Conditions: Melanoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
This study is for patients with advanced stage III or stage IV melanoma not adequately treated by surgery who have progressed after treatment with nivolumab or pembrolizumab. The purpose of this study is to see if giving high dose interleukin-2 (IL-2) after progression on nivolumab or pembrolizumab is effective in treating metastatic melanoma. This study is also being done to look at the severity of side effects of IL-2 in patients.

IL-2 is approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced melanoma.

Detailed description:
This is a phase II study of high dose bolus interleukin-2 (HD IL2) in patients with advanced inoperable stage III or stage IV melanoma who have prior anti-PD1 immunotherapy.

Each course consists of 2 cycles of HD IL2 as follows: high-dose IL2 at 600,000 IU/kg is given intravenously (IV) every 8 hours for up to 14 doses (one cycle), followed by a rest period of 1-2 weeks and readmission for a second HD IL2 cycle for up to 14 doses (second cycle).

The planned treatment consists of 3 courses (6 cycles) of HD IL-2. Response assessment will occur at the end of each course of therapy and patients without evidence of disease progression (Response Evaluation Criteria in Solid Tumors, RECIST, version 1.1) or limiting toxicities will be offered additional courses of treatment of HD IL2 for a maximum of 3 courses.

Arms:
arm 1: None

Interventions: intervention 1: High dose bolus interleukin-2 (HD IL2)
Intervention descriptions: intervention 1: Each course consists of 2 cycles of HD IL2 as follows: high-dose IL2 at 600,000 IU/kg is given intravenously (IV) every 8 hours for up to 14 doses (one cycle), followed by a rest period of 1-2 weeks and readmission for a second HD IL2 cycle for up to 14 doses (second cycle).

The planned treatment consists of 3 courses (6 cycles) of HD IL-2.

Protocol document:
Prot_SAP_000.pdf: 
 
UPCI Protocol #:  
15-114 
 
TITLE: A Phase II Study of High Dose Bolus IL2 in Patients with Inoperable Stage III or Stage 
IV Melanoma Who Have Failed Prior Anti-PD1 Immunotherapy: Efficacy and Biomarker Study 
 
Coordinating Center: 
University of Pittsburgh Cancer Institute  
 
5150 Centre Avenue, Pittsburgh, PA, 15232 
 
Phone:  412 647-8587 
 
Fax:      412 623-7862 
 
 
 
 
 
Principal Investigator: 
Ahmad A. Tarhini, MD, PhD 
Associate Professor of Medicine and Translational Science 
University of Pittsburgh School of Medicine  
UPMC Cancer Pavilion 
5150 Centre Ave., 5th floor  
Pittsburgh, PA 15232 
Phone: 412-648-6578 
Fax:      412-648-6579 
E-mail: tarhiniaa@upmc.edu  
 
 
Statistician:  
 
Yan Lin, Ph.D. 
University of Pittsburgh Cancer Institute & 
Biostatistics Dept, University of Pittsburgh 
 
Study Chair Liaison:   
Amy Rose, RN BSN OCN 
University of Pittsburgh Cancer Institute 
5150 Centre Avenue 
Third Floor 
Pittsburgh, PA 15232 
Phone: (412) 647-8587 
Fax: (412) 623-7862 
E-mail: kennaj@upmc.edu 
 
 
Commercial Agent: 
Aldesleukin (Interleukin-2) 
 
Protocol Version Date:  
July 12, 2015  
 
Initial Protocol 
 
 
Sept 15, 2016 
 
Amendment 1 
 
 
Dec 7, 2016  
 
Amendment 2 
 
IND:                                         Exempt 
 
NCT#:                                     NCT02796352 


2 
 
SCHEMA 
This is a phase II study of high dose bolus interleukin-2 (HD IL2) in patients with advanced 
inoperable stage III or stage IV melanoma who have failed prior anti-PD1 immunotherapy.  
 
The planned treatment consists of 3 courses (6 cycles) of HD IL-2. Response assessment will occur 
at the end of each course of therapy and patients without evidence of disease progression (RECIST 
v.1.1) or limiting toxicities will be offered additional courses of treatment of HD IL2 for a maximum 
of 3 courses. 
 
 
 
 
 
 
 
 
 
 
 
*Local variations are allowed as per local site standard practice, patient recovery from adverse events and 
scheduling requirements.  
 
Primary Objective: To determine the response rate (CR+PR) of HD IL2 in patients with inoperable 
stage III or stage IV melanoma who have either failed prior treatment with anti-PD1 immunotherapy 
(nivolumab or pembrolizumab) or who have demonstrated tumor progression following such 
therapy. 
 
Secondary Objectives: (1) Evaluate the toxicities of HD IL2 in this patient population (CTCAE 
v.4). (2) Evaluate the progression free survival (PFS) and overall survival (OS). (3)  Bank biological 
specimens for the future testing of laboratory correlative studies within the circulation and the tumor 
microenvironment (TME) to better understand the impact of HD IL2 in this setting. 
 
The primary endpoint is (CR+PR) as assessed by RECIST criteria version 1.1.  The total accrual goal 
is 45 patients.  
 
 
Definitions: 
 
1. A cycle of IL-2: eligible patients receive HD IL2 at 600,000 IU/kg IV every 8 hours for up to 
14 doses. This constitutes one cycle of IL2. 
2. Each course consists of 2 cycles of HD IL2 as follows: high-dose IL2  at 600,000 IU/kg is 
given IV every 8 hours for up to 14 doses (one cycle), followed by a rest period of  1-2 weeks 
and readmission for a second HD IL2 cycle for up to 14 doses (2nd cycle).  
Course of HD IL2* 
 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
HD IL-2 
600,000 U/kg/dose 
IV Q8h x 5 days 
(max 14 doses) 
X 
 
X 
 
 
 
 
 
Response 
Assessment 
 
 
 
 
 
 
 
X 


3 
 
3. Based on the occurrence of treatment-related toxicities and requirements for dose 
adjustments or delays, a patient may or may not receive the full planned treatment, but 
response assessment will continue to be carried out at the end of each course. 
 
Patients will receive HD IL-2 following the institutional standard of care guidelines. Patients will 
receive a maximum of 3 courses (6 cycles; 1 course of IL2 = 2 cycles of IL2). Response 
assessment will be carried out at the end of each course. In the absence of disease progression by 
RECIST v.1.1, patients will be offered additional courses of therapy for a maximum of 3 courses 
(6 cycles). 
 
