Clinical trial NCT03472586
Conditions: Metastatic Malignant Neoplasm in the Liver Metastatic Uveal Melanoma Stage IV Uveal Melanoma AJCC v7
Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University
Start date: 2018-05-02; Completion date: 2024-12-31
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies ipilimumab and nivolumab with immunoembolization in treating patients with uveal melanoma that has spread to the liver. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Immunoembolization may kill tumor cells due to loss of blood supply and develop an immune response against tumor cells. Giving ipilimumab and nivolumab with immunoembolization may work better in treating patients with uveal melanoma.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine the clinical benefit of treatment with immunoembolization (IEMBO) in combination with ipilimumab and nivolumab.

SECONDARY OBJECTIVES:

I. Determine all treatment and immune related toxicities. II. Determine progression free survival. III. Determine overall survival.

Arms: arm 1: Patients receive ipilimumab IV over 30 minutes and nivolumab IV over 30 minutes on day 1. Patients also undergo immunoembolization on day 2. Cycles repeat every 3 weeks for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients with complete response, partial response, or stable disease may receive nivolumab IV on day 1 and undergo immunoembolization on day 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. The interval between treatments may be extended up to every 6 weeks at the discretion of the treating physician.
Interventions: intervention 1: Ipilimumab intervention 2: Nivolumab intervention 3: Embolization Therapy
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Undergo immunoembolization

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
THOMAS JEFFERSON UNIVERSITY 
Kimmel Cancer Center 
 
 
Ipilimumab and Nivolumab in Combination with Immunoembolization 
for the Treatment of Metastatic Uveal Melanoma 
 
Principal Investigator: 
Marlana Orloff, MD 
Division of Medical Oncology 
Thomas Jefferson University 
215-503-9549 
Co-Investigator(s): 
Takami Sato, MD, PhD  
Melissa Wilson, MD, PhD 
Michael Mastrangelo, MD  
Robert Adamo, MD 
Carin Gonsalves, MD  
David Eschelman, MD 
Erin Sharpe-Mills, CRNP 
Haley Klose, CRNP 
Regine Nshimiyimana, CRNP, BPharm, MSN 
Katelyn Clancy, AGPCNP-BC, MSN 
Alizabeth Berry, PA-C, MMS  
Inna Chervoneva, PhD 
Funding Sponsor: 
BMS 
IND/IDE Holder: 
Takami Sato, MD 
IND/IDE Number: 
BB-IND 8260 
BMS Protocol Number: 
CA209-9CH 
Study Product: 
Ipilimumab and Nivolumab in combination with 
Immunoembolization (GM-CSF) 
 
Version: 
Date: 
1 
11.10.16 
2 
9.18.17 
3 
2.25.19 
4 
10.23.19 
5 
12.12.19 
6 
03.17.20 
7 
09.01.20 
 
 
CONFIDENTIAL 
 
This document is confidential and the property of THOMAS JEFFERSON 
UNIVERSITY.  No part of it may be transmitted, reproduced, published, or used by 
other persons without prior written authorization from the study sponsor. 


 
 
 
 
 
2 
Table of Contents 
STUDY SUMMARY ...................................................................................................................................... 5 
STUDY SCHEMA ......................................................................................................................................... 8 
1.0 INTRODUCTION .................................................................................................................................. 9 
1.1 
BACKGROUND ................................................................................................................................ 9 
2.0 STUDY OBJECTIVES ....................................................................................................................... 10 
2.1 
PRIMARY OBJECTIVE .................................................................................................................... 10 
2.2 
SECONDARY OBJECTIVE(S) .......................................................................................................... 10 
2.3 
EXPLORATORY OBJECTIVE(S) ....................................................................................................... 10 
3.0 STUDY DESIGN ................................................................................................................................. 10 
3.1 
GENERAL DESIGN ........................................................................................................................ 10  
3.2 
PRIMARY STUDY ENDPOINTS ........................................................................................................ 11 
3.3 
SECONDARY STUDY ENDPOINTS ................................................................................................... 11 
3.4 
EXPLORATORY STUDY ENDPOINTS ............................................................................................... 11 
4.0 SUBJECT SELECTION AND WITHDRAWAL .................................................................................. 12 
4.1 
INCLUSION CRITERIA .................................................................................................................... 12 
4.2 
EXCLUSION CRITERIA ................................................................................................................... 12 
4.2.1 
Guidance for Women of Childbearing Potential .................................................................... 13 
4.3 
EARLY WITHDRAWAL OF SUBJECTS............................................................................................... 13 
4.3.1 
When and How to Withdraw Subjects ................................................................................... 13 
4.3.2 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ 13 
4.3.3 
Replacement of Subjects ...................................................................................................... 14 
5.0 STUDY DRUG/THERAPY ................................................................................................................. 14 
5.1 
DESCRIPTION/FORMULATION/PROCUREMENT ................................................................................ 14 
5.1.1 
GM-CSF ................................................................................................................................ 14 
5.1.2 
Ethiodized oil ......................................................................................................................... 15 
5.1.3 
Gelatin Sponge ...................................................................................................................... 15 
5.1.4 
Ipilimumab ............................................................................................................................. 15 
5.1.5 
Nivolumab .............................................................................................................................. 17 
5.2 
DOSE RATIONALE ......................................................................................................................... 18 
5.3 
PROCEDURE OF IMMUNOEMBOLIZATION......................................................................................... 18 
5.3.1 
Hospital Admission ................................................................................................................ 18 
5.3.2 
Access of Hepatic Artery ....................................................................................................... 18 
5.3.3 
Embolization .......................................................................................................................... 19 
5.4 
TREATMENT REGIMEN COMBINATION ............................................................................................ 19 
5.5 
RISKS .......................................................................................................................................... 19 
5.6 
PRIOR AND CONCOMITANT THERAPIES .......................................................................................... 20 
6.0 STUDY PROCEDURES ..................................................................................................................... 20 
6.1 
STUDY VISIT SCHEDULE ............................................................................................................... 20 
6.1.1 
Initial Visit .............................................................................................................................. 20 
6.1.2 
Evaluation during treatment  ................................................................................................. 21 
6.1.3 
Post embolization liver biopsy ............................................................................................... 21 
6.1.4 
Office visit at 12 weeks .......................................................................................................... 21 
6.1.5 
Outpatient infusion visits ....................................................................................................... 22 
6.1.6 
Completion of study ............................................................................................................... 23 
6.1.7 
Follow up after study completion ........................................................................................... 23 


 
 
 
 
 
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6.2 
ADVERSE EVENTS AND POTENTIAL RISKS ..................................................................................... 24 
6.3 
DOSE DELAYS AND DOSE MODIFICATIONS. .................................................................................... 24 
6.3.1 
Attributed to immunoembolization with GMCSF ................................................................... 24 
6.3.2 
Attributed to Ipilimumab and Nivolumab or Nivolumab ......................................................... 24 
6.3.3 
Attributed to combination ....................................................................................................... 24 
7.0 STATISTICAL PLAN ......................................................................................................................... 24 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 24 
7.2 
STATISTICAL METHODS ................................................................................................................ 25 
7.2.1 
Analysis Population ............................................................................................................... 25 
7.2.2 
Primary Endpoint ................................................................................................................... 25 
7.2.3 
Secondary and Exploratory Endpoints .................................................................................. 25 
8.0 SAFETY AND ADVERSE EVENTS ................................................................................................... 26 
8.1 
DEFINITIONS ................................................................................................................................ 26 
          8.1.1      Adverse Event…………………………………………………………………………………………………26 
          8.1.2       Serious Adverse Event…………………………………………………………………...…………….…….26 
          8.1.3       Adverse Event Reporting Period………………………………………………………………………….....27 
          8.1.4       Preexisting Condition………………………………………………………………………………………….27 
          8.1.5      General Physical Exam Findings……………………………………………………………………….........27 
          8.1.6      Post-study Adverse Event……………………………………………………………………………………..27 
          8.1.7      Abnormal Laboratory Values………………………………………………………………………………….28 
          8.1.8      Hospitalization, Prolonged Hospitalization, or Surgery………………………………………………….…28 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 28 
    8.3        REPORTING OF ADVERSE EVENTS………………………………………………………………………….29 
8.4 
EVENTS OF SPECIAL INTEREST ..................................................................................................... 30 
8.5 
DATA AND SAFETY MONITORING PLAN .......................................................................................... 30 
8.5.1 
Medical Monitoring and AE/SAE Reporting .......................................................................... 30 
8.5.2 
Data and Safety Monitoring Committee ................................................................................ 30 
    8.6         UNANTICIPATED PROBLEMS……………………………………………………………………………….…32 
    8.7         ADVERSE EVENTS………………………………………………………………………………………………32 
    8.8         SERIOUS ADVERSE EVENTS………………………………………………………………………………….32 
9.0 EVALUATION OF RESPONSE ......................................................................................................... 32 
9.1 
EVALUATION OF CLINICAL RESPONSE……………………………………………………………..………32 
9.2          DEFINITION OF MEASURABLE DISEASE ....................................................................................... 32 
9.3 
BASELINE DOCUMENTATION OF TARGET AND NONTARGET LESIONS ............................................... 33 
9.4 
EVALUATION OVERALL RESPONSE IN LIVER LESIONS ....................................................................... 33 
9.5 
RESPONSE CRITERIS FOR LIVER LESIONS ....................................................................................... 34 
9.6 
PROGRESSION FREE SURVIVAL .................................................................................................... 34 
9.7 
OVERALL SURVIVAL ..................................................................................................................... 35 
10.0 CORRELATIVE STUDIES ................................................................................................................. 35 
10.1 
COLLECTING SAMPLES ................................................................................................................. 35 
10.2 
BIOPSIES ..................................................................................................................................... 35 
10.3 
EVALUATIONS .............................................................................................................................. 35 
11.0 DATA HANDLING AND RECORD KEEPING ................................................................................... 35 
11.1 
CONFIDENTIALITY ......................................................................................................................... 35 
11.2 
SOURCE DOCUMENTS .................................................................................................................. 36 
11.3 
DATA COLLECTION ..................................................................................................................... 36 
11.4 
RECORDS RETENTION .................................................................................................................. 36 
 


 
 
 
 
 
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12.0 STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 36 
12.1 
STUDY MONITORING PLAN ............................................................................................................ 36 
12.2 
AUDITING AND INSPECTING ........................................................................................................... 37 
12.2.1 Independent External and Internal Audits ............................................................................. 37 
13.0 ETHICAL CONSIDERATIONS .......................................................................................................... 38 
13.1 
CONFLICT OF INTEREST ................................................................................................................ 38 
13.2 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 38 
14.0 REFERENCES ................................................................................................................................... 39 
15.0 APPENDICES .................................................................................................................................... 40 
15.1 
STUDY SCHEDULE ........................................................................................................................ 40 
15.2 
ADVERSE EVENTS AND POTENTIAL RISKS ..................................................................................... 41 
15.3       MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS……………………………………………….56 
15.4      PROTOCOL REVISION HISTORY………………………………………………………………………………64 
 
 


 
5 
 
 
Study Summary 
Title 
Ipilimumab and Nivolumab in Combination with Immunoembolization 
for the Treatment of Metastatic Uveal Melanoma 
Lay Title 
A research study to investigate whether closure of the liver artery after 
injection of GM-CSF in combination with ipilimumab and nivolumab 
stops the growth of secondary liver tumors from primary uveal 
melanoma 
BMS Protocol 
Number 
CA209-9CH 
Phase 
Phase II 
Methodology/Study 
Design 
Open label, prospective, Phase II single arm trial. Patients will receive 
immunoembolization (IEMBO) every 3 weeks in combination with 
ipilimumab (IPI )+ nivolmuab (NIVO) initially to be given every 3 weeks 
for 4 doses. Dose of IPI + NIVO will be the reverse lower dose of IPI 
1mg/kg every 3 weeks x4 doses and NIVO 3mg/kg every 3 weeks x 4 
doses then NIVO flat dose 480mg every 4 weeks. In the event of 
toxicity during the first four IPI + NIVO + IEMBO combination 
treatments, IPI and/or NIVO may be dropped at the investigator’s 
discretion and patient can continue on with NIVO + IEMBO or IEMBO 
alone. Once patient completes the first four doses of combination and 
moves onto the maintenance NIVO phase, IEMBO will then be given 
every 4 weeks. In the event of NIVO-related toxicity during this phase, 
NIVO can be dropped at the investigator’s discretion. Initial scans will 
be performed following two IPI+NIVO and IEMBO treatments, before 
treatment #3, to ensure no evidence of rapid progression. Initial 
radiographic response will be determined following all 4 doses of 
IPI+NIVO and/or NIVO alone if IPI dropped and/or four IEMBO 
treatments if both IPI and NIVO are dropped. Subsequent scans will 
be done every two IEMBO treatments. Immune-related side effects will 
be managed as per protocol. Steroid treatment will be allowed if it is 
tapered to 5 mg of prednisone or less before initiation of next cycle. 
Combination treatment could be postponed for up to 10 weeks (from 
the date of next scheduled treatment).   if patients need a 
treatment break for immune-related toxicity. Safety will also be 
assessed and the toxicity of the treatment will be monitored using the 
NCI Common Toxicity Criteria. Immunologic parameters will also be 
evaluated as detailed in the protocol. 
Study Duration 
18-24 months to accrue. Subjects will receive study treatment for a 
maximum of 2 years  and will subsequently be followed for a minimum 
of one year. 
Study Center(s) 
Thomas Jefferson University Hospital 


 
6 
 
Objectives 
Primary Objective:  Determine the clinical benefit of combination 
treatment with IEMBO, Ipilimumab, and Nivolumab. 
 
Secondary Objective(s):  
1. Determine all treatment and immune related toxicities 
2. Determine PFS 
3. Determine OS 
 
Exploratory Objective: 
1. Determine and correlate clinical response with the degree and 
change in inflammatory/immune response 
Number of Subjects 
35 
Diagnosis and Main 
Inclusion Criteria 
Inclusion criteria: 
1. 
Histologically confirmed metastatic uveal melanoma in the 
liver.  Patients must have at least one measurable liver 
metastasis that is ≥ 10 mm in longest diameter by CT scan or 
MRI.  The total volume of the tumors must be less than 50% of 
the liver volume. 
2. 
Willingness and ability to give informed consent. 
3. 
ECOG performance status of 0, or 1  
4. 
Adequate renal and bone marrow functions: serum creatinine ≤ 
2.0 mg/dl, granulocyte count ≥ 1000/mm3, and platelet count ≥ 
100,000/mm3. 
5. 
Adequate liver function: bilirubin ≤ 2.0 mg/ml, albumin ≥ 3.0 
g/dl, PT/PTT less than 1.5 times of upper normal limit (UNL), 
and AST and ALT less than 3.0 and alkaline phosphatase less 
than 1.5  times of UNL. 
6.        Age ≥ 18 years of age. 
Study Therapy, 
Dose, Route, 
Regimen 
1. Recombinant human GM-CSF (Sargramostim, 
Leukine, Sanofi US). GM-CSF 1,500 mcg) will be 
mixed with ethiodized oil (Ethiodol). The GM-
CSF/ethiodized oil mixture will be injected 
selectively into one of the hepatic lobes.  This will 
be followed by infusion of gelatin sponge particles to 
achieve the stasis of blood flow 
(immunoembolization). This will repeat every 3 
weeks x 4 then every 4 weeks 
2. Ipilimumab (Yervoy) at 1mg/kg every 3 weeks x 4 
doses. 
3. Nivolumab (Opdivo) at 3mg/kg every 3 weeks x 4, 
then flat dose 480mg every 4 weeks. 
Duration of 
administration and 
follow-up 
Patients will receive combination treatment of immunoembolization, 
ipilimumab, and nivolumab every 3 weeks for 12 weeks and in patients 
with CR, PR, and SD at 12 weeks, maintenance therapy with 
combination immunoembolization and nivolumab every 4 weeks will 
be offered until disease progression or unacceptable toxicity, for a 
maximum of 2 years.  Follow-up contact will take place every 3 months 
for minimum of one year or until death to determine clinical status. 


 
7 
 
Statistical 
Methodology 
We propose an increase in hepatic metastasis stabilization rate 
(SD+PR+CR) of 60%, as experienced with IEMBO alone, to 80% with 
IEMBO + IPI + NIVO. We plan to enroll 35 patients to have a power > 
80% (alpha = 0.05) and to detect our proposed response rate. Simon's 
two-stage design will be used (Minimax). The null hypothesis that the 
true response rate is 60% will be tested against a one-sided alternative. 
In the first stage, 13 patients will be accrued. If there are 8 or fewer 
responses in these 13 patients, the study will be stopped. Otherwise, 22 
additional patients will be accrued for a total of 35. The null hypothesis 
will be rejected if 26 or more responses are observed in 35 patients. 
This design yields a type I error rate of 0.05 and power of 80% when 
the true response rate is 80%. 


