A Randomized Phase II Trial of Ipilimumab With or Without Bevacizumab in Patients With Unresectable Stage III or Stage IV Melanoma
Phase: PHASE2
Conditions: Stage IIIC Cutaneous Melanoma AJCC v7, Stage IV Cutaneous Melanoma AJCC v6 and v7, Unresectable Melanoma
Sponsor: National Cancer Institute (NCI)

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E3612 
1 
A Randomized Phase II Trial of Ipilimumab with or without 
Bevacizumab in Patients with Unresectable Stage III or 
Stage IV Melanoma 
STUDY CHAIR: 
, M.D.
STUDY CO-CHAIR: 
, M.D., Ph.D. 
STUDY STATISTICIAN: 
, ScD 
MELANOMA COMMITTEE CHAIR: 
, M.D. 
PATHOLOGY CO-CHAIR: 
, M.D. 
Version Date:  May 24, 2019 
NCI Update Date: September 24, 2013 
STUDY PARTICIPANTS 
ACTIVATION DATE 
US Sites Only 
December 13, 2013 
SWOG / SWOG 
NRG / NRG Oncology Foundation, Inc 
PRE-ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in Oncology 
September 26, 2013 
Addendum #1 - Incorporated Prior to Activation 
Update #1- Incorporated Prior to Activation 
Addendum #2 - 8/14 
Addendum #3 - 10/14 
Addendum #4 - 5/15 
Addendum #5 – 3/16 
Addendum #6 – 11/16 
Addendum #7 – 2/17 
Addendum #8 
Addendum #9 
Addendum #10  
Agents 
IND# 
NSC# 
Supply 
Ipilimumab 
 
732442 
NCI-Supplied 
Bevacizumab 
 
704865 
NCI-Supplied 
Rev. 8/14 
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ECOG-ACRIN 
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Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
2 
Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 Research Hypothesis ................................................................................. 7 
1.2 Disease Background .................................................................................. 7 
1.3 CTLA-4 and T Cell Activation ..................................................................... 8 
1.4 Summary of Results of Investigational Program ..................................... 10 
1.5 Bevacizumab CLINICAL Experience ......................................................... 29 
1.6 Overall Risk/Benefit Assessment ............................................................ 33 
1.7 Study Rationale ....................................................................................... 34 
2. Objectives ......................................................................................................... 35 
2.1 Primary Endpoint .................................................................................... 35 
2.2 Secondary Objectives .............................................................................. 35 
3. Selection of Patients ......................................................................................... 36 
3.1 Eligibility Criteria ..................................................................................... 36 
4. Registration Procedures.................................................................................... 41 
4.1 Protocol Number ..................................................................................... 44 
4.2 Investigator Identification ....................................................................... 44 
4.3 Patient Identification .............................................................................. 44 
4.4 Eligibility Verification .............................................................................. 44 
4.5 Stratification Factors ............................................................................... 44 
4.6 Additional Requirements ........................................................................ 44 
4.7 Instructions for Patients who Do Not Start Assigned Protocol Treatment45 
5. Treatment Plan ................................................................................................. 46 
5.1 Administration Schedule ......................................................................... 46 
5.2 Adverse Event Reporting Requirements ................................................. 48 
5.3 Comprehensive Adverse Events and Potential Risks List (CAEPR) .......... 57 
5.4 Dose Modifications ................................................................................. 69 
5.5 Prohibited and Restricted Therapies During the Study .......................... 80 
5.6 Supportive Care ....................................................................................... 81 
5.7 Duration of Therapy ................................................................................ 81 
5.8 Duration of Follow-up ............................................................................. 81 
6. Measurement of Effect ..................................................................................... 82 
6.1 Antitumor Effect-Solid Tumors-RECIST ................................................... 82 
7. Study Parameters .............................................................................................. 95 
7.1 Therapeutic Parameters.......................................................................... 95 
7.2 Arms A and B: Patients Treated with Ipilimumab alone (Arm A) or 
Ipilimumab and Bevacizumab (Arm B) .................................................... 95 
7.3 Biological Sample Submissions ............................................................... 98 
8. Drug Formulation and Procurement ................................................................. 99 
8.1 Ipilimumab ............................................................................................ 100 
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8.2 Bevacizumab ......................................................................................... 104 
9. Statistical Considerations ................................................................................ 107 
9.1 Study Design and Objectives ................................................................. 107 
9.2 Study Endpoints .................................................................................... 107 
9.3 Sample Size Considerations and Monitoring Plan ................................ 107 
9.4 Statistical Analysis Plan ......................................................................... 108 
9.5 Gender and Ethnicity ............................................................................ 109 
9.6 Study Monitoring .................................................................................. 109 
10. Biological Sample Submissions ....................................................................... 110 
10.1 Sample Collection and Submission Schedule ........................................ 110 
10.2 Submissions to the ECOG-ACRIN Central Biorepository and Pathology 
Facility (CBPF) ........................................................................................ 110 
10.3 Submissions to Immunologic Monitoring and Cellular Products 
Laboratory (IMCPL) ............................................................................... 112 
10.4 ECOG-ACRIN Sample Tracking System .................................................. 114 
10.5 Use of Specimens in Research .............................................................. 115 
10.6 Sample Inventory Submission Guidelines ............................................. 115 
11. Electronic Data Capture .................................................................................. 116 
11.1 Records Retention ................................................................................. 116 
12. Patient Consent and Peer Judgment .............................................................. 116 
13. References ...................................................................................................... 116 
Appendix I  Pathology Submission Guidelines ...................................................... 119 
Appendix II  Patient Thank You Letter ................................................................... 124 
Appendix III  CRADA/CTA ....................................................................................... 125 
Appendix IV  ECOG Performance Status................................................................ 127 
Appendix V  Instructions for Reporting Pregnancies on a Clinical Trial ................ 128 
Appendix VI  Shipping Kit Request Facsimile Form ............................................... 130 
Appendix VII  Specimen Shipment Requisition Form ............................................ 131 
Appendix VIII GI Toxicity Management Algorithm ................................................ 132 
Appendix IX Hepatotoxicity Management Algorithm ........................................... 133 
Appendix X Skin Toxicity Management Algorithm ................................................ 134 
Appendix XI Neurological Toxicity Management Algorithm ................................. 135 
Appendix XII Endocrinopathy Management Algorithm ........................................ 136 
 
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Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
5 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments:  
For study data 
submission: 
Regulatory documentation can be 
submitted to the CTSU via: 
ONLINE: 
Regulatory Submission Portal 
(Sign in at www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory 
tab.)  
EMAIL: 
CTSURegulatory@ctsu.coccg.org 
(regulatory documentation only) 
FAX:  
215-569-0206 
MAIL:  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
For regulatory questions call the 
CTSU Regulatory Help Desk at 1-
866-651-CTSU 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN SYSTEM/ 
or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave. Please 
see the data submission 
section of the protocol for 
further instructions. 
Do not submit study data 
or forms to CTSU Data 
Operations. Do not copy 
the CTSU on data 
submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program – Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS. 
For clinical questions (i.e. patient eligibility or treatment-related questions) Contact the Study PI of 
the lead protocol organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at   https://www.ctsu.org. 
 
Rev. 8/14 
Rev. 11/16 
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ECOG-ACRIN 
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NCI Update Date: September 24, 2013 
7 
1. 
Introduction 
1.1 
Research Hypothesis 
Ipilimumab has been shown to prolong survival in patients with metastatic 
melanoma. Means to improve upon this foundation of clinical benefit for patients 
are worthy of pursuit. Experience thus far suggests that the combination of 
bevacizumab plus ipilimumab can result in enhanced immune activation with 
clinical benefits for patients. The adverse events have been easily managed. 
Given our preliminary data so far including clinical outcomes, immune activation, 
and pathologic evaluations of post-treatment biopsies, the ability to make a 
definitive assessment of clinical benefit regarding the addition of bevacizumab to 
ipilimumab would best be performed in a prospective, randomized fashion. 
1.2 
Disease Background 
In the United States, 60,000 patients will be discovered to have cutaneous 
melanoma  and of these 8,300 patients will succumb [1].  The disease will 
account for 4% of all new cancers and 1.4% of all cancer deaths.  The neoplasm 
is the second and third most frequently diagnosed cancer from birth to age 39 in 
females and males, respectively.  As a result, melanoma has a significant impact 
in the loss of expected years of life from cancer.  Moreover, with an annual 
incidence increasing at 4% per year[2], the largest of any cancer type, an 
individual’s lifetime risk for developing melanoma in the United States is currently 
greater than 1 in 55. 
Surgical excision of melanoma is curative for most patients who present with 
relatively thin lesions (<1.0 mm)[3].  Those with melanoma limited to the primary 
site show a ten-year survival ranging from 60-90%, with the prognosis most 
strongly correlated with the primary tumor thickness[4].  For patients with lymph 
node metastases, adjuvant therapy with α-interferon affords a modest increase in 
overall survival, but this advantage is associated with substantial toxicities[5-8].  
Dacarbazine is the most active single chemotherapy agent for disseminated 
disease, but complete responses are infrequent and of short duration[9].  High 
dose interleukin-2 (IL-2) offers a 15% response rate with approximately a 3% 
durable complete response rate in selected patients[10]. 
Recently, the use of a selective BRAF inhibitor vemurafenib has shown to offer a 
survival advantage in patients whose tumors harbor BRAF mutations in the front 
line setting with a 63% reduction of death[11].  The median progression-free 
survival for patients receiving BRAF inhibitors approximates 7 months.  CTLA-4 
blockade with ipilimumab has been shown to provide a survival advantage when 
compared to a peptide vaccine in previously treated patients[12] or in conjunction 
with dacarbazine in comparison to dacarbazine alone in the front line setting[13].  
A subset of patients receiving ipilimumab experience durable clinical benefit 
lasting many months to years.  As a result, it becomes increasingly important to 
build upon these successes with rational combinatorial approaches. 
Preliminary results of Phase I combination study of iilimumab plus bevacizumab. 
We have conducted a phase I study testing the combination of ipilimumab plus 
bevacizumab in patients with unresectable stage III or stage IV melanoma.  To 
date, twenty-two patients have been enrolled (5 patients to cohort 1 (ipilimumab 
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10 mg/kg plus bevacizumab 7.5 mg/kg), 5 patients to cohort 2 (ipilimumab 10 
mg/kg plus bevacizumab 15 mg/kg), and 12 patients in dose expansion of cohort 
2) and are evaluable.  There have been 6 confirmed partial responses, 1 
complete response, and 7 patients who experienced prolonged stable disease of 
6 months or more in duration.  The median follow-up is currently 14 months, with 
a 6-month PFS of 59% (95% CI 36-76%, and a 1-year OS of 72% (95% CI 48-
86%). 
Adverse events to date have included: hypophysitis (5) and thyroiditis (3) that 
have been easily managed medically, one patient developed grade 2 colitis and 
giant cell arteritis (occurring at week 14, and with the patient experiencing a 
durable partial response continuing for greater than 6 months), grade 4 hepatitis 
(1), and uveitis/retinitis (2). 
Monitoring of the peripheral blood mononuclear cells has revealed a statistically 
significant increase in the CCR7+/CD45R)+ and CCR7-/CD45RO+ phenotypes for 
both CD4 and CD8 cells as a function of treatment with ipilimumab and 
bevacizumab.  These changes were not observed in a comparative cohort of 
patients who received ipilimumab alone. 
Post-treatment biopsies.  We have obtained biopsies of pre-existing sites of 
disease post-treatment in 12 patients date.  Pathologic examination has revealed 
marked activation of the tumor vascular endothelium with brisk perivascular 
trafficking of tumor infiltrating lymphocytes. Post-treatment biopsies reveal brisk 
extravasation of tumor infiltrating lymphocytes surrounding tumor blood vessels.  
The vascular endothelium is columnar and are morphologically activated, similar 
to that seen in the high endothelia of lymph nodes representing areas of active 
lymphocyte trafficking with upregualtion of E-selection.  There is also pathologic 
evidence for peripheral angiogenic T-cell recruitment.  
From the phase I experience with ipilimumab plus bevacizumab, treatment is 
safe and tolerable with adverse events reversible.  The combination has 
demonstrated activity in metastatic melanoma. 
1.3 
CTLA-4 and T Cell Activation 
Figure 1 
Mechanism of Action 
 
Advances in the understanding of the mechanisms that regulate T cell activation 
have allowed the rational design of new strategies for immunotherapy of tumors, 
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ECOG-ACRIN 
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including melanoma. It has been known for some time that engagement of the T 
cell antigen receptor by itself is not sufficient for full T cell activation; a second 
co-stimulatory signal is required for induction of IL-2 production, proliferation and 
differentiation to effector function of naive T cells. Abundant data now indicate 
that the primary source of this costimulation is mediated by engagement of CD28 
on the T cell surface by members of the B7 family on the antigen-presenting cell 
(APC).[14, 15] (Figure 1.) 
Expression of B7 has been shown to be limited to “professional” antigen 
presenting cells; that is, specialized cells of the hematopoietic lineage, including 
dendritic cells, activated macrophages, and activated B cells. It has been 
suggested that this sharply-defined restriction of B7 expression is a fail-safe 
mechanism for maintenance of peripheral T cell tolerance, insuring that T cell 
activation can only be stimulated by appropriate APCs. The fact that tumor cells 
do not express B7 contributes to their poor capacity to elicit immune 
responses.[16, 17] 
The demonstration that induction of expression of B7 on many tumor cells by 
transfection, transduction, or other mechanisms can heighten tumor 
immunogenicity led to great interest in pursuing this as an approach to tumor 
immunotherapy. As demonstrated in vivo in murine tumor models, the utility of B7 
expression as a vaccination approach is limited by the following factors: (1) 
B7-expressing tumor cell vaccines are only effective when the tumor cells have a 
high degree of inherent immunogenicity; (2) while B7-expressing vaccines have 
been shown in many cases to be effective in inducing protective immune 
responses, they have demonstrated only limited utility in inducing responses to 
established tumors; and (3) inactivation of tumor cells by radiation has been 
shown to destroy the immuno-enhancing activity of the B7 gene product[16, 17]. 
In the past few years it has become apparent that co-stimulation is even more 
complex than originally thought. After activation, T cells express CTLA-4, a close 
homologue to CD28. CTLA-4 binds members of the B7 family with a much higher 
affinity than CD28.[17] Although there was initially some controversy as to the 
role of CTLA-4 in regulating T cell activation, it has become clear that CTLA-4 
down-regulates T cell responses.[16]  
This was initially suggested by the following in vitro observations: (1) blockade of 
CTLA-4/B7 interactions with antibody enhanced T cell responses; (2) cross-
linking of CTLA-4 with CD3 and CD28 inhibited T cell responses; and (3) 
administration of antibodies to CTLA-4 in vivo enhanced the immune response to 
peptide antigens or superantigens in mice.[16-19] Blocking CTLA-4-B7 
interaction while preserving signaling via CD28 resulted in enhanced T cell 
responses in vitro[19]. 
Perhaps the most convincing demonstration of the down-regulatory role of CTLA-
4 came from examination of mice with a null mutation.[16-18] CTLA-4 knockout 
mice appear to have spontaneously activated T cells evident at approximately 1 
week after birth, followed by rampant lymphoproliferation and lymphadenopathy. 
These mice die at approximately 3 weeks of age, either as a result of polyclonal 
T cell expansion and tissue destruction or as a result of toxic shock resulting from 
lymphokine production by the T cells. Since thymocyte differentiation and 
selection proceed normally in CTLA-4-deficient mice, the rampant T cell 
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ECOG-ACRIN 
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10 
expansion that occurs in the mice indicates that CTLA-4 plays a critical role in 
down-regulating T cell responses in the periphery.[20] 
1.4 
Summary of Results of Investigational Program 
1.4.1 
Pharmacology of Ipilimumab 
Ipilimumab is a human immunoglobulin G (IgG1)κ anti-CTLA-4 
monoclonal antibody (mAb). In vitro studies were performed with 
ipilimumab to demonstrate that it is specific for CTLA-4, actively 
inhibits CTLA-4 interactions with B7.1 and B7.2, does not show any 
cross-reactivity with human B7.1, B7.2 negative cell lines, and stains 
the appropriate cells without non-specific cross-reactivity in normal 
human tissues, as demonstrated by immunohistochemistry. 
Ipilimumab does cross-react with CTLA-4 in non-human primates 
including cynomolgus monkeys. 
1.4.2 
Animal Toxicology of Ipilimumab 
The effects of ipilimumab on prenatal and postnatal development in 
monkeys have not been fully investigated. Preliminary results are 
available from an ongoing study in cynomolgus monkeys. Pregnant 
monkeys received ipilimumab every 21 days from the onset of 
organogenesis in the first trimester through delivery, at dose levels 
either 2.6 or 7.2 times higher than the clinical dose of 3 mg/kg of 
ipilimumab (by AUC). No treatment-related adverse effects on 
reproduction were detected during the first two trimesters of 
pregnancy. Beginning in the third trimester, the ipilimumab groups 
experienced higher incidences of abortion, stillbirth, premature 
delivery (with corresponding lower birth weight), and higher 
incidences of infant mortality in a dose-related manner compared to 
controls. 
Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-), 
the target for ipilimumab, appeared healthy and gave birth to healthy 
CTLA-4+/- heterozygous offspring. Mated CTLA-4+/- heterozygous 
mice also produced offspring deficient in CTLA-4 (homozygous 
negative, CTLA-4-/-). The CTLA-4-/- homozygous negative offspring 
appeared healthy at birth, exhibited signs of multiorgan 
lymphoproliferative disease by 2 weeks of age, and all died by 3–4 
weeks of age with massive lymphoproliferation and multiorgan tissue 
destruction. 
Complete information on the pre-clinical toxicology studies can be 
found in the Ipilimumab Investigator Brochure (IB). Non-clinical toxicity 
assessments included in vitro evaluation for the potential of 
ipilimumab to mediate complement-dependent cellular cytotoxicity 
(CDCC) or antibody-dependent cellular cytotoxicity (ADCC), and 
toxicology assessments in cynomolgus monkeys alone and in the 
presence of vaccines. 
The in vitro studies demonstrated that ipilimumab did not mediate 
CDCC of PHA- or (CD)3-activated human T cells. However, low to 
moderate ADCC activity was noted at concentrations up to 50 ug/mL. 
These data are consistent with the requirement of high levels of 
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ECOG-ACRIN 
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antigen expression on the surface of target cells for efficient ADCC or 
CDCC. Since ipilimumab is a human IgG1, an isotype generally 
capable of mediating CDCC and ADCC, the lack of these activities is 
likely due to a very low expression of CTLA-4 on activated T cells. 
Therefore, these data suggest that ipilimumab treatment would not 
result in depletion of activated T cells in vivo. Indeed, no depletion of 
T cells or T cell subsets were noted in toxicology studies in 
cynomolgus monkeys. 
No mortality or signs of toxicity were observed in three independent 
14-day intravenous toxicology studies in cynomolgus monkeys at 
multiple doses up to 30 mg/kg/dose. Furthermore, ipilimumab was 
evaluated in sub-chronic and chronic toxicology studies in 
cynomolgus monkeys with and without Hepatitis B (HepB) Vaccine 
and Melanoma Vaccine. Ipilimumab was well tolerated alone or in 
combination in all studies. There were no significant changes in 
clinical signs, body weight values, clinical pathology values or T cell 
activation markers. In addition, there were no significant 
histopathology changes in the stomach or colon. 
1.4.3 
Clinical Pharmacology 
1.4.3.1 
Mechanism of Action 
CTLA-4 is a negative regulator of T-cell activation. 
Ipilimumab binds to CTLA-4 and blocks the interaction of 
CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 
has been shown to augment T-cell activation and 
proliferation. The mechanism of action of ipilimumab’s 
effect in patients with melanoma is indirect, possibly 
through T-cell mediated anti-tumor immune responses. 
1.4.3.1.1 
Pharmacokinetics of Ipilimumab 
The pharmacokinetics of ipilimumab was 
studied in 499 patients with unresectable or 
metastatic melanoma who received doses 
of 0.3, 3, or 10 mg/kg administered once 
every 3 weeks for four doses. Peak 
concentration (C max), trough concentration 
(Cmin), and area under the curve (AUC) of 
ipilimumab were found to be dose 
proportional within the dose range 
examined. Upon repeated dosing of 
ipilimumab administered every 3 weeks, 
ipilimumab clearance was found to be time-
invariant, and minimal systemic 
accumulation was observed as evident by 
an accumulation index of 1.5-fold or less. 
Ipilimumab steady-state concentration was 
reached by the third dose. The following 
mean (percent coefficient of variation) 
parameters were generated through 
population pharmacokinetic analysis: 
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terminal half-life of 14.7 days (30.1%); 
systemic clearance (CL) of 15.3 mL/h 
(38.5%); and volume of distribution at 
steady-state (Vss) of 7.21 L (10.5%). The 
mean (±SD) ipilimumab Cmin achieved at 
steady-state with the 3-mg/kg regimen was 
21.8 mcg/mL (±11.2). 
Specific Populations: Cross-study 
analyses were performed on data from 
patients with a variety of conditions, 
including 420 patients with melanoma who 
received single or multiple infusions of 
ipilimumab at doses of 0.3, 3, or 10 mg/kg. 
The effects of various covariates on 
ipilimumab pharmacokinetics were 
assessed in population pharmacokinetic 
analyses. 
Ipilimumab CL increased with increasing 
body weight; however, no dose adjustment 
of ipilimumab is required for body weight 
after administration on a mg/kg basis. The 
following factors had no clinically 
meaningful effect on the CL of ipilimumab: 
age (range 26 to 86 years), gender, 
concomitant use of budesonide, 
performance status, HLA-A2*0201 status, 
positive anti-ipilimumab antibody status, 
prior use of systemic anticancer therapy, or 
baseline lactate dehydrogenase (LDH) 
levels. The effect of race was not examined 
as there were insufficient numbers of 
patients in non-Caucasian ethnic groups. 
Renal Impairment: Creatinine clearance at 
baseline did not have a clinically important 
effect on ipilimumab pharmacokinetics in 
patients with calculated creatinine clearance 
values of 29 mL/min or greater. 
Hepatic Impairment: Baseline AST, total 
bilirubin, and ALT levels did not have a 
clinically important effect on ipilimumab 
pharmacokinetics in patients with various 
degrees of hepatic impairment. 
Pharmacokinetic (PK) profiles for 
ipilimumab have been analyzed. The 
primary objective of Protocol MDX010-015 
was to determine the safety and PK profile 
of single and multiple doses of ipilimumab 
derived from a transfectoma or hybridoma 
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ECOG-ACRIN 
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cell line. Mean plasma concentrations of 
ipilimumab administered at doses of 
3 mg/kg (hybridoma-derived drug product); 
2.8 mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 
15 mg/kg, and 20 mg/kg (transfectoma-
derived drug product) demonstrated 
approximate dose proportionality. Equimolar 
doses of hybridoma-derived and 
transfectoma-derived drug product had 
comparable PK profiles. The range of mean 
volume of distribution at steady state (Vss) 
across cohorts 2.8, 3, 5, 7.5, 10, 15, and 20 
mg/kg, was 57.3 to 82.6 mL/kg, indicating 
drug distribution was mostly limited to the 
intravascular space. The clearance was low 
(range 0.11 to 0.29 mL/h/kg) and reflective 
of the half-life (range 297 to 414 h), which is 
consistent with the long terminal disposition 
phase of ipilimumab. There was moderate 
variability in the PK parameters among 
subjects, with CV of 11% to 48% in AUC(0-
21d), 20% to 59% in CL, and 17% to 46% in 
Vss. 
Ipilimumab was originally produced and 
purified from a hybridoma clone. Ipilimumab 
drug substance is currently manufactured 
using Process B. A new drug substance 
manufacturing process (Process C) has 
been developed utilizing a higher producing 
sub-clone of the current Master Cell Bank, 
and modified cell culture and purification 
steps. The new drug substance 
manufacturing process is intended to 
replace the current drug substance 
manufacturing process. The 
biocomparability of Process C relative to 
Process B was assessed in Study 
CA184087. 
PK in Phase 1 Study CA184087 (Process 
B and Process C)  
The PK of ipilimumab was assessed when 
manufactured by a newer process C relative 
to current process B as an IV infusion (1.5-
hr), in subjects with advanced melanoma 
(CA184087). Upon meeting eligibility 
criteria, subjects were randomized (1:1) to 
receive either ipilimumab Process B (Arm A, 
reference) or ipilimumab Process C (Arm B, 
test) at a dose of 10 mg/kg IV administered 
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over 90 minutes every 3 weeks on Days 1, 
22, 43, and 64 (Weeks 1, 4, 7, and 10) 
during induction therapy. Randomization 
was stratified by baseline body weight (BW) 
and LDH values since both were identified 
as potential covariates in a population PK 
assessment. 
The primary endpoint of PK data at week 4 
demonstrated that the PK of Process B and 
Process C are biocomparable as the 90% 
CIs for the ratio of geometric means of 
AUC(0-21d) and Cmax - both adjusted or 
not adjusted for covariates - were entirely 
contained with the pre-specified 
equivalence interval (80 - 125%). 
Population Pharmacokinetics 
The population pharmacokinetics (PPK) of 
ipilimumab was developed with 420 
subjects (1767 serum concentrations) with 
advanced melanoma in phase 2 studies 
(CA184007, CA184008, and CA184022). 
Subsequently, the final PPK model was 
evaluated by an external model validation 
dataset from CA184004 (79 subjects with 
328 serum concentration data). The PPK 
analysis demonstrated that PK of 
ipilimumab is linear and exposures are dose 
proportional across the tested dose range of 
0.3 to 10 mg/kg, and the model parameters 
are time-invariant. The ipilimumab CL of 
15.3 mL/h from PPK analysis is consistent 
with that determined by PK analysis as 
assessed in MDX010-15 as 12.8 mL/h for a 
dose of 2.8 mg/kg and 15.7 mL/h for a dose 
of 10 mg/kg. The terminal half-life and Vss 
of ipilimumab calculated from the model 
were 14.7 days, and 7.21 L, which are 
consistent with that determined by non-
compartmental analysis (NCA). Volume of 
central and peripheral compartment were 
found to be 4.16 and 3.22 L, respectively, 
suggesting that ipilimumab first distributes 
into plasma volume and subsequently into 
extracellular fluid space. Clearance of 
ipilimumab was found to increase with 
increase in body weight, supporting dosing 
of ipilimumab based on a weight normalized 
regimen. Other covariates had effects that 
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were either not statistically significant or 
were of minimal clinical relevance. 
1.4.4 
Clinical Safety with Ipilimumab 
1.4.4.1 
Overview of Clinical Trials Experience with Ipilimumab 
Because clinical trials are conducted under widely varying 
conditions, the adverse reaction rates observed cannot be 
directly compared with rates in other clinical trials or 
experience with therapeutics in the same class and may 
not reflect the rates observed in clinical practice. 
The clinical development program excluded patients with 
active autoimmune disease or those receiving systemic 
immunosuppression for organ transplantation. Exposure to 
ipilimumab 3 mg/kg for four doses given by intravenous 
infusion in previously treated patients with unresectable or 
metastatic melanoma was assessed in a randomized, 
double-blind clinical study (MDX010-20). One hundred 
thirty-one patients (median age 57 years, 60% male) 
received ipilimumab as a single agent, 380 patients 
(median age 56 years, 61% male) received ipilimumab with 
an investigational gp100 peptide vaccine (gp100), and 132 
patients (median age 57 years, 54% male) received gp100 
peptide vaccine alone. Patients in the study received a 
median of 4 doses (range 1 to 4 doses). Ipilimumab was 
discontinued for adverse reactions in 10% of patients. 
The most common adverse reactions (≥ 5%) in patients 
who received ipilimumab at 3 mg/kg were fatigue, diarrhea, 
pruritus, rash, and colitis. 
Table 1 presents selected adverse reactions from 
MDX010-20, which occurred in at least 5% of patients in 
the ipilimumab-containing arms and with at least 5% 
increased incidence over the control gp100 arm for all-
grade events and at least 1% incidence over the control 
group for Grade 3–5 events. 
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Table 1: Selected Adverse Reactions in MDX010-20 
 