ABBREVIATIONS 
 
High dose bolus interleukin-2: HD IL-2 
Complete response: CR 
Overall survival: OS 
Progression free survival: PFS  
Partial response: PR 
Pulmonary function tests: PFTs 
Stable disease: SD 
Tumor microenvironment: TME 
University of Pittsburgh Cancer Institute: UPCI 


4 
 
TABLE OF CONTENTS 
1. 
OBJECTIVES ................................................................................................................. 5 
1.1. 
Primary Objectives ...................................................................................................... 5 
1.2. 
Secondary Objectives .................................................................................................. 5 
2. 
BACKGROUND ............................................................................................................ 5 
2.1. 
Metastatic Melanoma .................................................................................................. 5 
2.2. 
High Dose Interleukin-2 .............................................................................................. 6 
2.3. 
Rationale ..................................................................................................................... 7 
3. 
PATIENT SELECTION ................................................................................................. 7 
3.1. 
Eligibility Criteria ....................................................................................................... 7 
3.2. 
Exclusion Criteria ....................................................................................................... 9 
3.3. 
Inclusion of Women and Minorities ......................................................................... 10 
4. 
REGISTRATION PROCEDURES ............................................................................... 11 
4.1. 
General Guidelines .................................................................................................... 11 
4.2. 
Registration Process .................................................................................................. 11 
5. 
TREATMENT PLAN ................................................................................................... 11 
5.1. 
Overall Treatment Plan ............................................................................................. 11 
5.2. 
Aldesleukin (Interleukin-2) Administration .............................................................. 12 
5.3. 
General Concomitant Medication and Supportive Care Guidelines ......................... 13 
5.4. 
Duration of Therapy .................................................................................................. 13 
5.5. 
Duration of Follow Up .............................................................................................. 14 
6. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ........................ 14 
6.1. 
Interleukin-2 Adverse Event Summary List .............................................................. 14 
6.2. 
Adverse Event Characteristics .................................................................................. 17 
6.3. 
Expedited Adverse Event Reporting ......................................................................... 18 
6.4 Data and Safety Monitoring Plan .................................................................................. 19 
7. 
PHARMACEUTICAL INFORMATION ..................................................................... 20 
7.1. 
Commercial Agents .................................................................................................. 20 
8. 
CORRELATIVE/SPECIAL STUDIES ........................................................................ 21 
8.1. 
Laboratory Correlative Studies ................................................................................. 21 
9. 
STUDY CALENDAR................................................................................................... 23 
10. 
MEASUREMENT OF EFFECT ............................................................................... 25 
10.1. Antitumor Effect – Solid Tumors ............................................................................. 25 
11. 
STATISTICAL CONSIDERATIONS ...................................................................... 26 
11.1. Study Design/Endpoints ............................................................................................ 26 
11.2. Sample Size/Accrual Rate ......................................................................................... 27 
11.3. Statistical Analyses.................................................................................................. 27 
12. 
REFERENCES ......................................................................................................... 29 
APPENDIX A – Performance Status Criteria ....................................................................... 31 
 
 
 


5 
 
1. 
OBJECTIVES 
1.1. 
Primary Objectives 
• To determine the response rate (CR+PR) of HD IL-2 in patients with inoperable stage 
III or stage IV melanoma who have either failed prior treatment with anti-PD1 
immunotherapy (nivolumab or pembrolizumab) or who have demonstrated tumor 
progression following such therapy. 
1.2. 
Secondary Objectives 
• Evaluate the toxicities of HD IL-2 in this patient population (CTCAE v.4).  
• Evaluate the progression free survival (PFS) and overall survival (OS). 
• Test laboratory correlative studies within the circulation and the tumor 
microenvironment (TME) to better understand the impact of HD IL2 in this 
setting. 
 
2. 
BACKGROUND 
2.1. 
Metastatic Melanoma 
Annually, more than 8,000 patients are found to have metastatic melanoma presenting as 
a recurrence of an earlier primary melanoma, and this number closely approximates the 
annual number of deaths from this disease [1]. This statistic illustrates the lack of 
progress that has been made in the treatment of stage IV melanoma over the last several 
decades. Therapeutic approaches that have been studied in metastatic melanoma include 
chemotherapy, biochemotherapy, protein kinase inhibitors, nonspecific immune 
adjuvants, cancer-specific vaccines, cytokines, monoclonal antibodies, and specific 
immunostimulants [1]. Chemotherapy with single agent dacarbazine was the only US-
FDA approved chemotherapy agent for metastatic melanoma. Immunological approaches 
later yielded the only US-FDA approved agent for metastatic disease in 30 years, high-
dose bolus interleukin-2 (IL-2), based on prolonged durable responses in some patients 
with metastatic melanoma [2]. However, a lack of progress for several decades has 
recently changed dramatically, driven by a deepening understanding of melanoma 
biology and host immunology.[3, 4] This progress at the molecular levels has been 
translated into the clinic with new molecularly targeted agents (BRAF and MEK kinase 
inhibitors) and immune checkpoint modulators (CTLA4 and PD-1 blocking antibodies) 
that have made major improvements in disease control and the survival of patients with 
metastatic melanoma. First line therapy in patients with metastatic melanoma in practice 
currently primarily consists of immune checkpoint inhibitor or targeted kinase inhibitor 
therapy. Unfortunately, only a proportion of patients derive long term clinical benefits 
and the majority of patients eventually progress where there is a need for effective 
salvage systemic therapy. In this setting, there appears to be an important role of HD IL2 
which is not well defined at this time. Therefore, participation of patients receiving 
salvage HD IL2 in clinical trials is presently the best strategy in order to define its clinical 
and biological impact in this setting and help guide the development of future salvage 
strategies.  
 


6 
 
 
 
2.2. 
High Dose Interleukin-2 
IL-2  plays a central role in immune regulation as it affects the survival of key cells of the 
immune system that are responsible for the antitumor cytotoxicity of T-lymphocytes and 
natural-killer (NK) cells, and it has a cofactor role in the activation of B cells and 
macrophages [5]. The administration of IL-2 at high bolus IV doses once every eight 
hours was a regimen developed by the National Cancer Institute (NCI) based on animal 
models indicating that antitumor activity with this agent was dose-dependent [6-8].  
Initial studies with HDB IL-2 utilized doses of 600,000-720,000 units/kg every 8 hours 
from days 1-5 (cycle 1) and days 15-19 (cycle 2) with a maximum of 14 doses per cycle 
or 28 doses per course (1 course = 2 cycles).  Responding or stable patients were offered 
a second course of therapy 8-12 weeks later. IL-2 was administered either as a single 
agent or in combination with immunologically active cells, so-called adoptive 
immunotherapy. The latter technique utilized two types of immune cells: the 
lymphokine- activated-killer (LAK) cells and the tumor infiltrating lymphocytes (TIL). 
Eight clinical trials conducted between 1985 and 1993 and using the HDB IL-2 regimen 
described above, with or without LAK cells, were reviewed in a retrospective analysis. 
These trials had an enrollment of 270 patients with advanced metastatic melanoma [7-
11]. In those studies that involved the concurrent administration of LAK cells, these cells 
were obtained using leukapheresis from patients during the rebound lymphocytosis that 
occurs following treatment and cessation of bolus IL-2 (days 8 to 12). LAK cells were 
then cultured in IL-2 for 3 to 4 days. These generated LAK cells were reinfused with IL-2 
during the second cycle of IL-2 administration. The retrospective analysis of these trials 
with a follow-up through December 1998 along with a more recent update demonstrated 
an objective response rate of 16% with durable responses in 4% of patients [2, 10-12]. 
The median response duration was 8.9 months (range 4 to 106+ months). Twenty eight 
percent of the responding patients, including 59% of those patients who had achieved a 
complete response, have remained progression free at a median follow-up of 62 months. 
Furthermore, no patient who had responses longer than 30 months has relapsed, 
suggesting the possibility that these patients may be “cured”. The frequency of the 
responses was similar in patients with visceral metastases and/or large tumor burdens, 
but the responses were less in patients with poor performance status or those who had 
received prior systemic therapy. Based on these data, HDB IL-2 received approval by the 
US-FDA for the treatment of metastatic melanoma [11-13]. In addition to being 
logistically challenging, randomized studies have not shown superiority for IL-2 
administered with LAK cells versus therapy with HD IL-2 alone [12-14]. Furthermore, a 
randomized phase III trial of CD8+ TIL given in combination with rIL-2 in metastatic 
renal cell carcinoma has been negative [13-15]. We have previously shown that HD IL2 
is an active therapy for patients who progress on biochemotherapy; this observation has 
implications regarding the importance of dose intensity for IL-2 therapy [16]. Continuous 
infusion of IL-2 at intermediate dosage is a critical component of biochemotherapy 
regimens and it was previously unknown whether patients treated with biochemotherapy 
and failing to obtain response, or responding and then demonstrating progression, are 
capable of subsequently responding and benefiting clinically from the HD IL2 regimen.  


