RADVAX: A Stratified Phase II Dose Escalation Trial of Stereotactic Body Radiotherapy Followed by Ipilimumab in Metastatic Melanoma
Phase: PHASE2
Conditions: Recurrent Melanoma, Stage IV Skin Melanoma
Sponsor: University of Washington

 
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CLINICAL RESEARCH PROTOCOL 
 
 
University of Washington 
 
 
 
 
 
 
RADVAX: A STRATIFIED PHASE II DOSE ESCALATION 
TRIAL 
OF 
STEREOTACTIC 
BODY 
RADIOTHERAPY 
FOLLOWED BY IPILIMUMAB IN METASTATIC MELANOMA 
 
 
 
 
Principal Investigator: 
Ramesh Rengan MD PhD 
University of Washington 
Department of Radiation Oncology 
Phone: (206) 598-4110 
Fax: (206)598-3498 
Email: Rengan@uw.edu 
 
Funding Sponsor: 
 
 
Sub-Investigators 
Department of Radiation Oncology 
University of Washington 
 
Shailender Bhatia, MD 
John Thompson, MD 
Scott Tykodi, MD 
Sylvia Lee, MD 
 
Statistician: 
Barry Storer, PhD 
Version date: 
 
Protocol Amendment 7: version November 15, 2016  
(replacing Protocol Amendment 6: version January 15, 2016) 
 
 
 
 
 
 
 
 
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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 2 
2 
STUDY OBJECTIVES ......................................................................................................................... 4 
3 
STUDY DESIGN ................................................................................................................................... 4 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 6 
5 
STUDY DRUG ...................................................................................................................................... 7 
6 
STUDY PROCEDURES ....................................................................................................................... 7 
7 
ASSESSMENT OF TUMOR REPONSE………………..…………………………………………………12 
8  
STATISTICAL PLAN ....................................................................................................................... 144 
9 
SAFETY ASSESSMENT AND ADVERSE EVENT REPORTING .................................................... 18  
10 
REGULATORY, QUALITY AND ADMINISTRATIVE REQUIREMENTS .......................................... 22 
 
REFERENCES ................................................................................................................................... 23 
 
 
 
 
 
 
 
List of Abbreviations 
 
SBRT: Stereotactic body radiation therapy 
CTLA 4: Cytotoxic t-lymphocyte antigen 4 
 
 
 
 
 
 
 
 
 
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Study Summary 
Title 
RADVAX: A STRATIFIED PHASE II DOSE ESCALATION TRIAL OF 
STEREOTACTIC BODY RADIOTHERAPY FOLLOWED BY IPILIMUMAB IN 
METASTATIC MELANOMA 
Short Title 
RADVAX 
Protocol Number 
CC IRB # 9031 
Phase 
Phase II 
Methodology 
Open Label 
Study Duration 
3 years 
Objectives 
1. The primary objectives are to determine feasibility and immune-related 
clinical responses associated with SBRT when given in conjunction with 
ipilimumab 
 
2. The secondary objectives are to determine late toxicity and immune 
pharmacodynamic changes after SBRT followed by ipilimumab 
Number of Subjects 
40 
Diagnosis and Main 
Inclusion Criteria 
Patients with previously untreated or previously treated metastatic melanoma 
with bone, lung, liver, or subcutaneous or nodal involvement but without 
evidence of active brain involvement. Patients who have previously been 
treated with radiation will be included in the study, so long as a suitable plan 
for treatment can be developed.  
Study Product, Dose, 
Route, Regimen 
Stereotactic Body Radiation Therapy 
Duration of 
administration 
Radiation Treatment to be delivered prior to initiation of ipilimumab 
Reference therapy 
Ipilimumab 
Statistical 
Methodology 
This is a stratified phase II study of escalating fractions of stereotactic body 
radiotherapy (SBRT) combined with immunotherapy for previously untreated or 
previously treated metastatic melanoma patients. Phase I was stratified by 
site: bone or lung vs. liver or s.c. Six patients were enrolled per dose cohort. 
Phase II is stratified by site: bone or lung vs. liver or s.c. In phase II, 20 
patients will be treated at the MTD in each stratum. Descriptive statistics will 
be generated for both phases of the study.  
 
 
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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 312 
and International Conference on Harmonization guidelines), applicable government regulations 
and Institutional research policies and procedures.  
1.1 
Background 
Malignant melanoma is a virulent disease claiming almost 8600 patients annually in the United 
States.(1) the median survival with metastatic disease is usually less than one year. Systemic 
therapies are largely ineffective in this disease and there are no approved therapies beyond first 
line treatment.(2) In 2010 Hodi, et al, published the first phase III randomized trial demonstrating 
a survival benefit in metastatic melanoma using the immunotherapeutic agent ipilimumab, an 
anti-CTLA-4 antibody.(3) This was a multi-institutional randomized, double-blind phase III trial in 
previously treated patients with a diagnosis of unresectable stage III or IV melanoma. Patients 
were randomized in a 3:1:1 ratio, to treatment with an induction course of ipilimumab, at a dose 
of 3 mg per kilogram of body weight, plus a gp100 peptide vaccine; ipilimumab plus gp100 
placebo; or gp100 plus ipilimumab placebo — all administered once every 3 weeks for four 
treatments. The median overall survival was 10.0 months among patients receiving ipilimumab 
plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio 
for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months 
(hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in 
overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus 
gp100, 1.04; P = 0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of 
patients treated with ipilimumab and in 3% treated with gp100 alone. The best overall response 
rate was 5.7% and 10.9% in the two ipilimumab arms. Although these results are promising, the 
fact that only approximately 10% of patients responded to ipilimumab suggests that this strategy 
is not effective for all patients with metastatic disease.  
 
Mechanism of action of ipilimumab and relevance for melanoma 
T lymphocytes are prime mediators of tumor immuno-surveillance, particularly for patients with 
melanoma in whom T cell infiltration into tumors predicts clinical outcome and for whom 
immunotherapeutic strategies have in some cases shown clinical utility. In the course of 
interactions between antigen presenting cells (APC) and T cells, surface expression of the co-
stimulatory molecules CD80 and CD86 is upregulated.  Initially, CD80/86 ligates and activates 
CD28 which is constitutively expressed on T-cells resulting in their activation. Cytotoxic T-
lymphocyte antigen-4 (CTLA-4; CD152) is a cell-surface receptor that is expressed (within 
approximately 72 hours in vitro) on T-lymphocytes in response to their activation by interaction 
with APCs or pharmacologic stimulation of the T-cell receptor.  CTLA4 has a substantially 
higher affinity for CD80 and CD86 than CD28; its activation down-modulates T-cell proliferation 
and cytokine secretion, effectively limiting the immune reactivity directed against a given antigen 
stimulus. Therefore, inhibition of CD80/86 binding to CTLA4 is a potential strategy to prevent 
down-regulation of the immune response. Ipilimumab, a fully human monoclonal antibody 
(IgG1) blocks CTLA-4 and has been shown to promote antitumor immunity in patients with 
metastatic melanoma and was approved for use by the FDA in March 2011 for patients with 
metastatic melanoma.(4) The effectiveness of this strategy is predicated upon T-lymphocyte 
activation through interaction with the APC to have occurred. CTLA-4 blockade can then 
prevent the down-regulation of the anti-tumor immune response. The development of novel 
strategies that successfully “vaccinate” patients to their melanoma prior to the delivery of CTLA-
4 are important area clinical research.  
 