Percentage (%) of Patientsa 
 
YERVOY 3 
mg/kg 
n = 131 
YERVOY 3mg/kg 
+ gp100  
n = 380 
gp100 
n = 132 
System Organ Class/Preferred Term 
Any 
Grade 
Grade 
3-5 
Any 
Grade 
Grade 
3-5 
Any 
Grade 
Grade 
3-5 
Gastrointestinal Disorders 
 
 
 
 
 
 
Diarrhea 
32 
5 
37 
4 
20 
1 
Colitis 
8 
5 
5 
3 
2 
0 
Skin and Subcutaneous Tissue Disorders 
 
 
 
 
 
 
Pruritus 
31 
0 
21 
< 1 
11 
0 
Rash 
29 
2 
25 
2 
8 
0 
General Disorders and Administration Site Conditions 
 
 
 
 
 
 
Fatigue 
41 
7 
34 
5 
31 
3 
a Incidences presented in this table are based on reports of adverse events regardless of causality.  
Source: Yervoy Prescribing Information, Bristol-Myers Squibb, March 2011. 
Table 2 presents the per-patient incidence of severe, life-
threatening, or fatal immune-mediated adverse reactions 
from MDX010-20. 
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Table 2: Severe to Fatal Immune-mediated Adverse Reactions in MDX010-20 
 
Percentage (%) of Patients  
 
YERVOY 3 mg/kg 
n = 131 
YERVOY 3 mg/kg + 
gp100  
n = 380 
Any Immune-mediated Adverse Reaction  
15 
12 
Entercolitis a,b 
7 
7 
Hepatotoxicity a 
1 
2 
Dermatitis a 
2 
3 
Neuropathy a 
1 
< 1 
Endocrinopathy 
4 
1 
Hypopituitarism 
4 
1 
Adrenal insufficiency 
0 
1 
Other 
 
 
Pneumonitis 
0 
< 1 
Meningitis 
0 
< 1 
Nephritis 
1 
0 
Eosinophilia c 
1 
0 
Pericarditis a,c 
0 
< 1 
a Including fatal outcome 
b Including intestinal perforation 
c Underlying etiology not established 
Source: Yervoy Prescribing Information, Bristol-Myers Squibb, March 2011. 
CA184024 evaluated the addition of 10 mg/kg ipilimumab 
to dacarbazine in patients with previously untreated, 
metastatic melanoma. A total of 502 patients were 
randomized to receive up to 8 cycles of dacarbazine 850 
mg/m2 q3w, with either ipilimumab 10 mg or placebo for 
cycles 1-4 and as maintenance after completion of 
chemotherapy. Ipilimumab AEs were consistent with 
previous studies and predominately affected skin, GI tract, 
liver, and the endocrine system. Events were managed 
with established guidelines and were generally responsive 
to dose interruption/discontinuation, corticosteroids and/or 
other immunosuppresants. Select adverse events 
associated with the mechanism of action of ipilimumab, 
regardless of attribution by the investigator) are shown in 
Table 3. 
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Table 3: CA184024 Select Adverse Events 
 
Ipilimumab + DTIC 
n = 247 
Placebo + DTIC 
n = 251 
Total 
Grade 3 - 4 
Total 
Grade 3 - 4 
% Patients 
Dermatologic 
 
 
 
 
 Pruritis 
29.6 
2.0 
8.8 
0 
 Rash 
24.7 
1.2 
6.8 
0 
Gastrointestinal (GI) 
 
 
 
 
 Diarrhea 
36.4 
4.0 
24.7 
0 
 Colitis 
4.5 
2.0 
0.4 
0 
 GI perforation 
0 
0 
0 
0 
Hepatic 
 
 
 
 
 Increased ALT 
33.2 
21.9 
5.6 
0.8 
 Increased AST 
29.1 
18.2 
5.6 
1.2 
Endocrine 
 
 
 
 
 Hypothyroidism 
1.6 
0 
0.4 
0 
 Autoimmune thyroiditis 
0.8 
0 
0 
0 
 Hyperthyroidism 
0.4 
0 
0.4 
0 
 Hypophysitisa 
0 
0 
0 
0 
a 1 (0.4%) hypophysitis was reported on Day 364. 
 
Table 4: Summary of irAE Safety Data for 10 mg/kg in Melanoma 
 
Total 
Low-grade 
(Grade 1 - 2) 
(%) 
High-grade 
(Grade 3 - 4) 
(%) 
Median Time to 
Resolution of 
Grade 2 - 4 irAEs 
(weeks) 
All irAEs 
72.3 
46.2 
25.2 
- 
Skin (eg, rash, pruritus) 
52.0 
49.2 
2.8 
6.14 
GI (eg, colitis, diarrhea) 
37.2 
24.9 
12.3 
2.29 
Liver (eg, LFT elevations) 
8.0 
0.9 
6.8 
4.0 
Endocrine (eg, hypophysitis, hypothyroid) 
6.2 
3.7 
2.5 
20.1 
Overall, the 10 mg/kg had an acceptable safety regimen, 
while being the most active dose. The study drug related 
deaths across the program are in Section 5 of the 
investigators brochure. 
Across clinical studies that utilized ipilimumab doses 
ranging from 0.3 to 10 mg/kg, the following adverse 
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1.4.4.4 
Immune-mediated Adverse Reactions with Ipilimumab.  
Ipilimumab can result in severe and fatal immune-mediated 
reactions due to T-cell activation and proliferation. 
Immune-related Gastrointestinal Events 
The clinical presentation of GI immune-related AEs 
included diarrhea, increase in the frequency of bowel 
movements, abdominal pain, or hematochezia, with or 
without fever. Fatalities due to GI perforation have been 
reported in clinical trials of ipilimumab. Patients should be 
carefully monitored for GI symptoms that may be indicative 
of immune-related colitis, diarrhea, or GI perforation. 
Diarrhea or colitis occurring after initiation of ipilimumab 
therapy should be evaluated to exclude infectious or 
alternate etiologies. In clinical trials, immune-related colitis 
was associated with evidence of mucosal inflammation, 
with or without ulcerations, and lymphocytic infiltration. 
Immune-related Hepatotoxicity 
Hepatic immune-related AEs were mostly clinically silent 
and manifested as transaminase or bilirubin laboratory 
abnormalities. Fatal hepatic failure has been reported in 
clinical trials of ipilimumab. Serum transaminase and 
bilirubin levels must be evaluated before each dose of 
ipilimumab as early laboratory changes may be indicative 
of emerging immune-related hepatitis. Elevations in liver 
function tests (LFTs) may develop in the absence of 
clinical symptoms. Increase in LFT or total bilirubin should 
be evaluated to exclude other causes of hepatic injury, 
including infections, disease progression, or medications, 
and monitored until resolution. Liver biopsies from patients 
who had immune-related hepatotoxicity showed evidence 
of acute inflammation (neutrophils, lymphocytes, and 
macrophages). 
Immune-related Skin Toxicity 
Skin immune-related AEs presented mostly as a rash 
and/or pruritus. Some subjects reported vitiligo associated 
with ipilimumab administration. Fatal toxic epidermal 
necrolysis has been reported in clinical trials of ipilimumab.  
Immune-related Endocrinopathy 
Ipilimumab can cause inflammation of the endocrine 
system organs, specifically hypophysitis, hypopituitarism, 
and adrenal insufficiency and patients may present with 
nonspecific symptoms, which may resemble other causes 
such as brain metastasis or underlying disease. The most 
common clinical presentation includes headache and 
fatigue. Symptoms may also include visual field defects, 
behavioral changes, electrolyte disturbances, and 
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hypotension. Adrenal crisis as a cause of the patient’s 
symptoms should be excluded. Based on the available 
data with known outcome, most of the subjects 
symptomatically improved with hormone replacement 
therapy. It is possible that long-term hormone replacement 
therapy will be required for subjects developing 
hypophysitis/hypopituitarism after treatment with 
ipilimumab. 
Immune-related Neurological Events 
Neurological manifestations included muscle weakness 
and sensory neuropathy. Fatal Guillain-Barré syndrome 
has been reported in clinical trials of ipilimumab. Patients 
may present with muscle weakness. Sensory neuropathy 
may also occur. Unexplained motor neuropathy, muscle 
weakness, or sensory neuropathy lasting more than 4 days 
should be evaluated and non-inflammatory causes such as 
disease progression, infections, metabolic syndromes, and 
medications should be excluded. 
Other Immune-related AEs 
Ocular inflammation, manifested as Grade 2 or Grade 3 
episcleritis or uveitis, was associated with concomitant 
diarrhea in a few subjects (< 1%) and occasionally 
occurred in the absence of clinically apparent GI 
symptoms. Other presumed immune-related AEs reported 
include, but were not limited to, arthritis/arthralgias, 
pneumonitis, pancreatitis, autoimmune (aseptic) 
meningitis, autoimmune nephritis, pure red cell aplasia, 
noninfective myocarditis, polymyositis, and myasthenia 
gravis, of which were individually reported for < 1% of 
subjects. 
Overall, immune-related AEs commonly started within 3 to 
10 weeks from first dose, were successfully managed in 
most instances by omitting doses, discontinuing dosing, 
and/or through administering symptomatic or 
immunosuppressive therapy, including corticosteroids, as 
mentioned above and detailed in Section 5.4.1. Immune-
related AEs generally resolved within days to weeks in the 
majority of subjects.  
1.4.5 
Clinical Efficacy of Ipilimumab in Melanoma 
The clinical efficacy of ipilimumab as a single agent at a dose of 3 
mg/kg administered every 3 weeks for 4 doses has been established 
in MDX010-20 (a randomized, controlled study in second line, locally 
advanced/metastatic melanoma), which led to approval of ipilimumab 
by the FDA for the treatment of unresectable or metastatic melanoma. 
In study CA184024, the addition of 10 mg/kg ipilimumab to 
dacarbazine led to a prolongation of overall survival in patients with 
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previously untreated melanoma  and was feasible with an acceptable 
safety profile. 
Overall survival and other efficacy endpoints were assessed in 
ipilimumab studies. 
Overall Survival: Prolongs survival in patients with metastatic 
melanoma who have failed prior treatment. 
Best Objective Response Rate (BORR): By the conventional mWHO 
criteria confirmed objective responses have been observed in 
subjects receiving ipilimumab. These responses tend to be durable 
with the majority of subjects who achieve objective responses 
progression-free at the end of long observation periods. 
Disease Control Rate (DCR): Disease stabilization in subjects 
receiving ipilimumab is a key characteristic of anti-tumor activity. 
Stable disease, sometimes of long duration, or slow steady decline of 
tumor lesion size over long periods of time, has been observed. 
Consequently, SD as well as objective responses (both captured in 
DCR) are important for completely characterizing anti-tumor activity of 
ipilimumab 
Progression-Free Survival (PFS): Some subjects demonstrate initial 
tumor volume increase before response, possibly due to T-cell 
infiltration as shown by biopsies. Consequently, PFS incompletely 
captures all patterns of activity and may underestimate the clinical 
activity of ipilimumab. 
1.4.5.1 
Rationale for Using Immune-Related Tumor Assessment 
Criteria (irRC) 
Ipilimumab is an immuno-stimulating antibody with 
evidence of anti-cancer activity (durable objective 
response and stable disease) in subjects with advanced 
melanoma, including subjects with established brain 
disease. Observations of clinical activity defined by tumor 
response endpoints defined by conventional criteria (eg, 
mWHO) may be inadequate to realize the kinetics and 
magnitude of clinical benefit achieved with ipilimumab. 
Histopathologic evidence has demonstrated ipilimumab 
can produce an influx or expansion of tumor infiltrating 
lymphocytes. Therefore, early increases in lesion size 
detected radiologically or upon gross examination could be 
misinterpreted as progressive tumor growth and precede 
objective tumor shrinkage. In addition the appearance of 
new lesions may have categorized a subject to have 
progressive disease using conventional tumor assessment 
criteria despite the concurrent observation of objective 
tumor responses in pre-existing lesions and a net reduction 
in global tumor burden that includes the new lesions. 
Hence the appearance of new lesions in and of 
themselves may not necessarily constitute progressive 
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disease. The immune-related response criteria (irRC) were 
developed as a tool to gauge tumor response using the 
changes in global tumor burden. In addition, the irRC may 
be useful to inform a physician’s decision to continue 
dosing in subjects who may receive benefit from additional 
ipilimumab therapy. The ir-response assessment is based 
solely on objective measurements (SPD) of index and new 
lesions. Non-index lesions are not considered. 
1.4.5.2 
MDX010-20 (Phase 3, 3 mg/kg, previously treated 
melanoma) 
MDX010-20, a randomized (3:1:1), double-blind, double-
dummy study included 676 randomized subjects with 
unresectable or metastatic melanoma previously treated 
with one or more of the following: aldesleukin, 
dacarbazine, temozolomide, fotemustine, or carboplatin. Of 
these 676 subjects, 403 were randomized to receive 
ipilimumab at 3 mg/kg in combination with an 
investigational peptide vaccine with incomplete Freund’s 
adjuvant (gp100), 137 were randomized to receive 
ipilimumab at 3 mg/kg, and 136 were randomized to 
receive gp100 alone. The study enrolled only subjects with 
HLA A2*0201 genotype; this HLA genotype facilitates the 
immune presentation of the investigational peptide 
vaccine. The study excluded subjects with active 
autoimmune disease or those receiving systemic 
immunosuppression for organ transplantation. 
Ipilimumab/placebo was administered at 3 mg/kg as an 
intravenous infusion every 3 weeks for 4 doses. 
Gp100/placebo was administered at a dose of 2 mg 
peptide by deep subcutaneous injection every 3 weeks for 
four doses. Assessment of tumor response was conducted 
at Weeks 12 and 24, and every 3 months thereafter. 
Subjects with evidence of objective tumor response at 12 
or 24 weeks had assessment for confirmation of durability 
of response at 16 or 28 weeks, respectively. 
The major efficacy outcome measure was overall survival 
(OS) in the ipilimumab + gp100 arm compared to that in 
the gp100 arm. Secondary efficacy outcome measures 
were OS in the ipilimumab + gp100 arm compared to the 
ipilimumab arm, OS in the ipilimumab arm compared to the 
gp100 arm, best overall response rate (BORR) at Week 24 
between each of the study arms, and duration of response.  
Of the randomized subjects, 61%, 59%, and 54% in the 
ipilimumab + gp100, ipilimumab, and gp100 arms, 
respectively, were men. Twenty-nine (29%) percent were ≥ 
65 years of age, the median age was 57 years, 71% had 
M1c stage, 12% had a history of previously treated brain 
metastasis, 98% had ECOG performance status of 0 and 
1, 23% had received aldesleukin and 38% had elevated 
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LDH level. Sixty-one (61%) percent of subjects randomized 
to either ipilimumab -containing arm received all 4 planned 
doses. The median duration of follow-up was 8.9 months. 
The OS results are shown in Table 5 and Figure 2. 
Table 5: MDX010-20 Overall Survival Results 
 
Ipilimumab 
n = 137 
Ipilimumab + 
gp100 
n = 403 
gp100 
n = 136 
Hazard Ratio (vs gp100) 
 
(95% CI) 
0.66 
(0.51, 0.87) 
0.68 
(0.55, 0.85) 
 
 
p-value 
p = 0.0026a 
p = 0.0004 
 
Hazard Ratio (vs ipilimumab) 
 
(95% CI) 
 
1.04 
(0.83, 1.30) 
 
Median (months) 
 
(95% CI) 
10 
(8.0, 13.8) 
10 
(8.5, 11.5) 
6 
(5.5, 8.7) 
a Not adjusted for multiple comparisons. 
Figure 2: MDX010-20 - Overall Survival by Treatment (ITT Population) 
 
The best overall response rate (BORR) as assessed by the 
investigator was 5.7% (95% CI: 3.7%, 8.4%) in the 
ipilimumab + gp100 arm, 10.9% (95% CI: 6.3%, 17.4%) in 
the ipilimumab arm, and 1.5% (95% CI: 0.2%, 5.2%) in the 
gp100 arm. The median duration of response was 11.5 
months in the ipilimumab + gp100 arm and has not been 
reached in the ipilimumab or gp100 arm. 
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1.4.5.3 
CA184024 (Phase 3, previously untreated melanoma, 10 
mg/kg) 
CA184024 evaluated the addition of 10 mg/kg ipilimumab 
to dacarbazine in patients with previously untreated, 
metastatic melanoma. A total of 502 patients were 
randomized to receive up to 8 cycles of dacarbazine 850 
mg/m2 q3w, with either ipilimumab 10 mg/kg or placebo 
cycles 1-4, and as maintenance after completion of 
chemotherapy.  
The two arms were well balanced regarding most baseline 
characteristics, as shown in Table 6. 
Table 6: CA184024 Baseline Characteristics 
 
Ipilimumab + DTIC 
n = 250 
Placebo + DTIC 
n = 252 
Age (years) 
 
 
 Mean 
57.5 
56.4 
Gender (%) 
 
 
 Male 
60.8 
59.1 
 Female 
39.2 
40.9 
M Stage (%) 
 
 
 M0 
2.4 
3.2 
 M1a 
14.8 
17.1 
 M1b 
25.6 
24.6 
 M1c 
57.2 
55.2 
ECOG PS (%) 
 
 
 0 
70.8 
71.0 
 1 
29.2 
29.0 
LDH (%) 
 
 
 ≤ ULN  
62.8 
55.6 
 > ULN  
37.2 
43.7 
 ≤ 2x ULN 
86.4 
85.3 
 > 2x ULN 
13.6 
13.9 
Prior adjuvant  
therapy (%) 
26.4 
26.6 
Prior therapy for 
advanced disease (%) 
0 
0 
Patients on the ipilimumab arm received a median of 3 
ipilimumab induction doses, versus 4 placebo induction 
doses on the placebo arm. A total of 17.4% and 21.1% of 
patients continued to receive maintenance ipilimumab or 
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Table 7: CA184024 Tumor Response 
 
Ipilimumab + DTIC 
n = 250 
Placebo + DTIC 
n = 252 
Disease Control Rate, n (%) 
83 (33.2) 
76 (30.2) 
BORR (CR + PR), n (%) 
38 (15.2) 
26 (10.3) 
 
Complete response 
4 (1.6) 
2 (0.8) 
 
Partial response 
34 (13.6) 
24 (9.5) 
 
Stable disease 
45 (18.0) 
50 (19.8) 
 
Progressive disease 
111 (44.4) 
131 (52.0) 
Duration of response, months 
19.3 
8.1 
1.4.5.4 
10 mg/kg Dosing with Ipilimumab 
In melanoma, Phase 3 studies show improved survival at 
both 3 mg/kg (study MDX010-20) as well as with 10 mg/kg 
(study CA184024). Several additional conducted trials 
studied the efficacy and safety of 10 mg/kg dosing, and 
additional information gained from these trials is listed 
below: 
• 
A dose of 10 mg/kg is necessary to ensure a blockade 
of the CTLA-4 pathway: in vitro a concentration of 20 
µg/mL of ipilimumab was the minimal concentration 
able to fully abrogate the binding of CTLA-4 to B7.1 
and B7.2. With a dose of 3 mg/kg q3w 30% achieved a 
trough concentration of ipilimumab greater than 20 
µg/mL, compared to 95% of subjects treated at 10 
mg/kg q3w. 
• 
In addition, in all ipilimumab trials examined to date, 
mean Absolute Lymphocyte Count (ALC) increased 
after ipilimumab treatment throughout the 12-week 
induction-dosing period, in a dose-dependent manner. 
In an analysis of ipilimumab at 0.3, 3, or 10 mg/kg in 
melanoma studies CA184007, CA184008, and 
CA184022 combined, the rate of change in ALC after 
ipilimumab treatment was significantly associated with 
dose (p = 0.0003), with the largest rate at 10 mg/kg 
ipilimumab. Moreover, the rate of change in ALC over 
the first half of the induction-dosing period was 
significantly associated with clinical activity in these 
studies (p = 0.009), where clinical activity was defined 
as CR, PR, or prolonged SD (ie, SD lasting at least 6 
months from first dose). Although these analyses alone 
could not determine whether the rate of change in ALC 
was specifically associated with clinical activity in 
response to ipilimumab treatment, as opposed to being 
generally prognostic, these results do suggest a 
potential benefit to higher rates of ALC increase after 
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ipilimumab treatment. Among the 3 doses evaluated, 
10 mg/kg ipilimumab led to the greatest such rates. 
• 
In the 3 primary studies conducted in advanced 
melanoma (CA184007, CA184008, and CA184022), 
subjects treated with 10 mg/kg during the induction 
period had the highest response, disease control rates, 
median OS as well as 1-year and 2-year survival rates 
compared to other doses. The CA184022 data are 
summarized in Table 8. 
Table 8: Summary of Phase 2 Response Data in Melanoma (CA184022) 
 
