Conditions: Melanoma
Keywords: skin DACTINOMYCIN MDX-010 (Ipilimumab) MELPHALAN Isolated Limb Infusion 10-101
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 26
Healthy volunteers: no

Brief summary:
The purpose of this study is to see the effect of adding a systemic study drug, Ipilimumab, to two standard chemotherapy drugs, Melphalan and Dactinomycin. The study drug Ipilimumab is an antibody to a normal protein found in the body, CTLA-4. This protein normally allows the immune system (the body's natural defense system that helps fight infections) uses to quiet an immune response. The study drug works by blocking this protein and allowing the immune system to become more active. This study will investigate the effects, of combining ILI (using two standard drugs to treat melanoma, Melphalan and Dactinomycin), with the study drug, Ipilimumab on advanced Melanoma cancer.

Detailed description:

Arms:
arm 1: This is a single-institution phase II trial with a primary outcome of progression free survival (PFS).

Interventions: intervention 1: Ipilimumab, Melphalan and Dactinomycin
Intervention descriptions: intervention 1: Isolated limb infusion ((ILI) with Melphalan and Dactinomycin- MSKCC operating room. Ipilimumab- IV administration in outpatient chemotherapy clinic. Induction therapy with Ipilimumab will start 1-3 weeks after ILI in the standard dose of 10mg/kg every 3 weeks for a total of 4 doses. Patients will then receive chronic therapy every 3 months. Patients will be followed every 3 months for 2 years.

Protocol document:
Prot_SAP_000.pdf: 
 
 
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
 
 
 
IRB#: 10-101A(7) 
 
 
Phase II Trial Of The Addition Of Ipilimumab (MDX-010) To Isolated Limb Infusion 
(ILI) With Standard Melphalan And Dactinomycin In The Treatment Of Advanced 
Unresectable Melanoma Of The Extremity 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Charlotte E. Ariyan, MD, PhD 
Surgery 
Co-Principal 
Investigator(s)/Department: 
Mary S. Brady, MD, FACS 
Surgery 
Investigator(s)/Department: 
Jedd Wolchok, MD, PhD 
Paul Chapman, MD 
Michael Postow, MD 
Kathy Panageas, DrPH 
Gerald O’Neill Lloyd 
J. Old, MD Robert 
Lefkowitz, MD 
Medicine 
Medicine 
Medicine 
Epidemiology and 
Biostatistics 
Pharmacy 
Sloan-Kettering Institute 
Radiology 
Consenting Professional(s)/Department: Charlotte E. Ariyan, MD, PhD 
Mary S. Brady, MD, FACS 
Jedd Wolchok, MD, PhD 
Michael Postow, MD 
Surgery 
Surgery 
Medicine 
Medicine 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
OneMSK Sites 
Manhattan 
West Harrison 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
 
 
 
 
 
 
Amended: 09/16/15 
 
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Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ......................................................................... 5 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 5 
 
2.1. 
Primary Objective ................................................................................................................ 5 
 
2.2. 
Secondary Objectives ......................................................................................................... 5 
 
3.0 
BACKGROUND AND RATIONALE ....................................................................................... 6 
 
3.1. 
Research Hypothesis .......................................................................................................... 6 
 
3.2. 
Product Development Rationale .......................................................................................... 6 
 
3.2.1. 
CTLA-4 and T Cell Activation ....................................................................................... 6 
 
3.3. 
Summary of Results of Investigational Program .................................................................. 7 
 
3.3.1. 
Pharmacology of Ipilimumab ........................................................................................ 7 
 
3.3.2. 
Pre-Clinical Toxicology of Ipilimumab........................................................................... 8 
 
3.3.3. 
Human Pharmacokinetics of Ipilimumab ...................................................................... 8 
 
3.3.4. 
Clinical Safety with Ipilimumab ..................................................................................... 9 
 
3.3.5. 
Immune-Related Adverse Events (IRAEs) with Ipilimumab .......................................... 9 
 
3.3.6. 
Clinical Efficacy of Ipilimumab .................................................................................... 11 
 
3.4. 
Overall Risk/Benefit Assessment....................................................................................... 12 
 
3.5. 
Study Rationale................................................................................................................. 13 
 
3.5.1. 
Treatment Options for Patients with Melanoma .......................................................... 13 
 
3.5.2. 
Isolated Limb Infusion ................................................................................................ 13 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION.............................................................. 14 
 
4.1 
Design............................................................................................................................... 14 
 
4.2 
Intervention ....................................................................................................................... 14 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................. 16 
 
5.1. 
Investigational Product: IPILIMUMAB................................................................................ 16 
 
5.1.1. 
Identification .................................................................................................................. 17 
 
5.1.2. 
Packaging and Labeling ................................................................................................ 17 
 
5.1.3. 
Storage, Handling, and Dispensing................................................................................ 17 
 
5.1.4. 
Drug Ordering and Accountability .................................................................................. 17 
 
5.1.5. 
Ipilimumab Accountability .............................................................................................. 18 
 
5.1.6. 
Ipilimumab Destruction .................................................................................................. 18 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................. 19 
 
6.1 
Subject Inclusion Criteria................................................................................................... 19 
 
6.2 
Subject Exclusion Criteria ................................................................................................. 20 
 
1) Any other malignancy that requires active treatment. ............................................................... 20 


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6.3. 
Prohibited and Restricted Therapies During the Study ...................................................... 21 
 
6.3.1. 
Prohibited Therapies .................................................................................................. 21 
 
6.3.2. 
Restricted Therapies .................................................................................................. 21 
 
6.3.3. 
Precautions ................................................................................................................ 21 
 
7.0 
RECRUITMENT PLAN ......................................................................................................... 21 
 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 22 
 
9.0 
TREATMENT/INTERVENTION PLAN.................................................................................. 22 
 
9.1. 
Ipilimumab......................................................................................................................... 25 
 
9.1.1. 
Dose Calculations.......................................................................................................... 25 
 
9.1.2. 
Storage, Preparation, and Administration ...................................................................... 26 
 
9.1.3. 
Preparation and Administration Guidelines .................................................................... 26 
 
9.1.4. 
Dose Modifications ........................................................................................................ 27 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 28 
 
10.1. 
Procedures by Visit ........................................................................................................ 28 
 
10.2. 
Study Completion or Early Discontinuation Visit ............................................................ 28 
 
10.3. 
Study Drug Discontinuation ........................................................................................... 29 
 
10.4. 
Study Materials .............................................................................................................. 29 
 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................... 29 
 
11.1. 
Safety Assessments ...................................................................................................... 29 
 
11.2. 
Safety Evaluation........................................................................................................... 29 
 
11.2.1. Safety with Ipilimumab ............................................................................................... 29 
 
11.2.2. Safety related to ILI .................................................................................................... 30 
 
11.3. 
Immune-Related Adverse Events (IRAEs): Definition, Monitoring, and Treatment ......... 31 
 
11.3.1. Treatment of Infusion Reactions Associated with Ipilimumab ..................................... 32 
 
11.3.2. Treatment of Ipilimumab-Related Isolated Drug Fever ............................................... 33 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 33 
 
12.1. 
Efficacy Evaluation ........................................................................................................ 33 
 
12.2. 
Definition of Measurable/Non-Measurable and Index/Non-Index Lesions ...................... 33 
 
12.3. 
Definition of Measurable and Non-Measurable Lesions ................................................. 33 
 
12.4. 
Definition of Index/Non-Index Lesions............................................................................ 34 
 
12.5. 
Definition of Tumor Response Using irRC ..................................................................... 34 
 
12.6. 
Definition of Index Lesions Response Using irRC .......................................................... 34 
 
12.7. 
Definition of Non-Index Lesions Response Using irRC .................................................. 35 
 
12.8. 
Impact of New Lesions on irRC...................................................................................... 35 
 
12.9. 
Definition of Overall Response Using irRC..................................................................... 35 


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12.10. 
Immune-Related Best Overall Response Using irRC (irBOR) ........................................ 36 
 
12.11. 
Response Endpoints...................................................................................................... 36 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 37 
 
13.1. 
Discontinuation of Study Therapy .................................................................................. 37 
 
13.2. 
Permanent Discontinuation for Related Adverse Events ................................................ 37 
 
13.3. 
Exceptions to Permanent Discontinuation...................................................................... 38 
 
14.0 BIOSTATISTICS .................................................................................................................. 38 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES... 39 
 
15.1 Research Participant Registration ..................................................................................... 39 
 
15.2 Randomization .................................................................................................................. 39 
 
This study does not involve randomization................................................................................... 39 
 
16.0 DATA MANAGEMENT ISSUES ........................................................................................... 39 
 
16.1 Quality Assurance ............................................................................................................. 39 
 
16.1.1. Compliance with the Protocol and Protocol Revisions ................................................ 39 
 
16.1.2. Informed Consent....................................................................................................... 40 
 
16.1.3. Records and Reports ................................................................................................. 40 
 
16.1.4. Good Clinical Practice ................................................................................................ 40 
 
16.1.5. Institutional Review Board/Independent Ethics Committee (IRB/IEC)......................... 41 
 
16.1.6. Records Retention ..................................................................................................... 41 
 
16.2 Data and Safety Monitoring ............................................................................................... 41 
 
17.0 PROTECTION OF HUMAN SUBJECTS .............................................................................. 42 
 
17.1 Privacy .............................................................................................................................. 42 
 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................... 42 
 
17.2.1 ....................................................................................................................................... 43 
 
18.0 INFORMED CONSENT PROCEDURES .............................................................................. 48 
 
19.0 REFERENCES ..................................................................................................................... 49 
 
20.0 APPENDICES ...................................................................................................................... 50 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
 
 
 
Research 
Hypothesis: 
The addition of systemic Ipilimumab to regional therapy in patients with 
Stage IIIB, IIIC or Stage IV Melanoma will improve progression free 
survival.  The hypothesis is that the cell death occurring with regional 
chemotherapy can be a priming event for the immune system. 
Systemic administration of Ipilimumab may then augment the immune 
response and may delay disease progression. 
Study Schema: 
Drugs / Doses / 
Length of 
Treatment) 
Patients with Stage IIIB, IIIC or IV melanoma eligible for an isolated 
limb infusion (ILI), will be considered for the trial in which they will 
receive additional systemic treatment with Ipilimumab. Induction 
therapy with Ipilimumab will start 1-3 weeks after ILI in the standard 
dose of 10mg/kg every 3 weeks for a total of 4 doses.  Patients will 
then receive chronic therapy every 3 months.  Patients will be followed 
every 3 months for 2 years, with PFS measured by CT Scan and 
physical exam at one year. 
Study 
Objectives: 
Primary: 
Secondary: 
The primary objective is to determine progression free survival (PFS), 
over historical controls at one year. 
The secondary objectives are: 
1)  To determine the safety of additional Ipilimumab. 
2)  To determine response rates and evaluate the distribution of 
PFS (within the affected limb or systemically) with combination 
therapy. 
3)  To define the immunologic events and signatures at the tumor 
site and in the periphery that correspond to response to 
Ipilimumab. 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1. Primary Objective 
The primary objective is to determine progression free survival at one year. 
 
2.2. Secondary Objectives 
The secondary objectives are: 
 
1)  To determine the safety of additional Ipilimumab. 
 
2)  To determine response rates of combination therapy. 
 
3)  To define the immunologic events and signatures at the tumor site and in the periphery that 
corresponds to response to Ipilimumab. 
 
This protocol will investigate the effect of the addition of immunotherapy with Ipilimumab (MDX-010) 
to standard regional chemotherapy in the setting of advanced extremity melanoma (Stage IIIB, IIIC 


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or Stage IV melanoma).  Patients eligible to undergo an isolated limb infusion (ILI) will be offered 
additional systemic treatment with Ipilimumab.   Patients will be treated with systemic Ipilimumab 
after ILI in the standard dose of 10 mg/kg every 3 weeks for a total of 4 doses, followed by 
maintenance therapy every 3 months (+/- 2 weeks) for 2 years.  Patients will be on-study for 2 years. 
The primary objective is to study the safety and efficacy in this patient population with the primary 
efficacy measure defined as progression-free survival at 1 year (48-54 weeks). 
 
 
 
3.0     BACKGROUND AND RATIONALE 
 
3.1.   Research Hypothesis 
 
The addition of systemic Ipilimumab to regional therapy in patients with Stage IIIB, IIIC, or Stage IV 
melanoma will improve progression free survival.   The hypothesis is that the cell death occurring 
with regional chemotherapy can be a priming event for the immune system.  Systemic administration 
of Ipilimumab may then augment this immune response, and delay melanoma progression. 
 
3.2.   Product Development Rationale 
 
3.2.1.  CTLA-4 and T Cell Activation 
 
Figure 1     Mechanism of Action 
 
 
 
Advances in the understanding of the mechanisms that regulate T cell activation have allowed the 
rational design of new strategies for immunotherapy of tumors, including melanoma. It has been 
known for some time that engagement of the T cell antigen receptor by itself is not sufficient for full T 
cell  activation;  a  second  co-stimulatory  signal  is  required  for  induction  of  IL-2  production, 
proliferation and differentiation to effector function of naive T cells. Abundant data now indicate that 
the primary source of this costimulation is mediated by engagement of CD28 on the T cell surface by 
members of the B7 family on the antigen-presenting cell (APC)[1].(See Figure 1.) 
 
Expression of B7 has been shown to be limited to “professional” antigen presenting cells; that is, 
specialized cells of the hematopoietic lineage, including dendritic cells, activated macrophages, and 
activated B cells. It has been suggested that this sharply-defined restriction of B7 expression is a 
fail-safe mechanism for maintenance of peripheral T cell tolerance, insuring that T cell activation can 


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only be stimulated by appropriate APCs.[2] The fact that tumor cells do not express B7 contributes 
to their poor capacity to elicit immune responses.[3, 4] 
 
The demonstration that induction of expression of B7 on many tumor cells by transfection, 
transduction, or other mechanisms can heighten tumor immunogenicity led to great interest in 
pursuing this as an approach to tumor immunotherapy. As demonstrated in vivo in murine tumor 
models, the utility of B7 expression as a vaccination approach is limited by the following factors: (1) 
B7-expressing tumor cell vaccines are only effective when the tumor cells have a high degree of 
inherent immunogenicity; (2) while B7-expressing vaccines have been shown in many cases to be 
effective in inducing protective immune responses, they have demonstrated only limited utility in 
inducing responses to established tumors; and (3) inactivation of tumor cells by radiation has been 
shown to destroy the immuno-enhancing activity of the B7 gene product.[5, 6] 
 
In the past few years it has become apparent that  co-stimulation is even more complex than 
originally thought. After activation, T cells express CTLA-4, a close homologue to CD28. CTLA-4 
binds members of the B7 family with a much higher affinity than CD28[7]. Although there was initially 
some controversy as to the role of CTLA-4 in regulating T cell activation, it has become clear that 
CTLA-4 down-regulates T cell responses[8]. This was initially suggested by the following in vitro 
observations: (1) blockade of CTLA-4/B7 interactions with antibody enhanced T cell responses; 
(2) cross-linking of CTLA-4 with CD3 and CD28 inhibited T cell responses; and (3) administration of 
antibodies to CTLA-4 in vivo enhanced the immune response to peptide antigens or superantigens 
in mice.[9-12] Blocking CTLA-4-B7 interaction while preserving signaling via CD28 resulted in 
enhanced T cell responses in vitro[10] 
 
Perhaps the most convincing demonstration of the down-regulatory role of CTLA-4 came from 
examination of mice with a null mutation[13-15]. CTLA-4 knockout mice appear to have 
spontaneously activated T cells evident at approximately 1 week after birth, followed by rampant 
lymphoproliferation and lymphadenopathy. These mice die at approximately 3 weeks of age, either 
as a result of polyclonal T cell expansion and tissue destruction or as a result of toxic shock resulting 
from lymphokine production by the T cells. Since thymocyte differentiation and selection proceed 
normally in CTLA-4-deficient mice, the rampant T cell expansion that occurs in the mice indicates 
that CTLA-4 plays a critical role in down-regulating T cell responses in the periphery[7]. 
 