7 
 
 
 
2.3. 
Rationale 
First line therapy in patients with metastatic melanoma in practice currently primarily 
consists of immune checkpoint inhibitor or targeted kinase inhibitor therapy. 
Unfortunately, only a proportion of patients derive long term clinical benefits and the 
majority of patients eventually progress where there is a need for effective salvage 
systemic therapy. In this setting, there appears to be an important role of HD IL2 which 
is not well defined at this time. Therefore, participation of patients receiving salvage HD 
IL2 in clinical trials is presently the best strategy in order to define its clinical and 
biological impact in this setting and help guide the development of future salvage 
strategies. 
 
Immunologically, we expect that HD IL2 will be effective as salvage immunotherapy 
in patients in patients failing anti-PD1. In an animal model, IL2 was found to 
synergize with PD-L1 blockade in reinvigorating exhausted T cells [17]. This model 
showed that CD8+ T cell expansion and T cell function were upregulated in a 
regimen consisting of IL2 and anti-PD-L1.  
 
Immunotherapy using checkpoint inhibitors represents a major advance in cancer therapy 
with an approach distinct from chemotherapy and targeted therapies. However, this new 
strategy of treatment is also associated with a unique spectrum of adverse events, mostly 
immune-related (irAEs), occurring via nonspecific immunologic activation that can 
sometimes be serious and even fatal [18]. Early recognition and management of these 
irAEs are of paramount importance for practicing clinicians in order to successfully and 
safely implement the use of these agents in routine clinical practice. These irAEs may 
have long term effects and it is not well understood how subsequent therapies may be 
affected by prior exposure to these agents. Therefore, it is important to define the safety 
of HD IL2 in this setting. Overall, we expect that HD IL2 will be safe in patients who 
failed prior anti-PD1 immunotherapy, primarily because anti-PD-1 and HD IL-2 have 
largely non-overlapping toxicities [11, 18]. 
 
3. 
PATIENT SELECTION 
3.1. 
Eligibility Criteria 
3.1.1. Patients must have histologically or cytologically confirmed metastatic melanoma. 
This includes AJCC stage IV or advanced/inoperable stage III. This also includes 
patients with a history of lower stage melanoma and subsequent recurrent metastatic 
disease that is either locally/regionally advanced/inoperable disease or distant 
metastases.   
 
3.1.2. Patients must have measurable disease, according to RECIST version 1.1 [19].  See 
Section 10 for the evaluation of measurable disease. 
 


8 
 
3.1.3. Patients must be free of active brain metastasis by contrast-enhanced CT/MRI scans 
within 4 weeks prior to enrollment. If known to have prior brain metastases, these 
must have been adequately managed with standard of care radiation therapy, 
stereotactic radiosurgery or surgery prior to registration on the study. 
 
3.1.4. A patient must have previously received anti-PD1 immunotherapy (nivolumab or 
pembrolizumab) and later experienced disease progression, within 3 months of 
registration on this study.  
 
Patients must not have received systemic therapy or radiotherapy within the 
preceding 3 weeks. Patients must have recovered from adverse events from previous 
therapy by the time registration. 
Patients must be at least 4 weeks from major surgery and have fully recovered from 
any effects of surgery, and be free of significant detectable infection prior to 
registration. 
 
For patients who have received prior anti-CTLA4 monoclonal antibody therapy 
(ipilimumab or tremelimumab), there is a risk of bowel perforation with IL-2 therapy. 
Therefore, for these patients if they have a history of colitis or diarrhea during anti-
CTLA4 monoclonal antibody therapy, it is recommended that they have a formal 
evaluation by a gastroenterologist and a colonoscopy/endoscopy should be 
considered to demonstrate the absence of active bowel inflammation before initiating 
IL-2 therapy on this protocol.    
 
3.1.5. Age ≥ 18 years.   
 
3.1.6. Life expectancy of greater than 3 months in the opinion of the investigator. 
 
3.1.7. ECOG performance status 0 or 1 (Karnofsky ≥70%; see Appendix A). 
 
3.1.8. Patients must have normal organ and marrow function as defined below: 
 
- 
leukocytes  
 
 
 
 
>3,000/mcL 
- 
absolute neutrophil count  
>1,500/mcL 
- 
platelets 
 
 
 
 
 
>100,000/mcL 
- 
total bilirubin  
 
 
 
< 1.5 x institutional upper limit of normal 
- 
AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of normal 
- 
creatinine  
 
 
 
 
<1.5 x institutional upper limit of normal 
OR 
- 
creatinine clearance 
 
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal 
 
3.1.9. Patients on full-dose anticoagulants (e.g., warfarin) with PT INR >1.5 are eligible 
provided that both of the following criteria are met: 
 


9 
 
a) The patient has an in-range INR (usually between 2 and 3) on a stable dose 
of oral anticoagulant or on a stable dose of low molecular weight heparin. 
 
b) The patient has no active bleeding or pathological condition that carries a 
high risk of bleeding (e.g., tumor involving major vessels or known varices). 
 
 
3.1.10. Pulmonary:  FEV1 > 2.0 liters or > 75% of predicted for height and age.  Pulmonary 
function tests (PFTs) are required for patients over 50 years old or with significant 
pulmonary or smoking history.  
 
3.1.11. Cardiac:  No evidence of congestive heart failure, symptoms of coronary artery 
disease, myocardial infarction less than 6 months prior to entry, serious cardiac 
arrhythmias, or unstable angina.  
 
Patients who are over 40 years old or have had previous myocardial infarction greater 
than 6 months prior to study entry or have significant cardiac family history (CAD or 
serious arrhythmias) will be required to have a negative or low probability cardiac 
stress test (for example, thallium stress test, stress MUGA, stress echo or exercise 
stress test) for cardiac ischemia within 8 weeks prior to registration. 
 
3.1.12. CNS:  No history of cerebrovascular accident or transient ischemic attacks within the 
past 6 months from registration.  
 
3.1.13. Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry, for the 
duration of study participation, and for at least 6 months after completion of study 
therapy. Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately. 
 
Women should not be lactating and, if of childbearing age, should have a negative 
pregnancy test (b-HCG test; serum or urine, minimum sensitivity 25 IU/L or 
equivalent units of b-HCG) within two week of registration in the study. 
 
3.1.14. Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2. 
Exclusion Criteria 
3.2.1. Patients who have had systemic therapy for melanoma or radiotherapy within 3 
weeks prior to registering on the study or those who have not recovered from adverse 
events due to agents administered more than 3 weeks earlier. Patients with a history 
of endocrinopathies (e.g. hypothyroidism, adrenal insufficiency, hypopituitarism) are 
eligible if they are stable on hormone replacement therapy. 
 