 
8 
 
 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
9 
 
1.0 INTRODUCTION 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 
312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures.  
1.1 Background and Rationale 
Uveal melanoma is the most common primary intraocular cancer in adults. Incidence in the 
United States is four to seven per million people and noted to make up approximately 3% of 
all melanomas.1 Despite the availability of effective treatments for primary uveal melanoma, 
there is no standard adjuvant therapy and up to 50% of patients subsequently develop 
metastasis.1 Hepatic involvement is often the first manifestation of systemic disease, and in 
more than half of patients it remains the only site of metastases. Other sites of metastases 
include lungs, bones, brain, subcutaneous tissues, peritoneal cavity, and other visceral 
organs. Survival after liver metastases is reportedly less than 6 months without treatment.  
 
The major challenge in management of metastatic uveal melanoma is the lack of effective 
treatments.  Metastatic uveal melanoma is highly resistant to standard systemic 
chemotherapies that have been used for metastatic skin melanoma.2 A novel approach 
using a MEK inhibitor showed a modest but improved response (15% RECIST response) in 
metastatic uveal melanoma.3 However, the progression free survival was short (15.9 weeks) 
and there was no significant overall survival benefit.  
 
Over the past decade, there have been paradigm-altering advances in cutaneous melanoma 
due to the advent of effective systemic immunotherapy interventions including immune-
checkpoint-pathway blockades such as anti–CTLA-4 antibody (ipilimumab) and anti–PD-1 
antibody (pembrolizumab and nivolumab).4 Despite encouraging clinical study results in 
metastatic cutaneous melanoma, these immune checkpoint blockades have not shown 
dramatic response in metastatic uveal melanoma. Ipilimumab resulted in regression in only 
5% of metastatic uveal melanoma patients.5,6 On the other hand, toxicity to ipilimumab, 
especially immune-related toxicity, is considered to be similar to that of metastatic skin 
melanoma (~30% grade 3 or greater).  Published data now for anti-PD1 and anti-PDL1 
antibodies when used alone note an approximate 3.6% response rate and 9% stable 
disease rate.7  
 
Since the liver is usually the dominant site of metastasis and hepatic metastasis is life-
limiting in the majority of uveal melanoma patients, liver-targeted locoregional treatment is 
a preferred standard of care since there are no effective systemic treatments available at 
this time.8 Considering resistance to standard chemotherapeutic treatment, we have 
developed a new therapy called Immunoembolization (IEMBO)9-11.   This technique involves 
embolization of the hepatic artery with gelatin sponge particle in conjunction with 
administration of granulocyte-macrophage colony stimulating factor (GM-CSF) mixed with 
ethiodized oil through the tumor-feeding hepatic artery. IEMBO provides several advantages 
beyond the ischemic damage consequent to bland embolization alone. Some of these 
advantages include attraction and stimulation of antigen-presenting cells in the hepatic 
tumor sites and improved uptake of tumor antigens released from necrotic tumor cells. In 
addition, local stimulation of the immune system may produce a systemic immune response 
against tumor cells, which thereby suppresses the growth of extrahepatic metastases.11 This 


 
10 
 
approach resulted in stabilization of multiple hepatic metastasis in approximately 60% of 
uveal melanoma patients.  Furthermore, this liver-directed treatment induced a systemic 
response against melanoma, including the development of inflammatory responses in 
remote metastasis and the prolongation of progression-free survival in extra-hepatic 
metastasis.9-11  
 
Due to the low response rate of systemic single agent immune checkpoint inhibitor therapy 
in metastatic uveal melanoma, we have been combining with IEMBO with systemic 
ipilimumab as well as pembrolizumab and nivolumab as our institutional standard of care. 
It is hypothesized that inflammation induced by IEMBO with GM-CSF coupled with 
systemic immune checkpoint therapy could be synergistic.  We have published on our 
experience with combination IEMBO and ipilimumab.12 The combination was well tolerated 
and incidence of serious hepatic toxicity was low. Our experience with IEMBO in 
combination with anti-PD1 antibodies has been similar.  
 
In cutaneous melanoma the combination of Ipilimumab and Nivolumab over each agent 
alone has proven to result in improved response rate and deeper responses.13 While we do 
not have data regarding this combination in metastatic uveal melanoma, there is reason to 
believe that the combination may prove also to be superior to each agent when used alone.  
 
To further enhance local and systemic anti-tumor immune responses, we proposed to 
investigate the safety and efficacy of IEMBO + Ipilimumab + Nivolumab combination 
treatment.   
2.0 STUDY OBJECTIVES 
 
2.1 Primary Objective: Determine the clinical benefit of combination treatment with 
IEMBO in combination with Ipilimumab and Nivolumab. 
 
2.2 Secondary Objective: 
a. Determine all treatment and immune related toxicities 
b. Determine progression free survival 
c. Determine overall survival 
 
2.3  Exploratory Objective: 
a. Determine and correlate clinical response with the degree and change in 
inflammatory/immune responses 
3.0 STUDY DESIGN 
3.1 General Design 
 
This study is an open label, prospective, phase II, two-stage, single arm trial with the 
potential for improved outcome with treatment of IEMBO in combination with IPI + NIVO.  
Patients will receive study treatment for a maximum of two years or until disease 
progression. The design will be a two-stage minimax design using the method of Simon.  
Choice of design is guided by a desire to stop the trial early if the actual hepatic metastasis 
stabilization rate is 60% or less.  If the stabilization rate rate is 80% or greater, we would like 
to have a low probability of failing to conclude effective.   


 
11 
 
 
Patients will receive IEMBO every 3 weeks in combination with IPI + NIVO initially to be 
given every 3 weeks for 4 doses. Dose of IPI + NIVO will be the reverse lower dose of IPI 
1mg/kg every 3 weeks x4 doses and NIVO 3mg/kg every 3 weeks x 4 doses then NIVO 
flat dose 480mg every 4 weeks. In the event of toxicity during the first four IPI + NIVO + 
IEMBO, IPI and/or NIVO may be dropped at the investigator’s discretion and patient can 
continue on with NIVO + IEMBO or IEMBO alone. Once patient completes the first four 
doses of combination and moves onto the maintenance NIVO phase, IEMBO will then be 
given every 4 weeks. In the event of NIVO-related toxicity during this phase, NIVO may be 
dropped at the investigator’s discretion and the patient may continue on with IEMBO only, 
if the investigator feels patient is receiving clinical benefit from it. Initial scans will be 
performed between cycles 2 and 3 to ensure no evidence of rapid progression. Initial 
radiographic response will be determined following all 4 doses of IPI+NIVO and/or NIVO 
alone if IPI dropped,and/or four IEMBO treatments if both IPI and NIVO are dropped. 
Subsequent scans will be done after every two IEMBO treatments. Immune-related side 
effects will be managed as per protocol. Steroid treatment will be allowed if it is tapered to 
5 mg of prednisone or less before initiation of next cycle. Combination treatment could be 
postponed for up to 10 weeks (from the date of next scheduled treatment), if patients need 
a treatment break for immune-related toxicity. Safety will also be assessed and the toxicity 
of the treatment will be monitored using the NCI Common Toxicity Criteria. Immunologic 
parameters will also be evaluated as detailed in the protocol. 
 
3.2 Primary Study Endpoint 
1. Best hepatic response (CR + PR +SD) by response criteria (RECIST 1.1) starting at 
week 12 
 
3.3 Secondary Study Endpoints 
1. All toxicities using the NCI CTCAE Version 4.0. 
2. Progression Free Survival (hepatic and systemic PFS) 
3. Overall survival 
 
3.4  Exploratory (Correlative) Endpoints 
      Systemic and local immune/inflammatory response:  
a. Degree and classification of tumor-infiltrating cells  
b. Presence and changes in PD-L1 expression in tumor and tumor-infiltrating 
cells 
c. Changes in immune tumor microenvironment (immune gene signature) 
d. Tumor mutational burden prior to treatment 
e. Changes in TCR repertoire analysis  (ImmunoSeq) 
f. Changes in cytokine productions (multiplex cytokine assay) 
g. Changes in PBMC cell populations, including T cells and MDS. 
 
 


 
12 
 
4.0 SUBJECT SELECTION AND WITHDRAWAL 
4.1 Inclusion Criteria 
1. Histologically confirmed metastatic uveal melanoma in the liver.  Patients must have 
at least one measurable liver metastasis that is ≥ 10 mm in longest diameter by CT 
scan or MRI.   
2. The total volume of the tumors must be less than 50% of the liver volume. 
3. Willingness and ability to give informed consent. 
4. Agreement to access archival tissue or agreement for tumor biopsy prior to 
treatment 
5. ECOG performance status of 0, or 1  
6. Adequate renal and bone marrow functions: serum creatinine ≤ 2.0 mg/dl, 
granulocyte count ≥ 1000/mm3, and platelet count ≥ 100,000/mm3. 
7. Adequate liver function: bilirubin ≤ 2.0 mg/ml, albumin ≥ 3.0 g/dl, PT/PTT less than 
1.5 times normal, AST and ALT less than 3x ULN and alkaline phosphatase less 
than 1.5 times ULN (grade 1). 
8. Age ≥ 18 years of age. 
9. Women must not be pregnant or breast-feeding. See section 4.2.1 
10. Women of child-bearing potential must use at least two other accepted and effective 
methods of contraception and/or to abstain from sexual intercourse for at least 23 
weeks after the last dose of nivolumab and/or ipilimumab and sexually active males 
must use at least two other accepted and effective methods of contraception and/or 
to abstain from sexual intercourse for at least 31 weeks after the last dose of 
nivolumab and/or ipilimumab. See section 4.2.1 
4.2 Exclusion Criteria 
1. 
Failure to meet any of the criteria set forth in the Inclusion criteria section  
2. 
Previous systemic exposure to anti-CTLA-4 antibody or anti-PD1 antibody 
3. 
Previous liver-directed treatments including chemoembolization, radiosphere, 
hepatic arterial perfusion, or drug-eluting beads; liver resection and focal 
ablation are permitted. 
4. 
Presence of symptomatic liver failure including ascites and hepatic 
encephalopathy. 
5. 
Presence of untreated brain metastases.  If patients have had previous 
treatment for the brain metastasis, an MRI or CT scan of the brain must 
confirm the stabilization of the brain metastasis for more than 2 months. 
6. 
Presence of uncontrolled hypertension or congestive heart failure, or acute 
myocardial infarction within 6 months of entry. 
7. 
Presence of any other medical complication that implies survival of less than 
six months 
8. 
Uncontrolled severe bleeding tendency or active GI bleeding.  
9. 
Significant allergic reaction to contrast dye or GM-CSF. 
10. 
Immunosuppressive treatments within 4 weeks prior to embolization, unless 
prednisone ≤ 5mg or equivalent 
11. 
Pregnancy or breast-feeding women. 
12. 
Patients with active hepatitis with SGOT and SGPT equal or greater than 5 
times normal  
13. 
Biliary obstruction, biliary stent or prior biliary surgery except cholecystectomy 
14. 
Positive for known HIV Infection 


 
13 
 
15. 
Uncontrolled Chronic Obstructive Pulmonary Disease or previous known 
pulmonary fibrosis 
16. 
Active infection. 
17. 
Auto-immune disease including inflammatory bowel disease, lupus, 
rheumatoid arthritis, but not including hypothyroidism or psoriasis if condition 
has been stable for 2 months or greater. 
 
4.2.1 Guidance for Women of Child Bearing Potential  
Women must not be pregnant or breast-feeding. All females of childbearing potential must 
have a blood test or urine study within 2 weeks prior to start of treatment to rule out 
pregnancy. A female of childbearing potential is any woman, regardless of sexual 
orientation or whether they have undergone tubal ligation, who meets the following criteria: 
1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been 
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any 
time in the preceding 24 consecutive months).  
 
Women of child-bearing potential must use at least two other accepted and effective 
methods of contraception and/or to abstain from sexual intercourse for at least 23 weeks 
after the last dose of nivolumab and/or ipilimumab and sexually active males must use at 
least two other accepted and effective methods of contraception and/or to abstain from 
sexual intercourse for at least 31 weeks after the last dose of nivolumab and/or 
ipilimumab. Should a woman become pregnant or suspect she is pregnant while she is 
participating in this study, she should inform her treating physician immediately. 
4.3 Early Withdrawal of Subjects 
4.3.1 When to Withdraw Subjects 
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question: 
1. 
Withdraw of consent or lost to follow up. 
2. 
Subject is determined to have met one or more of the exclusion criteria and 
continuing therapy may be a safety risk 
3. 
Pregnancy or intent to become pregnant 
4. 
Any adverse event that meets criteria for discontinuation 
5. 
Subject non-compliance that in the opinion of the investigator or sponsor 
warrants withdrawal 
6. 
Initiation of alternative anti-cancer therapy 
7. 
Confirmation of progression of disease 
 
4.3.2 Data Collection and Follow-up for Withdrawn Subjects 
Subjects who are withdrawn from the study and permanently discontinued from receiving 
on study treatment will be followed for safety, including the collection of any protocol-
specified blood specimens, unless consent if withdrawn or the subject is lost to follow up or 
enrolled in another clinical trial. All subjects will be followed for survival. Any subjects who 
are unable to return to the site for visits will be offered to follow up by phone every three 
months for at least one year. 
 
 


 
14 
 
4.3.3 Replacement of Subjects 
Should a subject be withdrawn from the study prior to the assessment at the fourth cycle 
for any other reason besides clinical deterioration or toxicity they will be replaced as they 
will not be evaluable. 
 
5.0 STUDY DRUG/THERAPY 
• GM-CSF, Ethiodol, and Gelatin Sponge as part of IEMBO will be given as standard 
of care in this study.  
• Ipilimumab and Nivolumab will be given as investigational in this study. 
5.1 Drug Descriptions/Formulation/Procurement  
Receipt of Study Drug Supplies [ipilimumab and nivolumab] 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a 
drug receipt log filled out and signed by the person accepting the shipment.  It is important 
that the designated study staff counts and verifies that the shipment contains all the items 
noted in the shipment inventory.  Any damaged or unusable study drug in a given shipment 
(active drug or comparator) will be documented in the study files.  The investigator must 
notify study sponsor of any damaged or unusable study treatments that were supplied to 
the investigator’s site. 
 
5.1.1 GM-CSF (yeast-derived recombinant human GM-CSF) 
• Other Names; Leukine, Sargramostim 
• Classification: Hematopoietic growth factor 
• Mode of Action: Stimulates proliferation and differentiation of hematopoietic 
progenitor cells.  Increases the cytotoxicity of monocytes toward certain neoplastic 
cell lines and activates polymorphonuclear neutrophils to inhibit the growth of tumor 
cells (41).   
• Storage and stability: Leukine Liquid (500 mcg/ml) will be refrigerated at 2-8 oC until 
use.  The Leukine Liquid may be stored for up to 20 days at 2-8 oC once the vial 
has been entered.   
• Preparation: Three vials of Leukine Liquid (500 mcg) will be used to make a 2,000 
mcg GM-CSF solution in 4 ml. 
• Side Effects: In uncontrolled Phase I/II studies with Leukine in 215 patients, the 
most frequent adverse events were fever, asthenia, headache, bone pain, chills and 
myalgia (>10%). These systemic events were generally mild or moderate and were 
usually prevented or reversed by the administration of analgesics and antipyretics 
such as acetaminophen. In these uncontrolled trials, other infrequent events 
reported were dyspnea, peripheral edema, and rash.  
o Reports of events occurring with marketed Leukine include arrhythmia, 
fainting, eosinophilia, dizziness, hypotension, injection site reactions, pain 
(including abdominal, back, chest, and joint pain), tachycardia, thrombosis, 
and transient liver function abnormalities (<1% occurrence post-marketing).  
o In patients with preexisting edema, capillary leak syndrome, pleural and/or 
pericardial effusion, administration of Leukine may aggravate fluid retention. 
Body weight and hydration status should be carefully monitored during 
Leukine administration. Occurred 1% patients.  


 
15 
 
o In patients with preexisting liver or renal insufficiency, increased creatinine or 
bilirubin and hepatic enzymes would be observed.  Transient increase of 
WBC counts may develop after the local infusion of GM-CSF into hepatic 
artery.   
o Rarely, patients have developed acute allergic reactions or hemiplegia (<1% 
occurence).  
 
5.1.2 Ethiodized Oil 
• Other Names; Ethiodol 
• Classification; Injectable radio-opaque diagnostic agent 
• Drug specifics: Ethiodol, brand of ethiodized oil, is a sterile injectable radio-opaque 
diagnostic agent for use in hysterosalpingography and lymphography.  It contains 
37 % iodine (475 mg/ml) organically combined with ethyl esters of fatty acids 
(primarily as ethyl monoiodostearate and ethyl diiodostearate) of poppyseed oil.   
Ethiodized oil has been used widely for chemoembolization of the hepatic artery for 
primary and metastatic liver cancer. 
• Side Effects: One of the major side effects of ethiodized oil is impairment of liver 
function (38).  Since ethiodized oil causes ischemic changes in the liver, special 
attention to liver function should be considered. Visualization of the portal vein is a 
sign of portal reflux through sinusoids.  Infusion of ethiodized oil should be stopped 
if the larger order portal vein branches are visualized.  Another rare complication is 
pulmonary oil embolization, which is also seen when more than 20 ml of ethiodized 
oil is infused (50).  In this study, the maximum dose of ethiodized oil for 
embolization will be 20 ml or less.  Erosive gastroduodenal lesions or ischemic 
change in biliary ducts were reported in patients who received chemoembolization 
(51, 52).  However, most of them are clinically insignificant and managed medically.  
 