3.3.    Summary of Results of Investigational Program 
 
3.3.1.  Pharmacology of Ipilimumab 
 
Ipilimumab is a human immunoglobulin G (IgG1)κ anti-CTLA-4 monoclonal antibody (mAb). In vitro 
studies were performed with ipilimumab to demonstrate that it is specific for CTLA-4, actively inhibits 
CTLA-4 interactions with B7.1 and B7.2, does not show any cross-reactivity with human B7.1, B7.2 
negative cell lines, and stains the appropriate cells without non-specific cross-reactivity in normal 
human tissues, as demonstrated by immunohistochemistry. Ipilimumab does cross-react with CTLA- 
4 in non-human primates including cynomolgus monkeys. 
 
Ipilimumab was originally produced and purified from a hybridoma clone. Subsequently, a 
transfectoma (CHO cell) has been generated that is capable of producing more ipilimumab on a per 
cell basis than the hybridoma. Material from the transfectoma will be utilized in this and future 


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ipilimumab clinical studies. Biochemical, immunologic and in vivo preclinical primate assessments 
demonstrated similarity between hybridoma and transfectoma-derived ipilimumab. 
 
3.3.2.  Pre-Clinical Toxicology of Ipilimumab 
 
Complete information on the pre-clinical toxicology studies can be found in the Ipilimumab 
Investigator Brochure (IB). Non-clinical toxicity assessments included in vitro evaluation for the 
potential of ipilimumab to mediate complement-dependent cellular cytotoxicity (CDCC) or antibody- 
dependent cellular cytotoxicity (ADCC), and toxicology assessments in cynomolgus monkeys alone 
and in the presence of vaccines. 
 
The in vitro studies demonstrated that ipilimumab did not mediate CDCC of PHA- or (CD)3-activated 
human T cells. However, low to moderate ADCC activity was noted at concentrations up to 50 
ug/mL. These data are consistent with the requirement of high levels of antigen expression on the 
surface of target cells for efficient ADCC or CDCC. Since ipilimumab is a human IgG1, an isotype 
generally capable of mediating CDCC and ADCC, the lack of these activities is likely due to a very 
low expression of CTLA-4 on activated T cells. Therefore, these data suggest that ipilimumab 
treatment would not result in depletion of activated T cells in- vivo. Indeed, no depletion of T cells or 
T cell subsets were noted in toxicology studies in cynomolgus monkeys. 
 
No mortality or signs of toxicity were observed in three independent 14-day intravenous toxicology 
studies in cynomolgus monkeys at multiple doses up to 30 mg/kg/dose. Furthermore, ipilimumab 
was evaluated in sub chronic and chronic toxicology studies in cynomolgus monkeys with and 
without Hepatitis B (HepB) Vaccine and Melanoma Vaccine. Ipilimumab was well tolerated alone or 
in combination in all studies. There were no significant changes in clinical signs, body weight values, 
clinical pathology values or T cell activation markers. In addition, there were no significant 
histopathology changes in the stomach or colon. 
 
3.3.3.  Human Pharmacokinetics of Ipilimumab 
 
Pharmacokinetic (PK) profiles for ipilimumab have been analyzed. The primary objective of Protocol 
MDX010-015 was to determine the safety and PK profile of single and multiple doses of ipilimumab 
derived from a transfectoma or hybridoma cell line. Mean plasma concentrations of ipilimumab 
administered at doses of 3 mg/kg (hybridoma-derived drug product); 2.8 mg/kg, 5 mg/kg, 7.5 mg/kg, 
10 mg/kg, 15 mg/kg, and 20 mg/kg (transfectoma-derived drug product) demonstrated approximate 
dose proportionality. Equimolar doses of hybridoma-derived and transfectoma-derived drug product 
had comparable PK profiles. The range of mean volume of distribution at steady state (Vss) across 
cohorts 2.8, 3, 5, 7.5, 10, 15, and 20 mg/kg, was 57.3 to 82.6 mL/kg, indicating drug distribution was 
mostly limited to the intravascular space. The clearance was low (range 0.11 to 0.29 mL/h/kg) and 
reflective of the half-life (range 297 to 414 h), which is consistent with the long terminal disposition 
phase of ipilimumab. There was moderate variability in the PK parameters among subjects, with CV 
of 11% to 48% in AUC(0-21d), 20% to 59% in CL, and 17% to 46% in Vss. 


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3.3.4.  Clinical Safety with Ipilimumab 
 
Ipilimumab immunotherapy is currently under investigation in patients with unresectable advanced 
melanoma (unresectable Stage III or Stage IV) to potentially demonstrate an improvement on a 
large unmet medical need in this population. 
 
Ipilimumab has been administered to approximately 2633 patients with different cancers in 24 
completed or ongoing clinical trials as of 31-Mar-2008 with a dose range between 0.3 mg/kg and 
20 mg/kg. Most experience with ipilimumab exists at the 3 mg/kg and 10 mg/kg dose levels. Patients 
who  received  ipilimumab  at  3 mg/kg  were  treated  in  clinical  studies  conducted  early  in  the 
development  program  and  received  either  a  single  or  multiple  injections.  Intra-patient  dose 
escalation indicated that patients who were unresponsive at the 3 mg/kg dose level may have 
responded to 9 mg/kg. Based on preliminary data on the 10 mg/kg dose level of ipilimumab, the 
ongoing clinical program investigating ipilimumab in metastatic melanoma utilizes the 10 mg/kg dose 
level with the expectation that 10 mg/kg will prove more beneficial than 3 mg/kg.   Most recently, 
treatment with Ipilimumab was demonstrated to improve survival at 3mg/kg in patients with Stage IV 
melanoma[16]. 
 
3.3.4.1. 
Details of Drug-Related Adverse Events 
 
Drug-related adverse events (AEs) were reported in studies with ipilimumab as monotherapy as well 
as in combination studies with vaccines, cytokines or chemotherapy. The AE profile of ipilimumab is 
relatively well characterized, with most drug-related AEs being immune-related adverse events 
(IRAEs), which are considered to be associated with the mechanism of action of ipilimumab. The 
most common IRAEs are colitis and diarrhea, rash, pruritis, deficiencies of endocrine organs 
(pituitary, adrenal or thyroid), hepatitis, and uveitis. Rare complications are bowel perforations (~1%) 
resulting from underlying severe colitis, which have required surgical intervention. 
 
3.3.4.2. 
Drug-Related Serious Adverse Events 
 
Drug-related  Grade 3  or  Grade 4  serious  adverse  events  (SAEs)  include:  rash/desquamation, 
pruritus, uveitis, speech impairment, abdominal pain, diarrhea/colitis, nausea/vomiting, transaminase 
elevation, adrenal insufficiency, panhypopituitarism and atrial fibrillation. Some of these events, such 
as  rash/desquamation,  pruritus,  uveitis,  diarrhea/colitis,  transaminase  elevation,  adrenal 
insufficiency and panhypopituitarism, may represent drug induced IRAEs (see Section 4.3.4). Refer 
to the most recent version of the Ipilimumab Investigator Brochure for the latest update on SAEs. 
 
Among subjects treated with ipilimumab 10 mg/kg, SAEs considered possibly, probably, or definitely 
related to study drug were reported for 26% of subjects (176/675). Drug related SAEs reported in at 
least 1% of the 675 subjects at 10 mg/kg included diarrhea (10%), colitis (7%), vomiting (3%), 
dehydration (3%), autoimmune hepatitis (2%), hypopituitarism (2%), nausea (2%), abdominal pain 
(2%), pyrexia (2%), aspartate aminotransferase increased (1%), alanine aminotransferase increased 
(1%), and fatigue (1%). 
 
3.3.5.  Immune-Related Adverse Events (IRAEs) with Ipilimumab 
 
Many of the adverse events considered related to ipilimumab may be immune in nature and 
presumably a consequence of the intrinsic biological activity of ipilimumab. An IRAE is defined as 


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any adverse event associated with drug exposure and consistent with an immune-mediated event. 
Disease progression, infections and other etiologic causes are ruled out or deemed unlikely as 
contributing to the event. Supportive data, such as autoimmune serology tests or biopsies, are 
helpful but  not  necessary to deem  an event  an IRAE. Events of  unclear  etiology which  were 
plausibly “immune-mediated” have been conservatively categorized as IRAEs even if serologic or 
histopathology data are absent. These IRAEs likely reflect a loss of tolerance to some self antigens 
or an unchecked immune response to gut or skin flora. Some breakthrough of immunity may be 
inseparably linked to the clinical antitumor activity of ipilimumab. 
 
Approximately 60% of subjects developed any grade IRAEs which involved predominately the 
gastrointestinal (GI) tract, endocrine glands, liver, or skin. Based on data from the safety database, 
the number of subjects with serious IRAEs was approximately 15% (401/2633), including 8.2% for 
serious GI IRAEs (diarrhea and/or colitis), 2.2% of serious endocrinopathy (primarily 
hypophysitis/hypopituitarism) and <1% of serious skin IRAEs. Bowel perforation was reported in 
approximately 1% of subjects. With few exceptions these IRAEs were clinically manageable and 
reversible with supportive care or corticosteroids. In responding patients, addition of corticosteroids 
does not appear to have a temporal relationship to change in objective tumor response. 
 
Additionally, as of February 2006, there has been observation from a National Cancer Institute (NCI) 
study of bowel wall perforation in some patients who were administered a high-dose IL-2 following 
treatment  with  ipilimumab.  Of  the  22  patients  administered  high-dose  IL-2,  three  patients 
experienced bowel wall perforations. This is a higher rate than would be expected with high-dose IL- 
2 treatment alone. All three patients had metastatic melanoma and had previously received their last 
dose of ipilimumab > 77 days before the first dose of IL-2. Two of the patients had clinically 
significant ipilimumab-related diarrhea or colitis and the symptoms had completely resolved prior to 
IL-2  administration.  One  patient  did  not  experience  ipilimumab-related  diarrhea.  It  is  unknown 
whether this observation represents a true association or is mechanistically unrelated to prior 
ipilimumab exposure. 
 
3.3.5.1. 
Drug-Related Deaths 
 
Based on reports from the safety data base as of June 30, 2008, there have been reports of death 
(approximately 1% [28/3000]), deemed by the investigator as possibly related to the administration 
of study drug. The most common cause of drug related deaths was GI perforation. Other causes 
included multiorgan failure, sepsis, hypotension, acidosis, and adult respiratory distress syndrome. 
For details on all drug-related deaths, refer to the current version of the Ipilimumab Investigator 
Brochure. 
 
3.3.5.2. 
Safety of 10 mg/kg Multiple Doses 
 
Based on a review of the program-wide SAE data as previously reported, evidence had suggested 
that ipilimumab-associated irAEs were dose dependent in frequency, and higher irAE rates had 
been observed at 10 mg/kg than at lower doses of ipilimumab. Subsequently, this dose-dependent 
effect  was further  demonstrated  in  CA184-022 in  which  three  dose  levels  of  ipilimumab  were 
studied, including 0.3 vs 3 vs 10 mg/kg. Table 1 summarizes the overall irAE frequencies by dose 
from CA184-022 based on safety data from the locked clinical database. 


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Qualitatively, the safety profile of ipilimumab at 10 mg/kg remains consistent with the low-dose 
safety profile in that most of the drug-related SAEs are characteristic of immune-related toxicity, and 
most of the irAEs are reported in the GI, hepatic, and endocrine systems. However, the data 
presented in Table 1 suggest that the frequency of irAEs in association with 10 mg/kg of ipilimumab 
at multiple doses is higher compared with the irAE frequency reported for lower doses. 
 
Table 1.          Summary of Immune-Related AEs by Treatment Groups - Treated Subjects 
(CA184-022) 
 
 
Number of Subjects (%) 
 
 
 
 
 
 
 
Overall irAEs 
Grade 3-4 
 
GI irAEs 
Grade 3-4 
 
Hepatic irAEs 
Grade 3-4 
 
Endocrine irAEs 
Grade 3-4 
 
Skin irAEs 
Grade 3-4 
 
 
0.3 mg/kg 
(N=72) 
 
26.4 
0 
 
16.7 
0 
 
0 
0 
 
0 
0 
 
12.5 
0 
Ipilimumab 
 
3 mg/kg 
(N=71) 
 
64.8 
7.0 
 
32.4 
2.8 
 
0 
0 
 
5.6 
2.8 
 
45.1 
1.4 
 
 
10 mg/kg 
(N=71) 
 
70.4 
25.4 
 
39.4 
15.5 
 
2.8 
2.8 
 
4.2 
1.4 
 
46.5 
4.2 
 
 
 
 
3.3.5.3. 
Neuropathies 
 
Isolated cases of motor neuropathy of an autoimmune origin have been reported among patients 
treated with ipilimumab. Two cases have been diagnosed as Guillain-Barre syndrome (GBS), only 
one of which was considered study related. As of July 2, 2008, 15 cases of neuropathy SAEs have 
been reported.  Of these, 13 were assessed as unrelated to study therapy because alternative 
etiologies,  including  brain  metastases,  spinal  cord  compression,  or  aterial  thrombosis,  were 
identified in almost every case. 
 
3.3.6.  Clinical Efficacy of Ipilimumab 
 
Treatment with ipilimumab has demonstrated clinically important and durable tumor responses in 
several malignancies including melanoma, prostate cancer, and renal cell carcinoma. The most 
extensively studied tumor type has been malignant melanoma. Based on preliminary results, 
ipilimumab is active in patients with advanced stage malignant melanoma. The objective responses 
observed with ipilimumab may be considered durable as they have occurred across a spectrum of 
doses and schedules. 