3.2.2. Patients may not be receiving any other investigational agents. 
 


10 
 
3.2.3. Patients with active brain metastases should be excluded from this clinical trial 
except as noted above under section 3.1.3.  
3.2.4. Patients with clinically significant cardiovascular or cerebrovascular disease: 
• history of cerebrovascular accident or transient ischemic attack within past 6 
months from registration. 
• myocardial infarction, CABG or unstable angina within the past 6 Months from 
registration. 
• New York Heart Association grade III or greater congestive heart failure (Appendix 
E), serious cardiac arrhythmia requiring medication, unstable angina pectoris 
within past 6 months from registration. 
• clinically significant peripheral vascular disease within past 6 months from 
registration. 
 
3.2.5. PT INR >1.5 unless the patient is on full-dose warfarin. 
 
3.2.6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
 
3.2.7. Patients who have other current malignancies are not eligible. Patients with other 
malignancies are eligible if they have been continuously disease free for > 2 years 
prior to the time of registration. Patients with prior history at any time of any in situ 
cancer, lobular carcinoma of the breast in situ, cervical cancer in situ, atypical 
melanocytic hyperplasia or melanoma in situ are eligible. Patients with prior history 
of basal or squamous skin cancer are eligible. Patients who have had multiple 
primary melanomas are eligible. 
 
3.2.8. Patients must not have autoimmune disorders or conditions of immunosuppression 
that require current ongoing treatment with systemic corticosteroids (or other 
systemic immunosuppressants), including oral steroids (i.e., prednisone, 
dexamethasone) or continuous use of topical steroid creams or ointments or 
ophthalmologic steroids or steroid inhalers.  
 
If a patient had been taking steroids, at least 2 weeks must have passed since the last 
dose. Patients stable on physiologic replacement doses of steroids or other forms of 
hormone replacement therapy are eligible.  
 
3.3. 
Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.  


11 
 
4. 
REGISTRATION PROCEDURES 
4.1. 
General Guidelines 
Eligible patients will be entered on study centrally at the Data Coordinating Center 
(DCC) at the University of Pittsburgh Cancer Institute (UPCI). All sites should e-mail the 
DCC at Melanoma_Team@upmc.edu to verify slot availabilities.   
 
Following registration, patients should begin protocol treatment within 2 weeks.  Issues 
that would cause treatment delays should be discussed with the Principal Investigator.  If 
a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled.  The DCC should be notified of cancellations 
as soon as possible. 
 
4.2. 
Registration Process 
Once the signed informed consent has been obtained, all pretreatment evaluations have 
been performed, and patient’s eligibility has been confirmed by the data coordinating 
center a patient will be entered on study.   
 
To register a patient, the research nurse or data manager must complete the 
eligibility/registration form and contact the DCC at UPCI: 
 
• 
E-mail a copy of the completed eligibility checklist, required pre-study tests 
(laboratory and pathology report), signed Informed Consent, and HIPAA 
authorization form to Melanoma_Team@upmc.edu.   
• 
To complete the registration process, the data coordinating center coordinator 
will: 
 
• 
Verify the eligibility 
• 
Register the patient on study 
• 
Assign a patient study number 
• 
E-mail the confirmation of registration to the participating site 
 
5. 
TREATMENT PLAN 
5.1. 
Overall Treatment Plan 
 
This is a phase II study of high dose bolus interleukin-2 (HD IL2) in patients with 
advanced inoperable stage III or stage IV melanoma who have prior anti-PD1 
immunotherapy.  
 
Definitions: 
 
1. A cycle of IL-2: eligible patients receive HD IL2 at 600,000 IU/kg IV every 8 
hours for up to 14 doses. This constitutes one cycle of IL2. 


12 
 
2. Each course consists of 2 cycles of HD IL2 as follows: high-dose IL2  at 600,000 
IU/kg is given IV every 8 hours for up to 14 doses (one cycle), followed by a rest 
period of  1-2 weeks and readmission for a second HD IL2 cycle for up to 14 
doses (2nd cycle).  
3. Based on the occurrence of treatment-related toxicities and requirements for dose 
adjustments or delays, a patient may or may not receive the full planned treatment, 
but response assessment will continue to be carried out at the end of each course. 
 
The planned treatment consists of 3 courses (6 cycles) of HD IL-2. Response assessment 
will occur at the end of each course of therapy and patients without evidence of disease 
progression (RECIST v.1.1) or limiting toxicities will be offered additional courses of 
treatment of HD IL2 for a maximum of 3 courses. 
 
 
 
 
 
 
 
 
 
 
 
*Local variations are allowed as per local site standard practice, patient recovery from adverse events and 
scheduling requirements.  
 
 
Patients will receive HD IL-2 following the institutional standard of care guidelines. Patients will 
receive a maximum of 3 courses (6 cycles; 1 course of IL2 = 2 cycles of IL2). Response 
assessment will be carried out at the end of each course. In the absence of disease progression by 
RECIST v.1.1, patients will be offered additional courses of therapy for a maximum of 3 courses 
(6 cycles). 
 
Research biospecimens will be collected at the multiple time points as noted in section 8.1.1.  
 
 
5.2. 
Aldesleukin (Interleukin-2) Administration 
Aldesleukin (Interleukin-2, IL-2) will be administered on an inpatient basis.  Reported 
adverse events and potential risks for aldesleukin are described in Section 7.   
 
• Patients will receive a total of 6 cycles (1 cycle = 5 days) of IL-2 as described in 
section 5.1. A cycle of IL-2 may be delayed for up to 2 weeks in case of 
unresolved toxicity. 
 
• Aldesleukin will be administered at 600,000 IU/kg IV bolus q 8 hours during 
Course of HD IL2* 
 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
HD IL-2 
600,000 U/kg/dose 
IV Q8h x 5 days 
(max 14 doses) 
X 
 
X 
 
 
 
 
 
Response 
Assessment 
 
 
 
 
 
 
 
X 


13 
 
days 1-5 of each cycle (maximum 14 doses per 5 day cycle).  
 
• As all institutions participating in this protocol have established and experienced 
high dose interleukin-2 programs, the administration of aldesleukin (at the 
protocol’s specified dose and frequency) and the dose delay/discontinuation 
criteria during a cycle of IL-2 will follow the institutional standard of care 
guidelines. Useful guides are provided by: 
o 
Schwartzentruber DJ.  J Immunother. 2001 Jul-Aug;24(4):287-
93[20]. 
o 
Janice P Dutcher, Douglas J Schwartzentruber, Howard L Kaufman, 
Sanjiv S Agarwala, Ahmad A Tarhini, James N Lowder and Michael B 
Atkins.  High Dose Interleukin-2 (Aldesleukin) - Expert Consensus on 
Best Management Practices—2014. Journal for Immunotherapy of 
Cancer 2014, 2:26 (16 September 2014). 
 
5.3. 
General Concomitant Medication and Supportive Care Guidelines 
 
Concomitant medications should be kept to a minimum during the study. However, if 
these are considered necessary for the patient’s welfare and are unlikely to interfere with 
the investigational products, they may be given at the discretion of the investigator and 
recorded in the CRF. 
 
5.4. 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for    
per study protocol until one of the following criteria applies: 
 
 
Disease progression, 
 
 
Intercurrent illness that prevents further administration of treatment, 
 
 
Unacceptable adverse events(s), 
 
 
Patient decides to withdraw from the study, or 
 
 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
 
Subject non-compliance if deemed severe enough to impact the quality of the 
data collected. Such cases must be discussed between the local physician 
investigator and study chair. 
 