5.1.3 Gelatin sponge  
• Other Names; Gelfoam, Surgifoam 
• Classification; Medical device for hemostasis  
• Drug specifics: Absorbable gelatin sponge is a medical device intended for 
application to bleeding surface as a hemostatic.  It is a sterile, water-insoluble, non-
elastic, pliable product prepared from purified porcine skin gelatin. Gelatin sponge is 
usually absorbed completely in from four to six weeks, without inducing excessive 
scar tissues. 
• Side Effects: When gelatin sponge was used during intravascular catheterization for 
the purpose of producing vessel occlusion, the following adverse events have been 
reported; fever, necrosis of specific anatomical areas, duodenal and pancreatic 
infarcts and abscess.  Since smaller sizes of the occlusive agents cause more 
ischemic complications and development of collateral circulation, gelatin sponge 
powder will not be used in this study.   
 
5.1.4 Ipilimumab: In this study, ipilimumab is considered investigational.  
• Other Names: Anti-CTLA-4 monoclonal antibody, MDX-010 (MDX-CTLA4, 
Transfectoma-derived), Yervoy®  
• Classification: Human monoclonal antibody, IgG1 subclass 
• Mode of Action: Ipilimumab is specific for the CTLA4 antigen expressed on a subset 
of activated T-cells and regulatory T cells. CTLA4 interaction with the B7 molecule, 


 
16 
 
one of its ligands expressed on professional antigen presenting cells, can down-
regulate T-cell response. Ipilimumab is, thought to act by blocking the interaction of 
CTLA4 with the B7 ligand, resulting in a blockade of the inhibitory effect of T-cell 
activation. 
• Storage and Stability - Ipilimumab must be stored in a secure area according to 
local regulations. The investigator must ensure that it is stored at a temperature 
between 2°C to 8°C. Ipilimumab is given undiluted or further diluted in 0.9% NaCl 
Injection, USP or 5% Dextrose Injection, USP to a concentration between 1 mg/mL 
and 2 mg/mL. Undiluted or diluted ipilimumab solution is stable in a polyvinyl 
chloride (PVC), non- PVC/non DEHP (di-(2-ethylhexul) phthalate) IV bag or glass 
container up to 24 hours refrigerated at (2°C to 8°C) or at room temperature/ room 
light. Do not freeze. Shelf-life surveillance of the intact vials is ongoing.  
• CAUTION: Ipilimumab does not contain antibacterial preservatives. Vials are for 
single use only. Use prepared IV solution immediately. Discard partially used vials. 
• Dose Specifics Calculate Total Dose as follows: Patient body weight in kg x 1 mg/kg 
= total dose in mg  
• Preparation: The supplies needed for ipilimumab preparation and administration 
include calibrated syringes and infusion containers. Ipilimumab is to be 
administered as an intravenous infusion using an in-line filter (pore size of 0.2 
micrometer to 1.2 micrometer) and a volumetric pump, at 1 mg/kg dose, to 
complete the infusion in 30 minutes, with a 3-mL normal saline flush at the 
completion of the infusion. Reduced duration of infusion as compared to the 90 
minutes for 3mg/kg dosing was approved by BMS.  
• 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.  
• Mix by GENTLY inverting several times. DO NOT shake. 
• Route of Administration: Ipilimumab is administered as an IV infusion only. Infusions 
should be administered over 30 minutes +/- 5 minutes. Ipilimumab should be 
administered under the supervision of a physician experienced in the use of 
intravenous (IV) agents.  
• Incompatibilities: No compatibility information is available.  
• Availability: Ipilimumab is available in 5 mg/mL single-use vials (40 mL). The sterile 
solution in the vial is clear and colorless.  
• Side Effects: See the BMS Comprehensive Adverse Events and Potential Risks List 
(CAEPR) in Section 6.2 for list of side effects  
• Nursing/Patient Implications: Monitor patients for immune-related adverse events, 
e.g., rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, hepatitis and hypothyroidism. If 
you suspect toxicity, refer to the protocol guidelines for ruling out other causes. 
Ipilimumab may be excreted in milk or cross the placenta; therefore, nursing women 
and women with known or suspected pregnancy should not take ipilimumab. 
Closely monitor patients who are on narcotics during the treatment with ipilimumab. 
Narcotics may mask GI signs and symptoms such as diarrhea or abdominal pain, 
which are relevant complications of a bowel perforation. Minor diarrhea can be a 
potential sign of colitis and require immediate attention.  
• 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 


 
17 
 
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.  
• Ipilimumab Destruction: Partial vials can be destroyed on site per institution policy. 
Intact vials of the expired drug, recalled, or when protocol is closed to treatment 
cannot be destroyed on site without the PMB/NCI approval. 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.  
 
5.1.5 Nivolumab (NSC748726): In this study, nivolumab is considered investigational.  
• Other Names: BMS-936558; MDX1106; ONO-4538; anti-PD-1  
• Classification: Fully humanized monoclonal antibody  
• Mode of Action: Nivolumab is a fully human monoclonal immunoglobulin G4 (IgG4) 
antibody (HuMAb) that targets the programmed death – 1 (PD-1) cell surface 
membrane receptor. PD-1 is a negative regulatory molecule expressed by activated 
T and B lymphocytes. Binding of PD-1 to its predominant ligand, PD-L1, results in 
the down regulation of lymphocyte activation. Loss of effective immune response to 
antigens expressed by tumors may be a significant factor in tumor progression. PD-
L1 expression has been found on a number of tumors & may also be a mechanism 
by which tumors can directly engage PD-1 to evade an effective anti-tumor immune 
response. Inhibition of PD-1 interaction with PD-L1 promotes immune responses 
and antigen specific T cell responses to both foreign antigens as well as self-
antigens. Nivolumab was shown to promote the proliferation of human T-cells in a 
variety of assays, which is an anticipated pharmacologic result of PD-1 inhibition.  
• Storage and Stability: Intact vials: 2-8°C (36-46°F); Protect from light, protect from 
freezing; Infusion – room temp: 4 hours max including infusion and up to 24 hours if 
refrigerated for the first 20 hours.  
• Dose Specifics:The dosing calculations should be based on the actual body weight. 
If the patient’s weight on the day of dosing differs by > 10% from the weight used to 
calculate the original dose, the dose must be recalculated. All doses should be 
rounded to the nearest milligram. There will be no dose modifications allowed.  
• Preparation: Nivolumab is available as 100 mg vials (10 mg/mL), which include an 
overfill. It is supplied in 10 mL type I flint glass vials, with butyl stoppers and 
aluminum seals. Nivolumab injection can be infused diluted (10 mg/mL) or diluted 
with 0.9% Sodium Chloride Injection, USP to concentrations no less than 0.35 
mg/mL.  
• Route of Administration: IV using a volumetric pump with 0.22 micron pre size, low-
protein binding polyethersulfone membrane in-line filter. Nivolumab should be 
administered over 30 minutes +/- 5 minutes. Should be administered ahead of 
ipilimumab on days when both to be administered  
• Incompatibilities: No incompatibilities between Nivolumab injection and polyolefin 
bags have been observed.  
• Side Effects: See the Comprehensive Adverse Events and Potential Risks List 
(CAEPR) in Section 6.2 for list of side effects.  


 
18 
 
• Nursing/Patient Implications: Infuse over 30 minutes +/- 5 minutes in a minimum of 
60 ml infusion volume through a 0.22 micron in-line filter. Monitor carefully for 
infusion reactions and treat accordingly.  
• Handling and Disposal: Use appropriate precaution for handling and disposal.  
5.2 Dose Rationale  
Patients will receive immunoembolization using GM-CSF at dose of 1500mcg every 3 
weeks for the first four treatments then offered every 4 weeks maintenance. In the phase 1 
dose escalation study, there was no dose-limiting toxicity up to 2,000mcg of GM-CSF dose; 
however, there was possible negative correlation between very high serum GM-CSF levels 
and PFS in patients with small liver metastasis.  Therefore, our current standard care 
treatment uses 1,500 mcg of GM-CSF to avoid potential detrimental effects of high-dose 
GM-CSF.   
 
The dosing of IPI+NIVO noted to be IPI 1mg/kg and 3mg/kg for the first four doses has 
been studied in a number of cancer types. It has been shown to be safe, and with less 
toxicity as evidenced in [NCT01454102]. 
 
Regarding the dosing of nivolumab, following the combination IPI+NIVO dosing for the first 
four doses the every 4-week schedule (Q4W) of NIVO will be more convenient for subjects. 
Based on pharmacokinetic modeling, the 480 mg Q4W (after steady state is reached with 3 
mg/kg or 240 mg every 2 weeks) will provide steady-state average concentrations similar 
to 3 mg/kg or 240 mg Q2W, which has been shown to provide longer survival in NSCLC 
patients. However, 480 mg Q4W is expected to result in higher (approximately 20%) 
steady-state maximum concentration (peaks), and lower (approximately 10%) steady-state 
trough concentrations compared to steady state of 3 mg/kg Q2W. Nivolumab was 
adequately tolerated up to 10 mg/kg, the highest dose level tested, and no maximum 
tolerated dose was identified. In addition, the exposure-response relationship for safety is 
flat. Thus, a slight increase in the steady-state maximum concentration is not expected to 
increase the safety risk of nivolumab. However, a marginal decrease in steady-state trough 
concentration is not expected to reduce the efficacy as high trough concentrations and > 
90% intra-tumoral receptor occupancy are still maintained at 480 mg Q4W dose. 
Nivolumab 480 mg Q4W is expected to have similar efficacy and safety profile to 3 mg/kg 
Q2W. 
 
5.3 Procedure of Immunoembolization 
 
5.3.1 Hospital Admission 
Patients will be admitted to Thomas Jefferson University Hospital and undergo 
immunoembolization on Day #2, following IPI + NIVO on Day #1.   
 
5.3.2 Access of the hepatic artery 
An angiogram of the hepatic arteries will be obtained by the established technique.  Non-
ionized contrast will be used for angiographic studies to minimize the risk for allergic 
reactions.  One of the hepatic lobes will then be treated based on the locations and sizes 
of the tumors. The proper arterial catheter placement, appropriate perfusion pattern to 
targeted tumors and existence of arteriovenous shunting that may cause pulmonary 
embolism by ethiodized oil will be thoroughly evaluated by angiography prior to the 


 
19 
 
embolization procedure.  Such a degree of shunting is rarely ever seen in this patient 
population but discretion of the interventional radiologist will be used if shunting identified.  
 
5.3.3 Embolization 
For the patients who receive immunoembolization with GM-CSF, 3.5ml of Leukine Liquid 
(1,500 mcg of GM-CSF) will be used.  This solution will be emulsified in ethiodized oil 
(Ethiodol) by repeated transfer of the two liquids between syringes connected via a 
stopcock. The amount of ethiodized oil administered is calculated based on tumor volume 
(1 ml per cm of summed tumor diameters). The actual amount of ethiodized oil will be 
decided based on the angiographic findings, including the degree of tumor vascularity and 
flow within the target hepatic artery.  However, the maximum dose of ethiodized oil will 
not exceed 20 ml.  The GM-CSF/ethiodized oil mixture will be done in the angiography 
suite immediately prior to the intraarterial delivery. When an emulsion has formed, the GM-
CSF/ethiodized oil mixture will be slowly injected into the hepatic artery.  Endpoints for the 
infusion of ethiodized oil will be delivery of the planned volume or the appearance of larger 
order portal vein branches.  The perfusion pattern to the targeted tumors will be monitored 
during the injection of the ethiodized oil.  Following this injection, gelatin sponge particles 
(1-2 mm size) will be infused into the hepatic artery until stasis of antegrade flow is 
obtained. 
 
The immunoembolization procedure will be repeated every 3 weeks for the first 4 cycles 
and then if patient has shown evidence of tumor response, IEMBO may continue on 
maintenance every 4 weeks until disease progression or limiting toxicities.  If the tumor is 
confined to a single lobe of the liver, embolization will be repeated to that lobe but interval 
between treatments may be extended up to every 6 weeks at the discretion of the treating 
physician. If the liver metastases are located in the both lobes of the liver, each hepatic 
lobe will be treated alternately. Variant arterial anatomy may require departure from this 
principle. Examples include a left lobe with dual supply from the left gastric artery and 
proper hepatic artery. The latter may be treated along with the right lobe.   
5.4 Treatment Regimen Combination  
Patients will be seen in the outpatient office on Day #1 of every cycle and receive 
administration of ipilimumab and nivolumab or once in maintenance phase nivolumab 
alone. On Day #2 they will undergo IEMBO consisting of intra hepatic artery administration 
of GM-CSF (1500mcg) mixed with ethiodized oil emulsion, followed by embolization of the 
hepatic artery with gelatin sponge particles under the care of interventional radiology. 
Patients will undergo this combination intervention every 3 weeks for 12 weeks unless 
significant disease progression, limiting toxicity, or withdrawal of consent. Interim imaging 
after 2 cycles will be peformed to ensure there has not been rapid progression. After four 
combination treatments if noted to have CR, PR, or SD patients will be offered 
maintenance therapy with combination intervention every 4 weeks until disease 
progression, limiting toxicity, or withdrawal of consent. When undergoing every 4 week 
maintenance patients will receive NIVO on Day #1 and IEMBO on Day #2 of each 28 day 
cycle. 
5.5 Risks 
There may be an increased risk of adverse events such as immune hepatitis or other liver 
toxicities with the combination therapy than would be seen with each treatment alone. See 


 
20 
 
section 6.2 for list of comprehensive adverse events and potential risks associated with the 
treatment.  
 
5.6 Prior and Concomitant Therapy 
For immune-related adverse events, steroid treatment will be allowed if it is tapered to 5 
mg of prednisone or less before initiation of next cycle. Patients cannot have had prior 
exposure to anti-CTLA4 or anti-PD1 therapy. They cannot have had prior regional liver 
directed therapy but may have had liver resection or focal ablation. Palliative radiation is 
allowed during treatment. Patients who had cellular immunotherapy must have a washout 
period of at least 90 days prior to first treatment cycle. Patients who had other systemic 
therapies or radiation treatment must have a least a two week washout period prior to first 
treatment cycle. Bone strengthening agents such as zolendronic acid or denosumab are 
also allowed for bone metastases.   
6.0 STUDY PROCEDURES 
 
6.1 Study Visit Schedule 
See Appendix (Section 15.1) 
 
6.1.1 Initial visit   
A complete physical examination will be done within the four weeks prior to the initiation of 
the treatment.  The tests and procedures described will be discussed with patients. The 
detailed treatment procedure and possible side effects will be discussed with patients and 
verbal and written consent for the treatment will be obtained.  The tests and procedures 
listed below will be ordered after patients sign the consent form.  If patients already have 
had tests performed as part of their standard care, the results of the tests will be recorded.   
 
Once eligibility for the study is confirmed, the embolization procedure will be scheduled 
through Cardiovascular Interventional Radiology (CVIR).   
 
The following studies and procedures must be performed within 4 weeks of initiation of 
treatment except pregnancy test (within 2 weeks).  All abnormal and normal results must 
be recorded.  
1. Medical history to include determination of tumor-related symptoms  
2. Physical examination to include ECOG performance status, patient height and 
weight, vital signs. 
3. Liver biopsy: Core biopsy of the liver tumor to confirm the diagnosis of metastatic 
uveal melanoma and to evaluate the host response to tumor. A separate 
standard procedure consent form must be obtained for biopsy of liver tumor.  
4. Contrast-enhanced CT or MRI of the brain, CT of the chest (without contrast), CT 
of abdomen and pelvis (with and without contrast), and MRI of the abdomen (with 
and without contrast)  
5. Blood tests to include the following: 
Complete blood count (CBC) with differential white blood cell count 
Serum laboratory studies including total bilirubin, SGOT (AST), SGPT (ALT), 
LDH, alkaline phosphatase, albumin, creatinine, BUN, glucose, calcium, 
phosphorus, CRP, PT, PTT, INR, TSH, T3, T4, ACTH and Cortisol 
6. Pregnancy test (only in women of childbearing potential). The test must be done 
within 2 weeks prior to initiation of treatment. 


 
21 
 
 
6.1.2 Evaluation during treatment 
An interim history and physical examination will be performed prior to each subsequent 
treatment cycle to assess toxicities and disease status.  This is to be done upon admission 
to the hospital and at outpatient appointments for immunotherapy infusion.  
 
 
CBC with differential, platelet count, liver function tests and renal function tests and LDH 
will be done prior to the treatment, day of IEMBO, day after IEMBO and, and then weekly 
unless more frequently is required.  In the event that a subject is no longer receiving 
infusion on Day 1 (IPI and/or NIVO), and only receiving IEMBO – Day 1 labs (CRP, TSH, 
& T4) will be drawn prior to IEMBO on Day 2.  
 