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Based on a preliminary analysis for study MDX010-15 involving ipilimumab 10 mg/kg multiple doses, 
34.8% of patients (N = 23) were progression-free at 6 months and about 17.4% were progression- 
free at 1 year. In comparison, for Study MDX010-08 involving ipilimumab 3 mg/kg multiple doses, 
10.8% patients (N = 37) had progression-free survival at 6 months and 8.4% at 1 year. Ipilimumab 
has  also  been  studied  in  combination  with  chemotherapy  (dacarbazine),  melanoma  vaccines 
(gp100), and cytokines (IL-2). Further details on clinical results can be found in the current version of 
the Ipilimumab Investigator Brochure. 
 
3.3.6.1. 
Relationship Between Response and Immune Related Adverse Events in 
Patients with Metastatic Melanoma 
Drug-related AEs of any grade considered to be immune-mediated in nature (irAEs) were reported 
for 54.0% of subjects in clinical studies of ipilimumab. These irAEs are a consequence of inhibiting 
CTLA-4 function and most were reported as Grade 1 or 2. An association between BORR and 
higher grade (Grade 3-4) irAEs was suggested in early studies of ipilimumab 3 mg/kg but this 
association was not observed in 4 Phase 2 studies of ipilimumab (CA184022, CA184008, CA184007 
and CA184004). There were proportionally more subjects with irAEs of any grade who experienced 
response  or  stable  disease  than  subjects  without  irAEs  who  experienced  response  or  stable 
disease, but due to the small sample sizes, these observations were statistically inconclusive[17-19]. 
 
3.4.   Overall Risk/Benefit Assessment 
 
Results from the 3 primary efficacy studies of ipilimumab suggest that the 10 mg/kg dose is active 
and offers the best benefit to risk ratio based on a 27.1% to 35.1% rate of disease control and a 
favorable 1-year survival rate of 48.6% to 59.1% compared with that   reported in the literature 
(25.5% to 35%)[20-23]. Substantial reductions in total tumor burden, including widely disseminated 
disease in the skin, lung, and/or other visceral disease sites, were reported. More than half the 
responses were reported in subjects staged with M1b or M1c advanced melanoma disease, which is 
most resistant to approved therapies. The kinetics of ipilimumab resulted in known patterns of 
clinical activity (CR, PR and SD) as well as novel patterns, characterized by reductions in total tumor 
burden, including existing and new lesions, after initial tumor volume increase and/or after 
appearance of new lesions. In the pretreated population at 10 mg/kg in 2 of the 3 studies, disease 
control after initial tumor volume increase and/or new lesions was reported for 9.7% of subjects. 
Across all 3 studies, stable disease was often accompanied by clinically relevant reductions in tumor 
burden compared to baseline. All patterns of response, including SD, appeared to result in favorable 
survival, based on 1-year survival rates. 
 
Characteristic organ-specific inflammatory irAEs were reported with ipilimumab therapy, typically 
during induction therapy. IrAEs were mostly reversible within days to weeks following cessation of 
therapy or treatment with symptomatic therapy, corticosteroids or other anti-inflammatory agents, 
depending upon severity. Accumulated clinical experience resulted in detailed toxicity management 
guidelines (also termed algorithms), by use of which irAEs can be effectively managed, especially 
when irAEs are recognized early and subjects are treated in a timely fashion. This can minimize the 
occurrence of irAE complications, such as GI perforation/colectomy or hepatic failure. 
 
Treatment with ipilimumab resulted in clinical activity in pretreated and previously untreated subjects 
with advanced melanoma. Clinically relevant reductions in the tumor burden from baseline were 


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reported, together with a preliminary evidence of improved overall survival compared with published 
survival rates. 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. 
 
3.5. Study Rationale 
 
3.5.1.  Treatment Options for Patients with Melanoma 
Up to ten percent of patients with melanoma will develop local-regional recurrence, defined as in 
transit lesions or satellitosis, in the extremity after treatment[24]. Administration of systemic 
chemotherapy has poor results, yet local control with surgical amputation has resulted in a 30% five- 
year survival[25].  Because a substantial percentage of patients can be salvaged by aggressive 
treatment, strategies to refine the approach to local-regional recurrence have evolved over the 
years, and include regional chemotherapy. 
 
 
 
3.5.2.  Isolated Limb Infusion 
 
Isolated limb infusion is a technique used to deliver high doses of chemotherapy agents locally. 
Since systemic absorption is minimal, and doses of chemotherapy 15-25 x the systemic dose can be 
used[26]. Most often, Melphalan is used alone or in combination with other agents. Technically this 
occurs by exclusion of the limb with a tourniquet, percutaneous vascular isolation of the inflow and 
outflow, and infusion of chemotherapeutic agents. Isolated limb infusion (ILI) was developed at the 
Sydney Melanoma Unit, which also has the world’s largest experience. In a recent report, the overall 
response to the therapy was 84%, (38% of patients having a complete response, and 46% having a 
partial response), with a median survival of 38 months[27].26 The response rate is highly variable 
across studies. This is in part secondary to the differences in which response is measured. In the 
Australian studies, a response is measured by the WHO criteria with 2 observations no less than 4 
weeks apart.  At MSKCC, we have measured response at a set time point at week 13-15. This is to 
allow the edema of the extremity to abate and therefore not record an early response that either 1) 
do not last for at least 3 months, or 2) is inflated by the lack of ability to accurately measure a 
swollen extremity.  In the only prospective study, with careful follow-up by Dr. Brady and colleagues 
at MSKCC, ILI with Melphalan and Dactinomycin resulted in a 50% response rate with 23% of 
patients having a complete response(CR). The median duration of the CR was 12 months[28]. 
Biopsies of some responding lesions demonstrated pigment laden microphages, suggesting that the 
ILI may involve the immune system. The toxicity of this regime was acceptable and no patients 
required an amputation. 
 
 
The results of these studies demonstrate that limb infusion is a well tolerated procedure.  Yet this 
approach remains palliative as most patients will have distant recurrence[29, 30]. Even in the 
Australian studies with high initial response rates, the median survival of Stage IV patients is only 16 
months[30]. Prior studies with Ipilimumab and systemic chemotherapy with dacarbazine, have 
demonstrated safety and potentially an augmented clinical responses[31]. Therefore, one approach 
to maximize the results in regional disease would be to combine local chemotherapy with ILI with a 


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systemic therapy, such as Ipilimumab. The overall risk-benefit ratio for patients entering this 
protocol is therefore at least comparable to and possibly better than alternative options. 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
1)  To determine the progression free survival with the addition of Immunotherapy with 
Ipilimumab to standard limb infusion chemotherapy of Melphalan and Dactinomycin. 
2)  To determine the response rate, distribution of PFS, and safety of the addition of Ipilimumab. 
3)  To define the correlative immunologic events and signatures that correspond to response to 
Ipilimumab 
 
Patients with Stage IIIB, IIIC or IV melanoma eligible for an isolated limb infusion (ILI), will be 
considered for the trial in which they will receive additional systemic treatment with Ipilimumab. 
Induction therapy with Ipilimumab will start 1-3 weeks after ILI in the standard dose of 10mg/kg 
every 3 weeks for a total of 4 doses.  Patients will then receive chronic therapy every 3 months (+/- 2 
weeks). Patients who have discontinued the study drug and have not progressed will be seen at all 
specified time points for the intended duration of the trial (+/- 4 weeks). Patients will be followed 
every 3 months for 2 years, with PFS measured by CT Scan and physical exam at one year. 
 
4.2 
Intervention 
 
This is a single-institution phase II trial with a primary outcome of progression free survival (PFS). 
Patients with advanced Stage IIIB, Stage IIIC, or Stage IV melanoma requiring ILI will be candidates 
for the trial. These patients will be identified by the attending physician and offered participation. 
Prior to ILI, patients will undergo an extent of disease evaluation consisting of a CT scan or MRI of 
the brain, and a CT scan of the chest, abdomen and pelvis. The extremity lesions will be measured 
and photographed by medical photography.  In the case of diffuse, numerous extremity lesions, 
three index lesions will be chosen to measure and characterize.  In patients with deep lesions which 
are difficult to quantitate, a CT Scan or MRI of the extremity will also be performed. The patient will 
then undergo an ILI in the operating room under anesthesia as previously described and currently 
performed at MSKCC[28]. 
 
 
Melphalan and dactinomycin are added to 400 mL of heparinized normal saline for the lower 
extremity and 200 mL of heparinized normal saline for the upper extremity. The dose of Melphalan 
will be calculated by limb volume (7.5 – 10mg/L) corrected for ideal body weight, and not limited by 
anatomic site. The dose of Dactinomycin to be used is 75 mcg/L limb volume (maximum 500 mcg). 
 
 
 
Calculating the Melphalan Dose 
The dosage of melphalan should be corrected for ideal body weight by using the formula described 
below. 
 
 
Melphalan dose per liter of limb volume to be infused (mg/L) × Calculated Volume of 


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extremity(L) × Ideal body weight(kg) ÷ Actual body weight(kg) = Corrected Melphalan Dose. 
EXAMPLE for a leg with a calculated volume of 7 liters: 7.5mg/L × 7 liters x 80 ÷ 100 = 42 mg 
 
 
Estimated Ideal Body Weight (kg) will be calculated as follows: 
Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet. 
Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet. 
 
 
Melphalan-Dactinomycin Infusion 
For the lower extremity, melphalan should be admixed with 400 mL of normal saline containing 1 
unit/mL heparin, and for the upper extremity, melphalan should be admixed with 200 mL of normal 
saline containing 1 unit/mL heparin. The bag should be spiked with a secondary set. 
 
 
Blood samples will be taken for research from each patient at the following time points: at ILI (pre- 
treatment), during induction phase of Ipilimumab ( week 1-3, week 4-6, week 7-9, week 10-12, week 
13-15), and at each infusion of Ipilimumab during the maintenance phase. If a patient is no longer 
receiving Ipilimumab while still on study, the patient will not have research bloods drawn. Tissue 
samples will be taken from each patient at the following time points throughout the study: during ILI, 
week 1-3 (optional, patient can refuse), and week 13-15 unless there is no lesion or pigmented scar 
to identify previous target lesion. An additional biopsy may be performed during the induction phase 
(prior to week 13-15), if the physician feels the patient is responding and the lesion is likely to be 
gone by week 13-15. 
 
 
After recovery from ILI patients will be seen in the office to start therapy with Ipilimumab, 1-3 weeks 
after the ILI procedure. The variable time of dosing is to allow patients to recover from the toxicity of 
limb infusion.  Patients who have resolution of toxicity to Wiederbink I-III will then receive Ipilimumab 
every 3 weeks (+/- a week) for a total of 4 total doses. Within, three weeks following the final dose 
of Ipilimumab the lesion site will be biopsied, unless there is no identifiable lesion or pigmented scar, 
and blood samples will again be taken for analysis.  Patients will be allowed to skip a dose of 
Ipilimumab if the performance status is not adequate, but the dosing cannot be delayed (see 
Appendix 8 for study schema). This is, in part, secondary to the fact that Ipilimumab has a long half 
life, and it has been noted in the other previous trials that the safest approach is to skip a dose if 
there is any question of the patient’s ability to tolerate the dose.  Patients with severe swelling of an 
extremity may defer the biopsy after ILI (before Ipilimumab). In this case, a biopsy pre-treatment 
and after Ipilimumab will be the only biopsies the patient may have. In the case of a complete 
response by the week 13-15 evaluation time point, where there is no identifiable lesion or pigmented 
scar, a biopsy will not be performed. Patients that appear to be progressing on the 4 cycles of 
Ipilimumab will be re-imaged with a CT Scan to accurately evaluate for progression of disease 
(POD).  Any demonstration of POD at that time point will allow for discontinuation of drug and switch 
to another therapy for metastatic melanoma. Patients who have not progressed will begin 
maintenance therapy with Ipilimumab. They will receive Ipilimumab every 3 months (+/- 2 weeks) 
for 2 years and will have research blood drawn at each dose of Ipilimumab during the maintenance 
therapy phase (months 6, 9, 12, 15, 18, 21, 24). Patients who have discontinued the study drug and 
have not progressed will be seen at all specified time points for the intended duration of the trial. 


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The Wiederbink criteria will be used to assess toxicity, as shown in Appendix 7.  A partial and 
complete response of the extremity will be assessed by using the extremity tumor measurement 
forms (see appendix 10) together with the immune-related response criteria (irRC) that incorporates 
the contribution of new measurable lesions. 
 
 
During the maintenance phase CT Scans will be performed every 3 months (+/- 2 weeks). This will 
include a scan at 1 year (48-54 weeks) to assess for PFS. 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1. Investigational Product: IPILIMUMAB 
 
 
 
The investigational product is defined as a pharmaceutical form of an active ingredient being tested 
as a reference in the study, whether blinded or unblinded. In this study, the investigational product is 
ipilimumab.  It should be noted that Ipilimumab was FDA approved for patients with metastatic 
melanoma in March of 2011. 
 
Other medications used in the study as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, are considered 
noninvestigational products. In this protocol, noninvestigational product(s) is/are: Melphalan and 
Dactinomycin, as well as 5-HT anti-emetics. 
 
Melphalan has been used for regional chemotherapy for metastatic melanoma since 1957 and is of 
proven efficacy and safety[19]. Melphalan is a phenylalanine derivative of nitrogen mustard and acts 
as an alkylating agent.  It is actively transported in cells that actively take up phenylalanine or 
tyrosine such as melanoma.  Melphalan uptake by the cell results in impaired transcription and 
single and double strand DNA breaks. 
 
Melphalan is manufactured by Galazo Wellcome Co.  The agent used in this trial will be stored in 
and maintained in the pharmacy at MSKCC.  The intact package will be stored at room temperature 
and protected from light. Melphalan is supplied as a sterile diluent in a 10 ml volume.  Each vial 
contains 6 ml of propylene glycol, 0.2 gm of sodium citrate and 0.5 ml of 95% ethanol.  After 
reconstitution of the melphalan with the solvent the final concentration is 5mg/ml. The stock solution 
is diluted with sterile 0.9% NaCl to a concentration no greater than 2mg/ml prior to administration. 
 
Reconstitution of Melphalan results in a solution that undergoes hydrolysis at room temperature. 
Reconstituted Melphalan retains 90% potency for approximately 3 hours at 30◦C.  Melphalan used in 
this investigation will be reconstituted within 20 minutes of administration. 
 
The most common toxicity of systemic melphalan is myelosuppression, usually occurring with a 
nadir of 14-21 days, however, this effect is seen with systemic administration and has not occurred 
in patients undergoing ILI. 
 
Dactinomycin is an antitumor antibiotic produced by streptomyces species in culture. The 
compound binds to DNA and inhibits DNA-dependent RNA synthesis. It is also a topoisomerase II 


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inhibitor. The major toxicity of dactimonycin is myelosuppression, usually beginning after the first 
week after treatment and reaching a nadir at 21 days.  Nausea and vomiting occur with systemic 
administration, usually resolving within hours.  Both agents will be prepared by the operating room 
pharmacy just prior to the procedure. 
 