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Stereotactic Body Radiation Therapy (SBRT) 
Stereotactic body radiotherapy (SBRT) is a highly precise treatment technique that delivers 
large tumoricidal doses of radiation to a small tumor. Although this represents one of the most 
exciting and active frontiers of research in the radiotherapeutic management of early stage 
NSCLC, this treatment technique was originally developed in 1951 by a Swedish neurosurgeon, 
Lars Leksell for the treatment of intracranial metastases.(5) SBRT allows for escalation of dose 
without extending the overall treatment duration, as would be the case with conventional 
fractionated radiotherapy. A Phase I dose-escalation trial evaluated patients with T1-2 N0 
NSCLC with no restriction on tumor location. Each treatment course was administered over 3 
fractions with a starting dose of 8 Gy per fraction. Patients were stratified into 3 dose-escalation 
groups based on T stage and size (T1, T2 <5 cm, and T2 5–7 cm). This trial demonstrated that 
the maximally tolerated dose for T2 tumors larger than 5 cm was 22 Gy × 3 for, and was not 
reached at 20 Gy × 3 for T1 tumors or at 22 Gy × 3 for T2 tumors smaller than 5 cm.(6). There 
were a total of 10 local failures in the 47 patients treated in this study with nine local failures in 
patients treated to the lower dose levels (<16Gy x 3). A Phase II trial from the same group of 
investigators treated 70 patients with Stage I NSCLC with the doses established in the phase I 
study. With a median follow-up of 17.5 months, the local control was 95%, which appears at 
least as effective as a definitive surgical resection. Severe toxicity occurred at a median of 10.5 
months in 17% of those patients with peripheral lesions versus 46% with central lesions.(7) 
Several other institutions have subsequently published their experience utilizing SBRT for early 
lung cancer with a variety of dose fractionation and prescription schemes. The initial data 
appear promising with 80%–100% local control, 40%–100% 2- to 3-year survival, and 0%–4% 
grade 3 toxicity), although in general the median follow-up for these studies is relatively short.(8-
14). Given these promising results, the RTOG (RTOG 0618) has initiated a phase II study of 
stereotactic body radiotherapy for operable patients with early stage operable NSCLC.  
Additionally, Dr. Robert Timmerman initiated a randomized trial of surgical resection vs. 
stereotactic body radiation for early stage lung cancer in early 2010 (RTOG 1021). While the 
results of these studies are eagerly anticipated, the ability to treat early stage lung cancer with 
SBRT is rapidly being incorporated into most Radiation Oncology facilities here in the United 
States.  
 
SBRT in the setting of metastatic disease 
SBRT is being used increasingly in the setting of metastatic disease. Initially, it was integrated 
as an ablative approach with a goal of tumor sterilization in oligometastatic disease with minimal 
morbidity and good long-term clinical outcome in these highly selected patients.(15-17) 
Subsequently, data have emerged that SBRT provides effective palliation in the metastatic 
setting for palliation of bone, lung, liver, and subcutaneous/nodal metastases with minimal 
morbidity.(15, 16, 18-20) As such, SBRT is being increasing utilized in the metastatic setting for 
palliative intent. 
 
SBRT and Immune Activation 
There is emerging evidence that hypofractionated radiotherapy is immunostimulatory. In a 
recently published study in Blood, Lee et al demonstrated that the therapeutic effect with 
ablative hypofractionated radiotherapy was dependent upon activation of CD8+ T- 
lymphocytes.(21) Additionally, there are pre-clinical data to suggest that CTLA-4 blockade along 
with ablative radiotherapy to an index lesion can prevent metastatic dissemination of 
disease.(22, 23) Finally, there are clinical data to suggest that SBRT provides greater local 
control and a reduction in regional and distant dissemination of disease when compared with 
surgery alone in NSCLC. One hypothesis to explain these surprising data is that the 
 
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immunostimulatory effect of SBRT results in improved control of disease and prevention of 
spread.(24) 
 
Summary 
We propose a stratified phase I/II clinical trial of SBRT to an isolated index lesion followed by 
ipilimumab in patients with previously untreated or previously treated metastatic melanoma in 
patients eligible for CTLA-4 blockade. In our protocol, the goal is to “vaccinate” patients against 
their melanoma via SBRT and then to elaborate the induced immune response with the FDA-
approved CTLA-4 blocking antibody ipilimumab. 
 
 
2 Study Objectives 
The overall objective of the study is to determine the feasibility of delivery of SBRT to an index 
lesion in patients with metastatic melanoma prior to standard of care immunotherapy with 
ipilimumab.  
 
Primary Objective 
The primary objectives are to determine feasibility and immune-related clinical responses 
associated with SBRT when given in conjunction with ipilimumab.  
 
Secondary Objective 
The secondary objectives are to determine late toxicity and immune pharmacodynamic changes 
after SBRT followed by ipilimumab.  
 
 
3 Study Design 
3.1 
General Design 
This is a stratified phase II study of escalating fractions of stereotactic body radiotherapy 
(SBRT) combined with immunotherapy for previously untreated or previously treated metastatic 
melanoma patients. Patients will undergo a short course of high dose SBRT to a single index 
lesion that measures 1 cm to 5 cm. These fractions will be administered several days apart. 
Radiotherapy will be immediately followed by ipilimumab, at the FDA-approved dose and 
schedule.  
 
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Study Duration: The expected accrual rate = 15 pts/yr. The protocol is designed for a maximum total of 40 
patients.  The expected total study duration is 3 to 3 ½ yrs needed to complete both phases, allowing for 
suspensions for interim analyses. 
*Study Enrollment is intended to mean consultation 
3.2 
Primary Study Endpoints 
 
Late toxicity is defined generally as an adverse event associated with the treatment which 
occurs beyond 30 days after last injection of ipilimumab (i.e., adverse events which are 
observed months after treatment are most likely associated with SBRT) and is defined more 
precisely in Section 5.2. 
 
Clinical response will be scored on a non-index lesion or lesions using immune-related 
response criteria (irRC). Immune-related progression-free survival (irPFS) is defined as the time 
from first day of radiotherapy to first documented irPD, death due to any cause or last patient 
contact alive. Immune pharmacodynamic changes will be examined, as described in Section 
7.22.(25) Overall immune response is defined as >2-fold pre-treatment/post-treatment increase 
in any of the key T cell parameters. 
 