10 mg/kg 
(n = 72) 
3 mg/kg 
(n = 72) 
0.3 mg/kg 
(n = 73) 
BORR (mWHO) – % 
(95% CI) 
11.1 
(4.9 - 20.7) 
4.2 
(0.9 - 11.7) 
0 
(0.0 - 4.9) 
DCR (mWHO) – % 
(95% CI) 
29.2 
(19.0 - 41.1) 
26.4 
(16.7 - 38.1) 
13.7 
(6.8 - 23.8) 
Survival rate at 1 year - % 
%, 95% CI 
48.64 
(36.84, 60.36) 
39.32 
(27.97, 50.87) 
39.58 
(28.20, 51.19) 
Survival rate at 2 year - % 
%, 95% CI 
29.81 
(19.13, 41.14) 
24.20 
(14.42, 34.75) 
18.43 
(9.62, 28.22) 
Overall median survival 
95%CI (months) 
11.43 
(6.90, 16.10) 
8.74 
(6.87, 12.12) 
8.57 
(7.69, 12.71) 
Finally, the dose and schedule in study CA184156 is the 
one that was evaluated in the signal finding study 
CA184041, with an acceptable safety profile and 
improvement of irPFS and OS. 
Treatment with ipilimumab has demonstrated clinically 
important and durable tumor responses in several 
malignancies including melanoma, prostate cancer, and 
renal cell carcinoma.  
1.4.5.5 
Advanced Melanoma 
Ipilimumab prolonged survival in subjects with pre-treated 
advanced melanoma are based on results from MDX010-
20 (Phase 3) supported by data from Phase 2 studies; the 
primary efficacy and safety studies are summarized in 
Table 9. The primary endpoint in MDX010-20 was OS, 
which was also a key secondary endpoint in Phase 2 
studies. 
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Table 9: Studies Supporting the Efficacy and Safety of Ipilimumab in Subjects with Advanced Melanoma 
 
 
 
 
# Randomized or 
Enrolled/Treated 
Study No. 
(Phase) 
Populations 
Primary 
Efficacy 
Endpoint 
Doses Studies 
3 mg/kg 
10 mg/kg 
Total 
MDX010-20 
(Phase 3) 
HLA-A2*0201-
positive, previously 
treated, unresectable 
Stage III or IV 
melanoma 
OS 
3 mg/kg q3 wk x 4 ± 
gp100 (induction) 
followed by re-
induction 
540/512 
--/-- 
676/643a 
CA184022 
(Phase 2)  
Previously treated, 
unresectable Stage III 
or IV melanoma 
BORR 
0.3, 3, or 10 mg/kg q3 
wk x 4 (induction) 
followed by 
maintenance dosing 
q12 wk 
72/71 
72/71 
217/214 
CA184004 
(Phase 2) 
Biomarker 
Study 
Unresectable Stage III 
or IV melanoma 
BORR 
3 or 10 mg/kg q3 wk x 
4 (induction) followed 
by maintenance dosing 
q12 wk 
40/40 
42/42 
82/82 
CA184008 
(Phase 2) 
Previously treated 
unresectable State III 
or IV melanoma 
BORR 
10 mg/kg q3 wk x 4 
(induction) followed by 
maintenance dosing 
q12 wk 
--/-- 
155/155 
155/155 
CA184007 
Unresectable Stage III 
or IV melanoma 
BORR 
10 mg/kg q3 wk x 4 ± 
budesonide (induction) 
followed by 
maintenance dosing 
q12 wk 
--/-- 
115/115 
115/115 
Additional Studies  
MDX010-
08(Phase 2) 
Chemotherapy-naive 
advanced melanoma 
ORR 
3 mg/kg q4 wk x 4 ± 
DTIC (induction) 
78/74 
--/-- 
78/74 
CA184042 
(Phase 2) 
Stage IV melanoma 
with brain metastases 
DCR 
10 mg/kg q3 wk x 4 
(induction) followed by 
maintenance dosing 
q12 wk 
--/-- 
28/28b 
28/28b 
MDX010-28 
(Phase 2) 
Survival 
Follow-up 
Study 
Subjects enrolled in 
earlier Medarex 
studies, including 
MDX010-08 and 
MDX010-15c 
OS 
N/A 
--/N/A 
--/NA 
--/N/A 
BORR = best overall response rate; DCR = disease control rate; DTIC = dacarbazine; N/A = not 
applicable; ORR = overall response rate; OS = overall survival; PK = pharmacokinetics. 
a Total includes 136 randomized/131 treated subjects in the gp100 treatment group. 
b Information is presented only for subjects enrolled in MDX010-20, Arm A. 
c MDX010-15 was primarily a PK study that evaluated ipilimumab at single and multiple doses.  
Source:  Reference 16-23 
1.5 
Bevacizumab CLINICAL Experience 
Bevacizumab has been studied in a multitude of Phase I, II, and III clinical trials 
in more than 5000 patients and in multiple tumor types. The following discussion 
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summarizes bevacizumab’s safety profile and presents some of the efficacy 
results pertinent to this particular trial.  
In a large phase III study (AVF2107g) in patients with metastatic colorectal 
cancer, the addition of bevacizumab, a monoclonal antibody directed against 
vascular endothelial growth factor (VEGF), to irinotecan/5-fluorouracil/leucovorin 
(IFL) chemotherapy resulted in a clinically and statistically significant increase in 
duration of survival, with a hazard ratio of death of 0.67 (median survival 15.6 vs. 
20.3months; p< 0.001). Similar increases were seen in progression-free survival 
(6.2 vs. 10.6 months; p< 0.001), overall response rate (35% vs. 45%; p< 0.01) 
and duration of response (7.1vs. 10.4 months; p< 0.01) for the combination arm 
versus the chemotherapy only arm (bevacizumab Investigator Brochure, October 
2005). 
Based on the survival advantage demonstrated in Study AVF2107g, 
bevacizumab was designated for priority review and was approved on 26 
February 2004 in the United States for first-line treatment in combination with IV 
5 FU-based chemotherapy for subjects with metastatic colorectal cancer. 
Pharmacokinetic data with 5 mg/kg every 2 weeks shows comparability with 7.5 
mg every three weeks and 10 mg/kg every 2 weeks is comparable to 15 mg/kg 
every 3 weeks. 
1.5.1 
Safety Profile 
In the initial Phase I and II clinical trials, four potential bevacizumab-
associated safety signals were identified: hypertension, proteinuria, 
thromboembolic events, and hemorrhage.  Additional completed 
Phase II and Phase III studies of bevacizumab as well as 
spontaneous reports have further defined the safety profile of this 
agent. Bevacizumab-associated adverse events identified in phase III 
trials include congestive heart failure (CHF), gastrointestinal 
perforations, wound healing complications, and arterial 
thromboembolic events (ATE). These and other safety signals are 
described in further detail as follows and in the bevacizumab 
Investigator Brochure. 
Hypertension: Hypertension has been commonly seen in 
bevacizumab clinical trials to date and oral medications have been 
used to manage the hypertension when indicated. Grade 4 and 5 
hypertensive events are rare. Clinical sequelae of hypertension are 
rare but have included hypertensive crisis, hypertensive 
encephalopathy, and reversible posterior leukoencephalopathy 
syndrome (RPLS)[21, 22]. RPLS may include signs and symptoms of 
headache, altered mental function, seizures, and visual disturbances / 
cortical blindness and requires treatment, which should include control 
of hypertension, management of specific symptoms, and 
discontinuation of bevacizumab. 
Proteinuria: Proteinuria has been commonly seen in bevacizumab 
clinical trials to date. The severity of proteinuria has ranged from 
asymptomatic and transient events detected on routine dipstick 
urinalysis to nephrotic syndrome; the majority of proteinuria events 
have been grade 1 or 2. In study AVF2107g, none of the 118 patients 
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receiving bolus-IFL plus placebo, three of 158 patients (2%) receiving 
bolus-IFL plus bevacizumab, and two of 50 (4%) patients receiving 5-
FU/LV plus bevacizumab who had a 24-hour collection experienced 
grade 3 proteinuria (> 3.5 g protein/24 hr). Rare events of nephrotic 
syndrome have occurred, and bevacizumab should be discontinued in 
patients with nephrotic syndrome.  
Thromboembolic Events: Both venous and arterial thromboembolic 
(TE) events, ranging in severity from catheter-associated phlebitis to 
fatal, have been reported in patients treated with bevacizumab in the 
colorectal cancer trials and, to a lesser extent, in patients treated with 
bevacizumab in NSCLC and breast cancer trials. In the phase III 
pivotal trial in metastatic CRC, there was a slightly higher rate of 
venous TE events that was not statistically significant in patients 
treated with bevacizumab plus chemotherapy compared with 
chemotherapy alone (19% vs. 16%). There was also a higher rate of 
arterial TE events (3% vs. 1%) such as myocardial infarction, 
transient ischemia attack, cerebrovascular accident/stroke and 
angina/unstable angina. A pooled analysis of the rate of arterial TE 
events from 5 randomized studies (1745 patients) showed that 
treatment with chemotherapy plus bevacizumab increased the risk of 
having an arterial TE event compared with chemotherapy alone (3.8% 
vs. 1.7%, respectively) (Skillings et al., 2005). Furthermore, subjects 
with certain baseline characteristics (age ≥ 65 years and/or a history 
of a prior arterial TE event) may be at higher risk of experiencing such 
an event. See the bevacizumab Investigator Brochure for additional 
information on risk factors. 
Aspirin is a standard therapy for primary and secondary prophylaxis of 
arterial thromboembolic events in patients at high risk of such events, 
and the use of aspirin ≤ 325 mg daily was allowed in the five 
randomized studies discussed above. Use of aspirin was assessed 
routinely as a baseline or concomitant medication in these trials, 
though safety analyses specifically regarding aspirin use were not 
preplanned. Due to the relatively small numbers of aspirin users and 
arterial thromboembolic events, retrospective analyses of the ability of 
aspirin to affect the risk of such events were inconclusive. However, 
similarly retrospective analyses suggested that the use of up to 325 
mg of aspirin daily does not increase the risk of grade 1-2 or grade 3-
4 bleeding events, and similar data with respect to metastatic 
colorectal cancer patients were presented at ASCO 2005 (Hambleton 
et al., 2005). Further analyses of the effects of concomitant use of 
bevacizumab and aspirin in colorectal and other tumor types are 
ongoing. 
Gastrointestinal perforation Patients with metastatic carcinoma may 
be at increased risk for the development of gastrointestinal perforation 
when treated with bevacizumab and chemotherapy. Bevacizumab 
should be permanently discontinued in patients who develop 
gastrointestinal perforation. A causal association of intra-abdominal 
inflammatory process and gastrointestinal perforation to bevacizumab 
has not been established. Nevertheless, caution should be exercised 
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when treating patients with intra-abdominal inflammatory processes 
with bevacizumab. Gastrointestinal perforation has been reported in 
other trials in non-colorectal cancer populations (e.g., ovarian, renal 
cell, pancreas, and breast) and may be higher in incidence in some 
tumor types. 
Wound healing complications: Wound healing complications such 
as wound dehiscence have been reported in patients receiving 
bevacizumab. In an analysis of pooled data from two trials in 
metastatic colorectal cancer, patients undergoing surgery 28-60 days 
before study treatment with 5-FU/LV plus bevacizumab did not appear 
to have an increased risk of wound healing complications compared 
to those treated with chemotherapy alone[23]. Surgery in patients 
currently receiving bevacizumab is not recommended. No definitive 
data are available to define a safe interval after bevacizumab 
exposure with respect to wound healing risk in patients receiving 
elective surgery; however, the estimated half life of bevacizumab is 20 
days. Bevacizumab should be discontinued in patients with severe 
wound healing complications. 
Hemorrhage: Overall, grade 3 and 4 bleeding events were observed 
in 4.0% of 1132 patients treated with bevacizumab in a pooled 
database from eight phase I, II, and III clinical trials in multiple tumor 
types (bevacizumab Investigator Brochure, October 2005). The 
hemorrhagic events that have been observed in bevacizumab clinical 
studies were predominantly tumor-associated hemorrhage (see 
below) and minor mucocutaneous hemorrhage. 
Tumor-associated hemorrhage was observed in phase I and phase II 
bevacizumab studies. Six serious events, of which 4 had fatal 
outcome, were observed in a phase II trial of patients with non-small 
cell lung cancer receiving bevacizumab. These events occurred 
suddenly and presented as major or massive hemoptysis in patients 
with either squamous cell histology and/or tumors located in the 
center of the chest in close proximity to major blood vessels. In five of 
these cases, these hemorrhages were preceded by cavitation and/or 
necrosis of the tumor. Tumor-associated hemorrhage was also seen 
rarely in other tumor types and locations, including central nervous 
system (CNS) bleeding in a patient with hepatoma with occult CNS 
metastases and continuous oozing of blood from a thigh sarcoma with 
necrosis.  
Across all bevacizumab clinical trials, mucocutaneous hemorrhage 
has been seen in 20%-40% of patients treated with bevacizumab. 
These were most commonly grade 1 epistaxis that lasted less than 5 
minutes, resolved without medical intervention and did not require any 
changes in bevacizumab treatment regimen. There have also been 
less common events of minor mucocutaneous hemorrhage in other 
locations, such as gingival bleeding and vaginal bleeding.  
Congestive heart failure: CHF has been reported in bevacizumab 
clinical trials and may be increased in incidence in patients with prior 
exposure to anthracyclines or prior irradiation to the chest wall. In a 
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phase III trial (AVF2119g) of capecitabine with or without 
bevacizumab for metastatic breast cancer, 7 subjects (3.1%) who 
received capecitabine plus bevacizumab developed clinically 
significant CHF compared with 2 subjects (0.9%) treated with 
capecitabine alone; of note, all subjects in this trial had had prior 
anthracycline treatment. In addition, 2 subjects had a left ventricular 
ejection fraction < 50% at baseline and 2 others had prior left chest 
wall irradiation. A recently published phase II study in subjects with 
refractory acute myelogenous leukemia reported 5 cases of cardiac 
dysfunction (CHF or decreases to < 40% in left ventricular ejection 
fraction) of 48 subjects treated with sequential cytarabine, 
mitoxantrone, and bevacizumab. All but one of these subjects had 
significant prior exposure to anthracyclines as well[24]. Other studies 
are ongoing in this patient population. Patients receiving 
anthracyclines or with prior exposure to anthracyclines should have a 
baseline MUGA or ECHO with a normal ejection fraction. 
Additional Adverse Events: See the bevacizumab Investigator 
Brochure for additional details regarding the safety experience with 
bevacizumab. 
1.6 
Overall Risk/Benefit Assessment 
Ipilimumab is the first drug to demonstrate prolonged survival in subjects with 
pre-treated advanced melanoma, based on a large, multinational, double-blind, 
pivotal, Phase 3 study supported by a comprehensive Phase 2 program.  
The unique immune-based mechanism of action is reflected in the clinical 
patterns of anti-cancer activity in some patients. Ipilimumab impacts tumor cells 
indirectly, and measurable clinical effects emerge after the immunological effects. 
Tumor infiltration with lymphocytes and the associated inflammation 
(documented by biopsy in some subjects) is likely the cornerstone of the effect of 
ipilimumab and can manifest in various patterns of clinical activity leading to 
tumor control. In some cases, inflammation may not be noted by radiological 
examination and objective response is observed with the first tumor assessment 
in a manner seen in patients receiving other types of anti-cancer treatments. In 
other cases, response may be preceded by an apparent increase in initial tumor 
volume and/or the appearance of new lesions, which may be mistaken for tumor 
progression on radiological evaluations. Therefore, in subjects who are not 
experiencing rapid clinical deterioration, confirmation of progression is 
recommended, at the investigator’s discretion, to better understand the prognosis 
as well as to avoid unnecessarily initiating potentially toxic alternative therapies in 
subjects who might be benefitting from treatment. Immune-related (ir) response 
criteria were developed based on these observations to systematically categorize 
novel patterns of clinical activity and are currently being prospectively evaluated 
in clinical studies. 
In metastatic diseases, stabilization is more common than response, and in some 
instances is associated with slow, steady decline in tumor burden over many 
months, sometimes improving to partial and/or complete responses. Thus, the 
immune-based mechanism of action of ipilimumab results in durable disease 
control, sometimes with novel patterns of response, which contribute to its 
improvement in OS. 
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The immune-based mechanism of action is also reflected in the safety profile. 
The most common drug-related AEs are immune-mediated, consistent with the 
mechanism of action of the drug and generally medically manageable with topical 
and/or systemic immunosuppressants. As previously discussed, the immune-
mediated adverse reactions primarily involve the GI tract, skin, liver, endocrine 
glands, and nervous system. 
The early diagnosis of immune-mediated adverse reactions is important to initiate 
therapy and minimize complications. Immune-mediated adverse reactions are 
generally manageable using symptomatic or immunosuppressive therapy as 
recommended through detailed diagnosis and management guidelines, as 
described fully in the current IB. The management guidelines for general 
immune-mediated adverse reactions and ipilimumab-related GI toxicities, 
hepatotoxicity, endocrinopathy, and neuropathy are provided in the appendices 
of the current IB. 
In summary, ipilimumab offers clinically meaningful and statistically significant 
survival benefit to patients with pre-treated advanced melanoma and evidence of 
clinical activity in randomized studies in other tumor types. These findings, 
together with evidence of a safety profile that is manageable with careful 
monitoring and appropriate intervention for treatment of immune-mediated 
toxicities, suggest an acceptable benefit to risk ratio. 
Ipilimumab has been shown to prolong survival in patients with metastatic 
melanoma.  Means to improve upon this foundation of clinical benefit for patients 
are worthy of pursuit.  Experience thus far suggests that the combination of 
bevacizumab plus ipilimumab can result in enhanced immune activation with 
clinical benefits for patients.  The adverse events have been easily managed.  
Given our preliminary data so far including clinical outcomes, immune activation, 
and pathologic evaluations of post-treatment biopsies, the ability to make an 
adequate assessment of clinical activity and effects on immune function to the 
combination of ipilimumab plus bevacizumab versus ipilimumab alone would best 
be performed in a randomized fashion. 
The overall risk-benefit ratio for patients entering this protocol is therefore at least 
comparable to and possibly better than alternative options. 
1.7 
Study Rationale 
To better define the potential benefit of adding bevacizumab to ipilimumab in 
patients with metastatic melanoma, this is best performed in a prospective 
randomized manner. In the current trial, patients will be randomized to 
ipilimumab 3 mg/kg every 3 weeks x 4 with maintenance every 12 weeks versus 
ipilimumab 3 mg/kg plus bevacizumab 15 mg/kg every 3 weeks x 4, continued 
with every three week bevacizumab and every 12 week ipilimumab maintenance.  
Patients will be previously untreated for unresectable stage III or stage IV 
disease or are permitted to have received up to one prior therapy.
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2. 
Objectives 
2.1 
Primary Endpoint 
To compare overall survival for patients receiving ipilimumab plus bevacizumab 
versus ipilimumab alone. 
2.2 
Secondary Objectives 
2.2.1 
To evaluate the progression free survival, response rate and safety in 
patients receiving ipilimumab plus bevacizumab versus ipilimumab 
alone. 
2.2.2 
To evaluate the utility of immune related response criteria (irRC) in 
patients receiving ipilimumab plus bevacizumab versus ipilimumab 
alone. 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to randomization by the treating 
physician. 
3.1 
Eligibility Criteria 
3.1.1 
Age ≥ 18 years 
3.1.2 
ECOG Performance status:  0 or 1 
3.1.3 
Untreated or previously received one treatment regimen for 
measurable unresectable Stage III or Stage IV melanoma (AJCC 
2010) (for BRAF wild-type, and regardless of HLA type). Untreated or 
previously received up to two treatment regimens for measurable 
unresectable Stage III or Stage IV melanoma (AJCC 2010) (for BRAF 
mutant, and regardless of HLA type; If 2 prior regimens, one should 
be a BRAF inhibitor). This does not include any therapies given in the 
adjuvant setting. 
3.1.4 
Prior treatment (chemo, radiation, hormone, and immune therapies) 
must be completed > 4 weeks prior to randomization (> 6 weeks prior 
to randomization for nitrosoureas, mitomycin C, and checkpoint 
inhibitors). 
3.1.5 
Patients who received prior therapy with anthracylines should have a 
baseline MUGA or echo with a normal ejection fraction within 28 days 
prior to randomization. 
3.1.6 
Patients must have recovered from any acute toxicity associated with 
prior therapy by the start of study treatment. 
3.1.7 
Women must not be pregnant or breast-feeding due to the unknown 
effects on the fetus or infant. 
All females of childbearing potential must have a blood test or urine 
study within 2 weeks prior to randomization to rule out pregnancy. 
Rev. 8/14 
Rev. 11/16 
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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). 
Female? ______ (Yes or No)      
Date of blood test or urine study: ___________ 
3.1.8 
All sites of disease must be evaluated within 4 weeks prior to 
randomization. Patients must have measurable disease as defined in 
Section 6.  
3.1.9 
Patients must have the following required values for initial laboratory 
tests obtained within 4 weeks prior to randomization (ULN: 
institutional upper limit of normal): 
• 
WBC ≥ 2000/uL 
• 
ANC ≥ 1000/uL 
• 
Platelets ≥ 75 x 103/uL 
• 
Hemoglobin ≥ 9 g/dL  
• 
Creatinine ≤ 2.0 x ULN 
• 
AST/ALT ≤ 2.5 x ULN for patients without liver metastases and ≤ 5 
x ULN for patients with liver metastases 
• 
Serum Bilirubin ≤ 2.0 x ULN (except patients with Gilbert’s 
Syndrome, who must have a total bilirubin less than 3.0 mg/dL) 
3.1.10 
Patients BRAF mutation status must be known. 
3.1.11 
No Concomitant therapy with any of the following: IL 2, interferon, or 
other non-study immunotherapy regimens; cytotoxic chemotherapy; 
immunosuppressive agents; other investigational therapies; or chronic 
use of systemic corticosteroids; must have been discontinued ≥ 4 
weeks prior to randomization. 
3.1.12 
No infection with HIV.  Due to the mechanism of action of ipilimumab 
and bevacizumab, activity and side effects in an immune 
compromised patient are unknown. 
3.1.13 
No active infection with Hepatitis B. 
3.1.14 
No active or chronic infection with Hepatitis C. 
3.1.15 
Patients are ineligible if they have any history of CNS metastases. 
3.1.16 
Patients are ineligible if they have a history of any other malignancy 
from which the patient has been disease-free for less than 2 years, 
with the exception of adequately treated and cured basal or 
squamous cell skin cancer, superficial bladder cancer or carcinoma in 
situ of the cervix. 
3.1.17 
Patients are ineligible if they have a history of autoimmune disease, 
as follows: Patients with a history of inflammatory bowel disease are 
______
______
______
______
______
Rev. 8/14 
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excluded from this study as are patients with a history of symptomatic 
disease (e.g., rheumatoid arthritis, systemic progressive sclerosis 
[scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis 
[e.g., Wegener’s Granulomatosis]). Patients with motor neuropathy 
considered of autoimmune origin (e.g., Guillain-Barre Syndrome and 
Myasthenia Gravis) are excluded. Patients with a history of 
autoimmune thyroiditis are eligible if their current thyroid disorder is 
treated and stable with replacement or other medical therapy. 
3.1.18 
Patients are ineligible if they have an active infection. 
3.1.19 
Patients are ineligible if they have a history of prior treatment with 
ipilimumab, bevacizumab, or prior CD137 agonist or CTLA-4 inhibitor 
or agonist. Patients may be treatment naïve or have had one prior 
systemic therapy for metastatic disease as outlined in the eligibility 
criteria. Patients may have received prior anti-PD-1 or anti-PD-L1 as 
per current protocol eligibility, although they are not currently 
commercially approved in the front line setting. 
3.1.20 
Patients are ineligible if they have a history of any underlying medical 
or psychiatric conditions or require any medications or treatment that 
in the opinion of the principal investigator may interfere with 
compliance, make the administration of study drug hazardous or 
obscure the interpretation of adverse events, such as a condition 
associated with frequent diarrhea. 
3.1.21 
Patients are ineligible if they have any concurrent medical condition 
requiring the use of systemic steroids. (Use of inhaled or topical 
steroids is acceptable). 
3.1.22 
Patients are ineligible if they have inadequately controlled 
hypertension (defined as systolic blood pressure > 150 and/or 
diastolic blood pressure > 100 mmHg on antihypertensive 
medications). 
3.1.23 
Patients are excluded if they have any prior history of hypertensive 
crisis or hypertensive encephalopathy. 
3.1.24 
Patients are excluded if they have New York Heart Association 
(NYHA) Grade II or greater congestive heart failure. 
3.1.25 
Patients are excluded if they have a history of myocardial infarction or 
unstable angina within 6 months prior to randomization. 
3.1.26 
Patients are excluded if they have a history of stroke or transient 
ischemic attack within 6 months prior to randomization. 
3.1.27 
Patients are excluded if they have known significant vascular disease 
(e.g., aortic aneurysm, aortic dissection). 
3.1.28 
Patients are excluded if they have symptomatic peripheral vascular 
disease.  
3.1.29 
Patients are excluded if they have evidence of bleeding diathesis or 
coagulopathy. 
3.1.30 
Patients are excluded if they have had a surgical procedure or a 
significant traumatic injury within 28 days prior to randomization. 
Rev. 5/15 
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3.1.31 
Patients are excluded if they have had a biopsy or other minor 
surgical procedure, excluding placement of a vascular access device, 
within 7 days prior to randomization. 
3.1.32 
Patients are excluded if they have history of abdominal fistula, 
gastrointestinal perforation, or intra-abdominal abscess within 6 
months prior to randomization. 
3.1.33 
Patients are excluded if they have a non-healing wound or ulcer. 
3.1.34 
Patients are excluded if they have proteinuria at screening as 
demonstrated by either: 
• 
Urine dipstick for proteinuria ≥ 2+ (patients discovered to have  
≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo 
a 24 hour urine collection and must demonstrate ≤ 1g of protein in 
24 hours to be eligible) OR 
• 
Urine protein: creatinine (UPC) ratio ≥ 1.0 at screening. For UPC 
ratio > 1, a 24-hour urine protein should be obtained and the level 
should be <1000mg. 
NOTE: Urine protein should be screened by urine analysis for 
Urine Protein Creatinine (UPC) ratio. UPC ratio of spot urine is an 
estimation of the 24 hour urine protein excretion. A UPC ratio of 1 
is roughly equivalent to a 24-hour urine protein of 1 g. UPC ratio is 
calculated using one of the following formulas: 
[urine protein]/[urine creatinine] – if both protein and creatinine are 
reported in mg/dL 
[(urine protein) x 0.088]/[urine creatinine] – if urine creatinine is 
reported in mmol/L 
3.1.35 
Patients must not have known hypersensitivity to Chinese hamster 
ovary cell products or other recombinant human antibodies. 
3.1.36 
Patients are excluded if they have a history of hemoptysis (bright red 
blood of 1/2 teaspoon or more per episode) within 3 months prior to 
randomization. 
3.1.37 
Patients are excluded if they have current, ongoing treatment with full-
dose warfarin or its equivalent (i.e., unfractionated and/or low 
molecular weight heparin). Subjects should have not taken full-dose 
warfarin or equivalent for at least 2 weeks prior to randomization. 
3.1.38 
Patients are excluded if they have current or recent (within 10 days of 
enrollment) use of aspirin (> 325 mg/day) or chronic use of other 
NSAIDs. 
3.1.39 
Patients are excluded if they use medications that inhibit platelet 
function (e.g., dipryidamolde, epoprostenol, epitfibatide, clopidogrel, 
cilostazol, abciximab, ticlopidine, and ibuprofen and related 
compounds) unless subject has been off treatment for at least 2 
weeks prior to randomization. 
3.1.40 
Patients are excluded if they have known involvement of melanoma 
within the gastrointestinal tract. 
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3.1.41 
Patients are excluded for any non-oncology vaccine therapy used for 
prevention of infectious diseases (for up to 1 month before or after 
any dose of ipilimumab). 
3.1.42 
Women of childbearing potential and sexually active males must 
agree to practice abstinence or use an accepted and effective method 
of contraception. 
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4. 
Registration Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
Registration requires the submission of: 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator registration.htm>.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate registration.htm>.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data 
to make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to: an active Federal Wide Assurance (FWA) number, an active roster 
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affiliation with the Lead Network or a participating organization, a valid IRB approval, and 
compliance with all protocol specific requirements. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study 
are not required to submit IRB approval documentation to the CTSU Regulatory Office. 
For sites using the CIRB, IRB approval information is received from the CIRB and 
applied to the RSS in an automated process. Signatory Institutions must submit a Study 
Specific Worksheet for Local Context (SSW) to the CIRB via IRBManager to indicate 
their intent to open the study locally.  The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office.  In order for the SSW approval to be 
processed, the Signatory Institution must inform the CTSU which CIRB-approved 
institutions aligned with the Signatory Institution are participating in the study.. 
Downloading Site Registration Documents:   
Site registration forms may be downloaded from the E3612 protocol page located on the 
CTSU members’ website.  
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol E3612 
• 
Click on the Site Registration Documents link 
Requirements for E3612 site registration: 
• 
CTSU Transmittal Sheet (optional) 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted ) 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office, where they 
will be entered and tracked in the CTSU RSS. 
ONLINE: www.ctsu.org  (members’ section)  Regulatory Submission Portal 
EMAIL: CTSURegulatory@ctsu.coccg.org (for regulatory document submission 
only) 
FAX: 215-569-0206 
MAIL: CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Required Protocol Specific Regulatory Documents 
1. CTSU Regulatory Transmittal Form. 
2. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning 
risks or alternative procedures contained in the sample informed 
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consent document must be justified in writing by the investigator 
and approved by the IRB. 
3. A. CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU 
website. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements as outlined by the 
Lead Network. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status 
with the NCI or their affiliated networks. 
Patient Enrollment: 
Patients must not start protocol treatment prior to registration. 
Treatment should start within seven working days after registration. 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at <https://eapps-
ctep.nci.nih.gov/iam/index.jsp>) and a ‘Registrar’ role on either the LPO or participating 
organization roster. 
All site staff (Lead Group and CTSU Sites) will use OPEN to enroll patients to this study. 
It is integrated with the CTSU Enterprise System for regulatory and roster data. OPEN 
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can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’ 
side of the website at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes. 
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com.  
The following information will be requested: 
4.1 
Protocol Number  
4.2 
Investigator Identification  
• 
Institution and affiliate name (Institution CTEP ID) 
• 
Investigator’s name (NCI number) 
4.3 
Patient Identification  
• 
Patient’s initials(first and last)  
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence  
4.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3.1.  
4.5 
Stratification Factors 
• 
Prior systemic therapy for unresectable stage III or IV melanoma (no vs. yes) 
• 
BRAF mutation status (wild type vs. mutation) 
4.6 
Additional Requirements  
4.6.1 
Patients must provide a signed and dated, written informed consent 
form. 
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NOTE: 
Copies of the consent are not collected by the ECOG-ACRIN 
Operations Office - Boston. 
4.6.2 
Pathological samples are required to be submitted for central 
diagnostic review (mandatory) and for future undefined research (per 
patient consent) as indicated in Section 10. 
4.6.3 
Biological samples are to be submitted for future undefined research 
as outlined in Section 10. 
4.6.4 
Data collection for this study will be done exclusively through the 
Medidata Rave clinical data management system.  Access to the trial 
in Rave is granted through the iMedidata application to all persons 
with the appropriate roles assigned in Regulatory Support System 
(RSS).  To access Rave via iMedidata, the site user must have an 
active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and the appropriate Rave role (Rave 
CRA, Read-Only, Site Investigator) on either the LPO or participating 
organization roster at the enrolling site. 
Upon initial site registration approval for the study in RSS, all persons 
with Rave roles assigned on the appropriate roster will be sent study 
invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata page. Please 
note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. 
Trainings will be listed in the upper right pane of the iMedidata screen. 
Users that have not previously activated their iMedidata/Rave 
accounts at the time of initial site registration approval for the study in 
RSS will also receive a separate invitation from iMedidata to activate 
their account.  Account activation instructions are located on the 
CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance).  
Additional information on iMedidata/Rave is available on the CTSU 
members’ website under the Rave tab at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.7 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
Rave according to the schedule in the E3612 Forms Completion Guidelines. 
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5. 
Treatment Plan 
5.1 
Administration Schedule 
Patients will be randomized to either Arm A or Arm B. 
Patients must receive their first induction dose within seven working days of 
randomization. 
The total dose must be calculated using the most recent subject actual weight 
(obtained within 3 days of the dosing visit, and prior to the infusion). The dose will 
not be recalculated unless the patient has ±10% weight change for both agents. 
5.1.1 
Arm A 
Induction Therapy: Cycles 1-4 
Ipilimumab 3 mg/kg IV Day 1 Cycles 1-4  
Maintenance Therapy: Cycles 5 and higher 
Ipilimumab 3 mg/kg IV Day 1 of every 4th cycle (12 weeks) starting 
Cycle 8* 
*Maintenance until excessive toxicity, progression or 
determination that treatment is no longer clinically beneficial. 
Cycle=21 days 
5.1.2 
Arm B 
Induction Therapy: Cycles 1-4 
Ipilimumab 3 mg/kg IV Day 1 Cycles 1-4 
plus 
Bevacizumab 15 mg/kg IV Day 1 Cycles 1-4 
Maintenance Therapy: Cycles 5 and higher 
Ipilimumab 3 mg/kg IV Day 1 of every 4th cycle (12 weeks) starting 
Cycle 8* 
plus 
Bevacizumab 15 mg/kg IV Day 1 of each cycle starting Cycle 5*  
* Maintenance until excessive toxicity, progression or 
determination that treatment is no longer clinically beneficial. 
Patients will receive ipilimumab first followed by bevacizumab. 
There is no planned delay between the ipilimumab and 
bevacizumab administration. If it is found that pre-medication is 
necessary prior to bevacizumab administration, then a delay is 
allowed.  
Cycle=21 days 
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5.1.3 
Ipilimumab Dose Calculation 
Each patient will receive ipilimumab 3 mg/kg IV over 90 minutes every 
21 days x 4, followed by 3 mg/kg IV over 90 minutes every 12 weeks 
during maintenance. 
Ipilimumab infusions should be given over 90 minutes (not bolus or IV 
push). 
Calculate Total Dose as follows: 
Patient body weight in kg x 3 mg/kg = total dose in mg 
Calculate Ipilimumab Infusion Volume as follows: 
Total dose in mg ÷ 5 mg/mL = ipilimumab volume in mL 
Ipilimumab should be diluted with 0.9% Sodium Chloride Injection, 
USP or 5% Dextrose Injection, USP to prepare a diluted solution with 
a final concentration ranging from 1 mg/mL to 2 mg/mL.  
Calculate Total Infusion Volume and Rate of Infusion as follows: 
Total infusion volume in mL ÷ 90 minutes = rate of infusion in mL/min. 
For example, a patient weighing 114 kg (250 lb) would be 
administered 342 mg of ipilimumab (114 kg x 3 mg/kg = 342 mg) with 
an infusion volume of 69 mL (342 mg ÷ 5 mg/mL = 69 mL) + 273 mL 
0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP 
at a rate of approximately 3.8 mL/min (342 mL ÷ 90 minutes) over 90 
minutes.  
5.1.4 
Bevacizumab Dose Calculation 
Each patient in Arm B will receive bevacizumab 15 mg/kg IV over 90 
minutes (first dose). Subsequent doses may be administered over 60 
minutes if tolerated. If tolerated at 60 minutes, may administer over 30 
minutes. Bevacizumab will be given following ipilimumab every 21 
days (3 weeks) throughout induction and maintenance phases. 
Bevacizumab infusions should not be given bolus or IV push.  Pre-
medications may be given prior to bevacizumab according to 
institutional standards. 
Calculate Total Dose as follows: 
Patient body weight in kg x 15 mg/kg = total dose in mg 
Calculate Bevacizumab Infusion Volume as follows: 
Total dose in mg ÷ 25 mg/mL = bevacizumab volume in mL 
Bevacizumab should be diluted in a 100 mL 0.9% Sodium Chloride 
Injection, USP. 
Calculate Rate of Infusion as follows: 
Total infusion volume in mL ÷ 90 minutes = rate of infusion in mL/min 
(first dose). 
Total infusion volume in mL ÷ 60 minutes = rate of infusion in mL/min 
(second dose). 
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Total infusion volume in mL ÷ 30 minutes = rate of infusion in mL/min 
(subsequent doses). 
For example, a patient weighing 114 kg (250 lb) would be 
administered 1710 mg bevacizumab (114 kg x 15 mg/kg = 1710 mg) 
with an infusion volume of 68.4 mL (1710 mg ÷ 25 mg/mL = 68.4 mL) 
+ 31.6 mL 0.9% Sodium Chloride Injection, USP at a rate of 
approximately 1.1 mL/min over 90 minutes or 1.7 mL/min over 60 
minutes or 3.3 mL/min over 30 minutes. 
5.2 
Adverse Event Reporting Requirements 
 NOTE: 
Effective April 1, 2018 all expedited adverse event reporting 
done via CTEP-AERS will use CTCAE version 5.0 terminology and grading.  
Routine adverse event reporting and dose modifications guidelines for this 
study will continue to be based on CTCAE version 4.0 terminology and 
grading. 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents.  
• 
Routine reporting:  Adverse events are reported in a routine 
manner at scheduled times during a trial using Medidata Rave.   
• 
Expedited reporting:  In addition to routine reporting, certain 
adverse events must be reported in an expedited manner via 
CTEP-AERS for timely monitoring of patient safety and care. The 
following sections provide information and instructions regarding 
expedited adverse event reporting. 
5.2.2 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
• 
Attribution:  An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
Unlikely 
The AE is doubtfully related to treatment. 
Possible 
The AE may be related to treatment. 
Probable 
The AE is likely related to treatment. 
Definite 
The AE is clearly related to treatment. 
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• 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List):  An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND.  Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports.   
• 
CTCAE:  The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting.  A grade (severity) is provided for each AE term.  
• 
Hospitalization (or prolongation of hospitalization):  For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours.   
• 
Life Threatening Adverse Event:  Any AE that places the 
subject at immediate risk of death from the AE as it occurred.   
• 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes:  
• 
Death  
• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours).  
• 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
• 
A congenital anomaly/birth defect.  
• 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
considered a serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
• 
SPEER (Specific Protocol Exceptions to Expedited 
Reporting):  A subset of AEs within the CAEPR that contains list 
of events that are protocol specific exceptions to expedited 
reporting.  If an AE meets the reporting requirements of the 
protocol, and it is listed on the SPEER, it should ONLY be 
reported via CTEP-AERS if the grade being reported exceeds the 
grade listed in the parentheses next to the event.  If the protocol 
uses multiple investigational agents and has an AE listed on 
multiple SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
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In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (617-632-3610) and 
• 
the NCI (301-897-7497)  
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the NCI (301- 230-0159) in the same 
timeframe.  
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.4 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both 
• 
the seriousness of the event 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
• 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
• 
when the adverse event occurred (within 30 days of the last 
administration of investigational agent vs. ≥ 30 days after the last 
administration of investigational agent)  
• 
the relationship to the study treatment (attribution) 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol E3612 and outline 
the specific expedited adverse event reporting requirements for 
study E3612.   
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5.2.5.2 
Guidelines for adverse events OCCURRING GREATER 
THAN 30 DAYS after the last administration of the 
investigational agent(s). 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.2.6, AND has an 
attribution of possible, probably or definite, the following 
events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
• 
All Grade 4 and Grade 5 AEs  
NOTE: 
Any death occurring greater than 30 days after 
the last dose of investigational agent with an 
attribution of possible, probable or definite must 
be reported via CTEP-AERS even if the patient 
is off study. 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization 
• 
Grade 3 adverse events   
5.2.6 
Expedited Reporting Requirements for Arms A and B on protocol 
E3612 
Investigational Agents:  Ipilimumab and Bevacizumab 
Commercial Agents: None 
Late Phase 2 and Phase 3 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention.1 
NOTE: 
Footnote 1 instructs how to report serious adverse events 
that occur more than 30 days after the last administration 
of investigational agent/intervention. 
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5.2.7 
Additional instructions, requirements and exceptions for protocol 
E3612 
Additional Instructions: 
• 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, 
or birth defect events via CTEP-AERS, please contact the 
AEMD Help Desk at 301-897-7497 or aemd@tech-res.com. 
This will need to be discussed on a case-by-case basis. 
• 
Reporting a death on study:  A death occurring while on study 
or within 30 days of the last dose of treatment requires both 
routine and expedited reporting, regardless of causality.  
Attribution to treatment or other cause must be provided.  
NOTE: 
A death due to progressive disease should be 
reported as a Grade 5 “Disease progression” under 
the System Organ Class (SOC) “General disorder 
and administration site conditions”.  Evidence that 
the death was a manifestation of underlying disease 
(e.g. radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with 
a disease process) should be submitted. 
 