5.1.1. Identification 
Ipilimumab is available in 5 mg/mL single-use vials (10 mL or 40 mL). The sterile solution in the vial 
is clear and colorless. Ipilimumab is administered via intravenous infusion only. 
 
5.1.2. Packaging and Labeling 
BMS will provide ipilimumab at no cost for this study. Ipilimumab will be provided in open-label 
containers. The labels will contain the protocol prefix, batch number, content, storage conditions, 
and dispensing instructions along with the Investigational New Drug (IND) caution statement. 
Ipilimumab will be supplied at a concentration of 5 mg/mL in vials containing 10 ml or 40 mL 
solution. 
 
5.1.3. Storage, Handling, and Dispensing 
 
5.1.1.1. 
Storage 
Ipilimumab must be stored in a secure area according to local regulations. The investigator must 
ensure that it is stored in accordance with the environmental conditions as determined by BMS and 
defined in the Investigator Brochure or SmPC/reference label. Ipilimumab must be stored at a 
temperature ≥ 2°C and ≤ 8°C. 
 
5.1.1.2. 
Handling and Disposal 
As with all injectable drugs, care should be taken when handling and preparing ipilimumab. 
Whenever possible, ipilimumab should be prepared in a laminar flow hood or safety cabinet using 
standard precautions for the safe handling of intravenous agents applying aseptic technique. Latex 
gloves are required. If ipilimumab concentrate or solution comes in contact with skin or mucosa, 
immediately and thoroughly wash with soap and water. After final drug reconciliation, unused 
ipilimumab solution should be disposed at the site following procedures for the disposal of 
anticancer drugs. 
 
5.1.1.3. 
Dispensing 
It is the responsibility of the investigator to ensure that ipilimumab is only dispensed to study 
subjects. The ipilimumab must be dispensed only from official study sites by authorized personnel 
according to local regulations. 
 
5.1.4. Drug Ordering and Accountability 
 
5.1.1.4. 
Initial Orders 
Following submission and approval of the required regulatory documents, a supply of ipilimumab 
may be ordered from BMS.  Investigators must complete a Drug Request Form and email it to: 
distribution.allentown@thermofisher.com.  If for any reason the e-mail drug request form is not 
successfully transmitted, contact Emily Kahora at Fisher Clinical Services T: +1 484.538.2121 F: +1 
610.871.9382 E: emily.kahora@thermofisher.com| or  www.fisherclinicalservices.com. 
 
It is recommended you send a test message to the Fisher Clinical Service e-mail address upon 
receipt of the Drug Request Form. Please include in the subject line: BMS IST Drug Order -Test . 


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This will ensure your site is recognized by Fisher and your future orders will be received without 
incident. 
 
Ipilimumab vials (40 mL) are shipped in quantities of five. The initial order should be limited to 25 
vials (5 cartons of 5 vials each).  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 product will be shipped via 
Federal Express in a temperature-controlled container. Shipments will be made from Fisher Clinical 
Services on Monday through Thursday for delivery onsite Tuesday through Friday. There will be no 
weekend or holiday delivery of drugs. 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 
number be used for this study. To help segregate product for this study from other investigational or 
marketed product, stickers bearing the BMS protocol number will be provided and should be affixed 
to the front of the outer carton just above the company names so as not to obscure any marking. 
 
5.1.1.5. 
Re-Supply 
 
Reorders should be emailed directly to Fisher Clinical Services 
(distribution.allentown@thermofisher.com) for shipment within 5 business days. When assessing 
need for resupply, institutions should keep in mind the number of vials used per treatment dose, and 
that shipments may take 5 business days from BMS receipt of request. Drug is not patient specific. 
Be sure to check with your pharmacy regarding existing investigational stock to assure optimal use 
of drug on hand. 
 
5.1.5. Ipilimumab Accountability 
It is the responsibility of the investigator to ensure that a current record of ipilimumab disposition is 
maintained at each study site where ipilimumab is inventoried and disposed. Records or logs must 
comply with applicable regulations and guidelines, and should include: 
 
• 
Amount received and placed in storage area. 
 
• 
Amount currently in storage area. 
 
• 
Label ID number or batch number and use date or expiry date. 
 
• 
Dates and initials of person responsible for each ipilimumab inventory entry/movement. 
 
• 
Amount dispensed to and returned by each subject, including unique subject identifiers. 
 
• 
Amount transferred to another area/site for dispensing or storage. 
 
• 
Non-study disposition (e.g., lost, wasted, broken). 
 
• 
Amount destroyed at study site. 
 
5.1.6. Ipilimumab Destruction 
If ipilimumab is 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. Appropriate 
records of the disposal must be maintained. 


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6.0     CRITERIA FOR SUBJECT ELIGIBILITY 
 
For entry into the study, the following criteria MUST be met. Any exceptions from the protocol- 
specific selection criteria must be approved by the Principal Investigator and/or the Institutional 
Review Board (IRB) before enrollment. 
 
 
 
6.1     Subject Inclusion Criteria 
 
1)  Willing and able to give written informed consent. 
 
2)  Histologic diagnosis of melanoma with in transit metastasis Stage IIIB, IIIC, or IV 
 
3)  Required values for initial laboratory tests: 
 
•   WBC                   ≥ 2000/uL 
 
•   ANC                    ≥ 1000/uL 
 
•   Platelets              ≥ 50 x 103/uL 
 
•   Hemoglobin        ≥ 8 g/dL 
 
•   Creatinine           ≤ 3.0 x ULN 
 
•   AST/ALT             ≤ 2.5 x ULN 
 
• 
Bilirubin 
≤ 3.0 x ULN, (except patients with Gilbert’s Syndrome, who   must   have 
a total bilirubin less than 3.0 mg/dL) 
 
 
4)  No active or chronic infection with HIV, Hepatitis B, or Hepatitis C. 
 
5)  Karnofsky performance status ≥60 
 
6)  Men and women, ≥ 18 years of age. 
 
Women of childbearing potential (WOCBP) must be using an adequate method of 
contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last 
dose of investigational product, in such a manner that the risk of pregnancy is minimized. 
 
WOCBP include any female who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or is not post-menopausal. Post-menopause is defined as: 
 
•   Amenorrhea ≥ 12 consecutive months without another cause, or 
 
•   For women with irregular menstrual periods and taking hormone replacement therapy 
(HRT), a documented serum follicle stimulating hormone (FSH) level ≥ 35 mIU/mL. 
 
Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, 
skin patches, or implanted or injectable products), or mechanical products such as an 
intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent 
pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) 
should be considered to be of childbearing potential. 


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WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of HCG) within 72 hours before the start of ipilimumab. 
 
 
6.2 
Subject Exclusion Criteria 
 
1)  Any other malignancy that requires active treatment. 
 
2)  Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded 
from this study, as are patients with a history of  symptomatic disease (eg, rheumatoid 
arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, 
autoimmune vasculitis [eg, Wegener’s Granulomatosis]); motor neuropathy considered of 
autoimmune origin (e.g. Guillain-Barre Syndrome). 
3)  Any underlying medical or psychiatric condition, which in the opinion of the investigator will 
make the administration of ipilimumab hazardous or obscure the interpretation of AEs, such 
as a condition associated with frequent diarrhea. 
4)  Patients with underlying heart conditions who are deemed ineligible for surgery by cardiology 
consult 
5)  Any history of prior treatment with ipilimumab or prior CD137 agonist or CTLA-4 inhibitor or 
agonist. 
6) Concomitant therapy with any of the following: IL-2, interferon, or other non-study 
immunotherapy regimens; immunosuppressive agents; other investigation therapies; or 
chronic use of systemic corticosteroids. 
7)  Women of childbearing potential (WOCBP), defined above in Section 4.1, who: 
 
a. are unwilling or unable to use an acceptable method of contraception to avoid 
pregnancy for their entire study period and for at least 8 weeks after cessation of 
study drug, or 
b.  have a positive pregnancy test at baseline, or 
c.   are pregnant or breastfeeding. 
8)  Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment 
of either a psychiatric or physical (eg, infectious) illness. 
9)  Persons of reproductive potential must agree to use an adequate method of contraception 
throughout treatment and for at least 8 weeks after ipilimumab is stopped. 
 
Sexually active WOCBP must use an effective method of birth control during the course of the study, 
in a manner such that risk of failure is minimized. Before study enrollment, WOCBP must be advised 
of the importance of avoiding pregnancy during study participation and the potential risk factors for 
an unintentional pregnancy. All WOCBP MUST have a negative pregnancy test before first receiving 
ipilimumab. If the pregnancy test is positive, the patient must not receive ipilimumab and must not be 
enrolled in the study. 


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6.3. 
Prohibited and Restricted Therapies During the Study 
 
6.3.1.  Prohibited Therapies 
Patients in this study may not use vaccines for the treatment of cancer or prevention of disease 
unless indicated as a component of the protocol regimen (including those for common medical 
conditions) for up to one month pre and post dosing with ipilimumab. 
 
Patients may not use any of the following therapies during the study: 
 
•   Any non-study anti-cancer agent (investigational or non-investigational) 
•   Any other investigational agents 
•   Any other (non-CA184024 related) CTLA-4 inhibitors or agonists 
•   CD137 agonists 
•   Immunosuppressive agents 
•   Chronic systemic corticosteroids 
• 
Any non-oncology vaccine therapies used for the prevention of infectious diseases (for up to 30 
days prior to or after any dose of study drug). 
 
 
6.3.2.  Restricted Therapies 
 
 
Not applicable 
 
6.3.3.  Precautions 
Caution is advised when considering treatment with high-dose IL-2 in patients who have previously 
been administered ipilimumab, particularly in patients who experienced ipilimumab-related 
diarrhea/colitis. Colonoscopy or sigmoidoscopy with biopsy may be advisable prior to IL-2 
administration once the patient is no longer receiving ipilimumab. 
 
7.0       RECRUITMENT PLAN 
 
This is a single-institution phase II trial with a primary outcome of progression free survival. Patients 
with advanced Stage IIIB, Stage IIIC, or Stage IV melanoma with in transit disease requiring ILI will 
be  candidates  for  the  trial.  These  patients  will  be  identified  by  the  research  assistant  and/or 
attending physician and offered participation. 
 
Protocol investigators treating patients at both MSKCC Manhattan and West Harrison sites will 
screen their patient’s medical records to identify potential research subjects. Protocol treatment and 
procedures, however, can only take place at the Manhattan sites. Potential research subjects 
identified at the West Harrison site will be offered study participation and treatment at the Manhattan 
sites. Only consent can be obtained at the West Harrison site. 
 
Potential research subjects will be identified by a member of the patient’s treatment team, the 
protocol investigator, or research team at Memorial Sloan-Kettering Cancer Center (MSKCC). If the 
investigator is a member of the treatment team, s/he will screen their patient’s medical records for 
suitable research study participants and discuss the study and their potential for enrolling in the 
research study. Potential subjects contacted by their treating physician will be referred to the 
investigator/research staff of the study. 


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The principal investigator may also screen the medical records of patients with whom they do not 
have a treatment relationship for the limited purpose of identifying patients who would be eligible to 
enroll in the study and to record appropriate contact information in order to approach these patients 
regarding the possibility of enrolling in the study. 
 
During the initial conversation between the investigator/research staff and the patient, the patient 
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process. The investigator/research staff may also review portions of their medical records 
at MSKCC in order to further assess eligibility. They will use the information provided by the patient 
and/or medical record to confirm that the patient is eligible and to contact the patient regarding study 
enrollment. If the patient turns out to be ineligible for the research study, the research staff will 
destroy all information collected on the patient during the initial conversation and medical records 
review, except for any information that must be maintained for screening log purposes. 
 
In most cases, the initial contact with the prospective subject will be  conducted either by the 
treatment team, investigator or the research staff working in consultation with the treatment team. 
The recruitment process outlined presents no more than minimal risk to the privacy of the patients 
who are screened and minimal PHI will be maintained as part of a screening log. For these reasons, 
we seek a (partial) limited waiver of authorization for the purposes of (1) reviewing medical records 
to identify potential research subjects and obtain information relevant to the enrollment process; (2) 
conversing with patients regarding possible enrollment; (3) handling of PHI contained within those 
records and provided by the potential subjects; and (4) maintaining information in a screening log of 
patients approached (if applicable). 
 
 
 
8.0     PRETREATMENT EVALUATION 
 
Prior to ILI, patients will undergo an extent of disease evaluation consisting of a CT scan or MRI of 
the brain, and a CT scan of the chest, abdomen and pelvis (a body PET/CT scan will suffice).  The 
lesions will be measured and photographed.   In the case of diffuse, numerous extremity lesions, 
three index lesions will be chosen to measure and characterize.  In patients with deep lesions which 
are difficult to quantitate, a CT Scan of the extremity will also be performed.  The patient will then 
undergo an ILI in the operating room under anesthesia as previously described and currently 
performed here at MSKCC[28]. Prior to receiving the first dose of Ipilimumab, patients will also have 
TSH drawn. 
 
 
 
 
 
 
9.0      TREATMENT/INTERVENTION PLAN 
 
Briefly, ILI consists of placement of angiographic catheters in the interventional radiology suite from 
the contralateral vessels into the femoral or axillary vessels of the affected extremity. The patient is 
placed on systemic heparin at the time of the catheter placement and then transported to the 
operating room.  As prophylaxis against nausea, a single dose of a 5-HT3 receptor antagonist, such 
as palonosetron 250mcg IV and dexamethasone or methylprednisolone 20mg IV is given.  A 
pneumatic tourniquet is placed at the appropriate level around the extremity to exclude it from the 


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systemic circulation.  A hot air blanket is wrapped around the extremity and the OR room is warmed, 
temperature probes are placed in the skin, and once the extremity reaches a temperature of 37, the 
procedure begins.  Papaverine, 60 mg over 1 to 3 minutes is delivered through the extremity and the 
tourniquet is inflated.  Melphalan and dactinomycin are added to 400ml of heparinized normal saline 
for the lower extremity and 200ml of heparinized normal saline for the upper extremity. The dose of 
melphalan used is 5-10 mg/L limb volume (maximum 100 mg). The dose of Dactinomycin to be 
used is 50-100 mcg/L limb volume (maximum 500 mcg). The drugs are infused via a pressurized 
circuit into the isolated limb via the arterial catheter. The infusate is then circulated using a large 
syringe and a wide-bore, high-flow, three-way stopcock.  Blood is repeatedly withdrawn from the 
venous catheter and re-injected into the arterial catheter manually using the stopcock. The tubing 
passes through a blood warming coil maintained at 41◦C.  After 30 minutes, the limb is flushed with 
500 cc to 1000 cc of crystalloid solution at room temperature and discarded using the 3-way 
stopcock and syringe. When the effluent is cleared and 60 to 80% of the flush volume has been 
extracted, the arterial and venous catheters are removed and protamine is administered to reverse 
the heparin.  A percutaneous closure device may be used in selected patients (Perclose, Inc, Menlo 
Park, CA) by the interventional radiologist, or, firm pressure will be held for 20-30 minutes. 
 
