Conditions: Leptomeningeal Carcinomatosis
Keywords: Leptomeningeal Metastases
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 18
Healthy volunteers: no

Brief summary:
This research study is studying a combination of two drugs as a possible treatment for Leptomeningeal Metastases.

The names of the study interventions involved in this study are:

* Ipilimumab
* Nivolumab

Detailed description:
This research study is a Phase II clinical trial.

Researchers hope to study the effects of the combination of Nivolumab and Ipilimumab. Many cancers use specific pathways, such as programmed death-1 (PD-1), programmed death-ligand-1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4), to evade the body's immune system. Nivolumab and ipilimumab work by blocking the PD-1/PD-L1 and CTLA-4 pathways and thus releasing the brakes on the immune system so it can stop or slow cancer.

The FDA (the U.S. Food and Drug Administration) has approved Nivolumab and Ipilimumab as a treatment option for melanoma, but has not approved them for use when cancer cells spread to the cerebrospinal fluid

Arms:
arm 1: All patients will be treated based on their primary tumor diagnosis with a combination regimen of Nivolumab and Ipilimumab. Each treatment cycle is 6 weeks; exceptions below.

* Melanoma:

  * Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg, every 3 weeks for 4 doses.
  * Followed by Nivolumab 480 mg every 4 weeks until disease progression. Each cycle of monotherapy is defined as 8 weeks.
* Non-small Cell Lung Cancer / Head and Neck Cancer:

  \- Nivolumab 3 mg/kg every 2 weeks, and Ipilimumab 1 mg/kg every 6 weeks.
* Small Cell Lung Cancer / Breast Cancer / Bladder Cancer:

  * Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg, every 3 weeks for 4 doses.
  * Followed by Nivolumab 240 mg every 2 weeks until disease progression.
* Renal Cell Carcinoma / Other Solid Tumors (not listed above):

  * Nivolumab 3 mg/kg and Ipilimumab 3 mg/kg, every 3 weeks for 4 doses.
  * Followed by Nivolumab 480 mg every 4 weeks until disease progression. Each cycle of monotherapy is defined as 8 weeks.

Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab
Intervention descriptions: intervention 1: * Melanoma:

  \- Combination therapy with Nivolumab 1 mg/kg for 4 doses followed by monotherapy Nivolumab 480 mg per cycle.
* Non-small Cell Lung Cancer / Head and Neck Cancer:

  \- Combination therapy with Nivolumab 3 mg/kg
* Small Cell Lung Cancer / Breast Cancer / Bladder Cancer:

  \- Combination therapy with Nivolumab 1 mg/kg for 4 doses followed by monotherapy Nivolumab 240 mg per cycle.
* Renal Cell Carcinoma / Other Solid Tumors (not listed above):

  * Combination therapy with Nivolumab 3 mg/kg for 4 doses followed by monotherapy Nivolumab 480 mg per cycle. intervention 2: * Non-small Cell Lung Cancer / Head and Neck Cancer:

  \- Combination therapy with Ipilimumab 1 mg/kg
* Small Cell Lung Cancer / Breast Cancer / Bladder Cancer:

  \- Combination therapy with Ipilimumab 3 mg/kg for 4 doses
* Renal Cell Carcinoma / Other Solid Tumors (not listed above):

  * Combination therapy with Ipilimumab 3 mg/kg for 4 doses

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
STATUS PAGE 
PROTOCOL 16-136 
 
 
 
 
Closed to New Accrual 
 
 
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 


NCI Protocol #: 
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 
NCT02939300


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Protocol Version Date:  January 24, 2019 
 
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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 
 
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 ] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Study Design ............................................................................................................7 
1.2 
Primary Objectives...................................................................................................7 
1.3 
Secondary Objectives...............................................................................................7 
1.4 
Correlative Objectives .............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Study Disease(s).......................................................................................................7 
2.2 
IND Agents ..............................................................................................................8 
2.3 
Rationale ................................................................................................................15 
2.4 
Correlative Studies Background ............................................................................16 
3. 
PARTICIPANT SELECTION ...........................................................................................17 
3.1 
Eligibility Criteria ..................................................................................................17 
3.2 
Exclusion Criteria ..................................................................................................19 
3.3 
Inclusion of Women and Minorities ......................................................................20 
4. 
REGISTRATION PROCEDURES ...................................................................................21 
4.1 
General Guidelines for DF/HCC Institutions ........................................................21 
4.2 
Registration Process for DF/HCC Institutions .......................................................21 
4.3 
General Guidelines for Other Investigative Sites ..................................................21 
4.4 
Registration Process for Other Investigative Sites.................................................21 
5. 
TREATMENT PLAN ........................................................................................................21 
5.1 
Treatment Regimen ................................................................................................21 
5.2 
Pre-Treatment Criteria ...........................................................................................22 
5.3 
Agent Administration.............................................................................................23 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................24 
5.5 
Criteria for Taking a Participant Off Protocol Therapy .........................................24 
5.6 
Duration of Follow Up ...........................................................................................25 
5.7 
Criteria for Taking a Participant Off Study ...........................................................25 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................25 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................30 
7.1 
Adverse Event Characteristics ...............................................................................30 
7.2 
Expedited Adverse Event Reporting ......................................................................31 
7.3 
Expedited Reporting to Hospital Risk Management .............................................31 
7.4 
Routine Adverse Event Reporting .........................................................................31 
7.5 
Definitions..............................................................................................................32 
7.6 
Potential Drug Induced Liver Injury (DILI) ..........................................................33 


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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 
• 
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 


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12.2 
Data Safety Monitoring..........................................................................................63 
12.3 
Multicenter Guidelines...........................................................................................64 
12.4 
Collaborative Agreements Language .....................................................................64 
13. 
STATISTICAL CONSIDERATIONS...............................................................................64 
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 
13.6 
Analysis of Secondary Endpoints ..........................................................................65 
13.7 
Analysis of Exploratory Endpoints ........................................................................66 
13.8 
Reporting and Exclusions ......................................................................................66 
14. 
PUBLICATION PLAN .....................................................................................................67 
REFERENCES ..............................................................................................................................68 
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. 
 
1.2 
Primary Objectives 
 
To estimate the overall survival of the combination of nivolumab and ipilimumab in 
leptomeningeal metastases  
 
1.3 
Secondary Objectives 
 
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. 
 
1.4 
Correlative Objectives 
 
1. To determine molecular biomarkers of response using next generation sequencing 
techniques. 
 
 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
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, 


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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. 
 
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 anti-
tumor 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). 
 
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.  
 
Effects in Humans  
Bristol-Myers Squibb (BMS) and Medarex, Inc. (MDX, acquired by BMS in Sep-2009) have co-
sponsored 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 


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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 


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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 self-
antigens. 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). 
 
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 T-
cells 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 down-
regulation 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 


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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(0-
168 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. 
 
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 dose-
proportional 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 


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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. 
 
2.2.3 Nivolumab combined with Ipilimumab 
Preclinical Data 
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 


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the death of 1 animal, attributed to acute gastric dilatation without histopathological evidence of 
colitis upon pathology evaluation of the GI tract. 
 
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 


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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.  
 
 
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 


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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. 
 
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 


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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. 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
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 


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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 OR 
Measured or calculateda 
creatinine clearance 
(GFR can also be used in place 
of creatinine or CrCl) 
≤ Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) 
≥ 40 mL/min (if using the Cockcroft-Gault formula below): 
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) 
 
Activated Partial 
Thromboplastin Time (aPTT) 
≤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 
aCreatinine clearance should be calculated per institutional standard. 
 
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 


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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. 
 
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, intra-
articular, 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. 
 


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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 marrow-
suppressive 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 
 
3.3 
Inclusion of Women and Minorities 
 


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Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
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.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
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 
 
5. TREATMENT PLAN 
 
 
5.1 
Treatment Regimen by histology: 
 
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 


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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. 
 
 
5.2 
Pre-Treatment Criteria 
 
5.2.1 Cycle 1, Day 1 
 
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. 
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 OR 
Measured or calculateda 
creatinine clearance 
(GFR can also be used in place 
of creatinine or CrCl) 
≤ Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) 
≥ 40 mL/min (if using the Cockcroft-Gault formula below): 
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 


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Protocol Version Date:  January 24, 2019 
 
23 
 
 
 
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) 
 
 
 
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 
(INR) or Prothrombin Time 
(PT) 
 
Activated Partial 
Thromboplastin Time (aPTT) 
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 
aCreatinine clearance should be calculated per institutional standard. 
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 OR 
Measured or calculateda 
creatinine clearance 
(GFR can also be used in place 
of creatinine or CrCl) 
≤ Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) 
≥ 40 mL/min (if using the Cockcroft-Gault formula below): 
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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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. 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
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. 
 
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
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 


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25 
 
 
• 
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. 
 
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. 
 
 
5.7 
Criteria for Taking a Participant Off Study 
 
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.  
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 


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26 
 
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. 
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. 
Dose Delay Criteria 


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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. 
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 


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• 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. 
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.  


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29 
 
• 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 
Treatment of Nivolumab or Ipilimumab Related Infusion Reactions 
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 


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(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). 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
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. 
 
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 


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31 
 
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. 
 
• For expedited reporting purposes only:   
- 
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 Protocol-
Specific 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. 
 
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.  
 
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.  
 
7.3 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
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 Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
• 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) 


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− 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.  
 
7.6 
Potential Drug Induced Liver Injury (DILI) 
 
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. 
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.  


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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. 
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. 
7.10 
Adverse event reporting to BMS 
 
• 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 


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35 
 
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. 
• SAE Email Address:  Worldwide.Safety@BMS.com 
• SAE Facsimile Number:  609-818-3804 
• 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.  


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Protocol Version Date:  January 24, 2019 
 
36 
 
• 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. 
8. PHARMACEUTICAL INFORMATION 
 
 
8.1 
Product Description of Ipilimumab and Nivolumab 
 
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 
mg/mL) 
10 
mL 
viall 
5 
vials 
per 
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 
mg/mL) 
40 
mL 
vial 
4 
vials 
per 
carton/Open-
label 
Clear, colorless to 
pale yellow liquid. 
May 
contain 
particles 
2 to 8°C. Protect 
from 
light 
and 
freezing. 
 
8.1.1 Storage and Stability 
 
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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Protocol Version Date:  January 24, 2019 
 
37 
 
 
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. 
 
8.1.4 Administration 
 
See Section 8.2 for Nivolumab instructions and 8.3 for Ipilimumab instructions. 
 
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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Protocol Version Date:  January 24, 2019 
 
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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. 
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,  In-
line filters and infusion tubing 
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. 


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Protocol Version Date:  January 24, 2019 
 
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Drug is not patient-specific. Be sure to check with your pharmacy regarding existing 
investigational stock to assure optimal use of drug on hand. 
Drug Excursions 
• Drug  excursions should be reported immediately to BMS on the form provided with the 
study-specific drug order form 
 
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-936558-
01 injection in the IV bag includes the product administration period. 


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Protocol Version Date:  January 24, 2019 
 
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Nivolumab infusions are to be administered as an IV infusion through a 0.2-micron to 1.2-
micron pore size, low-protein binding polyethersulfone membrane in-line filter at the protocol-
specified doses. It is not to be administered as an IV push or bolus injection. 
 
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. 
 
 
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 (2-
8°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. 
 
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. 


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Protocol Version Date:  January 24, 2019 
 
41 
 
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.  
 
Preparation and Administration 
As this is provided for guidance only, please see investigator brochure for additional 
information regarding preparation and administration. 
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 1.2-
micron pore size, low-protein binding polyethersulfone membrane in-line filter at the protocol-
specified doses. It is not to be administered as an IV push or bolus injection. 


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Protocol Version Date:  January 24, 2019 
 
42 
 
 
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 
 
 
9.1 
Background of exploratory biomarker studies:  
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.  
 
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 solution-
phase 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 copy-
number 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 


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Protocol Version Date:  January 24, 2019 
 
43 
 
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 RNA-
Sequencing 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.  
 
9.3 
Collection and Shipping of Tissue Specimen(s) 
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 
 


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Protocol Version Date:  January 24, 2019 
 
44 
 
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. 
 
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. 
 
Brastianos Lab 
185 Cambridge Street 
CPZN 3700 
Boston, MA 02114 
 
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. 
 


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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. 


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Protocol Version Date:  January 24, 2019 
 
46 
 
 
Calendar During Induction Phase for Melanoma, Small Cell Lung Cancer, Breast Cancer, 
Bladder Cancer, Renal Cancer and Other Solid Tumors 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Off Studyh 
 
Follow-up 
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 
 
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 
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 


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47 
 
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 
13 
Wk 
14 
Wk 
15 
Wk 
16 
Wk 
17 
Wk 
18 
Wk 
19 
Wk 
20 
Wk 
21 
Wk 
22 
Wk 
23 
Wk 
24 
Off 
Treatment
h 
 
Follow-
up visitsi 
To be repeated beyond 24 
weeks until patient goes off 
study 
Nivolumab  (for melanoma 
and renal cell carcinoma) 
B 
 
 
 
B 
 
 
 
B 
 
 
 
 
 
Nivolumab (for small cell 
lung cancer, breast cancer and 
bladder cancer) 
C 
 
C 
 
C 
 
C 
 
C 
 
C 
 
 
 
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 
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 


NCI Protocol #: 
DF/HCC Protocol #: 16-136 
Protocol Version Date:  January 24, 2019 
 
48 
 
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 
 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Off Studyh 
 
Follow-up 
visitsi 
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 


NCI Protocol #: 
DF/HCC Protocol #: 16-136 
Protocol Version Date:  January 24, 2019 
 
49 
 
A: 
Ipilimumab 1mg/kg Q6W  
B: 
Nivolumab 3mg/kg Q2W 
 
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 


NCI Protocol #: 
DF/HCC Protocol #: 16-136 
Protocol Version Date:  January 24, 2019 
 
50 
 
 
11. MEASUREMENT OF EFFECT 
 
Response in the CNS and response in non-CNS sites will be evaluated and recorded separately in 
this trial.  
 
11.1 
Antitumor Effect – Extracranial lesion assessments 
 
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. 
 
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.  
 
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. 


NCI Protocol #: 
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Protocol Version Date:  January 24, 2019 
 
51 
 
 
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 non-
cystic 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.  
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 


NCI Protocol #: 
DF/HCC Protocol #: 16-136 
Protocol Version Date:  January 24, 2019 
 
52 
 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable.  
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT  scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 


NCI Protocol #: 
DF/HCC Protocol #: 16-136 
Protocol Version Date:  January 24, 2019 
 
53 
 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both approaches 
may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 


NCI Protocol #: 
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Protocol Version Date:  January 24, 2019 
 
54 
 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
 
11.1.4.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Participants with Measurable Disease (i.e., Target Disease) 
 
Target 
Non-Target 
New 
Overall 
Best Overall Response when 


NCI Protocol #: 
DF/HCC Protocol #: 16-136 
Protocol Version Date:  January 24, 2019 
 
55 
 
Lesions 
Lesions 
Lesions 
Response 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 


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56 
 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
Overall Survival: Overall Survival (OS) is defined as the time from registration to death 
due to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
registration to the earlier of progression or death due to any cause. Participants alive 
without disease progression are censored at date of last disease evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported. 
 
 
11.2 
Antitumor Effect – Intracranial lesion assessments 
 
For the purposes of this study, participants should be re-evaluated for intracranial response every 
6 weeks.  In addition to a baseline scan, confirmatory scans should also be obtained at 4 weeks 
following initial documentation of objective response. Response and progression will be 
evaluated in this study using the modified RANO Response Criteria. 
 
11.2.1 Definitions 
 
Evaluable for objective response.  Only those participants who have measurable CNS 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response in the CNS.  
These participants will have their response classified according to the definitions stated 
below.  (Note:  Participants who exhibit objective disease progression prior to the end of 
cycle 1 will also be considered evaluable.) 
 
Evaluable non-measurable evaluable disease.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 


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Protocol Version Date:  January 24, 2019 
 
57 
 
11.2.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter  to be recorded) as ≥10 mm with 
CT scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded 
in millimeters (or decimal fractions of centimeters). 
 
For multifocal intracranial disease, no more than 5 target measurable lesions (each 
≥10mm in diameter in both dimensions) should be selected for measurement. Target 
lesions should be selected on the basis of their size (lesions with longest diameter), be 
representative of other lesions and lend themselves to reproducible repeated 
measurements. 
 
Non-measurable disease.  Unidimensionally measurable lesions, masses with margins not 
clearly defined, lesions with maximal diameter < 1cm. 
11.2.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  
 
Conventional head CT and brain MRI. This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT thickness is 5mm or less. If CT 
scans have slice thickness greater than 5 mm, the minimum size of a measurable lesion 
should be twice the slice thickness.  
 
11.2.4 Response Criteria 
 
11.2.4.1 
Evaluation of Intracranial Lesions 
 
Complete Response (CR):  Requires all of the following:  
• complete disappearance of all enhancing measurable and nonmeasurable 
disease sustained for at least 4 weeks 
• no new lesions 
• stable or decreasing corticosteroids (the steroid dose at the time of the scan 
evaluation should be no greater than the dose at time of baseline scan) 
• stable or improved clinically 
 


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58 
 
Participants with non-measurable disease cannot have a complete response. The best 
possible response is stable disease. 
 
Partial Response (PR):  All of the following criteria must be met: 
• Greater than or equal to 50% decrease compared to baseline in the sum of 
products of perpendicular diameters of all measurable enhancing lesions 
sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks 
later, this scan will be considered only stable disease.  
• no progression of non-measurable disease. 
• no new lesions 
• stable or reduced corticosteroid dose (the steroid dose at the time of the scan 
evaluation should be no greater than the dose at time of baseline scan) 
• stable or improved clinically 
 
Progressive Disease (PD): At least one of the following must be true:  
• > 25% increase in the sum of products of all measurable lesions over smallest 
sum observed (over baseline if no decrease) using the same techniques as 
baseline  
• clear worsening of any nonmeasurable disease* 
• appearance of any new enhancing lesion/site 
• clear clinical worsening (unless clearly unrelated to this cancer, e.g. seizures, 
medication side effects, complications of therapy, cerebrovascular events, 
infecion) 
• failure to return for evaluation due to death or deteriorating condition 
* Progression of non-measurable CNS lesions is defined as follows:  
• a lesion initially at baseline </=5mm in diameter that increases to >/= 10mm 
in diameter, or 
• a lesion initially at baseline 6-9 mm in diameter that increases by at least 5 
mm in diameter. 
 