 


14 
 
5.5. 
Duration of Follow Up 
Patients will be followed for 5 years after removal from study or until death, whichever 
occurs first.  Patients removed from study for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. The frequency and the  
type of evaluations during this follow up period will follow the Study Calendar. For 
patients who complete the study procedures wish not to have long term follow up with a 
study investigator, they can be followed by their treating physician of choice and also 
following local standard of care practices. Data on disease progression and survival for 
these patients during long term follow up will be collected on all patients every 3-6 
months.  
 
 
6. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 6.1) and the characteristics of an observed AE (Section 6.2) 
will determine whether the event requires expedited reporting in addition to routine 
reporting.  
 
6.1. 
Interleukin-2 Adverse Event Summary List 
 
The following AE list was adapted from the Comprehensive Adverse Event and 
Potential Risks list (CAEPR) for IL2 and provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation 
of events by body system.  
 
Adverse Events with Possible 
 Relationship to Interleukin-2  
(CTCAE 4.0 Term) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
CARDIAC DISORDERS 
 
 
Conduction disorder 
 
 
Left ventricular systolic dysfunction 
 
 
Myocardial infarction 
 
 
Myocarditis 
 
 
Palpitations 
 
 
Sinus tachycardia 
 
 
Supraventricular tachycardia 
 
 
Ventricular arrhythmia 
 
EAR AND LABYRINTH DISORDERS 
 
 
Hearing impaired 
 


15 
 
EYE DISORDERS 
 
 
Blurred vision 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
 
Diarrhea 
 
 
Dry mouth 
 
 
Gastrointestinal disorders - Other 
(Perforation, GI – Select) 
 
 
Gastrointestinal disorders - Other (small 
bowel fistula) 
 
 
Mucositis oral 
 
 
Nausea 
 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 
 
Chills 
 
 
Edema limbs 
 
 
Fatigue 
 
 
Fever 
 
IMMUNE SYSTEM DISORDERS 
 
 
Allergic reaction 
 
 
Autoimmune disorder 
 
INFECTIONS AND INFESTATIONS 
 
 
Infections and Infestations – Other 
(Infection – Select) 
 
INVESTIGATIONS 
 
 
Activated partial thromboplastin time 
prolonged 
 
 
Alanine aminotransferase increased 
 
 
Alkaline phosphatase increased 
 
 
Aspartate aminotransferase increased 
 
 
Blood bilirubin increased 
 
 
Creatinine increased 
 
 
GGT increased 
 
 
INR increased 
 
 
Lymphocyte count decreased 
 
 
Platelet count decreased 
 
 
Weight gain 
 
 
White blood cell decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Acidosis 
 


16 
 
 
Anorexia 
 
 
Hyperuricemia 
 
 
Hypocalcemia 
 
 
Hypoglycemia 
 
 
Hypomagnesemia 
 
 
Hyponatremia 
 
 
Hypophosphatemia 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
 
 
Arthralgia 
 
 
Myalgia 
 
 
Myositis 
 
NERVOUS SYSTEM DISORDERS 
 
 
Depressed level of consciousness 
 
 
Dizziness 
 
 
Headache 
 
 
Memory impairment 
 
 
Nervous system disorders - Other (sleep 
disturbances) 
 
 
Peripheral sensory neuropathy 
 
 
Seizure 
 
PSYCHIATRIC DISORDERS 
 
 
Anxiety 
 
 
Confusion 
 
 
Personality change 
 
 
Psychosis 
 
RENAL AND URINARY DISORDERS 
 
 
Acute kidney injury 
 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
 
 
Adult respiratory distress syndrome 
 
 
Allergic rhinitis 
 
 
Apnea 
 
 
Cough 
 
 
Dyspnea 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Alopecia 
 
 
Pruritus 
 
 
Rash maculo-papular 
 
VASCULAR DISORDERS 
 
 
Capillary leak syndrome 
 


17 
 
 
Hypotension 
 
 
Peripheral ischemia 
 
 
Thromboembolic event 
 
 
Vascular disorders - Other (vasodilation)  
 
 
Also reported on interleukin-2 trials but with the relationship to interleukin-2 still 
undetermined: 
 
CARDIAC DISORDERS - Mobitz type I; Pericardial effusion 
EYE DISORDERS - Eye disorders - Other (mydriasis) 
GASTROINTESTINAL DISORDERS - Gastrointestinal disorders – Other (Hemorrhage, GI – 
Select); Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - General disorders 
and administration site conditions - Other (phospholipid syndrome); Hypothermia; Multi-organ 
failure 
INFECTIONS AND INFESTATIONS – Infections and infestations – Other (Infection 
(documented clinically or microbiologically with Grade 3 or 4 neutrophils [ANC <1.0 x 10e9/L]) – 
Select) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Soft tissue necrosis 
lower limb 
NERVOUS SYSTEM DISORDERS - Encephalopathy; Syncope 
PSYCHIATRIC DISORDERS - Agitation 
RENAL AND URINARY DISORDERS - Renal and urinary disorders - Other (acute tubular 
necrosis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Bronchospasm; Hypoxia; Pneumothorax; Pulmonary edema 
VASCULAR DISORDERS – Phlebitis, splenic infarction (in a patient with a history of 
thrombocytosis treated with the combination of IL2 and aflibercept). 
 
Note: Interleukin-2 in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
 
6.2. 
Adverse Event Characteristics  
• 
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.   
 
• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting 
purposes only.  ‘Expected’ AEs are those found in Section 6.1 above or in the 
Aldesleukin package insert as per the standard of care. 


18 
 
 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
6.3. 
Expedited Adverse Event Reporting 
 
6.3.1. Expedited Reporting Guidelines – Reporting Requirements for Adverse Events that 
occur within 30 Days of the Last Dose of IL-2 on this trial will adopt the following 
guidelines:  
 
 
Phase 2 and 3 Trials 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 and 4 
 
Grade 3 and 4 
Grades 
5 
Grades 
5 
Unexpected 
and 
Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unex- 
pected  
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
Not 
Required 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
• 
Expedited AE reporting timelines defined: 
➢ “24 hours; 5 calendar days” – The investigator must initially report the AE within 
24 hours of learning of the event followed by a complete report within 5 calendar 
days of the initial 24-hour report. 
➢ “10 calendar days” - A complete report on the AE must be submitted within 10 
calendar days of the investigator learning of the event.  
 
6.3.2 
Expedited Reporting Procedure 
 
 
If the criteria for expedited reporting are met, the Coordinating Center and the local institutional 
review board (per institutional reporting requirements) will be notified using the departmental 
SAE form.   
 
All events meeting the criteria for expedited reporting should be recorded on the departmental 
SAE form and submitted to: 


19 
 
1. Study Chair: tarhiniaa@upmc.edu 
2. Study Chair Liaison: kennaj@UPMC.EDU  
3. Coordinating Center: Melanoma_Team@upmc.edu and CRSSafetySubmissions@upmc.edu  
4. Local Institutional Review Board per institutional reporting requirements 
 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include as applicable the following information that is available at the time of 
report within the Narrative (Section C) on the departmental SAE form: 
 
• CTCAE term(s) and grade(s)  
• current status of study drug 
• all interventions to address the AE (testing and result, treatment and response) 
• hospitalization and/or discharge dates 
• event relationship to study drug 
 
Follow-up reports:   
Additional information may be added to a previously submitted report by adding to the original 
departmental SAE form and submitting it as follow-up. 
 