Due to possibility of abrupt onset endocrinopathy TSH,ACTH, T3, T4, cortisol will also be 
ordered as part of monitoring for side effects related to IPI+NIVO and NIVO the week prior 
to scheduled infusion. On Day 1 of each cycle TSH and T4 will also be ordered.. Lipase 
will be ordered on as needed basis. 
 
Coagulation tests (PT, PTT, INR) will be done prior to each embolization. 
 
Sixty (60) ml of blood will be drawn for immunological testing prior to each cycle beginning.  
Additionally, 10 ml of blood will be drawn before, 1 hours and on Day 3 after the individual 
IEMBO for cytokine measurements. Also up to an additional 10ml of blood will be drawn 
prior to the initial cycle for purposes of determining tumor mutational load. Study blood will 
be collected for the first 6 cycles of treatment, then at 12 and 24 months and at End of 
Treatment visit, even if visit is before the completion of 6th cycle. 
 
Eligibility criteria will be applied to each treatment. Only the patients who fulfill the eligibility 
criteria will be offered further embolization treatment.  If follow-up test results indicate that 
patients have become ineligible for treatment, the next treatment will be postponed for a 
maximum of 4 weeks.  If sufficient improvement is not seen during this period to restore 
eligibility for the next treatment, they will be removed from the study.   
 
6.1.3 Post-embolization liver biopsy 
Three weeks after the first embolization and prior to the second embolization, the second 
liver biopsy will be performed to evaluate the host response to tumor if technically feasible. 
A separate standard procedure consent form must be obtained for biopsy of the liver 
tumor. 
 
6.1.4 Office visit after 4 cycles 
After the fourth cycle patients will be evaluated for response. The tests and procedures 
described below will be performed.  
 
1. Medical history to include determination of tumor-related symptoms  
2. Physical examination to include ECOG performance status, patient height and 
weight, vital signs 
3. CT of the chest (with contrast), CT of abdomen and pelvis (with and without 
contrast), and MRI of the abdomen (with and without contrast) 
4. Blood tests to include the following 


 
22 
 
 
Complete blood count (CBC) with differential white blood count. Serum laboratory 
studies including total bilirubin, SGOT, SGPT, LDH, alkaline phosphatase, 
albumin, TSH, creatinine, BUN, glucose, calcium, and phosphorus.  Sixty (60) ml 
of blood will also be drawn for immunological testing.   
 
After the completion of 4 treatments, continuation of the treatment will be offered to 
patients who have demonstrated clinical benefit from the treatment and have not 
experienced any CTC grade 4 toxicity while participating in this study. If the patient started 
with unilobar disease but develops liver metastases in the contralateral lobe treatment to 
the contralateral lobe with immunoembolization and continuation of the treatment will be 
allowed.  
 
If patients have progression of liver metastases, or progression of extra-hepatic 
metastases that require a change in systemic therapy (palliative radiation or surgery 
allowed as per discretion of investigator) determined by RECIST 1.1, or experienced 
serious side effects, patients will be removed from the study and appropriate medical 
advice regarding alterative treatment options will be provided (See Section 6.1.6  
Completion of the study).   
 
If patients have unequivocal progression of hepatic metastasis prior to the visit after 4 
treatments, they may  be removed from the study at the discretion of the investigators and 
appropriate medical advice will be provided. In that case, patients will be followed every 3 
months to document their medical condition until their death.  Follow-up over the telephone 
will be performed for patients unable to return for examination. If there is a mixed response 
seen at the interim scan completed between cycles 2 and 3, and it is deemed patient is 
getting clinical benefit,  they will be allowed to continue with study treatment.  
 
If patients have stabilization of hepatic metastasis but progression of extra-hepatic 
metastasis after 4 treatments, two additional IEMBO treatments, 4 weeks apart, will be 
allowed as long as hepatic metastasis is stable.  This would prevent the early removal of 
patients with pseudo-progression of extra-hepatic metastasis. If follow-up imaging studies 
show further progression of extra-hepatic metastasis after 2 additional IEMBO + NIVO 
treatments, patients will be removed from the study.   In that case, patients will be followed 
every 3 months to document their medical condition until their death.  Follow-up over the 
telephone will be performed for patients unable to return for examination. 
 
After the completion of first four treatment cycles, if disease stabilization is determined (at 
12 weeks), continuation of treatment on maintenance phase may be offered as a 
combination of IEMBO +NIVO or, in the event of NIVO-related toxicity, IEMBO alone. 
 
6.1.5 Additional outpatient visits prior to infusion of IPI+NIVO or NIVO alone. 
Patients will be seen in the outpatient setting prior to each infusion of IPI+NIVO or NIVO 
alone during maintenance. 
 
During maintenance phase, after the completion of every two treatments patients will be 
seen by both medical oncology and interventional radiology for evaluation. A complete 
physical examination will be done by a study physician.  
 


 
23 
 
CT scan of the chest (with contrast), CT of abdomen and pelvis (with and without contrast) 
and MRI of the abdomen (with and without contrast) will be obtained prior to the 
subsequent follow-up office visits after every two treatments (NIVO + IEMBO). 
 
 
The decision to continue treatment will be based on the results of the imaging and 
laboratory tests and the physical status of the patients.  Unless patients become ineligible 
based on the inclusion/exclusion criteria, or unless patients develop rapid progression, or 
unless patients experience an unacceptable serious adverse event, the combination 
treatment will be continued.  
 
Patients who experience progressive disease by RECIST criteria without clinical 
deterioration may continue on protocol therapy until their next scheduled scan if the 
investigator feels the patient may be having clinical benefit and may experience a delayed 
or atypical response.  Only patients who have no progression of symptoms of cancer, no 
decline in performance status, and no progression of tumor at a critical anatomic site (e.g., 
cord compression) will be eligible for the treatment beyond progression.  If the next 
scheduled scan shows a further  increase in tumor measurements (˃10% RECIST target 
lesions or unequivocal progression of non-target lesions) from the scan that first suggested 
progression, patient will be deemed to have true progression and patient will be removed 
from study.  It the next scheduled scan does not show further progression, patient will 
remain on study treatment. 
 
For patients who achieved PR, CR, or SD in the liver metastases after embolization, tumor 
measurements should be continued after every 2 IEMBO treatments for up to 2 years after 
initiation of protocol therapy or until PD is confirmed. 
 
6.1.6 Completion of the study 
Patients will receive study treatment for a maximum of two years or until disease 
progression. The study will be completed if progression of liver metastases is confirmed by 
the follow-up imaging studies. Patients will also be removed if they develop progression of 
extra-hepatic metastases for two consecutive imaging studies unless palliative radiation or 
surgical resection of progressive disease is feasible. Patients will be removed if they 
develop an unacceptable serious adverse event. If they fail to fulfill the eligibility criteria for 
the combination treatment, the patient will also be removed from the study.  
 
At the time of study completion, the following studies and procedures will be performed:   
1. Medical history to include determination of tumor-related symptoms  
2. Physical examination to include ECOG performance status, weight, and vital 
signs  
3. CT of the chest (with contrast), CT of abdomen and pelvis (with and without 
contrast), and MRI of the abdomen (with and without contrast)…if they are not 
ordered within 4 weeks of completion of the study  
4. Blood draw for tests to include the following: 
 
Routine: complete blood count (CBC) with differential white blood count, serum 
laboratory studies including total bilirubin, SGOT, SGPT, LDH, alkaline 
phosphatase, albumin, TSH, creatinine, BUN, glucose, calcium, and phosphorus; 
Research: biomarker testing (60 ml) and immunological testing (10 ml). 
 
6.1.7 Follow-up after study completion 


 
24 
 
All patients, including patients who discontinue protocol therapy because of toxicity or 
progressive disease must be followed every three months up to a minimum of 1 year to 
determine clinical status and to document time to progression and duration of survival.  
Telephone contact is allowed for this purpose.   
 
6.2 Adverse Events and Potential Risks  
 
Please see appendix 16.2 detailing potential adverse drug events (ADRs) that may be 
attributable to ipilimumab and nivolumab combination or nivolumab alone. In general side 
effects related to ipilimumab and nivolumab are considered immune related adverse 
events and include but are not limited to dermatitis, hepatitis, pneumonitis, colitis, 
endocrinopathy (including hypophysitis and thyroiditis), and nephritis. Appendix tables 
adopted from Investigator Brochure addendum.  
 
6.3 Dose Delays and Dose Modifications 
 
6.3.1 Attributed to Immunoembolization with GM-CSF 
If CTC Grade 4 systemic and or local toxicities related to GM-CSF are observed, no further 
dose will be offered, with the exception of Grade 4 AST/ALT elevation as long as resolves 
within 7 days. 
 
6.3.2 Attributed to Ipilimumab, Ipilimumab or Nivolumab, or Nivolumab alone. 
See Appendix 3 for management of immune related toxicities. 
 
6.3.3 Attributed to combination of Ipilimumab and Nivolumab and Immunoembolization or 
Nivolumab and Immunoembolization 
Combination treatment could be postponed for up to 10 weeks (from the date of next 
scheduled treatment).   if patients need a treatment break for immune related toxicity. 
During combination treatment with IPI and NIVO, depending on type and severity of 
toxicity, patient may be able move onto the maintenance phase of NIVO + IEMBO and 
drop the IPI before the full four combination doses are given. Likewise, NIVO may also be 
dropped and patient may be able to continue on with IEMBO only, if the investigator feels 
patient is receiving clinical benefit from it.  These determinations may be made at the 
investigator’s discretion, in consideration of patient safety.  
 
A window of +/- 3 days is permitted between each treatment cycle beginning at cycle 2 and 
will not be characterized as dose or treatment delay.  
7.0 STATISTICAL PLAN 
7.1 Sample Size Determination 
The trial will enroll 13 patients in the first stage. If there are 8 or fewer responses in these 
13 patients, the study will be stopped. If the trial goes on to the second stage, 22 additional 
patients will be accrued for a total of 35 patients. The sample sizes for each stage are 
computed for optimal minimax design to test the null hypothesis that hepatic metastasis 
stabilization rate ≤ 60% versus the alternative that stabilization rate > 80% using one-sided 
test with a target a type I error rate of 0.05.  


 
25 
 
7.2 Statistical Methods 
The trial is designed with the potential for early termination in the case of a poor hepatic 
metastasis stabilization rate (hepatic response). The design will be a two-stage optimal 
minimax design using the method of Simon, augmented with admissible choices. Choice of 
design is guided by a desire to stop the trial early if the actual metastasis stabilization rate 
is 60% (as experienced with IEMBO alone) or less. If the metastasis stabilization rate is 80% 
or greater, we would like to have a low probability of failing to conclude that IEMBO + IPI + 
NIVO is effective.  The trial will enroll 13 patients in the first stage. If in these 13 patients, 8 
or fewer patients have hepatic metastasis stabilizations, the study will be stopped. If the trial 
goes on to the second stage, 22 additional patients will be accrued for a total of 35 patients. 
The combination IEMBO + IPI + NIVO will be considered ineffective if there are 25 or fewer 
responses (hepatic metastasis stabilizations) in 35 patients.  With this design, we have no 
more than a 19% chance of concluding that combination IEMBO + IPI + NIVO is ineffective 
(≤60% success rate) when the success rate is at least 80%.  Similarly, we have no more 
than a 5% chance of concluding effective (≥60% success rate) when it is ineffective.  If the 
actual metastasis stabilizations rate is 60% or worse, we have at least a 0.65 probability that 
the trial will stop after the first 13 subjects. 
 
7.2.1 Analysis Population 
The evaluable population includes all subjects enrolled who receive at least four 
combination treatments (IPI + NIVO + IEMBO at initial every 3 week intervals or NIVO + 
IEMBO if IPI dropped due to toxicity and IEMBO alone if NIVO dropped due to toxicity) and 
complete assessment after four treatments.  
 
The As-treated population includes all subjects who receive any treatment and will be used 
to evaluate baseline characteristics as well as all secondary endpoints for safety and 
efficacy as the collected data allows. 
 
7.2.2 Primary Endpoint:  
The primary endpoint is the best hepatic response (CR + PR + SD) by response criteria 
(RECIST 1.1) after four combination treatments. The estimate of the hepatic metastasis 
stabilization rate will be presented with corresponding 95% confidence intervals.  The 
method of Atkinson and Brown will be used to adjust for the two-stage design. 
 
7.2.3 Secondary and Exploratory (Correlative) Endpoints  
1. All toxicities using the NCI CTCAE Version4.0. 
2. PFS (hepatic and systemic PFS) 
3. Overall survival 
4. Systemic and local immune/inflammatory response correlatives 
a. Degree and classification of tumor-infiltrating cells  
b. Presence and changes in PD-L1 expression in tumor and tumor-infiltrating 
cells 
c. Changes in immune tumor microenvironment (immune gene signature) 
d. Tumor mutational burden prior to treatment 
e. Changes in TCR repertoire analysis  (ImmunoSeq) 
f. Changes in cytokine levels (multiplex cytokine measurements) 
g. Changes in PBMC cell populations, including T cells and MDS. 
 


 
26 
 
The PFS and OS will be estimated using the Kaplan-Meier method.  The toxicity rates will 
be estimated with corresponding 95% confidence intervals. Correlative endpoints including 
repeated measures of cytokine and molecular marker levels in tissue or serum will be 
analyzed using appropriate linear mixed effects models. 
8.0 SAFETY AND ADVERSE EVENTS 
8.1 Definitions 
8.1.1 Adverse Event 
An adverse event is any untoward or unfavorable medical occurrence in a human 
participant, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the participant’s 
participation in the research, whether or not considered related to the participant’s 
participation in the research. 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens 
in severity during the course of the study.  Intercurrent illnesses or injuries should be 
regarded as adverse events.  Abnormal results of diagnostic procedures are considered to 
be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
8.1.2 Serious Adverse Event 
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
• Results in death 
• Is life-threatening (places the participant at immediate risk of death from the event 
as it occurred) 
• Is disabling or incapacitating 
• Results in inpatient hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant disability or incapacity 
• Results in a congenital anomaly or birth defect  
• An important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the participant or may require 
intervention to prevent one of the outcomes listed in this definition. 
Adverse events are classified as serious or non-serious.   
 
A serious adverse event is any AE that is:  
• fatal 


 
27 
 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance. They may jeopardize the subject, and may require 
intervention to prevent one of the other serious outcomes noted above.  For example, drug 
overdose or abuse, a seizure that did not result in in-patient hospitalization, or intensive 
treatment of bronchospasm in an emergency department would typically be considered 
serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events.  
8.1.3 Adverse Event Reporting Period 
The adverse event reporting period for this trial begins when the patient receives the first 
treatment and ends 3 months after completion or withdrawl from the study. All adverse 
events that occur in trial subjects during the adverse event reporting period specified in the 
protocol will be reported, whether or not the even is considered treatment related. 
 
The PI will follow adverse events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of 
study participation. At each study visit, the investigator (or designee) will inquire about the 
occurrence of AE/SAEs since the last visit. Events will be followed for outcome information 
until resolution or stabilization. 
8.1.4 Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
 
8.1.5 General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an 
adverse event.  
 
8.1.6 Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved to grade 1 or less, or become chronic, the subject is lost to follow-up, or the 
adverse event is otherwise explained.  At the last scheduled visit, the investigator should 
instruct each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study.  The 
investigator should notify the study sponsor of any death or adverse event occurring at any 
time after a subject has discontinued or terminated study participation that may reasonably 
be related to this study.  The sponsor should also be notified if the investigator should 


 
28 
 
become aware of the development of cancer or of a congenital anomaly in a subsequently 
conceived offspring of a subject that has participated in this study.  
 
 
8.1.7 Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of 
the following conditions is met:  
• Grade 3 or 4 lab abnormality other than what is otherwise explained elsewhere 
in the protocol 
• The abnormality is of a degree that requires active management; e.g. change 
of dose, discontinuation of the drug, more frequent follow-up assessments, 
further diagnostic investigation, etc. 
 
8.1.8 Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed 
otherwise in this protocol.  Any condition responsible for surgery should be documented as 
an adverse event if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported 
as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or 
diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of 
the study, unless it is a worsening or increase in frequency of hospital 
admissions as judged by the clinical investigator. 
8.2 Recording of Adverse Events 
The following subsections detail what information must be documented for each adverse 
event occurring during the time period specified. 
 
Relationship to Study Intervention 
The relationship to study intervention or study participation must be assessed and 
documented for all adverse events. Evaluation of relatedness must consider etiologies 
such as natural history of the underlying disease, concurrent illness, concomitant therapy, 
study-related procedures, accidents, and other external factors.  
The following guidelines are used to assess relationship of an event to study intervention: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention. 


 
29 
 
b. There is a temporal relationship between the intervention and event onset. 
c. The event abates when the intervention is discontinued. 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
a. There is no temporal relationship between the intervention and event onset. 
b. An alternate etiology has been established. 
 