E3612 specific expedited reporting requirements: 
• 
Pregnancy:  
Pregnancies and suspected pregnancies (including a 
positive/inconclusive pregnancy test regardless of age or 
disease state) occurring while the subject is on Ipilimumab or 
Bevacizumab, or within 28 days of the subject’s last dose of 
Ipilimumab or Bevacizumab, are considered immediately 
reportable events. The pregnancy, suspected pregnancy, or 
positive/inconclusive pregnancy test must be reported via 
CTEP-AERS within 24 hours of the Investigator’s 
knowledge.  Please refer to Appendix V for detailed instructions 
on how to report the occurrence of a pregnancy as well as the 
outcome of all pregnancies. 
• 
Immune Related Adverse Events (IRAEs): Any grade 3 or 
higher immune related adverse events (see Section 5.4.1.5 for 
definitions) must be reported via CTEP-AERS within 10 
calendar days of learning of the event, regardless of whether 
hospitalization is required. If available, please submit any 
supporting data as well (ie: autoimmune serology tests or biopsy 
reports). 
NOTE: 
In order to appropriately report these events to 
regulatory agencies, please be sure to state that the 
event being reported is an IRAE in the ‘Description of 
Event’ section of the CTEP-AERS report. 
Rev. 8/14 
Rev. Add8 
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• 
Vasculitis: Any grade 3 or higher vasculitis must be reported 
via CTEP-AERS within 10 calendar days of learning of the 
event, regardless of whether hospitalization is required. 
• 
Bowel Perforation:  Any grade 3 or higher bowel perforation 
must be reported via CTEP-AERS within 10 calendar days of 
learning of the event, regardless of whether hospitalization is 
required. 
 
 
 
E3612 specific expedited reporting exceptions: 
The adverse events listed below do not require expedited reporting 
via CTEP-AERS: 
If an AE meets the reporting requirements of the protocol, and it is 
listed on the SPEER, it should ONLY be reported via CTEP-AERS 
if the grade being reported exceeds the grade listed in the 
parentheses next to the event. 
NOTE: Since Arm B is a combination protocol arm using multiple 
investigational agents, if the AE being reported appears on 
both the Ipilimumab AND Bevacizumab SPEERs, use the 
lower of the grades to determine if expedited reporting is 
required. 
5.2.8 
Other recipients of adverse event reports and supplemental data 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to the FDA. Any additional written AE information 
requested by ECOG-ACRIN MUST be submitted to BOTH the NCI 
and ECOG-ACRIN. 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.2.9 
Reporting Second Primary Cancers 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
Rev. 5/15 
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2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form. 
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hypophysitis/hypopituitarism, and adrenal insufficiency), ocular manifestations (e.g., uveitis, iritis, 
conjunctivitis, blepharitis, and episcleritis), sarcoid granuloma, myasthenia gravis, polymyositis, and 
Guillain-Barre syndrome.  The majority of these reactions manifested early during treatment; however, a 
minority occurred weeks to months after discontinuation of ipilimumab especially with the initiation of 
additional treatments. 
 
3Late bowel perforations have been noted in patients receiving MDX-010 (ipilimumab) in association with 
subsequent IL-2 therapy. 
 
4Complications including hyperacute graft-versus-host disease (GVHD), may occur in patients receving 
allo stem cell transplant (SCT) after receiving Ipilimumab (MDX-010).  These complications may occur 
despite intervening therapy between receiving Ipilimumab (MDX-010) and allo-SCT. 
 
5In rare cases diplopia (double vision) has occurred as a result of muscle weakness (Myasthenia gravis). 
 
6Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal 
hemorrhage, 
Oral 
hemorrhage, 
Pancreatic 
hemorrhage, 
Rectal 
hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
7Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
 
Adverse events reported on Ipilimumab (MDX-010) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that Ipilimumab (MDX-010) caused the 
adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system disorders - 
Other (pure red cell aplasia)2; Febrile neutropenia 
CARDIAC DISORDERS - Conduction disorder; Restrictive cardiomyopathy 
EYE DISORDERS - Extraocular muscle paresis5; Eye disorders - Other (retinal pigment changes) 
GASTROINTESTINAL DISORDERS - Colonic ulcer; Dyspepsia; Dysphagia; Gastrointestinal disorders - 
Other (gastroenteritis); Gastrointestinal hemorrhage6; Proctitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; Non-cardiac 
chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure2 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INFECTIONS AND INFESTATIONS - Infection7 
INVESTIGATIONS - Creatinine increased; Investigations - Other (rheumatoid factor); Lipase increased; 
Platelet count decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Joint range of motion 
decreased; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysphasia; Ischemia cerebrovascular; Seizure 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Cough; Dyspnea; 
Laryngospasm 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Skin 
hypopigmentation 
VASCULAR DISORDERS - Flushing; Hypertension; Vascular disorders - Other (temporal arteritis) 
 