Blood samples will be taken for research from each patient at the following time points: at ILI (pre- 
treatment), during induction phase of Ipilimumab (week 1-3, week 4-6, week 7-9, week 10-12, week 
13-15, and with each dose of Ipilimumab during the maintenance phase. If a patient is no longer 
receiving Ipilimumab while still on study, the patient will not have research bloods drawn. Tissue 
samples of the tumor will be taken from each patient at the following time point throughout the study: 
during ILI, week 1-3, and week 13-15. If the lesions are decreasing in size prior to week 13-15, a 
biopsy may be performed prior to the week 13-15 time point. As noted, a patient may refuse any 
biopsy and stay on study, and no biopsy will be performed at the week 13-15 evaluation if there is no 
identifiable lesion or pigmented scar. In the latter case, photographs of the lesion site will still be 
taken. An additional biopsy may be performed during the induction phase (prior to week 13-15), if 
the physician feels the patient is responding and the lesion is likely to be gone by week 13-15. 
 
 
 
After recovery from ILI patients will be seen in the office to assess recovery, and to start systemic 
immunotherapy.  Ipilimumab will begin 1-3 weeks, or until resolution of Weiderbink Toxicity 
(appendix 7) to grade I-III after the ILI procedure.  If a patient has severe toxicity after ILI (grade IV 
or V), they will not receive Ipilimumab therapy. 
 
 
Again, the lesions will be photographed and measured and blood sampled for research purposes. 
Patients will then receive Ipilimumab every 3 weeks for a total of 4 total doses.  Blood will be taken 
at each dose of Ipilimumab. Three weeks (+/- a week) following the final dose of Ipilimumab the 
lesion site will be biopsied, if there is an identifiable lesion or pigmented scar, and blood samples will 
again be taken for analysis. The lesion site will also be photographed. Patients will be allowed to skip 
a dose of Ipilimumab, after the first dose, if the performance status is not adequate, but the dosing 
cannot be delayed (see Appendix 8 for study schema).  Patients completing this induction phase will 
then be entered into the maintenance stage of the study, with dosing of Ipilimumab dosing every 3 
months (+/- 2 weeks). After completing the induction phase, a CT scan will be completed 
with a finalized report before ordering and infusing the maintenance dose of Ipilimumab. Patients 


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who have discontinued the study drug and have not progressed will be seen at all specified time 
points for the intended duration of the trial (+/- 4 weeks). 
 
 
 
 
The Wiederbink criteria will be used to assess toxicity, as shown in Appendix 7.  A partial and 
complete response will be assessed as previously described.27 
 
Biopsies will be performed with in the OR or the clinic with a punch biopsy needle.  If not already 
under general anesthesia, this will require infiltration of local anesthesia, a punch biopsy and a 
suture to close the lesion.  One portion of the tissue will be snap frozen, and another will be kept 
sterile for immediate analysis of T cell infiltrate.  Slides will be made for analysis of presence of 
melanoma and additional stains will be performed to characterize the immune infiltrate, as described 
below.  All biopsies and blood samples will be processed at the Ludwig Center for Cancer 
Immunology at MSKCC, Dr. Wolchok is the associate director of this laboratory which is in 
Zuckerman. 
 
 
 
Phenotypic staining: The Ludwig Center has developed several panels of phenotypic markers to 
assess T cell before and after therapy. These include activated/memory cells and regulatory T cells. 
A typical experiment can be summarized as follows: One million PBMCs, or Tumor infiltrating 
lymphocytes are stained with the antibodies in Table above. Acquisition is done on a CYAN flow 
cytometer with Summit software (DakoCytomation California Inc., Carpinteria, CA). Analysis is 
performed using FlowJo software (version 8.1; TreeStar, Inc., Ashland, OR). 
 
 
 
 
T-cell stimulation ex vivo and intracellular cytokine staining: In order to study the impact of 
ILI/Ipilimumab on T cell function, we have standardized an ex vivo T cell assay to assess the T cell 
response to CEF peptide pools (AnaSpec Inc. Fremont, CA) or Staphylococcus Enterotoxin B (SEB, 
Sigma-Aldrich, St. Louis, MO). The CEF peptide pools contain a group of 32 peptides that cover 
HLA class I restricted T cell epitopes of Cytomegalovirus, Epstein-Barr Virus, and Flu Virus (CEF). 
CEF peptide pools are used to activate viral antigen specific CD8+ T cells. Freshly thawed 
lymphocytes are stimulated with CEF (1 mg/ml) or staphylococcal enterotoxin B (SEB, 1 mg/ml). The 
cells are stained for CD3, CD8 and CD4 and then fixed and permeabilized before staining with FITC- 
IFN-g. Samples are acquired on a CYAN flow cytometer and analyzed as above. Gating for each 
cytokine is based on a positive control sample stimulated with SEB and on an unstimulated sample. 


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Antibody responses: Antibody responses to the tumor antigens TYRP-1, TYRP-2, tyrosinase, Melan 
A, and NY-ESO-1 will be measured using a standard ELISA with recombinant antigens produced in 
E. coli as previously described. Positive results in the ELISA will be defined as extrapolated 
reciprocal titers > 100. 
 
 
 
T-cell responses: Intracellular cytokine staining using pools of overlapping peptides covering 
antigens which are frequently recognized by T cells in melanoma patients will be employed to assay 
CD4+ and CD8+ T cell responses. The antigens which we will focus on include: TYRP-1, TYRP-2, 
tyrosinase, Melan A, gp100 and NY-ESO-1. Pentadecapeptides overlapping by 10 amino acids will 
be synthesized for the above antigens and any other targets which are found in the serologic 
screening. Flow cytometry will be performed as above. We define a positive response if at any post- 
vaccination time point there was an increase of ≥3 SDs from baseline and a frequency of IFNg+ 
CD4+ or CD8+ > 0.1% after 10-day in vitro stimulation. 
 
In situ immune monitoring: For each tumor biopsy we will analyze the immune infiltrate. We have 
experience with this and have been able to identify the phenotype of infiltrating cells using flow 
cytometry and have even been able to monitor tetramer+ and/or tumor antigen specific IFN-γ+ T 
cells in situ by flow cytometry. In situ tumor monitoring focuses on three major methodologies: the 
phenotypic characterization of tumor-infiltrating lymphocytes (TILs) with multiparametric flow 
cytometry, the characterization of antigen-specific T cell responses and immunohistochemical (IHC) 
characterization of tumor and peri-tumoral tissue. Phenotypic characterization of TILs includes the 
quantitation of CD25 and FOXP3 expression, as well as inducible costimulator (ICOS) expression. 
The phenotype of TILs are compared to that of PBMCs to determine if there are illustrative 
differences. 
 
Treatment/Location: 
 
ILI with Melphalan and Dactinomycin- MSKCC operating room. 
Ipilimumab- IV administration in outpatient chemotherapy clinic 
9.1. Ipilimumab 
Each patient will receive ipilimumab 10mg/kg every 3 weeks for a total of four doses. Infusions will 
be given over 90 minutes, not by bolus or IV push. 
 
Ipilimumab (BMS-734016) is a human immunoglobulin G (IgG1)κ anti-CTLA-4 monoclonal antibody 
(mAb). In vitro studies were performed with ipilimumab to demonstrate that it is specific for CTLA-4, 
actively inhibits CTLA-4 interactions with B7.1 and B7.2, does not show any cross-reactivity with 
human B7.1, B7.2 negative cell lines, and stains the appropriate cells without nonspecific cross- 
reactivity in normal human tissues, as demonstrated by immunohistochemistry. Ipilimumab does 
cross-react with CTLA-4 in non-human primates, including cynomolgus monkeys. 
 
9.1.1. Dose Calculations 
Calculate Total Dose as follows: 
 
Patient body weight in kg x [10 mg ] = total dose in mg 
 
Calculate Total Infusion Volume as follows: 


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Total dose in mg ÷ 5 mg/mL = infusion volume in mL 
Calculate Rate of Infusion as follows: 
Infusion volume in mL ÷ 90 minutes = rate of infusion in mL/min. 
 
For example, a patient weighing 114 kg (250 lb) would be administered 1140 mg of ipilimumab (114 
kg x 10 mg/kg = 1140 mg) with an infusion volume of 228 mL (1140 mg ÷ 5 mg/mL = 228 mL) at a 
rate of approximately 2.5 mL/min (228 mL ÷ 90 minutes) in 90 minutes. 
 
9.1.2. Storage, Preparation, and Administration 
Ipilimumab Injection, 50 mg/vial (5 mg/mL) or 200 mg/vial (5 mg/mL), must be stored refrigerated 
(2°C to 8°C) and protected from light. Ipilimumab injection must not be frozen. Partially used vials or 
empty vials of Ipilimumab Injection should be discarded at the site according to appropriate drug 
disposal procedures. 
 
Ipilimumab injection may be diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP to concentrations between 1 mg/mL and 4 mg/mL and stored in PVC, non-PVC or 
glass containers for up to 24 hours at 2-8ºC or RT/RL. 
 
Recommended safety measures for preparation and handling include protective clothing, gloves, 
and safety cabinets. 
 
9.1.3. Preparation and Administration Guidelines 
The supplies needed for ipilimumab preparation and administration include calibrated syringes and 
infusion containers. The product may be infused using a volumetric pump at the protocol-specific 
dose(s) and rate(s) through a PVC IV solution infusion set with a 0.2 μm or 1.2 μm in-line 
polyethersulfone or 1.2 μm positively charged nylon filter to complete the infusion in 90 minutes, with 
a 10-mL normal saline flush at the completion of the infusion. 
 
 
 
1)  As ipilimumab is stored at refrigerated temperatures (2-8ºC), allow the appropriate number of 
vials of ipilimumab to stand at room temperature for approximately five minutes. 
 
2)  Aseptically withdraw the required volume of ipilimumab solution into a syringe. Insert the needle 
at an angle into the ipilimumab vial by placing the needle – bevel side down – against the glass, with 
the tip touching the neck of the vial. The initial solution concentration is 5 mg/mL. [Note: A sufficient 
excess of ipilimumab is incorporated into each vial to account for withdrawal losses]. 
 
3)  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. 
 
4)  Inject ipilimumab solution withdrawn into an appropriate size evacuated infusion bag to produce a 
final infusion volume that has been calculated from the weight of the patient. For example, if 
preparing a 10mg/kg treatment for a 65 kg patient you will use 13 vials (or 650 mg), the drug solution 
volume will be 10 mL per vial or 130 mL total. 


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5)  If the total dose calculates to less than 90 mL of solution then the total dose needed should be 
diluted to a total volume of 90 mL in 0.9% sodium chloride. 
 
6)  Mix by GENTLY inverting several times. DO NOT shake. 
 
7)  Visually inspect the final solution. If the initial diluted solution or final dilution for infusion is not 
clear or contents appear to contain precipitate, the solution should be discarded. 
 
8)  Do not draw into each vial more than once. Any partial vials should be safely discarded and 
should not be stored 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. 
 
In accordance with the FDA approved label, patients participating will have their TSH level drawn at 
baseline and before each dose.  However, the TSH level does not have to be known at the time of 
dosing with Ipilimumab as treatment modifications should be based on signs and symptoms related 
to endocrinopathies consistent with existing guidelines within the investigator brochure and protocol.. 
If a subject has thyroid dysfunction and concomitant symptoms (i.e. fatigue), the subject should be 
monitored more frequently and be treated as per standard medical practice. Appendix 6 references 
the Endocrinopathy Management Algorithm. Dose modifications for study medication should follow 
protocol guidelines. 
 
9.1.4. Dose Modifications 
Patients may develop study drug-related toxicities that may require skipping doses or dose 
discontinuation. Some of these adverse events may be consistent with potentially drug-related 
immune-mediated phenomena; termed IRAEs (Appendix 2, Appendix 3). Details of how to dose 
study medication in the present of adverse drug reactions that may or may not be IRAEs are 
addressed below. 
 
Treatment modifications will be made based on specified safety criteria. Patients will delay or 
discontinue treatment with ipilimumab if they experience at least one adverse event, specified below, 
considered by the investigator to be certainly, probably, or possibly related to ipilimumab treatment. 
Additionally, refer to appendix 3 and 4 for treatment and dose modification clarification. The following 
criteria will be used to determine dosing delay, restarting doses, or discontinuing ipilimumab. 
 
Delay ipilimumab dosing for the following related adverse events: 
 
It may be necessary to skip study drug dosing for the following related adverse event(s): 
 
• 
Any ≥ Grade 2 non-skin related adverse event (including IBEs), except for laboratory 
abnormalities 
 
• 
Any ≥ Grade 3 laboratory abnormality. 
 
It is necessary to skip study drug dosing for the following adverse events: 
 
• 
Any ≥ Grade 3 skin-related adverse event regardless of causality. 
 
Restart ipilimumab dosing if/when the adverse event(s) resolve(s) to ≤ Grade 1 severity or returns to 
baseline within 3 weeks of initial dose administration: 


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• 
If the adverse event has resolved, restart ipilimumab dosing at the next scheduled time point per 
protocol. 
 
• 
If the adverse event has not resolved in the protocol-specified dosing window (3 weeks [+/- 3 
days], the next scheduled dose will be omitted. 
 
 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
Table 2: 
Time and Events Schedule for Protocol 10-101 
 
Pre- 
study 
ILI 
Wk 1 
Wk 
1-3 
Wk 
4-6 
Wk 
7-9 
Wk 
10- 
12 
Wk 
13- 
15 
(+/- 1 
week) 
3 
Months 
(+/- 2 
weeks) 1 
Consent 
X 
PE 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor 
Assess 
X 
X 
X 
Normal Labs 
(CBC, Comp) 
X 
X 
X 
X 
X 
X 
X 
Pre-study 
Labs 
(CBC, Comp, 
HIV/ Hep B/ 
Hep C) 
X 
EKG 
X 
PBMC/Serum 
X 
X 
X 
X 
X 
X 
X 
Biopsy 
X 
X 
X 
ILI 
X 
Ipilimumab 
X 
X 
X 
X 
X 
KPS 
X 
X 
Photograph 
X 
X 
Body PET/CT 
or CT C/A/P 
X 
CT C/A/P 
X 
X 
Finalized 
Report 
X 
CT/MRI 
Brain 
X 
Limb Toxicity 
Form 
X 
X 
X 
X 
Ipilimumab 
Tox 
Assessment 
X 
X 
X 
X 
X 
Lesion 
Measurement 
Form 
X 
X 
X 
 
 
 
 
 
10.1. 
Procedures by Visit 
The Time and Events Schedule summarizes the frequency and timing of various measurements. 
 
10.2. 
Study Completion or Early Discontinuation Visit 
At the time of study early withdrawal, the reason for early withdrawal and any new or continuing 
adverse events should be documented. 
 
1 +/- 4 weeks for patients off treatment 


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10.3. 
Study Drug Discontinuation 
If study drug administration is discontinued, the reason for discontinuation will be recorded. 
 
