the maintenance phase to assess disease status (will be sent for cell count, protein, glucose, cytology) and 10 cc will be saved for correlative studies as described in Section 9.0 gTissue collected as part of clinical care (e.g. from prior biopsy, craniotomy) will be collected. See Section 9 for specimen collection requirements h: Off-treatment evaluation: End of treatment assessments to be performed within 7 days after last day drug administration or within 7 days after decision to end treatment. Assessments may continue for ongoing reportable adverse events. In participants who discontinue study treatment without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic imaging every 6 weeks (+/- 7 days) until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death or (4) the end of the study, whichever occurs first i: Follow-up visit 1 = 30 days from the last dose +/- 7 days or coincide with the date of discontinuation (+/- 7 days) if date of discontinuation is greater than 37 days after last dose, Follow-up visit 2 (FU2) = 8-10 weeks (+/- 7 days) from follow-up visit 1. After 2 followup visits, patients will be followed with a phone call every 10-12 weeks for survival information.  
jBlood will be collected at screening, Day 1, then every 3 weeks during the induction phase and every 4 weeks during the maintenance phase (two 10 mL EDTA/lavender top tube) and at the end of treatment Calendar for Nonsmall Cell Lung Cancer Histology and Head and Neck Cancer  
| Wk                       | Wk                                                                                              | Wk                                                                                                                                                         | Wk   | Wk   | Wk   |            |                                                              |    |    |    |    |    |    |    |    |
|--------------------------|-------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|------|------|------|------------|--------------------------------------------------------------|----|----|----|----|----|----|----|----|
| 7                        | 8                                                                                               | 9                                                                                                                                                          | 10   | 11   | 12   | Off Studyh | Follow-up  visitsi                                           |    |    |    |    |    |    |    |    |
| Pre                          | Wk                                                                                              | Wk                                                                                                                                                         | Wk   | Wk   | Wk   | Wk         |                                                              |    |    |    |    |    |    |    |    |
| Study                    | 1                                                                                               | 2                                                                                                                                                          | 3    | 4    | 5    | 6          | To be repeated beyond 12 weeks until  patient goes off study |    |    |    |    |    |    |    |    |
| Ipilimumab               | A                                                                                               | A                                                                                                                                                          |      |      |      |            |                                                              |    |    |    |    |    |    |    |    |
| Nivolumab                | B                                                                                               | B                                                                                                                                                          | B    | B    | B    | B          |                                                              |    |    |    |    |    |    |    |    |
| Informed consenta        | X                                                                                               |                                                                                                                                                            |      |      |      |            |                                                              |    |    |    |    |    |    |    |    |
| Demographicsa            | X                                                                                               |                                                                                                                                                            |      |      |      |            |                                                              |    |    |    |    |    |    |    |    |
| Medical historya         | X                                                                                               |                                                                                                                                                            |      |      |      |            |                                                              |    |    |    |    |    |    |    |    |
| Concurrent meds          | X                                                                                               | X---------------------------------------------------------------------------------------------X                                                            |      |      |      |            |                                                              |    |    |    |    |    |    |    |    |
| Physical examb           | X                                                                                               | X                                                                                                                                                          | X    | X    | X    | X          | X                                                            | X  | X  | X  | X  | X  | X  | X  | X  |
| Vital signs              | X                                                                                               | X                                                                                                                                                          | X    | X    | X    | X          | X                                                            | X  | X  | X  | X  | X  | X  | X  | X  |
| Height                   | X                                                                                               |                                                                                                                                                            |      |      |      |            |                                                              |    |    |    |    |    |    |    |    |
| Weight                   | X                                                                                               | X                                                                                                                                                          | X    | X    | X    | X          | X                                                            | X  | X  |    |    |    |    |    |    |
| Performance status       | X                                                                                               | X                                                                                                                                                          | X    | X    | X    | X          | X                                                            | X  | X  |    |    |    |    |    |    |
| CBC w/diff, plts         | X                                                                                               | X                                                                                                                                                          | X    | X    | X    | X          | X                                                            | X  | X  |    |    |    |    |    |    |
| Serum chemistryc         | X                                                                                               | X                                                                                                                                                          | X    | X    | X    | X          | X                                                            | X  | X  |    |    |    |    |    |    |
| EKG (as indicated)d      | X                                                                                               |                                                                                                                                                            |      |      |      |            |                                                              |    |    |    |    |    |    |    |    |
| Adverse event evaluation | X---------------------------------------------------------------------------------------------X | X                                                                                                                                                          | X    |      |      |            |                                                              |    |    |    |    |    |    |    |    |
| Tumor measurements       | X                                                                                               | Tumor measurements are repeated every 6 weeks. Documentation (radiologic) must  be provided for participants removed from study for progressive disease. X |      |      |      |            |                                                              |    |    |    |    |    |    |    |    |
| Radiologic evaluation    | X                                                                                               | Radiologic measurements should be performed every 6 weeks (Brain MRI and CT  Chest/Abd/Pelvis) X                                                           | X    |      |      |            |                                                              |    |    |    |    |    |    |    |    |
| B-HCG                    | Xe                                                                                              | X                                                                                                                                                          | X    |      |      |            |                                                              |    |    |    |    |    |    |    |    |
| Cerebrospinal fluid      | Xf                                                                                              | X                                                                                                                                                          | X    | X    |      |            |                                                              |    |    |    |    |    |    |    |    |
| Bloodj                   | X                                                                                               | X                                                                                                                                                          | X    | X    | X    | X          |                                                              |    |    |    |    |    |    |    |    |
| Archival tissueg         | X                                                                                               | X                                                                                                                                                          | X    |      |      |            |                                                              |    |    |    |    |    |    |    |    |
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a ipilimumab 1mg/kg q6w b