Expectedness 
The PI is responsible for determining whether an AE is expected or unexpected. An AE will 
be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the intervention. Risk 
information to assess expectedness can be obtained from preclinical studies, the 
investigator’s brochure, published medical literature, the protocol, or the informed consent 
document. 
 
Severity of Event 
Adverse events will be graded for severity according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0. 
 
Intervention 
Any intervention implemented to treat the adverse event must be documented for all 
adverse events. 
At each contact with the subject, the investigator must seek information on adverse events 
by specific questioning and, as appropriate, by examination.  Information on all adverse 
events should be recorded immediately in the source document, and also in the 
appropriate adverse event module of the case report form (CRF).  All clearly related signs, 
symptoms, and abnormal diagnostic procedures results should be recorded in the source 
document, though should be grouped under one diagnosis. 
 
The clinical course of each event should be followed until resolution to grade 1 or less, 
stabilization, becoming chronic, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of 
the study period must be followed up to determine the final outcome.  Any serious adverse 
event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
 
See form in appendix OHR-10 for recording of these events. 
8.3 Reporting of Adverse Events 
Any adverse events that is associated with study treatment and that is both serious and 
unexpected will be reported to the FDA by telephone, email, or fax within 7 days. All of the 


 
30 
 
investigators and the Thomas Jefferson University IRB will be notified as well. A follow-up 
safety report will be submitted within 15 days of initial notification. 
 
In addition, Bristol-Myers Squibb will be notified within 24 hours of becoming aware of any 
serious adverse event. 
 
8.4 Events of Special Interest 
Adverse events of special interest are events of scientific and medical interest specific to 
the further understanding of the safety profile of this treatment and require close 
monitoring and rapid identification as there is specific guidelines for management of these 
toxicities. Notably, immune related adverse events, including Grade 4 hepatitis. Please 
see list of side effects and Immune-Related Adverse Event Guidance section and 
appendix 3 to further classify these events and subsequent management. 
8.5 Data and Safety Monitoring Plan 
All AEs and SAEs, safety and toxicity data, and any corrective actions will be submitted to 
the DSMC per the frequency described in the SKCC DSMP. The report to the SKCC 
DSMC will also include any unanticipated problems that in the opinion of the PI should be 
reported to the DSMC. 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above, as well as the compliance and implementation of the Sidney 
Kimmel Cancer Center at Jefferson (SKCC) data and safety-monitoring plan.  Medical 
monitoring will include a regular assessment of the number and type of serious adverse 
events by both the assigned Medical Monitor and the KCC DSMC. 
 
8.5.1 Medical Monitoring and AE/SAE Reporting 
Study site will reconcile the clinical database SAE cases transmitted to BMS Global 
Pharmacovigilance(Worldwide.Safety@bms.com).  
 
BMS GPV&E will email, upon request from the Investigator, the GPV&E reconciliation report. 
Requests for reconciliation should be sent to aepbusinessprocess@bms.com.   
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to 
BMS within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies 
must be reported on a Pregnancy Surveillance Form. 
 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  609-818-3804 
 
8.5.2 Data and Safety Monitoring Committee 
A Medical Monitor is assigned to this study at the Thomas Jefferson University.  This is a 
physician/pharmacist who is not directly involved in the trial, and is not currently collaborating 
with the sponsor/investigator on any other trial.  The role of the Medical Monitor is to review 
all reportable AEs/SAEs (in real-time) including grading, toxicity assignments, non-reportable 
AEs (quarterly), protocol violations/deviations, as well as all other safety data and activity 
data observed in the ongoing clinical trial occurring at) Thomas Jefferson University. The 


 
31 
 
Medical Monitor may recommend reporting of adverse events and relevant safety data, and 
may also recommend suspension or termination of the study to the DSMC and TJU IRB.   
 
Every KCC investigator initiated protocol includes requirements for reporting of adverse 
events based on CTC 4.0. All events are reported to the IRB and Medical Monitor using a 
password protected web-site. In addition all unexpected and serious adverse events 
(SAEs) are reported to the TJU IRB and to the Food and Drug Administration (FDA) if 
applicable. The investigator is required to submit all unexpected and serious adverse 
events to the TJU IRB and the Medical Monitor within the timeframes outlined in the below 
table. All AE/SAEs will be reported to the DSMC at the quarterly DSMC review meetings; 
however, if the Medical Monitor determines corrective action is necessary, an “ad hoc” 
DSMC meeting will be called. Fatal adverse events related to treatment which are 
unexpected must be reported within 24 hours to the TJU IRB and the DSMC. 
Fatalities not related to the study drug/device must be reported within 5 days. A 
summary of the reporting requirements for KCC investigator initiated Phase I and Phase II 
studies are presented below. 
 
For expedited reporting requirements, see table below: 
                                             
DSMC AE/SAE Reporting Requirements 
 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 4 
and 5 
 
Unexpected 
and 
Expected 
Unexpected 
Expected 
Unexpected 
with 
Hospitalization 
Unexpected 
without 
Hospitalization 
Expected with 
Hospitalization 
Expected 
without 
Hospitalization 
Unexpected 
and 
Expected 
Unrelated 
Unlikely 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
5 Working 
Days 
Reviewed at 
Quarterly 
DSMC Meeting 
and IRB 
Annual Review 
5 Working 
Days 
Reviewed at 
Quarterly 
DSMC Meeting 
and IRB 
Annual Review 
Phase 1 -     
48 Hours   
(Death: 24 
Hours) 
 
Phase 2 -     
5 Working 
Days         
Possible 
Probable 
Definite 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
5 working 
days 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
48 Hours    
(Death: 24 
Hours) 
Phase 1 -       
48 Hours   
 
Phase 2 -       
5 Working 
Days 
48 Hours    
(Death: 24 
Hours) 
Reviewed at 
Quarterly 
DSMC Meeting 
and IRB 
Annual Review 
Phase 1 and 
Phase 2 -     
48 Hours      
(Death: 24 
Hours) 
 
 
**NOTE: This table is based on the NCI AE/SAE reporting Guidelines and the TJU IRB 
Policy and Procedures. Please follow the individual protocol AE/SAE reporting guidelines if 
more stringent reporting procedures are specified. 


 
32 
 
8.6 Unanticipated Problems 
All incidents or events that meet criteria for unanticipated problems (UAPs) require the 
creation and completion of an unanticipated problem report form (OHR-20).  
UAPs that pose risk to participants or others, and that are not AEs, will be submitted to the 
IRB on an OHR-20 form via the eazUP system within 10 working days of the investigator 
becoming aware of the event.  
UAPs that do not pose risk to participants or others will be submitted to the IRB at the next 
continuing review.  
8.7 Adverse Events  
Grade 1 AEs will be reported to the IRB at continuing review.  
Grade 2 AEs will be reported to the IRB at the time of continuing review.  
8.8 Serious Adverse Events  
SAEs will be reported to the IRB on OHR-10 forms via the electronic reporting system 
(eSAEy) according to the required time frames described below. 
Grade 3-4 AEs that are unexpected and deemed to be at least possibly related to the 
study will be reported to the IRB within 2 working days of knowledge of the event. 
Grade 3-4 AEs that are deemed unrelated to the study will be reported to the IRB within 5 
working days.  
Grade 5 AEs will be reported to the IRB within one working day of knowledge of the event. 
All SAEs will be submitted to the IRB at continuing review, including those that were 
reported previously. 
9.0 EVALUATION OF RESPONSE 
9.1 Evaluation of Clinical Response 
Patients who receive at least one IEMBO treatment will be evaluable for clinical response, 
including survival. Patients who were not treated with IEMBO due to technical problems 
will not be included for evaluation of clinical response. Patients will first be evaluated with 
scans between Cycles 2 and 3 to insure no evidence of rapid progression. Initial 
radiographic response will be determined following four IEMBO treatments if both. Patients 
with SD, PR, or CR at this time will have repeat scans after every two treatment cycles.  
 
9.2 Definition of Measurable Disease 
Measurable disease 
Measurable disease is defined by the presence of at least one measurable lesion as 
defined below and adapted from the RECIST 1.1 criteria (Eur J Cancer. 2009 
Jan;45(2):228-47).  All measurements must be recorded in metric notation.  If measurable 
disease is restricted to a solitary lesion, its malignant nature should previously have been 
confirmed by cytology/histology.  
 


 
33 
 
Since some melanoma metastases contain melanin pigment and since successfully 
treated liver metastases tend to retain infused ethiodized oil, evaluation of radiological 
response after embolization treatments is generally difficult.  Therefore, we will obtain both 
CT scan and MRI of the liver for the precise evaluation of radiological responses.  
However, the same modality will be used for measurement of the liver metastases and 
assessment of the response.   
 
The longest diameter (LD) of the largest liver lesion should be ≥ 10 mm by CT scan or MRI 
in order to become eligible for the study.   
Non-measurable disease 
All other lesions including small lesions (<10 mm on  CT scans) are considered “non-
measurable”.  The following lesions are also considered as “non-measurable”: Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, abdominal masses 
that are not confirmed and followed by imaging techniques, tumors treated by irradiation or 
by intra-tumor injection therapy.   
 
9.3     Baseline Documentation of "Target" and "Non-Target" Lesions  
 
Target Lesions (Indicator Lesions) 
The target lesions are defined as measurable lesions that will be used for evaluation of 
response. For this protocol, target lesions require serial measurement of a longest 
diameter (LD) and should be ≥10 mm by CT scan or MRI at the time of study entry.  
 
Target lesions (up to a maximum number of 6 for the liver metastases) must be identified 
and measured at baseline prior to the initiation of embolization.  Target lesions must be 
selected on the basis of their size (LD) and suitability for repetitive measurements. 
 
 
Non-Target Lesions 
All other lesions (or sites of melanoma) must be identified as “non-target” and their location 
and characteristics must be recorded at baseline.  During follow-up evaluations, these 
lesions must be followed as “present” or “absent”.  
 
9.4 
Evaluation of overall response in the liver metastases 
Clinical response in the liver metastases will be evaluated using CT scans or MRI of the 
abdomen initially following four combination treatments and then after every two IEMBO 
treatments.  The same modality must be used for serial measurements of target lesions.  
The sum of the longest diameter (LD) of up to 6 target liver lesions will be used to 
determine response.  The investigators must identify target indicator lesions and measure 
them prior to the first embolization as baseline. The investigators will then measure the 
same target lesions after every two IEMBO treatments.   
 
The sum of the baseline LDs will be compared to the sum of LDs after every two IEMBO 
treatments following the scans after the first four treatments.  New lesions will be defined 
as lesions that appear in the treated lobe(s) of the liver after the last evaluation and should 
be ≥ 10 mm in longest diameter. Development of new lesion(s) in an untreated lobe (area) 
of the liver will not be considered as “Progressive Disease” for evaluation of liver 
response.  These lesions will be treated in the subsequent embolization procedures and 


 
34 
 
they will be included in the evaluation for response after completion of two additional 
embolizations.   
 
 
 
 
 
 
 
 
 
 
 
 
To be assigned a status of CR or PR, changes in tumor measurements must be  
confirmed by the follow-up assessment using the same imaging test at a minimum  
interval of 4 weeks. The patients who have a CR or PR without confirmatory assessment  
will be categorized as SD.  In the case of SD, follow-up measurements must have met  
the SD criteria at least once at a minimum interval of 4 weeks. The patients who have a  
SD without confirmatory assessment will be categorized as PD.     
 
9.5 
Response criteria for liver metastases 
The response of liver metastases will be evaluated by MRI or CT scans using the criteria 
adapted from the international criteria proposed by RECIST 1.1. However, since there can 
be post embolization changes in liver tumors that can sometimes be read as lesion 
enlargement, post treatment changes will be considered when lesions are measured. 
 
9.6  Progression Free Survival 
 
Progression Free Survival (PFS) is measured from the start of the treatment to 
confirmation of progression of disease by either imaging tests or physical examination. 
Date and sites of progression will be recorded. Progression free interval for hepatic 
metastases and progression free interval for extra-hepatic metastasis will be measured in 
aggregate and separately.   
 
 
9.7 Overall survival  
 
Target 
Liver 
Lesions 
Non-Target 
Liver Lesions 
New Liver 
Lesions in the 
treated lobes 
Overall Liver 
Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Complete Response 
(CR) 
Disappearance of all target and non-target liver lesions  
Partial Response 
(PR) 
> 30% decrease in the sum of the longest diameters (“sum LD”) relative 
to baseline sum LD with at least stable non-target liver lesions 
Stable Disease 
(SD) 
Absence of change which would qualify as response or progression 
Progression 
(PD) 
> 20% increase in the sum LD in target liver lesions or unequivocal 
progression of non-target liver lesions in the treated lobe(s)   
Appearance of one or more new liver lesions >10 mm in the treated 
lobe(s) 


 
35 
 
Overall survival (OS) is measured from the start of the treatment to death of patients. Date 
and cause of death will be recorded. The cause of death will be categorized as either 
cancer-related or cancer-unrelated.   
 
10.0 CORRELATIVE STUDIES 
 
10.1 Collecting Samples 
Peripheral blood samples will be collected prior to and following combination treatments as 
outlined in the study calendar.  
 
10.2 Biopsies 
Patients will need to have biopsy or access to archival tissue prior to treatment. Three 
weeks after the first embolization and prior to the second embolization, the second liver 
biopsy will be performed to evaluate the host response to tumor if patients consent and 
technically feasible. A separate standard consent form must be obtained for biopsy of the 
liver tumor. Biopsy at time of progression is also options if patients consent and technically 
feasible.  
 
10.3 Evaluations 
Systemic and local immune/inflammatory response correlatives 
 
Local Immune Responses: 
a. Degree and classification of tumor-infiltrating cells  
b. Presence and changes in PD-L1 expression in tumor and tumor-infiltrating 
cells 
c. Changes in immune tumor microenvironment (immune gene signature) 
 
Systemic immune responses: 
d. Changes in leukocyte subpopulations in the peripheral blood, including 
activated T cells as well as MDSC 
e. Changes of serum cytokine levels before and after treatment to include IL-6, 
IL-8, TNF-alpha, IFN-gamma, and GM-CSF by multiplex cytokine assays.  
f. Changes in TCR repertoire analysis  (ImmunoSeq) 
 
Tumor mutational load will also be assessed on the primary liver tumor biopsy prior to 
treatment and corresponding blood sample will be obtained to provide as control for 
possible characterization of germline mutations.  
 
Any residual blood or tissue samples may be subjected to additional testing where 
appropriate.  
 
11.0 DATA HANDLING AND RECORD KEEPING 
11.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following:  


 
36 
 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive) at the end of their scheduled study period. 
11.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents   Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate 
and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
11.3 Data Collection 
The Redcap database utilized for this study will be the primary data collection instrument for 
the study.  All data requested in Redcap must be recorded.  All missing data must be 
explained.   
11.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years 
after the last approval of a marketing application in their country and until there are no 
pending or contemplated marketing applications in their country or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product.  These documents should be retained for a longer period if required by an 
agreement with the sponsor.  In such an instance, it is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be 
retained.  
 
12.0 STUDY MONITORING, AUDITING, AND INSPECTING 
 
12.1 Study Monitoring Plan 
The investigator will allocate adequate time for monitoring activities.  The Investigator will 
also ensure that the medical monitor or other compliance or quality assurance reviewer is 
given access to all the above noted study-related documents and study related facilities 
(e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct the 
monitoring visit. 
 
 


 
37 
 
KCC Investigator Initiated Phase II Studies  
Phase II studies require continuous monitoring by the PI of the study with quarterly safety 
and monitoring reports submitted to the CRMO and the DSMC. Each protocol is assigned 
to a medical monitor (a physician or other member of the DSMC who has expertise in the 
therapeutic area of the protocol and is not directly involved in this trial). The medical 
monitor reviews all adverse events (in addition to unexpected adverse events), safety data 
and activity data observed in the ongoing clinical trial at each new dose level, prior to dose 
escalation.  
 
The PI provides a report to the DSMC of all AE/SAEs, safety and toxicity data, and any 
corrective action that occurred on a quarterly basis. The medical monitor also provides a 
summary of their review. The summary of all discussions of adverse events are submitted 
to the DSMC, and these reports are reviewed during the DSMC meetings that take place 
quarterly. Patients are only identified by initials, and no other personal health information 
(PHI) is included in the reports.  
 
The medical monitor may recommend reporting adverse events and relevant safety data 
not previously reported, and may recommend suspension or termination of the trial based 
on their review of AE/SAE data observed throughout the life of a clinical trial. In such 
circumstances, and “ad hoc” DSMC meeting will be called to discuss corrective action with 
the PI. If for any reason the PI of the trial disagrees with the conclusions of the Medical 
Monitor or DSMC, the issue will be referred to the Associate Director of Clinical 
Investigations, who will be responsible for dispute resolution.  
 