10.4. 
Study Materials 
Bristol-Myers Squibb (BMS) will provide ipilimumab at no cost for this study. 
 
 
 
 
 
 
 
 
 
11.0 TOXICITIES/SIDE EFFECTS 
 
11.1. 
Safety Assessments 
All patients who receive at least one dose of ipilimumab will be considered evaluable for safety 
parameters. Additionally, any occurrence of a SAE from time of consent forward, up to and including 
follow-up visits will be reported. See Section 17.2: Serious Adverse Event (SAE) Reporting. 
 
Safety will be evaluated for all treated patients using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.0 (http://ctep.cancer.gov). Safety 
assessments will be based on medical review of adverse event reports and the results of vital sign 
measurements, physical examinations, and clinical laboratory tests. 
 
11.2. 
Safety Evaluation 
 
 
 
11.2.1. Safety with Ipilimumab 
 
 
Prior trials with Ipilimumab have demonstrated that the medicine can cause mild symptoms with 
infusion such as diaphoresis, or headaches.  Patients may also develop low-grade constitutional 
symptoms such as fatigue, nausea, arthralgias, myalgias and fevers.  Females and males should be 
aware of the potential reproductive side effects while participating in this study. 
 
The high-grade toxicities associated with Ipilimumab are severe autoimmune reactions or immune 
breakthrough events (IBE).  For the purposes of this study, IBE is defined as any event immune 
event that is associated with drug exposure. These side effects have been well described and 
include diarrhea/colitis, hypophysitis, hepatitis, uvetitis, nephritis, vitiligo and rash. Depending on the 
trial, the risk of Grade 3-4 immune-related adverse events is 12 to 41% as discussed above. 
Diarrhea/colitis is one of the most serious and must be evaluated in a timely fashion (see diarrhea 
algorithm in Appendix 4).  All patients with diarrhea will be seen by physician and evaluated with a 
CT Scan/colonoscopy if necessary. The standard criteria for stopping Ipilimumab will be used.  This 
includes any grade 4 lab abnormality or any grade 3 lab abnormality related to Ipilimumab (except 
elevated AST/ALT, where values>8x upper limits of normal will be used). Any evidence of Grade 3 
diarrhea/colitis, ongoing symptomatic endocrinopathies will similarly be dose limiting. 
The following criteria will be used to determine if/when to skip, restart, or discontinue study drug 
dosing. 
 
 
Skip drug dosing for the following related adverse events: 


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• 
Any Grade 2 non-skin related adverse event (including IBE’s) 
• 
Any Grade 3 skin-related adverse event (including IBE’s) 
 
 
When the adverse events(s) resolve to ≤ Grade I severity 
• 
If the adverse event has resolved, restart dosing a the next scheduled time point per protocol 
• 
If the adverse event has not resolved in the protocol-specified dosing window, the next 
scheduled dose will be skipped and dosing will be resumed at the subsequent scheduled 
dose. 
• 
If > 1 dose is expected to be skipped, the dosing schedule modifications must be discussed 
with the clinical research organization (CRO) medical monitor prior to implementation. 
 
Permanent discontinuation of study drug for related adverse events or other criteria. 
Any ≥ Grade 3 eye pain or reduction of visual acuity or any ≤ Grade 2 ocular toxicity that does not 
respond to topical therapy. 
• 
Any ≥ Grade 3 bronchospam or other hypersensitivity or other hypersensitivity reaction 
• 
Any other ≥ Grade 3 Grade 3 non-skin related adverse event with the exception of the events 
listed under “Exceptions to Permanent Discontinuation” (below)” 
• 
Any ≥ Grade 4 adverse event 
• 
Any adverse event, laboratory abnormality or intercurrent illness which, in the judgment of 
the investigator, presents a substantial clinical risk to the patient wit the continued study drug 
dosing. 
 
Exceptions to Permanent Discontinuation 
In selected situations, temporary discontinuation will occur until toxicity resolves to ≤ Grade 1 
severity.  Re-starting of doses will be based on the criteria defined above.  Such exceptions are: 
 
 
• 
Potentially reversible inflammation (< Grade 4), attributable to a local anti-tumor reaction and 
a potential therapeutic response. This includes inflammatory reactions at sites of tumor 
resections or in draining lymph nodes, or at sites suspicious for, but not diagnostic of 
metastasis; 
• 
Hospitalization for ≤ Grade 2 adverse events where the primary reason for hospitalization is 
to expedite the clinical work-up 
• 
Patients with the following conditions where the investigators opinion continuing study drug 
administration is justified: 
• 
Any ≤ Grade 2 ocular toxicity that has responded to topical therapy 
• 
Endocrinopathies where clinical symptoms are controlled with appropriate hormone 
replacement therapy. 
 
Note:  Study drug may not be restarted while the patient is being treated with systemic 
corticosteroids except for patients on stable doses of hormone replacement therapy such as 
hydrocortisone. 
 
 
11.2.2. Safety related to ILI 


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Melphalan has been used for regional chemotherapy for metastatic melanoma since 1957. It has 
proven efficacy and safety in conjunction with Dactinomycin in the use of ILI. The most common 
side effects of both of these drugs is myelosuppression, however, none of the patients had 
myelosuppression in the ILI trial performed at MSKCC.  Dactinomycin, a chemotherapy that will be 
used in ILI has also caused Myelosuppression. 
 
ILI has been shown to be effective and safe. The most common toxicity from limb perfusion is soft 
tissue damage. This includes erythema of the skin, blistering and sloughing of the epidermis, nail 
loss, edema of the soft tissues, limb pain, and pain at site of biopsy.  A well established system to 
score acute limb toxicity (Weiderbink Toxicity Scale, Appendix 7) will be used to grade limb toxicity. 
 
All patients experiencing Grade 4 or 5 limb toxicity will be removed from treatment. We will keep 
them on the study, and continue to follow them within the intention to treat anaylsis, but they will not 
receive any more therapy with Ipilimumab. If a Grade 4 or 5 toxicity occurs again, the study will be 
terminated. 
 
If Grade 3 limb toxicity occurs, the Ipilimumab will be held until it returns to Grade 0-1.  Patients 
receiving Ipilimumab must be monitored carefully for the development of immune breakthrough 
events, as blocking CTLA-4 may allow the emergence of auto-reactive T cells as discussed above. 
 
 
11.3. 
Immune-Related Adverse Events (IRAEs): Definition, Monitoring, 
and Treatment 
 
Blocking CTLA-4 function may permit the emergence of auto-reactive T cells and resultant clinical 
autoimmunity. Rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, hepatitis, and hypopituitarism were 
drug-related, presumptive autoimmune events, now termed IRAEs, noted in previous ipilimumab 
studies. 
 
For the purposes of this study, an IRAE is defined as an AE of unknown etiology associated with 
drug exposure and consistent with an immune phenomenon. Efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin or other etiologic causes prior to labeling an AE an IRAE. 
Serological, immunological, and histological (biopsy) data should be used to support the diagnosis of 
an immune-mediated toxicity. Suspected IRAEs must be documented on an AE or SAE form. 
 
Patients should be informed of and carefully monitored for evidence of clinically significant systemic 
IRAE (e.g., systemic lupus erythematosus-like diseases) or organ-specific IRAE (e.g., rash, colitis, 
uveitis, hepatitis or thyroid disease). If an IRAE is noted, appropriate work-up (including biopsy if 
possible) should be performed, and steroid therapy may be considered if clinically necessary. See 
Appendix 3 for suggested work-up and treatment of IRAEs. 
It is unknown if systemic corticosteroid therapy has an attenuating effect on ipilimumab activity. 
However, clinical anti-tumor responses have been maintained in patients treated with corticosteroids 
and discontinued from ipilimumab. If utilized, corticosteroid therapy should be individualized for each 
patient. Prior experience suggests that colitis manifested as ≥ Grade 3 diarrhea requires 
corticosteroid treatment. See Appendix 4 for additional details. 


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11.3.1. Treatment of Infusion Reactions Associated with Ipilimumab 
 
 
Since ipilimumab contains only human protein sequences, it is less likely that any allergic reaction 
will be seen in patients. However, it is possible that infusion of ipilimumab will induce a cytokine 
release syndrome that could be evidenced by fever, chills, rigors, rash, pruritus, hypotension, 
hypertension, bronchospasm, or other symptoms. No prophylactic pre-medication will be given 
unless indicated by previous experience in an individual patient. Reactions should be treated based 
upon the following recommendations. 
 
 
• 
For mild symptoms (e.g., localized cutaneous reactions such as mild pruritus, flushing, rash): 
− Decrease the rate of infusion until recovery from symptoms, remain at bedside and monitor 
patient. 
− Complete the ipilimumab infusion at the initial planned rate. 
− Diphenhydramine 50 mg IV may be administered at the discretion of the treating physician 
and patients may receive additional doses with close monitoring. 
− Premedication with diphenhydramine may be given at the discretion of the investigator for 
subsequent doses of ipilimumab. 
 
 
• 
For moderate symptoms (any symptom not listed above [mild symptoms] or below [severe 
symptoms] such as generalized pruritus, flushing, rash, dyspnea, hypotension with systolic BP 
>80 mmHg): 
− Interrupt ipilimumab. 
− Administer diphenhydramine 50 mg IV. 
− Monitor patient closely until resolution of symptoms. 
− Corticosteroids may abrogate any beneficial immunologic effect, but may be administered at 
the discretion of the treating physician. 
− Resume ipilimumab infusion after recovery of symptoms. 
− At the discretion of the treating physician, ipilimumab infusion may be resumed at one half 
the initial infusion rate, then increased incrementally to the initial infusion rate. 
− If symptoms develop after resumption of the infusion, the infusion should be discontinued 
and no additional ipilimumab should be administered that day. 
− The next dose of ipilimumab will be administered at its next scheduled time and may be 
given with pre-medication (diphenhydramine and acetaminophen) and careful monitoring, 
following the same treatment guidelines outlined above. 
− At the discretion of the treating physician additional oral or IV antihistamine may be 
administered prior to dosing with ipilimumab. 
• 
For severe symptoms (e.g., any reaction such as bronchospasm, generalized urticaria, systolic 
blood pressure <80 mm Hg, or angioedema): 
− Immediately discontinue infusion of ipilimumab, and disconnect infusion tubing from the 
subject. 
− Consider bronchodilators, epinephrine 1 mg IV or subcutaneously, and/or diphenhydramine 
50 mg IV, with solumedrol 100 mg IV, as needed. 
− Patients should be monitored until the investigator is comfortable that the symptoms will not 
recur. 
− No further ipilimumab will be administered. 


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• 
In case of late-occurring hypersensitivity symptoms (e.g., appearance within one week after 
treatment of a localized or generalized pruritus), symptomatic treatment may be given (e.g., oral 
antihistamine, or corticosteroids). 
 
 
11.3.2. Treatment of Ipilimumab-Related Isolated Drug Fever 
 
 
In the event of isolated drug fever, the investigator must use clinical judgment to determine if the 
fever is related to the ipilimumab or to an infectious etiology. If a patient experiences isolated drug 
fever, for the next dose, pre-treatment with acetaminophen or non-steroidal anti-inflammatory agent 
(investigator discretion) should be instituted and a repeated antipyretic dose at 6 and 12 hours after 
ipilimumab infusion, should be administered. The infusion rate will remain unchanged for future 
doses. If a patient experiences recurrent isolated drug fever following premedication and post dosing 
with an appropriate antipyretic, the infusion rate for subsequent dosing should be decreased to 50% 
of the previous rate. If fever recurs following infusion rate change, the investigator should assess the 
patient’s level of discomfort with the event and use clinical judgment to determine if the patient 
should receive further ipilimumab. 
 
 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1. Efficacy Evaluation 
The physician will identify assessable extremity lesions pre-infusion which will be measured and 
recorded on the pre-infusion data sheet. This will involve marking the selected sites on an anatomic 
diagram of the extremity and supplying the measurements of these sites, using the diagram supplied 
in appendix 10.  In patients with extensive, small deposits of tumor, a description of the size of 3 
index lesions and approximate number will suffice for pre-infusion documentation.  Pre-infusion 
photographs will be taken with a ruler along lesions. 
 
Tumor assessment will be measured by the immune related response criteria (irRC), as discussed 
below.  Progression free survival, from time of ILI, will be determined by measuring the index 
lesions, non-index lesions, and new lesions as described below. Patients with deep lesions will have 
repeat CT Scan evaluation to quantitate the lesions.  Since many patients have been noted to have 
lesions which initially progress on therapy with Ipilimumab, progression free survival rate will be 
determined at 12 months. 
 
12.2. Definition of Measurable/Non-Measurable and Index/Non-Index Lesions 
 
Definitions of lesions are based on modified immune related response criteria, irRC, developed by 
Dr. Wolchok and described below[32]. 
 
12.3. Definition of Measurable and Non-Measurable Lesions 
• 
Measurable  Lesions  are  lesions  that  can  be  accurately  measured  in  two  perpendicular 
diameters, with at least one diameter ≥ 20 mm and the other dimension ≥ 10 mm (10 mm x 10 
mm for spiral CT). The area will be defined as the product of the largest diameter with its 
perpendicular. Skin lesions can be considered measurable, and are the primary lesions being 
measured in this study. 


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• 
Non-Measurable   (evaluable)   Lesions   are   all   other   lesions,   including   unidimensionally 
measurable disease and small lesions (lesions without at least one diameter ≥ 20 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. 
− All measurable and non-measurable lesions should be measured at screening and at the 
defined tumor assessment time points (section 6, table).   Extra assessments may be 
performed, as clinically indicated, if there is a suspicion of progression. 
 
12.4. Definition of Index/Non-Index Lesions 
 
All measurable lesions, up to a maximum of three lesions per extremity and ten lesions in total, 
should be identified as index lesions to be measured and recorded on the medical record at 
Screening. In addition, index lesions should be selected based on their size (lesions with the longest 
diameters), their suitability for accurate repeat assessment by imaging techniques, and how 
representative they are of the patient’s tumor burden. At Screening, a sum of the products of 
diameters (SPD) for all index lesions will be calculated and considered the baseline sum of the 
products of diameters. Response criteria to be followed are listed below. The baseline sum will be 
used as the reference point to determine the objective tumor response of the index lesions at tumor 
assessment (TA). 
 
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 recorded on the medical record and should 
be evaluated at the same assessment time points as the index lesions. In subsequent assessments, 
non-index lesions will be recorded as “stable or decreased disease,” “absent,” or “progression.” 
 
12.5. Definition of Tumor Response Using irRC 
 
The sum of the products of diameters at tumor assessment using the immune-related response 
criteria (irRC) for progressive disease incorporates the contribution of new measurable lesions. Each 
net Percentage Change in Tumor Burden per assessment using irRC criteria accounts for the size 
and growth kinetics of both old and new lesions as they appear[32]. 
 