 
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7 Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation. 
8 Gastrointestinal ulcer may include: Duodenal ulcer, Esophageal ulcer, Gastric ulcer, and other sites 
under the GASTROINTESTINAL DISORDERS SOC. 
9Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
10 Anastomotic leak may include Gastric anastomotic leak; Gastrointestinal anastomotic leak; Large 
intestinal anastomotic leak; Rectal anastomotic leak; Small intestinal anastomotic leak; Urostomy leak; 
Vaginal anastomotic leak. 
11 There have been reports of non-mandibular osteonecrosis (avascular necrosis) in patients under the 
age of 18 treated with bevacizumab. 
12 Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth plates. 
13 Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients in association with 
bevacizumab treatment, the majority of whom had received prior or concomitant treatment with i.v. 
bisphosphonates. 
14 Increased rate of peripheral sensory neuropathy has been observed in trials combining bevacizumab 
and chemotherapy compared to chemotherapy alone.  
15 Ovarian failure, defined as amenorrhea lasting 3 or more months with follicle-stimulating hormone 
(FSH) elevation (≥30 mIU/mL), was increased in patients receiving adjuvant bevacizumab plus 
mFOLFOX compared to mFOLFOX alone (34% vs. 2%).  After discontinuation of bevacizumab, 
resumption of menses and an FSH level <30 mIU/mL was demonstrated in 22% (7/32) of these women.  
Long term effects of bevacizumab exposure on fertility are unknown. 
16 Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, heart 
attack, and stroke. 
Adverse events reported on bevacizumab (rhuMAb VEGF) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that bevacizumab 
(rhuMAb VEGF) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Disseminated 
intravascular coagulation; Hemolysis; Thrombotic thrombocytopenic purpura 
CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block first degree; 
Cardiac arrest; Myocarditis; Pericardial effusion; Restrictive cardiomyopathy; Right ventricular 
dysfunction 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (tympanic 
membrane perforation); Hearing impaired; Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye 
disorders - Other (blindness); Eye disorders - Other (conjunctival hemorrhage); Eye disorders - 
Other (corneal epithelial defect); Eye disorders - Other (ischemic CRVO); Eye disorders - Other 
(macular pucker); Eye disorders - Other (transient increased IOP > or =30 mm Hg); Eye pain; 
Floaters; Keratitis; Optic nerve disorder; Photophobia; Retinal detachment; Retinal tear; 
Retinopathy; Vitreous hemorrhage; Watering eyes 
GASTROINTESTINAL DISORDERS - Ascites; Cheilitis; Colonic stenosis; Dry mouth; 
Dysphagia; Enterocolitis; Esophageal pain; Esophageal stenosis; Flatulence; Gastrointestinal 
disorders - Other (peritonitis); Oral pain; Pancreatitis; Proctitis; Rectal mucositis; Rectal 
stenosis; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema 
face; Edema limbs; Edema trunk; Facial pain; Fever; Flu like symptoms; Gait disturbance; 
Injection site reaction; Localized edema; Multi-organ failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder necrosis; Gallbladder obstruction; 
Hepatic failure; Hepatic necrosis 
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INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Bruising; Burn; 
Dermatitis radiation; Fracture 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood antidiuretic 
hormone abnormal; CD4 lymphocytes decreased; CPK increased; Carbon monoxide diffusing 
capacity decreased; Electrocardiogram QT corrected interval prolonged; Forced expiratory 
volume decreased; GGT increased; INR increased; Lipase increased; Lymphocyte count 
decreased; Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; 
Hypocalcemia; Hypomagnesemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone 
pain; Chest wall pain; Fibrosis deep connective tissue; Head soft tissue necrosis; Joint effusion; 
Muscle weakness lower limb; Muscle weakness upper limb; Musculoskeletal and connective 
tissue disorder - Other (polymyalgia rheumatica); Neck pain; Osteonecrosis; Pain in extremity; 
Pelvic soft tissue necrosis; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Arachnoiditis; Ataxia; Central nervous system necrosis; 
Cerebrospinal fluid leakage; Cognitive disturbance; Depressed level of consciousness; 
Dysesthesia; Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; Facial nerve 
disorder; Hydrocephalus; Leukoencephalopathy; Memory impairment; Myasthenia gravis; 
Nervous system disorders - Other (increased intracranial pressure); Paresthesia; Peripheral 
motor neuropathy; Pyramidal tract syndrome; Seizure; Somnolence; Tremor; Vasovagal 
reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Libido 
decreased; Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis 
noninfective; Dysuria; Renal and urinary disorders - Other (ureterolithiasis); Renal hemorrhage; 
Urinary frequency; Urinary incontinence; Urinary retention; Urinary tract obstruction; Urinary 
tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Erectile dysfunction; 
Irregular menstruation; Pelvic pain; Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Atelectasis; Hypoxia; Nasal congestion; Pulmonary fibrosis; Respiratory failure; 
Respiratory, thoracic and mediastinal disorders - Other (dry nares); Respiratory, thoracic and 
mediastinal disorders - Other (pulmonary infarction) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; Nail loss; Pain 
of skin; Photosensitivity; Purpura; Rash acneiform; Skin and subcutaneous tissue disorders - 
Other (diabetic foot ulcer); Skin and subcutaneous tissue disorders - Other (skin breakdown/ 
decubitus ulcer); Skin hyperpigmentation; Skin induration; Skin ulceration; Stevens-Johnson 
syndrome 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Lymphocele; Phlebitis; 
Vasculitis 
NOTE: 
Bevacizumab (rhuMAb VEGF) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, 
or the combination may result in events never previously associated with either 
agent. 
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ECOG-ACRIN 
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69 
5.4 
Dose Modifications  
All toxicity grades below are described using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
5.4.1 
Ipilimumab Dose Modification and Toxicity Management 
5.4.1.1 
Dose and Schedule Modifications for Ipilimumab  
Patients may develop study drug-related toxicities that may 
require dose delay, skipping doses or dose 
discontinuation. Treatment modifications will be made 
based on specified safety criteria. Patients will delay, skip 
or discontinue treatment with ipilimumab if they experience 
at least one adverse event, specified below, considered by 
the investigator to be definitely, probably, or possibly 
related to ipilimumab treatment. There will be no dose 
reductions. The following criteria will be used to determine 
dosing delay, restarting doses, or discontinuing ipilimumab.  
NOTE: 
During induction, if ipilimumab is held, 
bevacizumab should also be held to maintain 
concurrent administration. 
5.4.1.1.1 
Criteria to delay one dose of ipilimumab 
Delay ipilimumab dosing for the following 
treatment related adverse events: 
• 
Any > Grade 2 non-skin related adverse 
event (including Immune-Related 
Adverse Events (IRAEs), except for 
laboratory abnormalities. 
• 
Any ≥ Grade 3 skin related adverse 
events regardless of causality (including 
Immune-Related Adverse Events 
(IRAEs). Resolution to grade 1 or better 
required before continuing treatment. 
• 
Further with regards to skin rashes, all 
study drugs should be held as well as 
any other agents possibly associated 
with toxic epidermal necrolysis (TEN) or 
Stevens-Johnson Syndrome (SJS) until 
an evaluation has been done.  This 
would include any patient with possible 
erythema multiforme (EM) or SJS and 
for any grade 2 purpuric or bullous rash. 
• 
Any ≥ 2 laboratory abnormality believed 
to be related to study treatment. 
Rev. 8/14 
Rev. 8/14 
Rev. 8/14 
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• 
All study drugs should be held for 
suspected colitis until an appropriate 
evaluation has been completed. Please 
refer to Appendix VIII for GI Toxicity 
Management Algorithm. 
• 
Patients who develop hypophysitis may 
continue treatment once they are on a 
stable replacement regimen. Please 
refer to Appendix XII Neurological 
Toxicity Management Algorithm. 
• 
Patients with hepatitis may continue 
once their liver function tests resolve to 
pretreatment grade.  Please refer to 
Appendix IX Hepatotoxicity 
Management Algorithm for management 
recommendations. 
5.4.1.1.2 
Criteria to resume ipilimumab treatment 
Restarting ipilimumab applies only to grade 
2 events and some grade 3 events as 
excepted (skin rash, aseptic meningitis, 
encephalitis, and thryroiditis).  Restart 
ipilimumab dosing if/when the adverse 
event(s) resolve(s) to ≤ Grade 1 severity or 
returns to baseline within 3 weeks of initial 
dose administration: 
• 
If the adverse event has resolved, 
restart ipilimumab dosing at the next 
scheduled time point per protocol. 
• 
If the adverse event has not resolved in 
the protocol-specified dosing window (3 
weeks [+/- 3 days] during first 4 cycles 
and 12 weeks [+/- 1 week] during 
maintenance phase), the next 
scheduled dose will be omitted. 
• 
If > 1 dose is expected to be skipped, 
the dosing schedule modifications must 
be discussed with the primary 
investigator (or co-primary investigator, 
if the PI is not available) prior to 
implementation. 
• 
Drug may be restarted following any 
grade 2 or greater immune-related 
adverse event after complete resolution 
of ≤ Grade 1 severity or returns to 
baseline. 
• 
Patients with hepatitis, pancreatitis, 
pneumonitis, and colitis  are at risk for 
exacerbation and should resolve to  
Rev. 8/14 
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Grade 0 or grade at baseline before 
retreatment. 
5.4.1.2 
Criteria for permanent discontinuation of ipilimumab 
5.4.1.2.1 
Permanent Discontinuation for Related 
Adverse Events 
Ipilimumab administration must be 
permanently discontinued if any of the 
following Related Adverse Events occurs:  
• 
Any ≥ Grade 2 eye pain or reduction of 
visual acuity that does not respond to 
topical therapy and does not improve to 
≤ Grade 1 severity within 2 weeks of 
starting therapy, OR, requires systemic 
treatment. 
• 
Any ≥ Grade 3 bronchospasm or other 
hypersensitivity reaction. 
• 
Any other ≥ Grade 3 non-skin related 
adverse event with the exception of 
events listed in Section 5.4.1.2.3. 
• 
Any adverse event, laboratory 
abnormality or intercurrent illness which, 
in the judgment of the investigator, 
presents a substantial clinical risk to the 
patient with continued dosing. 
• 
Grade 3 uveitis 
• 
For all grade 3 or greater immune-
related adverse events, the patient 
should be taken off treatment with the 
exception listed in Section 5.4.1.2.3. 
• 
All patients treated with steroids for 
grade ≥ 3 events should have 
ipilimumab discontinued.  All patients 
treated with steroids for grade ≥ 2 
events should have ipilimumab held until 
resolution to ≤ Grade 1 for at least 2 
weeks following removal of steroid 
treatment. 
• 
New immune related events or 
exacerbation of existing events during 
steroid treatment or taper suggest the 
presence of ongoing immune activation 
and should require permanent 
discontinuation of ipilimumab. 
Rev. 8/14 
Rev. 8/14 
Rev. 8/14 
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5.4.1.2.2 
Skipped Dose Maximum 
A maximum of 1 missed scheduled dose is 
allowed. If more than 1 dose is missed, 
patient must discontinue study treatment. 
5.4.1.2.3 
Exceptions to permanent discontinuation of 
ipilimumab 
Ipilimumab administration may be resumed 
in the following cases:  
• 
Potentially reversible inflammation (< 
Grade 4), attributable to a local anti-
tumor reaction and a potential 
therapeutic response. This includes 
inflammatory reactions at sites of tumor 
resections or in draining lymph nodes, 
or at sites suspicious for, but not 
diagnostic of metastasis. 
• 
Hospitalization for ≤ Grade 2 adverse 
events where the primary reason for 
hospitalization is to expedite the clinical 
work-up. 
• 
Patients with the following conditions 
where in the investigator’s opinion 
continuing study drug administration is 
justified: 
• 
Ocular toxicity that has responded to 
topical therapy. 
• 
Endocrinopathies where clinical 
symptoms are controlled with 
appropriate hormone replacement 
therapy. Note: Ipilimumab may not 
be restarted while the patient is 
being treated with systemic 
corticosteroids except for patients on 
stable doses of hormone 
replacement therapy such as 
hydrocortisone. 
• 
Patients with thyroiditis hypophysitis 
who are stable as above may be 
restarted with replacement 
hormones including thyroid hormone 
and physiologic doses only of 
corticosteroids. 
5.4.1.3 
Treatment of Infusion Reactions Associated with 
Ipilimumab 
Since ipilimumab contains only human protein sequences, 
it is less likely that any allergic reaction will be seen in 
patients. However, it is possible that infusion of ipilimumab 
Rev. 8/14 
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will induce a cytokine release syndrome that could be 
evidenced by fever, chills, rigors, rash, pruritis, 
hypotension, hypertension, bronchospasm, or other 
symptoms. No prophylactic pre medication will be given 
unless indicated by previous experience in an individual 
patient. Reactions should be treated based upon the 
following recommendations. 
For mild symptoms (e.g., localized cutaneous reactions 
such as mild pruritis, flushing, rash): 
• 
Decrease the rate of infusion by half until recovery from 
symptoms, remain at bedside and monitor patient. 
• 
Complete the ipilimumab infusion at the initial planned 
rate. 
• 
Diphenhydramine 50 mg IV may be administered at the 
discretion of the treating physician and patients may 
receive additional doses with close monitoring. 
• 
Premedication with diphenhydramine may be given at 
the discretion of the investigator for subsequent doses 
of ipilimumab. 
For moderate symptoms (any symptom not listed above 
[mild symptoms] or below [severe symptoms] such as 
generalized pruritis, flushing, rash, dyspnea, hypotension 
with systolic BP < 80 mmHg): 
• 
Interrupt ipilimumab. 
• 
Administer diphenhydramine 50 mg IV. 
• 
Monitor patient closely until resolution of symptoms. 
• 
Corticosteroids may abrogate any beneficial 
immunologic effect, but may be administered at the 
discretion of the treating physician. 
Resume ipilimumab infusion after recovery of symptoms. 
At the discretion of the treating physician, ipilimumab 
infusion may be resumed at one half the initial infusion 
rate, then increased incrementally to the initial infusion 
rate. 
• 
If symptoms develop after resumption of the infusion, 
the infusion should be discontinued and no additional 
ipilimumab should be administered that day. 
• 
The next dose of ipilimumab will be administered at its 
next scheduled time and may be given with pre-
medication (diphenhydramine and acetaminophen) and 
careful monitoring, following the same treatment 
guidelines outlined above. 
• 
At the discretion of the treating physician additional oral 
or IV antihistamine may be administered prior to dosing 
with ipilimumab. 
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For severe symptoms (e.g., any reaction such as 
bronchospasm, generalized urticaria, systolic blood 
pressure < 80 mm Hg, or angioedema): 
• 
Immediately discontinue infusion of ipilimumab, and 
disconnect infusion tubing from the subject. 
• 
Consider bronchodilators, epinephrine 1 mg IV or 
subcutaneously, and/or diphenhydramine 50 mg IV, 
with methylprednisolone 100 mg IV, as needed. 
• 
Patients should be monitored until the investigator is 
comfortable that the symptoms will not recur. 
• 
No further ipilimumab will be administered. 
In case of late-occurring hypersensitivity symptoms (e.g., 
appearance within one week after treatment of a localized 
or generalized pruritis), symptomatic treatment may be 
given (e.g., oral antihistamine, or corticosteroids). 
5.4.1.4 
Treatment of Ipilimumab-Related Isolated Drug Fever 
In the event of isolated drug fever, the investigator must 
use clinical judgment to determine if the fever is related to 
the ipilimumab or to an infectious etiology. If a patient 
experiences isolated drug fever, for the next dose, pre-
treatment with acetaminophen or non-steroidal anti-
inflammatory agent (investigator discretion) should be 
instituted and a repeated antipyretic dose at 6 and 12 
hours after ipilimumab infusion, should be administered. 
The infusion rate will remain unchanged for future doses. If 
a patient experiences recurrent isolated drug fever 
following premedication and post dosing with an 
appropriate antipyretic, the infusion rate for subsequent 
dosing should be decreased to 50% of the previous rate. If 
fever recurs following infusion rate change, the investigator 
should assess the patient’s level of discomfort with the 
event and use clinical judgment to determine if the patient 
should receive further ipilimumab. 
5.4.1.5 
Immune-Related Adverse Events (IRAE’s) 
5.4.1.5.1 
Definition of Immune-Related Adverse 
Events (IRAE’s) 
Blocking CTLA 4 function may permit the 
emergence of auto-reactive T cells and 
resultant clinical autoimmunity. Rash/vitiligo, 
diarrhea/colitis, uveitis/episcleritis, hepatitis, 
and hypopituitarism were noted in previous 
ipilimumab studies. These drug-related 
events are presumptive immune-related 
adverse events, now termed IRAEs. 
For the purposes of this study, an IRAE is 
defined as an AE of unknown etiology 
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ECOG-ACRIN 
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associated with drug exposure and 
consistent with an immune phenomenon. 
Efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin or 
other etiologic causes prior to labeling an 
AE an IRAE. Serological, immunological, 
and histological (biopsy) data should be 
used to support the diagnosis of an 
immune-mediated toxicity. Suspected 
IRAEs must be documented on an AE or 
SAE form. 
5.4.1.5.2 
Monitoring and Treatment of Immune-
Related Adverse Events (IRAE’s) 
Patients should be informed of and carefully 
monitored for evidence of clinically 
significant systemic IRAE (e.g., systemic 
lupus erythematosus-like diseases) or organ 
specific IRAE (e.g., rash, colitis, uveitis, 
hepatitis or thyroid disease). If an IRAE is 
noted, appropriate work-up (including 
biopsy if possible) should be performed, and 
steroid therapy may be considered if 
clinically necessary.  
It is unknown if systemic corticosteroid 
therapy has an attenuating effect on 
ipilimumab activity. However, clinical anti-
tumor responses have been maintained in 
patients treated with corticosteroids and 
discontinued from ipilimumab. If utilized, 
corticosteroid therapy should be 
individualized for each patient. Prior 
experience suggests that colitis manifested 
as ≥ Grade 3 diarrhea requires 
corticosteroid treatment.  
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5.4.1.6 
Management/Next Dose for Ipilimumab Cardiac Toxicities 
Cardiac* 
Management/Next Dose for Ipilimumab Cardiac Toxicities 
≤ Grade 1 
Hold dose pending evaluation and observation.**  Evaluate for signs and 
symptoms of CHF, ischemia, arrhythmia or myositis.  Obtain history EKG, 
CK (for concomitant myositis), CK-MB.  Repeat troponin, CK and EKG 2-
3 days.  If troponin and labs normalize may resume therapy.  If labs 
worsen or symptoms develop then treat as below.  Hold pending 
evaluation. 
Grade ≥ 2 with suspected 
myocarditis 
Hold dose.** Admit to hospital. Cardiology consult. Rule out MI and other 
causes of cardiac disease. Cardiac Monitoring. Cardiac Echo. Consider 
cardiac MRI and cardiac biopsy. Initiate high dose methylprednisolone. If 
no improvement within 24 hours, add either infliximab, ATG or tacrolimus. 
Resume therapy if there is a return to baseline and myocarditis is 
excluded or considered unlikely. 
Grade ≥ 2 with confirmed 
myocarditis 
Off protocol therapy. Admit to CCU (Consider transfer to nearest Cardiac 
Transplant Unit). Treat as above.  Consider high dose 
methylprednisolone.  Add ATG or tacrolimus if no improvement.  Off 
treatment. 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated according as “other event”   
Note: The optimal treatment regimen for immune mediated myocarditis has not been established. Since 
this toxicity has caused patient deaths, an aggressive approach is recommended.  
• Drug will be held for grade 2 cardiac dysfunction pending evaluation 
• Drug will be permanently discontinued for grade 3 or 4 cardiac dysfunction and grade 2 events that do 
not recover to baseline or that reoccur 
• Treatment with steroids as clinically indicated 
 
5.4.2 
Bevacizumab Dose Modification and Toxicity Management 
There are no reductions in the bevacizumab dose. If adverse events 
occur that require holding bevacizumab, the dose will remain the 
same once treatment resumes. 
Any toxicities associated or possibly associated with bevacizumab 
treatment should be managed according to standard medical practice. 
Bevacizumab has a terminal half-life of 2 to 3 weeks; therefore, its 
discontinuation results in slow elimination over several months. There 
is no available antidote for bevacizumab.  
Subjects should be assessed clinically for toxicity prior to, during, and 
after each infusion. If unmanageable toxicity occurs because of 
bevacizumab at any time during the study, treatment with 
bevacizumab should be discontinued.  
Infusion Reaction: Infusion of bevacizumab should be interrupted for 
subjects who develop dyspnea or clinically significant hypotension. 
Subjects who experience a NCI CTCAE v. 4.0 Grade 3 or 4 allergic 
reaction / hypersensitivity, adult respiratory distress syndrome, or 
bronchospasm (regardless of grade) will be discontinued from 
bevacizumab treatment. 
Rev. 2/17 
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(including those for common medical conditions) for up to one month pre and 
post dosing with ipilimumab. Concomitant systemic or local anti-cancer 
medications or treatments are prohibited in this study while receiving ipilimumab 
and/or bevacizumab treatments.  
Patients may not use any of the following therapies during the study: 
• 
Any non-study anti-cancer agent (investigational or non-investigational) 
• 
Any other investigational agents 
• 
Any other (non-CA184024 related) CTLA-4 inhibitors or agonists 
• 
CD137 agonists 
• 
Immunosuppressive agents 
• 
Chronic systemic corticosteroids 
• 
Physiologic replacement doses of corticosteroids are permitted if required 
• 
Any non-oncology vaccine therapies used for the prevention of infectious 
diseases (for up to 30 days prior to or after any dose of study drug) 
5.6 
Supportive Care  
5.6.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.6.2 
Please refer to Appendices V-VII for algorithms pertaining to immune 
related adverse events. 
5.7 
Duration of Therapy  
Patients will receive protocol therapy unless: 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the schedule in the 
E3612 Forms Completion Guidelines. 
• 
Patient withdraws consent. 
• 
Excessive or unexpected toxicity (see Section 5.4), pregnancy, change in 
medical condition or noncompliance with the study protocol that in the opinion 
of the investigator, necessitates removal of patient from treatment. 
• 
Progression of disease after 12 weeks of treatment: Patients who progress 
clinically at or before the 12th week of treatment will discontinue protocol 
therapy if other therapy (surgery, radiation, chemotherapy) is needed 
urgently. However, patients who experience progression of disease that does 
not require urgent change in therapy are eligible to receive 24 weeks of 
treatment. See Section 6.1.6. 
5.8 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression, even if non-protocol therapy 
is initiated, and for survival for 5 years from the date of registration. All patients 
must also be followed through completion of all protocol therapy. 
 
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6. 
Measurement of Effect 
6.1 
Antitumor Effect-Solid Tumors-RECIST 
For the purposes of this study, patients should be re-evaluated for response 
every 12 weeks. In addition to a baseline scan, confirmatory scans should also 
be obtained 4 weeks following initial documentation of objective response. 
Response and progression will be evaluated in this study using the international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in RECIST. 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor 
burden at baseline to which subsequent measurements will be compared. All 
baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than four weeks before registration. 
2. Measurable disease is defined by the presence of at least one measurable 
lesion. 
3. All measurements should be recorded in metric notation by use of a ruler or 
calipers.  
4. The same method of assessment and the same technique must be used to 
characterize each identified lesion at baseline and during follow-up.  
6.1.1 
Definitions 
Evaluable for Objective Response 
Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had 
their disease re-evaluated will be considered evaluable for response. 
These patients will have their response classified according to the 
definitions stated below. 
NOTE: 
Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable. 
Evaluable Non-Target Disease Response 
Patients who have lesions present at baseline that are evaluable but 
do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target lesion assessment. The 
response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 
6.1.2 
Disease Parameters 
Measurable Disease 
Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) 
as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm 
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with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
NOTE: 
Tumor lesions that are situated in a previously irradiated 
area might or might not be considered measurable. If the 
investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered 
must be defined in the protocol. 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph 
node must be  
≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm 
short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
NOTE: 
Cystic lesions that meet the criteria for radiographically 
defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured 
reproducibly should be selected.   
A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the 
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sum, then only the short axis is added into the sum. The baseline sum 
of the diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the 
disease. 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence or absence of 
unequivocal progression of each should be noted throughout follow-
up.  
6.1.3 
Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation 
using a ruler or calipers. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment and never more 
than 4 weeks before registration. 
The same method of assessment and the same technique must be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 
mm in diameter as assessed using calipers (e.g., skin nodules). In the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest X-ray 
Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, 
CT is preferable.  
Conventional CT and MRI  
This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue. MRI has excellent contrast, 
spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up must 
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be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases.  
Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
PET-CT 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements. However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET 
portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken 
from one assessment to the next.  If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may 
be used instead of CT in selected instances. 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor Markers 
Tumor markers alone cannot be used to assess response. If markers 
are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin 
Oncol 26:1148-1159, 2008]. In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
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Cytology, Histology 
These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., 
residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 
FDG-PET 
While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning 
to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following 
algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at 
follow-up is generally a sign of PD based on a new lesion. 
However, immunotherapeutic agents such as ipilimumab as 
known to generate a systemic immune response leading to 
enhanced immune cellular infiltration or tumor or lymph nodes. 
Therefore, a positive FDG-PET lesion at follow-up needs to be 
carefully assessed to ensure accurate response assessment and 
a biopsy should be pursued if in doubt.  
No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is generally a sign of PD, but care 
must be taken in assessing the tumor response, as noted in the 
prior paragraph.  If the positive FDG-PET at follow-up is not 
confirmed as a new site of disease on CT, additional follow-up CT  
scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that 
is not progressing on the basis of the anatomic images, this is not 
PD. 
 b. FDG-PET may be used to upgrade a response to a CR in a 
manner similar to a biopsy in cases where a residual radiographic 
abnormality is thought to represent fibrosis or scarring. However, it 
must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
NOTE:  A ‘positive’ FDG-PET scan lesion means one which is 
FDG avid with an uptake greater than twice that of the 
surrounding tissue on the attenuation corrected image. 
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6.1.4 
Response Criteria 
6.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction 
in short axis to < 10 mm. To be assigned a status of 
complete response, changes in tumor measurements must 
be confirmed by a repeat assessment performed no less 
than four weeks after the criteria for response is met. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters. To be assigned a status of partial response, 
changes in tumor measurements must be confirmed by a 
repeat assessment performed no less than four weeks 
after the criteria for response is met. 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm. 
NOTE: 
The appearance of one or more new lesions is 
also considered progression, See Section 
6.1.4.3. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. (Note: a change of 20% or 
more that does not increase the sum of the diameters by 5 
mm or more is coded as stable disease). 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 12 weeks. 
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (< 10 mm short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesions. 
Progressive Disease (PD) 
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Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (see 
Section 6.1.4.3). Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, not a 
single lesion increase. 
When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest 
“increase” in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy. 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
Principal Investigator). 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
A growing lymph node that did not meet the criteria for 
reporting as a measurable or non-measurable lymph node 
at baseline should only be reported as a new lesion (and 
therefore progressive disease) if it:  
a) increases in size to ≥ 15 mm in the short axis, or  
b) there is new pathological confirmation that it is disease 
(regardless of size). 
new effusion or ascites that appears during treatment 
should only be reported as a new lesion (and therefore 
progressive disease) if it has cytological confirmation of 
malignancy. 
6.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
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progression/recurrence or non-protocol therapy (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). The 
patient’s best response assignment will depend on the 
achievement of both measurement and confirmation 
criteria. 
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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target  
Lesions 
New 
Lesions* 
Best Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
 