The summary of all discussions of adverse events are included in the KCC investigator’s 
reports to the TJU IRBs as part of its annual progress report. The DSMC and the TJU 
IRBs may, based on the monitor’s recommendation suspend or terminate the trial. The 
quarterly safety and monitoring reports include a statement as to whether this data has 
invoked any stopping criteria in the clinical protocol.  
12.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
the funding sponsor, government regulatory bodies, and University compliance and quality 
assurance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.).  The investigator will ensure the 
capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality 
assurance offices. 
 
12.2.1 Independent External and Internal Audits  
In addition to review by the DSMC, all studies initiated by KCC investigators are audited by 
an independent auditor once they have achieved 10% of target accrual. However, a study 
can be audited at any time based on recommendations by the IRB, DSMC, CCRRC and/or 
the Director of Clinical Investigations, KCC. Studies are re-audited once they have 
achieved 50% of target accrual. Special audits may be recommended by the IRB, DSMC 
or CCRRC based on prior findings, allegations of scientific misconduct and where 


 
38 
 
significant irregularities are found through quality control procedures. Any irregularities 
identified as part of this process would result in a full audit of that study.  
 
In addition to the audits at 10 and 50%, the CRMO randomly audits at least 10 percent of 
all patients entered into therapeutic KCC trials and other trials as necessary, on at least a 
bi-annual basis, to verify that there is a signed and dated patient consent form, the patient 
has met the eligibility criteria, and that SAEs are documented and reported to the TJU IRB.  
 
All audit reports are submitted to the DSMC for review and action (when appropriate). A 
copy of this report and recommended DSMC action is sent to the CCRRC and TJU IRB. 
The committee regards the scientific review process as dynamic and constructive rather 
than punitive. The review process is designed to assist Principal Investigators in ensuring 
the safety of study subjects and the adequacy and accuracy of any data generated. The 
TJU IRB may, based on the DSMC and auditor’s recommendation, suspend or terminate 
the trial.  
13.0 ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the IRB concerning the conduct of the 
study will be made in writing to the investigator before commencement of this study.   
 
All subjects for this study will be provided a consent form that is compliant with local and 
federal regulations, describing this study and providing sufficient information for subjects to 
make an informed decision about their participation in this study.  See Attachment for a 
copy of the Subject Informed Consent Form.  This consent form will be submitted with the 
protocol for review and approval by the IRB for the study.  The formal consent of a subject, 
using the IRB-approved consent form, must be obtained before that subject is submitted to 
any study procedure.  This consent form must be signed by the subject or legally 
acceptable surrogate, and the investigator-designated research professional obtaining the 
consent.  
13.1 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by a properly constituted Conflict of Interest Committee with a 
Committee-sanctioned conflict management plan that has been reviewed and approved by 
the study sponsor prior to participation in this study.  All Jefferson University Investigators 
will follow the TJU Conflicts of Interest Policy for Employees (107.03). 
13.2 Subject Stipends or Payments 
There is no compensation for participation in this study. 
 
 


 
39 
 
14.0 REFERENCES 
 
1. Shields CL, Kaliki S, Furuta M, Mashayekhi A, Shields JA. Clinical spectrum and 
prognosis of uveal melanoma based on age at presentation in 8,033 cases.Retina. 
2012 Jul;32(7):1363-72. 
2. Bedikian AY, Papadopoulos N, Plager C, Eton O, Ring S. Phase II evaluation of 
temozolomide in metastatic choroidal melanoma. Melanoma Res. 2003 
Jun;13(3):303-6. 
3. Carvajal RD, Sosman JA, Quevedo JF, Milhem MM, Joshua AM, Kudchadkar RR, 
Linette GP, Gajewski TF, Lutzky J, Lawson DH, Lao CD, Flynn PJ, Albertini MR, 
Sato T, Lewis K, Doyle A, Ancell K, Panageas KS, Bluth M, Hedvat C, Erinjeri J, 
Ambrosini G, Marr B, Abramson DH, Dickson MA, Wolchok JD, Chapman PB, 
Schwartz GK. Effect of selumetinib vs chemotherapy on progression-free survival in 
uveal melanoma: a randomized clinical trial. JAMA. 2014 Jun 18;311(23):2397-405. 
4. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez 
R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky 
J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel 
C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, 
Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma.  
N Engl J Med. 2010 Aug 19;363(8):711-23.  
5. Rodriguez J, Olsa M, Codes M, et al. Phase II study evaluating ipilimumab as a 
single agent in the first line treatment of adult patients with metastatic uveal 
melanoma. The GEM-1 trial. J Clin Oncol 32:5s, 2014 (supple; absr 9033) 
6. Deo, M. Long term survival benefit from ipilimumab treatment in metastatic uveal 
melanoma patients. J Clin Oncol 32:5s, 2014 (suppl; absr 3060) 
7. Algazi A, Tsai K, Shoustari A, et al. Clinical outcomes in metastatic uveal melanoma 
treated with PD-1 and PD-L1 antibodies. Cancer. doi:10.1002/cncr.30258. 
8. Eschelman DJ, Gonsalves CF, Sato T. Transhepatic therapies for metastatic uveal 
melanoma. Semin Intervent Radiol. 2013 Mar;30(1):39-48. 
9. Sato T, Eschelman D J, Gonsalves C F. et al. Immunoembolization of malignant 
liver tumors, including uveal melanoma, using granulocyte-macrophage colony-
stimulating factor. J Clin Oncol. 2008;30(1):5436–5442. 
10. Yamamoto A, Chervoneva I, Sullivan K L. et al. High-dose immunoembolization: 
survival benefit in patients with hepatic metastases from uveal melanoma. 
Radiology. 2009;30(1):290–298. 
11. Eschelman D J, Gonsalves C F, Terai M. et al. The results of a randomized phase II 
study using embolization with or without granulocyte-macrophage colony-
stimulating factor (GM-CSF) in uveal melanoma patients with hepatic metastasis. J 
Clin Oncol. 2011;30:544s. 
12. Orloff M, Pan K, Gonzalves C, Eschelman D, Sato T. Combination treatment with 
ipilimumab and immunoembolization in metastatic uveal melanoma, a feasibility 
study. J Clin Oncol 33, 2015 (suppl; abstr e20015) 
13. Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or 
Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Sep 24;373(13):1270-1. 
doi:10.1056/NEJMc1509660. 
 
 
 
 


 
40 
 
15.0 APPENDICES 
 
15.1 Study Schedule 
 
 
 
 *1: Comprehensive metabolic panel including total bilirubin, SGOT (AST), SGPT (ALT), alkaline phosphatase, albumin, creatinine,   
       BUN, glucose, calcium, phosphate. 
*2: For females of childbearing potential and within 2 weeks of start of treatment, and on Day 1 of every cycle or (Day 2 if only 
receiving Iembo.). 
*3: 60 ml blood for immunologic testing prior to each cycle, 10 ml drawn before, 1 hour and at Day 3  after IEMBO for cytokines 
There is a 15 minute window for initial blood draw as patients are sometimes mid-transport at one hour post IEMBO.   
*4: Tests can be skipped if screening evaluation is performed within 4 weeks prior to scheduled treatment. 
*5: May be done within 3 days prior for Day 1 visit. 
*6: Biopsy or access to Archival tissue needed prior to treatment. Biopsy Day 2 of Cycle 2 before second  
       Immunoembolization but may be performed one week before Cycle 2 
*7: Endrocrine labs will be checked one week prior to each infusion and at the next infusion.   
*8: If not completed within 4 weeks of Exit. 
*9: There is a window of 3 days +/- permitted between each treatment cycle, beginning at Cycle 2. 
*10 In the event pt. is no longer receiving infusion on Day 1, 60 ml study blood and CRP can be drawn on Day 2 prior to IE. 
* 11 Study blood will be taken at the first 6 cycles of treatment, then yearly, and at Exit/EOT.  
 
 
Events 
Screening 
Evaluation 
Pretreat 
assessment 
Initial 
IPI+NIVO 
IEMBO 
 
 
After 4 
cycles 
Subsequent 
NIVO 
Subsequent 
IEMBO 
Follow up 
Visits 
Exit 
TIME 
Within 4 
weeks prior 
to 
enrollment 
Within 4 
weeks prior 
to 
treatment 
Day 1 of 
each 21 
day cycle 
for first 
four 
Day 2 of 
each 21 
day cycle 
for first 
four 
Day 3 
of each 
21 and 
28 day 
cycle 
Weekly 
while 
getting 
IEMBO 
Appt. 
after 
first 4 
cycles 
Day 1 of each 
28 day cycle 
after first four 
(*9) 
Day 2 of 
each 28 day 
cycle after 
first four  
Every 8 
week 
outpatient 
appt after 
12 weeks 
Exit 
  Informed  Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X (*4) 
X 
X 
 
 
X 
X 
X 
X 
X 
Physical Exam 
X 
X (*4) 
X 
X 
 
 
X 
X 
X 
X 
X 
Performance Status 
X 
X (*4) 
X 
 
 
 
X 
X 
X 
X 
X 
Concomittent 
Medications 
X 
X (*4) 
X 
 
 
 
X 
X 
X 
X 
X 
CBC with Diff 
X 
X (*4) 
X(*5) 
X 
X 
X 
X 
X(*5) 
X 
 
X 
PT, INR, PTT 
X 
 
 
X 
 
 
 
 
X 
 
 
Serum  
Chemistry (*1) 
X 
X (*4) 
X(*5) 
X 
X 
X 
X 
X(*5) 
X 
 
X 
TSH 
 
X (*4) 
X(*5) 
 
 
X(*7) 
X 
X(*5, 7, 10) 
 
 
 
LDH 
X 
X (*4) 
X(*5) 
X 
X 
X 
X 
X(*5) 
X 
 
X 
CRP 
 
X 
X (10) 
 
X 
 
X 
X(10) 
 
 
 
Pregnancy Test (*2) 
X 
X (*2) 
 
 
 
 
 
 
 
 
 
Study Blood 
 
 
X (*3, 
10, 11) 
X(*3) 
X 
 
X 
X(*3, 5, 10, 11) 
X(*3) 
 
X(*11
) 
Liver Tumor Bx 
 
X (*6) 
 
X(*6) 
 
 
 
 
 
 
 
CT C/A/P 
X 
X (*4) 
 
 
 
 
X 
 
 
X 
X(*8) 
MRI Abdomen 
X 
X (*4) 
 
 
 
 
X 
 
 
X 
X(*8) 
CT or MRI Brain 
x 
X (*4) 
 
 
 
 
 
 
 
 
 
Tumor 
Measurement 
 
X 
 
 
 
 
X 
 
 
X 
X(*8) 
IPI+NIVO 
 
 
X 
 
 
 
 
 
 
 
 
NIVO 
 
 
 
 
 
 
 
X 
 
 
 
IEMBO 
 
 
 
X 
 
 
 
 
X 
 
 
Toxicities and AEs 
 
X (*4) 
X 
X 
X 
 
X 
X 
X 
X 
X 


 
41 
 
15.2 Adverse Events and Potential Risks 
 
The following tables and text are adopted from Investigator Brochure Addendum No. 1 
28-Sep-2016 Addendum No. 1 to Investigator Brochure Version 15, dated 24-Jun-2016, 
for BMS-936558 (Nivolumab). 
 
Adverse Drug Reactions from Clinical Studies 
Any adverse drug reactions (ADRs) included in this section were identified by the Sponsor 
based on the nature and frequency of observed events (from both open-label and blinded 
clinical studies) and reasonable evidence of causal association with nivolumab. The ADRs 
as described in this section are considered to be expected. For example, if an ADR is 
described as serious (indicated by “Y”) in the table below but not life threatening or fatal 
(indicated by “n”), then the Sponsor would not consider a life-threatening or fatal 
occurrence to be expected. Similarly, if ADRs are described as non-serious, then serious, 
life threatening, and/or fatal occurrences would not be considered expected. Additionally, if 
an ADR is described as fatal then a less severe outcome of life threatening is expected. 
 
The ADRs for nivolumab are listed by System Organ Class in Table 16.2-1 and Table 16.2-
2. The overall frequency of the ADR represents the frequency for all ADRs regardless of 
seriousness. The sponsor has included information in the table as to the nature of the ADR, 
including serious, life threatening or fatal outcomes. For all events in the table, non-serious 
events are expected. 
 
Frequency categories are defined using the following convention: very common ≥ 1/10); 
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 
1/1,000); very rare (< 1/10,000). 
 
Table 15.2-1: Adverse Drug Reactions in Patients Treated with Nivolumab Monotherapy in Clinical 
Studies (N=9,212) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious 
ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Cardiac 
Disorder 
Tachycardia 
Atrial fibrillationa 
Arrhythmia 
Uncommon 
17 (0.18) 
Rare 
6 (0.07) 
Rare 
n 
n 
n 
Y 
2 (0.02) 
n 
n 
n 
n 
n 
 


 
42 
 
 
Table 15.2-1: 
Adverse Drug Reactions in Patients Treated with Nivolumab 
Monotherapy in Clinical Studies (N=9,212) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious 
ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Ear and 
Labyrinth 
Disorders 
Endocrine 
Disorders 
Eye Disorders 
Ventricular 
arrhythmia 
Vertigo 
Hypothyroidism 
Hyperthyroidism 
Hyperglycaemia 
Adrenal 
Insufficiency 
Hypophysitis 
Thyroiditis 
Diabetes mellitus 
Hypopituitarism 
Autoimmune 
thyroiditis 
Autoimmune 
hypothyroidism 
Diabetic 
ketoacidosis 
Dry eyea 
Vision blurred 
Uveitis 
Iridocyclitis 
2 (0.02) 
Rare 
1 (0.01) 
Uncommon 
22 (0.24) 
Common 
440 (4.78) 
Common 
141 (1.53) 
Uncommon 
72 (0.78) 
Uncommon 
52 (0.56) 
Uncommon 
32 (0.35) 
Uncommon 
25 (0.27) 
Uncommon 
19 (0.21) 
Uncommon 
16 (0.17) 
Uncommon 
11 (0.12) 
Rare 
3 (0.03) 
Rare 
3 (0.03) 
Uncommon 
42 (0.46) 
Uncommon 
32 (0.35) 
Uncommon 
12 (0.13) 
Rare 
Y 
1 (0.01) 
n 
n 
n 
n 
n 
Y 
14 (0.14) 
n 
n 
Y 
5 (0.05) 
n 
n 
Y 
16 (0.17) 
Y 
1 (0.01) 
n 
Y 
28 (0.31) 
Y 
1 (0.01) 
n 
Y 
16 (0.17) 
n 
n 
n 
n 
n 
Y 
4 (0.04) 
n 
n 
Y 
5 (0.05) 
n 
n 
Y 
1 (0.01) 
n 
n 
n 
n 
n 
Y 
3 (0.03) 
Y 
1 (0.01) 
n 
n 
n 
n 
n 
n 
n 
Y 
2 (0.02) 
n 
n 
Y 
n 
n 


 
43 
 
 
Table 15.2-1: 
Adverse Drug Reactions in Patients Treated with Nivolumab 
Monotherapy in Clinical Studies (N=9,212) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious 
ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Gastrointestina 
l Disorders 
General 
disorders and 
administration 
site conditions 
Diarrhea 
Nausea 
Vomiting 
Constipation 
Abdominal Pain 
Dry mouth 
Colitis 
Stomatitis 
Mucosal 
inflammation 
Gastritisa 
Pancreatitis 
Autoimmune colitis 
Mouth ulcerationb 
Pancreatitis acute 
Mucosal 
ulceration 
3 (0.03) 
Common 
783 (8.50) 
Common 
700 (7.60) 
Common 
289 (3.14) 
Common 
223 (2.42) 
Common 
222 (2.41) 
Common 
157 (1.70) 
Common 
98 (1.06) 
Uncommon 
86 (0.93) 
Uncommon 
68 (0.74) 
Uncommon 
16 (0.17) 
Uncommon 
15 (0.16) 
Rare 
5 (0.05) 
Rare 
4 (0.04) 
Rare 
4 (0.04) 
Rare 
1 (0.01) 
Very 
Common 
1390 (15.09) 
1 (0.01) 
Y 
68 (0.74) 
n 
n 
Y 
23 (0.25) 
n 
n 
Y 
26 (0.28) 
n 
n 
n 
n 
n 
Y 
13 (0.14) 
n 
n 
n 
n 
n 
Y 
70 (0.78) 
n 
Y 
2 (0.02) 
Y 
4 (0.04) 
n 
n 
Y 
4 (0.04) 
n 
n 
Y 
4 (0.04) 
n 
n 
Y 
7 (0.08) 
n 
n 
Y 
2 (0.02) 
n 
n 
Y 
1 (0.01) 
n 
n 
Y 
3 (0.03) 
n 
n 
n 
n 
n 
Y 
28 (0.30) 
n 
n 