12.6. Definition of Index Lesions Response Using irRC 
• 
irComplete  Response  (irCR):  Complete  disappearance  of  all  index  lesions.  This  category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
• 
irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum of the 
products of the two largest perpendicular diameters of all index and all new measurable lesions 
(ie., Percentage Change in Tumor Burden). 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. 
• 
irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of progressive 
disease. 


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• 
irProgressive Disease (irPD): At least 25% increase Percentage Change in Tumor Burden (i.e., 
taking sum of the products of all index lesions and any new lesions) when compared to SPD at 
nadir. 
 
12.7. Definition of Non-Index Lesions Response Using irRC 
• 
irComplete Response (irCR): Complete disappearance of all non-index lesions. This category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
• 
irPartial Response (irPR) or irStable Disease (irSD): non-index lesion(s) are not considered in 
the definition of PR, these terms do not apply. 
• 
irProgressive  Disease  (irPD):  Increases  in  number  or  size  of  non-index lesion(s)  does  not 
constitute progressive disease unless/until the Percentage Change in Tumor Burden increases 
by 25% (i.e., the SPD at nadir of the index lesions increases by the required amount). 
 
12.8. Impact of New Lesions on irRC 
 
New lesions in and by themselves 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 criteria for tumor 
response. Therefore, new non-measurable lesions will not discontinue any subject from the study. 
 
12.9. Definition of Overall Response Using irRC 
 
Overall response using irRC will be based on these criteria: 
 
• 
Immune-Related  Complete  Response  (irCR):  Complete  disappearance  of  all  tumor  lesions 
(index and nonindex together with no new measurable/unmeasurable lesions) for at least 4 
weeks from the date of documentation of complete response. 
• 
Immune-Related  Partial  Response  (irPR):  The  sum  of  the  products  of  the  two  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 two largest perpendicular 
diameters of all index lesions and of new measurable lesions are added together to provide the 
Immune Response Sum of Product Diameters (irSPD). A decrease, relative to baseline of the 
irSPD compared to the previous SPD baseline, of 50% or greater is considered an immune 
Partial Response (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 to confirm PD 
by serial imaging. Any of the following will constitute progressive disease: 
 
− At least 25% increase in the sum of the products of all index lesions over baseline SPD 
calculated for the index lesions. 
 
− At least a 25% increase in the sum of the products of all index lesions and new measurable 
lesions (irSPD) over the baseline SPD calculated for the index lesions. 


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Table 3: 
Immune-Related Response Criteria Definitions 
 
Index 
Lesion 
Definition 
Non-Index 
Lesion 
Definition 
New 
Measurable 
Lesions 
New 
Unmeasurable 
Lesions 
Percent change in 
tumor burden 
(including measurable 
new lesions when 
present) 
Overall 
irRC 
Response 
Complete 
Response 
Complete 
Response 
No 
No 
-100% 
irCR 
Partial 
Response 
Any 
Any 
Any 
> -50% 
irPR 
<-50% to <+25% 
irSD 
>+25% 
irPD 
Stable 
Disease 
Any 
Any 
Any 
<-50% to <+25% 
irSD 
>+25% 
irPD 
Progressive 
Disease 
Any 
Any 
Any 
>+25% 
irPD 
 
 
 
12.10. 
Immune-Related Best Overall Response Using irRC (irBOR) 
 
irBOR is the best confirmed irRC overall response over the study as a whole, recorded between the 
date of first dose until the last tumor assessment before subsequent therapy (except for local 
palliative radiotherapy for painful bone lesions) for the individual subject in the study. For the 
assessment of irBOR, all available assessments per subject are considered. 
 
irCR or irPR determinations included in the irBOR assessment must be confirmed by a second 
(confirmatory) evaluation meeting the criteria for response and performed no less than 4 weeks after 
the criteria for response are first met. 
 
12.11. 
Response Endpoints 
 
Ipilimumab is expected to trigger immune-mediated responses, which require activation of the 
immune system prior to the observation of clinical responses. Such immune activation may take 
weeks to months to be evident. Some patients may have objective volume increase of tumor lesions 
or other disease parameters (based on study indication, ie, hematologic malignancies) within 12 
weeks following start of ipilimumab dosing. Such patients may not have had sufficient time to 
develop the required immune activation or, in some patients, tumor volume or other disease 
parameter increases may represent infiltration of lymphocytes into the original tumor or blood. In 
conventional studies, such tumor volume or relevant laboratory parameter increases during the first 
12 weeks of the study would constitute PD and lead to discontinuation of imaging to detect 
response, thus disregarding the potential for subsequent immune-mediated clinical response. 


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Therefore, patients with tumor volume increase detected or lack of laboratory parameter response 
documentation prior to week 12 but without rapid clinical deterioration should continue to be treated 
with ipilimumab and clinically observed with a stringent imaging schedule to allow detection of a 
subsequent tumor response. This will improve the overall assessment of the clinical activity or 
ipilimumab and more likely capture its true potential to induce clinical responses. 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
13.1. Discontinuation of Study Therapy 
Subjects MUST be discontinued from study therapy AND withdrawn from the study for the following 
reasons: 
 
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
 
• 
Any clinical adverse event, laboratory abnormality or intercurrent illness which, in the opinion of 
the investigator, indicates that continued treatment with study therapy is not in the best interest 
of the subject 
 
• 
Pregnancy 
 
− All WOCBP should be instructed to contact the investigator immediately if they suspect they 
might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation. Institutional policy and local regulations should determine the frequency of on 
study pregnancy tests for WOCBP enrolled in the study. 
 
− The investigator must immediately notify BMS in the event of a confirmed pregnancy in a 
patient participating in the study. 
 
• 
Termination of the study by Bristol-Myers Squibb (BMS). 
 
• 
Imprisonment or the compulsory detention for treatment of either a psychiatric or physical (e.g., 
infectious disease) illness. 
 
13.2. Permanent Discontinuation for Related Adverse Events 
 
 
• 
Any ≥ Grade 2 eye pain or reduction of visual acuity that does not respond to topical therapy and 
does not improve to ≤ Grade 1 severity within 2 weeks of starting therapy, OR, requires systemic 
treatment. 
• 
Any ≥ Grade 3 bronchospasm or other hypersensitivity reaction. 
• 
Any other ≥ Grade 3 non-skin related adverse event with the exception of events listed under 
“No Discontinuation” (below). 
• 
Any adverse event, laboratory abnormality or intercurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the patient with continued dosing. 


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13.3. Exceptions to Permanent Discontinuation 
• 
Potentially reversible inflammation (< Grade 4), attributable to a local anti-tumor reaction and a 
potential therapeutic response. This includes inflammatory reactions at sites of tumor resections 
or in draining lymph nodes, or at sites suspicious for, but not diagnostic of metastasis. 
• 
Hospitalization for ≤ Grade 2 adverse events where the primary reason for hospitalization is to 
expedite the clinical work-up. 
• 
Patients with the following conditions where in the investigator’s opinion continuing study drug 
administration is justified: 
− Ocular toxicity that has responded to topical therapy. 
− Endocrinopathies where clinical symptoms are controlled with appropriate hormone 
replacement therapy. Note: Ipilimumab may not be restarted while the patient is being 
treated with systemic corticosteroids except for patients on stable doses of hormone 
replacement therapy such as hydrocortisone. 
 
 
14.0 
BIOSTATISTICS 
 
This is a phase II study of the addition of ipilimumab to isolated limb infusion with standard 
melphalan and dactinomycin.   The primary objective of the study is to safety and efficacy in this 
patient population with the primary efficacy measure defined as progression-free survival (starting 
from the date of ILI) at 1 year (week 48-54).  Due to the length of time required to observe the 
primary endpoint, efficacy evaluation will be based on a single stage design with an alpha level of 
0.1.  Based upon the only prospective trial of patients with ILI, performed at MSKCC, the 23% of 
patients had a complete response with a median duration of one year[29]. This trial estimates a 
progression-free survival in patients with advanced stage melanoma of approximately 30%; with the 
proposed treatment regimen it is hypothesized that one year progression-free survival will improve to 
50%. Thirty-nine patients will be accrued. If 16 or more out of 39 are progression-free at one year 
the regimen would have demonstrated acceptable effectiveness. With 39 patients the study will 
have 90% power with level of significance of 10%. 
 
Response rate will be assessed according to the immune related response criteria outlined in 
section 6.4.3.  Proportion of responding patients along with 95% confidence interval will be reported. 
Patients will be followed for toxicity.  Acute limb toxicity will be assessed using the Weiderbink 
Toxicity scale (Appendix 7). If at any point in the study a grade 4 or 5 Wiederbink toxicity is 
observed in any patients, the dose of ipilimumab will be reduced to 3mg/kg.  If grade 4 or 5 toxicity 
occurs again in a separate patient, the study will be terminated.  All other toxicities will be tabulated 
according NCI Common Toxicity Criteria. 
 
Summaries of antibody response, comparison of pretreatment with post-ipilimumab and end of 
treatment will be assessed for percent of CD4 and CD8 cells as well as CD25, FOXP3, ICOS, CD45, 
CD67 and CD152 cells among others. This will be exploratory and results will be descriptive. 
 
It is anticipated that 2 patients per month will be accrued to the study and the study will be 
completed in approximately 2-3 years. 


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15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
 
During the registration process registering individuals will be required to complete a protocol specific 
Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 8:30am – 
5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic Registration 
System (http://ppr/). The completed signature page of the written consent/RA or verbal script/RA, a 
completed Eligibility Checklist and other relevant documents must be uploaded via the PPR 
Electronic Registration System. 
 
 
 
15.2 
Randomization 
 
This study does not involve randomization. 
 
16.0 
DATA MANAGEMENT ISSUES 
 
All data will be collected by an RSA. A CRDB database will be created on a password locked server 
at MSKCC for access to the data limited to the study coordinators. It is estimated that this study will 
accrue approximately 39 patients over a 3 year period. 
 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the study team, 
at a minimum of two times per year, more frequently if indicated. 
 
16.1.1. Compliance with the Protocol and Protocol Revisions 
 
The study must be conducted as described in the final approved protocol. Documentation of 
approval signed by the chairperson or designee of the IRB(s) must be sent to your BMS protocol 
manager. 
 
All revisions (protocol amendments, administrative letters, and changes to the informed consent) 
must be submitted to your BMS protocol manager. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable opinion 


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from the IRB of an Amendment, except where necessary to eliminate an immediate hazard(s) to 
study patients. 
 
See also 21CFR for definitions of amendment and requirements. 
 
16.1.2. Informed Consent 
 
Investigators must ensure that subjects, or, in those situations where consent cannot be given by 
subjects, their legally acceptable representative, are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. Freely given written informed consent must be obtained from every subject or, in those 
situations where consent cannot be given by subjects, their legally acceptable representative, prior 
to clinical study participation, including informed consent for any screening procedures conducted to 
establish subject eligibility for the study. 
 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society. 
 
Study treatment and procedures, outlined in the Treatment/Intervention Plan above, will only take 
place at MSK Manhattan sites. Potential research subjects identified at the MSK West Harrison site 
will be offered study participation after being informed that all study treatment and procedures must 
take place at the Manhattan sites. Investigators and their research team, following the informed 
consent process described above, may obtain written informed consent from subjects at the MSK 
West Harrison site. Only consent, however, can be obtained at the West Harrison site. 
 
 
 
16.1.3. Records and Reports 
 
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation (e.g. medical record) on each 
individual treated with Ipilimumab or entered as a control in the investigation. The investigator is 
required to retain, in a confidential manner, the data pertinent to the study. 
 
16.1.4. Good Clinical Practice 
 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50). 
 
The study will be conducted in compliance with the protocol. The protocol and any amendments and 
the subject informed consent will receive Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) approval/favorable opinion prior to initiation of the study. 
 
All potential serious breaches must be reported to BMS immediately. A serious breach is a breach of 
the conditions and principles of GCP in connection with the study or the protocol, which is likely to 
affect, to a significant degree, the safety or physical or mental integrity of the subjects of the study or 
the scientific value of the study. 
 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective task(s). This study will not use the services of study personnel 


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where sanctions have been invoked or where there has been scientific misconduct or fraud (eg, loss 
of medical licensure, debarment). 
 
Systems with procedures that ensure the quality of every aspect of the study will be implemented. 
 
16.1.5. Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
 
Before study initiation, the investigator must have written and dated approval/favorable opinion from 
the IRB/IEC for the protocol, consent form, subject recruitment materials/process (eg, 
advertisements), and any other written information to be provided to subjects. The investigator 
should also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling, 
information to be provided to subjects and any updates. 
 
The investigator should provide the IRB/IEC with reports, updates and other information (eg, 
expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures 
 
16.1.6. Records Retention 
 
The investigator must retain Ipilimumab disposition records, source documents, and case histories 
designed to record all observations and other data pertinent to the investigation (e.g. medical record) 
for the maximum period required by applicable regulations and guidelines, or Institution procedures. 
 
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, IRB). Documentation of 
such transfer must be provided to BMS. 
 
Individuals treated with Ipilimumab or entered as a control in the investigation. The investigator is 
required to retain, in a confidential manner, the data pertinent to the study. 
 
Data will be captured in Clinical Research Database (CRDB) along with the clinical data capture 
tools in Appendix 7. 
 
 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new policies 
set forth by the NCI in the document entitled “Policy of the National Cancer Institute for Data and 
Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html.  The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and Safety 
Monitoring Plans can be found on the MSKCC Intranet at: http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety and 
quality. There are institutional processes in place for quality assurance (e.g., protocol monitoring, 
compliance and data verification audits, therapeutic response, and staff education on clinical 
research QA) and departmental procedures for quality control, plus there are two institutional 
committees that are responsible for monitoring the activities of our clinical trials programs. The 
committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, and the 
Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, report to the Center’s 
Research Council and Institutional Review Board. 


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During the protocol development and review process, each protocol will be assessed for it’s level of 
risk and degree of monitoring required.  Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) Will be addressed and the monitoring 
procedures will be established at the time of protocol activation 
 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
17.1 
Privacy 
 
Informed consent will be obtained from all research subjects. The informed consent document will 
explain to the subjects the risks, benefits, toxicities/side effects, alternatives/options for treatment, 
and financial costs/burdens. Participation in the study is voluntary. The study drug will be provided 
by Bristol Myers Squibb (BMS) at no cost to the patient. Patients will be billed for patient care 
services. 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information pursuant 
to a completed and signed Research Authorization form. The use and disclosure of protected health 
information will be limited to the individuals described in the Research Authorization form. A 
Research Authorization form must be completed by the Principal Investigator and approved by the 
IRB and Privacy Board (IRB/PB 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at  sae@mskcc.org. The report should contain the following 
information: 
 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 


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o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office. 
 
17.2.1 Serious Adverse Event Reporting 
 
17.2.1.1. Collection of Safety Information 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre- 
existing medical condition in a patient or 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 (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of investigational product, 
whether or not considered related to the investigational product. 
 
17.2.1.2. Serious Adverse Events 
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 that hypothetically might have caused death if it were more 
severe) 
 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see “note” 
below for exceptions) 
 
• 
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.) 
 