aAll screening procedures to be performed within 14 days of start of study treatment, with the exception of CSF with positive cytology, which can be 6 weeks prior to initiation of study treatment. C1D1 and Day 1 of subsequent cycles: For C1D1 only, screening assessments may serve as day 1 assessments, except serum pregnancy (within 72 hours of drug) and except in the event that there are any indications that the participant's condition is deteriorating for which laboratory evaluations should be repeated within 48 hours prior to initiation. For all subsequent cycles, required assessments should be performed within 3 days of scheduled cycle day 1.  
bPhysical examination must include neurologic assessment.  
cSerum chemistries: Serum chemistry tests include albumin, amylase, lipase, BUN, creatinine, ALT, AST, LDH, serum alkaline phosphatase, direct and total bilirubin, glucose, total protein, sodium, potassium, chloride, HCO3, calcium, uric acid and TSH. A reflexive free T4 and free T3 will be performed reflexively for out of range TSH values. Patients should also be tested for Hepatitis B virus surface antigens (HBV sAg) and hepatitis C virus ribonucleic acid
(HCV antibodies) at screening only. dEKG should be obtained at baseline for screening and then as clinically indicated eSerum pregnancy test (women of childbearing potential) is required within 72 hours of C1D1 dose. Pregnancy will be performed every 6 weeks while on treatment, and at 30 days and 70 days post last dose of Nivolumab. fCerebrospinal fluid will be collected every 4 weeks will be sent for cell count, protein, glucose, cytology) and 10cc will be saved for correlative studies as described in Section 9.0 gTissue collected as part of clinical care (e.g. from prior biopsy, craniotomy) will be collected. See Section 9 for specimen collection h: Off-study evaluation: End of treatment assessments to be performed within 7 days after last day drug administration or within 7 days after decision to end treatment. Assessments may continue for ongoing reportable adverse events. In participants who discontinue study treatment without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic imaging every 6 weeks (+/- 7 days) until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death or (4) the end of the study, whichever occurs first i: Follow-up visit 1 = 30 days from the last dose +/- 7 days or coincide with the date of discontinuation (+/- 7 days) if date of discontinuation is greater than 37 days after last dose, Follow-up visit 2 (FU2) = 8-10 weeks (+/- 7 days) from follow-up visit 1. After 2 followup visits, patients will be followed with a phone call every 10-12 weeks for survival information.  
jBlood will be collected at screening, Day 1, then every 4 weeks during the maintenance phase (two 10 mL EDTA/lavender top tube) and at the end of treatment
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11. measurement of effect

Response in the CNS and response in non-CNS sites will be evaluated and recorded separately in this trial.
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11.1 antitumor effect - extracranial

For the purposes of this study, participants should be re-evaluated for response every 6 weeks. In addition to a baseline scan, confirmatory scans should also be obtained 3 weeks following initial documentation of objective response.  
Response and progression will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [*Eur J Ca* 45:228-247, 2009]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.
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11.1.1 definitions

Evaluable for Target Disease response. Only those participants who have leptomeningeal disease present at baseline (as defined by positive cytology), have received at least one cycle of therapy, and have had their disease re-evaluated with restaging scans and cytology will be considered evaluable for target disease response. These participants will have their response classified according to the definitions stated below. Evaluable Non-Target Disease Response. Participants who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
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11.1.2 disease parameters

Measurable disease. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Note: Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable. Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis),
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all considered non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if noncystic lesions are present in the same participant, these are preferred for selection as target lesions. Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease.  
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow up.