 
44 
 
 
Table 15.2-1: 
Adverse Drug Reactions in Patients Treated with Nivolumab 
Monotherapy in Clinical Studies (N=9,212) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious 
ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Hepatobilliary 
Disorders 
Immune 
System 
Disorders 
Pyrexia 
Asthenia 
Chillsa 
Oedema peripheral 
Oedema 
Face oedema 
Localised oedema 
Peripheral swelling 
Generalised oedema 
Periorbital oedema 
Swelling face 
Autoimmune 
hepatitis 
Hepatitis 
Hepatitis acute 
Infusion related 
reaction 
Hypersensitivity 
Anaphylactic 
reaction 
Common 
326 (3.54) 
Common 
311 (3.38) 
Common 
146 (1.58) 
Common 
120 (1.30) 
Uncommon 
16 (0.17) 
Uncommon 
14 (0.15) 
Uncommon 
9 (0.10) 
Uncommon 
9 (0.10) 
Rare 
5 (0.05) 
Rare 
4 (0.04) 
Rare 
4 (0.04) 
Uncommon 
18 (0.20) 
Uncommon 
11 (0.12) 
Rare 
3 (0.03) 
Common 
152 (1.65) 
Uncommon 
70 (0.76) 
Rare 
Y 
41 (0.45) 
n 
n 
Y 
2 (0.02) 
n 
n 
Y 
4 (0.04) 
n 
n 
Y 
3 (0.03) 
n 
n 
n 
n 
n 
n 
n 
n 
Y 
1 (0.01) 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
Y 
1 (0.01) 
n 
n 
Y 
14 (0.15) 
Yb 
1 (0.01) 
n 
Y 
8 (0.09) 
n 
n 
Y 
3 (0.03) 
n 
n 
Y 
21 (0.23) 
Y 
1 (0.01) 
n 
Y 
9 (0.10) 
Y 
1 (0.01) 
n 
Y 
Y 
n 


 
45 
 
 
Table 15.2-1: 
Adverse Drug Reactions in Patients Treated with Nivolumab 
Monotherapy in Clinical Studies (N=9,212) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious 
ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Infections and 
Infestations 
Investigations 
Metabolism 
and Nutrition 
Disorders 
Musculoskeleta 
l and 
Connective 
Tissue 
Disorders 
Sarcoidosisa 
Upper respiratory 
tract infection 
Bronchitis 
Aspartate 
aminotransferase 
increased 
Alanine 
aminotransferase 
increased 
Lipase increased 
Blood alkaline 
phosphatase 
increaseda 
Amylase increased 
Blood creatinine 
increaseda, 
Blood thyroid 
stimulating 
hormone increaseda 
Blood bilirubin 
increased 
Decreased appetite 
Hyponatraemia 
Arthralgia 
4 (0.04) 
Rare 
4 (0.04) 
Uncommon 
31 (0.34) 
Uncommon 
10 (0.11) 
Common 
257 (2.79) 
Common 
239 (2.59) 
Common 
163 (1.77) 
Common 
127 (1.38) 
Common 
102 (1.11) 
Common 
100 (1.09) 
Common 
92 (1.00) 
Uncommon 
49 (0.53) 
Common 
536 (5.82) 
Uncommon 
87 (0.94) 
Common 
358 (3.89) 
3 (0.03) 
2 (0.02) 
Y 
2 (0.02) 
n 
n 
n 
n 
n 
n 
Y 
23 (0.25) 
n 
n 
Y 
27 (0.329) 
n 
n 
Y 
13 (0.14) 
n 
n 
Y 
6 (0.07) 
n 
n 
Y 
4 (0.04) 
n 
n 
Y 
3 (0.03) 
n 
n 
n 
n 
n 
Y 
4 (0.04) 
n 
n 
Y 
5 (0.05) 
n 
n 
Y 
17 (0.18) 
n 
n 
Y 
3 (0.03) 
n 
n 


 
46 
 
 
Table 15.2-1: 
Adverse Drug Reactions in Patients Treated with Nivolumab 
Monotherapy in Clinical Studies (N=9,212) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious 
ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Nervous 
System 
Disorders 
Myalgia 
Pain in extremity 
Back pain 
Musculoskeletal 
pain 
Arthritis 
Musculoskeletal 
chest pain 
Polyarthritis 
Bone pain 
Neck pain 
Polymyalgia 
rheumaticab 
Myositisa 
Musculoskeletal 
discomfort 
Osteoarthritis 
Pain in jaw 
Polymyositisa 
Rhabdomyolysisa 
Headache 
Common 
202 (2.19) 
Uncommon 
74 (0.80) 
Uncommon 
64 (0.69) 
Uncommon 
50 (0.54) 
Uncommon 
26 (0.28) 
Uncommon 
13 (0.14) 
Uncommon 
13 (0.14) 
Uncommon 
11 (0.12) 
Rare 
8 (0.09) 
Rare 
6 (0.07) 
Rare 
5 (0.05) 
Rare 
3 (0.03) 
Rare 
3 (0.03) 
Rare 
2 (0.02) 
Rare 
1 (0.01) 
Rare 
1 (0.01) 
Common 
215 (2.33) 
Y 
2 (0.02) 
n 
n 
n 
n 
n 
Y 
2 (0.02) 
n 
n 
n 
n 
n 
Y 
3 (0.03) 
n 
n 
n 
n 
n 
Y 
4 (0.04) 
n 
n 
n 
n 
n 
n 
n 
n 
Y 
1 (0.01) 
n 
n 
Y 
3 (0.03) 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
Y 
1 (0.01) 
Y 
1 (0.01) 
n 
Y 
1 (0.01) 
Y 
4 (0.04) 
n 
n 


 
47 
 
 
Table 15.2-1: 
Adverse Drug Reactions in Patients Treated with Nivolumab 
Monotherapy in Clinical Studies (N=9,212) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious 
ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Renal and 
Urinary 
Disorders 
Dizziness 
Neuropathy 
peripheral 
Peripheral sensory 
neuropathy 
Cranial nerve 
disordera 
Peripheral motor 
neuropathy 
Polyneuropathy 
Burning sensation 
Encephalitis 
Guillain-Barre 
syndrome 
Myasthenia gravis 
Demyelinating 
polyneuropathyb 
Demyelinationb 
Myasthenic 
syndrome 
Acute kidney injury 
Renal failure 
Tubulointerstitial 
nephritis 
Uncommon 
83 (0.90) 
Uncommon 
59 (0.64) 
Uncommon 
24 (0.26) 
Uncommon 
12 (0.13) 
Rare 
7 (0.08) 
Rare 
7 (0.08) 
Rare 
5 (0.05) 
Rare 
2 (0.02) 
Rare 
2 (0.02) 
Rare 
2 (0.02) 
Rare 
1 (0.01) 
Rare 
1 (0.01) 
Rare 
1 (0.01) 
Uncommon 
26 (0.28) 
Uncommon 
15 (0.16) 
Uncommon 
9 (0.10) 
Y 
3 (0.03) 
n 
n 
Y 
4 (0.04) 
n 
n 
Y 
1 (0.01) 
n 
n 
Y 
6 (0.07) 
n 
n 
Y 
2 (0.02) 
n 
n 
Y 
2 (0.02) 
n 
n 
n 
n 
n 
Y 
2 (0.02) 
n 
Yb 
1 (0.10) 
Y 
2 (0.02) 
n 
n 
Y 
2 (0.02) 
n 
n 
Y 
1 (0.01) 
n 
n 
Y 
1 (0.01) 
n 
n 
Y 
1 (0.01) 
n 
n 
Y 
20 (0.22) 
Y 
2 (0.02) 
n 
Y 
4 (0.04) 
n 
n 
Y 
8 (0.09) 
n 
n 


 
48 
 
 
Table 15.2-1: 
Adverse Drug Reactions in Patients Treated with Nivolumab 
Monotherapy in Clinical Studies (N=9,212) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious 
ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Respiratory, 
Thoracic, and 
Mediastinal 
Disorders 
Skin and 
Subcutaneous 
Tissue 
Disorders 
Autoimmune 
nephritis 
Nephritis 
Pneumonitis 
Dyspnoea 
Cough 
Interstitial lung 
disease 
Respiratory failurea 
Lung infiltration 
Organising 
pneumonia 
Respiratory distress 
syndromea 
Pruritus 
Rash 
Dry skin 
Rash maculo- 
papular 
Vitiligo 
Rare 
4 (0.04) 
Rare 
1 (0.01) 
Common 
247 (2.68) 
Common 
231 (2.51) 
Common 
222 (2.41) 
Uncommon 
27 (0.29) 
Uncommon 
17 (0.18) 
Rare 
7 (0.08) 
Rare 
2 (0.02) 
Rare 
1 (0.01) 
Common 
658 (7.84) 
Common 
580 (6.30) 
Common 
182 (1.98) 
Common 
182 (1.98) 
Common 
99 (1.07) 
Y 
3 (0.03) 
n 
n 
n 
n 
n 
Y 
Y 
Y 
133 (1.44) 
7 (0.08) 
9 (0.10) 
Y 
Y 
Y 
35 (0.38) 
1 (0.01) 
3 (0.03) 
Y 
3 (0.03) 
n 
n 
Y 
18 (0.20) 
Yb 
1 (0.01) 
n 
Y 
Y 
Y 
15 (0.16) 
2 (0.02) 
6 (0.07) 
Y 
2 (0.02) 
n 
n 
Y 
2 (0.02) 
n 
n 
Y 
1 (0.01) 
n 
Yb 
1 (0.01) 
Y 
1 (0.01) 
n 
n 
Y 
9 (0.10) 
n 
n 
n 
n 
n 
Y 
5 (0.05) 
n 
n 
n 
n 
n 


 
49 
 
 
Table 15.2-1: 
Adverse Drug Reactions in Patients Treated with Nivolumab 
Monotherapy in Clinical Studies (N=9,212) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious 
ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Erythema 
Pruritus generalised 
Alopecia 
Rash pruritic 
Dermatitis 
acneiform 
Rash macular 
Urticaria 
Rash papular 
Rash erythematous 
Psoriasis 
Dermatitis 
Rash generalised 
Rash pustular 
Erythema 
multiforme 
Dermatitis allergic 
Dermatitis 
exfoliative 
Stevens Johnson 
syndrome 
Uncommon 
75 (0.81) 
Uncommon 
64 (0.69) 
Uncommon 
60 (0.65) 
Uncommon 
52 (0.56) 
Uncommon 
48 (0.52) 
Uncommon 
45 (0.49) 
Uncommon 
40 (0.43) 
Uncommon 
22 (0.24) 
Uncommon 
21 (0.23) 
Uncommon 
18 (0.20) 
Uncommon 
17 (0.18) 
Uncommon 
16 (0.17) 
Uncommon 
13 (0.14) 
Rare 
7 (0.08) 
Rare 
4 (0.04) 
Rare 
4 (0.04) 
Rare 
3 (0.03) 
n 
n 
n 
Y 
1 (0.01) 
n 
n 
n 
n 
n 
Y 
1 (0.01) 
n 
n 
n 
n 
n 
Y 
1 (0.01) 
n 
n 
n 
n 
n 
Y 
2 (0.02) 
n 
n 
n 
n 
n 
Y 
3 (0.03) 
n 
n 
n 
n 
n 
Y 
1 (0.01) 
n 
n 
n 
n 
n 
Y 
3 (0.03) 
n 
n 
n 
n 
n 
n 
n 
n 
Y 
3 (0.03) 
n 
n 


 
50 
 
 
Table 15.2-1: 
Adverse Drug Reactions in Patients Treated with Nivolumab 
Monotherapy in Clinical Studies (N=9,212) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious 
ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Vascular 
Disorders 
Drug eruptionb 
Rash follicular 
Rash vesicular 
Rosacea 
Toxic epidermal 
necrolysis 
Hypotension 
Hypertension 
Vasculitis 
Rare 
2 (0.02) 
Rare 
2 (0.02) 
Rare 
2 (0.02) 
Rare 
2 (0.02) 
Rare 
1 (0.01) 
Uncommon 
43 (0.47) 
Uncommon 
42 (0.46) 
Rare 
2 (0.02) 
Y 
1 (0.01) 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
Y 
1 (0.01) 
n 
Y 
1 (0.01) 
Y 
5 (0.05) 
n 
n 
n 
n 
n 
n 
n 
n 
 
 
a 
ADR not included in previous IB version 14. 
b This event is an adverse drug reaction for nivolumab but serious, related occurrences will be reported as 
SUSARs due to the low observed frequency. 


 
51 
 
 
Table 15.2-2: 
Adverse Drug Reactions in Patients Treated with Nivolumab in  
                                           Combination with Ipilimumab in Clinical Studies (N=2,712) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Cardiac 
Disorder 
Ear and 
Labyrinth 
Disorders 
Endocrine 
Disorders 
Eye Disorders 
Tachycardia 
Atrial fibrillationa 
Myocarditisa 
Ventricular 
arrhythmia 
Vertigo 
Hypothyroidism 
Hyperthyroidism 
Adrenal 
Insufficiency 
Hypophysitis 
Hyperglycaemia 
Thyroiditis 
Hypopituitarism 
Diabetes mellitus 
Autoimmune 
thyroiditis 
Diabetic 
ketoacidosis 
Autoimmune 
hypothyroidism 
Vision blurred 
Uncommon 
19 (0.70) 
Uncommon 
7 (0.26) 
Uncommon 
4 (0.15) 
Rare 
2 (0.07) 
Uncommon 
3 (0.11) 
Common 
175 (6.41) 
Common 
98 (3.61) 
Common 
87 (3.21) 
Common 
77 (2.84) 
Uncommon 
27 (1.00) 
Uncommon 
23 (0.85) 
Uncommon 
18 (0.66) 
Uncommon 
14 (0.52) 
Uncommon 
10 (0.37) 
Uncommon 
6 (0.22) 
Rare 
1 (0.04) 
Common 
39 (1.44) 
n 
n 
n 
Y 
1 (0.04) 
n 
n 
Y 
Y 
Y 
4 (0.15) 
1 (0.04) 
2 (0.07) 
Y 
1 (0.04) 
n 
n 
n 
n 
n 
Y 
8 (0.29) 
n 
n 
Y 
14 (0.52) 
n 
n 
Y 
40 (1.47) 
Y 
1 (0.04) 
n 
Y 
37 (1.136) 
n 
n 
Y 
8 (0.29) 
n 
n 
Y 
6 (0.22) 
n 
n 
Y 
8 (0.29) 
n 
n 
Y 
10 (0.37) 
n 
n 
Y 
5 (0.18) 
n 
n 
Y 
6 (0.22) 
Y 
1 (0.04) 
n 
n 
n 
n 
Y 
3 (0.11) 
n 
n 


 
52 
 
 
Table 15.2-2: 
Adverse Drug Reactions in Patients Treated with Nivolumab in 
Combination with Ipilimumab in Clinical Studies (N=2,712) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Gastrointestina 
l Disorders 
Uveitis 
Dry eye 
Diplopia 
Iridocyclitis 
Diarrhea 
Nausea 
Vomiting 
Colitis 
Abdominal pain 
Dry mouth 
Constipation 
Stomatitis 
Pancreatitis 
Autoimmune colitis 
Enterocolitis 
Mucosal 
inflammation 
Gastritis 
Uncommon 
20 (0.74) 
Uncommon 
17 (0.63) 
Uncommon 
5 (0.18) 
Uncommon 
3 (0.11) 
Very Common 
555 (20.46) 
Very Common 
343 (12.65) 
Common 
171 (6.31) 
Common 
163 (6.01) 
Common 
135 (4.98) 
Common 
88 (2.99) 
Common 
57 (2.10) 
Uncommon 
26 (0.96) 
Uncommon 
24 (0.88) 
Uncommon 
14 (0.52) 
Uncommon 
10 (0.37) 
Uncommon 
9 (0.33) 
Uncommon 
Y 
3 (0.11) 
n 
n 
n 
n 
n 
Y 
2 (0.07) 
n 
n 
n 
n 
n 
Y 
163 (6.01) 
Y 
2 (0.07) 
n 
Y 
24 (0.88) 
n 
n 
Y 
29 (1.07) 
n 
n 
Y 
Y 
Y 
119 (4.39) 
2 (0.07) 
1 (0.04) 
Y 
11 (0.41) 
n 
n 
n 
n 
n 
Y 
2 (0.07) 
n 
n 
n 
n 
n 
Y 
18 (0.66) 
n 
n 
Y 
13 (0.48) 
n 
n 
Y 
9 (0.33) 
n 
n 
n 
n 
n 
Y 
n 
n 