6.4 
Data and Safety Monitoring Plan  
Investigator/Sub-investigators, regulatory, CRS management, clinical research coordinators, clinical 
research associates, data managers, and clinic staff meet monthly in disease center Data Safety 
Monitoring Boards (DSMB) to review and discuss study data to include, but not limited to, the 
following: 
serious adverse events 
subject safety issues 
recruitment issues 
accrual 
protocol deviations 
unanticipated problems 
breaches of confidentiality 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to the 
NCI Common Toxicity Criteria version 4.0. All study treatment associated adverse events that are 
serious, at least possibly related and unexpected will be reported to the IRB. Any modifications 
necessary to ensure subject safety and decisions to continue, or close the trial to accrual are also 
discussed during these meetings. If any literature becomes available which changes the risk/benefit 
ratio or suggests that conducting the trial is no longer ethical, the IRB will be notified in the form of 
an Unanticipated Problem submission and the study may be terminated. 
All study data reviewed and discussed during these meetings will be kept confidential. Any breach in 
subject confidentiality will be reported to the IRB in the form of an Unanticipated Problem 
submission. The summaries of these meetings are forwarded to the UPCI DSMC which also meets 


20 
 
monthly following a designated format. 
For all research protocols, there will be a commitment to comply with the IRB’s policies for 
reporting unanticipated problems involving risk to subjects or others (including adverse events). 
DSMC progress reports, to include a summary of all serious adverse events and modifications, and 
approval will be submitted to the IRB at the time of renewal. 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will be 
reviewed twice a year rather than monthly by the disease center DSMB. 
Both the UPCI DSMC as well as the individual disease center DSMB have the authority to suspend 
accrual or further investigate treatment on any trial based on information discussed at these meetings. 
All records related to this research study will be stored in a locked environment. Only the researchers 
affiliated with the research study and their staff will have access to the research records. 
 
7. 
PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the commercial agent 
administered in this study can be found in Section 6.1. 
 
7.1. 
Commercial Agents 
 
7.1.1. Interleukin-2 
 
Other Names:  Aldesleukin, IL-2, rlL-2, T-cell growth factor 
 
Classification:  Biological response modifier 
 
Mode of Action:  Endogenous substance secreted by OK-T4 cells and lymphocytes. 
Enhances primary and secondary cytotoxic T-cell responses, causes T-cell 
mitogenesis and proliferation, and enhances non-killer cell activity. 
 
Storage and Stability:  Intact vials are stored in the refrigerator (2-8°C) with 
protection from light. Each vial bears an expiration date. 
 
Reconstituted IL-2 should be further diluted with 5% Dextrose, USP. It is not to be 
mixed with saline-containing solutions. Reconstituted IL-2 may be diluted as 
necessary in volumes of 50 ml to 500 ml with 5% Dextrose, USP plus 0.1% Albumin 
Human, USP. When diluting, the Albumin Human, USP should be added to the 5% 
Dextrose Injection, USP prior to the addition of the IL-2. When diluted for IV 
administration in 5% Dextrose Injection, USP, a plastic bag (e.g., Viaflex, 
manufactured by Travenol Laboratories, Inc.) containing 0.1% Albumin Human. IL-2 
is chemically stable for 48 hours at refrigerated and room temperatures, 2-30°C. 
 


21 
 
Dose Specifics:  Interleukin-2 600,000 MIU/kg/dose or 720,000 MIU/kg/dose over 
15 minute IV infusion every 8 hours on Days 1-5 of each cycle for a maximum of 14 
doses. For the purpose of this study, interleukin-2 will be given at 600,000 MIU/kg. 
 
Preparation: Aseptically inject 1.2 ml of sterile water for injection into the vial to 
dissolve the lyophilized cake. Since contents of the vial are under vacuum, the diluent 
should be directed against the sides of the vial to avoid excess foaming. Remove flip-
off plastic cap and swab the target area of the stopper with antiseptic. 
 
Administration:  For sterility considerations, the reconstituted IL-2 should be 
administered immediately or held at 2-8°C for up to 12 hours in 1.2 ml of sterile 
water for injection, and is stable for at least 24 hours at room temperature. 
 
Incompatibilities:  Incompatible with normal saline (results in a precipitate). It 
should not be mixed with anything except D5W and sterile water. 
 
Availability:  IL-2 is a FDA approved therapy for melanoma and is commercially 
available. 
 
Toxicity:  See section 6.1. 
 
 
 
For more information please refer to the drug’s package insert. 
 
8. 
CORRELATIVE/SPECIAL STUDIES 
8.1. 
Laboratory Correlative Studies 
 
Correlatives studies will be done, utilizing research samples collected on this study that 
will primarily focus on biomarkers of prognosis or prediction of therapeutic benefit based 
on current or future scientific evidence.  
 
8.1.1. Collection of Specimens  
Blood specimens will be collected for the purpose of laboratory corollary studies as 
follows: 
 
Table. Blood sample Collection 
Course 1 
Red Top 
Tubes2 
Green Top 
Tubes3 
PAX 
tubes4 
Yellow 
Top 
Tube5 
Baseline1 
3 
10 
1 
1 
Cycle 2 of IL-2, within 1-
3 weeks after the last dose 
of IL-2 
3 
10 
1 
none 


22 
 
Course 2/3 
 
 
 
 
Cycle 2 of IL-2, within 1-
3 weeks after the last dose 
of IL-2 
3 
10 
1 
none 
Month 12 
3 
10 
1 
none 
Progression 
3 
10 
1 
none 
1. Baseline: within 2 weeks of the first dose of  IL-2. 
2. 10 cc RED top tubes (BDcat #367820 or SST 367988 gel separator/gold top/ tiger 
tubes if the center can centrifuge them) 
3. 10 cc GREEN top tubes (BD cat # 366480) 
4. PAX tube (Fisher #23 021 01) 
5. 10 cc YELLOW top tube. (BD cat # 364606) 
 
Transfer or, if applicable, ship blood samples by overnight courier Monday-
Thursday only to: 
 
Immunologic Monitoring and Cellular Products Laboratory 
University of Pittsburgh Cancer Institute 
UPCI-IMCPL, Suite 1.26 
Study Coordinator 
Hillman Cancer Center 
5117 Centre Avenue 
Pittsburgh, PA 15213 
Tel: (412) 624-0078 
FAX: (412) 623-6625 
 
Please submit the Specimen Submission Form (template to be provided 
separately) for each sample sent.  
 
Notify the IMCPL study coordinator by fax (412-623-6625) when the samples are 
shipped. If you are unable to get through to the laboratory by fax, telephone the study 
coordinator and provide the tracking number. 
 
The IMCPL has a great deal of experience in shipment and handling of blood, tumor 
and lymph node samples. The IMCPL provides contact information and a fax request 
form to the sites, and when a patient is scheduled, a tissue sample kit is shipped 
(generally via ground) to the site, containing all necessary blood tubes, tumor 
containers (containing sterile medium) sample instructions as well as return overnight 
shipping instructions. Upon receipt in the laboratory, the blood and tissue samples are 
logged in a processed according to the protocol-specific SOPs. Samples which are 
compromised (hemolyzed or which arrived more than 48 hours after draw/isolation) 
are discarded (currently less than 2% of >750 samples which arrive at the laboratory 
annually from ECOG-ACRIN sites).  
 