Stable Disease (SD):  All of the following criteria must be met: 
• Does not qualify for CR, PR or progression 
• All measurable and non-measurable sites must be assessed using the same 
techniques as baseline 
• Stable clinically.  
 
A summary of the response criteria is in the below: 
 
  
 
Complete 
Response 
Partial 
Response  
Stable Disease Progressive 
Disease 
T1-Gd+ 
None 
> 
50% 
decrease 
<50% 
decrease-
<25% increase 
>25% 
increase* 
New Lesion 
None 
None 
None 
Present* 


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Corticosteroids 
Stable 
or 
decrease 
Stable 
or 
decrease 
Stable 
or 
decrease 
Stable 
or 
increasing 
Clinical Status 
Stable 
or 
improved 
Stable 
or 
improved 
Stable 
or 
improved 
Decrease* 
Requirement for 
Response 
All 
All 
All 
Any* 
NA=not applicable 
#: Progression occurs when any of the criteria with * is present 
Increase in corticosteroids alone will not be taken into account in determining 
progression in the absence of persistent clinical deterioriation 
 
 
11.2.4.2 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. If a response recorded at one scheduled MRI does not persist at 
the next regular scheduled MRI, the response will still be recorded based on the prior 
scan, but will be designated as a non-sustained response. If the response is sustained, 
i.e. still present on the subsequent MRI at least four weeks later, it will be recorded as 
a sustained response, lasting until the time of tumor progression. Participants without 
measurable disease may only achieve SD or PD as their best “response.” 
11.2.4.3 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started, or death due to any cause. Participants without events reported are 
censored at the last disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from 
the time measurement criteria are first met for CR until the first date that progressive 
disease is objectively documented, or death due to any cause. Participants without 
events reported are censored at the last disease evaluation. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
11.2.5 Study Continuation Beyond Initial Progressive Disease 
 
Immunotherapeutic agents such as ipilimumab and nivolumab may produce antitumor 


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effects by potentiating endogenous cancer-specific immune responses which may 
manifest as initial worsening of enhancement and edema on MRI or CT scans (i.e. 
pseudo-progression). In addition, the response patterns seen with immunotherapeutics 
may extend beyond the typical time course of responses seen with cytotoxic agents, and 
can manifest a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. For these reasons, the immune- related response criteria 
(irRC) have endorsed continuation of study therapy beyond initial radiographic evidence 
of progression for clinically stable patients undergoing immune based therapies. 
Therefore, the following adaptations will be used to assess response for patients treated 
on this study: 
Potential Pseudo-progression: If radiologic imaging shows initial PD, subjects who are 
not experiencing significant clinical decline, may be allowed to continue study treatment 
for up to three months. Patients who have radiographic evidence of further progression 
after up to three months, or who decline significantly at anytime, will be classified as 
progressive with the date of disease progression back-dated to the first date that the 
subject met criteria for progression and such subjects will be discontinued from study 
therapy. Three months is the most common timeframe for pseudo-progression observed 
among patients with advanced melanoma or other solid tumors treated with PD-1/PD-L1 
immune checkpoint blockade17.  
Among patients on this study with initial radiographic PD, tumor assessment should be 
repeated regularly in order to confirm PD with the option of continuing treatment as 
described below while awaiting radiologic confirmation of progression. If repeat imaging 
shows a stabilization or reduction in the tumor burden compared to the initial scan 
demonstrating PD, treatment may be continued / resumed. If repeat imaging after up to 
three months confirms progressive disease, then the date of disease progression will be 
the first date the subject met criteria for progression and subjects will be discontinued 
from study therapy. Subjects who have confirmed disease progression will discontinue 
study medication and enter the follow up/survival phase of the study. In determining 
whether or not the tumor burden has increased or decreased, investigators should 
consider all target lesions as well as non-target lesions. 
Tumor Enhancement to Define Progression: RANO expanded the previously utilized 
Macdonald criteria18 to include the development of “significantly” increased T2 or 
FLAIR abnormality in the definition of progressive disease because such changes can be 
a major component defining radiographic progression following therapeutic use of 
VEGF/VEGFR-targeting therapeutics which are known to elicit potent anti-permeability 
changes that limit contrast uptake. However, immune based therapies are expected to be 
associated with inflammatory changes that may include edema. Therefore, our study will 
define radiographic progressive disease by assessment of enhancing tumor burden only 
and will not include assessment of T2 or FLAIR changes as outlined in RANO because: 
 
• There is no expectation that immunotherapy agents including PD-1 inhibitors will 
falsely diminish enhancing tumor burden as has been noted with anti-angiogenic 


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therapies; and  
• Immune based therapies are expected to induce inflammatory responses which 
may be associated with increased edema and T2/FLAIR changes. Such 
radiographic finding may inaccurately be interpreted to represent tumor 
progression (i.e. pseudoprogression).  
 
In subjects who have initial evidence of radiographic PD, it is at the discretion of the 
treating physician whether to continue a subject on study treatment for up to three months 
pending confirmation of PD on follow-up imaging. This clinical judgment decision 
should be based on the subject’s overall clinical condition, including performance status, 
clinical symptoms, and laboratory data. Subjects may receive study treatment while 
waiting for confirmation of PD if they are not experiencing significant clinical decline 
and if: 
• The subject is believed to demonstrate clinical benefit from the study regimen as 
determined by the treating physician; 
• The subject is adequately tolerating study therapy. 
 
When feasible, study therapy should not be discontinued until radiographic progression is 
confirmed. This allowance to continue treatment despite initial radiologic progression 
takes into account the observation that some subjects can have a transient tumor flare in 
the first few months after the start of immunotherapy, but with subsequent disease 
response19. Subjects that are exhibiting significant neurologic decline are not required to 
have repeat imaging for confirmation of progressive disease. 
Participants with progressive radiographic findings are encouraged to undergo surgical 
intervention in order to delineate pseudo-progression due to inflammation associated with 
PD-1 blockade from true tumor progression. Participants with histopathologic findings of 
significant immune infiltrate and evolving gliosis will be allowed to continue study 
therapy. In contrast, those with clear evidence of progressive tumor by histopathologic 
evaluation will be defined as progressive and discontinued from study therapy. For such 
patients, the date of tumor progression will be the first date the participant met 
radiographic criteria for PD. 
11.3 
Response Review 
 
All brain MRI scans will be reviewed centrally by the DF/HCC Tumor Imaging Metrics 
Core (TIMC). CNS response will be assessed centrally using the RANO criteria outlined 
in Section 12.1.4. 
All non-CNS scans will be reviewed centrally by the DF/HCC Tumor Imaging Metrics 
Core (TIMC). Extracranial response will be assessed centrally using RECIST criteria. 
11.4 
Other Response Parameters 
 
 
Cerebrospinal Fluid: Cerebrospinal fluid will collected as part of clinical care. 


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


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12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The ODQ will collect, manage, and perform quality checks on the data for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the ODQ according to the schedule set by the ODQ. 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with ODQ 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of treatment administration 
Adverse Event Report Form 
Within 
10 
days 
of 
AE 
assessment/notification 
Response Assessment Form 
Within 10 days of response assessment 
Off Treatment/Off Study Form 
Within 14 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined 
follow up visit date or call 
 
12.2 
Data Safety Monitoring 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
 


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12.3 
Multicenter Guidelines 
 
N/A 
 
12.4 
Collaborative Agreements Language 
 
N/A 
 
13. STATISTICAL CONSIDERATIONS 
 
This is a single arm phase II trial to investigate the therapeutic effect of ipilimumab and 
nivolumab in leptomeningeal carcinomatosis.  
 
13.1 
Study Design/Endpoints 
 
Primary endpoint: Rate of overall survival at 3 months 
 
Secondary Endpoints: 
1. Toxicity by CTCAE criteria (grade 3 or higher hematologic toxicity; grade 3 or higher 
neurologic toxicity)  
2. Intracranial response in patients with leptomeningeal metastases  
3. Extracranial response as determined by RECIST and irRC  
4. Leptomeningeal disease response as defined in section 11.4 
5. Time to the first occurrence of extracranial disease progression, or death from any cause  
6. Time to the first occurrence of intracranial disease progression, or death from any cause  
  
 
Exploratory Endpoints: Genetic alterations 
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 
Accrual of up to 20 patients may be required to achieve 18 evaluable patients.  
 
The primary endpoint is the rate of overall survival at 3 months (OS3). Any patient whose vital 
status at 3 months cannot be determined will be counted as having died.  A Simon two-stage 
design will be used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Nine 
patients will be enrolled in the first stage. If 0 or 1 patients are alive at 3 months, the trial will be 
stopped early. If 2 or more patients are alive at 3 months, we will enroll an additional 9 patients. 
If at least 6 patients among the total of 18 patients are alive at 3 months, then the treatment 
would be promising in the cohort. This design has a type-I error of 8% (target 10%) and power 
of 86% (target 85%). If the null hypothesis is true, then the probability is 0.50 of stopping at the 
end of the first stage. 
 
In addition, we will assess for the primary outcome of any histologic, molecular subtype (e.g., 
ER/PR-positive, HER2-positive breast cancer, EGFR mutant lung cancer) with 6 patients 


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enrolled for that particular subtype.  If no patient within a particular histologic subtype has 
achieved the primary outcome, then patients with that histology will no longer be eligible to 
enroll in the trial.   Under the alternative hypothesis (i.e., OS3 = 43%), the probability is 0.03 of 
observing no patients with OS3 among 6 patients.  
 
The accrual rate is based on our institutional patient volume of 3-4 patients per month with 
leptomeningeal carcinomatosis seen in our multidisciplinary brain metastasis clinic.  We estimate 
that 1-2 patients per month will be eligible for this protocol. Therefore, 20 patients will be 
accrued within 10-20 months. Based on six months of follow-up (median survival of patients is 
approximately 2-4 months), total study duration will be 24 months. 
 
13.3 
Stratification Factors 
 
N/A 
 
13.4 
Interim Monitoring Plan 
 
N/A 
 
13.5 
Analysis of Primary Endpoints 
 
The primary endpoint is the rate of overall survival at 3 months (OS3). Any patient whose vital 
status is unknown due to loss of follow-up will be classified as having died for purposes of 
estimating the primary endpoint.  The proportion of patients alive at 3 months will be 
summarized with a 90% confidence interval estimated using the method of Atkinson and Brown, 
which allows for the two-stage design.  Based on a sample of 18 patients, the confidence interval 
will be no wider than 0.42.   
 
13.6 
Analysis of Secondary Endpoints 
 
Safety and Tolerability:  All adverse events recorded during the trial will be summarized for all 
patients having received one or more doses of ipilimumab and nivolumab. The data for each 
cohort will be summarized separately, although safety data may be combined, if appropriate.  
The proportions of patients with grade-3 or higher hematologic toxicities or grade-3 or higher 
neurologic toxicities will be presented with 90% exact binomial confidence intervals.  The 
incidence of events that are new or worsening from the time of first dose of treatment will be 
summarized according to system organ class and/or preferred term, severity (based on CTCAE 
grade), type of adverse event, and relation to study treatment. Deaths reportable as SAEs and 
non-fatal serious adverse events will be listed by patient and tabulated by primary system organ 
class, and type of adverse event.  
 
Intracranial/Extracranial Response:  The proportion of patients with intracranial response of 
intraparenchymal brain metastases  (CR or PR by RANO) will be presented with a two-sided, 
90% exact binomial confidence interval. For a sample of 18 patients, the confidence interval will 
have maximum width of 0.42.  Extracranial response rates (CR or PR) according to RECIST and 
irRC will be summarized.  Rates will be accompanied by two-sided 90% exact binomial 


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confidence intervals.  Cases where RECIST and irRC responses do not agree will be 
documented. 
 
Leptomeningeal Disease Response: The proportion of patients with leptomeningeal disease 
response  (CR or PR) will be presented with a two-sided, 90% exact binomial confidence 
interval. For a sample of 18 patients, the confidence interval will have maximum width of 0.42.   
 
Extracranial PFS and Intracranial PFS:  Extracranial PFS (EPFS) is defined as the time from first 
dose of study drug to documented extracranial progression (per RECIST or irRC) or death, 
whichever occurs first.  Intracranial PFS (IPFS) is defined as the time from first dose of 
ipilimumab and nivolumab to documented intracranial progression (RANO) or death, whichever 
occurs first.  For both endpoints, the follow-up of patients who have neither died nor progressed 
at the time of analysis will be censored at the date of last adequate disease assessment.  Each 
cohort will be presented separately.  Median EPFS and IPFS will be presented and accompanied 
by 90% confidence intervals estimated using log(-log(survival)) methodology.  Point estimates at 
3 and 6 months will also be presented with confidence intervals. 
 
13.7 
Analysis of Exploratory Endpoints  
 
Biomarkers of blood and tissue:  Analyses of blood and tissue biomarkers will be based on 
descriptive statistics, as appropriate for the biomarker. 
 
To examine response according to pre-treatment levels of biomarkers, the study sample will be 
divided retrospectively according to the primary endpoint of response or non-response. Pre-
treatment biomarker levels will be summarized descriptively for the two response groups and 
compared using Wilcoxon rank-sum tests for markers measured on a continuous scale, or 
Fisher’s exact tests for those measured on a categorical scale. Where appropriate, visualization of 
the relationship between baseline marker levels and the distributions of PFS or OS will employ 
Kaplan-Meier estimates stratified by biomarker levels. Medians of the time-to-event endpoints 
will be shown with two-sided 90% confidence intervals; the distributions of PFS and OS will be 
compared across biomarker strata using the log-rank test. 
 
Changes in biomarkers between pretreatment and progression or treatment discontinuation will 
be calculated (post-pre) for each patient and summarized descriptively. In addition, the 
correlation of changes in tissue biomarkers with changes in measures of peripheral blood 
markers will be explored graphically, or by appropriate statistical methods based on data 
availability, to assess associations.  
 
13.8 
Reporting and Exclusions 
 
13.8.1 Evaluation of Toxicity 
 
All participants who have received at least one dose of nivolumab and ipilimumab will be 
evaluable for toxicity from the time of their first treatment. 
 


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13.8.2 Evaluation of the Primary Efficacy Endpoint 
 
To be included in the assessment of the primary objective, patients need to receive at 
least one cycle. 
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  


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REFERENCES 
 
 
1. 
Brastianos PK, Brastianos H, Eichler AF. Leptomeningeal Carcinomatosis. In: 
Palmieri D, ed. Central Nervous System Metastasis, the Biological Basis and Clinical 
Consideraiton. New York: Springer; 2013:187-201. 
2. 
Raizer JJ, Hwu WJ, Panageas KS, et al. Brain and leptomeningeal metastases from 
cutaneous melanoma: survival outcomes based on clinical features. Neuro-oncology 
2008;10:199-207. 
3. 
Glantz MJ, Jaeckle KA, Chamberlain MC, et al. A randomized controlled trial 
comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in 
patients with neoplastic meningitis from solid tumors. Clin Cancer Res 1999;5:3394-402. 
4. 
Grossman SA, Finkelstein DM, Ruckdeschel JC, Trump DL, Moynihan T, Ettinger 
DS. Randomized prospective comparison of intraventricular methotrexate and thiotepa in 
patients with previously untreated neoplastic meningitis. Eastern Cooperative Oncology Group. J 
Clin Oncol 1993;11:561-9. 
5. 
Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in 
melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16. 
6. 
Flaherty KT, Robert C, Hersey P, et al. Improved Survival with MEK Inhibition in 
BRAF-Mutated Melanoma. N Engl J Med 2012. 
7. 
Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic 
melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012;380:358-
65. 
8. 
Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in 
patients with metastatic melanoma. N Engl J Med 2010;363:711-23. 
9. 
Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment 
with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-
comparison cohort of a phase 1 trial. Lancet 2014;384:1109-17. 
10. 
Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously 
untreated metastatic melanoma. N Engl J Med 2011;364:2517-26. 
11. 
Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus Ipilimumab in 
Advanced Melanoma. N Engl J Med 2013. 
12. 
Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or 
Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-
label, phase 2 trial. Lancet Oncol 2012. 
13. 
Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and 
brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012;13:459-65. 
14. 
Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and 
brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012;13:459-65. 
15. 
Ahmed KA, Stallworth DG, Kim Y, et al. Clinical outcomes of melanoma brain 
metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol 2016;27:434-41. 
16. 
Bot I, Blank CU, Brandsma D. Clinical and radiological response of leptomeningeal 
melanoma after whole brain radiotherapy and ipilimumab. J Neurol 2012;259:1976-8. 
17. 
Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody 
in patients with advanced cancer. N Engl J Med 2012;366:2455-65. 


NCI Protocol #: 
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18. 
Macdonald DR, Cascino TL, Schold SC, Jr., Cairncross JG. Response criteria for 
phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8:1277-80. 
19. 
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune 
therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 
2009;15:7412-20. 


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 


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APPENDIX B 
TUMOR ASSESSMENT PER IMMUNE-RELATED RESPONSE CRITERIA 
 
Immune-related Response Criteria (irRC) are derived from modified World Health Organization 
(mWHO) conventions. Assessments of lymph nodes are derived from current RECIST 
guidelines. 
 
Definitions of Measurable/non-Measurable Lesions 
All measurable and non-measurable lesions should be assessed at Screening and at the defined 
tumor assessment time points. Additional assessments may be performed, as clinically indicated 
for suspicion of progression.  
 
Measurable Lesions 
Measurable lesions are lesions that can be accurately measured in 2 perpendicular diameters, 
with at least 1 diameter > 20 mm and the other dimension  > 10 mm (10 mm x 10 mm for spiral 
CT with cuts of 5 mm). The area will be defined as the product of the largest diameter with its 
perpendicular. 
 
Lymph nodes may also be considered measurable. To be considered pathologically enlarged and 
measurable, a lymph node must be at least 15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm). 
 
Non-Measurable Lesions 
Non-measurable (evaluable) lesions are all other lesions, including unidimensional measurable 
disease and small lesions (lesions without at least 1 diameter > 20 mm, or pathological lymph 
nodes with short axis  15 mm), and any of the following: lesions occurring in a previously 
irradiated area (unless they are documented as new lesions since the completion of radiation 
therapy), bone lesions, leptomeningeal disease, ascites, pleural or pericardial effusion, 
lymphangitis cutis/pulmonis, abdominal masses that are not pathologically/cytologically 
confirmed and followed by imaging techniques and cystic lesions. Lymph nodes that have a 
short axis < 10 mm are considered non-pathological and should not be recorded or followed. 
 