 
53 
 
 
Table 15.2-2: 
Adverse Drug Reactions in Patients Treated with Nivolumab in 
Combination with Ipilimumab in Clinical Studies (N=2,712) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
General 
Disorders and 
Administration 
Site Conditions 
Intestinal 
perforationa 
Autoimmune 
pancreatitis 
Gastritis erosiveb 
Mouth ulceration 
Fatigue 
Pyrexia 
Chills 
Asthenia 
Oedema peripheral 
Peripheral swelling 
Face oedema 
Oedema 
Periorbital oedema 
Localised oedema 
Multi-organ failureb 
Swelling face 
5 (0.18) 
Uncommon 
4 (0.15) 
Rare 
1 (0.04) 
Rare 
1 (0.04) 
Rare 
1 (0.04) 
Very Common 
589 (21.72) 
Common 
269 (9.92) 
Common 
109 (4.02) 
Uncommon 
42 (0.46) 
Common 
29 (1.07) 
Uncommon 
5 (0.18) 
Uncommon 
3 (0.11) 
Uncommon 
3 (0.11 
Uncommon 
3 (0.11) 
Rare 
2 (0.07) 
Rare 
1 (0.04) 
1 (0.04) 
2 (0.07) 
Y 
Y 
Yb 
4 (0.15) 
2 (0.07) 
1 (0.04) 
n 
n 
n 
Y 
1 (0.04) 
n 
n 
n 
n 
n 
Y 
21 (0.77) 
n 
n 
Y 
66 (2.43) 
n 
n 
Y 
5 (0.18) 
n 
n 
Y 
5 (0.18) 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
Y 
1 (0.04) 
n 
Y 
1 (0.04) 
n 
n 
n 


 
50 
 
 
Table 15.2-2: 
Adverse Drug Reactions in Patients Treated with Nivolumab in  
                                           Combination with Ipilimumab in Clinical Studies (N=2,712) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Hepatobilliary 
Disorders 
Immune 
System 
Disorders 
Infections and 
Infestations 
Investigations 
Autoimmune 
hepatitis 
Hepatitis 
Drug-induced liver 
injury 
Hyperbilirubinaemi 
a 
Infusion related 
reaction 
Hypersensitivity 
Autoimmune 
disorder 
Bronchitis 
Alanine 
aminotransferase 
increased 
Aspartate 
aminotransferase 
increased 
Lipase increased 
Amylase increased 
Blood alkaline 
phosphatase 
increased 
Blood creatinine 
increased 
Blood bilirubin 
increased 
Transaminases 
increased 
Common 
33 (1.22) 
Uncommon 
22 (0.81) 
Uncommon 
7 (0.26) 
Rare 
3 (0.11) 
Common 
39 (1.44) 
Uncommon 
16 (0.59) 
Uncommon 
5 (0.18) 
Uncommon 
6 (0.22) 
Very Common 
312 (11.50) 
Very Common 
299 (11.03) 
Common 
183 (6.75) 
Common 
128 (4.72) 
Common 
71 (2.62) 
Common 
48 (1.77) 
Common 
32 (1.18) 
Uncommon 
29 (1.07) 
Y 
19 (0.70) 
n 
n 
Y 
18 (0.66) 
n 
n 
Y 
6 (0.22) 
n 
Yb 
1 (0.04) 
Y 
2 (0.07 
n 
n 
Y 
5 (0.18) 
n 
n 
Y 
2 (0.07 
n 
n 
Y 
4 (0.15) 
n 
n 
Y 
2 (0.07 
n 
n 
Y 
75 (2.77) 
n 
n 
Y 
54 (1.99) 
n 
n 
Y 
11 (0.41) 
n 
n 
Y 
6 (0.22) 
n 
n 
Y 
2 (0.07) 
n 
n 
Y 
10 (0.37) 
n 
n 
Y 
8 (0.29) 
n 
n 
Y 
19 (0.55) 
n 
n 


 
51 
 
 
Table 15.2-2: 
Adverse Drug Reactions in Patients Treated with Nivolumab in 
Combination with Ipilimumab in Clinical Studies (N=2,712) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Metabolism 
and Nutrition 
Disorders 
Musculoskeleta 
l and 
Connective 
Tissue 
Disorders 
Decreased appetite 
Dehydration 
Hyponatraemia 
Arthralgia 
Myalgia 
Back pain 
Pain in extremityb 
Arthritis 
Musculoskeletal 
pain 
Myositisa 
Neck pain 
Polyarthritis 
Musculoskeletal 
chest pain 
Bone pain 
Rhabdomyolysisa 
Musculoskeletal 
discomfort 
Common 
208 (7.67) 
Common 
60 (2.21) 
Common 
58 (2.14) 
Common 
171 (6.31) 
Common 
103 (3.80) 
Common 
34 (1.25) 
Uncommon 
17 (0.63) 
Uncommon 
12 (0.44) 
Uncommon 
8 (0.29) 
Uncommon 
8 (0.29) 
Uncommon 
6 (0.22) 
Uncommon 
4 (0.15) 
Uncommon 
3 (0.11) 
Rare 
2 (0.07) 
Rare 
2 (0.07) 
Rare 
1 (0.04) 
Y 
4 (0.15) 
n 
n 
Y 
17 (0.63) 
n 
n 
Y 
21 (0.77) 
n 
n 
Y 
3 (0.11) 
n 
n 
Y 
3 (0.11) 
n 
n 
n 
n 
n 
Y 
1 (0.04) 
n 
n 
Y 
4 (0.15) 
n 
n 
n 
n 
n 
Y 
Y 
Y 
6 (0.22) 
1 (0.04) 
1 (0.04) 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
Y 
2 (0.07) 
Y 
1 (0.04) 
n 
n 
n 
n 


 
52 
 
 
Table 15.2-2: 
Adverse Drug Reactions in Patients Treated with Nivolumab in   
                                           Combination with Ipilimumab in Clinical Studies (N=2,712) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Nervous 
System 
Disorders 
Renal and 
Urinary 
Disorders 
Headache 
Dizziness 
Neuropathy 
peripheral 
Cranial nerve 
disordera 
Peripheral sensory 
neuropathy 
Encephalitis 
Meningitis 
noninfective 
Peripheral motor 
neuropathy 
Meningitis 
Myasthenia Gravis 
Guillain-Barre 
Syndrome 
Autoimmune 
encephalitis 
Miller Fisher 
Syndromeb 
Myasthenic 
syndrome 
Polyneuropathy 
Acute kidney injury 
Common 
170 (6.27) 
Common 
55 (2.03) 
Common 
24 (1.44) 
Uncommon 
9 (0.33) 
Uncommon 
9 (0.33) 
Uncommon 
5 (0.18) 
Uncommon 
5 (0.18) 
Uncommon 
5 (0.18) 
Uncommon 
4 (0.15) 
Uncommon 
3 (0.11) 
Rare 
2 (0.07) 
Rare 
1 (0.04) 
Rare 
1 (0.04) 
Uncommon 
1 (0.04) 
Rare 
1 (0.04) 
Common 
29 (1.07) 
Y 
6 (0.22) 
n 
n 
Y 
1 (0.05) 
n 
n 
Y 
5 (0.33) 
n 
n 
Y 
5 (0.18) 
n 
n 
Y 
1 (0.04) 
n 
n 
Y 
5 (0.18) 
n 
n 
Y 
5 (0.18) 
n 
n 
Y 
3 (0.11) 
n 
n 
Y 
4 (0.15) 
n 
n 
Y 
2 (0.07) 
n 
Yb 
1 (0.04) 
Y 
2 (0.07) 
n 
n 
Y 
1 (0.04) 
n 
n 
Y 
1 (0.04) 
n 
n 
Y 
1 (0.04) 
n 
n 
n 
n 
n 
Y 
Y 
Yb 
25 (0.92) 
1 (0.04) 
1 (0.04) 


 
53 
 
 
Table 15.2-2: 
Adverse Drug Reactions in Patients Treated with Nivolumab in 
Combination with Ipilimumab in Clinical Studies (N=2,712) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Respiratory, 
Thoracic, and 
Mediastinal 
Disorders 
Skin and 
Subcutaneous 
Tissue 
Disorders 
Renal failure 
Tubulointerstitial 
nephritis 
Autoimmune 
nephritis 
Nephritis 
Nephritis allergicb 
Pneumonitis 
Cough 
Dyspnea 
Lung infiltration 
Respiratory failure 
Respiratory distress 
Interstitial lung 
disease 
Pruritus 
Rash 
Rash maculo- 
papular 
Rash pruritic 
Uncommon 
7 (0.26) 
Uncommon 
5 (0.18) 
Uncommon 
3 (0.11) 
Rare 
2 (0.074) 
Rare 
2 (0.07) 
Common 
132 (4.87) 
Common 
95 (3.50) 
Common 
80 (2.95) 
Uncommon 
5 (0.18) 
Uncommon 
5 (0.18) 
Uncommon 
3 (0.11) 
Rare 
1 (0.04) 
Very Common 
405 (14.93) 
Common 
340 (12.54) 
Common 
201 (7.41) 
Common 
Y 
4 (0.15) 
n 
Yb 
1 (0.04) 
Y 
4 (0.15) 
n 
n 
Y 
3 (0.11) 
n 
n 
Y 
2 (0.07) 
n 
n 
Y 
1 (0.04) 
n 
n 
Y 
Y 
Y 
70 (2.58) 
1 (0.04) 
5 (0.18) 
n 
n 
n 
Y 
17 (0.63) 
n 
n 
Y 
2 (0.07) 
n 
n 
Y 
4 (0.15) 
n 
Y 
2 (0.07) 
Y 
3 (0.11) 
n 
n 
n 
n 
n 
Y 
2 (0.07) 
n 
n 
Y 
12 (0.44) 
n 
n 
Y 
4 (0.15) 
n 
n 
n 
n 
n 


 
54 
 
 
Table 15.2-2: 
Adverse Drug Reactions in Patients Treated with Nivolumab in 
Combination with Ipilimumab in Clinical Studies (N=2,712) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Dry skin 
Vitiligo 
Alopecia 
Rash generalised 
Dermatitis 
acneiform 
Rash macular 
Erythema 
Pruritus generalised 
Rash papular 
Rash erythematous 
Dermatitis 
Urticaria 
Rash pustular 
Psoriasis 
Erythema 
multiforme 
Rash follicular 
70 (2.58) 
Common 
50 (1.84) 
Common 
49 (1.81) 
Common 
28 (1.03) 
Common 
28 (1.03) 
Uncommon 
24 (0.88) 
Uncommon 
24 (0.88) 
Uncommon 
20 (0.74) 
Uncommon 
19 (0.70) 
Uncommon 
19 (0.70) 
Uncommon 
13 (0.48) 
Uncommon 
11 (0.41) 
Uncommon 
10 (0.37) 
Uncommon 
7 (0.26) 
Uncommon 
5 (0.18) 
Uncommon 
3 (0.11) 
Uncommon 
3 (0.11) 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
Yb 
1 (0.04) 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 


 
55 
 
 
Table 15.2-2: 
Adverse Drug Reactions in Patients Treated with 
Nivolumab in Combination with Ipilimumab in Clinical 
Studies (N=2,712) 
 
System Organ 
Class 
Preferred Term 
Overall 
Frequency 
N (%) 
Serious ADRs 
N (%) 
Life Threatening 
ADRs 
N (%) 
Fatal ADRs 
N (%) 
Vascular 
Disorders 
Dermatitis 
exfoliative 
Rosacea 
Stevens-Johnson 
Syndrome 
Toxic Epidermal 
Necrolysis 
Hypotensiona 
Hypertension 
Rare 
2 (0.07) 
Rare 
2 (0.07) 
Rare 
1 (0.04) 
Rare 
1 (0.04) 
Common 
29 (1.07) 
Uncommon 
16 (0.59) 
Yb 
1 (0.04) 
n 
n 
n 
n 
n 
Y 
1 (0.04) 
Y 
1 (0.04) 
n 
Y 
1 (0.04) 
n 
Y 
1 (0.04) 
Y 
9 (0.33) 
Yb 
1 (0.05) 
n 
n 
n 
n 
 
a ADR not included in previous IB version 14. 
b This event is an adverse drug reaction for nivolumab but serious, related occurrences will be reported 
as SUSARs due to the low observed frequency. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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15.3 Management of Immune-related Adverse Events 
 
These general guidelines constitute guidance to the Investigator and may 
be supplemented by discussions with the Medical Monitor representing the 
Sponsor. The guidance applies to all immuno-oncology agents and 
regimens. 
 
A general principle is that differential diagnoses should be diligently 
evaluated according to standard medical practice. Non-inflammatory 
etiologies should be considered and appropriately treated. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related 
adverse events. The oral equivalent of the recommended IV doses may be 
considered for ambulatory patients with low-grade toxicity. The lower 
bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an 
invasive diagnostic or therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these 
algorithms will depend on the immuno-oncology agent or regimen being 
used. 
 


 
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60 
 


 
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62 
 
 


 
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64 
 
15.4 PROTOCOL REVISION HISTORY 
 
Version 3: 25FEB2019 
    
Title Page: Co-Investigator change; delete Ryan Weight, DO; add Melissa   
                  Wilson, MD, PhD 
Section 1.0: Introduction: eliminate study objectives (redundant with Section 2) 
Section 3.1: General Design:  
• specify that in event of toxicity during first four IPI + NIVO + 
IEMBO cycles, administration of IPI may be halted and patient 
may continue with NIVO + IEMBO 
• clarify that initial radiographic scans will be performed between 
Cycles 2 and 3 to ensure no rapid disease progression  
• clarify that initial radiographic response will be determined 
following all 4 doses of IPI + NIVO (and/or NIVO alone, if IPI 
is halted) and four IEMBO treatments (also Section 9.1)       
Section 3.2: Primary Study Endpoint: clarify that primary endpoint is Best Hepatic 
                    Response starting at Week 12 
Section 5.3.3: Embolization: specify that interval between immunoembolization 
                       treatments may be extended for up to 6 weeks at the disecretion of 
                       treating physician 
Section 5.6: Prior and Concomitant Therapy: add that palliative radiation is  
                    allowed during treatment and that bone strengthening agents are  
                    allowed for bone metastases 
Sections 6.0: Study procedures:  
• 6.1.1, 6.1.2: added blood test for CRP; clarified timing of 
certain blood tests 
• 6.1.4:  
o clarify that end of fourth cycle = 12 weeks from start of 
treatment 
o clarify that patients who have unequivocal disease 
progression after 4 treatments may be removed from  
study at discretion of investigator and that patients will 
then be followed in person or over telephone every 3 
months until death. 
o Clarify that if a mixed response is seen at interim 6 
week scans, patients may be allowed to continue on 
study if investigator deems they are getting clinical 
benefit 
Section 8.0: Safety and Adverse Events:  
• sections cleaned up and re-numbered 
• 8.3: added section on adverse event reporting 
Section 9.0: Evaluation of Response: sections cleaned up and re-numbered 
Section 15.4: Protocol Revision History: add this section 
 
 


 
65 
 
Version 4: 23OCT2019 
 
Title Page: Co-Investigator updates  
 
Study Summary; Study Design (sec. 3.1); Study Procedures (sec. 6.1.4); Dose 
Delays and Dose Modifications (sec. 6.3.3); Statistical Plan (sec. 7.2.1); 
Evaluation of Response (sec. 9.1):  Clarification of investigator’s discretion to halt 
immunotherapy (ipilimumab and/or nivolumab) components of treatment in 
instances of toxicity and continuing treatment with immunoembolization alone if 
patient is receiving clinical benefit. 
 
 
Version 5: 22DEC2019 
 
Section 4.2: Exclusion criteria (#3): clarification that liver resection and focal 
ablation are permitted 
 
 
Version 6: 17MAR2020 
 
Study Summary and General Study Design (sec.3.1): 
• Clarify on-treatment radiographic scans will be performed after evert two 
IEMBO treatments 
• Specify subjects will receive study treatment for a maximum of two years 
or until disease progression 
• Clarify that combination treatment postponement duration begins from 
date of next scheduled treatment 
 
Section 3.4: Exploratory (Correrlative) Endpoints : Add changes in PBMC cell 
populations, including T cells and MDS 
 
Section 4.2: Exclusion Criteria: delete exclusion criteria #6 and #15: requirement 
of angiography 
 
Section 4.2.1: Guidance for Women of Childbearing Potential: clarify that 
pregnancy testing must occur within two weeks prior to the start of treatment 
 
Section 5.6: Prior and Concomitant Therapy: Add information about a washout 
period between certain prior therapies and first study treatment cycle 
 
Section 6.1.2: Evaluation during treatment: Add information about time points for 
collection of blood for lab tests 
 
Section 6.1.6: Completion of Study:  
• Specify subjects will receive study treatment for a maximum of two years 
or until disease progression 


 
66 
 
• Add research-related testing to end of study procedures 
 
Section 6.3: Dose Delays and Modifications: Clarify that combination treatment 
postponement duration begins from date of next scheduled treatment 
 
Section 9.1: Evaluation of Clinical Response: Clarify patients who are evaluable 
for clinical response 
 
Section 9.4: Evaluation of Overall Response in Liver Metastases: Clarify on-
treatment radiographic scans will be performed after every two IEMBO 
treatments 
 
 
Version 7: 01SEP2020 
 
Section 5.1.4: Ipilimumab: Clarify that IV infusion of ipilimumab is done over 30 
minutes with a +/- 5 minute window 
 
Section 5.1.5: Nivolumab: Clarify that IV infusion of nivolumab is done over 30 
minutes with a +/- 5 minute window 
 
Section 6.1: Study Visit Schedule: Clarify that all CT scans of the chest are done 
without use of contrast 
 
Section 11.3: Data Collection: Specify that the Redcap database (rather than 
standard case report forms) will be the primary data collection instrument for the 
study