HYPOFRACTIONATED 
STEREOTACTIC BODY RADIOTHERAPY (SBRT) 
TO A SINGLE INDEX LESION 
BONE OR LG DL-1 8GY X 2; DL1 8GY X 3 
LIVER OR SUB-Q DL-1 6GY X 2; DL1 6GY X 3 
CT (or MRI) FOR RT PLANNING 
(CAN SERVE AS BASELINE SCAN IF PRIOR 
IS >4 WEEKS OLD) 
DAY -14: STUDY 
ENROLL/CONSULT 
FIRST RADIOTHERAPY 
TREATMENT 
 
SECOND RADIOTHERAPY 
TREATMENT  
THIRD RADIOTHERAPY 
TREATMENT (DL1 ONLY) 
IPILIMUMAB 
3MG/KG EVERY  
THREE WEEKS 
FOR FOUR 
TREATMENTS 
IPILIMUMAB #1 
IPILIMUMAB #3  
IPILIMUMAB #4/PBC 
FOLLOW-UP IMAGING 
(per standard of care, usually  60 days  
POST-IPI AND THEN EVERY 3 MONTHS 
)
ELIGIBILITY: PREVIOUSLY UNTREATED OR PREVIOUSLY TREATED 
METASTATIC MELANOMA PATIENTS
RADVAX TRIAL 
BASELINE PBC 
OPTIONAL BIOPSY 
IPILIMUMAB #2   
Follow up within 30 days of last 
Ipi infusion /PBC DRAW
PBC draw 
 
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4 Subject Selection and Withdrawal 
4.1 
Inclusion Criteria 
 
Patient >18 years old 
 
Histologically confirmed diagnosis of melanoma 
 
Previously treated or previously untreated stage IV melanoma by AJCC staging 
criteria 
 
Presence of an index lesion between 1 and 5 cm 
 
ECOG Performance status 0 ,1, or 2 
 
Signed informed consent document  
 
Adequate renal, hepatic, and hematologic indices for ipilimumab therapy 
 
Ability to tolerate stereotactic body radiation therapy (e.g. lie flat and hold position for 
treatment) 
4.2 
Exclusion Criteria 
 
Prior systemic therapy within 14 days of study enrollment.  Patients must be 
adequately recovered from prior systemic therapy side effects as deemed by the 
treating investigator.   
 
Clinical contraindication to stereotactic body radiotherapy (e.g. active systemic 
sclerosis, active inflammatory bowel disease if bowel is within target field, etc) 
 
Presence of central nervous system metastasis (including active brain metastasis). 
Active brain metastasis would be defined as untreated brain metastases.  If the brain 
metastases have received prior treatment (usually either with surgery or radiation), 
they are no longer active. 
 
Long-term use of systemic corticosteroids. Patients with replacement steroids and not 
immunosuppressive steroids may enroll in the study. 
 
Prior RT that precludes the delivery of SBRT 
 
INCLUSION OF WOMEN AND MINORITIES 
Female and male patients of all ethnic groups will be eligible for treatment in this protocol.  
Protocol accrual will be reviewed annually to include a determination of minority representation.  
An attempt will be made to enroll patients with metastatic melanoma in a distribution that 
matches the frequency of melanoma in the general population.  The following melanoma 
incidence rates are reported by SEER: White 25.2 cases per 100,000; African-American 1.05 
cases per 100,000; Asian/Pacific Islander 1.4 cases per 100,000; Hispanic 3.95 cases per 
100,000.(26) 
 
4.3 
Subject Recruitment and Screening 
Patients will be referred and screened by institutional standard practice.   After the eligibility is 
established, a subject study number will be issued and the patient will be enrolled. 
 
 
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4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
 
Progressive Disease as determined by irRECIST 1.1 criteria.   
 
Extraordinary Medical Circumstances.  If at any time the constraints of this protocol are 
detrimental to the subject’s health, the subject will be removed from protocol therapy.  In 
this event, the reasons for withdrawal will be documented.   
 
 
Subject’s refusal to continue treatment.  In this event, the reasons for withdrawal will be 
documented. 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Every effort will be made to follow subjects off study for toxicity, disease progression and 
survival. 
5 Study Drug  
5.1 
Description 
Ipilimumab is FDA approved for patients with metastatic melanoma and the delivery of this drug 
will be performed according to the FDA-approved dose and schedule. The Scientific Review 
Committee (SRC) has advised that an IND exemption is appropriate and will therefore be 
sought prior to initiation of this trial.  
5.2 
Dose Limiting Toxicities Definitions 
 
Dose-limiting (Acute) Toxicity is defined as any treatment related Grade 4 or higher immune-
related toxicity or Grade 3 or higher non-immune related toxicity which is observed during 
treatment or within 30 days of the final ipilimumab injection and which is probably or definitely 
related to radiation treatment. This definition will be used for de-escalation to the -1 dose level. 
All toxicities will be graded by NCI CTC Version 4.0.  
 
Late toxicity Late toxicities will be graded according to the RTOG/EORTC late morbidity scoring 
system. The time frame for late toxicity is open-ended and late toxicities have been known to 
occur a year or more after therapy. Follow-up for late toxicity will cease when a patient 
experiences disease progression, since 2nd line therapies may then be initiated.  
 
Non immune-related toxicity (SBRT-related toxicity) is defined as any toxicity observed within 
the tissues contained within the radiation portal and is consistent with tissue reaction to radiation 
exposure at any time during follow-up. 
 
Immune-related toxicity is defined as an adverse event that is associated with exposure to 
ipilimumab and that is consistent with an immune phenomenon.  
 
 
 
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6 Study Procedures 
6.1 
General Study Design 
This is a stratified phase II (with allowance for a (-1) dose level) study of stereotactic body 
radiotherapy (SBRT) combined with immunotherapy for previously untreated or previously 
treated metastatic melanoma patients. Patients will undergo a short course of high dose SBRT 
to a single index lesion that measures 1 cm to 5 cm. These fractions will be administered 
several days apart. Radiotherapy will be immediately followed by ipilimumab, at the FDA-
approved dose and schedule. 
6.2 
Stereotactic Body Radiation Therapy 
All subjects will be immobilized in a custom designed device in the appropriate position to 
isolate the index lesion. Radiotherapy treatment planning CT scans (with contrast, unless 
contraindicated) will be required to define the gross target volume (GTV) and planning target 
volume (CTV). The treatment planning CT scan should be acquired with the subject in the same 
position and using the same immobilization device as for treatment. Treatment planning will be 
done using a 3D based CT treatment planning system.  All tissues to be irradiated must be 
included in the CT scan. Planning CT scan will be done at 3 mm intervals from encompassing 
the region of interest with sufficient margin for treatment planning.  
6.2.1 Stereotactic Targeting and Treatment 
SBRT has now been formally defined and described in a published guideline from the American 
College of Radiology and American Society for Therapeutic Radiology and Oncology (Potters 
2004). This protocol will respect that guideline. The term stereotactic, for the purposes of this 
protocol, implies the targeting, planning, and directing of therapy using beams of radiation along 
any trajectory in 3-D space toward a target of known 3-D coordinates. The coordinate system is 
defined by reliable “fiducial” markers. This differs from conventional radiation therapy, in which 
therapy is directed toward less-than-reliable skin marks or bony landmarks that are indirectly 
referenced to the tumor (surrogates). This protocol will require treatments to be conducted with 
the use of a fixed 3-D coordinate system defined by fiducials. The coordinate system defined by 
the fiducials should be directly related to the radiation-producing device in a reproducible and 
secure fashion. Capability should exist to define the position of targets within the patient 
according to this same 3-D coordinate system. As such, the patient is set up for each treatment 
with the intention of directing the radiation toward a target according to the known 3-D 
coordinates as determined in the process of treatment planning. The nature of the fiducials 
themselves may include radiopaque markers or rods placed at known locations in a frame or 
fixed structure adjacent to the patient as well as use of the tumor itself as a fiducial (e.g., 
acquiring tomographic views of the tumor simultaneously with the treatment). Metallic “seeds” 
placed within the tumor will be allowed to constitute a fiducial so long as the methods are 
validated and a plan is in place to identify seed migration (e.g., redundant seeds placed). 
 