Definitions of Index/non-Index Lesions 
Index Lesions 
Measurable lesions, up to a maximum of 5 lesions per organ and ten lesions in total, must be 
identified as index lesions to be measured at Screening. The index lesions should be 
representative of all involved organs. In addition, index lesions must be selected based on their 
size (eg, lesions with the longest diameters), their suitability for accurate repeat assessment by 
imaging techniques, and how representative they are of the subject’s tumor burden. At 
Screening, a Sum of the Product Diameters (SPD) for all index lesions will be calculated and 
considered the baseline SPD. The baseline sum will be used as the reference point to determine 
the objective tumor response of the index lesions at tumor assessment. 
 
Non Index Lesions 
Measurable lesions, other than index lesions, and all sites of non-measurable disease, will be 
identified as non-index lesions. Non-index lesions will be evaluated at the same assessment time 


NCI Protocol #: 
DF/HCC Protocol #: 16-136 
Protocol Version Date:  January 24, 2019 
 
72 
 
points as the index lesions. In subsequent assessments, changes in non-index lesions will 
contribute only in the assessment of complete response. 
 
Calculation of Sum of Product of Diameters (SPD) 
Sum of Product of Diameters is an estimate of tumor burden. The 2 greatest perpendicular 
diameters are used to estimate the size of each tumor lesion. The SPD is calculated as the sum of 
the product of the diameters for index tumor lesions. Several variations of the SPD are identified 
for the purpose of classification of tumor responses. 
 
SPD at Baseline: The sum of the product of the diameters for all index lesions identified at 
baseline prior to treatment on Day 1. 
 
SPD at tumor assessment: For every on-study tumor assessment collected per protocol or as 
clinically indicated, the SPD at tumor assessment will be calculated using tumor imaging scans. 
All index lesions and all new measurable lesions that have emerged after baseline will contribute 
to the SPD at tumor assessment (irSPD). 
 
SPD at NADIR: For tumors that are assessed more than 1 time after baseline, the lowest value of 
the SPD (SPD Baseline or SPD at tumor assessment) is used to classify subsequent tumor 
assessments for each subject. The SPD at tumor assessment using the irRC for progressive 
disease incorporates the contribution of new measurable lesions. Each net percentage change in 
tumor burden per assessment using irRC accounts for the size and growth kinetics of both old 
and new lesions as they appear. In this study the irRC as defined by the Investigator will serve as 
the basis of key endpoints for efficacy analyses and guide clinical care. 
 
Definition of Index Lesion Response 
Immune-related Complete Response (irCR), which is defined as complete disappearance of all 
index lesions. Lymph nodes that shrink to < 10 mm short axis are considered normal.  
 
Immune-related Partial Response (irPR), which is defined as a decrease, relative to baseline, of 
50% or greater in the sum of the products of the 2 largest perpendicular diameters of all index 
and all new measurable lesions (ie, Percentage Change in Tumor Burden), in the absence of 
irCR. 
 
Note: the appearance of new measurable lesions is factored into the overall tumor burden, but 
does not automatically qualify as progressive disease until the SPD increases by > 25% when 
compared to SPD at nadir 
 
Immune-related Stable Disease (irSD), which is defined as not meeting the criteria for irCR or 
irPR, in the absence of immune-related progressive disease (irPD) 
 
Immune-related Progressive Disease (irPD), which is defined as at least a 25% increase in 
Tumor Burden (ie, taking sum of the products of all index lesions and any new measurable 
lesions) when compared to SPD at nadir. 
 
Definition of Non-Index Lesion Response 


NCI Protocol #: 
DF/HCC Protocol #: 16-136 
Protocol Version Date:  January 24, 2019 
 
73 
 
Immune-related Complete Response (irCR), which is defined as complete disappearance of all 
non-index lesions. Lymph nodes that shrink to < 10 mm short axis are considered normal.  
 
Immune-related Partial Response (irPR), non-index lesion(s) are not considered in the definition 
of PR, this term does not apply. 
 
Immune-related Stable Disease (irSD), non-index lesion(s) are not considered in the definition of 
SD, this term does not apply. 
 
Immune-related Progressive Disease (irPD), increases in number or size of non-index lesion(s) 
does not constitute progressive disease unless/until Tumor Burden increases by 25% (ie, the SPD 
at nadir of index lesions and any new measurable lesions increases by the required amount). 
 
Impact of New Lesions on irRC 
New lesions alone do not qualify as progressive disease. However their contribution to total 
tumor burden is included in the SPD which in turn feeds into the irRC for tumor response. 
Therefore, new non-measurable lesions will not discontinue any subject from the study.  
 
Definition of Overall Response Using irRC Will Be Based on the Following Criteria: 
• Immune-related Complete Response (irCR): Complete disappearance of all tumor lesions 
(index and non-index), together with no new measurable or unmeasurable lesions, for at 
least 4 weeks from the date of documentation of irCR. All lymph nodes short axes must 
be < 10 mm. 
• Immune-related Partial Response (irPR): The sum of the products of the 2 largest 
perpendicular diameters of all index lesions is measured and captured as the SPD 
baseline. At each subsequent tumor assessment, the sum of the products of the 2 largest 
perpendicular diameters of all index lesions and of new measurable lesions are added 
together to provide the Immune Response Sum of the Product of the Diameters (irSPD). 
A decrease, relative to baseline of the irSPD of 50% or greater is considered an irPR, in 
the absence of irCR. Must be confirmed no less than 4 weeks from the first irPR. 
• Immune-related Stable Disease (irSD): irSD is defined as the failure to meet criteria for 
immune complete response or immune partial response, in the absence of progressive 
disease. 
• Immune-related Progressive Disease (irPD): It is recommended in difficult cases (eg, 
increase in SPD or irSPD accompanied with significant individual lesion regression, 
“mixed response”, or in presence of stable or improving performance status/clinical 
condition) to confirm PD at the following tumor assessment. Any of the following will 
constitute progressive disease: 
• At least 25% increase in the SPD of all index lesions over nadir SPD calculated 
for these lesions 
• At least a 25% increase in the SPD of all index lesions and new measurable 
lesions 
• (irSPD) over the nadir SPD calculated for the index lesions. 
 
 


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PROTOCOL NUMBER: 
NCI:  TBD  
BMS:CA209-405 
 
TITLE:  Phase II Trial of Ipilimumab and Nivolumab in Leptomeningeal Metastases from 
Melanoma 
 
  
  
 
 
PHARMACY  MANUAL 
Version 2.0 
 
May 14, 2018 
 
 
 
Bristol-Myers Squibb Research and Development 
 Pharmacy Services 
P.O. Box 4000 
Princeton, NJ  08543 


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DOCUMENT HISTORY 
Document 
Date of Issue 
Summary of Change 
Manual 
V 1.0 
 
May 19, 2016 
 
Version 1.0 
Manual 
V 2.0 
May 14, 2018 
Nivolumab and  Ipilimumab infusion times reduced to 30 minutes.  
 


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TABLE OF CONTENTS 
DOCUMENT HISTORY ..................................................................... 2 
TABLE OF CONTENTS .................................................................... 3 
1 
OBJECTIVE ....................................................................... 3 
2 
SPONSOR CONTACTS ..................................................... 4 
3 
STUDY TREATMENT ......................................................... 5 
3.1 
Nivolumab (BMS-936558) ................................................. 5 
3.1.1 
Product Description 
3.1.2 
Handling and Dose Preparation 
3.1.3 
Product storage and stability 
3.2          Ipilimumab......................................................................... 7 
3.2.1 
Product Description 
3.2.2 
Handling and Dose Preparation 
3.2.3 
Product storage and stability 
4  
SITE TEMPERATURE EXCURSIONS ................................... 10 
5             PRODUCT RECEIPT, ACCOUTABILITY, AND 
DESTRUCTION ................................................... 10 
6                    DATA COLLECTION .................................................................. 11 
APPENDIX 1 
TEMPERATURE EXCURSION RESPONSE 
FORM .................................................................. 12 
 
APPENDIX 2 
SAMPLE CALCULATION  FORM ....................... 13 
 
 
 


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1          OBJECTIVE 
The objective of this procedure manual is to provide the study site with clear and detailed 
information for the storage, handling, preparation and administration of clinical products 
used in the Bristol-Myers Squibb CA209-405. 
The information within this procedure manual is intended to supplement Section 8 of the 
CA209-405 clinical protocol. 
2          SPONSOR CONTACTS 
If concerns regarding the quality or appearance of the study drug, or questions regarding 
administration arise, do not dispense the study drug and contact the Bristol-Myers Squibb 
immediately: 
  
 
Questions with regard to drug preparation and manual content: 
 
Peter Trimboli, RPh 
Pharmacy Services, Drug Supply Management  
   
Bristol-Myers Squibb Research and Development 
Telephone: 609-252-4862 
 
Email: peter.trimboli@bms.com 
 
Medical lead contacts: 
 
            Priscilla Brastianos 
            Massachusetts General Hospital 
            55 Fruit Street, Yawkey 9E 
            pbrastianos@partners.org 
 
            Ryan Sullivan, MD 
            MGH Cancer Center 
            Boston, MA 
            RSULLIVAN7@mgh.harvard.edu 
 
 
 
 
 


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3.0 STUDY TREATMENT 
 
 
Diluents for drug Dilution (Dextrose 5%, 0.9% NaCl), syringes, tubing for intravenous 
administration, and filters will be provided for by the clinical site by Bristol-Myers Squibb. 
Refer to appropriate section of the clinical protocol (Study Drug) for dosing for Nivolumab 
and Ipilimumab.  
 
3.1 
NIVOLUMAB INJECTION 
 
3.1.1 DESCRIPTION 
  
Product Name   
Nivolumab Injection (or BMS 936558), 100 mg/vial (10 
mg/mL)    
Product description 
and Packaging  
Packaging:  Vials assembled into white dispensing boxes 
containing 5 - 10 x 100 mg vials each.   
Vials:  10 cc Type I glass vial. 20 mm stopper and seal, 
respectively.  
Appearance: Clear to opalescent, colorless to pale yellow 
liquid, light (few) particulates may be present. 
Product Ingredients 
 Each vial contains 100 mg Nivolumab    
 
3.1.2 Handling and Dose preparation  
As with all injectable drugs, care should be taken when handling and preparing Nivolumab.  
Whenever possible, Nivolumab infusions should be prepared in a laminar flow hood, 
glovebox, or safety cabinet using standard procedures for the safe handling of intravenous 
agents applying aseptic techniques. Gloves are required. If nivolumab solution comes in 
contact with the skin or mucosa, immediately and thoroughly wash with soap and water. 
Dose Preparation and administration 
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. Nivolumab is a clear to opalescent, colorless to pale yellow solution. 
Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate 
matter other than a few translucent-to-white, proteinaceous particles. DO NOT SHAKE the 
vial. 


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Preparation 
• Withdraw the required volume of Nivolumab and transfer into an 
intravenous container.  
• Dilute Nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP to prepare an infusion with a final concentration 
ranging from 1 mg/mL to 10 mg/mL (see example below) 
• Mix diluted solution by gentle inversion. Do not shake. 
• Discard partially used vials or empty vials of Nivolumab. 
Storage of Infusion 
The product does not contain a preservative. After preparation, store the Nivolumab 
infusion either: 
• at room temperature for no more than 4 hours from the time of 
preparation. This includes room temperature storage of the infusion 
in the IV container and time for administration of the infusion  
or 
• under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 
hours from the time of infusion preparation. 
Do not freeze. 
Administration 
Administer the infusion over 30 (+/- 6 minutes)  minutes through an intravenous line 
containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 
micrometer to 1.2 micrometer). Do not coadminister other drugs through the same 
intravenous line. Flush the intravenous line at end of infusion with appropriate amount 
of diluent (e.g. 15-20 ml) to ensure that the total dose is administered. Total infusion 
and flush time should equal to 30  (+/-) 6 minutes.  
Dose selection for Nivolumab should be assigned per subject as outlined in the study drug 
dosing section of the clinical protocol. When Nivolumab is administered in combination 
with Ipilimumab, the Nivolumab will be infused first, followed by the ipilimumab to start 
approximately 30 minutes after the Nivolumab infusion completion.  
 
Preparation examples are listed below assuming at 77.2  kg patient weight.  
 
Example 1:  1 mg/kg dose  (rounding to nearest mg dose) 
Nivolumab 77 mg (7.7 ml Nivolumab 10mg/ml solution, local rounding rules applicable) 
may be mixed with 52.3 ml NS or D5W to a total volume = 60 ml (concentration = 1.3 
mg/ml) which can be infused over 30 minutes (+/- 6 min) at 1ml/min followed by flush 


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 Example 2:   3 mg/kg dose (rounding to the nearest mg dose) 
 
Nivolumab 232 mg (23.2 ml Nivolumab 10mg/ml solution, local rounding rules applicable) 
may be mixed with 36.8 ml NS or D5W to a total volume = 60 ml(concentration = 3.9 
mg/ml) which can be infused over 30 minutes (+/- 6 min) at 1 ml/min followed by flush.  
 
 
3.1.3 Product Storage and Stability 
Nivolumab 100 mg vials for injection should be refrigerated at 2°C to 8°C (36°F to 46°F). 
Protected from light and should not be frozen. Do not use beyond the expiration date on 
the vial.  Protect the vials from light by storing in the original package until time of use.  
Vials do not contain preservative and thus are intended for single use only and should be 
discarded after use and product reconciliation. 
Nivolumab should not be infused concomitantly in the same intravenous line with other 
agents. No physical or biochemical compatibility studies have been conducted to evaluate 
the co-administration of Nivolumab with other agents. 
 
 
3.2 Ipilimumab Injection 
 
3.2.1 Description 
 
  
Product Name   
Ipilimumab Injection, 200 mg/vial (5 mg/mL), 40 ml.   
Product description 
and Packaging  
Packaging:  Vials assembled into cartons containing 4 vial(s) 
each. 
Vials: 50 cc Type I glass vial. 20 mm stopper and seal.  
 
Appearance: Clear, colorless liquid. Light (few) particles may 
be present 
Product Ingredients 
 Each vial contains 200 mg (40 ml) Ipilimumab for injection 
 
 
 


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3.2.2 Handling and Dose preparation  
 
As with all injectable drugs, care should be taken when handling and preparing ipilimumab.  
Whenever possible, ipilimumab infusions should be prepared in a laminar flow hood, 
glovebox, or safety cabinet using standard procedures for the safe handling of intravenous 
agents applying aseptic techniques. Gloves are required. If ipilimumab solution comes in 
contact with the skin or mucosa, immediately and thoroughly wash with soap and water. 
   
Dose Preparation and administration 
  
Inspect parenteral drug products visually for particulate matter and discoloration prior to 
administration. Discard vial if solution is cloudy, there is pronounced discoloration 
(solution may have pale-yellow color), or there is foreign particulate matter other than 
translucent-to-white, amorphous particles. DO NOT SHAKE THE VIAL. 
 
Preparation 
  
• Allow the vials to stand at room temperature for approximately 5 minutes prior to 
   preparation of infusion. 
 
• Withdraw the required volume of ipilimumab and transfer into an intravenous bag. 
 
• Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP 
to prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2       
mg/mL and stored in PVC, non-PVC or glass containers.  Mix diluted solution by 
gentle inversion. Discard partially used vials or empty vials of Ipilimumab as outlined in 
section 4.8 of the clinical protocol. 
 
 
Administration 
 
• Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
   Injection, USP after each dose. 
 
• Administer diluted solution over 30 minutes through an intravenous line containing a 
   sterile, non-pyrogenic, low-protein-binding in-line filter.  
 
Ipilimumab should be dosed per patient or subject as outlined in the clinical protocol, study 
drug dosing section  or as otherwise indicted by the principle investigator. When 
Ipilimumab is administered in combination with Nivolumab, the Nivolumab will be infused 
first, followed by the ipilimumab to start approximately 30 minutes after the Nivolumab 
infusion completion. 


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Example 
 
For ease of practical administration a total volume of 150 ml has been selected.  Other 
infusion volumes may be used however it is recommended to keep concentration range of 1 
- 2 mg/ml.  
 
3 mg/kg in a 77 kg patient 
 
Ipilimumab 231 mg (46.2 ml ipilimumab 5mg/ml solution) may be mixed with 103.8 ml 
(local rounding rules exception) NS or D5W to a total volume of 150 ml which can be 
infused over 90 minutes at 1.7 ml/min (concentration = 1.5 mg/ml). 
 
  
 
 3.2.3  Product Storage and Stability 
 
Ipilimumab 200 mg vials for injection should be refrigerated at 2°C to 8°C (36°F to 46°F). 
Protected from light and should not be frozen. Do not use beyond the expiration date on 
the vial.  Protect the vials from light by storing in the original package until time of use.  
Vials do not contain preservative and thus are intended for single use only and should be 
discarded as outlined in section 4.8 of the clinical protocol. 
 
Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C, 
36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F) including preparation 
time, transit time and administration time.    
 
Ipilimumab should not be infused concomitantly in the same intravenous line with other 
agents. No physical or biochemical compatibility studies have been conducted to evaluate 
the co-administration of ipilimumab with other agents.    
 
   
 


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4    SITE TEMPERATURE EXCURSIONS AND TRANSIT 
Drug must be stored under the proper conditions as listed on the clinical supply label and 
outlined in the respective drug supply sections of the clinical protocol.  If any temperature 
excursions are encountered during on site storage, please report these to BMS for 
assessment as outlined in the Bristol-Myers Squibb, “Investigational Medicinal Product ( 
IMP) handling at Investigational Sites: Shipment, Receipt, Storage, Use Date Extension 
and Return/Destruction” guideline using the Temperature Excursion Response Form. See 
Appendix 1 
Proper storage conditions must be maintained during movement of inventory within 
an investigational site. Storage conditions for medications requiring storage at 2ºC to 8ºC 
(36ºF-46ºF) must be maintained throughout the transport with documentation maintained 
within the site files. Where controlled storage conditions (for example, temperature, 
relative humidity, light, etc.) are required during transit, the necessary environmental 
controls must be in place to ensure that the drug product remains within the acceptable 
temperature range. Temperature monitoring devices such as min max device must be 
implemented during transit.  
 
5 PRODUCT RECEIPT, ACCOUTABILITY, AND DESTRUCTION 
Drug Receipt 
 
Shipment Inspection Instructions 
1. Open box immediately upon receipt.  
2. Carefully inspect kits ensuring all of the supplies were received in good condition, 
correct quantity received, and all of the container ID #s were received as noted on 
packing slip.   
3. Sign and date (date of receipt) packing slip and file with study-specific documents. 
4. Log in all supplies in each shipment on the appropriate Clinical Supplies Inventory 
Form (provided separately)    
 
 
Accountability 
 
As per the clinical protocol it is the responsibility of the investigator to ensure that a current 
disposition record of investigational product accountability and reconciliation is maintained 
at each study site where study drug is inventoried and dispensed.  
 
In addition, records or logs must comply with applicable country/local regulations and 
guidelines and should include: 
• Amount received and placed in storage area 
• Amount currently in storage area 


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• Label ID number or batch number 
• Amount dispensed to and returned by subject, including unique subject identifiers 
• Amount transferred to another area/site for dispensing or storage 
• Non-study disposition (e.g. lost, wasted) 
• Amount destroyed at study site, if applicable 
• Amount returned to the Sponsor, if applicable 
• Dates and initials of person responsible for Investigational Product (IP) 
• Dispensing/accountability, as per the Site Signature and Delegation Log. 
 
Study Drug Destruction 
Study drugs (those supplied by BMS or sourced by the site/investigator) can be destroyed on 
site if local policies allow to do so. It is the Investigator’s responsibility to ensure that 
arrangements have been made for the disposal, procedures for proper disposal have been 
established according to applicable regulations, guidelines and institutional procedures, and 
appropriate records of the disposal have been documented.  
All drug destruction whether performed on or off site should be documented according to 
local policies and procedures and should be documented accordingly. 
 
6 IRT and DATA COLLECTION 
Not applicable 
 
 


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


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APPENDIX 2 
 
Templates as provided via separate attachment or below may serve as a sample for dosage 
calculations and may be printed out and used to document any calculations and infusion times as 
required by the clinical study team. Content in this attachment may be added or omitted. 
 
Drug Dose and Volume Calculator  
for IV Infusion 
  
  
Drug Product : 
 
Protocol number 
 
Patient name or ID: 
 
Preparation date and time: 
 
  
 
Drug Strength (mg/mL) 
 
Subject body weight (kg) 
 
1Dose in mg 
 
Volume of Drug (mL) 
 
Total Volume of infusion (mL) 
 
Volume of Diluent (mL) NS or D5W 
 
Infusion duration (min) 
 
Infusion Rate (mL/min) 
 
Infusion hang time 
  
Infusion completion time 
  
Note: If required, flush line with separate volume of same diluent (15-20 ml) as outlined in the 
study pharmacy manual 
1Reference protocol appendix section 4 (Study Drug) for patient dose per tier or cohort 
 


Protocol #16-136: Drafted (03/28/16)(DCL)/Approved (1/23/17)(BF); Revised Am #6 (drafted 11/13/17 BF)(approved JS 
11.14.17) 
 
DANA-FARBER CANCER INSTITUTE 
Nursing Protocol Education Sheet 
Protocol Number: 
16-136 
Protocol Name: 
A Phase II Trial of Ipilumumab and Nivolumab in Leptomenigeal Metastases  
DFCI Site PI: 
David Reardon, MD 
DFCI Research Nurse: 
Debra LaFrankie, Sandra Ruland, Lisa Doherty, Jennifer Stefanik, Caroline Kane, Brittney Fontana 
Page the DFCI research nurse or DFCI site PI if there are any questions/concerns about the protocol.   
Please also refer to ONC 15: Oncology Nursing Protocol Education Policy 
*** Remember to check the ALERT PAGE*** 
              SPECIAL NURSING CONSIDERATIONS UNIQUE TO THIS PROTOCOL 
Study Design 
 
• 
Ipilimumab is a fully human monoclonal immunoglobulin (Ig) specific for human cytotoxic T lymphocyte antigen 
4, which is expressed on a subset of activated T cells (Section 2.2.1) 
• 
Nivolumab is a fully human monoclonal antibody that targets the PD-1 CD279 cell surface membrane receptor 
(Section 2.2.2) 
• 
A cycle is defined as six weeks, with the exception of the nivolumab maintenance monotherapy phase in 
melanoma and renal cell carcinoma a cycle when each cycle will be 8 weeks (Section 5.1) 
Dose 
Calc. 
• 
Nivolumab will be dosed as mg /kg 
• 
Ipilumumab will be dosed as mg /kg 
• 
The dosing calculations should be based on the body weight. If the subject’s weight on the day of dosing differs 
by > 5% from the weight used to calculate the dose, the dose must be recalculated (Section 5.3) 
Study Drug  
Administration 
Agent Administration Guidelines are found in Section 5.3 
• 
For treatment schedule by histology, see Section 5.1. When study drugs are to be administered on the same 
day, separate infusion bags and filters must be used for each infusion. 
• 
Nivolumab will be administered first. 
• 
Ipilumumab will be administered approximately 30 minutes after completion of Nivolumab. The Ipilimumab 
infusion will start no sooner than 30 minutes after completion of Nivolumab infusion. 
• 
An infusion window of +/- 10 minutes is allowed for both Nivolumab and Ipilimumab  
• 
The criteria to treat is outlined in Table 1, and in section 5.2. 
• 
Nivolumab is to be administered as a 30 minute IV infusion. 
• 
Ipilumumab is to be administered as a 30 minute IV infusion. 
 
Dose  
Mods & 
Toxicity 
Criteria to Treat, Dose Modifications/Dosing Delays for Toxicity are outlined in Sections 5.2 and 6 
• 
There will be no dose modifications permitted. Dose reductions or dose escalations are not permitted (Section 
5.3 and 6) 
• 
This protocol uses NCI CTCAE criteria, version 4.0 
 
Con 
Meds 
Concomitant Therapy Guidelines are in Section 5.4 
• 
Antiemetic premedications should not be routinely administered prior to dosing of drugs. See Section 6 for 
premedication recommendations following a nivolumab or ipilimumab related infusion reaction 
 
Required  
Data  
• 
The study calendars are in Section 10. 
• 
Vital signs: The time points are in Section 10. 
• 
ECGs are obtained at screening, and then as clinically indicated. 
• 
Biomarkers: The time points are in Section 10 
 
Charting Tips 
All study drugs require documentation of exact administration time. 
Please be sure to DOCUMENT study medication actual UP/DOWN times in medical record (e.g. LMR, eMAR, 
nursing notes). Edit eMAR as needed to match the exact time given. 
If there is a discrepancy in the infusion time, delay in administration, or the infusion takes longer than is 
permitted by the guidelines of the protocol, please document the reason for the discrepancy in the medical 
record.   
Please be sure to also DOCUMENT any required observation periods, any additional vital signs, routes of 
administration, injection sites, and exact time of PK collections. 
 
 


1
Bristol-Myers Squibb
Research and Development
Oncology Clinical Research
3401 Princeton Pike, Lawrenceville, NJ 08648
Administrative Letter Date: 24-Sep-2018
IND Number:  125,872
Site Number:  All
Re:
Protocol CA209568:  A Study of Nivolumab in Combination with Ipilimumab (part 1); 
and Nivolumab plus Ipilimumab in Combination with Chemotherapy (part 2) as First Line 
Therapy in Stage IV Non-Small Cell Lung Cancer (NSCLC)
CheckMate 568, CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 568)
Dear Investigator:
The Purpose of this Administrative Letter is to change the contact details of the Study Director.
This is an administrative protocol change and does not significantly affect the safety of subjects, 
study scope, or scientific quality of a Phase II or III protocol. Accordingly, it may be implemented 
immediately.
The changes made to the protocol are as follows:
1. Page Section, Title Page
Previously written:
Study Director/Medical Monitor
Xuemei Li, MD
Bristol-Myers Squibb
3401 Princeton Pike
Lawrenceville, NJ 08648
Telephone (office): 609-302-4597
Fax: 609-302-6804
1.0
Approved
930131591
1.0
v


Protocol Administrative Letter
CA209568
BMS-936558
nivolumab
2
Changed to:
Study Director
Ravi Kasinathan, PhD
Bristol-Myers Squibb
3401 Princeton Pike
Lawrenceville, NJ 08648
Telephone (office): 609-302-5742
Telephone (cell): (267) 516-7837
Fax: 609-302-6804
Medical Monitor
Xuemei Li, MD
Bristol-Myers Squibb
3401 Princeton Pike
Lawrenceville, NJ 08648
Telephone (office): 609-302-4597
Fax: 609-302-6804
Please maintain a copy of this administrative letter with your protocol. Please provide a 
copy to your Investigational Review Board / Ethics Committee, unless agreed otherwise 
with BMS.
Sincerely,
Ravi Kasinathan, PhD
Study Director
1.0
Approved
930131591
1.0
v





ICF_001.pdf: 
Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es  
O H R S 0 1. 0 8. 1 6
P a ge 1  of 2 3  
D F CI Pr ot oc ol N u m ber: 
1 6 -1 3 6
A p pr o ve d Date ( D F CI I R B A p pr o val): 
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use: 
0 4/ 0 3/ 2 0 1 9  
Pr ot o c ol Titl e:   P h a s e II Tri al of I pili m u m a b a n d Ni v ol u m a b i n L e pt o m e ni n g e al 
M et a st a s e s 
D F/ H C C Pri n ci p al R e s e ar c h D o ct or / I n stit uti o n:   
Pri s cill a Br a sti a n o s, M D/ M a s s a c h u s ett s G e n er al H o s pit al  
D F/ H C C Sit e -R e s p o n si bl e R e s e ar c h D o ct or / I n stit uti o n :  
E u d o ci a K al e m Q u a nt L e e, M D, M P H/ D a n a F ar b er C a n c er I n stit ut e 
A.
IN T R O D U C TI O N
Y o u ar e i n vit e d t o t a k e p art i n a cli ni c al tri al, a t y p e of r e s e ar c h st u d y, b e c a u s e 
y o u h a v e  l e pt o m e ni n g e al m et a st a s e s. T hi s r e s e ar c h st u d y i s st u d yi n g a 
c o m bi n ati o n of t w o dr u g s a s a p o s si bl e tr e at m e nt f or t hi s di a g n o si s .   
T h e n a m e s of t h e st u d y i nt er v e nti o n s i n v ol v e d i n t hi s st u d y ar e:  
•
I pili m u m a b
•
Ni v ol u m a b
F or  p ur p o s e s of t hi s r e s e ar c h, y o u will b e  r ef err e d t o a s a “ p arti ci p a nt.”  
It i s e x p e ct e d t h at a b o ut 1 8 p e o pl e will t a k e p art i n t hi s r e s e ar c h st u d y.  
M el a n o m a R e s e ar c h Alli a n c e, a n o n -pr ofit or g a ni z ati o n, i s s u p p orti n g t hi s 
r e s e ar c h st u d y b y pr o vi di n g f u n di n g f or t h e st u d y. Bri st ol -M e y er s S q ui b b, a 
p h ar m a c e uti c al c o m p a n y, i s s u p p orti n g t hi s r e s e ar c h st u d y b y pr o vi di n g t h e 
st u d y dr u g s.  
D a n a -F ar b er C a n c er I n stit ut e h a s a fi n a n ci al i nt er e st i n t h e i n v e sti g ati o n al a g e nt 
u s e d i n t hi s tri al ( Ni v ol u m a b) w hi c h m a y b e aff e ct e d b y t h e o ut c o m e of t hi s 
r e s e ar c h. T h e I n stit ut e h a s t a k e n st e p s t o m a n a g e a n y a ct u al or p ot e nti al c o nfli ct 
of i nt er e st cr e at e d b y t hi s fi n a n ci al i nt er e st, w hi c h ar e m or e f ull y d e s cri b e d i n t h e 
I nf or m ati o n S h e et a v ail a bl e t o all p arti ci p a nts. M or e i nf or m ati o n a b o ut t h e s e 
m e a s ur e s c a n b e o bt ai n e d b y c o nt a cti n g R o b ert a Dri s c oll, J D, Dir e ct or of t h e 
Offi c e of R e s e ar c h I nt e grit y at 6 1 7 -6 3 2 -4 5 5 7 or b y e m ail at 
R o b ert a _ Dri s c oll @ df ci. h ar v ar d. e d u  
T hi s r e s e ar c h c o n s e nt f or m e x pl ai n s w h y t hi s r e s e ar c h st u d y i s b ei n g d o n e, w h at 
i s i n v ol v e d i n p arti ci p ati n g i n t h e r e s e ar c h st u d y, t h e p o s si bl e ri s k s a n d b e n efit s 
of p arti ci p ati o n , alt er n ati v e s t o p arti ci p ati o n, a n d y o ur ri g ht s a s a r e s e ar c h 
p arti ci p a nt . T h e d e ci si o n t o p arti ci p at e i s y o ur s. If y o u d e ci d e t o p arti ci p at e, 
pl e a s e si g n a n d d at e at t h e e n d of t hi s f or m. W e will gi v e y o u a c o p y s o t h at y o u 
N C T 0 2 9 3 9 3 0 0
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 2  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
c a n r ef er t o it w hil e y o u ar e i n v ol v e d i n t hi s r e s e ar c h st u d y.  If y o u c h o o s e n ot t o 
p arti ci p at e i n t hi s r e s e ar c h st u d y, t h e r e s e ar c h d o ct or s will di s c u s s ot h e r 
tr e at m e nt o pti o n s wit h y o u a n d/ or r ef er y o u b a c k t o y o ur pri m ar y d o ct or.  
 
W e e n c o ur a g e y o u t o t a k e s o m e ti m e t o t hi n k t hi s o v er , t o di s c u s s it wit h ot h er 
p e o pl e a n d y o ur pri m ar y d o ct or , a n d t o a s k q u e sti o n s n o w a n d at a n y ti m e i n t h e 
f ut ur e. 
 
B.  W H Y I S T HI S R E S E A R C H S T U D Y B EI N G D O N E ?   
 
T hi s r e s e ar c h st u d y i s a P h a s e II cli ni c al tri al. P h a s e II cli ni c al tri al s t e st t h e 
s af et y a n d eff e cti v e n e s s of a n i n v e sti g ati o n al i nt er v e nti o n t o l e ar n w h et h er t h e 
i nt er v e nti o n w or k s i n tr e ati n g a s p e cifi c di s e a s e . “I n v e sti g ati o n al” m e a n s t h at t h e 
i nt er v e nti o n i s b ei n g st u di e d.   
 
T h e F D A (t h e U. S. F o o d a n d Dr u g A d mi ni str ati o n) h a s a p pr o v e d Ni v ol u m a b a n d 
I pili m u m a b a s a tr e at m e nt o pti o n f or m el a n o m a , b ut h a s n ot a p pr o v e d t h e m f or 
u s e w h e n c a n c er c ell s s pr e a d t o t h e c er e br o s pi n al fl ui d . 
 
R e s e ar c h er s h o p e t o st u d y  t h e eff e ct s of t h e c o m bi n ati o n of Ni v ol u m a b a n d 
I pili m u m a b. M a n y c a n c er s u s e s p e cifi c p at h w a y s ( s u c h a s P D -1/ P D -L 1 a n d 
C T L A -4) t o e v a d e t h e b o d y’ s i m m u n e s y st e m. Ni v ol u m a b a n d i pili m u m a b  w or k 
b y bl o c ki n g t h e P D -1/ P D -L 1 a n d C T L A -4 p at h w a y s a n d t h u s r el e a si n g t h e br a k e s 
o n t h e i m m u n e s y st e m s o it c a n st o p or sl o w c a n c er.  
 
C.  W H A T O T H E R O P TI O N S A R E T H E R E ?  
 
T a ki n g p art i n t hi s r e s e ar c h st u d y i s v ol u nt ar y. I n st e a d of b ei n g i n t hi s r e s e ar c h 
st u d y, y o u h a v e ot h er o pti o n s w hi c h m a y i n cl u d e t h e f oll o wi n g : 
 
•  R e c ei v e s t a n d ar d tr e at m e nt i n cl u di n g: r a di ati o n or c h e m ot h er a p y.                                
•  T a k e p art i n a n ot h er r e s e ar c h st u d y.  
•  R e c ei v e t h e s a m e dr u g s  al o n e , b ut n ot a s p art of a r e s e ar c h st u d y.  
•  R e c ei v e n o t h er a p y s p e cifi c t o y o ur c a n c er.  
•  C o mf ort c ar e, al s o c all e d p alli ati v e c ar e. T hi s t y p e of c ar e m a y h el p t o 
r e d u c e p ai n, tir e d n e s s, a p p etit e pr o bl e m s a n d ot h er pr o bl e m s c a u s e d 
b y t h e c a n c er. It d o e s n ot tr e at t h e c a n c er dir e ctl y, b ut i n st e a d tri e s  t o 
tr e at t h e s y m pt o m s.   
 
Pl e a s e t al k t o t h e r e s e ar c h d o ct or a b o ut y o ur o pti o n s b ef or e y o u d e ci d e w h et h er 
y o u will t a k e p art i n t hi s r e s e ar c h st u d y.  
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 3  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
 
D.  W H A T I S I N V O L V E D I N T H E R E S E A R C H S T U D Y ?  
 
M el a n o m a, s m all c ell l u n g c a n c er, br e a st c a n c er, bl a d d er c a n c er,  r e n al c a n c er, 
a n d ot h er s oli d t u m or  p arti ci p a nt s will b e tr e at e d wit h a  c o m bi n ati o n r e gi m e n of 
ni v ol u m a b wit h i pili m u m a b, f oll o w e d b y ni v ol u m a b o n it s o w n. Ni v ol u m a b a n d 
i pili m u m a b will b e gi v e n e v er y 3 w e e k s f or 4 d o s e s. T h e n, d e p e n di n g o n y o ur 
c a n c er t y p e, ni v ol u m a b will b e gi v e n e v er y 2  w e e k s  or e v er y 4 w e e k s .  
 
F or n o n s m all c ell l u n g c a n c er  a n d h e a d a n d n e c k c a n c er  p arti ci p a nt s, ni v ol u m a b 
will b e gi v e n e v er y 2 w e e k s a n d i pili m u m a b will b e gi v e n e v er y 6 w e e k s 
t hr o u g h o ut st u d y p arti ci p ati o n. 
 
Ni v ol u m a b a n d i pili m u m a b ar e b ot h a d mi ni st er e d i ntr a v e n o u sl y , a n d t h e i nfu si o n 
ti m e i s 3 0 mi n ut e f or e a c h. O n d a y s t h at ni v ol u m a b a n d i pili m u m a b ar e gi v e n 
t o g et h er, ni v ol u m a b will b e gi v e n fir st, f oll o w e d b y i pili m u m a b. T h e R e s e ar c h 
St u d y Pl a n o n t h e n e xt p a g e d e s cr i b e s t h e fr e q u e n c y of t h e vi sit s.  
 
S o m eti m e s it i s h ar d t o k e e p tr a c k of all of t h e d et ail s a n d pr o c e d ur e s t h at ar e 
p art of a r e s e ar c h st u d y. W e will d e s cri b e t h e m i n t hi s c o n s e nt f or m a n d y o u c a n 
r ef er t o t hi s at a n y ti m e d uri n g t h e r e s e ar c h st u d y. 
 
B ef or e t h e r e s e ar c h st art s ( s cr e e ni n g) :   
Aft er si g ni n g t hi s c o n s e nt f or m, y o u will b e a s k e d t o u n d er g o s o m e s cr e e ni n g 
t e st s or pr o c e d ur e s t o fi n d o ut if y o u c a n b e i n t h e r e s e ar c h st u d y. M a n y of t h e s e 
t e st s a n d pr o c e d ur e s ar e li k el y t o b e p art of r e g ul ar c a n c er c ar e a n d m a y b e 
d o n e e v e n if it t ur n s o ut t h at y o u d o n ot t a k e p art i n t h e r e s e ar c h st u d y. If y o u 
h a v e h a d s o m e of t h e s e t e st s or pr o c e d ur e s r e c e ntl y, t h e y m a y or m a y n ot h a v e 
t o b e r e p e at e d.  
 
•  A m e di c al hi st or y  a n d d e m o gr a p hi c s , w hi c h i n cl u d e s q u e s ti o n s a b o ut 
y o ur h e alt h, c urr e nt m e di c ati o n s, a n d a n y all er gi e s.  Y o ur h ei g ht will b e 
t a k e n. 
•  R e vi e w m e di c ati o n s  y o u ar e c urr e ntl y t a ki n g  
•  A p h y si c al e x a mi n ati o n, i n cl u di n g a n e ur ol o gi c al a s s e s s m e nt, r e c or di n g 
of y o ur w ei g ht,  a n d c oll e cti o n of vit al si g n s  ( bl o o d pr e s s ur e, b o d y 
t e m p er at ur e, p ul s e r at e, a n d br e at hi n g r at e) 
•  P erf or m a n c e st at u s , w hi c h e v al u at e s h o w y o u ar e a bl e t o c arr y o n wit h 
y o ur u s u al a cti viti e s.  
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 4  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
•  Bl o o d c oll e cti o n a n d t e sti n g, a p pr o xi m at el y 2 t a bl e s p o o n s of bl o o d . 
Bl o o d c oll e cti o n will b e u s e d  t o l o o k f or m ar k er s of c a n c er, i n cl u di n g 
g e n eti c m ar k er s  or m ar k er s of y o ur i m m u n e s y st e m i n t h e  bl o o d  
•  Di s e a s e t e sti n g o n bl o o d s a m pl e s:  bl o o d t e st s will b e p erf or m e d t o t e st 
f or H e p atiti s B, H e p atiti s C, a n d HI V a n d if y o u  ar e p o siti v e f or a n y of 
t h es e di s e a s e s y o u  c a n n ot p arti ci p at e i n t h e st u d y.  
•  El e ctr o c ar di o gr a m ( E K G),  a t e st t h at c h e c k s f or pr o bl e m s wit h t h e 
el e ctri c al a cti vit y of y o ur h e art. T hi s will b e d o n e at s cr e e ni n g a n d t h e n a s 
cli ni c all y i n di c at e d  
•  S er u m pr e g n a n c y t e st, f or w o m e n of c hil d b e ari n g p ot e nti al  
•  A n a s s e s s m e nt of y o ur t u m or b y o n e or m or e of t h e f oll o wi n g st a n d ar d 
a s s e s s m e nt t o ol s: C T ( C o m p ut eri z e d T o m o gr a p h y) s c a n, M RI ( M a g n eti c 
R e s o n a n c e I m a gi n g) or P E T ( P o sitr o n E mi s si o n T o m o gr a p h y) s c a n s  
•  C er e br o s pi n al fl ui d  will b e c oll e ct e d t o a s s e s s di s e a s e st at u s . A n y e xtr a 
c er e br o s pi n al fl ui d t h at i s c oll e ct e d m a y b e u s e d f or r e s e ar c h. W e will l o o k 
f or c o m m o n m ut ati o n s t h at c o ul d pr e di ct r e si st a n c e t o t h e t h er a pi e s. 
T h e s e st u di e s c o ul d pr o vi d e s u g g e sti o n s a s t o ot h er t h e r a pi e s t h at mi g ht 
h el p tr e at m el a n o m a.  
 
•  Ar c hi v al ti s s u e c oll e cti o n,  w hi c h i s t h e c oll e cti o n of a pr e vi o u sl y -t a k e n 
bi o p s y of y o ur t u m or , if t h er e i s s u c h  ti s s u e a v ail a bl e. W e will e x a mi n e t hi s 
d at a f or g e n eti c bi o m ar k er s t o h el p i d e ntif y p o s si bl e bi o m ar k er s  t h at will 
i d e ntif y t h o s e t h at will r e s p o n d t o t h er a p y. W e will l o o k f or c o m m o n 
m ut ati o n s t h at c o ul d pr e di ct r e si st a n c e t o t h e t h er a pi e s. T h e s e st u di e s 
c o ul d pr o vi d e s u g g e sti o n s a s t o ot h er t h er a pi e s t h at mi g ht h el p tr e at 
m el a n o m a . 
 
If t h e s e t e st s s h o w t h at y o u ar e eli gi bl e t o p arti ci p at e i n t h e r e s e ar c h st u d y, y o u 
will b e gi n t h e st u d y tr e at m e nt. If y o u d o n ot m e et t h e eli gi bilit y crit eri a, y o u will 
n ot b e a bl e t o p arti ci p at e i n t hi s r e s e ar c h st u d y.  
 
 
 
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 5  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
R e s e ar c h St u d y Pl a n f or P arti ci p a nt s of M el a n o m a, S m all C ell L u n g C a n c er, 
Br e a st C a n c er, Bl a d d er C a n c er, R e n al C a n c er , a n d Ot h er S oli d T u m or s: 
 
 
 
 
C y cl e 1 & C y cl e 2  
 
S  
W 1 
W 7  
W 2 
W 8  
W 3 
W 9  
W 4 
W 1 0  
W 5 
W 1 1  
W 6 
W 1 2  
M e di c al Hi st or y  
X  
 
 
 
 
 
 
C o n c urr e nt m e d s  
X  
X  
X  
X  
X  
X  
X  
P h y si c al e x a m a n d vit al s  
X  
X  
X  
X  
X  
X  
X  
W ei g ht  
X  
X  
 
 
X  
 
 
P erf or m a n c e st at u s  
X  
X  
 
 
X  
 
 
Bl o o d T e sti n g  
X  
X  
 
 
X  
 
 
R e s e ar c h Bl o o d  
X  
X  
 
 
X  
 
 
E K G  
X  
 
 
 
 
 
 
S er u m Pr e g n a n c y T e st  
X  
 
 
 
 
 
 
R a di ol o gi c e v al u ati o n  
X  
 
 
 
 
 
X  
C er e br o s pi n al fl ui d  
X  
X  
 
 
X  
 
 
Ar c hi v al ti s s u e c oll e cti o n  
X  
 
 
 
 
 
 
I pili m u m a b 
 
X  
 
 
X  
 
 
Ni v ol u m a b*  
 
X  
 
 
X  
 
 
 
 
S = S cr e e ni n g   W = W e e k   
 
* Ni v ol u m a b al o n e aft er C y cl e 2. F or m el a n o m a, r e n al c a n c er, a n d ot h er s oli d t u m or p arti ci p a nt s, 
ni v ol u m a b i s gi v e n e v er y 4 w e e k s; f or s m all c ell l u n g c a n c er, br e a st c a n c er, a n d bl a d d er c a n c er p arti ci p a nt s, 
ni v ol u m a b i s gi v e n e v er y 2 w e e k s.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 6  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
 
 
 
C y cl e 3 & C y cl e 4 & B e y o n d  
Off 
St u d y  
F oll o w 
U p  
 
W 1 3 
W 2 1  
W 1 4 
W 2 2  
W 1 5 
W 2 3  
W 1 6 
W 2 4  
W 1 7 
W 2 5  
W 1 8 
W 2 6  
W 1 9 
W 2 7  
W 2 0 
W 2 8  
 
 
M e di c al Hi st or y  
 
 
 
 
 
 
 
 
 
 
C o n c urr e nt m e d s  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
P h y si c al e x a m a n d vit al s  
X  
 
X  
 
X  
 
X  
 
X  
X  
W ei g ht  
X  
 
X  
 
X  
 
X  
 
X  
X  
P erf or m a n c e st at u s  
X  
 
X  
 
X  
 
X  
 
X  
X  
Bl o o d T e sti n g  
X  
 
X  
 
X  
 
X  
 
X  
X  
R e s e ar c h Bl o o d  
X  
 
 
 
X  
 
 
 
X  
X  
E K G  
 
 
 
 
 
 
 
 
 
 
S er u m Pr e g n a n c y T e st  
X  
 
 
 
 
 
 
 
 
X  
R a di ol o gi c e v al u ati o n  
 
 
 
 
 
 
 
X  
X  
 
C er e br o s pi n al fl ui d  
 X  
 
 
 
X  
 
 
 
 
 
Ar c hi v al ti s s u e c oll e cti o n  
 
 
 
 
 
 
 
 
X  
X  
I pili m u m a b 
 
 
 
 
 
 
 
 
 
 
Ni v ol u m a b*  
X  
 
X  
 
X  
 
X  
 
 
 
 
 
 
S = S cr e e ni n g   W = W e e k    
 
* Ni v ol u m a b al o n e aft er C y cl e 2 . F or m el a n o m a, r e n al c a n c er, a n d ot h er s oli d t u m or p arti ci p a nt s, 
ni v ol u m a b i s gi v e n e v er y 4 w e e k s; f or s m all c ell l u n g c a n c er, br e a st c a n c er, a n d bl a d d er c a n c er p arti ci p a nt s, 
ni v ol u m a b i s gi v e n e v er y 2 w e e k s.  
 
C er e br o s pi n al fl ui d will b e c oll e ct e d e v er y 3 w e e k s d uri n g t h e fir st 1 2 w e e k s a n d 
t h e n e v er y 4 we e k s aft er t h at. C er e br o s pi n al fl ui d will b e u s e d t o a s s e s s t h e 
r e s p o n s e of c a n c er t o t h er a p y. E xtr a c er e br o s pi n al fl ui d will b e s e nt f or a d diti o n al 
r e s e ar c h st u di e s. 
 
 
 
 
 
 
 
R e s e ar c h St u d y Pl a n f or P arti ci p a nt s of N o n s m all C ell L u n g C a n c er  a n d H e a d 
a n d N e c k C a n c er : 
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 7  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
 
 
 
C y cl e 1 & C y cl e 2 & B e y o n d  
Off St u d y  
F oll o w U p  
 
S  
W 1 
W 7  
W 2 
W 8  
W 3 
W 9  
W 4 
W 1 0  
W 5 
W 1 1  
W 6 
W 1 2  
 
 
M e di c al Hi st or y  
X  
 
 
 
 
 
 
 
 
C o n c urr e nt m e d s  
X  
X  
X  
X  
X  
X  
X  
 
 
P h y si c al e x a m a n d 
vit al s  
X  
X  
X  
X  
X  
X  
X  
X  
X  
W ei g ht  
X  
X  
 
 
X  
 
 
X  
X  
P erf or m a n c e st at u s  
X  
X  
 
 
X  
 
 
X  
X  
Bl o o d T e sti n g  
X  
X  
 
X  
 
X  
 
X  
X  
R e s e ar c h Bl o o d  
X  
X  
 
 
 
X  
 
 
X  
E K G  
X  
 
 
 
 
 
 
 
 
S er u m Pr e g n a n c y T e st  
X  
 
 
 
 
 
 
 
X  
R a di ol o gi c e v al u ati o n  
X  
 
 
 
 
 
X  
X  
X  
C er e br o s pi n al fl ui d  
X  
X  
 
 
 
X  
 
 
 
Ar c hi v al ti s s u e 
c oll e cti o n  
X  
 
 
 
 
 
 
X  
X  
I pili m u m a b 
 
X  
 
 
 
 
 
 
 
Ni v ol u m a b  
 
X  
 
X  
 
X  
 
 
 
 
 
Pl a n n e d F oll o w -u p:   
E n d of tr e at m e nt a s s e s s m e nt s (“ Off St u d y”) will b e p erf or m e d wit hi n 7 d a y s aft er 
l a st d a y of st u d y dr u g a d mi ni str ati o n or wit hi n 7 d a y s aft er  t h e d e ci si o n t o e n d 
tr e at m e nt.  
 
E.  H O W L O N G WI L L I B E I N T HI S R E S E A R C H  S T U D Y ?  
 
Y o u will b e i n t hi s r e s e ar c h st u d y f or a s l o n g a s y o u ar e r e s p o n di n g t o a n d 
t ol er ati n g st u d y t h er a p y.  
 
T h e r e s e ar c h d o ct or m a y d e ci d e t o t a k e y o u off t h e r e s e ar c h st u d y f or m a n y 
r e a s o n s i n cl u di n g if: 
•  It i s c o n si d er e d t o b e i n y o ur b e st i nt er e st 
•  T h e st u d y tr e at m e nt or pr o c e d ur e s ar e f o u n d t o b e u n s af e or i n eff e cti v e  
•  T h er e i s a n y pr o bl e m wit h f oll o wi n g st u d y tr e at m e nt s a n d pr o c e d ur e s  
•  Y o ur c o n diti o n w or s e n s  
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 8  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
•  A d e ci si o n i s m a d e t o cl o s e t h e st u d y  
•  Or f or ot h er u nf or e s e e n r e a s o n s t h at m a k e it n e c e s s ar y t o st o p y o ur 
p arti ci p ati o n i n t h e r e s e ar c h st u d y  
 
If y o u ar e r e m o v e d fr o m t h e r e s e ar c h st u d y, t h e r e s e ar c h d o ct or will e x pl ai n t o 
y o u w h y y o u w er e r e m o v e d.   
 
I n a d diti o n, y o u c a n st o p p arti ci p ati n g i n t h e r e s e ar c h st u d y at a n y ti m e, h o w e v er, 
t h e F D A r e q uir e s t h at a n y i nf or m ati o n c oll e ct e d u p t o t h e p oi nt of y o ur wit h dr a w al 
c a n n ot b e r e m o v e d fr o m t h e st u d y. If y o u d e ci d e t o st o p p arti ci p ati n g i n t hi s 
r e s e ar c h st u d y, w e e n c o ur a g e y o u t o t al k t o t h e r e s e ar c h d o ct or a n d y o ur 
pri m ar y d o ct or fir st.  
 
F.  W H A T A R E T H E RI S K S O R  DI S C O M F O R T S O F T H E R E S E A R C H S T U D Y ?  
 
T h er e ar e ri s k s t o t a ki n g p art i n a n y r e s e ar c h st u d y. O n e ri s k i s t h at y o u m a y g et 
a st u d y dr u g t h at d o e s n ot h el p tr e at y o ur di s e a s e or t h at m a k e s y o ur c o n diti o n or 
di s e a s e w or s e. A n ot h er ri s k i s t h at t h er e m a y b e si d e eff e ct s.   
 
All c a n c er tr e at m e nt s c a n h a v e si d e eff e ct s, w hi c h c a n r a n g e fr o m mil d a n d 
r e v er si bl e t o s e v er e, l o n g l a sti n g a n d p o s si bl y lif e-t hr e at e ni n g. T h er e i s a gr e at 
d e al of v ari a bilit y a m o n g si d e eff e ct s of diff er e nt c a n c er tr e at m e nt s  a n d b et w e e n 
i n di vi d u al s. I n a r e s e ar c h st u d y, all of t h e ri s k s  or si d e eff e ct s m a y n ot b e k n o w n 
b ef or e y o u st art t h e st u d y.  Y o u n e e d t o t ell y o ur d o ct or or a m e m b er of t h e 
st u d y t e a m i m m e di at el y if y o u e x p eri e n c e a n y si d e eff e ct s.  
 
E v er y o n e i n t h e r e s e ar c h st u d y will b e w at c h e d c ar ef ull y f or si d e eff e ct s. Y o u will 
b e m o nit or e d d uri n g t h e a d mi ni str ati o n of st u d y dr u g s t o  k e e p tr a c k of y o ur bl o o d 
c o u nt s a n d or g a n f u n cti o n, p arti c ul arl y y o ur ki d n e y a n d li v er f u n cti o n. If y o u 
e x p eri e n c e si d e eff e ct s, t h e y m a y g o a w a y aft er y o u st o p t a ki n g t h e st u d y dr u g.  
S o m e si d e eff e ct s c a n b e mil d; b ut ot h er s c a n b e l o n g l a sti n g a n d m a y n e v er g o 
a w a y. S o m e m a y b e lif e -t hr e at e ni n g or f at al.  
 
Si n c e t h e eff e ct of t h e st u d y dr u g( s) t a k e n wit h ot h er m e di c ati o n s m a y n ot b e 
k n o w n, it i s i m p ort a nt t h at y o u t ell t h e r e s e ar c h d o ct or a b o ut all pr e s cri pti o n a n d 
n o n -pr e s cri pti o n dr u g s, h er b al pr e p ar ati o n s a n d n utriti o n al s u p pl e m e nt s t h at y o u 
ar e t a ki n g or pl a n ni n g t o t a k e.  T h er e m a y al s o b e s o m e f o o d s t h at y o u s h o ul d 
a v oi d w hil e o n t hi s r e s e ar c h st u d y a n d y o ur r e s e ar c h d o ct or will r e vi e w t hi s 
i nf or m ati o n wit h y o u. 
 
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 9  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
D uri n g t h e r e s e ar c h st u d y, y o u will b e n otifi e d of n e wl y di s c o v er e d si d e eff e ct s or 
si g nifi c a nt fi n di n g s, w hi c h m a y aff e ct y o ur h e alt h or willi n g n e s s t o p arti ci p at e.  
Y o u m a y b e a s k e d t o si g n a n e w c o n s e nt f or m t h at s h o w s t h at y o u h a v e b e e n 
i nf or m e d of n e w i nf or m ati o n r el ati n g t o t hi s r e s e ar c h st u d y. 
 
L e pt o m e ni n g e al c ar ci n o m at o si s c a n b e di a g n o s e d wit h c a n c er i n t h e s pi n al fl ui d 
or b y M RI. I n s o m e v er y r ar e cir c u m st a n c e s, t h e M RI c a n h a v e a b err a nt p o siti v e 
r e s ult s w h e n t h e c yt ol o g y fr o m t h e s pi n al fl ui d i s n e g ati v e a n d c a n l e a d t o a 
diff er e nt di a g n o si s.  Alt h o u g h  t h er e i s a v er y s m all ri s k t h at y o u m a y b e tr e at e d 
wit h o ut l e pt o m e ni n g e al di s e a s e d u e t o t hi s i m a gi n g a b err a n c y, y o ur p h y si ci a n s 
will c ar ef ull y r e vi e w s c a n s a n d e n s u r e t h at t h e M RI s c a n s ar e c o n si st e nt wit h 
l e pt o m e ni n g e al c ar ci n o m at o si s t o tr y t o mi ni mi z e t hi s ri s k of a n a b err a nt r e s ult. 
 
Ri s k s A s s o ci at e d wit h Ni v ol u m a b  
 
M o st c o m m o n si d e eff e ct s ( 5 %-3 0 % c h a n c e of h a p p e ni n g) ar e:  
•  Dr o w si n e s s, f ati g u e  
•  S ki n r e a cti o n s: i n cl u di n g r a s h, it c hi n g, hi v e s, r e d n e s s, a n d dr y s ki n 
•  Di arr h e a, w hi c h i s fr e q u e nt, l o o s e w at er y st o ol s, w hi c h c a n c a u s e  
d e h y dr ati o n a n d m a y r e q uir e h o s pit ali z ati o n a n d tr e at m e nt wit h  
i ntr a v e n o u s fl ui d s. S e v er e a n d pr ol o n g e d di arr h e a c a n b e lif e-t hr e at e ni n g. 
•  N a u s e a  
•  A b d o mi n al p ai n  
•  D e cr e a s e d a p p etit e  
•  L o w n u m b er of r e d bl o o d c ell s  ( a n e mi a) t h at c a n c a u s e tir e d n e s s a n d 
s h ort n e s s of  br e at h. T hi s m a y  r e q uir e a bl o o d tr a n sf u si o n. 
•  F e v er  
•  J oi nt p ai n or stiff n e s s  
 
L e s s c o m m o n si d e eff e ct s  ( b et w e e n 2-4 % c h a n c e of h a p p e ni n g ) ar e:  
•  B o w el i nfl a m m ati o n, w hi c h m a y c a u s e a b d o mi n al p ai n, di arr h e a, a n d f e v er  
•  A b n or m all y hi g h l e v el s of e n z y m e s pr o d u c e d b y t h e li v er , m e a ni n g t h at 
y o ur li v er i s n ot f u n cti o ni n g pr o p erl y a n d c a n c a u s e f ati g u e a n d j a u n di c e 
( y ell o wi n g of t h e s ki n a n d e y e s). Alt h o u g h t hi s i s u s u all y mil d a n d 
r e v er si bl e, t hi s c a n b e s eri o u s or lif e t hr e at e ni n g. 
•  L o s s of c ol or ( pi g m e nt) fr o m ar e a s of s ki n  
•  Dr y m o ut h  
•  V o miti n g  
•  W ei g ht l o s s  
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 1 0  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
•  T h yr oi d gl a n d a b n or m aliti e s m a y c a u s e f ati g u e, w ei g ht g ai n, fl ui d 
r et e nti o n, w ei g ht l o s s, r a pi d h e art b e at, s w e ati n g, n er v o u s n e s s, s e n siti vit y 
t o c ol d, a n d  m e nt al a p at h y. C a n b e s eri o u s or lif e t hr e at e ni n g. M a y r e q uir e 
m e di c al i nt er v e nti o n t o r e s ol v e s y m pt o m s.  
•  Bl o o d c h e mi str y a b n or m aliti e s, i n cl u di n g l o w bl o o d p h o s p h at e, l o w l e v el s 
of m a g n e si u m i n t h e bl o o d w hi c h c a n c a u s e w e a k n e s s a n d m u s cl e 
cr a m pi n g a n d l o w p ot a s si u m l e v el s, w hi c h c a n c a u s e a n a b n or m al h e art 
r at e or a n irr e g ul ar h e art b e at, a n d m a y b e s eri o u s a n d lif e t hr e at e ni n g.  
•  E x c e s s a m o u nt of uri c a ci d i n t h e bl o o d ( g o ut), w hi c h c a n c a u s e p ai n i n 
t h e j oi nt s a s w ell a s d e cr e a s e ki d n e y f u n cti o n.  M a y c a u s e ki d n e y f ail ur e, 
w hi c h m a y b e r e v er si bl e . 
•  L u n g i nfl a m m ati o n: I nfl a m m ati o n of t h e l u n g s, w hi c h c a n c a u s e s h ort n e s s 
of br e at h a n d diffi c ult y br e at hi n g. If s e v er e, t hi s c a n b e lif e t hr e at e ni n g.  
•  C o u g h  
•  Di z zi n e s s  
•  H e a d a c h e  
•  D e cr e a s e d n u m b er of a t y p e of w hit e bl o o d c ell s. T hi s i s a s s o ci at e d wit h 
a n i n cr e a s e d ri s k of i nf e cti o n . 
•  C hill s  
•  M u s cl e s or e n e s s, w e a k n e s s, stiff n e s s, s p a s m s or p ar al y si s . M a y r e q uir e 
m e di c al i nt er v e nti o n t o r e s ol v e s y m pt o m s.  
•  P ai n i n ar m s or l e g s  
•  Ti n gli n g, b ur ni n g, or n u m b n e s s i n h a n d s a n d f e et  
•  S h ort n e s s of br e at h  
•  A b n or m al t a st e  
•  S u d d e n r e d d e ni n g of t h e f a c e a n d/ or n e c k  (fl u s hi n g) 
•  Hi g h or l o w bl o o d pr e s s ur e , w hi c h c a n c a u s e tr o u bl e br e at hi n g a n d ot h er 
i m p air m e nt s  
•  All er gi c r e a cti o n , w hi c h m a y c a u s e a r a s h, hi v e s, a n d/ or diffi c ult y 
br e at hi n g  
•  I n cr e a s e d s e n siti vit y of s ki n t o s u nli g ht 
•  C o n sti p ati o n  
•  Diffi c ult y s w all o wi n g  
•  H e art b ur n , w hi c h c a u s e s c h e st di s c o mf ort 
•  D e cr e a s e d n u m b er of bl o o d c ell s t h at h el p t o cl ot bl o o d ( pl at el et s). T hi s i s 
a s s o ci at e d wit h a n i n cr e a s e d ri s k of bl e e di n g.  
 
 
 
R ar e  (l e s s t h a n 2 % c h a n c e of t hi s h a p p e ni n g): 
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 1 1  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
•  L o w bl o o d o x y g e n l e v el , w hi c h m a y c a u s e s h ort n e s s of br e at h, c o nf u si o n, 
or dr o w si n e s s  
•  A c ut e l u n g i nj ur y or f ail ur e , w hi c h c a n c a u s e s e v er e i s s u e s wit h br e at hi n g 
•  C oll e cti o n of fl ui d ar o u n d t h e l u n g s , w hi c h c a n c a u s e s h ort n e s s of br e at h 
a n d m a y r e q uir e tr e at m e nt  
•  I nfl a m m ati o n of t h e a p p e n di x ( a p p e n di citi s), w hi c h c a u s e s a b d o mi n al p ai n, 
n a u s e a, a n d/ or v o miti n g  
•  I n cr e a s e i n i nfl a m m at or y bl o o d pr ot ei n s ( e. g., li p a s e) w hi c h m a y i n di c at e 
i nfl a m m ati o n of t h e p a n cr e a s, w hi c h c o ul d r e s ult i n a b d o mi n al p ai n a n d 
di s c o mf ort a n d c o ul d r e q uir e h o s pit ali z at i o n a n d i ntr a v e n o u s tr e at m e nt. 
•  A dr e n al gl a n d a b n or m aliti e s d u e t o  a d e cr e a s e d pr o d u cti o n  of st er oi d s b y 
t h e b o d y, w hi c h m a y c a u s e w e a k n e s s, c o nf u si o n, f ati g u e, li stl e s s n e s s, l o w 
bl o o d pr e s s ur e, di z zi n e s s, w ei g ht l o s s, a n d l o s s of  a p p etit e. M a y al s o 
c a u s e a b d o mi n al cr a m p s, n a u s e a, v o miti n g a n d  di arr h e a a n d c h a n g e s i n 
el e ctr ol yt e s ( b o d y s alt s). S y m pt o m s m a y b e  w or s e at ti m e s of str e s s, s u c h 
a s hi g h f e v er s, i nf e cti o n, s ur g er y or a  s eri o u s a c ci d e nt.  
•  I nfl a m m ati o n of t h e pit uit ar y gl a n d w hi c h m a y c a u s e h e a d a c h e s, c h a n g e s 
i n e y e si g ht, f e w t o n o m e n str u al c y cl e s (f or w o m e n), i n cr e a s e d t hir st, a n d 
i n cr e a s e d fr e q u e n c y of p a s si n g uri ne  
•  C h a n g e s i n vi si o n (i n cl u di n g d e cr e a s e d or bl urr y vi si o n), i nfl a m m ati o n of 
n er v e i n t h e b a c k of t h e e y e ( o pti c n er v e), or bl e e di n g i nt o t h e e y e, w hi c h 
c a n al s o c a u s e e y e p ai n  
•  Li v er i nfl a m m ati o n or a b n or m all y hi g h l e v el s of e n z y m e s pr o d u c e d b y t h e 
li v er w hi c h c o ul d b e c o m e s e v er e a n d c a u s e n a u s e a a n d  v o miti n g, f e v er 
a n d r a pi d h e art r at e. T hi s c o ul d r e q uir e h o s pit ali z ati o n a n d  m a y b e lif e 
t hre at e ni n g.  
•  Ki d n e y f ail ur e w hi c h i s w h e n b ot h of y o ur ki d n e y s f ail a n d y o ur b o d y h ol d s  
fl ui d w hi c h c a n b e s eri o u s or lif e t hr e at e ni n g. Y o ur bl o o d pr e s s ur e ri s e s 
a n d h ar mf ul w a st e s b uil d u p i n y o ur b o d y. Y o u m a y e x p eri e n c e f ati g u e,  
n a u s e a, a n d l o s s of a p p etit e. W h e n t hi s h a p p e n s, y o u n e e d tr e at m e nt t o  
r e pl a c e t h e w or k of y o ur f ail e d ki d n e y s s u c h a s di al y si s.  
•  A b n or m al bl o o d c ell pr o d u cti o n w hi c h r e s ult s i n a si g nifi c a nt d e cr e a s e i n 
r e d bl o o d c ell s ( w hi c h c arr y o x y g e n t o ti s s u e s), w hit e bl o o d c ell ( w hi c h 
fi g ht i nf e cti o n s), a n d pl at el et s ( w hi c h h el p i n bl o o d cl otti n g) 
•  I nfl a m m ati o n of t h e m o ut h a n d li ni n g of t h e di g e sti v e tr a ct, w hi c h c a n l e a d 
t o diffi c ulti e s wit h e ati n g a n d di g e sti n g 
•  S w elli n g of h a n d s, f a c e, ar m s or l e g s  
•  I nfl a m m ati o n of t h e p a n cr e a s c a u si ng p ai n i n t h e u p p er a b d o m e n. T hi s 
c o ul d b e c o m e s e v er e a n d c a u s e n a u s e a a n d v o miti n g, f e v er a n d r a pi d 
h e art r at e. T hi s c o ul d r e q uir e h o s pit ali z ati o n a n d m a y b e lif e t hr e at e ni n g.  
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 1 2  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
•  B a c k p ai n  
•  A ut oi m m u n e di s or d er s, i n cl u di n g G uill ai n -B arr e s y n dr o m e ( a s s o ci at e d  
w it h pr o gr e s si v e m u s cl e w e a k n e s s or p ar al y si s): A di s or d er i n w hi c h t h e 
b o d y’ s i m m u n e s y st e m att a c k s p art of t h e p eri p h er al n er v o u s s y st e m.  
S y m pt o m s of t hi s di s or d er i n cl u d e v ar yi n g d e gr e e s of w e a k n e s s or ti n gli n g  
s e n s ati o n s i n t h e l e g s. I n m a n y i n st a n c e s, t h e w e a k n e s s a n d a b n or m al 
s e n s ati o n s s pr e a d t o t h e ar m s a n d u p p er b o d y. T h e s e s y m pt o m s c a n  
i n cr e a s e i n i nt e n sit y u ntil c ert ai n m u s cl e s c a n n ot b e u s e d at all a n d, w h e n 
s e v er e, t h e p arti ci p a nt i s al m o st t ot all y p ar al y z e d. I n t h e s e c a s e s, t h e 
di s or d er  i s lif e t hr e at e ni n g, p ot e nti all y i nt erf eri n g wit h br e at hi n g a n d, at 
ti m e s, wit h bl o o d pr e s s ur e or h e art r at e.  
•  H e art b e at s t h at ar e f a st a n d h ar d ( h e art p al p it ati o n s) 
•  I nfl a m m ati o n of t h e h e art or it s li ni n g or c oll e cti o n of fl ui d ar o u n d t h e h e art 
w hi c h m a y m a nif e s t a s c h e st p ai n t h at v ari e s wit h e a c h br e at h. P ai n oft e n 
i n cr e a s e s w h e n l yi n g d o w n a n d d e cr e a s e s u p o n sitti n g u p. F e v er, c o u g h, 
a n d p al pit ati o n s ar e c o m m o n a s w ell.  
•  C oll e cti o n of fl ui d ar o u n d t h e h e art w h er e t h e h e art i s u n a bl e t o p u m p 
c orr e ctl y d u e t o t h e  e xt er n al pr e s s ur e.  
•  E x c e s s bl o o d s u g ar if s e v er e m a y r e q uir e h o s pit ali z ati o n a n d ur g e nt  
tr e at m e nt ( di a b et e s) 
•  D e h y dr ati o n : If s e v er e it m a y r e q uir e m e di c ati o n, I V fl ui d s a n d p o s si bl y 
h o s pit ali z ati o n.  
•  I nf e cti o n s: i n cl u di n g s e p si s, l u n g i nf e cti o n s, a n d s ki n i nf e cti o n s  
•  D e cr e a s e d m o v e m e nt of t h e i nt e sti n e s (Il e u s) , w hi c h c a n c a u s e a b d o mi n al 
cr a m p s, bl o ati n g a n d c o n sti p ati o n  
•  Di s ori e nt ati o n  
•  I nfl a m m ati o n or l o s s of t h e li ni n g of t h e br ai n ( w hi c h m a y c a u s e a 
h e a d a c h e) a n d s pi n al c or d  w hi c h m a y b e s eri o u s or lif e t h r e at e ni n g a n d 
m a y r e q uir e m e di c al i nt er v e nti o n  
•  Dr u g r e a cti o n wit h r a s h, bl o o d c ell a b n or m aliti e s, e nl ar g e d l y m p h n o d e s,  
a n d i nt er n al or g a n i n v ol v e m e nt (i n cl u di n g li v er, ki d n e y, a n d l u n g); k n o w n  
a s Dr u g R e a cti o n wit h E o si n o p hili a a n d S y st e mi c S y m pt o m s ( D R E S S) 
•  M y a st h e ni a gr a vi s : a n er v e di s e a s e t h at m a y c a u s e j oi nt p ai n, w e a k n e s s 
of e y e,  f a c e, br e at hi n g, a n d s w all o wi n g m u s cl e w hi c h c a n b e c o m e s e v er e 
a n d lif e  t hr e at e ni n g. 
•  A b n or m al br ai n f u n cti o n d u e t o br ai n i nfl a m m ati o n ( e n c e p h aliti s),  
p ot e nti all y lif e -thr e at e ni n g or f at al.  
•  T o xi c e pi d er m al n e cr ol y si s : a s e v er e s ki n a n d st o m a c h li ni n g r e a cti o n t h at 
m a y i n cl u d e r a s h a n d sl o u g hi n g or br e a k d o w n of ti s s u e. T hi s m a y 
m a nif e st a s v ari o u s bli st er s, hi v e s, a n d ot h er l e si o n s i n v ari o u s l o c ati o n s 
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 1 3  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
o n t h e b o d y i n cl u di n g p al m s a n d s ol e s, f a c e & ot h er e xtr e miti e s. T hi s i s 
s eri o u s a n d m a y b e lif e t hr e at e ni n g.  
•  R h a b d o m y ol y si s  i s a br e a k d o w n of m u s cl e fi b er s. It o c c ur s w h e n m u s cl e 
c ell s di e a n d r el e a s e c ell c o nt e nt s i nt o t h e bl o o d str e a m. It c a n c a u s e 
m u s cl e p ai n a n d a n u m b er  of h e alt h pr o bl e m s, i n cl u di n g d a m a g e t o t h e 
ki d n e y s. If s e v er e, t hi s c o ul d b e lif e t hr e at e ni n g.   
•  R ar el y, s u bj e ct s d e v el o p e d r a di ati o n n e cr o si s (t h e d e at h of ti s s u e c a u s e d 
b y r a di ati o n t h er a p y), w hi c h c a n c a u s e n e ur ol o gi c s y m pt o m s.  T h e s e 
c a s e s w er e r e p ort e d i n s u bj e ct s wit h a hi st or y of pri or br ai n r a di ati o n f or 
m et a st ati c m el a n o m a. It i s u n k n o w n w h et h er t hi s w a s d u e t o r a di ati o n 
al o n e or c o m bi n ati o n of r a di ati o n a n d i pili m u m a b. C er e br al ( br ai n) 
r a di ati o n n e cr o si s i s a k n o w n l at e o n s et r a di ati o n-i n d u c e d sid e eff e ct a n d 
i s o n e of t h e m o st fr e q u e nt f or m s of l at e r a di ati o n t o xi cit y f oll o wi n g br ai n 
irr a di ati o n 
 
Ri s k s A s s o ci at e d wit h I pili m u m a b: 
 
M o st c o m m o n si d e eff e ct s (5 % -3 0 % c h a n c e of h a p p e ni n g) : 
•  Di arr h e a, w hi c h i s fr e q u e nt, l o o s e w at er y st o ol s, w hi c h c a n c a u s e 
d e h y dr ati o n a n d m a y r e q uir e h o s pit ali z ati o n a n d tr e at m e nt wit h 
i ntr a v e n o u s fl ui d s. S e v er e a n d pr ol o n g e d di arr h e a c a n b e lif e-t hr e at e ni n g. 
•  I nfl a m m ati o n of t h e c ol o n ( c oliti s), w hi c h c a n c a u s e i s s u e s wit h t h e 
di g e sti v e tr a ct  
•  A b n or m all y hi g h l e v el s of e n z y m e s pr o d u c e d b y t h e li v er , m e a ni n g t h at 
y o ur li v er i s n ot f u n cti o ni n g pr o p erl y a n d c a n c a u s e f ati g u e, a n d j a u n di c e 
( y ell o wi n g of t h e s ki n a n d e y e s). Alt h o u g h t hi s i s u s u all y mil d a n d 
r e v er si bl e, t hi s c a n b e s eri o u s or lif e t hr e at e ni n g 
•  F ati g u e  
•  S ki n It c h i n e s s 
•  S ki n R a s h  
•  N a u s e a  
•  F e v er  
•  D e cr e a s e d A p p etit e  
•  V o miti n g  
•  A b d o mi n al P ai n  
•  H e a d a c h e  
•  C o n sti p ati o n  
•  A dr e n al Gl a n d A b n or m aliti e s, o c c ur s w h e n t h er e i s d e cr e a s e d pr o d u cti o n 
of st er oi d s b y t h e b o d y. T hi s m a y c a u s e w e a k n e s s, c o nf u si o n, f ati g u e, 
li stl e s s n e s s, l o w bl oo d pr e s s ur e, di z zi n e s s, w ei g ht l o s s, a n d l o s s of 
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 1 4  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
a p p etit e. M a y al s o c a u s e a b d o mi n al cr a m p s, n a u s e a, v o miti n g a n d 
di arr h e a a n d c h a n g e s i n el e ctr ol yt e s ( b o d y s alt s). S y m pt o m s m a y b e 
w or s e at ti m e s of str e s s, s u c h a s hi g h f e v er s, i nf e cti o n, s ur g er y or a 
s eri o u s a c ci d e nt.  
•  I nfl a m m ati o n of t h e pit uit ar y gl a n d w hi c h m a y c a u s e h e a d a c h e s, c h a n g e 
i n e y e si g ht, f e w t o n o m e n str u al c y cl e (f or w o m e n), i n cr e a s e d t hir st, a n d 
i n cr e a s e d fr e q u e n c y of p a s si n g uri n e  
 
L e s s c o m m o n si d e eff e ct s  ( b et w e e n 2-5 % c h a n c e of h a p p e ni n g):  
•  C hill s  
•  W e a k n e s s  
•  M u s cl e P ai n  
•  R e d n e s s of S ki n  
 
R ar e  (l e s s t h a n 2 % c h a n c e of t hi s h a p p e ni n g b ut p ot e nti all y s eri o u s): 
•  All er gi c r e a cti o n s , w hi c h c a n i n cl u d e r a s h, hi v e s, f e v er, a n d/ or diffi c ult y 
br e at hi n g.  
•  I nfl a m m ati o n of t h e li v er w hi c h c o ul d b e c o m e s e v er e a n d c a u s e n a u s e a 
a n d v o miti n g, f e v er a n d r a pi d h e art r at e.  
•  L o w n u m b er of r e d bl o o d c ell s ( a n e mi a) t h at c a n c a u s e tir e d n e s s a n d 
s h ort n e s s of br e at h. T hi s m a y r e q uir e a bl o o d tr a n sf u si o n.  
•  L o s s of c ol or ( pi g m e nt) fr o m ar e a s of s ki n  
•  P eri p h er al n e ur o p at h y ( w e a k n e s s, n u m b n e s s, a n d p ai n fr o m n er v e 
d a m a g e, u s u all y i n t h e h a n d s a n d f e et)  
•  I nfl a m m ati o n of t h e ki d n e y s, w hi c h m a y c a u s e y o u t o p a s s l e s s uri n e, 
h a v e cl o u d y uri n e, h a v e bl o o d  i n y o ur uri n e, h a v e s w elli n g a n d l o w er b a c k 
p ai n.  
•  M y a st h e ni a gr a vi s : a n er v e di s e a s e t h at m a y c a u s e j oi nt p ai n, w e a k n e s s 
of e y e, f a c e, br e at hi n g, a n d s w all o wi n g m u s cl e w hi c h c a n b e c o m e s e v er e 
a n d lif e t hr e at e ni n g.  
•  A s eri o u s c o n diti o n t h at o c c ur s i n r e s p o n s e t o a n i nf e cti o n t h at c a u s e s 
wi d e s pr e a d i nfl a m m ati o n, r e s ulti n g i n p o or bl o o d s u p pl y t o vit al or g a n s  
( s e p si s). S y m pt o m s m a y i n cl u d e a f a st h e art r at e, f e v er, c o nf u si o n a n d 
r a pi d br e at hi n g. S e p si s c a n r a pi dl y l e a d t o a lif e t hr e at e ni n g cli ni c al 
d et eri or ati o n), l u n g i nf e cti o n s, a n d s ki n i nf e cti o n s  
•  B o w el p erf or ati o n ( a h ol e i n t h e i nt e sti n e s) t h at c o ul d r e s ult i n a s eri o u s, 
lif e-t hr e at e ni n g i nf e cti o n t h at m a y r e q uir e s ur g er y. T hi s ma y o c c ur at 
hi g h er r at e s if b o w el m et a st a s e s ar e pr e s e nt.  
•  Ul c er s of t h e l ar g e i nt e sti n e s. T hi s m a y c a u s e a b d o mi n al p ai n, cr a m p s, 
a n d l o o s e di s c h a r g e s of p u s, bl o o d, a n d m u c o u s fr o m t h e b o w el. 
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 1 5  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
•  B li st eri n g a n d p e eli n g of t h e t o p l a y er of s ki n r e s e m bli n g t h at of a s e v er e 
b ur n h a s o c c urr e d  ( e pi d er m al n e cr ol y si s). T hi s c o n diti o n c a n b e lif e 
t hr e at e ni n g. 
•  E y e pr o bl e m s, i n cl u di n g i nfl a m m ati o n of v ari o u s p ar t s of t h e e y e a n d 
c h a n g e s i n t h e c ol or of t h e e y e. T h e s e c o n diti o n s m a y i nt erf er e wit h 
vi si o n, a n d c a u s e d o u bl e vi si o n, bl urr y vi si o n, e y e p ai n, a n d/ or bli n d n e s s if 
u ntr e at e d.  
•  T h yr oi d gl a n d a b n or m aliti e s m a y c a u s e f ati g u e, w ei g ht g ai n, fl ui d 
r et e nti o n, w eig ht l o s s, r a pi d h e art b e at, s w e ati n g, n er v o u s n e s s, s e n siti vit y 
t o c ol d, a n d  m e nt al a p at h y.  
•  A ut oi m m u n e di s or d er s, i n cl u di n g G uill ai n -B arr e s y n dr o m e ( a s s o ci at e d 
wit h pr o gr e s si v e m u s cl e w e a k n e s s o r p ar al y si s): A di s or d er i n w hi c h t h e 
b o d y’ s i m m u n e s y st e m att a c k s p art of t h e p eri p h er al n er v o u s s y st e m.  
S y m pt o m s of t hi s di s or d er i n cl u d e v ar yi n g d e gr e e s of w e a k n e s s or ti n gli n g 
s e n s ati o n s i n t h e l e g s. I n m a n y i n st a n c e s, t h e w e a k n e s s a n d a b n or m al 
s e n s ati o n s s pr e a d t o t h e ar m s a n d u p p er b o d y. T h e s e s y m pt o m s c a n 
in cr e a s e i n i nt e n sit y u ntil c ert ai n m u s cl e s c a n n ot b e u s e d at all a n d, w h e n 
s e v er e, t h e p arti ci p a nt i s al m o st t ot all y p ar al y z e d. I n t h e s e c a s e s, t h e 
di s or d er i s lif e t hr e at e ni n g, p ot e nti all y i nt erf eri n g wit h br e at hi n g a n d, at 
ti m e s, wit h bl o o d pr e s s ur e or he art r at e . 
•  M ulti or g a n s y st e m pr o bl e m s wit h li v er, ki d n e y, h e art, m u s cl e s, bl o o d 
v e s s el s, a n d l u n g  ( m a n y of t h e i s s u e s li st e d a b o v e o c c urri n g at o n c e) 
•  I nf e cti o n of t h e c o n n e cti v e ti s s u e s urr o u n di n g t h e br ai n a n d s pi n al c or d 
t h at o c c ur s w h e n t h e w hit e bl o o d c ell c o u nt i s l o w ( m e ni n giti s ). T hi s c a n 
c a u s e h e a d a c h e, n a u s e a a n d v o miti n g, stiff n e c k, a n d s e n siti vit y of y o ur 
e y e s t o li g ht.  
•  D e at h of h e alt h y ti s s u e c a u s e d b y r a di ati o n t h er a p y (r a di ati o n n e cr o si s)  
•  Dr u g r e a cti o n wit h r a s h, bl o o d c ell a b n or m aliti e s, e n l ar g e d l y m p h n o d e s, 
a n d i nt er n al or g a n i n v ol v e m e nt (i n cl u di n g li v er, ki d n e y, a n d l u n g); k n o w n 
a s Dr u g R e a cti o n wit h E o si n o p hili a a n d S y st e mi c S y m pt o m s ( D R E S S)  
•  A s u d d e n r a pi d d e at h of c a n c er c ell s i n r e s p o n s e t o tr e at m e nt, w hi c h 
c a u s e s t h e c a n c er c ell s t o s pill t h eir i n n er c o nt e nt s w hi c h t h e n a c c u m ul at e 
f a st er t h a n t h e y c a n b e eli mi n at e d. T h e d e bri s fr o m t h e c a n c er c ell s c a n 
c h a n g e t h e b al a n c e of t h e c h e mi str y of t h e b o d y, w hi c h c a n b e d a n g er o u s.  
T hi s m a y c a u s e s e v er e n a u s e a a n d v o miti n g, s h ort n e s s of br e at h,  a n d  
irr e g ul ar h e art b e at. 
 
R e pr o d u cti v e Ri s k s :  
T h e dr u g s u s e d i n t hi s r e s e ar c h st u d y m a y aff e ct a f et u s. W o m e n of c hil d b e ari n g 
p ot e nti al s h o ul d a v oi d pr e g n a n c y f or t h e d ur ati o n of tr e at m e nt a n d f or u p t o 2 3 
w e e k s aft er t h e l a st d o s e.    M al e s u bj e ct s s h o ul d a v oi d i m pr e g n ati n g a p art n er f or 
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 1 6  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
u p t o 3 1 w e e k s aft er t h e l a st d o s e.  W e c a n pr o vi d e c o u n s eli n g a b o ut pr e v e nti n g 
pr e g n a n c y f or eit h er m al e or f e m al e st u d y p arti ci p a nt s. L et y o ur d o ct or k n o w 
i m m e di at el y if y o u b e c o m e pr e g n a nt or fi n d o ut t h at y o u ar e g oi n g t o b e t h e 
f at h er of a c hil d. 
 
I n t h e e v e nt t h at y o ur p art n er b e c o m e s pr e g n a nt, it m a y b e criti c al t o s h ar e 
i nf or m ati o n r e g ar di n g y o ur p arti ci p ati o n i n t hi s r e s e ar c h st u d y wit h t h at p er s o n .  
Y o ur r e s e ar c h d o ct or s h o ul d al s o b e t ol d if t hi s h a p p e n s. T h e st u d y s p o n s or m a y 
w a nt t o c oll e ct d at a o n y o ur p art n er’s pr e g n a n c y.   
 
N o n -P h y si c al Ri s k s :  
B e c a u s e of si d e eff e ct s or t h e ti m e r e q uir e d f or t e st s a n d cli ni c vi sit s w hil e y o u 
ar e o n t hi s r e s e ar c h st u d y, y o u m a y b e u n a bl e t o k e e p u p wit h y o ur n or m al d ail y 
a cti viti e s.  
 
G.  W H A T A R E T H E B E N E FI T S  O F T H E R E S E A R C H S T U D Y ?  
 
T a ki n g p art i n t hi s st u d y m a y or m a y n ot h el p y o u b e c a u s e r e s e ar c h er s d o n ot 
k n o w h o w t hi s c o m bi n ati o n of dr u g s will c o m p ar e t o t h e u s u al a p pr o a c h. T hi s 
st u d y m a y h el p r e s e ar c h er s l e ar n t hi n g s t h at m a y h el p p e o pl e i n t h e f ut ur e.  
 
H.  C A N I S T O P B EI N G I N T H E R E S E A R C H S T U D Y A N D  W H A T A R E M Y RI G H T S ?  
 
Y o u h a v e t h e ri g ht t o c h o o s e n ot t o si g n t hi s f or m. If y o u d e ci d e n ot t o si g n t hi s 
f or m, y o u c a n n ot p arti ci p at e i n t hi s r e s e ar c h st u d y.  
 
Y o u c a n st o p b ei n g i n t h e r e s e ar c h st u d y at a n y ti m e. T ell t h e r e s e ar c h d o ct or if 
y o u ar e t hi n ki n g a b o ut st o p pi n g or d eci d e t o st o p. H e or s h e will t ell y o u h o w t o 
st o p. L e a vi n g t h e r e s e ar c h st u d y will n ot aff e ct y o ur m e di c al c ar e  o ut si d e of t h e 
r e s e ar c h st u d y.   
 
If y o u c h o o s e n ot t o p arti ci p at e, ar e n ot eli gi bl e t o p arti ci p at e, or wit h dr a w fro m 
t hi s r e s e ar c h st u d y, t hi s will n ot aff e ct y o ur pr e s e nt or f ut ur e c ar e a n d will n ot 
c a u s e a n y p e n alt y or l o s s of b e n efit s t o w hi c h y o u ar e ot h er wi s e e ntitl e d.  
 
It i s i m p ort a nt t o t ell t h e r e s e ar c h d o ct or if y o u ar e t hi n ki n g a b o ut st o p pi n g s o 
y o ur r e s e ar c h d o ct or c a n e v al u at e t h e ri s k s fr o m st o p pi n g t h e st u d y dr u g s. I n 
s o m e c a s e s, t h e a br u pt st o p pi n g of a dr u g c a n h a v e ri s k s i n it s elf. A n ot h er 
r e a s o n t o t ell y o ur r e s e ar c h d o ct or t h at y o u ar e t hi n ki n g a b o ut st o p pi n g i s t o 
di s c u s s w h at f oll o w -u p c ar e a n d t e sti n g c o ul d b e m o st h el pf ul f or y o u.  
 
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 1 7  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
I. W I L L I B E P AI D T O T A K E P A R T I N T HI S R E S E A R C H S T U D Y ?  
 
Y o u w ill n ot b e p ai d t o p arti ci p at e in t hi s st u d y. W e m a y u s e y o ur s a m pl e s a n d 
i nf or m ati o n t o d e v el o p a n e w pr o d u ct or m e di c al t e st t o b e s ol d. T h e s p o n s or a n d 
h o s pit al m a y b e n efit if t hi s h a p p e n s. T h er e ar e n o pl a n s t o p a y y o u if y o ur 
s a m pl e s ar e u s e d f or t hi s p ur p o s e.  
 
J.  W H A T A R E T H E C O S T S ?  
 
T a ki n g p art i n t hi s r e s e ar c h st u d y mi g ht l e a d t o a d d e d c o st s t o y o u or y o ur 
i n s ur a n c e c o m p a n y. 
 
Y o u will n ot b e c h ar g e d f or eit h er of t h e st u d y dr u g s. Y o u or y o ur i n s ur a n c e 
c o m p a n y will b e c h ar g e d f or p orti o n s of y o ur c ar e d uri n g t hi s r e s e ar c h st u d y t h at 
ar e c o n si d er e d st a n d ar d c ar e. Y o u m a y b e r e s p o n si bl e f or c o -p a y m e nt s a n d 
d e d u cti bl e s t h at  ar e t y pi c al f or y o ur i n s ur a n c e c o v er a g e.  
 
If y o u h a v e q u e sti o n s a b o ut y o ur i n s ur a n c e c o v er a g e, or t h e it e m s y o u mi g ht b e 
r e q uir e d t o p a y f or, pl e a s e c all fi n a n ci al s er vi c e s f or i nf or m ati o n. T h e c o nt a ct 
i nf or m ati o n f or fi n a n ci al s er vi c e s i s: 
 
•  Bri g h a m a n d W o m e n’ s H o s pit al: ( 6 1 7) 7 3 2 -5 5 2 4 or ( 6 1 7) 7 3 2 -7 4 8 5  
•  D a n a -F ar b er C a n c er I n stit ut e: ( 6 1 7) 6 3 2 -3 4 5 5  
•  M a s s a c h u s ett s G e n er al H o s pit al: ( 6 1 7) 7 2 6 -2 1 9 1  
 
T h e N ati o n al C a n c er I n stit ut e pr o vi d e s a n  o nli n e r e s o ur c e t o h el p p e o pl e 
p arti ci p ati n g i n c a n c er cli ni c al tri al s u n d er st a n d w hi c h s er vi c e s t h eir i n s ur a n c e 
c o m p a n y i s r e q uir e d b y l a w t o p a y. T hi s c a n b e f o u n d at t h e w e b sit e b el o w or 
c a n b e pr o vi d e d b y t h e st u d y t e a m:  
 
w w w. c a n c er. g o v or 1 -8 0 0 -4 -C A N C E R ( 1 -8 0 0 -4 2 2 -6 2 3 7)  
 
K.  W H A T H A P P E N S I F I A M I N J U R E D O R SI C K B E C A U S E I T O O K P A R T I N T HI S 
R E S E A R C H S T U D Y ?  
 
If y o u t hi n k y o u h a v e b e e n i nj ur e d a s a r e s ult of t a ki n g p art i n t hi s r e s e ar c h st u d y, 
t ell t h e p er s o n i n c h ar g e of t hi s r e s e ar c h st u d y a s s o on a s p o s si bl e. T h e r e s e ar c h 
d o ct or’ s n a m e a n d p h o n e n u m b er ar e li st e d i n t hi s c o n s e nt f or m.  
 
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 1 8  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
T h e tr e ati n g h o s pit al will off er y o u t h e c ar e n e e d e d t o tr e at i nj uri e s dir e ctl y 
r e s ulti n g fr o m t a ki n g p art i n t hi s r e s e ar c h. T h e tr e ati n g h o s pit al m a y bill y o ur 
i n s ur a n c e c o m p a n y or ot h er t hir d p arti e s, if a p pr o pri at e, f or t h e c o st s of t h e c ar e 
y o u g et f or t h e i nj ur y, b ut y o u m a y al s o b e r e s p o n si bl e f or s o m e of t h e m.  
 
T h er e ar e n o pl a n s f or a n y of t h e s p o n s or s of t hi s st u d y t o p a y y o u or gi v e y o u 
ot h e r c o m p e n s ati on f or t h e i nj ur y. Y o u d o n ot gi v e u p y o ur l e g al ri g ht s b y si g ni n g 
t hi s f or m. 
 
L.  W H A T A B O U T C O N FI D E N TI A LI T Y ?  
 
W e will t a k e m e a s ur e s t o pr ot e ct t h e pri v a c y a n d s e c urit y of all y o ur p er s o n al 
i nf or m ati o n, b ut w e c a n n ot g u ar a nt e e c o m pl et e c o nfi d e nti alit y of st u d y d at a.  
 
M e di c al i nf or m ati o n cr e at e d b y t hi s r e s e ar c h st u d y m a y b e c o m e p art of y o ur 
h o s pit al m e di c al r e c or d  a n d m a y b e f or w ar d e d t o y o ur pri m ar y d o ct or . 
I nf or m ati o n t h at d o e s n ot b e c o m e p art of y o ur m e di c al r e c or d will b e st or e d i n 
y o ur st u d y fil e. It m a y al s o b e c o m e p art of a D F/ H C C r e s e ar c h d at a b a s e. T h e 
r e s ult s of t hi s r e s e ar c h st u d y m a y b e p u bli s h e d. Y o u will n ot b e i d e ntifi e d i n 
p u bli c ati o n s wit h o ut y o ur p er mi s si o n.  
 
A d e s cri pti o n of t hi s cli ni c al tri al will b e a v ail a bl e o n htt p:// w w w. Cli ni c al Tri al s. g o v , 
a s r e q uir e d b y U. S. L a w. T hi s W e b sit e will n ot i n cl u d e i nf or m ati o n t h at c a n 
i d e ntif y y o u. At m o st, t h e W e b sit e will i n cl u d e a s u m m ar y of t h e r e s ult s. Y o u c a n 
s e ar c h t hi s W e b sit e at a n y ti m e.  
 
M.  W H O M D O I C O N T A C T I F I H A V E Q U E S TI O N S A B O U T T H E R E S E A R C H S T U D Y ?  
 
If y o u h a v e q u e sti o n s a b o ut t h e st u d y, pl e a s e c o nt a ct t h e r e s e ar c h d o ct or or 
st u d y st aff a s li st e d b el o w:  
 
M a s s a c h u s ett s G e n er al H o s pit al  
•  Pri s cill a Br a sti a n o s, M D: ( 6 1 7) 7 2 4 -8 7 7 0  
 
D a n a F ar b er C a n c er I n stit ut e  
•  E u d o ci a K al e m Q u a nt L e e, M D, M P H: ( 6 1 7) 6 3 2 -2 1 6 6  
 
2 4 -h o ur c o nt a ct: Pl e a s e c all M G H at ( 6 1 7) 7 2 4 -4 0 0 0 a n d a s k t h at t h e st u d y 
d o ct or b e p a g e d.  
 
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 1 9  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
F or q u e sti o n s a b o ut y o ur ri g ht s a s a r e s e ar c h p arti ci p a nt, pl e a s e c o nt a ct a 
r e pr e s e nt ati v e of t h e Offi c e f or H u m a n R e s e ar c h St u di e s at D F CI ( 6 1 7) 6 3 2 -
3 0 2 9. T hi s c a n i n cl u d e q u e sti o n s a b o ut y o ur p arti ci p ati o n i n t h e st u d y, c o n c er n s 
a b o ut t h e st u d y, a r e s e ar c h r el at e d i nj ur y, or if y o u f e el/f elt u n d er pr e s s ur e t o 
e nr oll i n t hi s r e s e ar c h st u d y or t o c o nti n u e t o p arti ci p at e i n t hi s r e s e ar c h st u d y.  
 
N.  P RI V A C Y O F P R O T E C T E D H E A L T H I N F O R M A TI O N  
 
F e d er al l a w r e q uir e s D a n a -F ar b er/ H ar v ar d C a n c er C e nt er ( D F/ H C C) a n d it s 
affili at e d r e s e ar c h d o ct or s, h e alt h c ar e pr o vi d er s, a n d p h y si ci a n n et w or k t o 
pr ot e ct t h e pri v a c y of i nf or m ati o n t h at i d e ntifi e s y o u  a n d r el at e s t o y o ur p a st, 
pr e s e nt, a n d f ut ur e p h y si c al a n d m e nt al h e alt h c o n diti o n s (“ pr ot e ct e d h e alt h 
i nf or m ati o n”). If y o u e nr oll i n t hi s r e s e ar c h st u d y, y o ur “ pr ot e ct e d h e alt h 
i nf or m ati o n” will b e u s e d a n d s h ar e d wit h ot h er s a s e x pl ai n e d b el o w. 
 
1.  W h at p r ot e ct e d h e alt h i nf or m ati o n a b o ut m e will b e u s e d or s h ar e d wit h 
ot h er s d uri n g t hi s r e s e ar c h ?  
 
•  E xi sti n g m e di c al r e c or d s , i n cl u di n g m e nt al h e alt h r e c or d s. 
•  N e w h e alt h i nf or m ati o n cr e at e d fr o m st u d y -r el at e d t e st s, pr o c e d ur e s, 
vi sit s, a n d/ or q u e sti o n n air e s  
 
2.  W h y will pr ot e ct e d i nf or m ati o n a b o ut m e b e u s e d or s h ar e d wit h ot h er s ?  
 
T h e m ai n r e a s o n s i n cl u d e t h e f oll o wi n g:  
•  T o c o n d u ct a n d o v er s e e t h e r e s e ar c h d e s cri b e d e arli er i n t hi s f or m  
•  T o e n s ur e t h e r e s e ar c h m e et s l e g al, i n stit uti o n al, a n d a c cr e dit ati o n 
r e q uir e me nt s  
•  T o c o n d u ct p u bli c h e alt h a cti viti e s (i n cl u di n g r e p orti n g of a d v er s e e v e nt s 
or sit u ati o n s w h er e y o u or ot h er s m a y b e at ri s k of h ar m)  
•  T o pr o vi d e t h e st u d y s p o n s or wit h i nf or m ati o n ari si n g fr o m a n a d v er s e 
e v e nt or ot h er e v e nt t h at r el at e s t o t h e s af et y  or t o xi cit y of t h e dr u g f or t h e 
p ur p o s e of t hi s or ot h er r e s e ar c h r el ati n g t h e st u d y dr u g a n d it s u s e i n 
c a n c er  
•  Ot h er r e a s o n s m a y i n cl u d e f or tr e at m e nt, p a y m e nt, or h e alt h c ar e 
o p er ati o n s. F or e x a m pl e, s o m e m e di c al i nf or m ati o n pr o d u c e d b y t hi s 
r e s e ar c h stu d y m a y b e c o m e p art of y o ur h o s pit al m e di c al r e c or d b e c a u s e 
t h e i nf or m ati o n m a y b e n e c e s s ar y f or y o ur m e di c al c ar e. ( Y o u will al s o b e 
gi v e n a n oti c e f or u s e a n d s h ari n g of pr ot e ct e d h e alt h i nf or m ati o n.)  
 
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 2 0  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
3.  W h o will u s e or s h ar e pr ot e ct e d h e alt h i nf or m ati o n a b o ut m e ?  
 
•  D F/ H C C a n d it s affili at e d r e s e ar c h d o ct or s a n d e ntiti e s p arti ci p ati n g i n t h e 
r e s e ar c h will u s e a n d s h ar e y o ur pr ot e ct e d h e alt h i nf or m ati o n. I n a d diti o n, 
ot h er D F/ H C C offi c e s t h at d e al wit h r e s e ar c h o v er si g ht, billi n g or q u alit y 
a s s ur a n c e will b e  a bl e t o u s e a n d s h ar e y o ur pr ot e ct e d h e alt h i nf or m ati o n.  
 
4.  Wit h w h o m o ut si d e of D F/ H C C  m a y m y pr ot e ct e d h e alt h i nf or m ati o n b e 
s h ar e d ?  
 
W hil e all r e a s o n a bl e eff ort s will b e m a d e t o pr ot e ct t h e c o nfi d e nti alit y of y o ur 
pr ot e ct e d h e alt h i nf or m ati o n, it m a y al s o b e s h ar e d wit h t h e f oll o wi n g e ntiti e s:  
 
•  O ut si d e i n di vi d u al s or e ntiti e s t h at h a v e a n e e d t o a c c e s s t hi s i nf or m ati o n 
t o p erf or m f u n cti o n s r el ati n g t o t h e c o n d u ct of t hi s r e s e ar c h s u c h a s 
a n al y si s b y o ut si d e l a b or at ori e s o n b e h alf of D F/ H C C a n d it s affili a t e s (f or 
e x a m pl e, d at a st or a g e c o m p a ni e s, i n s ur er s, or l e g al a d vi s or s).  
•  T h e s p o n s or  of t h e st u d y, it s s u b c o ntr a ct or s, a n d it s a g e nt( s ): D F/ H C C  
•  T h e f u n d er ( s) of t h e st u d y, it s s u b c o ntr a ct or s, a n d it s a g e nt( s): Bri st ol 
M y er s S q ui b b a n d M el a n o m a R e s e ar c h Alli a n c e  
•  Ot h er r e s e ar c h d o ct or s a n d m e di c al c e nt er s p arti ci p ati n g i n t hi s r e s e ar c h, 
if a p pli c a bl e 
•  F e d er al a n d st at e a g e n ci e s (f or e x a m pl e, t h e D e p art m e nt of H e alt h a n d 
H u m a n S er vi c e s, t h e F o o d a n d Dr u g A d mi ni str ati o n, t h e N ati o n al 
I n stit ut e s of H e alt h, a n d/ or t h e Offi c e f or H u m a n R e s e ar c h Pr ot e cti o n s), or 
ot h er d o m e sti c or f or ei g n g o v er n m e nt b o di e s if r e q uir e d b y l a w a n d/ or 
n e c e s s ar y f or o v er si g ht p ur p o s e s. A q u alifi e d r e pr e s e nt ati v e of t h e F D A 
a n d t h e N ati o n al C a n c er I n stit ut e m a y r e vi e w y o ur m e di c al r e c or d s.  
•  H o s pit al a c cr e diti n g a g e n ci e s  
•  A d at a s af et y m o nit ori n g b o ar d or g a ni z e d t o o v er s e e t hi s r e s e ar c h, if 
a p pli c a bl e  
 
S o m e w h o m a y r e c ei v e y o ur pr ot e ct e d h e alt h i nf or m ati o n m a y n ot h a v e t o 
s ati sf y t h e pri v a c y r ul e s a n d r e q uir e m e nt s. T h e y, i n f a ct, m a y s h ar e y o ur 
i nf or m ati o n wit h ot h er s wit h o ut y o ur p er mi s si o n.  
 
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Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 2 1  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
5.  F or h o w l o n g will pr ot e ct e d h e alt h i nf or m ati o n a b o ut m e b e u s e d or 
s h ar e d wit h ot h er s ?  
 
•  T h er e i s n o s c h e d ul e d d at e at w hi c h y o ur pr ot e ct e d h e alt h i nf or m ati o n t h at 
i s b ei n g u s e d or s h ar e d f or t hi s r e s e ar c h will b e d e str o y e d, b e c a u s e 
r e s e ar c h i s a n o n g oi n g pr o c e s s.   
 
6.  St at e m e nt of pri v a c y ri g ht s:  
 
•  Y o u h a v e t h e ri g ht t o wit h dr a w y o ur p er mi s si o n f or t h e r e s e ar c h d o ct or s 
a n d p arti ci p ati n g D F/ H C C e ntiti e s t o u s e or s h ar e y o ur pr ot e ct e d h e alt h 
i nf or m ati o n. W e will n ot b e a bl e t o wit h dr a w all t h e i nf or m ati o n t h at alr e a d y 
h a s b e e n u s e d or s h ar e d wit h ot h er s t o c arr y o ut r el at e d a cti viti e s s u c h a s 
o v er s i g ht, or t h at i s n e e d e d t o e n s ur e q u alit y of t h e st u d y. T o wit h dr a w 
y o ur p er mi s si o n, y o u m u st d o s o i n writi n g b y c o nt a cti n g t h e r e s e ar c h er 
li st e d a b o v e i n t h e s e cti o n: “ W h o m d o I c o nt a ct if I h a v e q u e sti o n s a b o ut 
t h e r e s e ar c h st u d y ?” 
•  Y o u h a v e t h e ri g ht t o  r e q u e st a c c e s s t o y o ur pr ot e ct e d h e alt h i nf or m ati o n 
t h at i s u s e d or s h ar e d d uri n g t hi s r e s e ar c h a n d t h at i s r el at e d t o y o ur 
tr e at m e nt or p a y m e nt f or y o ur tr e at m e nt, b ut y o u m a y a c c e s s t hi s 
i nf or m ati o n o nl y aft er t h e st u d y i s c o m pl et e d. T o r e q u e st t hi s i nfor m ati o n, 
pl e a s e c o nt a ct t h e r e s e ar c h er li st e d a b o v e i n t h e s e cti o n: “ W h o m d o I 
c o nt a ct if I h a v e q u e sti o n s a b o ut t h e r e s e ar c h st u d y ?”  
 
 
 
 
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8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 2 2  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
O.  D O C U M E N T A TI O N O F C O N S E N T  
 
M y si g n at ur e b el o w i n di c at e s : 
•  I h a v e h a d e n o u g h ti m e t o r e a d t h e c o n s e nt a n d t hi n k a b o ut 
p arti ci p ati n g i n t hi s st u d y;  
•  I h a v e h a d all of m y q u e sti o n s a n s w er e d t o m y s ati sf a cti o n; 
•  I a m willi n g t o p arti ci p at e i n t hi s st u d y; 
•  I h a v e b e e n t ol d t h at my p arti ci p ati o n i s v ol u nt ar y a n d I c a n wit h dr a w at 
a n y ti m e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Si g n at ur e of P arti ci p a nt  
 
 
 
D at e  
or L e g all y A ut h ori z e d R e pr e s e nt ati v e   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R el ati o n s hi p of L e g all y A ut h ori z e d R e pr e s e nt ati v e t o P arti ci p a nt   
 
 
 
8/ 4/ 2 0 2 2 1 0: 3 3 a m
8/4/2022 10:33 am


 
Rese arc h C o nse nt F o r m  
                  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 0 1. 0 8. 1 6  
 
P a ge 2 3  of 2 3  
D F CI Pr ot oc ol N u m ber:     1 6 -1 3 6  
A p pr o ve d Date ( D F CI I R B A p pr o val):  
0 3/ 0 7/ 2 0 1 9  
Date P oste d f or Use:  
0 4/ 0 3/ 2 0 1 9  
  
 
 
 
A d ult P arti ci p a nt s  
 
T o b e c o m pl et e d b y p er s o n o bt ai ni n g c o n s e nt:  
 
T h e c o n s e nt di s c u s si o n w a s i niti at e d o n   
 ( d at e). 
 
Si g n at ur e of i n di vi d u al o bt ai ni n g c o n s e nt:  
 
 
Pri nt e d n a m e of a b o v e:   
 
 
D at e:  
 
 
 A c o p y of t hi s si g n e d c o n s e nt f or m will b e gi v e n t o t h e p arti ci p a nt  or l e g all y a ut h ori z e d 
r e pr e s e nt ati v e, or, w h er e t h e p arti ci p a nt  i s a mi n or, t h e p arti ci p a nt ’ s p ar e nt or l e g al g u ar di a n. 
F or A d ul t P arti ci p a nt s  
 1)  T h e p arti ci p a nt i s a n a d ult a n d pr o vi d e d c o n s e nt t o p arti ci p at e.  
 
 1 a)  P arti ci p a nt ( or l e g all y a ut h ori z e d r e pr e s e n t ati v e) i s a n o n-E n gli s h s p e a k er a n d  
 
si g n e d t h e tr a n sl at e d S h ort F or m i n li e u of E n gli s h c o n s e nt d o c u m e nt:  
 
A s s o m e o n e w h o u n d er st a n d s b ot h E n gli s h a n d t h e l a n g u a g e s p o k e n b y t h e p arti ci p a nt, I 
i nt er pr et e d a n d/ or wit n e s s e d, i n t h e p arti ci p a nt’ s l a n g u a g e, t h e r e s e ar c h er’ s pr e s e nt ati o n 
of t h e E n gli s h c o n s e nt f or m.  T h e p arti ci p a nt w a s gi v e n t h e o p p ort u nit y t o a s k q u e sti o n s.  
Si g n at ur e of I nt er pr et er / Wit n e s s:  
 
Pri nt e d N a m e of I nt er pr et er / Wit n e s s:  
 
D at e:  
 
 
 
 1 b)  P arti ci p a nt i s illit er at e  
 
T h e c o n s e nt f or m w a s r e a d t o t h e p arti ci p a nt w h o w a s gi v e n t h e  o p p ort u nit y  
 
t o a s k q u e sti o n s.  
Si g n at ur e of Wit n e s s:  
 
Pri nt e d N a m e of Wit n e s s:  
 
D at e:  
 
 2)  T h e p arti ci p a nt  i s a n a d ult w h o l a c k s c a p a cit y t o pr o vi d e c o n s e nt a n d hi s/ h er l e g all y 
a ut h ori z e d r e pr e s e nt ati v e:  
 2 a) g a v e p er mi s si o n f or t h e a d ult p arti ci p a nt  t o p arti ci p at e  
 2 b) di d n ot gi v e p er mi s si o n f or t h e a d ult p arti ci p a nt  t o p arti ci p at e  
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