23 
 
Pathology Specimen Submissions for Banking for Research Studies (at baseline, then 
at disease progression): 
• 
Primary Melanoma (for patients with known primary cutaneous melanoma) 
Fifteen (15) unstained slides preferably from the thickest portion of the tumor for 
immunostains (please do not deparaffinise slides) OR, if the primary pathologist 
is willing, please request the corresponding block, which will be promptly 
returned upon request.  If the patient has more than one primary lesion, please 
include above slides and/or block for each primary. 
• 
Resected in-transit or satellite metastases, or cutaneous metastases, or lymph 
node metastases, or lung metastases 
Fifteen to twenty (15-20) unstained slides from the thickest part of the tumor or, 
if the primary pathologist is willing, please request the corresponding block, 
which will be promptly returned upon request.  
NOTE:  
Please provide a surgical pathology report to accompany the slides.  
• 
Progression/Relapse Biopsy (if performed, for banking for future research)  
Fifteen to twenty (15-20) unstained slides from the thickest part of the tumor or, 
if the primary pathologist is willing, please request the corresponding block, 
which will be promptly returned upon request.  
 
 Please transfer or, if applicable, ship to the IMCPL, as noted above. For shipping, 
regular mail may be used for these tissue samples OR these may be included in the 
same package with the blood samples shipped by overnight courier. Also please 
notify the IMCPL study coordinator as noted above.  
 
NOTE: Patients who do not have archival tumor (as part of a standard of care 
procedure) available for research at baseline or at progression will be asked whether 
they are willing to provide a biopsy for research in case they have an accessible tumor 
for a punch biopsy in clinic.  
 
8.1.2. Banking of Specimens for Future Laboratory Corollary Studies 
 
Specimens will be banked and laboratory corollary studies will  be conducted based 
on the availability of specimens and funding. 
 
9. 
STUDY CALENDAR 
Study investigators should follow the local institutional standard of care guidelines for safety 
monitoring and safety laboratory testing. Baseline evaluations are to be conducted within 2 
weeks prior to administration of HD IL2, unless indicated otherwise, elsewhere in the protocol.  
Scans and X-rays must be done not more than 28 days prior to the start of HD IL2.  In the event 
that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 
hours prior to initiation of the next cycle of IL2. 
 


24 
 
 
Course 1 
Pre-
Study 
Wk 
1 
Wk 
 2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Off 
Studyf 
Interleukin-2a 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
    X--------------------------------------------------------------X 
 
Physical exam 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital signs 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Performance status 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
CBC w/diff, plts 
Urinalysis 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Serum chemistry 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
PT/INR 
 
X 
 
 
 
 
 
 
 
 
 
Cardiac stress testb 
 
X 
 
 
 
 
 
 
 
 
 
PFTsc 
 
X 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
 
   X ---------------------------------------------------------------X 
 
Tumor measurements 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Radiologic evaluationd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
B-HCGe 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Biospecimen 
See Section 8.1.1 
 
a:   IL-2: 600,000 U/kg/dose IV Q8h x 5 days (max 14 doses) starting on day 1 of weeks 1 and 3. An IL-2 cycle may be delayed until the resolution of 
limiting toxicities.  
b:  Patients who are over 40 years old or have had previous myocardial infarction greater than 6 months prior to study entry or have significant cardiac 
family history (CAD or serious arrhythmias) will be required to have a negative or low probability cardiac stress test (thallium stress test, stress 
MUGA or exercise stress test) for cardiac ischemia within 8 weeks prior to registration. Patients who are not required to have a cardiac stress test 
should have an electrocardiogram at baseline to be reviewed by the treating physician investigator. Patients who undergo echocardiography as part of 
their cardiac stress test are not required to have a separate baseline echocardiogram. 
c:    Pulmonary function tests (PFTs) are required for patients over 50 years old or with significant pulmonary or smoking history.  PFTs may be done up 
to 4 weeks prior to registration. 
d:     Radiologic evaluation should include MRI or contrast CT of the brain at baseline and may be repeated at later time points as clinically indicated. 
e:    Serum pregnancy test (women of childbearing potential). 
f.   Off study evaluation. Patients will be followed for 5 years after removal from study or until death, whichever occurs first. The frequency and the type 
of evaluations during this follow up period will follow institutional standard of care practices. For patients who wish not to follow with a study 
investigator, they can be followed by their treating physician of choice and also following local standard of care practices. Data on disease 
progression and survival will be collected on all patients every 3-6 months. 
 
For the purposes of this study, patients should be reevaluated for response at the end of each 
course 1 (8 weeks -/+ 1 week). Following completion of treatment, and in the absence of disease 
progression will be done every 12 weeks -/+ 2week during the observation phase for the first 2 
years, then every 6 months (-/+ 2 weeks) for years 3-5, then yearly (-/+ 4 weeks) afterwards.  


25 
 
 
MRI or contrast CT of the brain is not required but should be done as clinically indicated. For 
those subjects who have progressed, Data on survival will be collected on all patients every 
6months for 5 years. 
 
10. 
MEASUREMENT OF EFFECT 
10.1. Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be reevaluated for response as noted in 
Section 9.  
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
Committee, version 1.1[Eur J Cancer, 2009. 45(2): p. 228-47.].  Changes in only the 
largest diameter (unidimensional measurement) of the tumor lesions are used in the 
RECIST criteria. See Eisenhauer et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 
10.1.1. Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first protocol drug administration. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least course 1 of therapy, and have had their 
disease re-evaluated will be considered evaluable for response.  These patients will 
have their response classified according to the definitions stated below.  (Note:  
Patients who exhibit objective disease progression prior to the end of course 1 will 
also be considered evaluable.) 
 
 
 
10.1.2. Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until 
the first date that recurrent or progressive disease is objectively documented (taking 
as reference for progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented. 
 


26 
 
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.  
 
10.1.3. Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression 
(or death if there is no progression date). Patients with neither a progression date nor 
date of death will be censored as of last contact. 
 
11. 
STATISTICAL CONSIDERATIONS 
11.1. Study Design/Endpoints 
This is a phase II study of high dose bolus interleukin-2 (HD IL2) in patients with 
advanced inoperable stage III or stage IV melanoma who have prior anti-PD1 
immunotherapy. The safety of HD IL2 is well studied and will be monitored. The focus 
of the study is to evaluate the efficacy of this HD IL-2 in this specific patient population. 
 
The primary endpoint is (CR+PR) as assessed by RECIST criteria version 1.1.  The total 
accrual goal is 45 patients. We will follow a Bayesian design to establish sequential 
stopping rules for futility (Thall, Simon and Estey 1995). The expected response rate for 
this patient population is between 5 and 10%. We would consider the HD IL-2 worth 
further investigation if a response rate of 20% is achieved. Thus, if there is sufficient 
evidence that the response rate of the regiment is 7% or less, we will stop the accrual. Let 
p0 and p1 denote the response rate of the standard treatment and the HD IL-2 respectively, 
by sufficient evidence, we mean that the posterior probability, Pr p0 + 0.05 > p1
(
), exceeds 
85%. Based on the existing data, it is safe to say that the response rate of the studied 
population under standard care is between 5 and 10%, therefore, we use a Beta(70,930) 
prior for the standard treatment, which corresponds to a distribution of  the response rate 
centered at 7%. We set a flat prior, Beta(0.4,1.6), for the response rate of HD IL-2.  
 