• 
Although overdose and cancer are not always serious by regulatory definition, these events 
should be reported on an SAE form and sent to BMS in an expedited manner. An overdose is 
defined as the accidental or intentional ingestion or infusion of any dose of a product that is 
considered both excessive and medically important. 
 
NOTE: The following hospitalizations are not considered SAEs in BMS clinical studies: 
 
• 
 vis it to th e e m e rg e n c y ro o m o r o th e r h o s p ita l d e p a rtm e n t fo r le s s th a n 2 4 hours that does not 
result in admission (unless considered an “important medical event” or a life-threatening event) 


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• 
 le c tive s u rg e ry, p la n n e d b e fo re s ig n in g c o n s e n t 
 
• 
admissions as per protocol for a planned medical/surgical procedure 
 
• 
routine health assessment requiring admission for baseline/trending of health status (eg, routine 
colonoscopy) 
 
• 
medical/surgical admission for purpose other than remedying ill health state and was 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 (e.g., lack of housing, economic inadequacy, care-giver 
respite, family circumstances, administrative). 
 
Note that all pregnancies, regardless of outcome, must be reported to the sponsor on a Pregnancy 
Surveillance Form, not an SAE form. All pregnancies must be reported and followed to outcome, 
including pregnancies that occur in the female partner of a male study subject. See Section 8.4 for 
instructions on reporting pregnancies. 
 
17.2.1.3. Nonserious Adverse Events 
All adverse events that are not classified as serious. 
 
17.2.1.4. Assignment of Adverse Event Intensity and Relationship to 
Investigational Product 
All adverse events, including those that are serious, will be graded according to the National Cancer 
Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE), Version 4.0. 
 
The following categories and definitions of causal relationship to investigational product as 
determined by a physician should be used for adverse events: 
 
• 
Certain: There is a reasonable causal relationship between the investigational product and the 
AE. The event responds to withdrawal of investigational product (dechallenge), and recurs with 
rechallenge when clinically feasible. 
 
• 
Probable: There is a reasonable causal relationship between the investigational product and the 
AE. The event responds to dechallenge. Rechallenge is not required. 
 
• 
Possible: There is reasonable causal relationship between the investigational product and the 
AE. Dechallenge information is lacking or unclear. 
 
• 
Not likely: There is a temporal relationship to investigational product administration, but there is 
not a reasonable causal relationship between the investigational product and the AE. 
 
• 
Not Related: There is not a temporal relationship to investigational product administration (too 
early, or late, or investigational product not taken), or there is a reasonable causal relationship 
between noninvestigational product, concurrent disease, or circumstance and the AE. 
 
The expression “reasonable causal relationship” is meant to convey in general that there are 
facts (eg, evidence such as de-challenge/re-challenge) or other arguments to suggest a 
positive causal relationship. 


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17.2.1.5. Collection and Reporting 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its 
individual symptoms. The following information should be captured for all AEs: onset, duration, 
intensity, seriousness, relationship to investigational product, action taken, and treatment required. If 
treatment for the AE was administered, it should be recorded in the medical record. 
 
The investigator shall supply the sponsor and Ethics Committee with any additional requested 
information, notably for reported deaths of subjects. 
 
17.2.1.6. Serious Adverse Events 
Following the subject’s written consent to participate in the study, all SAEs must be collected, 
including those thought to be associated with protocol-specified procedures. All SAEs must be 
collected that occur within 70 days of discontinuation of dosing of the investigational product. If 
applicable, SAEs must be collected that relate to any later protocol-specified procedure (eg, a follow- 
up skin biopsy). The investigator should notify BMS of any SAE occurring after this time period that 
is believed to be certainly, probably, or possibly related to the investigational product or protocol- 
specified procedure. 
 
All SAEs whether related or unrelated to the ipilimumab, must be immediately reported to BMS (by 
the investigator or designee) within 24 hours of becoming aware of the event. If only limited 
information is initially available, follow-up reports are required. The original SAE form must be kept 
on file at the study site. A copy of the SAE form required by Bristol-Myers Squibb Complany (BMS) 
is attached (appendix 9). 
 
All SAEs should be faxed or emailed to BMS at: 
 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
For studies conducted under an Investigator IND, any event that is both serious and unexpected 
must be reported to the FDA as soon as possible and, in no event, later than 7 days (death or life- 
threatening event) or 15 days (all other SAEs) after the investigator’s or institution’s initial receipt of 
the information. BMS will be provided with a simultaneous copy of all adverse events filed with the 
FDA. SAEs should be reported on the MedWatch Form 3500A, which can be accessed at: 
 
http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 


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All SAEs should simultaneously be faxed or e-mailed to BMS at: 
 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
Serious adverse events, whether related or unrelated to investigational product, must be recorded 
on the SAE page and reported expeditiously to BMS (or designee) to comply with regulatory 
requirements. An SAE report should be completed for any event where doubt exists regarding its 
status of seriousness. 
 
All SAEs must be immediately reported by confirmed facsimile transmission (fax) and mailing of the 
completed SAE page. In some instances where a facsimile machine is not available, overnight 
express mail may be used. 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.) In selected circumstances, the protocol may specify conditions that require additional 
telephone reporting. 
 
If the investigator believes that an SAE is not related to the investigational product, 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 page. 
 
If an ongoing SAE changes in its intensity or relationship to the investigational product, a follow-up 
SAE report should be sent immediately to the sponsor. As follow-up information becomes available it 
should be sent immediately using the same procedure used for transmitting the initial SAE report. All 
SAEs should be followed to resolution or stabilization. 
 
17.2.1.7. Handling of Expedited Safety Reports 
In accordance with local regulations, BMS will notify investigators of all SAEs that are suspected 
(certainly, probably, or possibly related to the investigational product) and unexpected (ie, not 
previously described in the Investigator Brochure). 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). 
 
Other important findings which may be reported by the sponsor as an ESR include: increased 
frequency of a clinically significant expected SAE, an SAE considered associated with study 
procedures that could modify the conduct of the study, lack of efficacy that poses significant hazard 
to study subjects, clinically significant safety finding from a nonclinical (eg, animal) study, important 
safety recommendations from a study data monitoring committee, or sponsor decision to end or 
temporarily halt a clinical study for safety reasons. 
 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the 
Investigator Brochure. 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. 


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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). 
 
17.2.1.8. Nonserious Adverse Events 
The collection of nonserious AE information should begin at initiation of investigational product. 
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. 
 
If an ongoing nonserious AE worsens in its intensity, or if its relationship to the investigational 
product changes, a new nonserious AE entry for the event should be completed. Nonserious AEs 
should be followed to resolution or stabilization, or reported as SAEs if they become serious. Follow- 
up is also required for nonserious AEs that cause interruption or discontinuation of investigational 
product, or those that are present at the end of study participation. Subjects with nonserious AEs at 
study completion should receive post-treatment follow-up as appropriate. 
 
All identified nonserious AEs must be recorded and described in the medical record. 
 
17.2.1.9. Pregnancy 
Sexually active WOCBP must use an effective method of birth control during the course of the study, 
in a manner such that risk of failure is minimized. Before enrolling WOCBP in this clinical study, the 
investigator must review the guideline about study participation for WOCBP which can be found in 
the GCP Manual for Investigators. The topics include the following: 
 
• 
General Information 
 
• 
Informed Consent Form 
 
• 
Pregnancy Prevention Information Sheet 
 
• 
Drug Interactions with Hormonal Contraceptives 
 
• 
Contraceptives in Current Use 
 
• 
Guidelines for the Follow-up of a Reported Pregnancy. 
 
Before study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during 
study participation and the potential risk factors for an unintentional pregnancy. The subject must 
sign an informed consent form documenting this discussion. 
 
All WOCBP MUST have a negative pregnancy test within 72 hours before receiving ipilimumab. The 
minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG. If the 
pregnancy test is positive, the subject must not receive ipilimumab and must not be enrolled in the 
study. 
 
In addition, all WOCBP should be instructed to contact the investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period) at any time during study participation. 
 
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 


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permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety). The investigator must immediately notify BMS of this event and record the pregnancy on the 
Pregnancy Surveillance Form (not an SAE form). Initial information on a pregnancy must be 
reported immediately to BMS, and the outcome information provided once the outcome is known. 
Completed Pregnancy Surveillance Forms must be forwarded to BMS according to SAE reporting 
procedures. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to the 
sponsor. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated. In addition, the investigator must report to 
BMS, and follow-up on information regarding the course of the pregnancy, including perinatal and 
neonatal outcome. Infants should be followed for a minimum of 8 weeks. 
 
17.2.1.10. 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 in the medical record. 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. 
 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 


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19.0 
REFERENCES 
 
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costimulation. Annual Review of Immunology, 1996. 14: p. 233-58. 
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Schwartz, R.H., Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 
in interleukin-2 production and immunotherapy. Cell, 1992. 71(7): p. 1065-8. 
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Chen, L., et al., Costimulation of antitumor immunity by the B7 counterreceptor for the 
T lymphocyte molecules CD28 and CTLA-4. Cell, 1992. 71(7): p. 1093-102. 
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Townsend, S.E. and J.P. Allison, Tumor rejection after direct costimulation of CD8+ T 
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Allison, J.P., A.A. Hurwitz, and D.R. Leach, Manipulation of costimulatory signals to 
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Linsley, P.S., et al., CTLA-4 is a second receptor for the B cell activation antigen B7. 
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Thompson, C.B. and J.P. Allison, The emerging role of CTLA-4 as an immune 
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Walunas, T.L., et al., CTLA-4 can function as a negative regulator of T cell activation. 
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Kearney, E.R., et al., Antigen-dependent clonal expansion of a trace population of 
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Krummel, M.F. and J.P. Allison, CD28 and CTLA-4 have opposing effects on the 
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12. 
Krummel, M.F., T.J. Sullivan, and J.P. Allison, Superantigen responses and co- 
stimulation: CD28 and CTLA-4 have opposing effects on T cell expansion in vitro and 
in vivo. International Immunology, 1996. 8(4): p. 519-23. 
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Tivol, E.A., et al., Loss of CTLA-4 leads to massive lymphoproliferation and fatal 
multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. 
Immunity, 1995. 3(5): p. 541-7. 
14. 
Waterhouse, P., et al., Lymphoproliferative disorders with early lethality in mice 
deficient in Ctla-4. Science, 1995. 270(5238): p. 985-8. 
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Chambers, C.A., T.J. Sullivan, and J.P. Allison, Lymphoproliferation in CTLA-4- 
deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. 
Immunity, 1997. 7(6): p. 885-95. 
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Hodi, F.S., et al., Improved survival with ipilimumab in patients with metastatic 
melanoma. New England Journal of Medicine, 2010. 363(8): p. 711-23. 
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Report, C.C.S., A Randomized, Double-Blind, Multi-center, Phase II Fixed Dose Study 
of Multiple Doses of Ipilimumab (MDX-010) Monotherapy in Patients with Previously 
Treated Unresectable Stage III or IV Melanoma. 2008, Bristol-Myers Squibb Company 
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Report, C.C.S., A Multicenter, Single Arm Phase 2 Study of MDX-010 (BMS 734016) 
Monotherapy in Patients with Previously Treated Unresectable Stage III or IV 
Melanoma. 2008, Bristol-Myers Squibb Company and Medarex Inc. 
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Report., C.C.S., Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study 
Comparing the Safety of Ipilimumab Administered With or Without Prophylactic Oral 
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Korn, E.L., et al., Meta-analysis of phase II cooperative group trials in metastatic stage 
IV melanoma to determine progression-free and overall survival benchmarks for future 
phase II trials. Journal of Clinical Oncology, 2008. 26(4): p. 527-34. 


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21. 
Chapman, P.B., et al., Phase III multicenter randomized trial of the Dartmouth regimen 
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Middleton, M.R., et al., Randomized phase III study of temozolomide versus 
dacarbazine in the treatment of patients with advanced metastatic malignant 
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Bedikian, A.Y., et al., Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients 
with advanced melanoma: the Oblimersen Melanoma Study Group. Journal of Clinical 
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Balch, C.M., et al., An evidence-based staging system for cutaneous melanoma. CA: a 
Cancer Journal for Clinicians, 2004. 54(3): p. 131-49; quiz 182-4. 
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Jaques, D.P., D.G. Coit, and M.F. Brennan, Major amputation for advanced malignant 
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Benckhuijsen, C., et al., Regional perfusion treatment with melphalan for melanoma in 
a limb: an evaluation of drug kinetics. European Journal of Surgical Oncology, 1988. 
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27. 
Kroon, H.M., et al., Outcomes following isolated limb infusion for melanoma. A 14-year 
experience. Annals of Surgical Oncology, 2008. 15(11): p. 3003-13. 
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Brady, M.S., et al., A phase II trial of isolated limb infusion with melphalan and 
dactinomycin for regional melanoma and soft tissue sarcoma of the extremity. Annals 
of Surgical Oncology, 2006. 13(8): p. 1123-9. 
29. 
Noorda, E.M., et al., Isolated limb perfusion: what is the evidence for its use? Annals 
of Surgical Oncology, 2004. 11(9): p. 837-45. 
30. 
Kroon, H.M., et al., Isolated limb infusion as palliative treatment for advanced limb 
disease in patients with AJCC stage IV melanoma. Annals of Surgical Oncology, 2009. 
16(5): p. 1193-201. 
31. 
Hersh, E., et al., Long-term survival of patients (pts) with advanced melanoma treated 
with ipilimumab with or without dacarbazine. J Clin Oncol (Meeting Abstracts), 2009. 
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32. 
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7412-20. 
 
 
 
20.0 
APPENDICES 
 
APPENDIX 1 
LIST OF ABBREVIATIONS 
 
APPENDIX 2 
GENERAL RECOMMENDATIONS FOR IMMUNE-RELATED 
ADVERSE EVENTS (IRAES) 
 
APPENDIX 3 
SUGGESTED WORK-UP AND TREATMENT FOR IMMUNE- 
RELATED ADVERSE EVENTS (IRAES) 
 
APPENDIX 4 
DIARRHEA MANAGEMENT ALGORITHM 
APPENDIX 5 
HEPATOTOXICITY MANAGEMENT ALGORITHM 
APPENDIX 6 
ENDOCRINOPATHY MANAGEMENT ALGORITHM 
APPENDIX 7 
WIEDERBINK CRITERIA 
APPENDIX 8 
SCHEMA STUDY 


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APPENDIX 9 
SAE FORM 
 
APPENDIX 10 
EXTREMITY TUMOR ASSESSMENT FORMS 
 
APPENDIX 11 
VIDEO FOR PATIENTS AVAILABLE ON MSKCC.ORG (EXTERNAL) 
APPENDIX 12 
SKIN TOXICITY MANAGEMENT ALGORITHM 
APPENDIX 13 
NEUROLOGICAL TOXICITY MANAGEMENT ALGORITHM 
APPENDIX 14 
10-101 PATIENT STUDY CALENDAR