Phase II Randomized Study of High Dose Interleukin-2 Versus Stereotactic Body Radiation (SBRT) and High Dose Interleukin-2 (IL-2) in Patients With Metastatic Melanoma
Phase: PHASE2
Conditions: Metastatic Melanoma
Sponsor: Providence Health & Services

EARLE A. CHILES RESEARCH INSTITUTE 
Page 1 
  
 
 
 
 
Protocol Number: 
PH&S IRB: 11-062A  
 
 
Title: 
Phase II Randomized Study of High Dose Interleukin-2 Versus 
Stereotactic Body Radiation (SBRT) and High Dose Interleukin-2 (IL-2) 
in Patients with Metastatic Melanoma 
 
Version Date: 
5/16/2013 
 
Previous Version: 
1/3/2013 
 
Coordinating Center: 
Providence Portland Medical Center 
Earle A. Chiles Research Institute 
Robert W. Franz Cancer Research Center 
4805 NE Glisan St.  Room 2N35 
Portland, OR  97213 
503-215-6805 
 
Co-Principal Investigators: 
Brendan D. Curti, MD 
 
Earle A. Chiles Research Institute 
4805 NE Glisan Street, 2N87 
Portland, OR 97213 
503-215-5696 
FAX 503-215-5695 
brendan.curti@providence.org  
 
Steven K. Seung, MD, PhD 
 
Earle A. Chiles Research Institute 
 
The Oregon Clinic 
4805 NE Glisan Street, Level B 
Portland, OR 97213 
503-215-6029  
503-215-6387 (FAX) 
steven.seung@providence.org  
 
 
 
Marka Crittenden, MD, PhD 
 
 
Earle A. Chiles Research Institute 
The Oregon Clinic 
 
4805 NE Glisan Street, Level B 
Portland, OR 97213 
503-215-6029  
503-215-6387 (FAX) 
marka.crittenden@providence.org  
 
Co-Investigator(s): 
Walter J. Urba, MD, PhD 
Rachel Sanborn, MD 
Todd Crocenzi, MD 
Roxanne Payne, FNP 
Providence Portland Medical Center  
4805 NE Glisan, 6N40 
Portland, OR 97213 
503-215-5696 
 

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Bernard Fox, PhD* 
Michael Gough, PhD* 
Edwin Walker, PhD* 
Keith Bahjat, PhD* 
Earle A. Chiles Research Institute 
4805 NE Glisan Street 
Portland, OR, 97213 
*not involved in patient care 
 
John W. Smith II 
Rob Lufkin, DO 
Compass Oncology 
5050 NE Hoyt, Suite 256 
Portland, OR  97213 
 
Stephen Bader, MD 
Alice Wang-Chesebro, MD 
Matthew Solhjem, MD 
Providence Portland Medical Center  
The Oregon Clinic 
4805 NE Glisan, Level B 
Portland, OR 97213 
503-215-1819 
 
 
Responsible Research Nurses: 
Chris Fountain, RN, ONC 
 
 
 
 
 
Providence Portland Medical Center 
 
 
 
 
 
Robert W. Franz Research Center 
4805 NE Glisan Street, 2N35 
 
 
 
 
 
Portland, OR 97213 
 
 
 
 
 
503-215-2691 
 
 
 
 
 
Fax 503-215-6725 
 
 
 
 
 
Christopher.Fountain@providence.org 
 
 
 
 
 
 
Sarah Linehan, RN, BSN 
 
 
 
 
 
Providence Portland Medical Center 
 
 
 
 
 
Robert W. Franz Research Center 
4805 NE Glisan Street, 2N35 
 
 
 
 
 
Portland, OR 97213 
 
 
 
 
 
503-215-2613 
 
 
 
 
 
Fax 503-215-6725 
 
 
 
 
 
Sarah.Linehan@providence.org 
 
 
Responsible Data Manager: 
Nelson Sanjuan Silva 
 
 
 
 
 
Providence Portland Medical Center 
 
 
 
 
 
Robert W. Franz Research Center 
4805 NE Glisan Street, 2N35 
 
 
 
 
 
Portland, OR 97213 
 
 
 
 
 
503-215-7715 
 
 
 
 
 
Fax 503-215-6725 
 
 
 
 
 
Nelson.SanjuanSilva@providence.org 
 
  

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PH&S IRB 11-062A 
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PROTOCOL SIGNATURE PAGE 
 
 
 
Protocol Number: 
PH&S IRB 11-062A 
 
 
Protocol Title: 
Phase II Randomized Study of High Dose Interleukin-2 Versus Stereotactic Body 
Radiation (SBRT) and High Dose Interleukin-2 in Patients with Metastatic 
Melanoma 
 
 
I have read this protocol and agree that it contains all necessary details for carrying out this study.  I 
will conduct the study as outlined herein and will complete the study within the time designated, in 
accordance with all stipulations of the protocol and in accordance with Good Clinical Practices, local 
regulatory requirements, and the Declaration of Helsinki.  
 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me 
who assist in the conduct of this study.  I will discuss this material with them to ensure that they are 
fully informed regarding the study agent(s) and the conduct of the study.  
 
 
 
 
 
 
 
Brendan Curti, MD 
 
 
Investigator Name (print) 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Steven Seung, MD, PhD 
 
Investigator Name (print) 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Marka Crittenden, MD, PhD  
Investigator Name (print) 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ................................................................................................................... 4 
1. 
BACKGROUND AND RATIONALE ......................................................................................................... 6 
1.1 
Melanoma and Interleukin-2 .......................................................................................................... 6 
1.2 
Stereotactic Body Radiation Therapy ............................................................................................. 6 
1.3 
High dose local radiation effects on immunity ................................................................................ 7 
1.4 
Rationale for Combining Radiation and IL-2 .................................................................................. 8 
1.5 
Rationale for Study Design .......................................................................................................... 10 
2. 
OBJECTIVES ........................................................................................................................................ 11 
2.1 
Primary objective: ........................................................................................................................ 11 
2.2 
Secondary objectives: .................................................................................................................. 11 
3. 
PATIENT SELECTION .......................................................................................................................... 11 
3.1 
Inclusion Criteria .......................................................................................................................... 11 
3.2 
Exclusion Criteria ......................................................................................................................... 12 
3.3 
Inclusion of Women and Minorities .............................................................................................. 12 
4. 
REGISTRATION PROCEDURES .......................................................................................................... 13 
4.1 
Registration and Cancellation Guidelines .................................................................................... 13 
4.2 
Assignment of Study Numbers .................................................................................................... 13 
5. 
STUDY DESIGN .................................................................................................................................... 13 
6. 
STUDY CALENDAR .............................................................................................................................. 13 
7. 
ADMINISTRATION OF STUDY TREATMENTS .................................................................................... 14 
7.1 
Radiation Therapy ....................................................................................................................... 14 
7.2 
Immunotherapy ............................................................................................................................ 22 
7.3 
Study Treatment Discontinuation ................................................................................................. 22 
8. 
MEASUREMENT OF EFFECT .............................................................................................................. 23 
8.1 
Evaluation of SBRT Target Lesions ............................................................................................. 23 
8.2 
Evaluation of Systemic Disease Response .................................................................................. 24 
9. 
REGULATORY AND REPORTING REQUIREMENTS .......................................................................... 27 
9.1 
Adverse Event Reporting ............................................................................................................. 27 
9.2 
Data Reporting ............................................................................................................................ 28 
9.3 
Continuing Review and Final Reports .......................................................................................... 28 
9.4 
Protocol Modifications and Amendments ..................................................................................... 28 
9.5 
Record Retention ......................................................................................................................... 29 
9.6 
Quality Assurance Plan ............................................................................................................... 29 
10. STATISTICAL CONSIDERATIONS ....................................................................................................... 30 
10.1 Study Endpoints .......................................................................................................................... 30 
10.2 Sample Size ................................................................................................................................ 30 
10.3 Patient Accrual ............................................................................................................................ 31 
10.4 Immunological Monitoring ............................................................................................................ 31 
REFERENCES .............................................................................................................................................. 33 
APPENDIX A ECOG PERFORMANCE SCALE ........................................................................................... 38 
APPENDIX B AJCC Staging for Melanoma and Renal Cell Carcinoma ................................................... 39 
APPENDIX C Management of Interleukin-2 Toxicity ................................................................................. 40 
APPENDIX D Immunologic Monitoring Schedule…………………………………………………………………...41 
 

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1. BACKGROUND AND RATIONALE 
1.1 Melanoma and Interleukin-2 
The American Cancer Society estimates that there were over 68,000 new diagnoses and 8,100 deaths from 
melanoma in the United States in 2009(1).  Metastatic melanoma has a poor prognosis with less than 5% of 
patients surviving five years from the manifestation of visceral organ involvement.  Disease-specific survival 
curves in all stages of melanoma have a negative slope, implying that metastatic disease can originate from 
thin primary lesions and that metastatic melanoma can develop many years after the initial diagnosis.  For 
instance, in survival data compiled by Balch, et al., up to 10% of patients presenting with stage I melanoma 
(primary site less than 1 mm in depth and no nodal involvement) will die as a consequence of metastatic 
disease within 10 years(2).(3) Disease recurrence can manifest years or even decades after the initial 
diagnosis.  The potential lethality of early stage melanoma distinguishes it from other solid tumors. 
 
The first publication describing the clinical results of IL-2 appeared in 1985(4).(5) Three of six patients had 
greater than 50% regression of their metastatic melanoma.  A subsequent publication describing the clinical 
outcomes of 270 patients reported a complete response (CR) rate of 6% and a partial response (PR) rate of 
10% (6).  The median duration of response was greater than 40 months.  An update of this initial report 
showed that at 15 years over 70% of those achieving a CR were alive and melanoma-free.(6) Approximately 
15% of the patients achieving a PR were also alive at 15 years. 
 
The durability of these responses was the main rationale for approval of IL-2 by the FDA, and is also the 
reason that IL-2 therapy persists in oncological practice.  Many regimens that used IL-2 in combination with 
other agents (e.g. IL-2 plus chemotherapy, IL-2 with interferon, adoptive transfer of various immune cell 
subsets, and IL-2 with monoclonal antibodies (7-10)) have been tested, but none of these more complex 
therapies has reported a convincing improvement in response rate or survival compared to IL-2 monotherapy.  
We and others have investigated the immunological effects of high dose per fraction radiation; which 
suggested that the combination of radiation and IL-2 could result in better anti-tumor responses.  We recently 
completed a phase I study of SBRT radiation and IL-2 in patients with melanoma and renal cancer showing a 
71% objective response rate in metastatic melanoma (reviewed in detail below), which provides the main 
rationale for this study.(11)  Even with the recent FDA approval of ipilimumab showing a 4 month 
improvement in median survival(12), and targeted agents such as PLX-4032 having a high initial response 
rate of 70% (with a median duration of response of approximately 7 months)(13), the findings of our pilot 
study are striking and warrant further investigation. 
 
1.2 Stereotactic Body Radiation Therapy 
Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) have become routine 
treatment options for patients with brain metastases.(14-19) When first introduced, the use of a limited 
number of large dose per fraction treatments in SRS and SRT challenged conventional wisdom in radiation 
biology and oncology.(20, 21) High fractional dose is more effective for radiation resistant cells.  This is 
suggested by the good local control seen in hypofractionated radiation therapy for nodal metastases and 
radiosurgery for brain metastases in melanoma.(22-24) However, the risk of long-term normal tissue 
complication is correlated with the fraction size.  In radiosurgery for brain metastases, the high conformality 
(and thus the avoidance of normal tissue) possible with radiosurgical techniques permits us to safely deliver 
single doses in the range of 15-20 Gy.  Using prototypes for image-guided radiation therapy (IGRT),(25) 
stereotactic body radiotherapy (SBRT) for small sized lung cancers has been reported where 
hypofractionated therapy in fractional doses of 12-20 Gy appeared to be relatively safe and effective resulting 
in local control rates of 80-90%.(26)  
 
The translation of SRS and SRT to extracranial sites was limited by two problems. First, tumors in the body 
are subject to motion related to natural physiological process like breathing and digestion. Second, because 

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the treatments are highly focused, image guidance needed to be such that the selected patients are properly 
treated with limited fields and that the target extent can be determined accurately. By the early 1990s, 
technological advances in both tumor motion tracking and image guidance allowed the concepts of SRS and 
SRT to be extended to extracranial sites where it is now known as SBRT. The American College of Radiology 
and the American Society of Therapeutic Radiology and Oncology have published guidelines that define 
SBRT and its proper conduct.(27) Patients selected for SBRT should have a limited number of demarcated 
tumors whose extent can be identified directly on treatment planning image platforms or reliably fused by 
image registration techniques. Some method of tumor motion control must be used to avoid large margin 
treatments.  
 
SBRT is an ablative therapy, and it should be understood that targeted tissue is likely to be destroyed. Many 
beams are brought in from multiple directions so that entrance dose is spread out. Beams are shaped to 
achieve conformality and rapid dose fall-off. The SBRT dosimetry approach is borrowed from intracranial 
SRS in which treatments have been well tolerated with long term follow-up.(28)  
 
1.3 High dose local radiation effects on immunity 
Curing cancer with immunotherapy has had limited success despite testing many agents and combinations 
over the last 50 years.  Prehn and Main performed one of the earliest experiments showing immunity against 
tumors in 1957.  Mice inoculated with MCA-induced sarcoma cell lines quickly developed tumors and died.  If 
the tumor was resected, then subsequent challenge with the same tumor cells was rejected and the mice 
survived.(29) This early observation clearly demonstrated that immunity against malignant cells exists.  It also 
suggested that the initial tumor burden somehow suppressed the development of effective initial defensive 
immune assault, and that by removing the tumor burden, the barrier to effective immunity could be lifted.  In 
clinical practice, surgical tumor debulking is often traumatic to the patient or just too impractical due to the 
location and/or number of lesions.  SBRT can serve as a virtual “scalpel” to reduce tumor burden in patients.    
 
The standard teaching is that radiation is immunosuppressive.  However, recent studies have shown that 
exposure of tumor cells to a single or a few fractions of high dose radiation can augment the release of 
inflammatory cytokines such as IL-1(30) and TNF-α(31).  It can also up-regulate expression of MHC class 
I(32), B7.1(33), and Fas/CD95(34, 35).  Most of these studies in vivo and in vitro have utilized single radiation 
doses in the range of 5-10 Gy to induce this response.  This fractional dose range is outside the scope of 
conventional radiation therapy and thus up to now the laboratory findings have not been easily translatable to 
the clinic.  SBRT is a technology by which high fractional doses of radiation can be delivered to sites of 
metastases, and in conjunction with immunotherapy, may augment immune responses. 
 
The evidence for this is suggested by Chakarborty et al.,(35) who demonstrated that treatment of 
carcinoembryonic Ag (CEA)-expressing MC38 adenocarcinoma cells with irradiation (20 Gy) in vitro 
enhanced Fas expression at molecular, phenotypic, and functional levels. Furthermore, radiation sensitized 
these targets to Ag-specific CTL killing via the Fas/Fas ligand pathway. Moreover, localized irradiation of the 
tumor in vivo significantly potentiated tumor rejection by these CEA-specific CTL. The same group later 
showed that in their model, mice cured of tumors not only demonstrated CD4+ and CD8+ T-cell responses 
specific for CEA, but also induced T-cell responses to two other antigens (gp70 and p53) overexpressed in 
the tumors.(36) This indicates epitope spreading induced by local irradiation. This hypothesis is corroborated 
by the results of Reits et al. who demonstrated that exposure of MC38 tumor cells to single doses of 7-25 Gy 
increases MHC class I expression, generates radiation injury-induced peptide formation, and makes tumors 
more susceptible to adoptively transferred cytolytic T cells (CTLs).(32)  Lugades et al. have also shown that 
tumors in murine hosts exposed to three doses of 5-15 Gy per fraction have increased infiltration of tumor-
specific CTLs.(37) For tumors that express low levels of antigen, 10 Gy increased antigen release by the 
tumors; the antigen subsequently was cross-presented by stromal cells making them susceptible to 
destruction by CTLs, which led to complete tumor rejection.(38) 
 

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If high local radiation dose in vivo can make tumor cells more immunogenic, then the tumor-specific CTLs 
that are generated could attack distant metastatic deposits.  Chakravarty et al inoculated the hind limb of 
mice with 3LL/D122 Lewis lung cancer cell line.  At week 3, 60Gy was administered.  Compared to controls, 
animals given Flt3/L (dendritic cell maturation factor) developed fewer lung metastases and survived longer.  
This effect was not seen in nude mice that lack CTLs.(39) 
 
More recently, Demaria et al. inoculated bilateral flanks of mice with 67NR mammary tumor cells and the 
rump with A20 lymphoma cells as controls.  One of the flanks was irradiated with 6Gy and the mice were 
given Flt3/L.  This study demonstrated that local high dose radiation plus Flt3/L induced a tumor-specific CTL 
response against the tumor located in the opposite flank but not the control tumor.(40) 
 
One of the potential impediments to effective tumor immunotherapy is CD4+CD25+ foxP3 expressing T cells 
(Treg) which are found in increased levels in cancer patients, suggesting that the Treg number correlates to the 
stage of disease and cancer progression.(41-43) Depleting the CD4+CD25+ population with anti-CD25 mAb at 
the time of vaccination against a tumor-expressed antigen with the combination of local radiation therapy 
resulted in elimination of established tumors, whereas the combination of any other two out of three 
modalities did not eliminate established tumors despite augmenting CD4 and CD8 responses to antigens.(44) 
Similar augmentation of protective tumor immunity was seen in mice depleted of CD4+CD25+ population 
when mice were immunized with dendritic cells pulsed with irradiated tumor cells.(45)   
 
One of the immunological effects of SBRT may be the elimination of CD4+CD25+ cells within the tumor and a 
decrease in their number or activity in the periphery.  Because SBRT involves multiple beams traversing 
through the body and intersecting at the tumor of interest, the body receives low dose exposure.  The effect 
of low dose exposure is unclear, but it is possible that this may preferentially augment immunity by 
suppressing the Treg population.  Animal data exist suggesting that this phenomenon exists:  1) 0.1 Gy TBI in 
mice given 6-15 hours prior to tumor transplantation increases TD50 of tumor cells(46); 2) 0.2 Gy TBI in rats 
transplanted with KDH-8 hepatoma cell lines decreases metastases to lung(47); 3) subset of Lyt-1,2+ CTL 
can be killed in vitro with 0.1-0.25Gy(48); and 4) tumor bearing rats given 0.2Gy TBI (but not to tumor) 
increased IFN-γ and TNF-α expression in splenocytes, but did not increase IL4, IL6 or IL10.(49) Safwat et al 
have also shown that the combination of low dose TBI and IL-2 has a synergistic effect in a murine metastatic 
melanoma model.(50)  
 
1.4 Rationale for Combining Radiation and IL-2  
As stated before, IL-2 is the only medical therapy that has the potential to cure metastatic melanoma, albeit 
only in a small minority of patients.  The reasons for the low probability of response are not completely 
understood despite greater than 25 years of investigation, but recent data show a strong link between Treg 
activity and response in patients receiving IL-2.  For instance, Cesana and colleagues reported that 
melanoma patients have high baseline Treg and those responding to high-dose IL-2 have decreased Treg 
number while patients who do not respond have increasing numbers.(50)  Similar data exist in RCC showing 
that Treg and myeloid-derived suppressor cells are elevated in many patients with metastatic disease and 
can decrease with successful treatment(51). Since radiation modulates Treg, it may counterbalance some of 
the inhibitory properties of IL-2 as IL-2 can also induce proliferation of Treg.  
 
IL-2 also causes proliferation of T lymphocytes.  If a population of melanoma antigen-specific cytotoxic T-cells 
is induced by radiation or radiation decreases the inhibitory influence of Treg, then IL-2 could induce 
proliferation of a T-cell subset with enhanced melanoma activity resulting in enhanced tumor regression. 
 
 
1.4.1: Clinical Experience with Radiation and IL-2 
Radiation has been used prior to IL-2 with no enhancement of IL-2 response(52). This study treated 14 
melanoma and 12 renal cell cancer patients with 500 cGy BID to a total of 10 Gy- 20 Gy over 1-2 days, 2-24 
hours prior to the initiation of IL-2 with no improvement in patient outcomes.  There are several possible 

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reasons why this radiation and IL-2 combination was ineffective.  The patients were treated between 1989-
1990, likely via 2-D treatment planning (the details of the treatment plan were not defined by the authors).  2-
D treatment plans generally overestimate the tumor volume, and often field sizes from this era were 
generous, possibly negating any synergistic effect from excess by-stander irradiation. Tumor draining lymph 
nodes are important in generating radiation-induced CTL tumor regression.(53) The wide margins from 2-D 
treatment planning techniques would likely include tumor draining lymph nodes as well, thus eradicating T 
cells and antigen-presenting cells that are instrumental to establishing an anti-tumor immune response.  In 
addition, the fractional radiation dose was not adequate to eradicate the melanoma or renal cancer metastatic 
deposits treated.   Most of the pre-clinical studies demonstrating the immune-enhancing effects of radiation 
utilized fraction sizes > 5 Gy.(31-33, 35, 37, 38)  It is probable that higher fractional radiation doses are more 
immunogenic than lower doses as evidenced by abscopal tumor regressions that have been observed in 
patients with renal cell cancer treated with SBRT using fractions sizes of at least 8 Gy.(54)   
 
  
We have maintained a database on patients receiving high-dose IL-2 since 1997 that encompasses over 
1000 immunotherapy admissions to our Biotherapy Program at PPMC.  We compiled an anecdotal 
experience in 8 melanoma patients and 2 renal cancer patients who had high-dose per fraction radiation for 
clinical palliation the week before starting IL-2.  Three patients had gamma knife or stereotactic radiosurgery 
for brain metastases, three had treatment of painful bone metastases and four had pulmonary lesions treated 
to relieve bronchial obstruction.  Five of the 8 patients with melanoma responded (PR = 2 and CR = 3) by 
RECIST criteria of the non-irradiated lesions for an overall response rate of 62.5%.  The two patients with 
renal cancer achieved PR by RECIST with minor radiographic abnormalities.  None of the responding 
patients has required additional therapy for their malignancy.  Based on these anecdotal experiences and the 
scientific rationale detailed above, we conducted and recently completed a phase I study of SBRT and IL-2. 
 
Our phase I study enrolled patients with metastatic melanoma or renal cell carcinoma who had received no 
prior medical therapy for their advanced disease and were not candidates for surgical resection.  The main 
eligibility requirements were sufficient cardiopulmonary reserve to tolerate high-dose IL-2 and at least one 
pulmonary or hepatic metastatic deposit to which SBRT could be safely administered.  Patients were enrolled 
in consecutive cohorts to 1, 2 or 3 doses of SBRT (20 Gy per fraction) with the last radiation dose 3 days 
before starting the first IL-2 cycle.  IL-2 was administered at 600,000 international units per kg via intravenous 
bolus infusion every 8 hours for a maximum of 14 doses per cycle.  A second cycle of IL-2 was repeated after 
a 2-week rest period.  Four weeks after the second IL-2 cycle imaging studies were repeated and patients 
with regressing disease received up to 6 cycles of IL-2 therapy.  Blood samples for immune monitoring were 
obtained at baseline, 3 days after SBRT (just before the first IL-2 dose) and 3 days after completing the first 
IL-2 cycle.  
 
Twelve patients were included in the intent-to-treat analysis and 11 completed treatment per the study 
design. RECIST criteria were used to assess overall response in non-irradiated measurable disease.  Eight 
out of 12 patients (66.6%) achieved a complete or partial response (1 CR and 7 PR).  Six of the patients with 
PR on CT had a CR by PET imaging. Five out of 7 patients with melanoma had disease regression (71.4%, 
all PET CRs), 3 of 5 patients with renal cancer had a partial response (60%) and one had stable disease.(11) 
Tumor regression occurred at all SBRT dose levels and all lesions treated with SBRT regressed.  Immune 
monitoring showed significantly greater proliferation of CD4+T cells with a memory phenotype 
(CD3+CD4+Ki67+CD25+FoxP3-CCR7-CD45RA-CD27+CD28+) in responding patients, a finding not described 
previously.  The expected toxicities of high-dose IL-2 were observed, but there was no increase in the 
severity or frequency of IL-2 toxicity associated with the addition of SBRT.  A maximum tolerated dose of 
SBRT was not reached. 
 
The response rate SBRT and IL-2 in patients with melanoma was significantly higher than expected and 
among the highest observed in any early phase trial in metastatic melanoma.  All of the visceral responses 
have been durable and no patient with a response has required subsequent medical therapy thus far 

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(although one required surgery for a brain metastasis, which in retrospect was present at the start of the 
SBRT + IL-2 treatment).  
1.5 Rationale for Study Design 
This randomized phase II study is designed to confirm the response rate of the SBRT + IL-2 compared to 
high-dose IL-2 with 80% power to detect a difference between the historical IL-2 response rate of 16% versus 
an assumed 60% response rate for SBRT + IL-2 (this is a more conservative assumption than the 71% 
response rate we observed in the completed phase I trial).  Twenty-two patients will be enrolled to each 
treatment arm.  All patients will receive IL-2 at 600,000 international units per kg IVB q8h x 14 planned doses 
with an additional cycle 14 days after the first (this is the current standard IL-2 regimen in our Biotherapy 
Program).  Responding patients with regressing disease are eligible for up to 6 IL-2 cycles.  Among the first 
20 patients enrolled, SBRT will be administered as a single 20Gy dose of radiation on the Friday before IL-2 
begins.  Patients 21 through the completion of the study will receive two SBRT dose fractions based on an 
interim analysis of data obtained from the first 14 patients who completed treatment on the study. The salient 
findings from this interim analysis are as follows: 
1) Serum uric acid on day 8 was significantly higher in patients receiving SBRT (p < 0.005), which 
indicates tumor break down as expected from radiation. 
2) Although as a group the patients who received SBRT had higher uric acid values on day 8, two of the 
individuals who received SBRT has no change in uric acid and did not respond.  This indicates that 
the goal of tumor destruction by radiation was not achieved in these individuals, 
3) In contrast to the pilot study where all SBRT-treated lesions regressed, at least one of the patients in 
the interim analysis had regrowth of a radiated lesion,   
4) The sum of the largest diameters of the tumor deposits treated with one fraction of radiation in the 
pilot study was significantly smaller than the sum of largest diameter of lesions treated with radiation 
in the interim analysis. 
5) There were also significant differences in serum IL-12 and RANTES on day 8 comparing the SBRT 
and IL-2 groups in the interim analysis. 
The findings of the interim analysis are consistent with our hypothesis that radiation causes tumor breakdown 
and re-directs inflammation to the site of the tumor.  A single dose of radiation is not sufficient in all patients 
to induce the biological changes that our hypothesis suggests are necessary to facilitate a systemic anti-
tumor effect from IL-2, therefore two SBRT fractions will be used for patients enrolled after patient 20 in the 
study accrual.  This modification will also permit a more extensive comparison of the clinical and 
immunological effects of one versus two SBRT doses.   
This SBRT dosing regimen was also based on our completed phase I trial that tested up to three SBRT 
doses of 20 Gy.  We found no increase in IL-2 toxicity of IL-2 after SBRT and also found no difference in 
response by SBRT dose (data submitted for publication).   
Patients assigned to the IL-2 arm who have melanoma progression after the first two IL-2 cycles (using 
RECIST criteria) are eligible for SBRT followed by 2 additional cycles of IL-2.  Melanoma responses that 
occur in this crossover group will not be counted in the initial response tabulation, which is the primary 
objective of this study.  Responses will be determined using modified response evaluation of solid tumors 
(RECIST) criteria 1.1 of lesions not treated by SBRT (detailed below).  Extensive immunological monitoring 
will be performed in an attempt to determine the mechanism of antitumor activity of SBRT + IL-2. 

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2. OBJECTIVES 
2.1 Primary objective:  
2.1.1 
Perform a randomized phase II study to compare the response rate of high dose IL-2 
to SBRT + IL-2 in patients with metastatic melanoma. 
2.2 Secondary objectives: 
2.2.1 
Measure the response of SBRT + IL-2 in patients with melanoma who have disease 
progression after high-dose IL-2. 
 
2.2.2 
Perform immunological monitoring to assess: 
2.2.3 
Proliferation of CD4+T cells with a memory phenotype (CD3+CD4+Ki67+CD25+FoxP3-
CCR7-CD45RA-CD27+CD28+) after high-dose IL-2 and SBRT + IL-2. 
2.2.4 
Pro-calcitonin, DAMPs and other inflammatory mediators that may influence the 
interaction between SBRT and IL-2. 
2.2.5 
Ab response and correlate with gene expression by autologous tumor  
2.2.6 
T cell response to melanoma cell lines and antigens identified by protein array. 
2.2.7 
Biopsies of melanoma lesions before and after SBRT to study histological changes 
and immune cell infiltrates.   
2.2.8 
Compare the immunological and clinical effects of one versus two SBRT doses. 
 
 
3. PATIENT SELECTION 
3.1 Inclusion Criteria 
3.1.1 
Histological confirmation of melanoma will be required by previous biopsy or cytology. 
3.1.2 
Patients must be ≥ 18 years of age. 
3.1.3 
Tumors amenable to SBRT in lungs (central locations preferred), mediastinum, chest 
wall, bones with a soft tissue component (other than long bones), or liver, liver hilum 
and associated lymph nodes (inclusive of immediately adjacent masses), 1 – 3 foci; 
no minimum size, but none greater than 7 cm.  Patients may have other 
metastases but only a maximum of 3 will be treated. 
3.1.4 
ECOG performance status of 0-1. 
3.1.5 
Women of childbearing potential must have a serum or urine pregnancy test 
performed within 72 hours prior to the start of protocol treatment.  The results of this 
test must be negative in order for the patient to be eligible.  In addition, women of 
childbearing potential as well as male patients must agree to take appropriate 
precautions to avoid pregnancy. 

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3.1.6 
Patients must sign a study-specific consent form. 
 
3.2 Exclusion Criteria 
3.2.1 
No metastatic site amenable to SBRT. 
3.2.2 
Patients with brain metastases not candidates for radiosurgery alone. 
3.2.3 
Previous radiation to sites proposed for SBRT. 
3.2.4 
Patients with active systemic, pulmonary, or pericardial infection. 
3.2.5 
Pregnant or lactating women, as treatment involves unforeseeable risks to the embryo 
or fetus. 
3.2.6 
Evidence of ischemia on exercise tolerance test, stress thallium study, or baseline 
EKG. 
3.2.7 
DLCO, FEV1 or FEV1/FVC less than 70% of predicted due to clinically significant 
underlying pulmonary disease.  For any pulmonary function test values less than 
predicted values, the PI will review, and document the patient's suitability for high 
dose IL-2 therapy. 
3.2.8 
WBC < 3.0 x 109/L, Hgb < 9.0 g/dL, AST/ALT > 3 times ULN, total bilirubin > 1.9 g/dL, 
creatinine > 1.9 g/dL. 
3.2.9 
Need for chronic steroids. 
3.3 Inclusion of Women and Minorities 
Both men and women and members of all ethnic groups are eligible for this trial. Given the racial 
demographics of Oregon, 86.6% white, and the reduced incidence of melanoma in the non-white 
population, we expect that few of the patients enrolled will be non-white. The expected distribution 
of men and women enrolled is based on our experience with other clinical trials at our Cancer 
Center. The anticipated study population is illustrated in the table below. 
Table 1.  
 
Race/Ethnicity 
Gender 
 
White, not of 
Hispanic 
Origin 
Black, not 
of Hispanic 
Origin 
 
Hispanic 
Asian or 
Pacific 
Islander 
 
Unknown 
 
Total 
Male 
 
24 
0 
0 
0 
0 
24 
Female 
 
20 
0 
0 
0 
0 
20 
Total 
 
44 
0 
0 
0 
0 
44 
 

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4. REGISTRATION PROCEDURES 
4.1 Registration and Cancellation Guidelines 
To register a patient, the investigator will call the Data Management Office of the Robert W. Franz 
Cancer Research Center at (503) 215-2613 and speak to one of the Nurse Coordinators for the trial. 
The following information will be requested: 
4.1.1 
Investigator's name 
4.1.2 
Patient's Identification 
4.1.3 
Patient's name or initials and chart number 
4.1.4 
Patient's Social Security number 
4.1.5 
Eligibility Verification 
Patients must meet all of the eligibility requirements and undergo all pre-study procedures. 
If a patient enrolls in the study, but does not receive study therapy, the patient’s enrollment may be 
canceled. Reasons for cancellation will be documented in writing. Any patient whose enrollment was 
canceled before receiving study therapy will be replaced.  Any patient who enrolled in the study but 
did not receive SBRT or IL-2 will be replaced. 
4.2 Assignment of Study Numbers 
Study Numbers will be assigned at enrollment based on order of enrollment and study ID, as 
follows: SI-01, SI-02, SI-03, etc. 
All case report forms, study reports, and laboratory samples for research tests, including immune 
parameters or pharmacokinetics, will be labeled with the full patient Study Number. 
5. STUDY DESIGN 
Eligible patients will be registered (see Section 4) and randomized to treatment arm using closed 
envelope method.  The patients will receive SBRT radiation as specified in Section 7.  
 
IL-2 treatment will begin on the Monday following the radiation treatment.  The dose level of interleukin-2 
will be the same for all enrolled patients (600,000 IU per kilogram IVB q8h x 14 planned doses with an 
additional cycle 14 days after the first cycle).   
 
6. STUDY CALENDAR 
 
Study Treatment* 
Follow Up 
Study Days 
Screening. 
-30 days 
 
SBRT 
Tx 2 
 
Days 
1-5 
 
Day 
8  
Week 4 
Days 
22-26 
Week 7  
(+/- 1 wk) 
Follow-
up/restaging7 
Surviv
al  
F/U7 
Medical history9 
X 
X 
X 
 
X 
X 
 
 
Physical exam 
X 
X 
X 
 
X 
X 
X 
 
Vital Signs weight 
X 
 
X 
 
X 
X 
X 
 
CBC, Diff, plt 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry panel1 
X 
 
X 
X 
X 
X 
X 
 
TSH/T4 
X 
 
 
 
 
 
X 
 
PT/PTT 
X 
 
 
 
 
 
 
 

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Tumor Biopsy8 
X 
 
 
X 
 
 
 
 
Immunologic 
monitoring6 
X 
X 
X 
X 
X 
       X 
 
 
ECG 
X 
 
 
 
 
 
 
 
CT 
(chest/abd/pelvis) 
X 
 
 
 
 
X 
X 
 
PET scan3 
X 
 
 
 
 
 
X 
 
PFTs4 
X 
 
 
 
 
 
 
 
Brain MRI 
X 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
Cardiac         
stress test5 
X 
 
 
 
 
 
 
 
* 
The last SBRT dose will be on a Friday, with IL-2 administered the following Monday. Biotherapy Program guidelines will be used to manage IL-
2-related toxicity. 
1 
Electrolytes, BUN/creatinine, LFTs, Magnesium Phosphorus.  Procalcitonin, LDH and uric acid on Days 1, 2, 5, and 8 
2 
SBRT will precede cycle 1 IL-2 in patients assigned to the SBRT + IL-2 arm.  For patients who are assigned to IL-2 monotherapy and have 
progressive disease after 2 IL-2 cycles, they can then receive SBRT before cycle 3 IL-2 commences.  
3 
PET scans are required after the completion of IL-2 and if clinically indicated at other time points. 
4 
Includes routine spirometry, lung volumes and diffusion capacity (within 8 weeks prior to study treatment). 
5 
For patients over 50 years of age or with significant cardiac risk factors. 
6 
Immunologic monitoring samples: collect baseline samples as follows: for patients randomized to receive radiation collect on the day radiation is 
to start before radiation is administered.  For patient randomized to Il-2 alone collection of sample during screening is acceptable ensuring that 
patient is eligible for study treatment.   For both arms collect samples on day 1 the day IL-2 starts (before IL-2 is administered), day 2 (at 9AM 
after planned dose 3 of IL-2), day 5, day 8 and at the investigators’ discretion, day 22-26 sample collect any day during week 4.For patients who 
receive SBRT prior to cycle 3 of IL-2 (crossover patients), samples should be obtained on the same schedule. Refer to Appendix D for description 
of tubes to be collected at each time point  
7 
Patients will be followed every 3 months for 2 years, then every 6 months during year 3, and yearly thereafter for years 4 and 5 with the indicated 
tests (starting three months after the last Course of IL-2). For patients who progress, patient status will be followed for survival.  Survival follow-up 
will consists of a follow-up phone call every 6 months to assess survival status of progressing patients from end of treatment to 5 years. 
8 
CT- or ultrasound-guided core biopsy of lesion to be treated with SBRT if technically feasible 
9    Collect medical history at screening and adverse events grade 3 or higher throughout the study up to week 7 or 8 (IL-2 restaging), report only the 
highest grade for any reportable event. 
10    To be collected at PI discretion as additional immunologic monitoring  
 
7. ADMINISTRATION OF STUDY TREATMENTS 
7.1 Radiation Therapy 
7.1.1 
Dose Specifications 
Stereotactic Targeting and Treatment: 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. 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 (e.g., couch and gantry) 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 an isocenter or target 
according to the known 3-D coordinates as determined in the process of treatment 
planning. The nature of the fiducials themselves may include radio-opaque 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).  
7.1.2 
Dose Fractionation 
Patients 1 – 20 will receive a single fraction of radiation. Patients 21 through the 
completion of the study will receive two fractions.  The dose for all patients will be 20 Gy 
per fraction to the prescription line at the edge of the planning treatment volume (PTV) with 

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the last dose delivered on a Friday before IL-2 administration.  For patients receiving two 
radiation doses, the doses can be administered on the Wednesday and Friday before IL-2 
starts.  Patients who are assigned to IL-2 monotherapy and have progressive disease after 
two IL-2 cycles are then eligible to receive SBRT before cycle 3 of IL-2 commences, single 
fraction for patients 1-20 and two fractions for patients 21- end of study. 
 
The target dose is determined based on the study dose level and the normal tissue 
requirements specified in 7.1.11. Treatment at the allocated dose level is only permitted if 
the normal tissue criteria are met. If the normal tissue criteria are not met at that dose, 
treatment at a lower dose level is permitted, as long as the normal tissue constraints are 
met at the lower dose level. No dose lower then 15Gy is allowed. If normal tissue 
constraints are not met at this lowest dose permitted, then the patient will not proceed with 
radiation on study. 
 
7.1.3 
Premedications 
Analgesic premedication to avoid general discomfort during long treatment durations also 
is recommended when appropriate. If a portion of the stomach or small intestine is treated, 
H2 blocker or proton pump inhibitors is recommended to attempt to decrease the chance 
of late GI bleeding 
 
7.1.4 
Physical Factors 
Only photon (x-ray) beams of energies 4-10 MV will be allowed. Photon beam energies 
greater than 10 MV but not more than 15 MV will only be allowed for a limited number (≤ 2) 
beams that must travel more than a cumulative distance of 10 cm through soft tissue (not 
lung) to reach the isocenter. 
 
7.1.5 
Minimum Field Aperture (Field Size) Dimension 
Due to uncertainties in beam commissioning resulting from electronic disequilibrium within 
small beam apertures, a minimum field dimension of 3.5 cm is required for any field used 
for treatment delivery for 3-D conformal techniques. It is understood that this may exceed 
the technical requirements for small lesions (< 2.5 cm axial GTV dimension or < 1.5 cm 
cranio-caudal GTV dimension). In such cases, the prescription dose is still prescribed to 
the edge of the defined PTV. This minimum field dimension does not apply to plans using 
IMRT, VMAT, or tomotherapy. 
 
7.1.6 
Patient Positioning 
Patients will be positioned in a stable position capable of allowing accurate reproducibility 
of the target position from treatment to treatment. Positions uncomfortable for the patient 
should be avoided so as to prevent uncontrolled movement during treatments. A variety of 
immobilization systems may be utilized including stereotactic frames that surround the 
patient on three sides and large rigid pillows (conforming to patients external contours) with 
reference to the stereotactic coordinate system (see Section 7.1.1). All positioning systems 
must be validated and accredited by the treating physician prior to enrolling or treating 
patients on this trial. Patient immobilization must be reliable enough to insure that the 
Gross Tumor Volume (GTV) does not deviate beyond the confines of the PTV with any 
significant probability (i.e., < 5%). 
 
7.1.7 
Inhibition of Effects of Internal Organ Motion 
Special considerations may be made to account for the effect of internal organ motion (i.e., 
breathing, etc.) on target positioning and reproducibility. Acceptable maneuvers include 
reliable abdominal compression, accelerator beam gating with the respiratory cycle, and 
active breath-holding techniques. All systems used to account for internal organ motion 
must be validated and accredited by the treating physician prior to enrolling or treating 

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patients on this trial. Internal organ inhibition maneuvers must be reliable enough to insure 
that the Gross Tumor Volume (GTV) does not deviate beyond the confines of the Planning 
Treatment Volume (PTV) with any significant probability (i.e., < 5%). 
 
7.1.8 
Localization 
Isocenter port localization films (anterior/posterior and lateral) should be obtained at each 
treatment on the treatment unit (or patients should undergo a tomographic imaging study, 
e.g., cone-beam CT (CBCT), if available) immediately before treatment to ensure proper 
alignment of the geometric center (i.e.: isocenter) of the simulated fields. Verification CT 
scans and portal films may be taken at the discretion of the treating physician, but are not 
required for protocol participation. 
 
7.1.9 
Image Acquisition 
Computed Tomography (CT) will be the primary image platform for targeting and treatment 
planning. The planning CT scans must allow simultaneous view of the patient anatomy and 
fiducial system for stereotactic targeting. Axial acquisitions with gantry 0 degrees will be 
required with spacing ≤ 3.0 mm between scans. 
 
The target lesion will be outlined by an appropriately trained physician and designated as 
the gross tumor volume (GTV).  All contours will be reviewed prior to treatment planning by 
the treating radiation oncologist and another radiation oncologist. Dr. Seung or Dr. 
Crittenden will review all treatment plans at all participating study sites.  The treatment plan 
reviews by Drs. Seung or Crittenden can occur after SBRT is administered. This primary 
target will not be enlarged for prophylactic treatment (including no “margin” for 
presumed microscopic extension); rather, only include abnormal CT signal 
consistent with gross tumor (i.e., the GTV = Clinical Target Volume, CTV). An 
additional 0.5-1.0 cm in the axial plane and in the longitudinal plane (cranio-caudal) may 
be added to the GTV to constitute the planning treatment volume (PTV).  If 4D-CT is 
performed to generate the internal tumor volume (ITV), the ITV will may be expanded up to 
3-5 mm (i.e.: ITV + 3 mm= PTV) uniformly. As multiple tumors may be treated, the 
respective volumes will be labeled as follows: GTV1 or ITV1, PTV1 for the first tumor; 
GTV2 or ITV2, PTV2 for the second etc. for all tumors treated up to a maximum of three 
tumors. 
 
7.1.10 Dosimetry 
Three-dimensional coplanar or non-coplanar beam arrangements will be custom designed 
for each case to deliver highly conformal prescription dose distributions. Non-opposing, 
non-coplanar beams are preferable. Typically, 7-10 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 this protocol, the isocenter is defined as the common point of gantry and 
couch rotation for the treatment unit. 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 build up at the edges of the blocks or MLC jaws beyond the PTV). The 
only exception will 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 (rather than 95-100%); however, higher isodoses (hotspots) 
must be manipulated to occur within the target and not in adjacent normal tissue. The 
isocenter in stereotactic coordinates will be determined from system fiducials (or directly 
from the tumor) and translated to the treatment record. 
 

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The treatment dose plan will be made up of multiple static beams or arcs as described 
above. The plan should be normalized to a defined point corresponding closely to the 
center of mass of the PTV (COMPTV). Typically, this point will be the isocenter of the beam 
rotation; however, it is not a protocol requirement for this point to be the isocenter. 
Regardless, the point identified as COMPTV must have defined stereotactic coordinates and 
receive 100% of the normalized dose. Because the beam apertures coincide nearly directly 
with the edge of the PTV (little or no added margin), the external border of the PTV will be 
covered by a lower isodose surface than usually used in conventional radiotherapy 
planning, typically around 80% but ranging from 60-90%. The prescription dose will be 
delivered to the margin of the PTV and fulfill the requirements below. As such, a “hot spot” 
will exist within the PTV centrally at the COMPTV with a magnitude of total dose (Gy) times 
the reciprocal of the chosen prescription isodose line (i.e., 60-90%). 
 
For purposes of dose planning and calculation of monitor units for actual treatment, 
correction for tissue heterogeneity is strongly encouraged.  
Successful treatment planning will require accomplishment of all of the following criteria:  
1) Normalization  
The treatment plan should be normalized such that 100% corresponds to the center of 
mass of the PTV (COMPTV). This point will typically also correspond (but is not required to 
correspond) to the isocenter of the treatment beams.  
 
2) 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, and 99% of the target volume 
(PTV) receives a minimum of 90% of the prescription dose.  
 
3) High Dose Spillage  
a) Location  
Any dose greater than 105% of the prescription dose should occur primarily within the 
PTV itself and not within the normal tissues outside of the PTV. Therefore, the 
cumulative volume of all tissue outside of the PTV receiving a dose greater than 105% 
of prescription dose should be no more than 15% of the PTV volume.  
 
 
 
7.1.11 Critical Organ Dose-Volume Limits 
The following table lists maximum dose limits to a point or volume within several critical 
organs. These are absolute limits, and treatment delivery that exceeds these limits 
will constitute a major protocol violation. The dose in table 1 is listed as a single 
fraction for the one fraction treatment. Total dose and dose per fraction are listed in table 2 
for 2-fraction treatment. These limits were extrapolated from RTOG using known tolerance 
data, radiobiological conversion models, norms used in current practice at academic 
centers, (55-61)
 
and the experience of several years of irradiation using these large 
fractions at Indiana University (62-64)
 
and centers in Sweden,
 
Germany, and Japan (65-
67), and the AAPM Task Group 101 report on SBRT.(68) 
 
In order to verify each of these limits, the organs must be contoured such that appropriate 
dose volume histograms can be generated. Instructions for the contouring of these organs 
will follow below. 
 
Table 1: Critical Organ Dose Volume Limits for One SBRT Dose 

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Organ 
Volume 
Dose 
Spinal Cord 
Any point 
12 Gy 
Esophagus* 
Any point 
15.4 Gy 
Ipsilateral Brachial Plexus 
Any point 
17.5 Gy 
Heart/Pericardium 
Any point 
20 Gy 
Great Vessels 
Any point 
37 Gy 
Trachea and Large Bronchus* 
Any point 
20 Gy 
Skin 
Any point 
20 Gy 
Rib** 
Any point 
20 Gy 
Liver 
D30% 
D50% 
<12 Gy 
<7 Gy 
Kidney 
35% of total kidney 
(L+R) 
<15 Gy 
Small bowel 
Any point 
12.4 Gy 
Stomach 
Any point 
12.4 Gy 
Parallel Tissue 
Critical Volume (cc) 
Critical Volume Dose Max 
(Gy) 
Lung (Right and Left) 
1500 cc 
7 Gy 
Lung (Right and Left) 
1000 cc 
7.4 Gy 
*Avoid circumferential radiation 
**If rib structure lies within PTV the limit may be exceeded 
 
Table 2: Critical Organ Dose Volume Limits for Two SBRT Doses 
Organ 
Volume 
Dose (Gy) 
Spinal Cord 
Any point 
14.6 (7.3 Gy/fx) 
Esophagus* 
Any point 
16.8 (8.4 Gy/fx) 
Ipsilateral Brachial Plexus 
Any point 
16 (8 Gy/fx) 
Heart/Pericardium 
Any point 
20 (10 Gy/fx) 
Great Vessels 
Any point 
30 (15 Gy/fx) 
Trachea and Large Bronchus* 
Any point 
20 (10 Gy/fx) 
Skin 
Any point 
22 (11 Gy/fx) 
Rib** 
Any point 
24.6 (12.3 Gy/fx) 
Liver 
700 cc 
9.6 (4.8 Gy/fx) 
Kidney 
35% of total kidney 
(L+R) 
12.4 (6.2 Gy/fx) 
Small bowel 
Any point 
16.8 (8.4 Gy/fx) 
Stomach 
Any point 
14.8 (7.4 Gy/fx) 
Parallel Tissue 
Critical Volume (cc) 
Critical Volume Dose Max 
(Gy) 
Lung (Right and Left) 
1500 cc 
5.8 (2.9 Gy/fx) 
Lung (Right and Left) 
1000 cc 
6.2 (3.1 Gy/fx) 
*Avoid circumferential radiation 
**If rib structure lies within PTV the limit may be exceeded 
 
a. 
Contouring of Normal Tissue Structures 
Spinal Cord: The spinal cord will be contoured based on the bony limits of the spinal canal. 
It should be contoured at least 10 cm above and below the superior and inferior extent of 
the PTV respectively. 

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Esophagus:
 
 The esophagus will be contoured starting at least 10 cm above and below the 
superior and inferior extent of the PTV respectively.  
Brachial Plexus
 
: The ipsilateral brachial plexus will for the purpose of this normal tissue 
constraint will include on the major trunks of the plexus and will be contoured using the 
subclavian and axial vessels as markers to identify the location of the plexus. It will 
originate at the bifurcation of the brachiocephalic trunk into the jugular subclavian veins 
and extend along the sublclavian vein to the axillary vein ending where the vein crosses 
the second rib.  
Heart
 
: The heart and pericardial sack will be contoured. The superior border will begin at 
the inferior aspect of the aortic arch and extend to the apex of the heart. 
Trachea and Proximal Bronchial Tree
 
: The trachea will be divided into two sections 
proximal and distal. The distal trachea will be included as a structure with the proximal 
bronchial tree.  
Proximal Trachea
 
: The proximal trachea should extend 10cm above the superior extent of 
the PTV or 5 cm superior to the carina (whichever is most superior) and continue inferiorly 
to 2 cm above the carina.  
Proximal Bronchial Tree
 
: This will include the inferior 2 cm of the trachea and the proximal 
airways on both sides. The following airways will be included: the distal 2 cm of the 
trachea, the carina, the right and left mainstem bronchi, the right and left upper bronchi, the 
bronchus intermedius, the right middle lobe bronchus, the lingular bronchus and the right 
and left lower lobe bronchi.  
Whole lung
 
: Both the right and left lungs should be contoured as one structure and as 
separate individual lungs. GTV should not be included in this structure. In most cases the 
dose limits will be met for the individual lung. 
Proximal Bronchial Tree Plus 2 cm
 
: Central lesion will be defined as lesions falling within 
the structure that is defined as 2 cm larger in all directions from the proximal bronchial tree. 
If the GTV (ITV) falls inside this structure, patients will be considered ineligible for this 
study.  
Skin
 
: The skin will be defined as the outer 0.5 cm of the body surface. 
Rib
 
: Ribs within 5 cm of the PTV will be contoured by outlining the bone and the marrow. 
The intervening soft tissue should not be contoured. 
Liver
 
: The liver is defined as the portion of liver not involved by gross tumor. There must be 
at least 1000 cc of normal liver. This may mean subtracting non-treated liver metastasis 
from the liver volume to get an accurate calculation of the functional liver that the patient 
has. 
Stomach
 
: The stomach will be contoured in its entirety 
Kidney
 
: Both the right and left kidney will be contoured in their entirety. They will be 
defined as 2 structures. 
Small Bowel: The entire small bowel will be contoured 5 cm above and below the GTV. 

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7.1.12 Documentation Requirements 
In general, treatment interruptions should be avoided by preventative medical measures 
and nutritional, psychological, and emotional counseling. Treatment breaks, including 
indications, must be clearly documented on the treatment record. 
 
7.1.13 Dosimetry Compliance 
Section 7.1.10 describes appropriate conduct for treatment planning dosimetry. Criteria for 
both major and minor deviations are provided in the table in Section 7.1.10.  See section 
7.1.11 for dose volume limits for specific organs and structures. Exceeding these limits by 
more than 2.5% constitutes a minor protocol violation. Exceeding these limits by more than 
5% constitutes a major protocol violation. 
 
7.1.14 Treatment Delivery Compliance 
Set-up films will be compared to digitally reconstructed radiographs from the same beam’s 
eye view. Deviations of less than 0.5 cm in the transverse plane and 1.0 cm in the cranio-
caudal plane will be considered compliant. Deviations from 0.5-1.0 cm in the transverse 
plane and 1.0-1.25 cm in the craniocaudal plane will be considered minor protocol 
deviations. Deviations greater than those listed as minor will be considered major protocol 
deviations. 
 
7.1.15 RT Quality Assurance Reviews 
The Principal Investigator will perform an RT Quality Assurance Review as appropriate 
during the study. 
 
7.1.16 Radiation Toxicity 
 
Radiation pneumonitis is a subacute (weeks to months from treatment) inflammation of the 
end bronchioles and alveoli. Any patient suspected of having radiation pneumonitis will be 
assessed by a medical oncologist, and radiation oncologist, as the clinical picture may be 
very similar to acute bacterial pneumonia with fatigue, fever, shortness of breath, non-
productive cough, and a pulmonary infiltrate on chest x-ray. The infiltrate on chest x-ray 
should include the area treated to high dose, but may extend outside of these regions. The 
infiltrates may be characteristically “geometric” corresponding to the radiation portal, but 
may also be ill-defined. 
Radiation pneumonitis 
 
Patients reporting symptoms as above will be promptly evaluated and treated. Mild 
radiation pneumonitis may be treated with non-steroidal anti-inflammatory agents. More 
significant pneumonitis will be treated with systemic steroids, bronchodilators, and 
pulmonary toilet after discussion with the biotherapy physician. Infections should be treated 
with antibiotics. Consideration of prophylaxis of opportunistic infections should be 
considered in immuno-compromised patients.  
 
It is unlikely that symptomatic pneumonitis will occur during the weeks radiation is actually 
delivered to the patients. However, if a patient experiences pneumonitis prior to completing 
therapy, therapy should be put on hold until symptoms resolve. At that point, a clinical 
decision whether to finish therapy will be made. 
 
In the Indiana University, the majority of patients treated at doses of 20 Gy times 3 
fractions = 60 Gy or higher ultimately experienced atelectasis (collapse) of lung 
Bronchial Injury 

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downstream from the area of treatment(69). This was felt to be related to injury of bronchi 
or bronchioles within or near the treated tumor. By unknown mechanisms over a period of 
3-6 months, damage to pulmonary parenchyma distal to the site of bronchial injury results 
in this focal lung collapse. In the majority of patients, this effect noted on imaging studies 
was asymptomatic. In others, the injury appeared to correlate with a drop in diffusing 
capacity and arterial oxygen tension on pulmonary function tests. This process of collapse 
was not reversible in the Indiana University experience. This injury is the justification for 
the fractional dose for central and hilar tumors from this protocol so as to avoid substantial 
(or total) lung collapse. 
 
Bronchial injury with subsequent focal collapse of lung may impair overall pulmonary 
status. It also makes further assessment of tumor response more difficult as the collapsed 
lung approximates the treated tumor. Since atelectatic lung and tumor have similar imaging 
characteristics, radiology reports will often describe the overall process as progressive 
disease while the actual tumor may be stable or shrinking. Investigators are referred to the 
strict criteria for local failure in Section 8.1.1 of this protocol to avoid such 
mischaracterization.  
 
The consequences of bronchial toxicity, e.g., cough, dyspnea, hypoxia, impairment of 
pulmonary function test parameters, pleural effusion or pleuritic pain (associated with 
collapse), should all be graded according to the NCI Common Terminology Criteria For 
Adverse Events (CTCAE) version 4.0.  
 
Radiation therapy should be held at any point in the protocol for CTCAE v4.0 hepatic 
adverse event Grade 4. It is expected that a proportion of patients treated for right lower 
lobe lung or liver lesions will have transient elevation of liver enzymes following treatment.  
If elevation of liver enzymes is observed up to Grade 3 levels, more frequent 
measurements (at least twice weekly) of the liver enzymes are recommended until the 
enzymes stabilize or return to baseline levels.  Repeat of all Grade 4 blood work is 
required at least 5 days following the first abnormal lab value to determine if the Grade 4 
levels are transient (defined here as < 5 days) or persistent.  
Liver Injury 
 
Radiation Induced Liver Disease (RILD) is a clinical syndrome of anicteric ascites, 
hepatomegaly and elevation of alkaline phosphatase (ALP) relative to other transaminases 
that may occur 2 weeks to 3 months following radiation to the liver. ALP must be at least 2-
fold increased above the baseline ALP. In this setting, due to the difficulty in distinguishing 
RILD from disease progression, if ascites develops at any time within 3 months following 
treatment, an abdominal CT and paracentesis with pathological evaluation of the ascitic 
fluid is required. If the ascitic fluid does not reveal malignancy and there is no evidence of 
disease progression in the liver or abdomen, it will be assumed that RILD has occurred. If 
disease progression in the liver or abdomen has occurred, no diagnosis of RILD can be 
made. Treatment for RILD with repeat paracenteses, diuretics (Spironolactone), and close 
follow-up is recommended. For ease of reporting, any patient with a Grade 3 or higher ALP 
(5-fold increase above upper limit of normal) in the presence of ascites and absence of 
disease progression will be labeled as having RILD. In patients who have elevation of liver 
enzymes near Grade 4 levels and/or in patients with early non-specific signs or symptoms 
of liver injury, close follow-up is recommended with repeat blood work. If no tumor 
progression is documented in these patients, liver injury will be presumed to be treatment 
related. 
 
 

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7.2 Immunotherapy 
7.2.1 
Schedule 
IL-2 shall commence on the Monday following completion of SBRT, administered at a dose 
of 600,000 IU per kilogram IVB every 8 hours for a maximum of 14 doses each cycle. The 
second cycle is planned 16 days after cycle 1 but may be delayed up to one week to allow 
toxicity to resolve. The maximum number of IL-2 doses that can be administered during 
two cycles (one course) will be 28 doses. 
 
7.2.2 
Administration 
The IL-2 (dose = 600,000 IU /kg) will be diluted in 50 ml of D5W and administered over 15 
minutes. 
 
7.2.3 
Venous Access Catheters 
Patients will have a triple lumen central venous catheter or PICC placed prior to initiating 
each course of therapy. Central venous catheters will be placed preferentially in the 
subclavian vein.  Catheters should be removed at the end of each treatment cycle.  
Patients will receive antibiotic prophylaxis with cephalexin 250 mg PO every 8 hours, or 
cefazolin 1 gm IV every 12 hours (or appropriate alternative for patients with allergies to 
cephalosporins) while the central catheter is in place.  If catheter related bacteremia 
develops, the catheter should be removed and parenteral antibiotic treatment (e.g. 
Vancomycin 1 gm IV q 12-24 hours depending on renal function) may be required. 
 
7.2.4 
Concurrent Therapy 
Steroids will not be permitted unless cleared by the biotherapy physician.   
 
Patients should discontinue any antihypertensive therapy at least 24 hours prior to initiating 
each cycle of IL-2.  
 
Supportive medications will be given according to institutional standard of care. 
 
7.2.5 
Additional Immunotherapy 
• 
Patients assigned to the SBRT + IL-2 treatment who achieve a complete or partial 
response or stable disease by RECIST criteria may receive up to 2 more courses of 
IL-2 under institutional standard of care (6 IL-2 cycles total). 
• 
Patients assigned to the IL-2 arm who have disease progression after cycle 2 and 
then receive SBRT before cycle 3 of IL-2 will receive a maximum of 6 IL-2 cycles if 
disease regression or stability is documented thereafter. 
• 
Treating physicians will follow the institutional standard of care for patients who 
continue on IL-2 treatment for additional courses (after Course 1) and for follow up 
after treatment is completed.   
• 
IL-2 patient treatment information and follow up will be tracked as appropriate in the 
institution’s IL-2 database. This database will be used to compile patient treatment 
response, complications and follow up.   
 
 
7.3 Study Treatment Discontinuation 
All reasons for discontinuation of treatment must be documented. All patients will be followed for 
survival or until death post-treatment. 
 
7.3.1 
Criteria for Removal from Study Treatment 

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• 
Disease progression after SBRT + IL-2 or the follow up period; the patient should be 
re-staged and sites of recurrence and/or progression documented. 
• 
Unacceptable toxicity 
• 
The patient may elect to withdraw from study treatment at any time for any reason. 
• 
Development of intercurrent, non-cancer related illnesses that prevent either 
continuation of therapy or regular follow up. 
 
8. MEASUREMENT OF EFFECT 
Patients should be reevaluated for response at the completion of Course 1 of IL-2 treatment (Week 7), 
and after each subsequent IL-2 course.  After completion of IL-2, imaging shall be done every 12 weeks 
until best response and as clinically indicated thereafter.  Baseline scans shall be done within 28 days of 
starting IL-2.   
8.1 Evaluation of SBRT Target Lesions 
SBRT target lesions, defined as the lesions treated with SBRT, will be evaluated with a modified 
version of the international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) Committee, version 1.1(70).  Additional definitions beyond the RECIST 1.1 guidelines 
specific to this protocol are incorporated to define local control as described in Section 8.1.1. 
 
The longest diameter (LD) for the SBRT target lesion will be calculated from the treatment 
planning CT scan using appropriate tissue-specific windowing and reported as the baseline LD. 
The baseline LD will be used as reference by which to characterize the objective tumor. For follow-
up assessment, diagnostic CT scans performed using a 5 mm contiguous reconstruction algorithm 
using pulmonary windowing taken as part of scheduled protocol follow-up are preferred as the 
method of evaluation for response. When CT scans are not available, chest x-ray determination will 
be allowed as long as the target lesion is clearly visible.  
 
Local treatment effects in the vicinity of the tumor target may make determination of tumor 
dimensions difficult. For example, bronchial or bronchiolar damage may cause patchy consolidation 
around the tumor that over time may coalesce with the residual tumor. In cases where it is 
indeterminate whether consolidation represents residual tumor or treatment effect, it should be 
assumed that abnormalities are residual tumor. 
 
 
8.1.1 
Response Criteria  
Local 
Enlargement 
(LE)  
At least a 20% increase in the LD of target lesion, taking as reference the smallest LD recorded 
since the treatment started; Ideally, this determination will be made based on CT image 
evaluation.  
Local 
Failure (LF)  
Refers to the primary treated tumor after protocol therapy and corresponds to meeting both of 
the following two criteria: 1) Increase in tumor dimension of 20% as defined above for local 
enlargement (LE); 2) The measurable tumor with criteria meeting LE should be avid on Positron 
Emission Tomography (PET) imaging with uptake of a similar intensity as the pretreatment 
staging PET, OR the measurable tumor should be biopsied confirming viable carcinoma. The 
EORTC criteria for post-treatment PET evaluation will be used as a basis for evaluation in 
cases more difficult to assign as to whether the uptake is pathological for cancer recurrence vs. 
inflammation. 
Local 
Control (LC)  
The absence of Local Failure.  

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8.2 Evaluation of Systemic Disease Response 
Response and progression will be evaluated in this study using the international criteria proposed by 
the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, Version 1.1(70). Changes 
in only the LD (unidimensional measurement) of the tumor lesions are used in the RECIST criteria. 
Note:  Lesions are either measurable or non-measurable using the criteria provided below.  
 
8.2.1 
Definitions 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (LD to be recorded) as >20 mm with conventional techniques (CT, MRI, x-
ray) or as >10 mm with spiral CT scan.  All tumor measurements must be recorded in millimeters
Non-measurable disease:  All other lesions (or sites of disease), including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using spiral CT scan), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, abdominal masses (not 
followed by CT or MRI), and cystic lesions are all non-measurable. 
 (or 
decimal fractions of centimeters).  
Target lesions:  All measurable lesions up to a maximum of five lesions per organ and 10 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) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  A sum of the LD for all target lesions will be calculated and reported as the 
baseline, which will be used as reference by which to characterize the objective tumor response. 
Non-target lesions:  All other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline.  Non-target lesions include measurable lesions 
that exceed the maximum numbers per organ or total of all involved organs as well as non-
measurable lesions.  Measurements of these lesions are not required but the presence or absence 
of each should be noted throughout follow-up. 
8.2.2 
Guidelines for Evaluation of Measurable 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 the beginning of the treatment.  Tumor lesions that are situated in 
a previously irradiated area will not be considered measurable, unless there is clear evidence of 
progression on physical exam or imaging studies. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 

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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:  These techniques should be performed with cuts of 10 mm or less in 
slice thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Head and neck 
tumors and those of extremities usually require specific protocols. 
Ultrasound (US):  When the primary endpoint of the study is objective response evaluation, US 
should not be used to measure tumor lesions.  It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules.  US 
might also be useful to confirm the complete disappearance of superficial lesions usually assessed 
by clinical examination. 
Endoscopy, Laparoscopy:  Can be useful to confirm complete pathological response when 
biopsies are obtained, but will not be used for tumor measurements. 
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 additional criteria for standardized usage of prostate-specific antigen (PSA) and 
CA-125 response in support of clinical trials are being developed. 
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory 
to differentiate between response or stable disease (an effusion may be a side effect of the 
treatment) and progressive disease.

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8.2.3 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions or no abnormal FDG uptake on PET. 
Partial Response (PR): 
At least a 30% decrease in the sum of the longest diameter (LD) of target 
lesions, taking as reference the baseline sum LD 
Progressive Disease (PD) 
At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum LD recorded since the treatment started or the 
appearance of one or more new lesions 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum LD since the treatment started 
 
Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level 
Incomplete Response/Stable Disease (SD) 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 
Although a clear progression of “non-target” lesions only is exceptional, in such circumstances the 
opinion of the treating physician should prevail, and the progression status should be confirmed at a 
later time by the PIs. 
8.2.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria.  
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
 
CR 
 
Incomplete 
response/SD 
 
No 
 
PR 
 
PR 
 
Non-PD 
 
No 
 
PR 
 
SD 
 
Non-PD 
 
No 
 
SD 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Any 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Any 
 
Yes 
 
PD 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 

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deterioration.”  Every effort should be made to document the objective progression, even after 
discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  When 
the evaluation of complete response depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before confirming the complete 
response status. 
8.2.5 
Confirmatory Measurement/Duration of Response 
Confirmation: 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed between 4 and 8 weeks after the criteria for response 
are first met.  In the case of SD, follow-up measurements must have met the SD criteria at least 
once after study entry at a minimum interval of eight weeks. 
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 recurrent 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 reference the smallest measurements recorded since the treatment started. 
9. REGULATORY AND REPORTING REQUIREMENTS 
9.1 Adverse Event Reporting 
 
9.1.1 
Definitions 
Serious adverse event
A serious adverse drug experience is defined as any adverse drug experience occurring at any 
dose that results in any of the following outcomes: Death, a life-threatening adverse drug 
experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that 
may not result in death, be life-threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate 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.  
:  
 
Unexpected adverse event
Any adverse drug experience, the specificity or severity of which is not consistent with the current 
investigator brochure; or, if an investigator brochure is not required or available, the specificity or 
:  

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severity of which is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application, as amended.  
 
Associated with the use of the drug / intervention
There is a reasonable possibility that the experience may have been caused by the drug. 
:  
 
Disability
A substantial disruption of a person's ability to conduct normal life functions. 
: 
 
Life-threatening adverse event
Any adverse drug experience that places the patient or subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had 
it occurred in a more severe form, might have caused death. 
: 
 
 
Unanticipated Problem 
An unanticipated problem is an adverse event that is (i) unexpected; (ii) serious; and (iii) felt by the 
investigator to be possibly, probably, or definitely related to the research intervention. Only adverse 
events that meet this definition need be reported to the IRB. 
 
For more information on the definition of an unanticipated problem and reporting requirement, 
consult the current PH&S AE Guidelines published on the IRB website 
(http://in.providence.org/or/departments/reviewboard/Pages/default.aspx). 
 
 
9.1.2 
Reporting 
PH&S IRB
An unanticipated event that is serious and definitely or probably caused by the study treatment 
(drugs or device) will be reported to the IRB in accordance with their guidelines and within their 
timelines. Collaborating sites must comply with all local IRB requirements and copies of all IRB 
approvals from these sites must be provided by the site’s clinical research staff to the PH&S 
Regional Research Office. 
:  
 
9.2 Data Reporting 
Clinical data will be recorded on study-specific case report forms (CRFs), which will be provided by 
PH&S clinical research staff. All forms must be legible and complete. Black ink must be used in 
completing these forms. All corrections must noted with a single line strike though inaccurate entries 
and will be initialed and dated. All data entries to CRFs must be supported by a clinical source 
document. No direct entry of patient data to the CRF is permitted. 
9.3 Continuing Review and Final Reports 
An annual progress report (continuing review) will be submitted to the IRB of record for the duration 
of the study. A final report to the IRB of record will be submitted at the summation of the study. 
9.4 Protocol Modifications and Amendments 
All modifications or amendments to the protocol or informed consent document must be approved 
by the Principal Investigator and submitted to the Providence Health & Services Regional 
Institutional Review Board (IRB) for review and approval. All modifications and amendments will be 

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documented with a new version number and date. All changes to the informed consent document 
will include the date of the revision on the form. 
No changes will be implemented until IRB approval is obtained except when a potential threat to 
patient safety exists. 
The IRB will be notified of any significant deviations from the approved protocol. Documentation of 
all IRB correspondence will be maintained in the central regulatory file according to section 10.5. 
Collaborating sites must comply with all requirements of the IRB of record, and copies of all IRB 
approvals from these sites must be provided by the site’s clinical research staff to the PH&S 
Regional Research Office. 
9.5 Record Retention 
According to 21 CFR 312.62(c), the investigator shall retain required records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it is 
being investigated. If no application is to be filed or if the application is not approved for such 
indication, the investigator shall retain these records until 2 years after the investigation is 
discontinued or the IND is withdrawn and the FDA is notified. 
The investigator must retain protocols, amendments, IRB/IBC approvals, completed, signed, dated 
consent forms, patient source documents, case report forms, quality monitoring reports, drug 
accountability records and all documents of any nature regarding the study or patients enrolled. All 
records will be maintained under restricted access by the Clinical Trials Department at Providence 
Portland Medical Center while the study remains active. Records may be placed in long-term 
storage after the study is completed. The location of long-term storage will be secure and easily 
accessed for regulatory purposes.  
9.6 Quality Assurance Plan 
The Providence Health System Quality Assurance (QA) plan for cancer clinical trials comprises 
Standard Operating Procedures (SOPs) that require ongoing review of activities associated with all 
investigator-initiated trials including protocol compliance, accuracy of data and safety of participants. 
9.6.1 
Study Monitoring 
Study monitoring activities (Quality Control Reviews) are performed by a Contract 
Research Organization (CRO) or clinical research staff members who have completed 
specialized training in study monitoring procedures and human subjects’ protections.  
Individuals who perform study monitoring activities do not report to Principal Investigators 
or research scientists and may not monitor studies for which they have direct responsibility. 
Study monitoring activities are conducted regularly and include (but are not limited to) 
review and verification of the following:  
• 
Eligibility 
• 
Informed Consent process 
• 
Adherence to protocol treatment plan 
• 
Case Report Forms (CRFs) 
• 
Source Documentation 
• 
Adverse Events 
• 
Regulatory Reporting 

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Results of study monitoring activities will be reported to applicable study personnel, the 
Clinical Trials Manager and Quality Assurance. 
 
9.6.2 
Quality Assurance 
Quality Assurance (QA) personnel review study monitoring reports and if necessary, 
determine follow-up actions to resolve significant findings. QA has the authority to request 
immediate corrective action if significant patient safety issues are identified.   
QA will track and trend results from study monitoring reports as well as associated 
corrective and preventive actions.  A QA summary report will be provided to the IRB at the 
time of continuing review. 
QA personnel do not have a direct reporting relationship to the Principal Investigator and 
are not responsible for enrollment or coordination of care for study participants. 
9.6.3 
Plans For Assuring Accuracy Of Data 
All case report forms will undergo quality assurance review.  All quality assurance reviews 
will include verification of the accuracy and integrity of data entered to case report forms. 
Incorrect data will be identified and corrected.  The existence of adequate source 
documents for all data will be verified.  All annual reports (continuing reviews) or 
publications will be reviewed by a staff person not associated with patient care 
coordination, data completion and submission, or writing such reports.  
 
10. STATISTICAL CONSIDERATIONS 
10.1 Study Endpoints 
The primary study endpoint is to determine the best overall tumor response of high dose IL-2 versus 
SBRT + high dose IL-2 using RECIST criteria applied to all target and non-target lesions with the 
exclusion of sites treated with SBRT.  For patients who have SBRT after progression on IL-2 
monotherapy, the response rate will be recorded, but not counted as a response for the primary 
objective.  There will be a comparison of the overall tumor response of patients receiving one versus 
two SBRT doses. 
 
The secondary objectives are hypothesis generating and have not been included in determining the 
sample size.  These include tests of the proliferation of CD4+T cells with a memory phenotype 
(CD3+CD4+Ki67+CD25+FoxP3-CCR7-CD45RA-CD27+CD28+) by flow cytometry, exploratory studies 
of pro-calcitonin, DAMPs and other inflammatory mediators that may influence the interaction 
between SBRT and IL-2 analysis of antibody response and correlations with gene expression by 
autologous tumor, characterization of T cell response to melanoma cell lines and antigens identified 
by protein array and study of biopsies of melanoma lesions before and after SBRT.  Descriptive 
statistics will be used in the analysis of these hypothesis-generating studies.    
10.2 Sample Size 
Our sample size determination is based on our initial phase I study in which we observed a 71% 
response rate.  The 95% confidence interval (Clopper-Pearson) for a response rate of 5 CRs out of 

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7 patients is (29%, 96%). If the high-dose IL-2 group has a response proportion of 0.16 based on 
the published literature versus a response proportion of 0.70 in the SBRT + IL-2 group, then15 
patients in each group (for a total of 30 patients) would have 80% power with a significance level of 
0.05 to detect the stated difference with the Pearson Chi-Square test with continuity correction.  The 
table gives the sample size per group (Two Group Test) to detect difference in response   80% 
power, α=0.05, Response Proportion of 0.16 vs. Column Heading and using Pearson Chi-Square 
test with continuity correction. 
 
 
 
 
Proportion Responders in SBRT + IL-2 Group 
.50 
.60 
.70 
.80 
.90 
34 
22 
15 
11 
8 
 
 
For this study we will assume a more conservative response rate of 60% in the SBRT + IL-2 group.  
This will require 22 patients to be treated in each group (44 total) to achieve an 80% power.  
 
 
10.3 Patient Accrual 
The IL-2 service currently treats approximately 3 melanoma patients per week. In addition to the IL-
2 service, Providence Cancer Center enrolls an average of two melanoma patients per month to 
clinical trials. It is estimated that we can enroll one patient per month to this trial and can complete 
accrual within one year. 
 
10.4 Immunological Monitoring 
As detailed in the study schema, samples for immunological monitoring will include blood and melanoma 
tumor biopsies.  The main objectives of the monitoring will be to characterize circulating T-cell subsets.   
The immunological monitoring lab will perform flow cytometry with a panel of markers including CD3, 
CD4, CD8, CD27, CD28, CD95, Ki-67, CD25, CD127, CCR-7, FoxP3, and CD45RA.  T cell sub-
populations of interest include Treg, central memory and effector cells.  This polychromatic flow assay will 
be used to identify proliferating T cells.  
T cell response to melanoma cell lines and antigens identified by protein array will be analyzed using a 
bank of 245 melanoma specimens that were triple enzyme digested and cryopreserved at the EACRI in 
Dr. Fox’s lab.  We will start by evaluating whether post treatment aphereses samples recognize HLA-
matched melanoma cells. If we identify patients with detectable responses against matched melanoma 
cells we will then evaluate whether the same response exists in the limited number of pretreatment 
cryopreserved PBMC.   
Markers of tumor lysis, inflammation and immune activation will be explored by measuring serum lactate 
dehydrogenase, uric acid and phosphate and test each of these as surrogate markers of cytotoxicity-
mediated antigen release.  We will also measure serum levels of danger associated molecular patterns 
(DAMPs) and pro-calcitonin. Radiation therapy has been shown to result in release of DAMPs and these 
DAMPs may be important immune adjuvants that influence the response to chemotherapy and radiation. 
Additional evaluations of the immune response will include a phenotypic analysis of changes in myeloid, 
T, B and NK cell populations, over time.  We will measure Treg (natural versus induced) and Treg 
activation status via a flow cytometry panel that includes CD3, CD4, Ki-67, CD25, FoxP3, PD-1, CTLA-4, 

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ICOS, CD134. HELIOS and ICOS.  The NK/ B cell panel includes CD3, CD8, CD25, CD56, NKG2A, 
NKG2D, KLR1, CD19.  The MDSC panel includes, CD14, CD15, CD45 and HLA-DR.  
We will also examine the frequency of tumor-specific T cells in collaboration with Dr. Ton Schumacher at 
The Netherlands Cancer Institute.  HLA typing will be performed using DNA from the first immune 
monitoring sample. Using these results, de-identified samples from HLA-A2+ patients will be shipped to 
the Netherlands Cancer Institute for analysis. Using a novel high throughput technology, researchers will 
screen patient material for reactivity against very large panels of melanoma-associated epitopes using 
peptide MHC multimers. Clinical data (without PHI) may also be shared (e.g., treatments, outcomes, 
lab/scan results, etc.) 
 
It is also possible that additional collaborations with other outside researchers will be established.  De-
identified biospecimen samples and clinical data (without PHI) may be shared in those efforts as well." 
 
 
 

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INFORMED CONSENT 
APPENDIX A 
ECOG PERFORMANCE SCALE 
 
 
 
0 
Fully active, able to carry on all predisease activities without restriction (Karnofsky 90-100).  
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature. For example, light housework, office work (Karnofsky 70-80).  
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 (Karnofsky 50-60).  
3 
Capable of only limited self-care, confined to bed or chair 50% or more of waking hours (Karnofsky 
30-40).  
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair (Karnofsky 10-
20).  
5 
Death (Karnofsky 0)  
 
 

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APPENDIX B 
AJCC Staging for Melanoma and Renal Cell Carcinoma 
 
 
Melanoma
Primary Tumor (T)  
: 
TX  
Primary tumor cannot be assessed. 
T0  
No evidence of primary tumor.  
Tis  
Melanoma in situ  
T1  
Melanoma < 1.0 mm in thickness with or without ulceration 
T1a 
Melanoma < 
T1b 
Melanoma 
1.0 mm in thickness and level II or III, no ulceration 
< 
T2  
Melanoma 1.01-2mm in thickness with or without ulceration 
1.0 mm in thickness and level IV or V or with ulceration 
T2a 
Melanoma 1.01-2mm in thickness, no ulceration 
T2b 
Melanoma 1.01-2mm in thickness, with ulceration 
T3  
Melanoma 2.01-4mm in thickness, with our without ulceration 
T3a 
Melanoma 2.01-4mm in thickness, no ulceration 
T3b 
Melanoma 2.01-4mm in thickness, with ulceration 
T4  
Melanoma > 4mm in thickness with or without ulceration 
T4a 
Melanoma > 4mm in thickness, no ulceration 
T4b 
Melanoma > 4mm in thickness, with ulceration 
 
Regional Lymph Nodes (N)  
NX  
Regional lymph nodes cannot be assessed.  
N0  
No regional lymph nodes metastasis  
N1  
Metastasis in one lymph node 
N1a 
Clinically occult (microscopic) metastases 
N1b 
Clinically apparent (macroscopic) metastases 
N2  
 
Distant Metastasis (M)  
MX Distant metastasis cannot be assessed  
M0 No distant metastasis  
M1 Distant metastasis present  
Note: M1 includes separate tumor nodule(s) in a different lobe (ipsilateral or contralateral)  
STAGE GROUPING  
Occult Carcinoma TX N0 M0  
Stage 0 Tis N0 M0  
Stage IA T1 N0 M0  
Stage IB T2 N0 M0  
Stage IIA T1 N1 M0  
Stage IIB T2 N1 M0  
T3 N0 M0  
Stage IIIA T1 N2 M0  
T2 N2 M0  
T3 N1 M0  
T3 N2 M0  
Stage IIIB Any T N3 M0  
T4 Any N M0  
Stage IV Any T Any N M1  

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APPENDIX C 
Management of Interleukin-2 Toxicity 
 
 
 
A. Dose Modification for Toxicity 
Modification of the treatment protocol will occur by withholding doses of IL-2 rather than continuing 
therapy at a reduced dose.   
 
Dose of IL-2 may be withheld for: 
• 
hypotension refractory to fluids and pressors or requiring unacceptably high pressor doses (≥ 
100 mcg neosynephrine); 
• 
anuria for>24 hours and unresponsive to fluid replacement and low-dose dopamine;  
• 
respiratory distress requiring oxygen>4 liters to maintain O2 saturation>95%; 
• 
confusion (mental status changes can progress to paranoia despite discontinuation of IL-2; it 
is imperative that the IL-2 be stopped at any sign of persistent confusion or disorientation); 
• 
sustained ventricular tachycardia or any sign or symptom of myocardial ischemia or 
myocarditis. Patients experiencing sustained ventricular tachycardia or myocardial ischemia 
should not receive further treatment with IL-2; 
• 
metabolic acidosis with HCO3<18, despite attempts to correct with IV HCO3; 
• 
atrial fibrillation or myocarditis; 
• 
documented systemic infection; 
• 
any other serious toxicity that is not controlled at time of next dose. 
 
B. 
 
Specific Toxicity Management 
Several treatment-related toxicities have been uniquely associated with the administration of high-
dose IL-2.  Recommendations for management of the more significant toxicities typically seen with 
high-dose bolus IL-2 are as follows (the following are only suggested
 
 guidelines for toxicity 
management):     
B1 
 
Fluid Replacement 
Excessive fluid replacement will increase the patient’s likelihood of developing pulmonary 
edema. Fluid replacement with normal saline at 75 ml/hr IV may be required for patients who 
do not have adequate oral intake or who experience significant diarrhea.  Once patients have 
gained greater than 5% of baseline weight, additional fluid boluses should not
 
 be given to 
maintain blood pressure.  Lasix should not be given unless symptomatic fluid retention 
develops and blood pressure is adequate.  
B2 
 
Hypotension 
Administration of high dose IL-2 leads to decreased peripheral vascular resistance and 
consequent hypotension. In order to manage this toxicity, the physician may utilize the 
following guidelines: 
 
1. 
Monitor patients in a setting capable of providing vasopressor support. 

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2.  
Prior to starting IL-2 therapy determine a minimum tolerated blood pressure (MTBP). 
For patients under age 40 and with no prior history of ischemic or valvular heart 
disease, the MTBP may be a systolic blood pressure (SBP) of 80 mmHg, while the 
MTBP for all other patients should be a SBP of 85-90 mmHg based on perceived risk 
of cardiac toxicity. 
 
3.  
When a patients systolic BP falls below the MTBP, suggested therapy may involve (in 
the following order):     
a) 
Begin fluid boluses (250cc normal saline IV over 15 min. may repeat x 2) until 
SBP is > MTBP. 
b) 
Should fluid boluses fail make the SBP>MTBP, treatment with neosynepherine 
should also be instituted (1-4 ug/kg/min) to maintain SBP ≥ MTBP. 
 
B3 
 
Management of Arrhythmias/Myocarditis 
If significant arrhythmias occur at any stage in the patient's treatment (whether on pressor 
agents or not), the possibility of myocardial ischemia/infarction must be excluded by both EKG 
and cardiac enzyme assessment.  Patients who develop atrial fibrillation should have IL-2 
doses held.  Therapy may resume when the patient converts to normal sinus rhythm and is 
hemodynamically stable. If a significant supraventricular arrhythmia occurs while a patient is 
on dopamine therapy; neosynepherine should also be substituted for dopamine as initial blood 
pressure support. Patients experiencing sustained ventricular tachycardia or documented 
myocardial ischemic episodes during therapy should not receive further treatment with IL-2. 
Patients with myocarditis may resume treatment in subsequent cycles if CPK returns to 
normal. A cardiac ECHO documenting normal cardiac function should be performed prior to 
restarting therapy. 
 
B4 Management of Neurotoxicity
 
 
Doses are held rather than reduced for neurotoxicity.  If Grade 4 neuro-cortical toxicity is 
encountered and is not reversible within 48 hours, no further treatment should be given and 
the patient should be removed from the study.  If Grade 4 toxicity is reversible to Grade 1 
within 48 hours, future treatment may be considered (in subsequent cycles) if the patients 
shows and evidence of tumor regression.   
 
B5 
 
Metabolic Acidosis 
During IL-2 therapy, when a patient’s HCO3 falls to below 20, NaHCO3 should be added to the 
maintenance IV infusion.  Should the HCO3 level fall below 18, IL-2 therapy should be held, 
and bolus infusions of NaHCO3 should be instituted.  IL-2 therapy may resume if repeat HCO3 
>
 
 18. 
B6 
 
Pulmonary Toxicity 
 
Pulse oximetry and clinical exam are routinely used at the time of each IL-2 dose to ascertain 
if the patient has sufficient pulmonary reserve to proceed with the planned dose.  Due to the 
concern that pulmonary toxicity may be exacerbated by the combination of SBRT and IL-2, 
routine chest radiography and DLCO will also be used in IL-2 dose decisions.  IL-2 doses will 
be held if the CXR shows an effusion greater than 1/3 the vertical dimension of the lung, if 
pneumonitis is present in areas outside those treated by SBRT or if DLCO is less than 75% on 
the first day of each IL-2 cycle.    
 
 

PH&S IRB 11-062A 
Version 5/6/13 
 
Page 42 
 
 
B7 
 
Other Toxicities 
Increases in the serum creatinine to 2.0-3.5 mg/dl and total bilirubin to 3.0-10.0 mg/dl are 
common and reversible upon cessation of treatment. Doses of IL-2 have not generally been 
withheld for renal and hepatic dysfunction alone.  Although toxicity may become severe, 
recovery usually occurs following cessation of IL-2 and vigorous supportive care is warranted.  
Additional IL-2 toxicity management guidelines are detailed in the Biotherapy Program 
Standard Operating Procedures.  
     
C.  
Management of Grade 4 Toxicity
 
  
 
Patients with Grade 4 (Life Threatening) toxicity may be treated with dexamethasone 4 mg qid 
until side effects improve to an acceptable level. In the clinical trials with IL-2, dexamethasone 
has been used to treat patients with pulmonary edema requiring assisted ventilation, although 
many patients may be managed successfully without steroids. 
     
 
D.  
 
Toxicity Criteria for Discontinuing Treatment 
Patients will not be considered for further therapy if the following toxicities are encountered: 
1. Pulmonary toxicity requiring endotracheal intubation not resolved within 72 hrs (to 
Grade1) 
2. Renal dysfunction requiring dialysis not reversible within 72 hrs 
3. Grade 4 cardiac dysrhythmia or Grade 2 or 3 dysrhythmia not easily controlled with 
medical management. 
4. Myocardial ischemia (Grade 3 or 4) or infarction or symptomatic myocarditis (note: 
asymptomatic CPK or CPK-MB band elevations without EKG changes are not a 
contraindication to further treatment). 
5. Coma 
6. Life-threatening sepsis 
7. Pericardial tamponade 
8. Bowel ischemia or perforation 
9. Any other severe or life-threatening toxicity which, in the opinion of the investigator, 
would preclude further treatment with these agents, or has not resolved to baseline 8 
weeks after treatment. 
 
 
 

PH&S IRB 11-062A 
Version 5/6/13 
 
Page 43 
 
APPENDIX D 
Immunologic Monitoring Schedule  
 
Baseline:  One 3cc lavender top tube 
                 Ten 10 cc green top tubes  
 
    One 10 cc tiger top tube 
 
Day 1:      One 3cc lavender top tube 
                Three10 cc green top tubes  
 
   One 10 cc tiger top tube 
 
Day 2:      One 3cc lavender top tube 
                Three10 cc green top tubes  
 
   One 10 cc tiger top tube 
 
Day 5 
One 3cc lavender top tube 
                Three10 cc green top tubes  
 
   One 10 cc tiger top tube 
 
Day 8:      One 3cc lavender top tube 
                Three10 cc green top tubes  
 
   One 10 cc tiger top tube 
 
Week 4:   One 3cc lavender top tube 
                Three10 cc green top tubes  
 
   One 10 cc tiger top tube 
 
Week 7 (+/- 1 week) if pheresis product cannot be collected: 
                                   One 3cc lavender top tube 
                                   Ten 10 cc green top tubes  
 
                      One 10 cc tiger top tube