6.2.2 Target Contouring 
 
Gross Tumor Volume (GTV) is defined as all known gross disease encompassing the selected 
index lesion. The GTV will consist of the index lesion as visualized on CT.   
 
Internal Gross Tumor Volume (IGTV) is defined for mobile index lesions at the discretion of the 
treating physician. A 4-D CT scan will be acquired in order to account for the motion of the 
lesion during. The IGTV will be defined as the union of the visualized index lesion on all gated 
CT data sets. 
 
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Planning Target Volume (PTV) will be defined as per the convention for photon beam 
radiotherapy. A 3-dimensional margin will be created on the GTV or IGTV (if available) to allow 
for daily set-up variance.  
 
6.2.2 Normal Structures  
 
Organ at risk volume (OAR) is contoured as visualized on the planning CT or MR scan.  
Planning PAR is the OAR expanded for setup uncertainty or organ motion.  The physician will 
contour the OAR.  The dosimetrist will create the PAR by expanding the OAR by 2-3 mm, 
depending on the situation. 
 
6.2.3 Dose fractionation and specification  
 
The prescription dose per fraction to the PTV will be 8 Gy per fraction for a bone or lung index 
lesion and 6Gy per fraction for any liver or subcutaneous index lesion.  
 
The total dose for dose level 1 (our starting dose level) will be one will be 24Gy over 3 fractions 
for a bone or lung index lesion and 18Gy over three fractions for any liver or subcutaneous 
index lesion. 
 
If we encounter a dose limiting toxicity, we will then reduce our total dose to dose level -1. The 
total dose for dose level -1 will be 16Gy over 2 fractions for a bone or lung index lesion and 
12Gy over two fractions for any liver or subcutaneous index lesion. 
 
Dose rate: For the purpose of this study, dose rate utilized will be that which is commissioned by 
the manufacturer and the medical physics group for external beam radiotherapy delivery by the 
University of Washington Department of Radiation Oncology. There will be no special dose rate 
modifications required for this study.  
 
6.2.4 Treatment Planning  
 
Three-dimensional coplanar or non-coplanar beam arrangements will be custom designed for 
each case to deliver highly conformal prescription dose distributions. Non-opposing, 
noncoplanar beams are preferable. Typically, ≥ 10 beams of radiation will be used with roughly 
equal weighting. Generally, more beams are used for larger lesion sizes. When static beams 
are used, a minimum of 7 non-opposing beams should be used. For arc rotation techniques, a 
minimum of 340 degrees (cumulative for all beams) should be utilized. For arc rotation 
techniques, a minimum of 340 degrees (cumulative for all beams) should be utilized. In order to 
obtain acceptable coverage, field aperture size and shape should correspond nearly identically 
to the projection of the PTV along a beam’s eye view (i.e., no additional “margin” for dose 
buildup at the edges of the blocks or MLC jaws beyond the PTV). The only exception should be 
when observing the minimum field dimension of 3.5 cm when treating small lesions (see 
above). As such, prescription lines covering the PTV will typically be the 60-90% line (where the 
maximum dose is 100%); however, higher isodoses (hotspots) must be manipulated to occur 
within the target and not in adjacent normal tissue. The treatment isocenter or setup point in 
stereotactic coordinates will be determined from system fiducials (and can be adjusted pre-
treatment depending on the results from localization imaging studies) and translated to the 
treatment record. 
 
 
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Dose specifications: Successful treatment planning will require accomplishment of all of the 
following criteria: 
 
1. 
Maximum dose: The treatment plan should be created such that 100% corresponds to 
the maximum dose delivered to the patient. This point must exist within the PTV. 
2. 
Prescription isodose: The prescription isodose surface must be ≥ 60% and < 90% of 
the maximum dose. 
3. 
Prescription Isodose Surface Coverage: The prescription isodose surface will be 
chosen such that 95% of the target volume (PTV) is conformally covered by the 
prescription isodose surface (PTV V95%RX = 100%) and 99% of the target volume 
(PTV) receives a minimum of 90% of the prescription dose (PTV V90%RX > 99%). 
4. 
High Dose Spillage: The cumulative volume of all tissue outside the PTV receiving a 
dose > 105% of prescription dose should be no more than 15% of the PTV volume. 
Conformality of PTV coverage will be judged such that the ratio of the volume of the 
prescription isodose meeting criteria 1 through 4 to the volume of the PTV is ideally < 1.2 
(see table below). These criteria will not be required to be met in treating very small 
tumors (< 2.5 cm axial GTV dimension or < 1.5 cm craniocaudal GTV dimension) in 
which the required minimum field size of 3.5 cm (see Section 6.2) results in the inability 
to meet a conformality ratio of 1.2. The “None” and “Minor” entries in this table define the 
Per Protocol, Variation Acceptable and Deviation Unacceptable Compliance Criteria 
(see Section 6.7). 
5. 
Intermediate Dose Spillage: The falloff gradient beyond the PTV extending into normal 
tissue structures must be rapid in all directions and meet the following criteria: 
a. 
Location: The maximum total dose over all fractions in Gray (Gy) to any point 2 cm 
or greater away from the PTV in any direction must be no greater than D2CM 
where D2CM is given by the table below. 
b. 
Volume: The ratio of the volume of the 34 or 12 Gy isodose volume to the volume 
of the PTV must be no greater than R50% where R50% is given by the table below 
(adapted from RTOG 0915). This table is used for all prescription requirements in 
Section 6.2.4 irrespective of calculation algorithm and total treatment dose. 
 
 
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6.3 
Ipilimumab Administration 
Ipilimumab will be given in the outpatient setting. Patients will receive ipilimumab at 3 mg/kg i.v. 
delivered as per the package insert every 3 weeks (+/- 2 days) for treatments. Patients will be 
monitored in the clinic after the infusion and discharged when deemed stable by the clinical 
staff. Medications to treat hypersensitivity reactions should be immediately available, and may 
include epinephrine, diphenhydramine, methylprednisolone and nebulized albuterol. 
 
6.4 
Study Visit Schedule 
After the subject consents and is deemed eligible for the study baseline imaging appropriate for 
RECIST criteria will be obtained (if not previously done or it has been greater than 60 days 
since the last scan) and a blood draw for purpose of immunological studies will be drawn.  
Baseline and post-treatment imaging will be evaluated by immune-related Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1. This will be referred to as irRECIST 1.1 criteria 
described in section 7.1.1.  Subjects will then be seen in the outpatient clinics to assess 
treatment-related toxicities once during radiation treatment.  At this visit, a history and targeted 
physical examination will be performed. 
 
During ipilimumab administration following radiotherapy, subjects will be evaluated by one of the 
investigators or their designated nurse practitioner at the time of each infusion.  A history and 
directed physical examination will be performed. 
6.5 
Study Calendar 
 
Eligibility/Pre
-Treatment 
Post-
SBRT; 
Pre- Ipi 
Ipilimumab 
Clinic Visits 
EOS visit  
Tests and 
Observations 
 
 
 
 
History and PE 
X 
 
X 
X(as per 
 
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standard of 
care, usually 
within 60 days 
of final 
ipilimumab 
infusion) 
ECOG score 
X 
 
X 
X 
Radiographic 
imaging appropriate 
for ir-RECIST 1.1 
criteria (should be the 
same modality at 
baseline and EOS) b 
X 
 
 
X(as per 
standard of 
care, usually 
within 60 days 
of final 
ipilimumab 
infusion) 
Biopsy  
X 
 
 
XC 
Laboratory 
 
 
 
 
CBC 
w/diff, 
Hgb, 
Platelets…b  
X 
Xd 
Xd 
 
CMPb 
 
X 
Xd 
Xd 
 
Pregnancy Test 
Xa 
 
 
 
Toxicity Assessment 
X 
X 
X 
X 
Immune studies 
(Eight  8.5 ml yellow 
top tubes and one 10 
ml SST tube) 
X 
Xd 
Xd 
x 
 
Xa- Required for women of childbearing potential.  If pre-treatment is 30 days from eligibility, you should repeat a 
pregnancy test within 24 hours of treatment initiation.   
Xb- Measurements cannot be more than 60 days from the beginning of treatment. 
XC- As clinically indicated, tumor blocks and/or slides from EOS biopsy or surgery will be collected on all patients.  
Xd- The post-SBRT; pre-Ipi  Ipilimumab #1 Immune studies and routine clinic blood draw may be combined if last 
SBRT and the first injection of Ipilimumab will occur within 5 days of each other.  
 
6.6 
Post-treatment Evaluation and follow-up 
Patients will be evaluated per standard of care, usually within 60 days after last ipilimumab 
treatment (End of Study visit, EOS) to determine feasibility and safety (acute toxicity) for the 
initial phase of the study.  Follow-up imaging appropriate for ir-RECIST 1.1 criteria will be 
obtained within 60 days of the final dose of ipilimumab for restaging.  The same imaging 
modality should be used at follow-up as at baseline. Specimens for immune correlates will also 
be drawn at this visit. Patients will then be referred to the referring physician for subsequent 
follow up, according to standard of care. Every effort will be made to obtain records of patients 
during this follow up, and permission will be sought for the investigators and/or study team to re-
contact the patient directly with regard to health status and toxicity. 
 
 
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7 Assessment of Tumor Response   
7.1.1 Tumor Response (Immune-related response criteria) 
Overall clinical response which will be assessed by Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1, using primarily CT scans, immune response criteria and/or 
clinical benefit as assessed by the investigator). This will be referred to as irRECIST 
7.1.2  1.1. Immunological Outcome Assessment 
 
Blood samples from patients for immune studies will be obtained as in the Schedule of Activities 
table for assays such as those noted below. The extent of immune assessment will depend on 
availability of cells or serum.  
 
Analysis of antigen presenting cell (APC) activation. For this assay, peripheral blood 
lymphocytes are analyzed for evidence of APC activation. Using unmanipulated peripheral 
blood, B cells and dendritic cells before and after treatment can be analyzed using flow 
cytometry to measure cell surface immune markers using a panel of immune parameters such 
as CD19, CD123, CD11c (to define the subsets) and CD86, MHC class I and II, CD70, and 
CD54 to measure activation. Dead cells are excluded using 7-AAD and non-B cells or non-DC 
are excluded using a panel of mAb, all analyzed on a “dump” channel. For each parameter and 
each APC, the percentage of cells positive for the marker and/or MFI at time points after CP-
870,893 infusion are compared to baseline and the change are calculated as %after/%baseline or 
MFIafter/MFIbaseline. 
 
 
Analysis of T cell activation. Three main assays are available to assess T cells before and after 
treatment:  
 
1. Multi-parameter flow cytometry. Together with complete blood count differentials, flow 
cytometry are used to measure both the percentages and absolute count (cells/mm3) of 
important T cell subsets defined by immunophenotyping, such as total CD3+ cells, CD3+ CD8+ 
T cells, CD3+ CD4+ T cells, and CD3+ CD4+ Foxp3+ regulatory T cells. For each subset, 
differentiation status (e.g. naïve, central memory, effector memory) or activation status are 
assessed using additional markers such as CD45RA, CD45RO, CCR7, CD28, CD27, CD57, 
CD25, CD69, HLA-DR, CTLA4, and PD-1. When possible, trends can be tracked in T cell 
subsets based on analysis of multiple post-treatment samples. NK cells subsets can also be 
assessed using CD16 and CD56, with CD69 as an activation marker.  
 
2. Antigen-specific T cell assays. To determine if treatment is associated with the 
induction of tumor antigen-specific CD8+ T cell responses, a series of assays to measure 
specific T cell responses, comparing pre and post treatment samples, are available. The 
immune assessment approach employed depends in large part on the patient’s HLA type. 
Priority will be placed on assessment of specific T cells after one round of in vitro stimulation. 
For patients expressing common HLA alleles such as HLA-A2, in vitro stimulation of peripheral 
T cells can be performed using peptides derived from melanoma antigens known to bind to HLA 
alleles that match the patient. For HLA-A2 patients, specific T cell induction can be enumerated 
with peptide/HLA-A2 tetramers and function can be measured by intracellular IFN-gamma 
production in response to peptide loaded T2 cells. For non-HLA-A2 patients, T cell response 
can be measured using peptide-loaded autologous PHA blasts.  
 
3. Tumor-specific T cell assays. For patients of any HLA type, tumor-specific responses 
can be measured using RNA loaded APC for in vitro stimulation of patient T cells. In this 
approach, CD40-activated B cells are generated from patient baseline samples, electroporated 
 
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with either total tumor RNA pooled from allogeneic melanoma cell lines or autologous total 
tumor RNA (when available) vs. GFP mRNA as a control. After 7 days in culture, stimulated 
autologous T cells can be scrutinized for responses specific for intracellular IFN-gamma 
response to autologous PHA blasts electroporated with tumor RNA vs. GFP mRNA.  
 
Serum cytokine analysis. For this assay, serum can be used to determine concentrations of 
cytokines including IL-1, TNF-alpha, IL-6 and others using Luminex or Cytokine Bead Array 
platforms.  
 
Specimens collected at the University of Washington and Seattle Cancer Center will be de-
identified, frozen, and analyzed at the end of the study. 
 
As research collaborations are developed with other immunology laboratories, de-identified 
specimens may be sent to labs for additional immunological testing.  In addition, some 
specimens may be retained at the University of Washington for future, immunological research.   
 
 
8 Statistical Plan 
 
8.1       Design 
 
This is a stratified Phase II study of escalating fractions of stereotactic body radiotherapy 
(SBRT) combined with immunotherapy for previously untreated or previously treated metastatic 
melanoma patients. Patients will undergo a short course of high dose SBRT to a single index 
lesion that is suitable for SBRT. These fractions will be administered several days apart. 
Radiotherapy will be immediately followed by ipilimumab, at the FDA-approved dose and 
schedule. 
 
Stratified Phase II study: With safety data from an identical University of Pennsylvania study, 
SBRT fractions of  two and three fractions has been shown to be safe.  At UW/SCCA the Phase 
II study begins with Dose Level 1. If three fractions of SBRT are found to not be safe, the dose 
level will be reduced to Dose level -1 for the phase II portion of that stratum. 
 
 
 
 
 
 
Stratification by Site of Index Lesion Site 
 
Dose 
Level 
Stratum 1: bone or lung 
Stratum 2: liver or subcutaneous 
Dose per 
fraction 
 
Fractions 
 
# Patients 
Dose per 
fraction 
 
Fractions 
 
# Patients 
-1 
8 Gy 
2 
6 
6 Gy 
2 
6 
1 
8 Gy 
3 
6 
6 Gy 
3 
6 
 
The MTD has been defined by the Phase I trial at the University of Pennsylvania as 3 fractions 
of SBRT.  The Phase II study can commence at UW/SCCA at dose level 1 (above). Patients will 
be treated at the MTD defined for their index lesion site. In Phase II, patients will be stratified by 
disease site: Stratum 1: phase 1 bone or lung and Stratum 2: phase 1 liver or subcutaneous. 
Stratum-specific response rates will be calculated. Enrollment will proceed independently for the 
 
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two strata. Forty total patients will be enrolled in this phase. Thus a maximum of 40 patients will 
be entered at the MTD. Twenty patients will be enrolled in each stratum 
 
8.2      Objectives: 
 
Phase II study: The primary objectives are to determine for each stratum, immune-related 
clinical response rate, immune-related progression-free survival rate at 6 months (irPFS6), and 
overall survival rate at 12 months (OS12). The secondary objectives are to gather additional 
data on acute and late toxicity and immune pharmacodynamic changes. 
 
8.3       Endpoints 
 
Toxicity: CTCAE version 4.0 grades will be employed. Any patient who receives any amount of 
radiotherapy or study medication will be included in the toxicity analysis.  
 
Dose-limiting toxicity (DLT) is defined generally as associated with the treatment, and for 
ipilimumab, that the event must be consistent with an immune-related effect. DLT is 
experienced during study treatment or within 30 days after last injection of ipilimumab, as long 
as the patient has not started another systemic treatment for cancer and is defined more 
precisely in Section 5.2.  
 
Maximum tolerated SBRT fraction (MTD) is defined as the SBRT fraction dose level at which 0-
1/6 patients experience DLT and at least 2 patients treated at the next higher dose level 
experience DLT (or the apparent MTD is Dose level 1). 
 
Late toxicity is defined generally as an adverse event associated with the treatment which 
occurs beyond 30 days after last injection (i.e., adverse events which are observed months after 
treatment are most likely associated with SBRT) and is defined more precisely in Section 5.2.   
 
Response: Immune-related clinical response will be scored on a non-index lesion using 
immune-related response criteria (irRC) according to irRECIST 1.1 (48). Patients who do not 
complete a clinical response evaluation, with the exception of those patients with rapidly 
progressing disease, will be scored as unevaluable. The immune-related clinical response rate 
is defined as the proportion of patients treated at the MTD who achieve either a complete or 
partial immune-related response. Unevaluable patients are included in denominator for the 
calculation of the objective response rate. 
 
 
Immunologic outcomes include: 1) analysis of lymphocyte subsets and lymphocyte activation, 2) 
analysis of antigen-specific T cells and 3) tumor-specific T cells, as described in Section 7.2.2. 
For T cell response analyses, overall immune response is defined as >2 fold pre-treatment/post-
treatment increase in any of the key T cell parameters. 
 
8.4       Plans for De-escalation 
 
A DLT rate >33% is considered unacceptable. Enrollment will proceed independently in the two 
strata.  If a DLT is observed, then all subsequent patients will be treated at Dose Level -1.   
 
8.4.1     Escalation Design  
 
 
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Because of the successful outcome with 2 and 3 fractions of SBRT in the University of 
Pennsylvania Phase 1 trial, the initial dose level in this study will be Dose level 1 (3 fractions of 
SBRT). 
 
Dose level 1. This trial will begin enrolling at dose level 1, 3 fractions of SBRT, which has been 
shown to be safe in the Phase 1 trial at University of Pennsylvania. However, if one DLT has 
been observed in any patient, then all remaining patients must be followed for 30 days after the 
4th or final injection. Two or more DLTs will cause de-escalation to Dose level -1, which will be 
the MTD. 
 
Dose level  -1. If two or more DLTs are observed in Dose Level 1, then all subsequent patients 
will be treated at Dose Level -1.  If DLTs are observed at dose level -1, this will cause 
termination of the study. 
 
Replacement of patients:  Subjects/patients who discontinue from the study for reasons 
unrelated to the study (e.g. personal reasons or adverse events after registration but prior to 
receiving study therapy) may be replaced as required for the study to meet its objectives. 
Patients that have received study therapy, but who withdraw for reasons unrelated to toxicity 
prior to the required observation period to determine absence of DLT, will not count toward dose 
escalation rules and may be replaced as required. The decision to remove a subject/patient and 
to replace dropouts will be made by the principal investigator. The replacement will receive the 
same treatment or treatment sequence (as appropriate) as the allocation number replaced.  
 
 
8.4.2     Operating Characteristics 
 
To assure safety in this Phase II trial, the operating characteristics of the above-defined 
escalation rule have been determined. The operating characteristics denote the probability of 
escalation to the next SBRT fraction dose level, for a true DLT rate at the current dose level. For 
a true DLT rate that is high, we desire the probability of escalation to be low. As noted in the 
table below, the probability of escalating beyond a certain dose level, if that dose level truly has 
e.g. a 40% DLT rate, is 0.23. 
 
 
Operating characteristics of the escalation rule 
 
True DLT rate at a particular dose level 
Probability 
of escalating 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
0.89 
0.66 
0.42 
0.23 
0.11 
0.04 
0.01 
0.002 
<0.001 
 
8.4.3 Assessment of Late Toxicity 
Late toxicity is defined as an adverse event which occurs beyond 30 days from last injection of 
ipilimumab, as detailed in Section 5.2. Adverse events which are observed months after 
treatment will be recorded. We will monitor for both immune-related and SBRT-related events 
as described in Section 5.2.  
 
8.5       Plans for Data Analysis 
 
Toxicity: Any patient who receives any amount of radiation or study medication will be analyzed 
for toxicity. All dose-limiting toxicities and late toxicities will be graded and tabled by lesion site 
 
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stratum and SBRT fraction dose level. Toxicity attribution to either SBRT or ipilimumab will be 
described if possible. 
 
Response: Clinical response at a non-index lesion will be scored using the immune-related 
response criteria (irRC) referred to as irRECIST 1.1 and discussed by others.(25,26)  The index 
lesion will not be included in measuring response. The number of immune-related responses 
will be tabled by stratum and SBRT fraction dose level. At the MTD, the immune-related 
response rate and 95% exact CI will be estimated separately for previously untreated and 
previously treated metastatic patients and will inform our decision-making. The table below 
displays 95% exact CIs for selected numbers of responses. 
 
95% Exact Confidence Interval for Event Rate based on 
14 patients in each stratum at the Maximum Tolerated SBRT Fraction 
No. of Events 
% 
95% exact CI 
No. of Events 
% 
95% exact CI 
2 
14.3 
1.8 – 42.8 
10 
71.4 
41.9 – 91.6 
4 
28.6 
8.4 – 58.1 
12 
85.7 
57.2 – 98.2 
6 
42.9 
17.7 – 71.1 
14 
100.0 
80.7* 
8 
57.1 
28.9 – 82.3 
* lower bound of 95% 1-sided CI 
 
Immune-related progression-free and overall survival will be estimated by the Kaplan-Meier 
method separately for previously untreated and previously treated metastatic patients who were 
treated at the MTD. The estimated 6 month irPFS and 12 month OS rates and 95% CIs will 
inform our decision-making, as they are considered by many to be better measures of clinical 
benefit. Interestingly, PFS6 and OS12 rates were approximately 25% and 45%, respectively, in 
137 previously treated metastatic melanoma patients treated with ipilimumab alone.(3) 
Evaluation using historical benchmarks has been proposed by Korn et. al. for Phase II decision-
making in metastatic melanoma (27).  
 
Immunologic Endpoints: For measures of lymphocyte activation, outcomes will first be described 
using plots and descriptive statistics. Natural log transformation may be applied, as necessary, 
prior to statistical comparison. Within-patient differences (e.g., baseline vs. post-treatment) will 
be examined by Student’s t test for paired data or nonparametric Wilcoxon signed ranks test. 
For lymphocyte analyses, outcomes will first be described using plots and descriptive statistics. 
For T cell response, the number of immune responses (>2 fold pre/post increase) will be tabled 
by fraction dose level. The overall immune response rate and 95% exact CI will be estimated 
separately for previously untreated and previously treated metastatic patients treated at the 
MTD. 
  
With several post-treatment samples intended, trends over time may be investigated by 
repeated measures ANOVA (if data are complete). Alternatively, mixed effects models will 
describe trends in individual APC and T cell outcomes measured during immunotherapy, 
including drug doses as fixed effects. Although the number of subjects is modest, serial blood 
measures for immune monitoring are intended.  (Thus, longitudinal modeling may be 
successful. We will attempt to extend this investigation to longitudinal methods for multivariate 
data with the goal of modeling jointly the inter-dependency among several longitudinal 
outcomes. For example, a joint analysis may determine how the association between the 
induction of CD86 on APCs and antigen-specific T cells evolves over time. Because the number 
of immunologic outcomes to be modeled jointly will be small (several at most), we will attempt to 
use the pairwise model fitting approach for maximum likelihood estimation as previously 
described.(27) 
 
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8.6       Sample Size/Power 
 
If the Phase II study investigates both SBRT fraction dose levels for both strata, then a total of 
40 patients will be enrolled on the study. There will be 40 patients enrolled at the Phase II dose. 
An objective response rate of 10.9% (by modified WHO criteria) was observed by Hodi et. al. in 
137 previously treated metastatic melanoma patients treated with ipilimumab alone.(3)  We 
anticipate that the combination of SBRT and ipilimumab will result greater efficacy for each 
stratum. If the true immune-related response rate is 20%, then the probability of observing no 
responses in 14 patients in either stratum, is <0.05.  
 
With regard to statistical power, our preliminary clinical data on 16 patients treated on the 
single-infusion CD40 mAb trial indicate the mean difference + SDdiff between post- and pre-
treatment percentages of CD19+ B cells expressing CD86 were: 17.1% + 11.1%, with effect 
size of 1.5 SDdiff units. By pooling over strata at the MTD, with a total of 28 patients enrolled, 
there is >80% power to detect a more modest effect  size of ¾ SDdiff units, based on a paired t-
test at 2-sided alpha level of 0.005 after adjusting for testing of multiple APC measures. 
Moreover, at the end of our current Phase I study of anti-CTLA-4 antibody (tremelimumab) and 
anti-CD40 antibody (CP-870,893) (UPCC 05609), we will evaluate pre/post differences in 
percentages of CD19+ B cells expressing CD86 and other relevant immune outcomes and we 
will update the power calculation for those effect sizes.    
 
8.7       Study Duration 
 
With an estimated accrual of 15 patients per year, it is anticipated that accrual will continue for 
3.0 to 3.5 years, allowing for observation time within and between dose levels.  
9 Safety Assessment and Adverse Event Reporting 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above, as well as the construction and implementation of a site data 
and safety-monitoring plan (see section 10).  Medical monitoring will include a regular 
assessment of the number and type of serious adverse events. 
 
9.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 
Unexpected in nature, severity, or frequency  (i.e. not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators 
brochure, etc) 
 
Related or possibly related to participation in the research (i.e. possibly related means 
there is a reasonable possibility that the incident experience, or outcome may have been 
caused by the procedures involved in the research) 
 
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
Adverse Event 
 
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An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
adverse events.  Abnormal results of diagnostic procedures are considered to be adverse 
events if the abnormality: 
 
results in study withdrawal 
 
is associated with a serious adverse event 
 
is associated with clinical signs or symptoms 
 
leads to additional treatment or to further diagnostic tests 
 
is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE 
that is:  
 
fatal 
 
life-threatening 
 
requires or prolongs hospital stay 
 
results in persistent or significant disability or incapacity 
 
a congenital anomaly or birth defect 
 
an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance.   They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, 
a seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm 
in an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
 
9.2 
Adverse Events 
Assessment of adverse events will include type, incidence, severity (graded by the National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 
4.03), timing, seriousness, and relatedness; and laboratory abnormalities. Patients who receive 
1 or more study treatments will be evaluable for toxicity. 
 
9.2 .1  Adverse Event Reporting 
In the event of an adverse event the first concern will be for the safety of the subject. The study 
period during which adverse events must be reported is normally defined as the period from the 
initiation of any study procedures to the end of the study treatment follow-up.  For this study, the 
study treatment follow-up is defined as 30 days following the last administration of study 
treatment. Thereafter, only non-hematological related AEs of Grade 3 and can reasonably be 
attributed to the study treatment will be reported. 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
General Physical Examination Findings 
 
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At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that meet 
the definition of an adverse event must also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the investigator should instruct each subject to report any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study.  The investigator should notify the study sponsor of any death or 
adverse event occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study.  The sponsor should also be notified if 
the investigator should become aware of the development of cancer or of a congenital anomaly 
in a subsequently conceived offspring of a subject that has participated in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met:  
 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
 
The abnormality suggests a disease and/or organ toxicity 
 
The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition.  Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
 
Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
   
9.2.2 Adverse Event Causality 
The Investigator will use the following definitions to assess the relationship of the adverse event 
to the use of study treatment: 
 
Related - An adverse event has a strong temporal relationship to study drug, recurs on 
rechallenge or is known to be an effect of the study drug. Another reasonable etiology either 
doesn’t exist or is unlikely. 
 
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Possibly Related - An adverse event has a strong temporal relationship to the study drug 
and an alternative etiology is either equally or less likely when compared to the potential 
relationship to study drug.  
Not Related - An adverse event is due to an underlying or concurrent illness or effect of 
another drug and is not related to the study drug (e.g., has little or no temporal relationship 
to study drug or has a much more likely alternative etiology). 
9.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
Investigators are required to report to the Sponsor-Investigator ANY serious adverse event 
(SAE) as soon as possible.  An SAE is any sign, symptom or medical condition that emerges 
during treatment or during a post-treatment follow-up period that (1) was not present at the start 
of treatment and it is not a chronic condition that is part of the patient’s medical history, OR (2) 
was present at the start of treatment or as part of the patient’s medical history but worsened in 
severity and/or frequency during therapy, AND that meets any of the following regulatory 
serious criteria: 
 
Results in death 
 
Is life-threatening 
 
Requires or prolongs inpatient hospitalization (planned hospitalizations are not 
considered an SAE) 
 
Is disabling or incapacitating 
 
Is a congenital anomaly/birth defect 
 
Is medically significant or requires medical or surgical intervention to prevent one of the 
outcomes listed above. 
 
Serious adverse events require immediate notification to the following party below, beginning 
from the time of the first study treatment through and including 30 calendar days after the last 
treatment administration of ipilumimab. All emergent SAEs should be communicated to: 
 
Ramesh Rengan MD PhD 
Phone: (206)598-4110 
Mobile: (206)890-7195 
Fax:  (206)598-3786 
or via the UW Paging operator (206)598-6190 
 
SAEs will be reported to the Cancer Consortium IRB in accordance with the AE reporting policy. 
 
 
10.0 Regulatory, Quality and Administrative Requirements 
10.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
 
What protected health information (PHI) will be collected from subjects in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research subject to revoke their authorization for use of their PHI.  
 
 
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This material is the property of the study sponsor.  Do not disclose or use except as authorized in writing by the study sponsor 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period. 
 
 
 
10.2  Data and Safety Monitoring Plan 
 
Institutional support of trial monitoring will be in accordance with the FHCRC/University of 
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan.  Under the 
provisions of this plan, FHCRC Clinical Research Support coordinates data and compliance 
monitoring conducted by consultants, contract research organizations, or FHCRC employees 
unaffiliated with the conduct of the study.  Independent monitoring visits occur at specified 
intervals determined by the assessed risk level of the study and the findings of previous visits 
per the institutional DSMP.  
 
The monitors are independent contractors and are external to the Cancer Consortium 
(University of Washington and Fred Hutchinson Cancer Research Center). Study monitors will 
perform ongoing source data verification to confirm that critical protocol data transcribed on the 
CRFs by authorized site personnel are accurate, complete, and verifiable from source 
documents. To facilitate source documentation verification, the investigator(s) and institution(s) 
must provide the Monitor direct access to applicable source documents and reports for trial-
related monitoring, audits, and IRB/EC review.  The investigational site must also allow 
inspection by applicable regulatory authorities. 
 
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and 
Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC) and the 
FHCRC/University of Washington Cancer Consortium Institutional Review Board (IRB).  The 
review committees evaluate accrual, adverse events, stopping rules, and adherence to the 
applicable data and safety monitoring plan for studies actively enrolling or treating patients.  The 
IRB reviews the study progress and safety information to assess continued acceptability of the 
risk-benefit ratio for human subjects.  Approval of committees as applicable is necessary to 
continue the study. 
 
The trial will comply with the standard guidelines set forth by these regulatory committees and 
other institutional, state and federal guidelines. 
 
 
10.3  Compliance with Laws and Regulations 
The proposed study will be conducted according to the International Conference on 
Harmonization E6 Guideline for Good Clinical Practice (GCP) and the Declaration of Helsinki 
and the requirements of the Federal Regulations. Please refer to: 
 International Conference on Harmonization and GCP: 
http://www.fda.gov/oc/gcp/guidance.html 
 Declaration of Helsinki: http://www.fda.gov/oc/health/helsinki89.html 
 Code of Federal Regulations, Title 21:  
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm]   
 
 
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10.4  Informed Consent 
The informed consent documents must be signed and dated by the patient, or the patient’s 
legally authorized representative, before his or her participation in the study. The case history 
for each patient shall document that informed consent was obtained prior to participation in the 
study. A copy of the informed consent documents must be provided to the patient or the 
patient’s legally authorized representative. 
 
10.5  Institutional Review Board 
This protocol, the informed consent document, and relevant supporting information must be 
submitted to the IRB for review and must be approved before the study is initiated. In addition, 
any advertising materials must be a proved by the IRB. The study will be conducted in 
accordance with applicable national and local health authority and IRB requirements. 
The Principal Investigator is responsible for keeping the IRB apprised of the progress of the 
study and of any changes made to the protocol as deemed appropriate, but in any case the IRB 
must be updated at least once a year. In addition, the Principal Investigator is required to 
promptly notify the IRB of all adverse drug reactions that are both serious and unexpected. This 
generally refers to serious adverse events that are not already identified in the Investigator 
Brochure and that are considered possibly or probably related to the study drug by the 
Investigator. 
 
 
10.6 Retention of Records 
 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period if required by an agreement with the sponsor.  In such an 
instance, it is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained.  
 
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Document Release Date: 01/11/2017
Printed on 1/31/2017