CR 
Non-CR/Non-PD*** 
No 
PR 
 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not evaluated 
No 
PR 
SD 
Non-PD***/not evaluated 
No 
SD 
Documented at least once 
≥ 12 wks. from study entry 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD** 
Yes or No 
   PD*** 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase. Please refer to the Evaluation of Non-
Target Lesions – Progressive Disease section for further explanation. 
NOTE: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
6.1.4.5 
Confirmation of Response 
To be assigned a status of complete or partial response, 
changes in tumor measurements must be confirmed by 
repeat assessments performed no less than four weeks 
after the criteria for response are first met. 
6.1.4.6 
Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is 
first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date 
that progressive disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as 
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reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 12 weeks. 
6.1.4.7 
Definition of Tumor Response Using irRC 
NOTE: 
This section is for secondary endpoint 
assessment. 
The sum of the products of the two largest diameters of 
lesions (SPD) at tumor assessment using the immune-
related response criteria (irRC) for progressive disease 
incorporates the contribution of new measurable lesions. 
Each net Percentage Change in Tumor Burden per 
assessment using irRC criteria accounts for the size and 
growth kinetics of both old and new lesions as they 
appear. 
6.1.4.7.1 
Definition of Target Lesions Response 
Using irRC 
• 
irComplete Response (irCR): 
Complete disappearance of all target 
lesions. This category encompasses 
exactly the same subjects as “CR” by 
the mWHO criteria. 
• 
irPartial Response (irPR): Decrease, 
relative to baseline, of 50% or greater in 
the sum of the products of the two 
largest perpendicular diameters of all 
target and all new measurable lesions 
(i.e., Percentage Change in Tumor 
Burden). Note: the appearance of new 
measurable lesions is factored into the 
overall tumor burden, but does not 
automatically qualify as progressive 
disease until the SPD increases by > 
25% when compared to SPD at nadir. 
• 
irStable Disease (irSD): Does not meet 
criteria for irCR or irPR, in the absence 
of progressive disease. 
• 
irProgressive Disease (irPD): At least 
25% increase Percentage   Change in 
Tumor Burden (i.e., taking SPD of all 
target lesions and any new lesions) 
when compared to SPD at nadir. 
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6.1.4.7.2 
Definition of Non-Target Lesions Response 
Using irRC 
• 
irComplete Response (irCR): 
Complete disappearance of all non-
target lesions. This category 
encompasses exactly the same subjects 
as “CR” by the mWHO criteria. 
• 
irPartial Response (irPR): Non-target 
lesion(s) are not considered in the 
definition of PR; this term does not 
apply. 
• 
irStable Disease (irSD): Does not meet 
the criteria for irCR or irPD. 
• 
irProgressive Disease (irPD): 
Increases in number or size of non-
target lesion(s) does not constitute 
progressive disease unless/until the 
Percentage Change in Tumor Burden 
increases by 25% (i.e., the SPD at nadir 
of the target lesions increases by the 
required amount). 
6.1.4.8 
Impact of New Lesions on irRC 
New lesions in and by themselves do not qualify as 
progressive disease. However their contribution to total 
tumor burden is included in the SPD which in turn feeds 
into the irRC criteria for tumor response. Therefore, new 
non-measurable lesions will not discontinue any subject 
from the study. 
6.1.4.9 
Definition of Overall Response Using irRC 
Overall response using irRC will be based on these 
criteria: 
• 
Immune-Related Complete Response (irCR): 
Complete disappearance of all tumor lesions (target 
and non-target together with no new 
measurable/unmeasurable lesions) for at least 4 weeks 
from the date of documentation of complete response.  
• 
Immune-Related Partial Response (irPR): The sum 
of the products of the two largest perpendicular 
diameters of all target lesions is measured and 
captured as the SPD baseline. At each subsequent 
tumor assessment, the SPD of the two largest 
perpendicular diameters of all target lesions and of new 
measurable lesions are added together to provide the 
Immune Response Sum of Product Diameters (irSPD). 
A decrease, relative to baseline of the irSPD compared 
to the previous SPD baseline, of 50% or greater is 
considered an immune Partial Response (irPR).  
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• 
Immune-Related Stable Disease (irSD): irSD is 
defined as the failure to meet criteria for immune 
complete response or immune partial response, in the 
absence of progressive disease.  
• 
Immune-Related Progressive Disease (irPD): It is 
recommended in difficult cases to confirm PD by serial 
imaging. Any of the following will constitute progressive 
disease: 
-At least 25% increase in the SPD of all target lesions 
over nadir SPD calculated for the target lesions. 
-At least a 25% increase in the SPD of all target lesions 
and new measurable lesions (irSPD) over the nadir 
SPD calculated for the target lesions. 
Table 3: 
Immune-Related Response Criteria Definitions 
Target 
Lesion 
Definition 
Non-
Target 
Lesion 
Definition 
New 
Measurable 
Lesions 
New 
Unmeasurable 
Lesions 
Percent change in tumor 
burden (including 
measurable new lesions 
when present) 
Overall 
irRC 
Response 
Complete 
Response 
Complete 
Response 
No 
No 
– 100% 
irCR 
Partial 
Response 
Any 
Any 
Any 
≥ – 50% 
irPR 
< – 50% to < + 25% 
irSD 
> +25% 
irPD 
Stable 
Disease 
Any 
Any 
Any 
< – 50% to < + 25% 
irSD 
> + 25% 
irPD 
Progressive 
Disease 
Any 
Any 
Any 
≥ + 25% 
irPD 
6.1.4.10 
Immune-Related Best Overall Response Using irRC 
(irBOR) 
irBOR is the best confirmed irRC overall response over the 
study as a whole, recorded between the date of first dose 
until the last tumor assessment before subsequent therapy 
(except for local palliative radiotherapy for painful bone 
lesions) for the individual subject in the study. For the 
assessment of irBOR, all available assessments per 
subject are considered. 
irCR or irPR determinations included in the irBOR 
assessment must be confirmed by a second (confirmatory) 
evaluation meeting the criteria for response and performed 
no less than 4 weeks after the criteria for response are first 
met. 
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6.1.5 
Response Endpoints 
Ipilimumab is expected to trigger immune-mediated responses, which 
require activation of the immune system prior to the observation of 
clinical responses. Such immune activation may take weeks to 
months to be evident. Some patients may have objective volume 
increase of tumor lesions or other disease parameters (based on 
study indication, ie, hematologic malignancies) within 12 weeks 
following start of ipilimumab dosing. Such patients may not have had 
sufficient time to develop the required immune activation or, in some 
patients, tumor volume or other disease parameter increases may 
represent infiltration of lymphocytes into the original tumor or blood. In 
conventional studies, such tumor volume or relevant laboratory 
parameter increases during the first 12 weeks of the study would 
constitute PD and lead to discontinuation of imaging to detect 
response, thus disregarding the potential for subsequent immune-
mediated clinical response.  
6.1.6 
Additional Criteria to Continue Treatment after Progression 
Patients with tumor volume increase detected or lack of laboratory 
parameter response documentation prior to week 12 but without rapid 
clinical deterioration should continue to be treated with ipilimumab and 
clinically observed with a stringent imaging schedule to allow 
detection of a subsequent tumor response. Patients may continue 
treatment with disease progression per RECIST at the discretion of 
the treating physician and in the absence of a declining performance 
status as long as there is less than 100% increase in tumor burden 
from beginning of treatment to the end of induction and less than 25% 
increase in tumor burden during maintenance ipilimumab following 
induction ipilimumab, inclusive of up to 4 potentially new lesions. 
Patients may continue to be treated in this scenario in the absence for 
the need for additional treatment, including any new CNS lesions that 
require immediate treatment.  This will improve the overall 
assessment of the clinical activity or ipilimumab and more likely 
capture its true potential to induce clinical responses. Tumor 
assessments will be made using RECIST criteria. 
6.1.7 
Survival  
Survival will be measured from the date of entry on study. 
6.1.8 
Time to Progression  
This interval will be measured from the date of entry on the study to 
the appearance of new metastatic lesions or objective tumor 
progression. 
 
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7. 
Study Parameters 
7.1 
Therapeutic Parameters  
1. Prestudy scans should be performed within 4 weeks prior to registration. 
2. All patients must have a pre-dosing weight taken at every visit, as appropriate. 
3. All required pretreatment laboratory studies should be done as outlined in the study calendars in Sections 7.2 and 
7.3 and should be done ≤ 4 weeks before randomization. 
7.2 
Arms A and B: Patients Treated with Ipilimumab alone (Arm A) or Ipilimumab and Bevacizumab (Arm B) 
Rev. 8/14 
Time and Events Schedule 
Screening: 
Within 4 weeks 
prior to 
Randomization 
Induction Phase 
Maintenance Phase 
End of 
TreatmentI 
(+/- 7 days 
Follow 
UpL 
 
Day 1 
Cycle 1 
Day 1 
Cycle 2 
Day 1 
Cycle 3 
Day 1 
Cycle 4 
Day 1 of each 
cycle  
(+/- 7 days) 
Day 1 of every
4th cycle 
(+/- 7 days) 
 
±3 days 
±3 days 
±3 days 
±3 days 
 
Medical HistoryA 
X 
  
  
  
  
  
  
  
  
 
Serum or urine Pregnancy TestB 
X 
X 
X 
X 
X 
  
X 
  
  
 
Physical Exam/ ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight/Vital SignsC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 XH 
 
HIV, HBV, HCVK 
X 
  
  
  
  
  
  
  
  
 
Hematology LabsD 
X 
X 
X 
X 
X 
 X 
 X 
X 
  
 
Chemistry LabsE 
X 
X 
X 
X 
X 
 X 
 X 
X 
  
 
Thyroid Function TestsF 
  
X 
X 
X 
X 
 X 
 X 
X 
  
 
UrinalysisG 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
Ipilimumab Infusion 
  
X 
X 
X 
X 
 
X 
  
  
 
Bevacizumab InfusionJ 
  
X 
X 
X 
X 
X 
  
  
  
 
Adverse Event AssessmentM 
 
X 
X 
X 
X 
X 
X 
X 
X 
Rev. 5/15 
Imaging StudiesN  
X 
 
 
XN 
X 
X 
 
BRAF Mutation StatusP 
X 
 
 
 
 
 
 
 
 
 
Biological Sample Submissions 
See Section 7.3 and 10 
Rev. 2/17 
EKG, echocardiogram 
XQ 
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A Medical history documented during screening should include previous toxicities from prior therapies. If the screening physical is conducted 
within 24 hours of dosing on Day 1, then a single examination may count as both the Screening and pre-dose evaluation. 
B Women of child-bearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to randomization for screening 
purposes and a negative serum or urine pregnancy test within 72 hours of each dose of ipilimumab. 
C Vital signs will be obtained 30, 60 and 90 Minutes after the start of the Ipilimumab infusion or every 30 minutes until the infusion is complete. 
Vital signs should be obtained 1 hour after the infusion is complete. 
D Hematology Labs should include CBC with differential, hemoglobin, hematocrit, white blood cells, platelets, neutrophils, lymphocytes, eosinophils 
and monocytes. Additional draws must be incorporated when monitoring recovery from any hematologic AE. 
E Chemistry Labs should include albumin, amylase, lipase, BUN, creatinine, ALT, AST, LDH, serum alkaline phosphatase, direct and total 
bilirubin, glucose, total protein, sodium, potassium, chloride, HCO3, calcium, and uric acid. 
NOTE: 
It is acceptable to perform a CO2 test instead of a HCO3 test as necessary. 
F Thyroid Function Tests should include TSH and Free T4. 
G Proteinuria will be monitored by dipstick or urine protein creatinine ratio (UPC) prior to treatment. If appropriate, 24 hour urine collection for 
protein may be obtained. 
H  Concomitant Medications will be collected up to 90 days from the end of study treatment. 
I End of Study Assessment will be done within 6 weeks (±1 week) of discontinuation of study treatment. 
J Bevacizumab should ONLY be administered in participants randomized to Arm B. 
K At screening, testing should be performed for HIV antibody, hepatitis C antibody, and HBs antigen utilizing local standard informed consent 
procedures prior to this laboratory collection. These tests could be repeated later during the course of the study if clinically indicated. 
L  Every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry. Patients who develop 
melanoma progression will be followed for survival. 
M Adverse Events Assessment on the study will continue for all patients until 90 days after the last study drug administration. All adverse events 
must be collected whether they occur on treatment or non-treatment weeks and must be submitted utilizing the corresponding E3612 Adverse 
Event Forms, covering all time periods specified on the forms. 
N CNS Imaging is preferred by MRI however, if an MRI is not clinically indicated, a CT of the head is allowed. Non CNS Imaging should include a 
chest, abdomen and pelvis CT. Imaging of other sites should be obtained when clinically indicated. If follow up scans indicate partial or complete 
response, a repeat confirmatory scan should be obtained in 4 weeks (but no sooner than 4 weeks). 
Patients who received prior therapy with anthracylines should have a baseline MUGA or echo with a normal ejection fraction within 28 days prior 
to randomization. 
Baseline imaging will be done within 4 weeks prior to randomization and then every 12 weeks (-/+ 2 weeks) if patient is < 2 years from study 
entry, then every 6 months (+/- 4 weeks) if patient is 2-5 years from study entry. 
If a patient discontinues treatment for any reason other than progression, scans will be done per the standard imaging schedule above. 
O [Deleted in Addendum 2] 
P The patient's BRAF mutation status must be known (see Section 3.1.10). 
Rev. 8/14 
Rev. 8/14 
Rev. 8/14 
Rev. 8/14 
Rev. 8/14 
Rev. 5/15 
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Q EKG and echocardiograms should be conducted as clinically indicated for any patients with a history of CHF or at risk because of underlying 
cardiovascular disease or exposure to cardiotoxic drugs. For patients with evidence of CHF, MI, cardiomyopathy, or myositis, further cardiac 
evaluation, lab tests and cardiology consultations, including EKG, CPK, troponin, and echocardiogram, should be conducted as clinically 
indicated. 
 
Rev. 2/17 
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7.3 
Biological Sample Submissions 
Specimens are to be submitted as outlined in Section 10.  
All specimens submitted must be entered and tracked via the online ECOG-
ACRIN Sample Tracking System (STS). 
Biological Materials 
Prior to Start 
of Treatment 
End of Cycle 
4 (Week 12) 
(Induction)4 
Day 1 Cycle 8 
(Week 24) 
(Maintenance)4 
End of 
Treatment Submit to: 
MANDATORY for central diagnostic review 
Tumor Tissue Biopsy  
(pretrial diagnostic material)1,2 
X 
 
CBPF 
Submit from patients who answer “yes” to “I agree to provide additional samples  for research” 
 
Tumor Tissue Biopsy6 
 
X 
CBPF 
Peripheral Blood  
(ten 10cc green top heparin tubes)3,5 
X 
X 
X 
X 
IMCPL 
Peripheral Blood  
(one10cc red top tube)3,5 
X 
X 
X 
X 
1. Representative tumor tissue (block preferred) and related pathology reports 
and completed ECOG-ACRIN Sample Tracking System shipment manifest 
must be submitted for central diagnostic review within one (1) month following 
randomization as outlined in Section 10. Failure to submit the required 
materials may render the case unevaluable. 
2. Tumor tissue will also be banked for future undefined research from patients 
who answer “Yes” to “My samples and related information may be kept in a 
Biobank for use in future health research.”   
3. Kits are being provided for the collection and shipment of the blood samples. 
See Section 10.3.1.1 for instructions. 
4. ±3 days. 
5. Please completely fill all blood tubes as full as possible. 
6. Whenever possible, biopsy of site(s) of pre-existing disease will be 
performed. Post-treatment biopsies, if obtained, should be performed 
following the induction phase (> 12 weeks from start of treatment; after all 
cycles of induction are completed). While on treatment, biopsies should try to 
be either small incisional/excisional or core biopsies and occur > 14 days 
from last dose of bevacizumab (after all cycles of induction are completed). If 
for any reason removal of tissue requires a greater procedure, the biopsy 
must be done > 28 days from the last and > 7 days from next dose of 
bevacizumab. In the maintenance phase, collect biopsy post week 24; please 
note patients may miss one dose of bevacizumab in order to obtain biopsy 
material if it is felt in the opinion of the treating physician a safety priority. 
Rev. 8/14 
Rev. 5/15 
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8. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
Availability 
Drug Ordering: Bristol-Myers-Squibb is supplying ipilimumab and Genentech is 
supplying bevacizumab, through the Division of Cancer Treatment and Diagnosis, NCI, 
for this protocol. Maintenance of NCI drug accountability records is required. Ipilimumab 
(NSC 732442) 
) and Bevacizumab (NSC 704865) (
 may be 
requested by the Principal Investigator (or their authorized designees) at each 
participating institution. Pharmaceutical Management Branch (PMB) policy requires that 
drug be shipped directly to the institution where the patient is to be treated. PMB does 
not permit the transfer of agents between institutions (unless prior approval from PMB is 
obtained – see general information). The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents. The responsible investigator at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF). If 
there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx). 
Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of 
an “active” account status and a “current” password. For questions about drug orders, 
transfers, returns, or accountability, call (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
NCI Supplied Agent(s) – General Information 
NOTE: 
Under no circumstances can commercially supplied ipilimumab or 
bevacizumab be used or substituted for the NCI-supplied ipilimumab or 
bevacizumab, respectively. 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling (240) 276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time. 
Drug Returns: All unused drug supplies must be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed vials remaining when a patient permanently 
discontinues protocol treatment, expired vials recalled by the PMB), investigators must 
return the study drug to the PMB using the NCI Return Agent Form available on the NCI 
home page (http://ctep.cancer.gov) or by calling the PMB at (240) 276-6575.  
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of all 
drugs received from the PMB using the NCI Investigational Agent Accountability Record 
available on the NCI home page (http://ctep.cancer.gov) or by calling the PMB at (240) 
276-6575.  
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8.1 
Ipilimumab 
In this study, the investigational product is ipilimumab. 
8.1.1 
Drug Name 
Ipilimumab (NSC 732442) 
8.1.2 
Other Names  
Anti-CTLA-4 monoclonal antibody, MDX-010 (MDX-CTLA4, 
Transfectoma-derived), Yervoy® 
8.1.3 
Classification  
Human monoclonal antibody, IgG1 subclass 
M.W.: 147, 991 Daltons 
Ipilimumab has two manufacturing processes- ongoing trials have 
been using substances manufactured using Process B. This trial, 
E3612, uses ipilimumab that is manufactured by Process C. The 
Process C has been developed using a higher producing sub-clone of 
the current Master Cell Bank, and modified cell culture and purification 
steps. 
8.1.4 
Mode of Action  
Ipilimumab is a recombinant human IgGI immunoglobulin monoclonal 
antibody which binds to the cytotoxic T-lymphtocyte associated 
antigen 4 (CTLA-4).  CTLA-4 is a down-regulator of T-cell activation 
pathways.  Blocking CTLA-4 allows for enhanced T-cell activation and 
proliferaton.  In melanoma, ipilimumab may indirectly mediate T-cell 
immune reponsoes against tumors.  (Lexicomp, 1978-2013) 
8.1.5 
Storage and Stability  
Ipilimumab is available in 5 mg/mL single-use vials (40 mL). The 
sterile solution in the vial is clear and colorless. Ipilimumab is 
administered via intravenous infusion only. Ipilimumab must be stored 
in a secure area according to local regulations. The investigator must 
ensure that it is stored at a temperature ≥ 2°C and ≤ 8°C. 
Ipilimumab is given diluted in 0.9% NaCl Injection, USP or 5% 
Dextrose Injection, USP to a concentration between 1 mg/mL and 2 
mg/mL. 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. 
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. 
Each vial is a Type I flint glass vial with gray butyl stoppers and 
sealed with aluminum seals. 
Rev. 5/15 
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Process C 
Component 
200 mg/ viala 
Ipilimumab 
213 mg 
Sodium Chloride, USP  
249 mg 
TRIS-hydrochloride 
134.3 mg 
Diethylenetriamine pentacetic acid 
1.67 mg 
Mannitol, USP 
426 mg 
Polysorbate 80 (plant-derived) 
4.69 mg 
Sodium Hydroxide 
QS to pH 7 
Hydrochloric acid 
QS to pH 7 
Water for Injection 
QS: 42.6 mL 
Nitrogenb 
Processing agent 
a Includes 2.6 mL overfill.  
b Nitrogen is used to transfer the bulk solution through the pre-filled and 
sterilizing filters into the aseptic area. 
8.1.6 
Dose Specifics  
Induction Phase: 
Ipilimumab at 3 mg/kg administered by IV infusion Day 1 Cycles 1-4 
Maintenance Phase: 
Ipilimumab at 3 mg/kg administered by IV infusion day 1 every 4th 
cycle (12 weeks) starting Cycle 8  
Dose delays are allowed as per the dosing criteria. Infusions should 
be given over 90 minutes (not bolus or IV push). 
Cycle=21 days 
Calculate Total Dose as follows: 
Patient body weight in kg x 3 mg/kg = total dose in mg 
Calculate Ipilimumab Infusion Volume as follows: 
Total dose in mg ÷ 5 mg/mL = ipilimumab volume in mL 
Ipilimumab should be diluted with 0.9% Sodium Chloride Injection, 
USP or 5% Dextrose Injection, USP to prepare a diluted solution with 
a final concentration ranging from 1 mg/mL to 2 mg/mL.  
Calculate Total Infusion Volume and Rate of Infusion as follows: 
Total infusion volume in mL ÷ 90 minutes = rate of infusion in mL/min. 
For example, a patient weighing 114 kg (250 lb) would be 
administered 342 mg of ipilimumab (114 kg x 3 mg/kg = 342 mg) with 
an infusion volume of 69 mL (342 mg ÷ 5 mg/mL = 69 mL) + 273 mL 
0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP 
at a rate of approximately 3.8 mL/min (342 mL ÷ 90 minutes) over 90 
minutes. 
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If a subject’s weight changes by > 10% during the course of the study, 
the ipilimumab dose should be recalculated. 
8.1.7 
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 3 
mg/kg dose, to complete the infusion in 90 minutes, with a 3-mL 
normal saline flush at the completion of the infusion. 
• 
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. 
• 
Aseptically withdraw the required volume of ipilimumab solution 
into a syringe. Insert the needle at an angle into the ipilimumab 
vial by placing the needle – bevel side down – against the glass, 
with the tip touching the neck of the vial. The initial solution 
concentration is 5 mg/mL. [Note: A sufficient excess of ipilimumab 
is incorporated into each vial to account for withdrawal losses]. 
• 
Ensure that the ipilimumab solution is clear colorless, essentially 
free from particulate matter on visual inspection. If multiple vials 
are needed for a subject, it is important to use a separate sterile 
syringe and needle for each vial to prevent problems such as 
dulling of needle tip, stopper coring, repeated friction of plunger 
against syringe barrel wall, etc. 
• 
Inject ipilimumab solution withdrawn into an appropriate size 
evacuated infusion bag to produce a final infusion volume that has 
been calculated from the weight of the patient. For example, if 
preparing a 10mg/kg treatment for a 65 kg patient you will use 4 
vials of the 200 mg vial size (or 650 mg). 
• 
If the total dose calculates to less than 90 mL of solution then the 
total dose needed should be diluted to at least 90 mL at a 
concentration between 1 mg/mL and 2 mg/mL. 
• 
Mix by GENTLY inverting several times. DO NOT shake. 
• 
Visually inspect the final solution. If the initial diluted solution or 
final dilution for infusion is not clear or contents appear to contain 
precipitate, the solution should be discarded. 
• 
Do not draw into each vial more than once. Any partial vials 
should be safely discarded and should not be stored for reuse. 
8.1.8 
Route of Administration  
Ipilimumab is administered as an IV infusion only. Infusions should be 
given over 90 minutes (not bolus or IV push). Ipilimumab should be 
administered under the supervision of a physician experienced in the 
use of intravenous (IV) agents. 
8.1.9 
Incompatibilities  
No compatability information is available. 
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8.1.10 
Availability  
Bristol-Myers-Squibb is supplying ipilimumab, through the Division of 
Pharmaceutical Management Branch (PMB), DCTD, NCI, for this 
protocol. 
8.1.11 
Side Effects  
See Section 5.3.1 (CAEPR). 
8.1.12 
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 ipilumumab. 
Closely monitor patients who are on narcotics during the treatment 
with ipilumumab. 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 
8.1.13 
Handling and Disposal 
As with all injectable drugs, care should be taken when handling and 
preparing ipilimumab. Whenever possible, ipilimumab should be 
prepared in a laminar flow hood or safety cabinet using standard 
precautions for the safe handling of intravenous agents applying 
aseptic technique. Latex gloves are required. If ipilimumab 
concentrate or solution comes in contact with skin or mucosa, 
immediately and thoroughly wash with soap and water. After final drug 
reconciliation, unused ipilimumab solution should be disposed at the 
site following procedures for the disposal of anticancer drugs. 
8.1.14 
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. 
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8.2 
Bevacizumab 
In this study, bevacizumab is considered an investigational agent. 
8.2.1 
Other names 
NSC 704865, RhuMAb VEGF, Recombinant Humanized Monoclonal 
Anti-VEGF Antibody, Avastin 
8.2.2 
Classification 
Antiangiogenesis agent; recombinant humanized monoclonal antibody 
M.W. = 149 kilodaltons 
Bevacizumab is a recombinant humanized anti-VEGF monoclonal 
antibody, consisting of 93% human and 7% murine amino acid 
sequences.  The agent is composed of human IgG framework and 
murine antigen-binding complementarity-determining regions. 
8.2.3 
Mechanism of Action 
Bevacizumab binds Vascular Endothelial Growth Factor (VEGF) 
preventing the binding of VEGF to its receptors (Flt-1 and KDR), thus 
inhibiting endothelial cell proliferation and new blood vessel formation. 
8.2.4 
Dose Form 
Bevacizumab is supplied as a clear to slightly opalescent, sterile liquid 
ready for parenteral administration. 
Each 400 mg (25 mg/mL - 16 mL fill) glass vial contains bevacizumab 
with phosphate, trehalose, polysorbate 20 and Sterile Water for 
Injection, USP. 
Vials do not contain a preservative and are suitable for single use 
only. 
8.2.5 
Storage/Stability 
Upon receipt of the study drug, vials are to be refrigerated at 2°C–8°C 
(36°F–46°F) and should remain refrigerated until just prior to use. DO 
NOT FREEZE. DO NOT SHAKE. 
Opened vials must be used within 8 hours.  VIALS ARE FOR SINGLE 
USE ONLY. Vials used for 1 subject may not be used for any other 
subject.  Once study drug has been added to a bag of sterile saline, 
the solution must be administered within 8 hours. Vials must be 
protected from light. 
8.2.6 
Preparation 
Opened vials must be used within 8 hours. Vials contain no 
preservative and are intended for single use only. Place the calculated 
dose of bevacizumab in 100mL of 0.9% sodium chloride for injection. 
Bevacizumab should NOT be administered or mixed with dextrose 
solutions. 
8.2.7 
Dose Specifics 
Induction Phase: 
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105 
All patients randomized to receive bevacizumab (Arm B) will receive 
the drug at 15 mg/kg administered by IV infusion Day 1 Cycles 1-4 
Maintenance Phase: 
Bevacizumab at 15 mg/kg administered by IV infusion Day 1 of each 
cycle starting Cycle 5. 
The dose will be calculated on the patient’s actual weight.  The dose 
will not be recalculated unless the patient has ±10% weight change. 
Cycle=21 days 
8.2.8 
Route of Administration 
Infuse the initial dose over 90 minutes.  The second infusion may be 
shortened to 60 minutes if the initial infusion is well tolerated.  The 
third and subsequent infusions may be shortened to 30 minutes if the 
60-minute infusion is well tolerated.  Monitor closely during the 
infusion for sign/symptoms of an infusion reaction.  DO NOT 
ADMINISTER IV PUSH. 
Once every 3 weeks, 15 mg/kg of bevacizumab will be given by IV 
infusion. The subject’s actual weight at screening should be used to 
calculate the bevacizumab dose. If a subject’s weight changes by > 
10% during the course of the study, the bevacizumab dose should be 
recalculated. 
A rate-regulating device should be used for all bevacizumab infusions. 
When the bevacizumab IV bag is empty, 50 mL of 0.9% Sodium 
Chloride Injection, USP, should be added to the IV bag or an 
additional bag should be hung. An alternative method of flushing the 
infusion line would be to replace the empty bevacizumab infusion bag 
with a 50 mL bag of 0.9% sodium chloride injection and infuse a 
volume equal to that of the tubing to ensure complete delivery of the 
bevacizumab. The infusion should be continued for a volume equal to 
that of the tubing to ensure complete delivery of the bevacizumab. If a 
patient experiences bevacizumab infusion-associated adverse events, 
patient may receive premedication at the investigators discretion prior 
to the next bevacizumab infusion. If premedication is required, the 
infusion time may not be decreased for the subsequent infusion. 
However, if the next infusion is well tolerated with premedication, the 
subsequent infusion time may then be decreased by 30 minutes per 
infusion to a minimum infusion time of 30 minutes as long as the 
patient continues to receive the same premedication. 
8.2.9 
Kinetics 
Estimated half-life of bevacizumab is approximately 20 days (range 
11-50 days). 
The clearance of bevacizumab was higher in males and in patients 
with a higher tumor burden. 
8.2.10 
Availability 
Genentech is supplying Bevacizumab, through the Pharmaceutical 
Management Branch (PMB), DCTD, NCI, for this protocol. 
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8.2.11 
Side Effects 
See Section 5.3.2 (CAEPR) 
8.2.12 
Nursing/Patient Implications 
• 
Monitor CBC and platelets. For patients on warfarin for venous 
access prophylaxis, routine PT monitoring. 
• 
Monitor patient closely during infusion, for infusion related events 
and for bleeding.  
• 
Monitor blood pressure prior to each dose to assess for 
development of hypertension. 
• 
Instruct patient to monitor and report signs/symptoms of: bleeding 
(nose bleeds, blood in sputum), wound healing problems, 
abdominal pain, thromboembolic problems (chest or leg pain, 
dyspnea, vision changes, severe headache, cough, swelling).  
• 
Urine analysis for calculation of Urine Protein: Creatinine Ratio 
(UPC ratio) should be performed at baseline then prior to every 
other course of bevacizumab (or more frequently as indicated).  
Treatment may proceed If UPC ratio is < 3.5. 
NOTE: 
UPC ratio must be obtained prior to treatment.  
Treatment may proceed if a urine protein dip stick 
result is 0-1+, however the UPC ratio must still be 
determined. If results of urine protein dip stick are 
higher, hold bevacizumab until the UPC ratio is known. 
UPC ratio of spot urine is an estimation of the 24 urine protein 
excretion – a UPC ratio of 1 is roughly equivalent to a 24-hour urine 
protein of 1 g.  UPC ratio is calculated using one of the following 
formulas: 
[urine protein]/[urine creatinine] – if both protein and creatinine are 
reported in mg/dL 
[urine protein) x0.088]/[urine creatinine] – if urine creatinine is 
reported in mmol/L 
Should infiltration of the bevacizumab infusion occur, the following 
steps are to be taken: 
Discontinue the IV 
If a significant volume of the bevacizumab infusion remains, restart 
the IV and complete the infusion. 
Treat the infiltration according to institutional guidelines for infiltration 
of a noncaustic agent. 
• 
Treat pain, arthralgias, etc. with acetaminophen, or other pain 
relief strategies that do not interfere with the clotting cascade. 
• 
In patients with bleeding, hemostasis evaluation should be 
performed as clinically indicated.   
• 
Patients who have an ongoing bevacizumab-related Grade 4 or 
serious adverse event at the time of discontinuation from study 
treatment will continue to be followed. 
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9. 
Statistical Considerations 
9.1 
Study Design and Objectives 
In this randomized phase II study, patients with advanced melanoma will be 
equally randomized to Arm A: Iplimumab (Ipi) or Arm B: Ipi + Bevacizumab using 
the stratification factors (Prior Therapy and BRAF mutation status). The stratified 
randomization will be based on the permuted block method. 
The primary objective is to compare overall survival between Arms A vs. B. The 
secondary objectives are to evaluate the progression-free survival, response 
rate, safety and utility of immune related response criteria (irRC) in patients in 
Arms A vs. B. 
9.2 
Study Endpoints 
Overall Survival (OS) is defined as the time from randomization to death from 
any cause. Patients who have not died will be censored at the date of last known 
alive.  
Progression-Free Survival (PFS) is defined as the time from randomization to 
disease progression or death (whichever occurs first). Cases who have not had 
an event will be censored at the date of last disease assessment documenting 
the patient was free of progression. Progression will be evaluated based on 
international criteria proposed by the revised Response Evaluation Criteria in 
Solid Tumors (RECIST) guideline (version 1.1) as described in Section 6.1.   
Response will be defined by the RECIST guidelines (version 1.1) as described in 
Section 6. 
Toxicity will be defined using the CTCAE version 4.0 criteria. 
The immune response will be assessed using the utility of Immune related 
response criteria (irRC) as outlined in Section 6.  
9.3 
Sample Size Considerations and Monitoring Plan  
The primary comparison will be overall survival (OS) in arms A vs. B.  It will be an 
ITT analysis in all eligible patients. It is assumed that the median OS in patients 
treated in arm A will be around 11 months and the median OS will be improved to 
16.5 months (50% improvement) in arm B.  If the OS follows an exponential 
distribution, this difference corresponds to an improvement of one-year OS rate 
from 47% (in arm A) to 60% (in arm B). 
A comparison of arms A vs. B will be made using a stratified logrank test with 
one-sided type I error of 10%. One interim analysis will be performed at 50% 
information time (57 deaths), with the final analysis at 114 deaths. To preserve 
the overall type I error rate, critical values at the analyses will be determined 
using the O’Brien and Fleming boundary. Under the accrual and failure rate 
assumptions below, one interim and final analyses are expected to occur at 12 
and 28 months after activation. The repeated confidence interval (RCI) of 
Jennison-Turnbull will also be evaluated at the interim analysis. This design will 
provide power of 80%. 
One-interim analysis conducted approximately at 50% information time will be 
conducted for both the efficacy and futility analysis.  For the efficacy analysis, 
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O’Brien-Fleming boundary will be used.  For the futility analysis, if the estimated 
hazard ratio is not trending toward in favor of alternative (i.e. estimated HR > 1) 
then arm B will be terminated for futility. 
Allowing for one interim analysis based on OS, a total of 160 eligible patients will 
be accrued and randomized to two arms and 113 deaths are expected. To 
account for the ineligibility rate of 5%, 168 patients will be accrued. Based on 
previous ECOG accrual of the same patient population, it is expected to 
complete the accrual in 8 months and follow patients for additional 20 months. 
In addition, toxicity data will be monitored and reviewed carefully.  Incidence data 
of specific toxicity type as well overall worst degree toxicity data will be 
summarized by treatment arm.  The result of this analysis will be discussed with 
the ECOG-ACRIN DSMC Committee. 
9.4 
Statistical Analysis Plan 
The primary and secondary efficacy (OS, PFS, Response, irRC) analyses will 
include all randomized patients (intent-to-treat analysis). Toxicity analysis will be 
based on all cases who received the treatment regardless of eligibility. 
OS and PFS distributions will be estimated using the Kaplan-Meier method. The 
distribution of OS will be compared using the stratified log rank test with one-
sided overall type I error rate of 0.100 (adjusting for the one interim analysis) and 
the hazard ratio of OS will be estimated using the stratified Cox proportional 
hazard model and one-sided 90% RCI will be constructed.  
PFS distributions will be compared using the log rank test and response rates will 
be compared using the Chi-square or Fisher’s exact test. Toxicity rate for 
individual AEs, categorized AEs and worst degree AEs will be compared using 
the Chi-square of Fisher’s exact test. Two-sided p-values will be reported for 
these comparisons. 
irRC data will be associated with the RECIST-based clinical response, PFS and 
OS. The method of Kaplan- Meier will be used to describe PFS and OS in each 
arm. The Kappa statistics which measures the degree of agreement between the 
RECIST-based response and irRC will be estimated. McNemar’s test will be 
used to evaluate the agreement between irRC and RECIST-based clinical 
response. The landmark analysis will be conducted to evaluate the association 
between PFS/OS and irRC.  
In the event of missing data, it will be assumed that the data will be missing at 
random and no imputation will be performed. 
Subset analyses are planned for all stratification factors and well known 
prognostic factors such as age, gender, ECOG PS, LDH, etc. Subset analyses 
are considered to be exploratory in nature. 
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9.5 
Gender and Ethnicity  
Based on previous data from E1608 and E2603, the anticipated accrual in 
subgroups defined by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
0  
1 
1 
Not Hispanic or Latino 
59 
108 
167 
Ethnic Category: Total of all subjects 
59 
109 
168 
 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
2 
0 
2 
Native Hawaiian or other Pacific 
Islander 
0 
0 
0 
White 
57 
109 
166 
Racial Category: Total of all subjects 
59 
109 
168 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
9.6 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
obtained from the ECOG-ACRIN Operations Office - Boston. 
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10. 
Biological Sample Submissions 
Diagnostic material from previously collected tissue must be submitted for central 
diagnostic review and future undefined research studies (per patient consent). 
Peripheral blood is to be submitted from consenting patients for future undefined 
research studies. 
It is required that all samples submitted on this trial be entered and tracked using the 
ECOG-ACRIN Sample Tracking System (see Section 10.4). An STS shipping manifest 
form is to be included with every submission. 
All samples must be labeled clearly with the ECOG-ACRIN protocol number (E3612), 
ECOG-ACRIN patient sequence number, patient’s initials, date of collection and sample 
type. 
10.1 
Sample Collection and Submission Schedule 
Samples are to be submitted as follows: 
• 
Pretrial diagnostic pathology samples must be submitted within one (1) month 
of randomization and post treatment pathology samples are to be submitted 
within one (1) month of collection.  See Section 10.2. 
• 
Peripheral blood samples are to be submitted as outlined in Section 10.3 on 
the day of collection.  Samples are to be collected at the following time points 
for each tube type: 
• 
Prior to start of treatment 
• 
End of Cycle Four (Week 12 of Induction) 
• 
Day One of Cycle Eight (Week 24 of Maintenance) 
• 
End of Treatment 
10.2 
Submissions to the ECOG-ACRIN Central Biorepository and Pathology Facility 
(CBPF) 
Submitting pathologist and clinical research associate may refer to Appendix I 
which outlines the Pathology Submission Guidelines. Submission of pretrial 
diagnostic pathology samples from all patients is mandatory.  Failure to submit 
the required materials may render the patient’s data unevaluable.  
The tissue samples are to be labeled with the Pathology ID as well as the 
information above. 
10.2.1 
Required Materials 
Forms: Must be submitted with all tissue submissions. 
• 
STS generated shipping manifest form. 
• 
If STS is unavailable, complete ECOG-ACRIN Generic 
Specimen Submission Form (#2981). Please identify the 
clinical status of the submitted material (i.e., pretreatment as 
opposed to remission and relapse). Please log information into 
STS once accessible. 
• 
Copy of the pathology report. 
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Rev. 8/14 
Rev. 5/15 
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Pathological Material Submission: 
• 
Representative diagnostic FFPE tumor tissue blocks 
NOTE: 
Whenever possible biopsy of site(s) of pre-existing disease 
will be performed. Post-treatment biopsies, if obtained, 
should be performed following the induction phase (>12 
weeks from start of treatment; after all cycles of induction 
are completed). While on treatment, biopsies should try to 
be either small incisional/excisional or core biopsies and 
occur >14 days from last dose of bevacizumab (after all 
cycles of induction are completed). If for any reason 
removal of tissue requires a greater procedure, the biopsy 
must be done >28 days from the last and >7 days from 
next dose of bevacizumab. In the maintenance phase, 
collect biopsy post week 24; please note patients may miss 
one dose of bevacizumab in order to obtain biopsy 
material if it is felt in the opinion of the treating physician a 
safety priority. 
NOTE: 
If a block is unavailable for submission, cores and slides 
are to be submitted.  All cores and slides must be 
adequately labeled, with slides numbered sequentially in 
the order cut.  Alternative submission requirement: 
• 
One (1) H&E slide from each source block, and 
• 
Twenty (20) 5 µm unstained, uncharged, air-dried 
plus slides from the thickest part of the tumor, and 
• 
One (1) or more core punches (minimum of 4mm 
diameter). If core punch tool is unavailable, request 
core punch kit from the ECOG-ACRIN CBPF (1-
844-744-2420). Adequately label every slide and 
core submitted. 
If these criteria cannot be met, please contact the ECOG-
ACRIN Central Biorepository and Pathology Facility 
(CBPF) (eacbpf@mdanderson.org) to obtain alternative 
submission requirements. 
10.2.2 
Shipping Procedures 
Pathology materials are to be shipped at ambient temperature within 
one (1) month following patient randomization or collection.  
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Ship using the CBPF’s FedEx account using the FedEx on-line ship 
manager. 
Ship to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or 
International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org  
Access to the FedEx shipping account for shipments to the ECOG-
ACRIN CBPF at MD Anderson Cancer Center can only be obtained 
by logging onto fedex.com with an account issued by the ECOG-
ACRIN CBPF. For security reasons, the account number will no 
longer be given out in protocols, over the phone, or via email. If your 
site needs to have an account created, please contact the ECOG-
ACRIN CBPF by email at eacbpf@mdanderson.org 
Pretrial diagnostic pathology materials will be forwarded to Dr. 
 
 by the CBPF for central review. 
10.3 
Submissions to Immunologic Monitoring and Cellular Products Laboratory 
(IMCPL) 
Blood samples should be shipped the day they are drawn. If you have any 
questions concerning sample collection and shipment, please contact the ECOG-
ACRIN Study Coordinator at (412) 624-0078 at the IMCPL. 
NOTE: 
Blood should NOT be collected on Fridays. 
Instructions to order kits are outlined in Section 10.3.1.1 
Submit from patients who answer “Yes” to “I agree to provide additional samples 
for research.” 
10.3.1 
Sample Preparation Guidelines 
Please completely fill all blood tubes as full as possible and 
collect the correct number and tube type as outlined below.  
Each tube must be clearly labeled to include: 
• 
ECOG-ACRIN protocol number E3612 
• 
ECOG-ACRIN five-digit patient sequence number 
• 
Patient initials 
• 
Originating institution/investigator name  
• 
Date and time drawn 
• 
Collection time point 
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At EACH time point please submit the following: 
• 
One (1) FULL 10 cc RED top tubes (BD cat #367820 or SST 
367988 gel separator/gold top/ tiger tubes if the center can 
centrifuge them) 
• 
Ten (10) FULL 10 cc GREEN top heparin tubes (BD cat # 366480) 
10.3.1.1 
Shipping Kits  
Shipping kits are available to order for the collection of the 
blood samples, and will contain the supplies and 
instructions for collecting, processing, and shipping the 
samples. To order kits please fax the request using 
Shipping Kit Request Facsimile Form (Appendix VI) to 
(412) 623-6625 or call the IMCPL at (412) 624-0078. 
Please allow ten (10) working days for shipment and 
provide the following information: 
• 
Study Number 
• 
Participating Site Number 
• 
Contact Person and Telephone Number 
The kits will be shipped via FedEx Express Saver. Please 
plan ahead, priority overnight shipment is not possible. 
All blood samples should be shipped the day of collection 
using the shipping kit. Follow the shipping instructions 
provided in the kit carefully. 
The shipping kit consists of the following: 
• 
Insulated shipping container and packing material 
• 
FedEx Priority Overnight return label 
• 
Shipping instructions 
• 
Shipping Kit Request Form 
10.3.2 
Shipping Procedures 
Blood collected into the appropriate tubes should be sealed, wrapped 
and placed in the specimen shipper kit and shipped on the same day 
they are drawn by Federal Express Priority Overnight courier using 
the return label provided in the kit. The green top tubes should be 
shipped at ambient temperature (no wet or dry ice) and the red top 
tubes should be refrigerated immediately and shipped at 2-8oC.  
Shipments must be timed to arrive during normal working hours and 
should be shipped in one box.   
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The laboratory will be open Monday through Friday to receive 
samples. Do NOT ship on Fridays or Saturdays, or the day before a 
legal holiday. Ship by overnight courier Monday - Thursday only to: 
Immunologic Monitoring and Cellular Products Laboratory 
University of Pittsburgh Cancer Institute 
UPCI-IMCPL 
ECOG-ACRIN Study Coordinator 
Hillman Cancer Center 
5117 Centre Avenue, L 1.26 
Pittsburgh, PA 15213 
Tel: (412) 624-0078 
FAX: (412) 623-6625 
Federal Guidelines for the Shipment of Blood Products: Sites should 
follow IATA regulations for Packaging UN3372 shipments. Please 
refer to FedEx guidelines. 
An STS shipping manifest form must be generated and shipped with 
all sample submissions.  
10.4 
ECOG-ACRIN Sample Tracking System  
It is required that all specimens submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the specimens 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst.  
Important:  Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software. A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html 
Please take a moment to familiarize yourself with the software prior to using the 
system. 
An STS generated shipping manifest form should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to ecog-
acrin.tst@jimmy.harvard.edu.  
Study Specific Notes 
Generic Specimen Submission Form (#2981) will be required only if STS is 
unavailable at time of specimen submission. Notify the laboratory of the shipment 
by faxing a copy of the completed form to the laboratory. For specimen 
submissions to the IMCPL, notify the ECOG-ACRIN Study Coordinator by FAX 
(412) 623-6625 using the Specimen Shipment Requisition Form (Appendix VII). If 
you are unable to get through to the laboratory by FAX, telephone the ECOG-
ACRIN Study Coordinator at (412) 624-0078 and provide the tracking number. 
Indicate the appropriate Lab ID# on the submission form: 
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• 
ECOG-ACRIN CBPF 
• 
ECOG-ACRIN Immunologic Monitoring and Cellular Products Laboratory 
Retroactively enter all specimen collection and shipping information when STS is 
available. 
10.5 
Use of Specimens in Research 
Pathological materials will be distributed to investigators for central diagnostic 
review. 
Specimens from patients who consented to allow their specimens to be used for 
future ECOG-ACRIN approved research studies, including residuals from the 
mandatory diagnostic review, will be retained in an ECOG-ACRIN designated 
central repository. 
For this trial, specimens will be retained at the ECOG-ACRIN and the ECOG-
ACRIN Immunologic Monitoring and Cellular Products Laboratory.  
Specimens submitted will be processed to maximize their utility for current and 
future research projects. Tissue processing may include, but not limited to, 
extraction of DNA and RNA and construction of tissue microarrays (TMAs). DNA, 
RNA, serum, and plasma (if appropriate) will be isolated from the submitted 
peripheral blood specimens. 
Any residual blocks will be available for purposes of individual patient 
management on specific written request.  
If future use is denied or withdrawn by the patient, the specimens will be 
removed from consideration for use in any future research study. Pathology 
materials may be retained for documentation purposes or returned to the site.  All 
other specimens will be destroyed per guidelines of the respective repository. 
10.6 
Sample Inventory Submission Guidelines  
Inventories of all samples submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory.  
Inventories of samples forwarded and utilized for approved laboratory research 
studies will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office - Boston on a monthly basis in an electronic format defined by 
the ECOG-ACRIN Operations Office - Boston. 
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11. 
Electronic Data Capture 
Please refer to the E3612 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office - Boston to CTEP by electronic means. 
11.1 
Records Retention 
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
This study will be used in support of a US marketing application (New Drug 
Application), all records pertaining to the trial (including source documents) must 
be maintained for: 
• 
two years after the FDA approves the marketing application, or 
• 
two years after the FDA disapproves the application for the indication being 
studied, or 
• 
two years after the FDA is notified by the sponsor of the discontinuation of 
trials and that an application will not be submitted.  
Please contact the ECOG-ACRIN Operations Office - Boston prior to destroying 
any source documents. 
12. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
13. 
References 
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3. Koh, H.K., Cutaneous melanoma. N Engl J Med, 1991. 325(3): p. 171-82. 
4. Clark, W.H., Jr., D.E. Elder, D.t. Guerry, L.E. Braitman, B.J. Trock, D. Schultz, M. 
Synnestvedt, and A.C. Halpern, Model predicting survival in stage I melanoma based 
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in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin 
Oncol, 2000. 18(12): p. 2444-58. 
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7. Kirkwood, J.M., J.G. Ibrahim, J.A. Sosman, V.K. Sondak, S.S. Agarwala, M.S. 
Ernstoff, and U. Rao, High-dose interferon alfa-2b significantly prolongs relapse-free 
and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with 
resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J 
Clin Oncol, 2001. 19(9): p. 2370-80. 
8. Kirkwood, J.M., M.H. Strawderman, M.S. Ernstoff, T.J. Smith, E.C. Borden, and R.H. 
Blum, Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: 
the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol, 1996. 14(1): 
p. 7-17. 
9. Cocconi, G., M. Bella, F. Calabresi, M. Tonato, R. Canaletti, C. Boni, F. Buzzi, G. 
Ceci, E. Corgna, P. Costa, and et al., Treatment of metastatic malignant melanoma 
with dacarbazine plus tamoxifen. N Engl J Med, 1992. 327(8): p. 516-23. 
10. Petrella, T., I. Quirt, S. Verma, A.E. Haynes, M. Charette, and K. Bak, Single-agent 
interleukin-2 in the treatment of metastatic melanoma: a systematic review. Cancer 
Treat Rev, 2007. 33(5): p. 484-96. 
11. Chapman, P.B., A. Hauschild, C. Robert, J.B. Haanen, P. Ascierto, J. Larkin, R. 
Dummer, C. Garbe, A. Testori, M. Maio, D. Hogg, P. Lorigan, C. Lebbe, T. Jouary, D. 
Schadendorf, A. Ribas, S.J. O'Day, J.A. Sosman, J.M. Kirkwood, A.M. Eggermont, 
B. Dreno, K. Nolop, J. Li, B. Nelson, J. Hou, R.J. Lee, K.T. Flaherty, and A.G. 
McArthur, Improved survival with vemurafenib in melanoma with BRAF V600E 
mutation. N Engl J Med. 364(26): p. 2507-16. 
12. Hodi, F.S., S.J. O'Day, D.F. McDermott, R.W. Weber, J.A. Sosman, J.B. Haanen, R. 
Gonzalez, C. Robert, D. Schadendorf, J.C. Hassel, W. Akerley, A.J. van den 
Eertwegh, J. Lutzky, P. Lorigan, J.M. Vaubel, G.P. Linette, D. Hogg, C.H. 
Ottensmeier, C. Lebbe, C. Peschel, I. Quirt, J.I. Clark, J.D. Wolchok, J.S. Weber, J. 
Tian, M.J. Yellin, G.M. Nichol, A. Hoos, and W.J. Urba, Improved Survival with 
Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med, 2010. 363: p. 711-
723. 
13. Robert, C., L. Thomas, I. Bondarenko, S. O'Day, D.J. M, C. Garbe, C. Lebbe, J.F. 
Baurain, A. Testori, J.J. Grob, N. Davidson, J. Richards, M. Maio, A. Hauschild, W.H. 
Miller, Jr., P. Gascon, M. Lotem, K. Harmankaya, R. Ibrahim, S. Francis, T.T. Chen, 
R. Humphrey, A. Hoos, and J.D. Wolchok, Ipilimumab plus dacarbazine for 
previously untreated metastatic melanoma. N Engl J Med. 364(26): p. 2517-26. 
14. Lenschow, D.J., K.C. Herold, L. Rhee, B. Patel, A. Koons, H.Y. Qin, E. Fuchs, B. 
Singh, C.B. Thompson, and J.A. Bluestone, CD28/B7 regulation of Th1 and Th2 
subsets in the development of autoimmune diabetes. Immunity, 1996. 5(3): p. 285-
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15. Lenschow, D.J., T.L. Walunas, and J.A. Bluestone, CD28/B7 system of T cell 
costimulation. Annu Rev Immunol, 1996. 14: p. 233-58. 
16. Schwartz, R.H., Costimulation of T lymphocytes: the role of CD28, CTLA-4, and 
B7/BB1 in interleukin-2 production and immunotherapy. Cell, 1992. 71(7): p. 1065-8. 
17. Chen, L., S. Ashe, W.A. Brady, I. Hellstrom, K.E. Hellstrom, J.A. Ledbetter, P. 
McGowan, and P.S. Linsley, Costimulation of antitumor immunity by the B7 
counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell, 1992. 
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18. Townsend, S.E. and J.P. Allison, Tumor rejection after direct costimulation of CD8+ 
T cells by B7-transfected melanoma cells. Science, 1993. 259(5093): p. 368-70. 
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Cancer Research Group 
Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
118 
19. Kearney, E.R., T.L. Walunas, R.W. Karr, P.A. Morton, D.Y. Loh, J.A. Bluestone, and 
M.K. Jenkins, Antigen-dependent clonal expansion of a trace population of antigen-
specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by 
CTLA-4. J Immunol, 1995. 155(3): p. 1032-6. 
20. Krummel, M.F., T.J. Sullivan, and J.P. Allison, Superantigen responses and co-
stimulation: CD28 and CTLA-4 have opposing effects on T cell expansion in vitro and 
in vivo. Int Immunol, 1996. 8(4): p. 519-23. 
21. Ozcan, C., S.J. Wong, and P. Hari, Reversible posterior leukoencephalopathy 
syndrome and bevacizumab. N Engl J Med, 2006. 354(9): p. 980-2; discussion 980-
2. 
22. Glusker, P., L. Recht, and B. Lane, Reversible posterior leukoencephalopathy 
syndrome and bevacizumab. N Engl J Med, 2006. 354(9): p. 980-2; discussion 980-
2. 
23. Scappaticci, F.A., L. Fehrenbacher, T. Cartwright, J.D. Hainsworth, W. Heim, J. 
Berlin, F. Kabbinavar, W. Novotny, S. Sarkar, and H. Hurwitz, Surgical wound 
healing complications in metastatic colorectal cancer patients treated with 
bevacizumab. J Surg Oncol, 2005. 91(3): p. 173-80. 
24. Karp, J.E., I. Gojo, R. Pili, C.D. Gocke, J. Greer, C. Guo, D. Qian, L. Morris, M. 
Tidwell, H. Chen, and J. Zwiebel, Targeting vascular endothelial growth factor for 
relapsed and refractory adult acute myelogenous leukemias: therapy with sequential 
1-beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer 
Res, 2004. 10(11): p. 3577-85. 
 
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ECOG-ACRIN 
E3612 
Cancer Research Group 
Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
119 
A Randomized Phase II Trial of Ipilimumab with or without Bevacizumab in Patients with 
Unresectable Stage III or Stage IV Melanoma 
 
Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. 
List of Required Materials for E3612 
2. 
Instructional memo to submitting pathologists 
3. 
ECOG-ACRIN Generic Specimen Submission Form (#2981) 
Rev. 5/15 
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ECOG-ACRIN 
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Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
120 
List of Required Material 
E3612: A Randomized Phase II Trial of Ipilimumab with or without Bevacizumab in 
Patients with Unresectable Stage III or Stage IV Melanoma 
The following materials are to be submitted within one (1) month of randomizing the 
patient to the trial or within one (1) month of collection:  
1. Required Diagnostic Materials 
• 
Pretrial Diagnostic Pathology Materials (MANDATORY): Representative 
diagnostic tumor tissue blocks  
• 
Post Treatment Tumor Biopsy (If performed, samples are to be submitted from 
consenting patients) 
NOTE: 
Whenever possible biopsy of site(s) of pre-existing disease will be 
performed. Post-treatment biopsies, if obtained, should be performed 
following the induction phase (> 12 weeks from start of treatment; after all 
cycles of induction are completed). While on treatment, biopsies should 
try to be either small incisional/excisional or core biopsies and occur > 14 
days from last dose of bevacizumab (after all cycles of induction are 
completed). If for any reason removal of tissue requires a greater 
procedure, the biopsy must be done > 28 days from the last and > 7 days 
from next dose of bevacizumab. In the maintenance phase, collect biopsy 
post week 24; please note patients may miss one dose of bevacizumab in 
order to obtain biopsy material if it is felt in the opinion of the treating 
physician a safety priority. 
NOTE: 
If a block is unavailable for submission, cores and slides are to be 
submitted.  All cores and slides must be adequately labeled, with slides 
numbered sequentially in the order cut.  Alternative submission 
requirements: 
• 
One (1) or more core punches (minimum of 4mm diameter). If core 
punch tool is unavailable, request core punch kit from the ECOG-
ACRIN CBPF 1-844-744-2420.  
• 
One (1) H&E slide from each source block, and  
• 
Twenty (20) 5 µm unstained, uncharged air-dried plus slides from the 
thickest part of the tumor, 
If these criteria cannot be met, please contact the ECOG-ACRIN Central 
Biorepository and Pathology Facility (eacbpf@mdanderson.org) to obtain alternative 
submission requirements. 
2. Forms and Reports: 
NOTE: 
Adequate patient identifying information must be included with every 
submission. It is strongly recommended that full patient names be 
provided. The information will be used only to identify patient materials, 
and will help to expedite any required communications with the institution 
(including site pathologists). 
The following items are to be included with the pathology materials: 
• 
Institutional Pathology Report 
• 
Sample Tracking System (STS) Shipping Manifest Form 
Rev. 8/14 
Rev. 5/15 
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ECOG-ACRIN 
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Cancer Research Group 
Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
121 
3. Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
If you have any questions concerning the above instructions or if you anticipate any 
problems in meeting the pathology material submission deadline of one month, contact 
the Pathology Coordinator at the ECOG-ACRIN Central Biorepository and Pathology 
Facility by telephone Toll Free 1-844-744-2420 (713-745-4440 Local or International 
Sites) or by fax 713-563-6506. 
 
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ECOG-ACRIN 
E3612 
Cancer Research Group 
Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
124 
A Randomized Phase II Trial of Ipilimumab with or without Bevacizumab in Patients with 
Unresectable Stage III or Stage IV Melanoma 
 
Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the ECOG web site at http://www.ecog.org. As this is a personal 
letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study.  Many questions 
remain unanswered in cancer.  With the participation of people like you in clinical trials, 
we will improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care.  I and my research staff will 
maintain very close contact with you.  This will allow me to provide you with the best 
care while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank 
you again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 
Rev. 8/14 
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ECOG-ACRIN 
E3612 
Cancer Research Group 
Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
125 
A Randomized Phase II Trial of Ipilimumab with or without Bevacizumab in Patients with 
Unresectable Stage III or Stage IV Melanoma 
 
Appendix III 
 
CRADA/CTA 
The agents supplied by CTEP, DCTD, NCI used in this protocol are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA) between the Pharmaceutical Companies (hereinafter 
referred to as “Collaborators”) and the NCI Division of Cancer Treatment and Diagnosis.  
Therefore, the following obligations/guidelines, in addition to the provisions in the “Intellectual 
Property Option to Collaborator” (http://ctep.cancer.gov/industry) contained within the terms of 
award, apply to the use of the Agent(s) in this study: 
1. 
Agents may not be used for any purpose outside the scope of this protocol, nor can 
Agents be transferred or licensed to any party not participating in the clinical study.  
Collaborators data for Agents are confidential and proprietary to Collaborators and shall be 
maintained as such by the investigators. The protocol documents for studies utilizing 
investigational Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI.  If a copy of this protocol is requested by a 
patient or patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
another investigational Agent, each the subject of different collaborative agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data.”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborators, the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order as described in the IP 
Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm). Additionally, all 
Clinical Data and Results and Raw Data will be collected , used and disclosed consistent 
with all applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
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ECOG-ACRIN 
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Cancer Research Group 
Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
126 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
5. 
Any data provided to Collaborators for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Safety Monitoring Committee (DSMC), if 
there is a DSMC for this clinical trial. 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP for 
immediate delivery to Collaborators for advisory review and comment prior to submission 
for publication.  Collaborators will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s confidential and proprietary data, 
in addition to Collaborator(s)’s intellectual property rights, are protected.  Copies of 
abstracts must be provided to CTEP for forwarding to Collaborators for courtesy review as 
soon as possible and preferably at least three (3) days prior to submission, but in any 
case, prior to presentation at the meeting or publication in the proceedings. Press releases 
and other media presentations must also be forwarded to CTEP prior to release. Copies of 
any manuscript, abstract and/or press release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborators. No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/ proprietary information. 
 
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ECOG-ACRIN 
E3612 
Cancer Research Group 
Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
127 
A Randomized Phase II Trial of Ipilimumab with or without Bevacizumab in Patients with 
Unresectable Stage III or Stage IV Melanoma 
 
Appendix IV 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without 
restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature e.g., light house work, office 
work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
 
 
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ECOG-ACRIN 
E3612 
Cancer Research Group 
Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
128 
A Randomized Phase II Trial of Ipilimumab with or without Bevacizumab in Patients with 
Unresectable Stage III or Stage IV Melanoma 
Appendix V 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy test 
regardless of age or disease state) of a female patient while she is on Ipilimumab or 
Bevacizumab, or within 28 days of the patient’s last dose of Ipilimumab or Bevacizumab must 
be reported in an expeditious manner.  The outcome of the pregnancy and neonatal status must 
also be reported. 
How should the pregnancy be reported? 
• 
The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy test must be 
reported via CTEP’s Adverse Event Reporting System (CTEP-AERS) 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm) 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy test 
need to be reported?  
An initial report must be done within 24 hours of the Investigator’s learning of the event, followed 
by a complete expedited CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
What other information do I need in order to complete the CTEP-AERS report for a 
pregnancy? 
• 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium and 
perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) “Pregnancy, 
puerperium and perinatal conditions” 
• 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.   
• 
The start date of the pregnancy should be reported as the calculated date of conception.   
• 
The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section of the CTEP-AERS 
report. 
What else do I need to know when a pregnancy occurs to a patient? 
• 
The Investigator must follow the female patient until completion of the pregnancy and must 
report the outcome of the pregnancy and neonatal status via CTEP-AERS.  
• 
The decision on whether an individual female patient can continue protocol treatment will be 
made by the site physician in collaboration with the study chair and ECOG-ACRIN 
Operations Office - Boston.  Please contact the ECOG-ACRIN Operations Office - Boston to 
ask for a conference call to be set up with the appropriate individuals.   
• 
It is recommended the female subject be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling. 
How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERS 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself. However, if 
Rev. 8/14 
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ECOG-ACRIN 
E3612 
Cancer Research Group 
Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
129 
the outcome of the pregnancy occurred on a subsequent cycle, a new CTEP-AERS report 
should be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions (formerly referred to as disabilities), congenital anomalies, or birth defects. For 
assistance in recording the grade or category of these events, please contact the CTEP AEMD 
Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed on a case 
by case basis. 
Reporting a Pregnancy Loss Death 
A pregnancy loss death is defined in CTCAE as “A death in utero.” 
It must be reported via CTEP-AERS as Grade 4 “Pregnancy, loss” under the System Organ 
Class (SOC) “Pregnancy, puerperium and perinatal conditions”. 
A fetal death should NOT be reported as a Grade 5 event as currently CTEP-AERS recognizes 
this event as a patient’s death. 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A death occurring during the first 28 days after birth” 
that is felt by the investigator to be at least possibly due to the investigational agent/intervention. 
However, for this protocol, any neonatal death that occurs within 28 days of birth, without regard 
to causality, must be reported via CTEP-AERS AND any infant death after 28 days that is 
suspected of being related to the in utero exposure to Ipilimumab or Bevacizumab must also be 
reported via CTEP-AERS. 
It must be reported via CTEP-AERS as Grade 4 “Neonatal loss”under the System Organ Class 
(SOC) “General disorder and administration site conditions”.  
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERS 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting CTEP-AERS reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any additional 
medical information to CTEP (301-230-0159). This form is available on CTEP's website 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/PregnancyReportFor
m.pdf) 
 
 
Rev Add8 
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ECOG-ACRIN 
E3612 
Cancer Research Group 
Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
130 
A Randomized Phase II Trial of Ipilimumab with or without Bevacizumab in Patients with 
Unresectable Stage III or Stage IV Melanoma 
Appendix VI 
 
Shipping Kit Request Facsimile Form 
ECOG-ACRIN PROTOCOL E3612 
Immunologic Monitoring and 
Cellular Products Laboratory 
UPCI Research Pavilion at the Hillman Cancer Center 
Room L 1.26 
5117 Centre Avenue 
Pittsburgh, PA  15213-1863 
Telephone: 412-624-0078 
FAX:  412-623-6625 
To: ECOG-ACRIN Study Coordinator 
 
 
Fax:  412-623-6625 
From: 
Name:_________________________________________ 
 
 
Institution:______________________________________ 
 
 
Telephone: _____________________________________ 
 
 
Fax:  __________________________________________ 
 
Number of Kits Requested:  
 
Shipping Address:  _______________________________________ 
 
 
 
_______________________________________ 
 
 
 
_______________________________________ 
PLEASE ALLOW 10 WORKING DAYS FOR RECEIPT OF SHIPPING KITS 
NOTE: To order collection and shipping kits for E3612, patients must be registered to or in 
the process of being worked up for the E3612 trial.  Due to funding restrictions 
institutions cannot order multiple collection and shipping kits in advance. 
 
This message is intended only for the use of the individual or entity to which it is addressed and may contain 
information that is privileged, confidential, and exempt from disclosure under applicable law.  If the reader of this 
message is not the intended recipient or the employee or agent responsible for delivering the message to the 
intended recipient, you are hereby notified that any dissemination, distribution, or copying of this communication is 
strictly prohibited.  If you have received this communication in error, please notify us immediately by telephone and 
return the original facsimile to us at the above address via the U.S. Postal Service.  Thank you. 
Rev. 5/15 
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ECOG-ACRIN 
E3612 
Cancer Research Group 
Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
131 
A Randomized Phase II Trial of Ipilimumab with or without Bevacizumab in Patients with 
Unresectable Stage III or Stage IV Melanoma 
Appendix VII 
 
Specimen Shipment Requisition Form 
ECOG-ACRIN – PROTOCOL E3612 
It is required that samples submitted from patients participating in E3612 be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System. This form is used only in 
the event that the STS is inaccessible and then the shipments are to be logged in 
retroactively, indicating the actual dates of collection and shipment. 
 
Immunologic Monitoring and 
Cellular Products Laboratory 
UPCI Research Pavilion at the Hillman Cancer Center 
Room L 1.26 
5117 Centre Avenue 
Pittsburgh, PA  15213-1863 
Telephone: 412-624-0078 
FAX:  412-623-6625 
 
Ship samples by FedEx Priority Overnight to arrive the next morning unless otherwise 
directed by the protocol. Do NOT ship on Friday or Saturday, or the day before a legal 
holiday. 
Call the IMCPL ECOG-ACRIN Study Coordinator at 412-624-0078 with questions on 
collection and shipping. 
Please complete the following information and include this form in the shipment. 
 
ECOG-ACRIN Patient Sequence Number:  _________________    
ECOG-ACRIN Patient Initials: __________ 
 
 
 
Last    First 
Clinical Site:_____________________________    
Site Contact: __________________________ 
Telephone Number:  ______________________     
Fax Number: _________________________ 
Federal Express® Air Bill No.: ________________________   
Date of Shipment: _____________ 
Specimen 
Collection Date 
 
___/___/___ 
MM/DD/YY 
Specimen 
Collection Time:  
 
____ ____:____ ____ 
(24 hour clock) 
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ECOG-ACRIN 
E3612 
Cancer Research Group 
Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
133 
A Randomized Phase II Trial of Ipilimumab with or without Bevacizumab in Patients with Unresectable Stage III or Stage IV 
Melanoma 
Appendix IX 
Hepatotoxicity Management Algorithm 
Severity of 
Hepatitis
Management
Follow-up
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue ipilimumab.
Caution: Infliximab is contraindicated in hepatic insufficiency
Grade 1 AST or ALT 
= 3.0 x ULN 
and/or
Total bilirubin 
= 1.5 x ULN
Grade 2 AST or ALT 
> 3 0 to = 5.0 x ULN 
and/or
Total bilirubin 
> 1 5 to = 3.0 x ULN
*
Ipilimumab may be held/delayed rather than discontinued if AST/ALT = 8 x ULN and Tbili = 5 x ULN. Resume ipilimumab when AST/ALT/Tbili return to 
grade 2 and meet protocol specific retreatment criteria.
** The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV.
***MMF, mycophenolate mofetil
Patients on IV steroids may be switched to oral corticosteroid (e.g., prednisone) at an equivalent dose at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of PO 
corticosteroids.
• Continue monitoring LFT prior to each dose
• Continue ipilimumab
Grade 3-4 AST or ALT 
> 5.0 x ULN 
and/or
Total bilirubin 
> 3.0 ULN
• Discontinue ipilimumab*
• Increase frequency of monitoring (q1-3d)
• High dose IV steroids (e g., 
methylprednisolone 1-2 mg/kg/day**)
• Increase frequency of monitoring  
(q3d)
• Withhold/delay ipilimumab while 
investigating alternative etiology
Return to baseline
• Resume q3w monitoring
• Resume ipilimumab
Elevations persist for > 5-7 days or worsen, and
no alternative etiologies are identified
• Consider moderate to high dose steroids PO (e g.,
0.5- 1 mg/kg/day prednisone or equivalent)
AST/ALT/Tbili return to grade 2
• Taper steroids over at least 1 month
Labs do not decrease over 3-5 days, worsen or 
rebound:
• Add MMF*** 1 g BID
• If no response within 3-5 days, consider other 
immunosuppressants per local guidelines
 
Rev. 8/14 
Rev. 8/14 
Rev. 8/14 
Use of this document is governed by the terms of use on the first page of this document.

ECOG-ACRIN 
E3612 
Cancer Research Group 
Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
134 
A Randomized Phase II Trial of Ipilimumab with or without Bevacizumab in Patients with Unresectable Stage III or Stage IV 
Melanoma 
Appendix X 
Skin Toxicity Management Algorithm 
Severity of 
Skin Toxicity
Management
Follow-up
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue ipilimumab.
Grade 1-2
Grade 3-4
Patients on IV steroids may be switched to oral corticosteroid (e.g., prednisone) at an equivalent dose at start of tapering or earlier, once sustained clinical improvement is 
observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of PO cortic osteroids.
• Symptomatic therapy, e.g. antihistamines, topical steroids
• Continue ipilimumab 
Symptoms resolve / return to grade 1: 
• Taper steroids over at least 1 month
• Resume ipilimumab if grade 3
• Discontinue if grade 4 toxicity considered 
related
• Hold/delay ipilimumab (regardless of relationship)
• Take photos of rash
• Consider skin biopsy
• Dermatology consult
• High dose IV steroids (e.g., methylprednisolone 1-2 mg/kg/day)
Symptoms resolve: Continue ipilimumab
Symptoms persist > 1-2 weeks or recur:
• Continue Ipilimumab
• Moderate to high dose steroids PO (e.g., 
prednisone 0.5 - 1 mg/kg/day)
• Once controlled, taper steroids over at 
least 1 month
 
Use of this document is governed by the terms of use on the first page of this document.

ECOG-ACRIN 
E3612 
Cancer Research Group 
Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
135 
A Randomized Phase II Trial of Ipilimumab with or without Bevacizumab in Patients with Unresectable Stage III or Stage IV 
Melanoma 
Appendix XI 
Neurological Toxicity Management Algorithm 
Severity of 
Neurological 
Toxicity
Management
Follow-up
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue ipilimumab.
Discontinue ipilimumab for any grade 3-4 motor neuropathy, regardless of relationship.
Grade 1
Grade 3-4 sensory
Patients on IV steroids may be switched to oral corticosteroid (e.g., prednisone) at an equivalent dose at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of PO 
corticosteroids.
Continue monitoring the patient. If symptoms worsen,
treat as below.
• Continue ipilimumab
Grade 3-4 motor
• Discontinue ipilimumab regardless of
relationship
• Obtain neuro consult
• Treat symptoms per local guidelines
• High dose IV steroids (e.g., 1-2 mg/kg/ 
day methylprednisolone)
• Discontinue ipilmumab if considered 
related
• Obtain neuro consult
• Treat symptoms per local guidelines
• High dose IV steroids (e.g., 1-2 mg/
kg/ day methylprednisolone)
Symptoms  resolve / return to grade 2:
• Taper steroids over at least 1 month
Symptoms  resolve / return to grade 2:
• Taper steroids over at least 1 month
Symptoms  do not resolve or progress; atypical 
presention:
• Consider IVIg or other immunosuppressive therapies 
per local guidelines
Grade 2
• Hold/delay ipilimumab
• Treat symptoms per local guidelines
Resume ipilimumab when resolved / grade 1
If symptoms worsen, treat as below.
 
Use of this document is governed by the terms of use on the first page of this document.

ECOG-ACRIN 
E3612 
Cancer Research Group 
Version Date: May 24, 2019 
 
NCI Update Date: September 24, 2013 
136 
A Randomized Phase II Trial of Ipilimumab with or without Bevacizumab in Patients with Unresectable Stage III or Stage IV 
Melanoma 
Appendix XII 
Endocrinopathy Management Algorithm 
Severity of 
Endocrinopathy
Management
Follow-up
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue ipilimumab.
Asymptomatic TSH 
elevation
Symptomatic 
endocrinopathy
Continue ipilimumab
If TSH < 0.5 x LLN, or TSH > 2.0 x ULN, or consistently out of range in 2 subsequent measurements: Include fT4 
at subsequent cycles as clinically indicated; consider endocrinology consult
Symptoms resolve (with our 
without hormone substitution): 
• Resume ipilimumab (if no 
diagnosis of hypophysitis)
• Taper steroids over at least 1 
month*
• Evaluate endocrine function
• Consider pituitary scan (e.g. MRI)
• Consider endocrinology consult
Symptomatic with abnormal lab/pituitary scan:
• Withhold/delay ipilimumab
• High dose IV steroids (e g., 1-2 mg/kg/day 
methylprednisolone)
• Initiate appropriate hormone therapy
No abnormal lab/pituitary scan but symptoms  persist:
• Repeat labs in 1-3 weeks / MRI in 1 month
Patients on IV steroids may be switched to oral corticosteroid (e.g., prednisone) at an equivalent dose at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of PO 
corticosteroids.
Suspicion of adrenal crisis 
(e.g. severe dehydration, 
hypotension, shock out of 
proportion to current 
illness)
• Rule out sepsis
• Stress dose of IV steroids with mineralocorticoid activity
• IV fluids
• Consult endocrinologist
*Patients with adrenal insufficiency 
might need to continue steroids 
with mineralcorticoid component 
as substitution
 
Use of this document is governed by the terms of use on the first page of this document.