We will allow the accrual to continue without interruption for the first 10 patients. The 
stopping boundaries for futility after the “burning period” can be presented as tables of 
possible outcomes for efficacy as shown in the following table: 
 
Table 1 Bayesian Stopping Rules  
Stop the Accrual to if  
Responses<= 
 
in No. Pts 
1  
 
         10-19 
2  
 
 
20-31 
3  
 
 
32-44 
4  
 
 
45 
 
The operating characteristics of this design can expressed in terms of the probability of 


27 
 
stopping the study early when the regimen is effective (i.e. response rate>0.2) and 
ineffective (i.e. response rate<0.07) and the median sample size under each situation. 
The following table summarizes this probability and the median sample size under this 
design based on 10,000 simulations of hypothetical trials  
under different assumptions of true response rates. 
 
Table 2 Frequentist Properties of the Stopping Rules  
 
True 
Response 
Rate 
Pr (Stop Early) 
Median 
Sample 
Size 
0.05 
0.92 
17.7 
0.1 
0.35 
27.9 
0.15 
0.32 
35.6 
0.2 
0.16 
40.2 
0.25 
0.07 
42.6 
0.3 
0.03 
43.9 
 
We used MultcLean software for the design of this trial. 
(http://biostatitics.mdanderson.org/SoftwareDownload/) 
 
11.2. Sample Size/Accrual Rate 
We plan 12-15 months of accrual for 45 patients (approximately 3-4 patients per month) 
and a minimum of 6 months follow-up.   
 
Evaluable patients include study subjects who received at least one cycle of HD IL-2 and 
had later formal imaging and clinical assessment of tumor response to treatment and 
those who failed to return for imaging because of cancer specific death or clinical 
determination of progression. Non-evaluable subjects will be replaced. 
 
With 45 evaluable subjects, we will have >90% power to declare a significant difference 
between an response rate of 20% or higher and 7% (the expected response rate of this 
population under standard care) by a 1-sided exact binomial test (=0.1).  
 
 
11.3. Statistical Analyses 
The study will be analyzed 6 months after the accrual is finished.  
 
11.3.1. 
Analysis Sets 
 
Safety population-the data from all patients who received initial treatment of HD IL-
2 will be used in the analyses of regimen safety. 
 
Efficacy population- data from patients received at least one cycle of HD IL-2 will 
be used in the analysis of PFS and OS. For response rate, patients failed to return for 


28 
 
imaging due to reasons other than cancer-specific death or clinical determination of 
progression will not be included.  
 
11.3.2. 
Baseline Characteristics  
Baseline descriptive statistics will be provided for all evaluable patients. Statistical 
summaries will be reported for demographic variables (age, sex, race/ethnicity), 
performance status, laboratory parameters, and disease characteristics.  
 
11.3.3. 
Analysis of Clinical Response  
All patients included in the study will be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  
 
All of the patients who met the eligibility criteria and completed at least one cycle of IL2 
should be included in the main analysis of the response rate.  Response rate will e 
estimated by the proportion of patients with a best response of complete response (CR), 
partial response (PR) by RECIST criteria, with corresponding exact 90% confidence 
limits being reported. The distribution of response duration (time to progression among 
patients achieving CR or PR) will be characterized by median and quartiles, with the 
corresponding Kaplan-Meier estimate being made of PFS among patients responding to 
treatment.  
 
11.3.4. 
Survival 
PFS will be measured from the initial date of treatment to the date of documented 
progression, or the date of death (in the absence of progression). 
OS will be measured from the initial date of treatment to the recorded date of death.   
PFS and OS will be estimated by the Kaplan-Meier method. The corresponding median 
survival times (with 90% confidence limits) will be determined, as will the cumulative 
percentage of patients remaining progression-free (and the cumulative percentage- alive) 
at selected time points after initial treatment (e.g., 3, 6,12, 18 months). 
 
11.3.5. 
Safety 
 
Toxicity will be primarily evaluated by examining the number of doses of HD IL-2 
administered during a cycle of therapy. Based on previous experience with high dose IL2 
at the University of Pittsburgh, the median number of doses per course 1 (first 2 cycles) 
as monotherapy [16], is 16 (range 8-26) and in sequential combination with 
temozolomide [21], is 15 (range 7-23). As a result, the median number of doses per 
course 1 will be considered in addition to toxicity reported via CTCAE criteria. 
 
 
 


29 
 
 
 
 
 
 
12. 
REFERENCES 
1. 
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Atkins, M.B., et al., High-dose recombinant interleukin 2 therapy for patients with 
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3. 
Davies, H., et al., Mutations of the BRAF gene in human cancer. Nature, 2002. 
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4. 
Kirkwood, J.M., et al., Immunotherapy of cancer in 2012. CA Cancer J Clin, 2012. 62(5): 
p. 309-35. 
5. 
Smith, K.A., Interleukin-2: inception, impact, and implications. Science, 1988. 
240(4856): p. 1169-76. 
6. 
Rosenberg, S.A., et al., Regression of established pulmonary metastases and 
subcutaneous tumor mediated by the systemic administration of high-dose recombinant 
interleukin 2. J Exp Med, 1985. 161(5): p. 1169-88. 
7. 
Dutcher, J.P., et al., A phase II study of interleukin-2 and lymphokine-activated killer 
cells in patients with metastatic malignant melanoma. J Clin Oncol, 1989. 7(4): p. 477-
85. 
8. 
Parkinson, D.R., et al., Interleukin-2 therapy in patients with metastatic malignant 
melanoma: a phase II study. J Clin Oncol, 1990. 8(10): p. 1650-6. 
9. 
Rosenberg, S.A., et al., Treatment of 283 consecutive patients with metastatic melanoma 
or renal cell cancer using high-dose bolus interleukin 2. Jama, 1994. 271(12): p. 907-13. 
10. 
Atkins, M.B., et al., High-dose recombinant interleukin-2 therapy in patients with 
metastatic melanoma: long-term survival update. Cancer J Sci Am, 2000. 6 Suppl 1: p. 
S11-4. 
11. 
Schwartzentruber, D.J., High-dose interleukin-2 is an intensive treatment regardless of 
the venue of administration. Cancer J, 2001. 7(2): p. 103-4. 
12. 
Rosenberg, S.A., et al., Prospective randomized trial of high-dose interleukin-2 alone or 
in conjunction with lymphokine-activated killer cells for the treatment of patients with 
advanced cancer. J Natl Cancer Inst, 1993. 85(8): p. 622-32. 
13. 
Figlin, R.A., et al., Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating 
lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell 
carcinoma. J Clin Oncol, 1999. 17(8): p. 2521-9. 
14. 
Sabatino, M., et al., Serum vascular endothelial growth factor and fibronectin predict 
clinical response to high-dose interleukin-2 therapy. J Clin Oncol, 2009. 27(16): p. 2645-
52. 
15. 
Kerbel, R.S., Tumor angiogenesis. N Engl J Med, 2008. 358(19): p. 2039-49. 
16. 
Tarhini AA, Kirkwood JM, Gooding WE, Cai C, Agarwala SS, Durable Complete 
Responses With High-Dose Bolus Interleukin-2 in Patients With Metastatic Melanoma 


30 
 
Who Have Experienced Progression After Biochemotherapy. J Clin Oncol, 2007. 25(25): 
p. 0000-0000. 
17. 
West, E.E., et al., PD-L1 blockade synergizes with IL-2 therapy in reinvigorating 
exhausted T cells. J Clin Invest, 2013. 123(6): p. 2604-15. 
18. 
Tarhini, A., Immune-Mediated Adverse Events Associated with Ipilimumab CTLA-4 
Blockade Therapy: The Underlying Mechanisms and Clinical Management. Scientifica 
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31 
 
APPENDIX A – Performance Status Criteria 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead.