Phase 2 Study of Recombinant Glycosylated Human Interleukin-7 (CYT107) After Completion of Standard Therapy With Sipuleucel-T (Provenge®) in Pts w/ Asymptomatic or Minimally Symptomatic Metastatic Castration-Resistant Prostate Cancer(mCRPC)
Phase: PHASE2
Conditions: Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, Stage IV Prostate Cancer
Sponsor: Fred Hutchinson Cancer Center

NCI Protocol #: CITN12-03 
Version Date: July 26, 2017 
1 
 
NCI Protocol #: CITN12-03 
 
Local Protocol #:  CITN12-03 
 
TITLE: A Phase 2 Study of recombinant glycosylated human interleukin-7 (CYT107) after 
completion of standard FDA approved therapy with sipuleucel-T (Provenge®) for patients 
with asymptomatic or minimally symptomatic metastatic castration-resistant prostate 
cancer (mCRPC) 
 
 
Coordinating Center: 
 
 
Cancer Immunotherapy Trials Network, Fred Hutchinson 
Cancer Research Center 
 
 
Principal Investigator: 
 
Lawrence Fong, M.D. 
 
University of California San Francisco 
 
Dept. of Medicine (Hematology/Oncology) 
 
513 Parnassus Ave., Room S775, Box 0511 
 
San Francisco, CA 94143-0511 
 
(415) 514-3160 
 
(415) 476-0459 
 
lfong@medicine.ucsf.edu 
 
 
Participating Organizations: 
CITN – Cancer Immunotherapy Trials Network  
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: CITN12-03 
Version Date: July 26, 2017 
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Statistician: 
 
Study Coordinator: N/A 
Bob Salim, PhD 
Axio Research, LLC 
2601, 4th Avenue, Suite 200 
Seattle, WA 98121 
(206) 577-0219 
bobs@axioresearch.com 
 
 
Responsible Research Nurse: N/A 
Responsible Data Manager: N/A 
 
 
 
NCI Supplied Agent: N/A 
 
Other Agents: Recombinant Glycosylated Human Interleukin-7 (CYT107) NSC #767713  
 
IND Sponsor: Martin A. “Mac” Cheever, M.D., IND# 124199 
 
Protocol Type / Version # / Version Date: 
Amendment #7/Version 1.0/July 26, 2017  
 
To submit site 
registration 
documents: 
For patient enrollments:  
Submit study data to:  
CTSU Regulatory Office 
1818 Market Street,  
Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Please refer to the patient enrollment section 
for instructions on using the OPEN system 
or you may access the OPEN system at: 
https://www.ctsu.org/OPEN_SYSTEM/ 
 Or https://OPEN.ctsu.org 
 
For problems using OPEN 
https://www.ctsu.org/CTSUCOntact.aspx 
Data collection for this 
study will be done via 
Medidata Rave 
(FHCRC/AXIO 
Research, Inc.) Please 
refer to the data 
submission section of the 
protocol for Medidata 
Rave instructions. 
The current version of the study protocol and all supporting documents must be downloaded from 
the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires user log on with 
CTEP-IAM username and password. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS. 
For patient eligibility or treatment-related questions: 
Contact the CITN Central Operations and Statistical Center at:   
206-667-6609 or email mailto: citn@fhcrc.org 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help 
Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at   https://www.ctsu.org 
 
 
 

NCI Protocol #: CITN12-03 
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Treatment Schema 
Cohort 
CYT107 Dose 
Frequency 
1 - Observation 
No CYT107 dose 
-------- 
2 - CYT107  
10 μg/kg 
Days 0, 7, 14 and 21 
 
 

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TABLE OF CONTENTS 
1. 
OBJECTIVES ......................................................................................................................6 
1.1  
Primary Objectives...................................................................................................6 
1.2  
Secondary Objectives...............................................................................................6 
2. 
BACKGROUND .................................................................................................................6 
2.1 
Study Disease ...........................................................................................................6 
2.2 
CTEP IND Agent: N/A ............................................................................................7 
2.3 
Other Agents ............................................................................................................7 
2.4 
Rationale ................................................................................................................13 
2.5 
Correlative Studies Background ............................................................................14 
3. 
PATIENT SELECTION ....................................................................................................16 
3.1 
Eligibility Criteria ..................................................................................................16 
3.2 
Exclusion Criteria ..................................................................................................17 
3.3 
Inclusion of Minorities ...........................................................................................19 
3.4 
Subject Recruitment ...............................................................................................19 
4. 
REGISTRATION PROCEDURES ...................................................................................19 
4.1 
General Guidelines.................................................................................................19 
4.2 
Registration Process ...............................................................................................20 
5. 
TREATMENT PLAN ........................................................................................................20 
5.1 
Agent Administration.............................................................................................20 
5.2 
Definition of Dose Limiting Toxicity: N/A ...........................................................22 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................22 
5.4 
Duration of Therapy ...............................................................................................23 
5.5 
Duration of Follow Up ...........................................................................................23 
5.6 
Criteria for Removal from Study ...........................................................................23 
5.7 
Laboratory Specimen collection ............................................................................23 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................24 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................26 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs): 
N/A .........................................................................................................................26 
7.2 
Adverse Event Characteristics ...............................................................................27 
7.3 
Expedited Adverse Event Reporting ......................................................................28 
7.4 
Routine Adverse Event Reporting .........................................................................30 
7.5 
Secondary Malignancy...........................................................................................30 
7.6 
Second Malignancy ................................................................................................30 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................30 
8.1 
CTEP IND Agent(s): N/A ......................................................................................30 
8.2 
Other Investigational Agent ...................................................................................30 
8.3 
Commercial Agent: N/A ........................................................................................32 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................32 

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9.1 
Biomarker Studies ..................................................................................................32 
9.2 
Laboratory Correlative Studies ..............................................................................32 
9.3 
Special Studies: Immunogenicity Testing .............................................................36 
10. 
STUDY CALENDAR .......................................................................................................38 
11. 
MEASUREMENT OF EFFECT........................................................................................40 
11.1 
Overall Survival .....................................................................................................40 
11.2 
PSA Kinetics ..........................................................................................................40 
11.3 
Progression free survival........................................................................................40 
11.4 
Circulating Tumor Cells ........................................................................................41 
11.5 
Measurement of Disease ........................................................................................41 
11.6 
Radiologic Progression-Free Survival of Bony Metastasis ...................................44 
11.7 
Evaluation of Best Overall Response ....................................................................45 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................46 
12.1 
Data Reporting .......................................................................................................46 
12.2 
CTEP Multicenter Guidelines ................................................................................47 
12.3 
Collaborative Agreements Language: N/A ............................................................47 
13. 
STATISTICAL CONSIDERATIONS...............................................................................47 
13.1 
Study Design/Endpoints.........................................................................................47 
13.2 
Sample Size/Accrual Rate ......................................................................................48 
13.3 
Stratification Factors ..............................................................................................49 
13.4 
Analysis of Secondary Endpoints ..........................................................................49 
13.5 
Reporting and Exclusions ......................................................................................50 
REFERENCES 
..........................................................................................................................51 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ........................................................54 
APPENDIX B 
CTEP MULTICENTER GUIDELINES ..........................................................55 
APPENDIX C 
COCKCROFT-GAULT FORMULA FOR CALCULATED CREATININE 
CLEARANCE..................................................................................................57 
APPENDIX D 
DOSE ADJUSTMENT FOR OBESE PATIENTS..........................................58 
 
 
 

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1. OBJECTIVES 
 
The goal of the trial is to determine whether treatment with recombinant glycosylated human 
interleukin-7 (CYT107, RevImmune, Inc.) after standard therapy with sipuleucel-T 
(PROVENGE®, Dendreon Corporation) can substantially increase and prolong immune 
responses to the sipuleucel-T fusion protein vaccine construct PAP-GM-CSF (PA2024) and the 
prostatic acid phosphatase (PAP) component and thereby provide a novel, nontoxic regimen to 
prolong the survival of patients with metastatic castration-resistant prostate cancer (mCRPC) 
with no or minimal symptoms.  
 
1.1  
Primary Objectives 
 
To determine whether CYT107 administration increases the vaccine-induced antigen-specific 
T-cell immune response to the sipuleucel-T fusion protein vaccine construct PAP-GM-CSF 
(PA2024)  
 
1.2  
Secondary Objectives 
 
1. To determine whether CYT107 administration increases the vaccine-induced antigen-
specific T-cell immune response to PAP. 
 
2. To assess the character of the T-cell immune response to PAP and PA2024 
 
3. To determine whether CYT107 administration increases the vaccine-induced antigen-
specific antibody immune responses to PAP and PA2024 
 
4. To quantify the effects of CYT107 on T-cell repertoire diversity 
 
5. To assess the effects of CYT107 on the immune competence of patients with advanced 
prostate cancer 
 
6. To assess the clinical efficacy and tolerability of sipuleucel-T plus CYT107 compared 
with sipuleucel-T alone  
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
The proposed clinical trial is a phase II, open-label, multicenter, randomized study of the 
administration of CYT107 after the completion of standard FDA-approved therapy with 
sipuleucel-T for patients with asymptomatic or minimally symptomatic mCRPC.   
 
Prostate cancer is the second leading cause of death from cancer in men [Cheever, 2011]. 
Localized prostate cancer may be cured with surgery or radiation therapy, but the disease 
recurs in approximately 20 to 30% of patients. Androgen-deprivation therapy, the most 
common treatment after recurrence, is effective, but the disease eventually progresses in most 
patients who receive such treatment [FDA.gov, 2010], termed castration-resistant prostate 

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cancer (mCRPC). For men with mCRPC, the median survival ranges from 12.2 to 21.7 
months [Kantoff, 2010]. A number of drugs for mCRPC have been approved. Previous 
therapies like prednisone and mitoxantrone showed no additive impact on median overall 
survival beyond the expected survival of 10-14 months seen in mCRPC. Current therapeutics 
such as docetaxel [Tannock, 2004], abiraterone [Ryan, 2013], and enzalutamide [Beer, 2014] 
increase overall survival by 2 to 8 months. Unfortunately, all patients eventually progress 
after receiving these therapies. Therefore, there is a critical need for improved therapies for 
mCRPC that can treat metastatic disease, improve quality of life, decrease morbidity, and 
prolong overall patient survival.   
 
Sipuleucel-T (PROVENGE®; Dendreon) is the first therapeutic cancer vaccine to be 
approved by the U.S. Food and Drug Administration. In men who have metastatic castration-
resistant prostate cancer with no or minimal symptoms, sipuleucel-T prolongs median 
survival by 4.1 months compared with results in those treated with placebo [Kantoff, 2010].  
 
IL-7 is a homeostatic growth factor for T cells and is capable of inducing proliferation, 
maintaining T-cell responsiveness, and preventing and reversing T-cell anergy [Mackall, 
2011].  The hypothesis of the trial is that CYT107 will increase and prolong the sipuleucel-T 
induced immune response and thereby further prolong survival.   
 
2.2 
 CTEP IND Agent: N/A 
 
2.3 
Other Agents 
 
Sipuleucel-T (PROVENGE®, Dendreon Corporation): 
 
Sipuleucel-T is not a direct component of this protocol. However, successful completion of 
standard sipuleucel-T therapy within 3-7 days is a mandatory entry criterion for the trial.   
 
Sipuleucel-T is a therapeutic vaccine formulated to stimulate an immune response to prostate 
cancer cells [Cheever, 2011] by generating PAP-specific T cells capable of recognizing and 
killing prostate cancer cells that express PAP. In sipuleucel-T, the PAP vaccine immunogen 
is formulated as PA2024, a fusion protein combining recombinant PAP with recombinant 
granulocyte-macrophage colony-stimulating factor (GM-CSF) [FDA.gov, 2010], [Kantoff, 
2010], [Cheever, 2011].  
 
Sipuleucel-T is constructed as an autologous cellular immunotherapy product consisting of 
peripheral blood mononuclear cells (PBMC), including antigen presenting cells (APC). To 
manufacture sipuleucel-T, a subject undergoes leukapheresis to collect PBMC. Mononuclear 
cells, including quiescent APC, are cultured ex vivo (serum and cytokine free conditions) at 
37oC in the presence of PAP-GM- CSF (PA2024) antigen. GM-CSF is used to activate APCs 
within the autologous PBMC product [FDA.gov 2010]. These activated APC are proficient at 
activating and inducing the replication of PAP-specific T cells. Three days after 
leukapheresis and 40 hours of subsequent incubation, the cells are washed to remove the 
fusion protein and suspended in Lactated Ringer’s Injection, USP, shipped to the patient care 
site, and infused as the sipuleucel-T product into the patient. The standard FDA approved 
therapy is three doses.  After infusing the first dose, increases in APC and T-cell activation 

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markers in PBMCs are detectable in treated patients as increased ex-vivo production of 
cytokines associated with T-cell activation. Thus, with each dose, increasing levels of 
activated APCs and T cells are infused into patients [Sheikh, 2010].  
 
Prior Sipuleucel-T Trials: The phase III randomized IMPACT trial led to FDA approval 
because of improvements in overall survival (OS) for patients with mCRPC [Kantoff, 2010]. 
IMPACT was a double-blind, placebo-controlled study involving 512 patients with 
asymptomatic or minimally symptomatic mCRPC randomly assigned 2:1 to receive 
sipuleucel-T (n = 341) or placebo (n = 171). Sipuleucel-T was administered every 2 weeks 
for a total of 3 doses. Of the 330 patients who received sipuleucel-T, 92% received all 3 
infusions. Median OS was 25.8 months in the treatment arm and 21.7 months in the control 
arm (P = 0.032). The adjusted hazard ratio for death was 0.78 (95% confidence interval, 
0.61–0.98). The Kaplan-Meier estimate for OS for each group at 36 months was 31.7% for 
sipuleucel-T vs. 23.0% for placebo, indicating a 38% increase in survival at 3 years for 
patients in the sipuleucel-T arm [Kantoff, 2010]. The median OS predicted by the Halabi 
prognostic model was 20.3 months for the treatment arm vs. 21.2 months for the control arm 
[FDA.gov, 2010], supporting the efficacy of sipuleucel-T. 
 
Vaccine-induced therapeutic responses sometimes appear to continue to function after the 
median time to progression. In the IMPACT trial, PSA reductions of at least 50% compared 
with baseline were confirmed at 4 weeks in 2.6% of treated patients vs. 1.3% of control 
patients [Kantoff, 2010]. However, in another double-blind, randomized, placebo-controlled 
study (P-11) of 176 men with rising PSA after prostatectomy receiving hormonal therapy 
followed by vaccine or control [Beer, 2007], sipuleucel-T did not significantly delay cancer 
progression (defined as PSA reaching 3.0 ng/mL); however, the rate of the PSA increase was 
slower in patients who received the vaccine.  
The FDA-approved regimen is three vaccinations administered on days 0, 14, and 28. The 
initial IMPACT trial publication reported that at week 6 after the first vaccination (2 weeks 
after the third vaccination), T-cell proliferation responses (stimulation index >5) to PA2024 
were observed in 73.0% of treated patients and 12.1% of control patients. In addition T-cell 
proliferation responses to PAP (stimulation index >5) were observed in 27.3% of treated 
patients compared with 8.0% of control patients [Kantoff, 2010]. Of note, the PA2024 fusion 
protein contains a joining-region segment that is not expressed by normal PAP or GM-CSF, 
which patient immune systems recognized as foreign. Eliciting an immune response to this 
foreign joining-region segment signals immune competence and is likely to facilitate epitope 
spreading to the PAP portion of the molecule. All patients with a T cell response to PAP also 
had a T cell response to PA2024.  
In a prespecified analyses, patients in the sipuleucel-T group who had an antibody titer of 
more than 400 against PA2024 or PAP at any time after baseline lived longer than did those 
who had an antibody titer of 400 or less (P < 0.001 and P = 0.08, respectively, by log-rank 
test). PA2024-specific antibody responses that exceeded the designated low value of 400 at 
any time after baseline were observed in 66.2% of treated patients and only 2.9% of control 
patients. By contrast, titers of antibodies against PAP that exceeded 400 at any time after 
baseline were observed in 28.5% of treated patients compared with 1.4% of control patients. 
Although the IgG antibody responses correlated with survival and cognate recognition of 
antigen by CD4+ T cells is required for such antibody responses, the initial publication 

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[Kantoff, 2010] reported that no survival difference could be detected between patients in the 
sipuleucel-T group who had T-cell proliferation responses to PA2024 or PAP at week 6 and 
those who did not [Kantoff, 2010]. The presumption is that the responses were present, but 
below the level of detection by the assay employed.  
 
A subsequent analysis of immune function (Figure 1) [Sheikh, 2012] provided additional 
credence to the correlation between immune response and overall survival (OS). Antigen-
specific peripheral cellular and humoral responses were assessed in a 237 patient subset of 
subjects enrolled in the IMPACT study. The IMPACT subset provided blood for immune 
response determination at baseline (week 0) as well as 6, 14, and 26 weeks following the first 
infusion. Antigen-specific immune responses were observed in 78.8% of monitored subjects 
and correlated with OS (p=0.003).  
 
Overall survival correlated significantly with the development of at least one post-baseline 
peripheral immune response to PA2024 or PAP (HR=0.47 [95% CI: 0.29, 0.78] P=0.003; 
Figure 1D), to PA2024 (HR=0.46 [95% CI: 0.28, 0.76] P=0.002; Figure 1E), or to PAP 
(HR=0.53 [95% CI: 0.31, 0.90] P=0.019; Figure 1F). The strongest correlation between 
survival and the development of a post-baseline immune response to PA2024 at any 
timepoint was observed with antibody responses (HR=0.42 [95% CI: 0.26, 0.67] P<0.001), 
while the correlation with memory IFNγ ELISPOT at any time point approached statistical 
significance (HR=0.55 [95% CI: 0.28, 1.08] P=0.08); T cell proliferation response did not 
significantly correlate with overall survival.  
 
Overall Survival is depicted in Figure 1 from Sheikh et al [Sheikh, 2012]. Data is presented 
as Kaplan-Meier survival plots for antigen-specific immune response for sipuleucel-T 
responders and non-responders for a subset of IMPACT subjects.  
 
Figure 1 [Sheikh, 2012] 
 
 
Figure 1.  The hazard ratio and p-value are based on a Cox regression analysis with response 

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(0 = non responder, 1 = responder) in the model. Median-based analysis of cumulative 
product parameters from a Cox regression model, stratified by study, and adjusted for 
baseline PSA and LDH. P-values in the table are from analyses of each parameter as a 
continuous measure. Hazard ratios and 95% confidence intervals from a Cox regression 
model, adjusted for baseline PSA and LDH.  
D) Response to PA2024 or PAP in at least one of the three immune response assays 
(HR=0.47 [95% CI: 0.29, 0.78] P=0.003) 
E) Response to PA2024 in at least one of the three immune response assays (HR=0.46 [95% 
CI: 0.28, 0.76] P=0.002) 
F) Response to PAP in at least one of the three immune response assays (HR=0.53 [95% CI: 
0.31, 0.90] P=0.02).  
 
The peripheral immune response parameters examined were log-transformed SI medians, 
ranked IFNγ ELISPOT medians, and ranked ELISA titers. Responder status was analyzed 
using a Cox regression model, with and without adjustment for baseline PSA and LDH 
[Sheikh, 2012]. All p-values reported are two-tailed. No adjustment for multiplicity of 
endpoints or time points was made. These correlations remained after adjusting for baseline 
prognostic factors (PSA and LDH) that are independently correlated with survival.  
 
Positive thresholds for treatment-related immune responses were selected in order to ensure 
<5% of subjects would exceed the value at baseline. Thresholds were proliferation: SI > 12 
for PA2024, > 8 for PAP; IFNγ ELISPOT (per 3x105 PBMC): >10 spots for PA2024, >40 
spots for PAP; ELISA titer: >400 for both anti-PA2024 and anti-PAP antibodies. Serum 
samples that gave a positive response to an initial ELISA were subsequently evaluated for 
IgM and IgG antibody isotypes.   
 
Figure 1 presents the impact of any positive immune response parameter to OS survival. 
Below are the hazard ratios and associated 95% confidence intervals, as well as the p-values, 
for comparison of the survival curves in the IMPACT study for responders versus non-
responders for the different immune response assays. 
 
For the primary endpoint of the current trial, IFN ELISpot to PA2024, the hazard ratio 
estimate of 0.53 (0.27, 1.04) for responders to IFN ELISpot to PA2024 compared to non-
responders. 
 
Table 1 (Data from Dendreon) 
Antigen 
Assay 
HR (95% CI) 
p-value 
PA2024 
Humoral 
0.45 (0.28, 0.71) 
p=0.0007 
PA2024 
Proliferation 
0.87 (0.46, 1.67) 
p=0.169 
PA2024 
IFN ELISpot 
0.53 (0.27, 1.04) 
p=0.065 
 
 
 
 
PAP 
Humoral 
0.60 (0.33, 1.08) 
p=0.087 
PAP 
Proliferation 
0.66 (0.27, 1.61) 
p=0.364 
PAP 
IFN ELISpot 
0.29 (0.04, 2.15) 
p=0.227 
The hazard ratio and p-value are based on a Cox regression analysis with response (0 = non 
responder, 1 = responder) in the model. Similar results are obtained with models adjusting for 
baseline PSA and LDH.  

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Data from a neoadjuvant trial demonstrate that sipuleucel-T can modulate the presence of 
lymphocytes at the prostate tumor site giving further credence to the influence of the anti-
tumor immune response to the effect of sipuleucel-T on OS. In the neoadjuvant trial 
[NeoACT (P07-1; NCT00715104)] [Fong, 2012] sipuleucel-T treatment has been shown to 
be associated with an increased frequency of T cells in prostate cancer tissue at the interface 
of the benign and malignant glands.  Patients received the standard sipuleucel-T regimen of 3 
infusions of sipuleucel-T at approximately 2-week intervals.  At 6-7 weeks after start, 
patients underwent radical prostatectomy. By IHC there was a significant observed increase 
in CD3+ and CD4+ T cell populations (≥3 fold) at the tumor interface (where benign and 
malignant glands interface), compared with the pre-treatment biopsy, benign radical 
prostatectomy tissue, and tumor tissue (ANOVA post hoc Newman-Keuls test: p<0.0001 for 
each comparison). FoxP3+ CD4+ T cells were also increased (p=0.0005) at the tumor 
interface, but represented a small fraction of the observed CD4+ T cells.  
 
Recombinant Glycosylated Human Interleukin -7) (CYT107) NSC #767713, 
RevImmune, Inc.: 
 
IL-7 is a homeostatic growth factor for T cells and is capable of inducing proliferation, 
maintaining T-cell responsiveness, and preventing and reversing T-cell anergy [Mackall, 
2011]. IL-7 signals through the IL-7 receptor (IL-7R) heterodimer composed of the common 
γ-chain (CD132) cytokine receptor and a unique IL-7Rα (CD127). During normal conditions, 
IL-7R expression is maintained on resting T cells [Mackall, 2011] and IL-7 is continuously 
available in secondary lymphoid organs as a result of stromal cell IL-7 production [Takada, 
2009]. In general, IL-7 has more potent effects on conventional CD8+ T cells and CD4+ cells 
than it does on CD4+ regulatory T cells (Tregs). IL-7Rα expression is notably low on 
FOXP3+ Treg cells compared with non-regulatory T-cell subsets [Seddiki, 2006], [Liu, 
2006]. Its continuous signaling induces antiapoptotic and costimulatory responses that are 
essential for the survival of naïve T cells. After either T-cell activation, IL-7 signaling, or 
both, IL-7Rα is down-regulated on terminally differentiated, senescent T cells [Fry, 2003], 
[Park, 2004] but becomes re-expressed after several days and remains expressed during the 
later contraction phase. The effects of IL-7 are most potent on recent thymic emigrants in 
which IL-7–mediated signaling can induce proliferation in the absence of T-cell receptor 
signaling [Swainson, 2007]. IL-7Rα is also selectively expressed on a small minority of 
effector T cells that are destined to enter the central memory T-cell pool, thus implicating IL-
7 as a modulator of the effector to memory cell transition [Kaech, 2003]. 
 
Prior Trials: Preclinical and clinical results support the rationale for developing trials testing 
IL-7 administration after sipuleucel-T therapy to increase or prolong the sipuleucel-T–
induced T-cell response to PAP. In animal models and in humans, IL-7 has been shown to 
increase by several-fold the number of peripheral blood T cells with little toxicity and to 
increase T-cell receptor diversity (i.e., naïve T cells and conventional CD4+ and CD8+ T 
cells), with the expansion of conventional T cells at a greater proportion than the expansion 
of Tregs [Levy, 2012]. In animal models, IL-7 administration augments vaccine-induced cell 
responses (e.g., CD8+ memory T-cell responses) and immune-mediated control of both 
tumors and viruses. In addition, IL-7 can maintain effector T-cell function and prevent T-cell 
exhaustion. Consistent with the preclinical work, human trials of IL-7 in chronic viral 
infections induce increased T-cell number and demonstrate beneficial effects. IL-7 has been 

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well tolerated in early phase clinical trials and can be administered on an outpatient basis. 
Furthermore, other animal studies show that IL-7 administration can augment immune 
reconstitution after lympholytic stem cell transplantation and chemotherapy [Mackall, 2001], 
[Morrissey, 1991], [Perales, 2011]. Important for the current protocol, IL-7 administration 
can augment vaccine-induced antigen-specific T-cell responses [Colombetti, 2009], 
[Melchionda, 2005]. In mice, transient administration of IL-7 around the time of vaccination 
or initial viral infection increases the number of antigen-specific effector and memory T-cell 
populations and has long-lasting effects on the memory T-cell pool [Colombetti, 2009], 
[Nanjappa, 2008], [Pellegrini, 2009], [Melchionda, 2005]. Therefore, administration of IL-7 
after a vaccine such as sipuleucel-T may have enhanced efficacy and substantial 
improvements in vaccine-induced responses.  
 
The effectiveness of IL-7 as a vaccine adjuvant depends on the timing of administration. 
Durable effects on the memory T-cell pool have been observed only when IL-7 was 
administered during the contraction phase of the CD8+ T-cell response [Nanjappa, 2008]. IL-
7 expanded the magnitude of the secondary CD8+ response when administered during the 
contraction phase of the primary or the secondary response, which is relevant to this 
proposal. 
 
Two IL-7 formulations have been successively developed by Cytheris. The technology for 
the second formulation, CYT107, as well as vialed material has been taken over by 
RevImmune, Inc. and is the agent used in this current protocol. Both had the same primary 
sequence similar to the sequence of the native protein. The IL-7 for this proposal (CYT107) 
is produced from recombined Chinese hamster ovary (CHO) mammalian cells and is highly 
glycosylated. Seven phase I/IIa dose escalation studies and two phase II studies have been 
initiated with CYT107 for the treatment of cancer and chronic viral infections (e.g., HIV, 
hepatitis B, hepatitis C) and for use after hematopoietic stem cell transplantation [Mackall, 
2011]. In those studies, CYT107 has been administered subcutaneously in a dose range of 3–
60 μg/kg with a schedule regimen of one weekly subcutaneous administration for 3 or 4 
weeks (corresponding to one cycle). In general, CYT107 has been well tolerated as an 
outpatient regimen with mild to moderate constitutional symptoms and reversible spleen and 
lymph node enlargement. In addition, marked dose-dependent increases in peripheral CD3+, 
CD4+, and CD8+ lymphocytes were seen, resulting in a rejuvenated circulating T-cell profile, 
resembling that seen earlier in life [Sportes, 2008]. The most common side effects have been 
low-grade fever, malaise, transient increases in liver enzyme levels, erythema and induration 
at the site of administration, and rash or allergic reaction with repeated cycles in patients with 
HIV. In marked contrast to IL-2 and IL-15, no significant capillary leak or acute toxicity 
have been observed following IL-7 therapy. 
 
The trial regimen administers CYT107 subcutaneously once a week on days 0, 7, 14 and 21 
and is expected to maintain increased T-cell number throughout this trial to at least week 12, 
although a sustained effect up to 1 year has been observed in an HIV trial (CLI-107-06) 
[Levy, 2012]. Although the measured half-life of CYT107 is 10–15 hours, the biologic 
effects persist well after circulating levels of IL-7 return to baseline. The biologic half-life is 
much longer possibly due to a depot effect from IL-7 binding to extracellular matrix and the 
slow release at lower than detectable levels [Mackall, 2011]. In a study of single-dose rhIL-7 
(CYT 99 007) administered to patients with HIV infection, CYT 99 007 induced early 

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13 
lymphopenia, followed by a significant increase in the rate of T-cell cycling on day 4 with 
increases in circulating CD4+ and CD8+ T-cell counts persisting for at least 14 days [Sereti, 
2009]. The administration of CYT107 is also likely to transiently increase the size of the 
spleen and lymph nodes as well as peripheral blood T cells. 
 
Specificities of IL-7/IL-7Rα pathway regulation and current data on CYT107 in humans 
favor injection once a week and short therapeutic cycles. According to monkey and human 
data, a 1-week interval between each injection of CYT107 should lead to full recovery of IL-
7Rα expression (CD127) at the surface of T cells that responded to a prior dose of IL-7. 
Furthermore, a sustained response of T cells to IL-7 should be fully restored, as measured 
1 week later by Ki-67 expression. Short cycles, limited to 3 doses, should avoid exhaustion 
of T-cell responsiveness to high doses of IL-7, which could occur despite the recovery of 
CD127 expression. 
 
T-cell proliferation rates in response to IL-7 are correlated with IL-7Rα expression. At 
present, the kinetics of IL-7Rα after other cancer vaccines in general and sipuleucel-T 
specifically is not known, but critical. T-cell activation and IL-7 itself can down-regulate IL-
7Rα expression. IL-7Rα expression is expected to be re-expressed at about the time of 
CYT107 administration and persist during the period of function of the administered IL-7. 
The once-weekly regimen beginning after sipuleucel-T is expected to increase proliferation 
and survival of PAP-specific T cells, possibly for an extended period, and increase the 
number of PAP-specific memory cells without equivalent expansion of Tregs to dampen the 
antitumor effect.  
 
CYT107 will be instituted 3 to 7 days after the third and final administration of sipuleucel-T. 
IL-7 function requires upregulated IL-7 receptors and upregulation will occur after 
completion of PAP vaccination and during the contraction phase. Because sipuleucel-T is 
manufactured from leukapheresed patient PBMC, provisions of CYT107 before 
leukapheresis would change the character of cells placed into culture and thus change the 
manufacturing scheme and would be disallowed by the FDA. Many insurance programs, 
including Medicare, will not pay for unapproved agents or regimens in clinical trials. 
Sipuleucel-T would be considered an experimental agent by some insurance programs if 
administered concurrent with CYT107. Therefore, testing of CYT107 will begin only after 
completing standard therapy with sipuleucel-T. 
 
2.4 
Rationale 
 
Sipuleucel-T is the first FDA-approved cancer vaccine, designed to elicit therapeutic immune 
responses to PA2024 and subsequently PAP.  Sipuleucel-T prolongs patient survival by 4.1 
months on average. IL-7 is a homeostatic growth factor for T cells. IL-7 induces substantial 
proliferation of antigen-specific T cells that express a unique IL-7 receptor, IL-7Rα with very 
little toxicity. IL-7 can maintain T-cell responsiveness and prevent and reverse T-cell anergy. 
IL-7 is also thymopoïetic and can expand recent thymic immigrants and thus the T-cell 
repertoire, which is known to be low in individuals the age of most patients with advanced 
prostate cancer.  
 

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We expect that CYT107 will increase and prolong T-cell and antibody immune responses to 
PA2024 and PAP and provide a novel, nontoxic regimen to prolong survival. We also expect 
that CYT107 will expand T-cell repertoire and reset the homeostatic total T-cell level 
potentially mitigating the immune compromise observed in patients with mCRPC because of 
age and prior treatment.   
 
Because clinical development of sipuleucel-T for FDA approval began in 1997, the 
formulation and regimen of sipuleucel-T have remained unchanged for almost 15 years. 
Given the advances made in immunology and immunotherapy in the last decade and a half, it 
is axiomatic that regimens based on current immunologic science would provide higher and 
longer lasting immune responses (i.e., greater areas under the curve) and, in the case of 
sipuleucel-T, enhanced patient benefit. The question remains “Which strategies are most 
likely to be effective and the most ripe for testing?” 
 
In answer to this question, a strong rationale supports therapy with IL-7. IL-7 is a 
homeostatic T-cell growth factor responsible for the expansion of T cells during lymphopenia 
[Mackall, 2011]. In human clinical trials, IL-7 induces dramatic expansions in peripheral T-
cell numbers and in total body CD4+ and CD8+ T cells without substantial toxicity. Yet, if an 
immunotherapy is to enhance the effects of an approved regimen, the agent must address 
many of the reasons an immunotherapy fails. Such reasons include (1) insufficient T-cell 
number, (2) insufficient CD8+ or CD4+ T-cell subsets, (3) a preponderance of regulatory T 
cells (Treg), (4) short-lived T cells unable to provide long-term tumor control, (5) a narrow 
repertoire of response (sometimes monoclonal), (6) little or no physical access of T cells to 
the tumor, and (7) strong local immunosuppressive effects of TGFß, one of the most potent 
tumor immunosuppressors.  
 
IL-7 can mitigate many of these problems. Regarding insufficient numbers and types of 
T cells, IL-7 administration increases the number of CD4+ and CD8+ T cells, an effect that is 
both potent and sustained [Mackall, 2011], [Fry, 2003], [Levy, 2009], [Levy, 2012]. This 
boost of CD4+ T cells provides efficient help to CD8+ T cells and warrants their 
functionality. IL-7 favors the homing of T cells to lymph nodes, gut, mucosa, and tumors 
[Kaech, 2003], [Beq, 2009], [Sereti, 2012] and thus potentially the ability of T cells to 
infiltrate tumors. With IL-7, the expansion of Treg is proportionally less than conventional 
CD8+ and CD4+ T cells and the produced T cells are long-lived because of various 
antiapoptotic effects and the boosting of central memory T cells [Kaech, 2003], [Seddiki, 
2006], [Liu, 2006]. In addition, IL-7 broadens the repertoire of T cells because IL-7 supports 
thymopoïetic activity that produces naïve T cells [Colombetti, 2009], [Nanjappa, 2008], 
[Levy 2012]. Finally, IL-7 antagonizes the production and signaling of TGFß [Pellegrini, 
2009]. 
 
2.5 
Correlative Studies Background 
 
The primary aim is to determine whether CYT107 administration increases the vaccine-
induced antigen-specific T-cell immune response to PA2024, as immune response to PA2024 
best correlates with survival. The level and character of T-cell immune response to PA2024 
as well as PAP will be assessed at day 0 (week 1) [before CYT107 administration], at day 35 
(week 6) [two weeks after last CYT107 to assess the presumed peak immune response], at 

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day 70 (week 11) [to assess persistence of immune response and to compare to Dendreon 
data] and, at day 154 (week 23),and day 365 (week 53) [to assess persistence of immune 
response]. Both T cell responses and antibody responses will be assessed.  The primary 
endpoint will be quantification of T-cell responses to PA2024 measured at day 70 (week 11), 
7 weeks after the last CYT107 injection. T cell responses will be measured by interferon-
gamma ELISPOT as the most quantifiable and reproducible assay. In the IMPACT study, 2 
weeks after last sipuleucel-T administration, the mean PA2024 ELISPOT was 40 with a 
standard deviation of 69 based on n = 63. At 10 weeks after the last administration the mean 
PA2024 ELISPOT was 23 with a standard deviation of 36 based on n = 42. This data is based 
on Dendreon performing the ELISPOT assay on PBMC. This assay has been performed in 
the UCSF neo-adjuvant program study and was shown to be robust. Dendreon is supplying 
reagents to the UW Central lab (Immune Monitoring Lab) for the development of assays 
needed to test for response to specific proteins. The UW Central Lab is validating and 
establishing standards for the assay.  
 
Longitudinal responses to PA2024 and PAP will be considered in the primary analysis; 
however power calculations are based on estimations of the magnitude of T cell responses at 
week 11. To meet the primary aim and determine whether CYT107 administration increases 
the vaccine-induced antigen-specific T-cell immune response to PA2024, the level and 
character of T-cell immune response to PA2024 will be determined at day 0 (week 1), day 35 
(week 6), day 70 (week 11), day 154 (week 23), and day 365 (week 53) evaluating T cell 
responses. T-cell responses to PA2024 will be measured by interferon-gamma ELISPOT and 
T-cell proliferative responses to PAP as a confirmatory assay. The effect on antigen-specific 
T-cell immune responses to PAP will be measured using the same assays and time points. 
The immune response to other ongoing and nascent antitumor responses (e.g., PRAME, NY-
ESO-1 and p53), additional tumor antigens specific to prostate cancer (e.g., PSA and PSMA), 
memory viral responses (influenza A), and chronic viral responses (cytomegalovirus) will 
also be assessed. Assays will be performed in the Cancer Immunotherapy Trials Network 
(CITN) Central Laboratory, IML (Immunologic Monitoring Laboratory), of the Tumor 
Vaccine Group led by Nora Disis, MD. 
 
A number of other (secondary) correlative studies will be conducted to evaluate the effects of 
IL-7 on T and B cell immunity. Certain blood and serum for secondary correlative studies 
will be collected and stored for future analysis pending funding availability.  
The effect on T lymphocyte number and phenotype (i.e., CD4+ and CD8+ subsets of naïve, 
effector memory, central memory cells, CD4+ Treg and activated T cells) will be assessed. 
The frequency and percentage of these and other PBMC subsets (i.e., T cells, NK cells, NKT 
cells, B cells, monocytes and dendritic cells) will be determined using multiparameter flow 
cytometric analysis on whole blood. 
 
IgM and IgG responses to PA2024 and PAP will be measured by standard ELISA. 
 
The T-cell repertoire will be characterized by T-cell receptor (TCR) deep sequencing and the 
analysis will be done with the Immunoseq Analyzer software (Harlan Robins, PhD, with 
Adaptive Biotechnologies, Seattle). 
 

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Thymic function will be assessed by measuring levels of T-cell receptor rearrangement DNA 
excision circles (TRECs). 
 
Adverse events will be graded and reported using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Therapeutic 
response will be assessed by consensus PSA response criteria for PSA blood tests, immune-
related response criteria for computed tomography and bone scan (only as clinically 
indicated), circulating tumor cells, and patient survival. 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer 
(mCRPC) 
 
3.1.2 Patients must have successfully completed therapy with sipuleucel-T within 3-7 days of 
planned CYT107 study drug treatment  
 
3.1.3 Assessable disease with a positive bone scan and/or measurable disease on CT scan 
and/or MRI of the abdomen and pelvis  
 
3.1.4 Prior orchiectomy or must be on ongoing LHRH agonist or antagonist (e.g., degarelix) 
therapy  
 
3.1.5 No ongoing anti-androgen therapy 
 Patients must be off anti-androgen therapy for at least 30 days 
 
3.1.6 Patients receiving any other hormonal therapy, including any dose of megestrol acetate 
(Megace), Proscar (finasteride), any herbal product known to decrease PSA levels (e.g. 
Saw Palmetto, PC-SPES), or any systemic corticosteroid, must discontinue the agent for 
at least 30 days prior to study treatment  
 
3.1.7 Laboratory requirements (assays within 7 days of first CYT107 injection) 
 Absolute neutrophil count (ANC) ≥ 1500/µL 
 Bilirubin < 1.5 x ULN 
 Hemoglobin ≥ 10 g/dL 
 Platelets > 100,000/mcL 
 AST and ALT < 2.5 x ULN  
 Creatinine clearance ≥ 60mL/min by the Cockcroft-Gault equation (see  
Appendix C) 
 

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3.1.8 Testosterone ≤ 50 ng/dL (documented at any time while on LHRH agonist or antagonists 
or s/p orchiectomy)  
 
3.1.9 ECOG performance status of 0-1 or a Karnofsky performance status of ≥ 80% 
 
3.1.10 Life expectancy of at least 6 months 
 
3.1.11 At least 18 years of age or older 
 
3.1.12 Prior local radiation therapy must be completed at least 30 days prior to enrollment and 
the patient must have recovered from all toxicity  
 
3.1.13 Prior “systemic” radiopharmaceuticals (strontium, samarium, radium 223 dichloride) 
must be completed ≥ 8 weeks prior to enrollment 
 
3.1.14 Patients must agree to use 2 methods of adequate contraception for the duration of study 
participation, and for four months after discontinuing therapy, because of the unknown 
potential risk to a gamete and/or developing embryo from this investigational therapy.  
 
3.1.15 Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Prior chemotherapy for castration resistant prostate cancer. Neoadjuvant chemotherapy 
and chemotherapy given for hormone sensitive prostate cancer are allowed.   
 
3.2.2 Prior investigational immunotherapy 
 
3.2.3 Prostate cancer pain requiring regularly scheduled narcotics 
 
3.2.4 Pathologic long-bone fractures, imminent pathologic long-bone fracture (cortical erosion 
on radiography > 50%) or spinal cord compression 
 
3.2.5 Current treatment with systemic steroid therapy (inhaled/topical steroids are acceptable) 
 Systemic corticosteroids must be discontinued for at least 30 days prior to first 
CYT107 injection. 
 
3.2.6 Known central nervous system metastases 
 
3.2.7 Documented cirrhosis or documented acute hepatitis 
Note: A positive hepatitis B serology indicative of previous immunization (i.e., HBsAb 
positive and HBcAb negative), or a fully resolved acute HBV infection is not an 
exclusion criterion. 
 

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3.2.8 History of severe asthma, as defined by prior or current use of systemic corticosteroids 
for disease control, with the exception of physiological replacement doses of cortisone 
acetate or equivalent, as defined by a dose of 10 mg or less 
 
3.2.9 Medical or psychiatric illness that would, in the opinion of the investigator, preclude 
participation in the study or the ability of patients to provide informed consent for 
themselves  
 
3.2.10 Cardiovascular disease that meets one of the following: congestive heart failure (New 
York Heart Association Class III or IV), active angina pectoris, or recent myocardial 
infarction (within the last 6 months) 
 
3.2.11 Concurrent or prior malignancy except for the following:  
 Adequately treated basal or squamous cell skin cancer 
 Adequately treated stage I or II cancer from which the patient is currently in complete 
remission 
 Any other cancer from which the patient has been disease-free for 5 years 
 
3.2.12 Known HIV or other history of immunodeficiency disorder. HIV-positive patients on 
combination antiretroviral therapy are ineligible because of the potential for 
pharmacokinetic interaction with CYT107. Other trials are examining the effect of 
CYT107 in patients with HIV infection.  
 
3.2.13 Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for 
treatment of either a psychiatric or medical (e.g. infectious) illness 
 
3.2.14 Any underlying medical or psychiatric condition, which in the opinion of the investigator 
will make the administration of CYT107 hazardous or obscure the interpretation of AEs, 
such as a condition associated with frequent diarrhea  
 
3.2.15 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to CYT107 
 
3.2.16 Patients who have received prior immunosuppressive therapy within 30 days prior to 
enrollment 
 
3.2.17 Active (as defined by requiring immunosuppressive therapy) or history of clinically 
significant autoimmune disease (as defined by previously requiring immunosuppressive 
therapy)  
 
3.2.18 Patients who have received hepatotoxic drugs less than 7 days prior to enrollment 
 
3.2.19 Patients who have received prior biologic agents less than 30 days prior to enrollment 
 

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3.2.20 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements 
 
3.2.21 Patients who have a history of any hematopoietic malignancy 
 
3.2.22 History of pulmonary disease such as emphysema or COPD, (FEV > 60% of predicted 
for height and age required in patients with prolonged smoking history or symptoms of 
respiratory dysfunction).  
 
3.3 
Inclusion of Minorities 
 
Men of all races and ethnic groups are eligible for this trial.  Prostate cancer does not occur in 
women.  
 
3.4 
Subject Recruitment 
 
Subjects will be identified through the clinical practices of the investigator or sub-
investigators at participating research sites and through referrals from outside hospitals and 
physicians. No direct-to-patient advertising will be performed.  
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Prior to the recruitment of a patient for this study, investigators must be registered and have a 
current CTEP-IAM account.  Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of a 
complete investigator registration packet (FDA Form 1572 with original signature, current 
CV, Supplemental Investigator Data Form with signature, and Financial Disclosure Form 
with original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, and NCI.  
These forms are available on the CTSU Web site (enter credentials at https://www.ctsu.org; 
then click on the Register tab) or by calling the PMB at (240) 276-6575 Monday through 
Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 
 
Each investigator or group of investigators at a CITN member site must obtain IRB approval 
for this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients. CITN member sites can check the status of 
their registration packets by querying the Regulatory Support System (RSS) site registration 
status page of the CTSU member web site by entering credentials at https://www.ctsu.org. 
 
Requirements for CITN12-03 site registration: 
 CTSU IRB Certification 
 CTSU IRB/Regulatory Approval Transmittal Sheet 
 IRB-approved consent form 

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4.2 
Registration Process 
 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS 
(Regulatory Support System).  Patients must have signed and dated all applicable consents 
and authorization forms. 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. 
 
All CITN member site staff will use OPEN to enroll patients to this study.  OPEN is 
integrated with the CTSU Enterprise System for regulatory and roster data and, upon 
enrollment, initializes the patient position in the RAVE database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website at 
https://www.ctsu.org. 
 
Prior to accessing OPEN CITN member site staff should verify the following: 
 
 All eligibility criteria have been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the group or CTSU web site as a tool to 
verify eligibility. 
 All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable).  
 
Access requirements for OPEN: 
 
 CITN member site staff will need to be registered with CTEP and have a valid and 
active CTEP-IAM account. This is the same account (user id and password) used for 
the CTSU members' web site.  
 To perform registrations, the site user must have been assigned the 'Registrar' role on 
the CITN roster.  
 
Note: The OPEN system will provide the site with a printable confirmation of 
registration information and treatment information. Please print this confirmation for 
your records. 
 
Further instructional information is provided on the OPEN tab of the CTSU members’ side of 
the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any additional 
questions contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
The patients will receive 10 μg/kg of CYT107 every week for 4 weeks, beginning between 3 
to 7 days (3 days preferred) after completion of standard sipuleucel-T therapy (i.e., after the 

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third and final dose of sipuleucel-T). At 10-20 µg/kg, some specific immune response or 
antiviral activity has been documented.  
 
CYT107 will be administered subcutaneously, which according to studies in monkeys, yields 
satisfactory bioavailability (> 75%), with an extended kinetic profile that may favor 
prolonged CYT107 activity. 
 
REGIMEN DESCRIPTION 
Agent 
Dose 
Route 
Schedule 
Treatment 
Phase 
CYT107 
(cohort 1) 
No therapy (observation) 
28 days 
(4 weeks) 
CYT107 
(cohort 2) 
10 μg/kg 
Subcutaneous 
Dose 1: (day 0) 3-7 days post sipuleucel-T  
Dose 2: (day 7) 10-14 days post sipuleucel-T  
Dose 3: (day 14) 17-21 days post sipuleucel-T  
Dose 4 (day 21) 24-28 days post sipuleucel-T 
 
Patients assigned to observation (cohort 1) and patients assigned to receive CYT107 (cohort 
2) will follow the same study procedures and blood collection schedule. However, the study 
visits on Week 2 (Day 7) and Week 4 (Day 21) are optional for patients assigned to 
observation (cohort 1). 
 
All patients randomly assigned to receive CYT107 (cohort 2) will remain under observation 
for 4 hours after each injection of CYT107 (Day 0, Day 7, Day 14 and Day 21). The vital 
signs will be monitored every 2 hours and patients will be observed for the development of 
any allergic reaction to the CYT107, such as hives, bronchospasm, rash, etc. 
 
The first six patients randomly assigned to receive CYT107 will be followed for an 
additional 4 weeks prior to the study expanding past six patients, as a lead-in phase to ensure 
safety and tolerability of the selected CYT107 dose. In order to continue enrollment, only 
one grade 3 or 4 Adverse Events related to CYT107 is allowed with the exception of 
transient lymphopenia (See Section 6). For the purpose of evaluating the first 6 patients, a 
Grade 3 or 4 ‘lymphocyte count decrease’ will be counted as an Adverse Event towards 
stopping enrollment, only if the count fails to return to a minimum of 500 cells/mm3 by the 
time of the scheduled start of the next cycle.  
Patients must complete standard sipuleucel-T therapy before receiving the CYT107 doses. 
The standard, FDA approved, sipuleucel-T therapy is three vaccinations administered on 
days 0, 14 and 28. CYT107 must be administered within 3 to 7 days of the patient receiving 
their last sipuleucel-T (Provenge®) vaccination. 
 
Patients may not use any of the following therapies during the administration of CYT107:  
 Concomitant systemic or local anti-cancer medications or treatments (investigational 
or non-investigational) are prohibited in this study while receiving CYT107 
treatments.  
 Treatment with hormones or other chemotherapeutic agents may not be administered 
except for hormones administered for non-disease-related conditions (e.g., insulin for 

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diabetes mellitus). Neoadjuvant chemotherapy and chemotherapy given for hormone 
sensitive prostate cancer are allowed.  
 Therapy with anti-androgens must be stopped for at least 30 days prior to first 
CYT107 injection.   
 Palliative radiation therapy may not be administered during protocol treatment.  
 Immunosuppressive agents including chronic systemic corticosteroids, except for 
those directed by the protocol or for toxicities such as hypersensitivity or other 
immune events.  
 Any non-oncology vaccine therapies used for the prevention of infectious diseases 
(for at least 30 days prior to or after any dose of study drug).  
 
Patients may continue to receive the following: 
 
 Continued LHRH agonist or antagonist therapy is allowed and is mandatory, except 
for patients with prior orchiectomy.   
 Continued bone targeted agents (e.g. zolendronate, denosumab) are allowed  
 Patients should receive full supportive care, including transfusions of blood and blood 
products, erythropoietin, antibiotics, antiemetics, etc. when appropriate.  
 
After the period of CYT107 administration, patients should not receive additional prostate 
cancer therapies until or unless substantial progression occurs. Therapies should be held until 
after day 70 if medically appropriate in the view of the primary treating physician. Adverse 
events noted following subsequent therapies within the 53 weeks duration of follow-up will 
be chronicled and attribution assessed.  
 
5.1.1 CTEP IND Agent: N/A 
 
5.1.2 Other Agent(s): N/A 
 
5.1.3 Other Modality(ies) or Procedures: N/A 
 
5.1.4 Investigational Imaging Agent Administration: N/A 
 
5.2 
Definition of Dose Limiting Toxicity: N/A   
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Studies performed to investigate the potential of CYT107 to inhibit or to act as a time 
dependent inhibitor of hepatic microsomal cytochrome P450 isozmyes (see Investigator 
Brochure) concluded that at the concentration investigated, it is unlikely that CYT107 will be 
involved in drug-drug interactions and CYT107 is not expected to cause clinically significant 
P450 inhibition or induction. However, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies including vitamins 
and nutritional supplements.   

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5.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for one 
cycle (4 doses total) or until one of the following criteria applies: 
 Unacceptable adverse event(s) 
 Intercurrent illness that prevents further administration of treatment 
 General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 Disease progression  
 Patient decides to withdraw from the study 
 
5.5 
Duration of Follow Up 
 
Patients will be followed for 53 weeks or until death, whichever occurs first.  Patients, in 
whom therapy is stopped due to unacceptable adverse event(s) will continue to be followed 
for 53 weeks or until resolution or stabilization of the adverse event if that takes more than 
53 weeks.  
 
Many patients will receive additional therapy for progression within the 53 weeks duration of 
follow-up. Additional therapy will be chronicled.  
 
Patients will be asked to be followed by phone, once a year, after completion of Week 53. 
Overall Survival data will be collected and reported (see Section 11.1) until the end of the 
study.   
 
5.6 
Criteria for Removal from Study 
 
Patients will not be removed from the study; however the patient may decide to withdraw 
from the study at any time. Patients with Adverse Events or progression will continue to be 
followed for a total of 53 weeks. If the patient elects to leave the study, notify the Principal 
Investigator, and document the reason for study removal and the date the patient was 
removed in the Case Report Form. The patient should otherwise be followed per protocol 
requirements.  
 
5.7 
Laboratory Specimen collection 
 
The Study Calendar in section 10 outlines the timing of procedures and follow up visits.  
 
The CITN12-03 Laboratory Manual outlines the timing of blood draws as well as the 
maximum total amount of the blood draws.  
 
Quantity of Blood Draws: The maximum total blood draw on weeks 1, 6, 11, 23, and 53 is 
between 276 and 286 mL. Due to the large quantity of blood scheduled to be drawn at these 
visits, assessment for anemia is necessary. Based on the safety laboratories the volume of 
blood drawn at weeks 1, 6, 11, 23, and 53 will be determined. 

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Inclusion criteria demand a hemoglobin (Hgb) of ≥10 g/dL for entry into the study.   
Thus, profound anemia is not likely to be an issue. If a substantial drop in Hgb is observed, 
patients should be assessed for cryptic bleeding and hemolysis. If Hgb is <10g/dL prior to the 
Week 1 Day 0, Week 6 Day 35, Week 11 Day 70, Week 23 Day 154 or Week 53 Day 365 
visits, less than the maximum total volume of blood should be drawn as follows:    
 On Week 1 Day 0, if the Hgb is ≥9 g/dL, up to 9.9 g/dL, then blood draw amounts may 
be decreased to 226 mL (from 286 mL), on Week 1 Day 0.  
 On Week 6 Day 35 and Week 11 Day 70, blood draw amount may be decreased to 216 
mL (from 276 mL).  
 On Week 23, blood draw amount may be decreased to 220 mL (from 270 mL)  
 On Week 53 Day 365, blood draw amount may be decreased to 226 mL (from 286 mL).  
If the Hgb is less than 9 g/dL, drawing blood only for local safety labs is recommended. 
 
If a site is unable to collect all specimens due to low hemoglobin or other issues such as vein 
access, specimens should be collected in the following order if required at the visit:  
1) Toxicity/safety specimens and local safety labs  
2) ELISA 
3) ELISPOT and other cellular assays 
4) Other assays 
   
If the Hgb is > 10 all labs will be drawn. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 will be used 
to grade adverse events. Patients enrolled in this study will be evaluated clinically and with 
standard laboratory tests before and at regular intervals during their participation in this study as 
specified in this section.  
 
Patients will be evaluated for adverse events (all grades), serious adverse events, and adverse 
events requiring study drug interruption or discontinuation at each study visit for the duration of 
their participation in the study. 
 
Delays in dosing will be allowed for delays such as weather factors resulting in delays getting to 
the clinic or hospital, travel delays, clinic schedules or emergencies. A delay of up to 72 hours 
will be allowed on one occasion during the course of a treatment cycle.  
 
Removing patients from protocol therapy for Adverse Events: Patients will come off protocol 
therapy if any grade 3 or 4 Adverse Events by CTCAE Version 4.0 criteria occur with the 
exception of transient lymphopenia. Three cases of Grade 3 lymphopenia have been documented 
with CYT107.  For purposes of this trial, since peripheral lymphopenia is a transient event, a 
Grade 3 ‘lymphocyte count decrease’ to <500-200 cells/mm3 and a Grade 4 ‘lymphocyte count 
decrease’ to <200 cells/mm3 will not require patients coming off protocol provided the 
lymphocyte count returns to a minimum of 500 cells/mm3 by the time of the scheduled start of 
the next weekly dose within the treatment phase. A Grade 3 or 4 ‘lymphocyte count decrease’ 

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will require patients coming off protocol if the count fails to return to a minimum of 500 
cells/mm3 by the time of the scheduled start of the next cycle.  
Dose modifications for Adverse Events: Substantial adverse events are not expected and thus 
dose modifications are not planned or recommended with the exception of fatigue (see below). In 
initial human trials with CYT107 adverse events were frequent, but transient and grade 2 or less 
(as noted in the Adverse Event list, section 7.1.2.). These include erythema or local reaction at 
site injection, peripheral adenopathies next to the site injection, rash, general reactions of fever 
and flu-like symptoms.   
 
Fatigue was infrequent; dose modification for this event is noted below: 
 
Event Name 
Nausea 
Grade of Event 
Management/Next Dose of CYT107 
≤ Grade 1 
No change in dosing schedule 
Grade 2 
No change in dosing schedule 
Grade 3 
Off protocol therapy if with adequate/maximal medical 
intervention symptoms persist 
Grade 4 
Off protocol therapy 
Patients requiring a delay of >72 hours should go off protocol therapy. 
Recommended management:  Anti-emetics 
 
Event Name 
Vomiting 
Grade of Event 
Management/Next Dose of CYT107 
≤ Grade 1 
No change in dosing schedule 
Grade 2 
No change in dosing schedule 
Grade 3 
Off protocol therapy if with adequate/maximal medical 
intervention symptoms persist 
Grade 4 
Off protocol therapy 
Patients requiring a delay of >72 hours should go off protocol therapy. 
Recommended management:  Anti-emetics 
 
Event Name 
Diarrhea 
Grade of Event 
Management/Next Dose of CYT107 
≤ Grade 1 
No change in dosing schedule 
Grade 2 
No change in dosing schedule 
Grade 3 
Off protocol therapy if with adequate/maximal medical 
intervention symptoms persist 
Grade 4 
Off protocol therapy 
Patients requiring a delay of >72 hours should go off protocol therapy. 
Recommended management:  Physician discretion 
 
Event Name 
Neutropenia 
Grade of Event 
Management/Next Dose of CYT107 
≤ Grade 1 
No change in dosing schedule 
Grade 2 
No change in dosing schedule 
Grade 3 
Hold* until ≤Grade 2.   

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Grade 4 
Off protocol therapy 
*Patients requiring a delay of >72 hours should go off protocol therapy. 
Recommended management: Treatment of infection as appropriate 
 
Event Name 
Thrombocytopenia 
Grade of Event 
Management/Next Dose of CYT107 
≤ Grade 1 
No change in dosing schedule 
Grade 2 
No change in dosing schedule 
Grade 3 
Off protocol therapy 
Grade 4 
Off protocol therapy 
Patients requiring a delay of >72 hours should go off protocol therapy. 
Recommended management: Platelet transfusions if indicated 
 
Event Name 
Fatigue 
Grade of Event 
Management/Next Dose of CYT107 
≤ Grade 1 
No change in dosing schedule 
Grade 2 
No change in dosing schedule 
Grade 3 
Hold* until ≤Grade 2.   
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >72 hours should go off protocol therapy. 
Recommended management: Physician discretion 
 
Event Name 
Hepatic damage 
Grade of Event 
Management/Next Dose of CYT107 
≤ Grade 1 
No change in dosing schedule 
Grade 2 
No change in dosing schedule1 
Grade 3 
Off protocol therapy 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >72 hours should go off protocol therapy. 
Recommended management: Physician discretion  
 
Note: 1CYT107 will be discontinued if patients have a concurrent elevation of ALT >3 x upper 
limit of normal (ULN) and total bilirubin > 2 x ULN in whom there is no evidence of 
biliary obstruction or other causes that can reasonably explain the concurrent elevation.   
 
7. 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 7.1.2) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting (via CTEP-AERS) in addition to 
routine reporting.   
 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs): N/A  
 
7.1.1 CAEPRs for CTEP IND Agent(s): N/A 
 

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7.1.2 Adverse Event List for CYT107 
 
IL-7 Tabular summary of adverse drug reactions for all clinical trials (as of May 2012) 
(See Investigator Brochure) 
CYT107 
(N = 256) 
Events 
Grade 
Frequency 
Transient events observed whatever the dose 
  
  
Erythema or local reaction at site injection 
Grade <1, 1 and 2 
Frequent: approximately 2/3 
of patients, mostly less 
than Grade 1 or Grade 1 
Peripheral adenopathies next to the  
injection site  
Grade 1 
Grade 2 
Frequent, but transient 
Rare (1 case)  
Transient events observed dependent on the dose 
administered 
  
  
General reactions: 
Fever, Flu-like symptoms 
Grade 1 or 2 
Uncommon 
Rash 
Grade 1 or 2 
Grade 3 
Rare 
2 cases 
Fatigue (PT in MedDRA), reported as 
“Asthenia” by investigative team 
Grade 1 or 2 
Grade 3 
Uncommon 
Rare (1 case) 
Hepatic damage (cytolysis and/or  
cholestasis) ALT and/or AST elevation  
Grade 1 or 2 
Grade 3 
Grade 4 
Uncommon 
2 cases 
Rare (1 case) 
Peripheral lymphopenia 
Grade 1 or 2 
Grade 3 
Uncommon 
3 cases 
Anaphylactic Reaction 
Grade 3 
Uncommon 
Other events 
 
 
Chest pressure 
Grade 2 
Rare (1 case) 
Immunogenicity 
Non applicable 
Frequent: about 25% 
Isolated transient HIV RNA VL “blips” (in patients 
Known to be HIV positive) 
Mostly Grade 1 
Uncommon (31 events/590 
measurements or 0.05%) 
Phlebitis 
Grade 3 
Rare (1 case) 
Henoch-Schoenlein Purpura  
Grade 2 
Rare (1 case) 
Lichen Planus 
Grade 3 
Rare (1 case) 
 
7.1.3 Adverse Event List(s) for Commercial Agent(s): N/A 
 
7.1.4 Adverse Event List(s) for CIP (e.g. Study-Specific) Commercial Imaging Agents: N/A 
 
7.2 
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.  A copy of the CTCAE 

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version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
 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. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (http://ctep.cancer.gov).  The 
reporting procedures to be followed are presented in the “NCI Guidelines for 
Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and 
DCP INDs and IDEs” which can be downloaded from the CTEP Web site 
(http://ctep.cancer.gov).  These requirements are briefly outlined in the tables below 
(Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 
provided. 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” 
under the system organ class (SOC) of the same name.  Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with a disease process) should be 
submitted.  

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Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions: N/A 
 
7.3.5   Serious Adverse Event Reporting to the Industry Partners 
 
The Sponsor will provide the industry partners with SAE Reports that are sent to the 
FDA. All SAE reports will include the investigator’s assessment of causality.  
 

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7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
through CTEP-AERS must also be reported in routine study data submissions. 
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe 
the event:  
 
 Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
 Myelodysplastic syndrome (MDS)  
 Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified.  
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 8.1. 
 
8.1 
CTEP IND Agent(s): N/A 
 
8.2 
Other Investigational Agent 
 
Recombinant Glycosylated Human Interleukin-7, (CYT107) rhIL-7  
 
Product description:  
Interleukin-7 (IL-7) is a multifunctional cytokine, mainly produced by non-hematopoietic 
cells, which is active on T cell development, expansion, response and protection from 
apoptosis. IL-7 has a critical and, at some steps, a non-redundant stimulating effect on T 
lymphocyte development, notably on thymopoiesis and downstream from the thymus, on 
homeostasis expansion of peripheral T cells. 
 

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CYT107, developed by Cytheris SA and owned by RevImmune, Inc., is a glycosylated 
recombinant human IL-7 produced from a recombinant Chinese Hamster Ovary (CHO) cell 
line (CHO S). 
 
Chemical Name or Amino Acid Sequence: 
CYT107 (rhIL-7) Drug Substance is a glycosylated 152 amino acid recombinant protein 
(same as the native protein) which comprises three putative N-glycosylation sites and one 
putative O-glycosylation site. The composition of CYT107 includes a majority of rhIL-7 
polypeptides which are glycosylated on at least three distinct amino acid residues (2 to 3 N-
glycans and one O-glycan) and a minority of di-glycosylated rhIL-7 polypeptide (one N-
glycan and one O-glycan). CYT107 has 3 disulfide bridges: Cys2- Cys 92, Cys 34- Cys 129, 
and Cys 47- Cys 141.  
 
Molecular Weight:  
CYT107 has an average molecular mass, as determined by mass spectrometry, of 22kDa; 
corresponding to an average apparent molecular weight of 27kDa as determined by SDS gel 
electrophoresis. 
 
Solution preparation: 
CYT107 (rhIL-7) Drug Product is supplied in 2 cc vials as a colorless solution suitable for 
subcutaneous administration, formulated at a concentration of 2 mg/ml in the following 
buffer: 10mM sodium acetate, 100 mM NaCl, 50mM glutamic acid, and 50mM arginine. The 
pH of the solution is in the range of 4.8 and 5.2. Vials are filled to deliver 1 mg/0.5 mL of 
CYT107.  
 
Storage requirements:   
CYT107 should be stored at -20°C. Store vials of CYT107 according to instructions on the 
label.  
 
Stability:  
Stability studies are ongoing and will be continued throughout the clinical study. Regular 
updates are submitted to the FDA through quality amendments. Stability information will be 
periodically communicated to the Hospital Pharmacy, to guarantee the stability of the drug 
product. The vial is for 1 injection only and any unused portion should not be re-used for a 
subject or for other purpose.  
 
Consideration for safe handling and administration:  
There are no specific guidelines for the safe handling of CYT107 Drug Product. Institutional 
guidelines for safe handling of proteins in general should be followed.  
 
Do not shake vials before injection.  
 
CYT107 should be administered slowly and strictly in the subcutaneous space. 
 
Route of administration:   
CYT107 will be administered subcutaneously, which according to studies in monkeys, yields 
satisfactory bioavailability (> 75%), with an extended kinetic profile that may favor 

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prolonged IL-7 activity.  
 
Dose adjustment: 
The appropriate quantity of CYT107 to be given at each injection will depend on the 
patient’s weight and dose level. For obese patients, a corrected weight will be used to 
calculate the final dose the patient will receive. Carefully check dose and dosing regimens 
before CYT107 administration (See Appendix D).  
 
Agent Ordering and Agent Accountability:  
CYT107 is produced in the USA by Laureate Biopharmaceuticals now operating as 
Patheon®. After manufacturing, the product is stored at CSM in Fargo, ND for clinical 
supply, packaging, and labeling. The label indicates the product name, strength, 
manufacturing date, and the study requirement information. CYT107 will be shipped from 
CSM to each participating site. (See the Study Procedures Manual for instructions on how to 
order CYT107). 
 
Agent Inventory Records: 
The investigator, or a responsible party designated by the investigator (e.g. institutional 
investigational pharmacy), must maintain a careful record of the inventory and disposition of 
all agents received from CSM in Fargo, ND using the Study Agent Drug Accountability 
Record. (See the Study Procedures Manual for the form to use and instructions on how to 
complete it).  
 
8.3 
Commercial Agent: N/A 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Studies 
 
The major focus will be to determine the relative level and persistence of vaccine induced 
immune response to PA2024 and PAP in patients receiving sipuleucel-T with and without 
CYT107. 
9.2 
Laboratory Correlative Studies 
 
9.2.1 T-cell interferon-gamma responses to PA2024 – Laboratory Correlative Study #1 
 
The primary endpoint will be the T-cell response to PA2024 measured at day 70 (week 
11), 7 weeks after last CYT107 injection. T-cell responses to PA2024 and PAP will be 
measured by a direct 48 hour interferon-gamma ELISPOT assay utilizing recombinant 
proteins PA2024 and PAP (provided by Dendreon Corp.). Cellular immune responses to 
other ongoing and nascent antitumor responses (PRAME, NY-ESO-1 and/or p53), 
additional tumor antigens specific to prostate cancer (e.g., PSA and/or PSMA), and 
memory viral responses (influenza A, CEF) will also be assessed. Longitudinal responses 
to PA2024 and PAP will be considered in the primary analysis; however power 
calculations are based on the magnitude of T cell ELISPOT responses measured at week 
11. 
 

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9.2.1.1     Collection of Specimen(s): Whole blood will be collected into heparinized (green top)  
tubes. 
 
9.2.1.2 
Handling of Specimens(s): Samples will be collected at room temperature and 
shipped to the CITN Central Laboratory the same day as the blood draw, so that the 
sample is received at the central laboratory within 24 hours of blood draw. PBMC 
will be isolated and cryopreserved prior to testing.  
 
9.2.1.3 
Shipping of Specimen(s): Samples will be shipped at ambient temperature for 
overnight FEDEX delivery. Clinical research sites will utilize a web-based specimen 
tracking system (BSI-II) to communicate with the CITN Central Laboratory.  
 
9.2.1.4 
Site(s) Performing Correlative Study: The interferon-gamma ELISPOT assay will be 
conducted at the CITN Central Laboratory at the University of Washington (UW) 
Immunologic Monitoring Laboratory (IML), Seattle, WA.  
 
 
9.2.2 T-cell proliferative responses – Laboratory Correlative Study #2 
 
 
Peripheral blood lymphocytes will be analyzed directly ex vivo for the presence of 
proliferating T cells using a flow cytometric Ki-67 assay. Other surface markers will 
include CD3, CD4, CD8, CD45RA and CCR7 (among others) to identify T cell memory 
subsets. In addition, T cell proliferative responses to protein antigens PA2024 and PAP 
(from Dendreon Corp.) will also be tested in vitro. Results from this latter assay should 
corroborate the antigen-specific data obtained from Correlative Study #1.  Longitudinal 
responses to PA2024 and PAP will also be evaluated. Cellular immune responses to other 
ongoing and nascent antitumor responses (PRAME, NY-ESO-1 and p53), additional 
tumor antigens specific to prostate cancer (e.g., PSA and PSMA), memory viral 
responses (influenza A and CEF) may also be tested.  
 
9.2.2.1 
Collection of Specimen(s): Whole blood will be collected into heparinized tubes.  
 
9.2.2.2 
Handling of Specimen(s): Samples will be collected at room temperature and shipped 
to the CITN Central Laboratory the same day as the blood draw, so that the sample is 
received at the central laboratory within 24 hours of blood draw. PBMC will be 
isolated and cryopreserved prior to testing.  
 
9.2.2.3 
Shipping of Specimen(s): Samples will be shipped at ambient temperature for 
overnight FEDEX delivery. Clinical research sites will utilize a web-based specimen 
tracking system (BSI-II) to communicate with the CITN Central Laboratory.  
 
9.2.2.4 
Site(s) Performing Correlative Study: The proliferation assays will be conducted at 
the CITN Central Laboratory at the University of Washington Immunologic 
Monitoring Laboratory, Seattle, WA.  
 
 

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9.2.3 Quantification of PBMC and T cell subsets – Laboratory Correlative Study #3 
 
The effect on the number and percentage of PBMC subsets and T lymphocyte subsets 
(i.e., CD4+ and CD8+ T cell naïve, effector memory, and central memory subsets, CD4+ 
Treg and activated CD4+ and CD8+ T cells) will be assessed using multiparameter flow 
cytometric analysis of whole blood. The PBMC immunophenotyping assay will quantify 
the absolute number and proportion of T cells (both CD8+ and CD4+), NK cells 
(CD56+CD3-), NKT cells (CD56+CD3+), B cells (CD19+), monocytes (CD16+), 
dendritic cells (HLA-DR+ CD123+ or CD11c+), and CD122 (IL15R-beta)-expressing 
cells.  
An additional panel will quantify the absolute number and proportion of memory and 
naïve T cell subsets using antibodies to CD45RA, CCR7, CD28, of regulatory T cells 
using antibody to CD25 (IL2R-alpha), the activation state of T cells using antibodies to 
PD-1, ICOS, and HLA-DR, among others and CD-127 (IL7R-alpha). The absolute 
change in each parameter as well as variance in change over time for each patient (mean, 
median, and SE/SD) will be evaluated. 
 
9.2.3.1 
Collection of Specimen(s): Whole blood will be collected into heparinized tubes.  
 
9.2.3.2 
Handling of Specimen(s): Samples will be collected at room temperature and shipped 
to the CITN Central Laboratory the same day as the blood draw, so that the sample is 
received at the Central Laboratory within 24 hours of blood draw.   
 
9.2.3.3 
Shipping of Specimen(s): Samples will be shipped at ambient temperature for 
overnight FEDEX delivery. Clinical research sites will utilize a web-based specimen 
tracking system (BSI-II) to communicate with the CITN Central Laboratory.  
 
9.2.3.4 
Site(s) Performing Correlative Study: The immunophenotyping assays will be 
conducted at the CITN Central Laboratory at the University of Washington 
Immunologic Monitoring Laboratory, Seattle, WA.  
 
 
9.2.4 PA2024 and PAP-specific Antibody Responses – Laboratory Correlative Study #4 
 
IgM and IgG responses to PAP and PA2024 will be quantified using standard ELISA. 
The level of antibody responses to these antigens will be compared between the groups. 
The absolute change in each parameter as well as variance in change over time for each 
patient (mean, median, and SE/SD) will also be evaluated. 
 
9.2.4.1 
Collection of Specimen(s): Whole blood will be collected into red top (serum) tubes. 
 
9.2.4.2 
Handling of Specimen(s): Samples will be centrifuged, and serum aliquoted at each 
collection site within 2-4 hours of blood draw. Samples will be frozen at -80C and 
stored for batch shipment to the CITN Central Laboratory. 
 

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9.2.4.3 
Shipping of Specimen(s): Batched samples will be shipped on dry ice for overnight 
FEDEX delivery. Clinical research sites will utilize a web-based specimen tracking 
system (BSI-II) to communicate with the CITN Central Laboratory. The Central 
Laboratory will ship coded, batched specimens to Dendreon Corp. for testing. 
 
9.2.4.4 
Site(s) Performing Correlative Study: The ELISA assays will be conducted at 
Dendreon Corp., Seattle, WA.  
 
 
9.2.5 T-cell receptor rearrangement DNA excision circles (TRECs) – Laboratory Correlative 
Study #5 
 
Thymic function will be assessed by measuring serum levels of T-cell receptor 
rearrangement DNA excision circles (TRECs), in order to determine the contribution of 
new thymic emigrants to the T cell receptor repertoire. TREC levels will be compared 
between the two arms. The absolute change in each parameter as well as variance in 
change over time for each patient (mean, median, and SE/SD) will be evaluated.  
 
9.2.5.1 
Collection of Specimen(s): Whole blood will be collected into red top (serum) tubes.  
 
9.2.5.2 
Handling of Specimen(s): Samples will be centrifuged, and serum aliquoted at each 
collection site within 2-4 hours of blood draw. Samples will be frozen at -80C and 
stored for batch shipment to the CITN Central Laboratory.  
 
9.2.5.3 
Shipping of Specimen(s): Batched samples will be shipped on dry ice for overnight 
FEDEX delivery. Clinical research sites will utilize a web-based specimen tracking 
system (BSI-II) to communicate with the CITN Central Laboratory.  
 
9.2.5.4 
Site(s) Performing Correlative Study: The TREC assays will be conducted at the 
laboratory of Dr. Bruce Blazar, CITN site at the University of Minnesota.  
 
 
9.2.6 T-cell receptor deep sequencing – Laboratory Correlative Study #6 
 
The T-cell repertoire will be characterized by T-cell receptor (TCR) deep sequencing 
(Harlan Robins, PhD, with Adaptive Biotechnologies, Seattle, WA) and compared 
between the two arms. These assays will evaluate the extent to which polyclonal or 
oligoclonal expansion of T cells has occurred with CYT107 therapy.  
 
9.2.6.1 
Collection of Specimen(s): Whole blood will be collected into ACD tubes.  
 
9.2.6.2 
Handling of Specimen(s): Samples will be collected at room temperature and shipped 
to the CITN Central Laboratory the same day as the blood draw, so that the sample is 
received at the Central Laboratory within 24 hours of blood draw. PBMC will be 
isolated and cryopreserved prior to isolation of genomic DNA.  
 

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9.2.6.3 
Shipping of Specimen(s): Samples will be shipped at ambient temperature for 
overnight FEDEX delivery. Clinical research sites will utilize a web-based specimen 
tracking system (BSI-II) to communicate with the CITN Central Laboratory. 
Processed samples will be batch-shipped by the Central Laboratory to Adaptive 
Biotechnologies for testing. 
 
9.2.6.4 
Site(s) Performing Correlative Study: The TCR deep sequencing assay will be 
conducted at the Adaptive Biotechnologies, Seattle, WA.  
 
 
9.2.7 Peripheral Blood Kyn/Trp Ratios – Laboratory Correlative Study #7 
 
 
Kyn/Trp ratios will be assayed in peripheral blood at baseline and at specified intervals 
throughout the trial. IDO catabolizes the conversion of Tryptophan to Kynurenine, which 
has potent immunosuppressant properties. An increase in Kynurenine levels over time, 
relative to Tryptophan levels, in patients who are failing therapy would indicate that IDO 
expression may be leading to treatment failure. This mechanism of resistance could 
potentially be overcome with an IDO inhibitor.  
9.2.7.1 
Collection of Specimen(s): Whole blood will be collected into heparinized tubes. 
 
9.2.7.2 
Handling of Specimen(s): Samples will be collected at room temperature and shipped 
to the CITN Central Laboratory the same day as the blood draw, so that the sample is 
received at the Central Laboratory within 24 hours of blood draw.   
 
9.2.7.3 
Shipping of Specimen(s): Samples will be shipped at ambient temperature for 
overnight FEDEX delivery. Clinical research sites will utilize a web-based specimen 
tracking system (BSI-II) to communicate with the CITN Central Laboratory. The 
Central Laboratory will subsequently ship batched plasma samples to the assay site. 
 
9.2.7.4 
Site(s) Performing Correlative Study:  
 
The Kyn/Trp analysis will be conducted at Incyte Corporation, Wilmington, 
Delaware. 
 
 
9.3 
Special Studies: Immunogenicity Testing  
 
The formation of anti-drug antibodies (ADA) and neutralizing anti-drug antibodies (NADA) 
to glyco-rhIL-7 (CYT107) will be evaluated at: Pre-treatment with IL-7 (CYT107), and 
Week 11 (Day 70). If positive at Week 11 (Day 70), immunogenicity testing will be repeated 
at the end of the study. 
 
9.3.1 Collection of specimen(s):  Whole blood will be collected into a Lithium Heparin tube. 
Samples will be centrifuged within 15 minutes and the plasma aliquoted into at least two 
vials. Please refer to the CITN-12-03 Laboratory Manual. 
 

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37 
9.3.2 Handling of specimen(s):  Plasma will be frozen at -80C and stored until shipped to the 
CITN Central Laboratory, Seattle, WA.  
 
9.3.3 Shipping of Specimen(s): Samples will be packed on dry ice and shipped for overnight 
FEDEX delivery to the CITN Central Laboratory, Seattle, WA.  
 
9.3.4 Site(s) Performing Immunogenicity Testing: RevImmune, Inc., Bethesda, Maryland will 
perform both ELISA Binding (non-neutralizing) and neutralizing antibody assays 
according to their Standard Operating Procedure.  
 
 
9.4 
Sample Storage 
 
 
PBMC, serum, and plasma that remain after conducting the above-described correlative 
assays will be saved for future ancillary studies (e.g. soluble IL-7 receptor levels). Residual 
cell pellets from whole blood processing (that would otherwise be discarded) will be stored 
for the possibility of isolating genomic DNA and conducting IL-7 receptor polymorphism 
analyses, should funding become available.

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10. 
STUDY CALENDAR 
Baseline evaluations are to be conducted following the last dose of sipuleucel-T, but prior to the first CYT107 injection. In the event 
that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next 
CYT107 administration.  
 
Pre-study 
Pre-IL7 
Week 
 1 
 
Week 
 2  
*(f) 
Week 
 3 
 
Week 
4  
*(f) 
Week  
6 
Week 
 11 
Week 
 23 
 
Week  
53 
 
Off Study 
*(d) 
 
 
Within 7 days of 
receiving CYT107 
Day 0 
Day 7 
± 2 days 
Day 14 
± 2 days 
Day 21 
± 2 days 
 
Day 35 
± 2 days 
Day 70 
± 7 days 
Day 154  
±14 days 
Day 365  
±14 days  
 
CYT107 *(A) 
 
 
X 
X 
X 
X 
 
 
 
 
 
Sipuleucel-T (Provenge®) *(B) 
Standard 
Sip-T  
X 
 
 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
 
X 
X*(e) 
X*(e) 
X*(e) 
X*(e) 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistry *(a) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Anti-nuclear antibody (ANA) 
 
X 
 
 
 
 
 
 
 
 
X 
CYT107 immunogenicity 
(ADA) assay *(b) 
 
X 
 
 
 
 
 
X 
 
X 
 
Adverse event evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor measurements 
 
Within 45 days 
 
Tumor measurements are repeated every 12 weeks. Documentation (radiologic) 
must be provided for patients removed from study for progressive disease. 
X 
CT, MRI or PET of chest, 
abdomen, pelvis *(c) 
 
Within 45 days 
 
Documentation (radiologic) must be provided for patients removed from study for 
progressive disease. 
X 

NCI Protocol #: CITN12-03 
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39 
 
Pre-study 
Pre-IL7 
Week 
 1 
 
Week 
 2  
*(f) 
Week 
 3 
 
Week 
4  
*(f) 
Week  
6 
Week 
 11 
Week 
 23 
 
Week  
53 
 
Off Study 
*(d) 
 
 
Within 7 days of 
receiving CYT107 
Day 0 
Day 7 
± 2 days 
Day 14 
± 2 days 
Day 21 
± 2 days 
 
Day 35 
± 2 days 
Day 70 
± 7 days 
Day 154  
±14 days 
Day 365  
±14 days  
 
CT or MRI Brain (as indicated) 
*(c)  
 
 
 
Documentation (radiologic) must be provided for patients with symptoms 
X 
Bone scan *(c) 
 
Within 45 days 
 
Radiologic measurements should be performed every 12 weeks 
X 
EBV serostatus 
 
X 
 
 
 
 
 
 
 
 
X 
CMV serostatus 
 
X 
 
 
 
 
 
 
 
 
X 
PSA measurement 
 
 
X 
 
 
 
X 
X  
X 
X  
 
CTC 
 
 
X 
 
 
 
 
 
 
X  
 
IFNg ELISPOT 
 
 
X 
 
 
 
X  
X 
X  
X  
 
Proliferation assay 
 
 
X 
 
 
 
X 
X 
X  
X  
 
PBMC and T cell subset 
quantitation 
 
 
X 
 
 
 
X  
X  
X  
X 
 
PAP Ab, PA2024 ELISA 
 
 
X 
 
 
 
X 
X  
X  
X   
 
TREC detection 
 
 
X 
 
 
 
X  
X  
X  
 
 
TCR deep sequencing 
 
 
X 
 
 
 
X  
 
 
 
 
Kyn/Trp ratio 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
*(A): CYT107; Dose as assigned; administration schedule. 
*(B): Sipuleucel-T (Provenge®); Dose as assigned; administration schedule. Standard Provenge® therapy (3 vaccinations) required prior to study entry. 
*(a): Serum chemistries include: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium. 
*(b):    CYT107 ADA testing will be repeated if positive at week 11 (Day 70 ± 7 days). Frozen plasma is required.   
*(c): CT, MRI or PET within 45 days (14 days preferred) is acceptable for imaging assessment purposes 
*(d):    Off-study evaluation  
*(e):    Vital signs will be repeated every 2 hours during the 4 hours observation period required after each injection of CYT107 (cohort 2 only). 
*(f):     Optional study visit for patients assigned to observation (cohort 1) 
 

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40 
11. 
MEASUREMENT OF EFFECT 
 
The primary endpoint for sizing the trial will be quantification of T-cell responses to PA2024 measured 
at day 70 (week 11), 7 weeks after the last CYT107 injection. Assessment of the primary endpoint is 
described in Sections 2.5 and 9.2.  
 
One secondary endpoint is an assessment of the clinical efficacy of sipuleucel-T plus CYT107 
compared to sipuleucel-T alone. To assess clinical efficacy the protocol will assess differences in (1) 
overall survival, (2) PSA kinetics (3) progression free survival and, (4) circulating tumor cells (CTC). 
 
11.1 Overall Survival 
 
Sipuleucel-T was approved by the FDA in men who have mCRPC with no or minimal symptoms 
due to a prolongation of median overall survival by 4.1 months compared with results in those 
treated with placebo. The protocol is not powered to discern modest effects on overall survival. 
However, data on overall survival will be collected and analyzed. Patients will not be formally 
followed on protocol after week 53; however, data on OS will be collected and reported. 
 
11.2 
PSA Kinetics 
 
In the pivotal trials, sipuleucel-T induced no substantial differences in PSA reductions. However, 
the rate of the PSA increase was slower in patients who received the vaccine in another double-
blind, randomized, placebo-controlled study (P-11) of 176 men with rising PSA after prostatectomy 
receiving hormonal therapy followed by vaccine or control [Beer, 2007]. The PSADT was 
calculated from day 90 after vaccine to biochemical recurrence.   
 
Patients will have PSA measurements on weeks 1, 6, 11, 23, and 53. The presumption is that 
immune response will not have immediate effects but will require a period of time to induce an 
effect on PSADT, if it occurs. Thus, for trial analysis PSADT will arbitrarily be calculated from 
week 11 to week 23, and 53 or until new therapeutic intervention is initiated, whichever comes first. 
The PSADT will be evaluated according to the recommendations from PSA Working Group 
(PSAWG) [Arlen, 2008].  
 
11.3 
Progression free survival 
 
There was no discernable prolongation of progression free survival in the pivotal trial.  However, if 
the addition of CYT107 substantially increases the immune response to PAP, it is possible that 
differences in progression free survival will be observed.  
 
PFS is defined as the duration of time from start of treatment to time of radiographic progression or 
death, whichever occurs first. PFS will consider both measurable disease and unmeasurable bony 
metastasis. Measurable disease will be measured by RECIST 1.1 criteria [Eisenhauer, 2009]. 
Unmeasurable bony metastasis will be measured by radiographic criteria [Scher, 2008]. PFS is not 
the primary endpoint. Thus, responses will not pro forma be reviewed by an expert(s) independent 
of the study at the study’s completion.   

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41 
11.4 
Circulating Tumor Cells 
 
Circulating tumor cells (CTC) will be enumerated by the approved Veridex assay as exploratory 
analysis. 
 
11.5 
Measurement of Disease 
 
For the purposes of this study, baseline scans must be done within 45 days prior to beginning 
treatment (14 days preferred). Scans can be done before or after sipuleucel-T given that sipuleucel-
T is not likely to have induced remissions. In addition to the patient’s baseline scan, tumor 
measurements are repeated every 12 weeks post therapy or per institutional standard of care.  
 
Response and progression for purpose of reporting data and publication will be evaluated in this 
study using the new international criteria proposed by the revised Response Evaluation Criteria in 
Solid Tumors (RECIST) guideline (version 1.1) [Eisenhauer, 2009]. 
 
Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray or as >10 mm with 
CT scan, MRI, or calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and 
followed. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurability described 
above. However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 

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42 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest 
lesion does not lend itself to reproducible measurement in which circumstance the next largest 
lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for 
non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis 
is added into the sum. The baseline sum diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the disease. 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over and 
above the 5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
11.5.1 Methods 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 within 7 days from the beginning of treatment. 
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 unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers (e.g., skin 
nodules). In the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 

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43 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be guaranteed 
that the same technique and measurements will be taken from one assessment to the next. If new 
lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in 
selected instances. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete response 
(CR) or surgical resection is an endpoint. 
Tumor markers: PSA 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.   
 
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. 
 
FDG-PET: FDG-PET usually not used in prostate cancer.  However, rarely it might be reasonable 
to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on 
a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-
PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT  scans 
are needed to determine if there is truly progression occurring at that site (if so, the date of PD will 
be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up 

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44 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported by 
disease-specific medical literature for the indication. However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.5.2 Response Criteria: Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 
mm. 
Partial Response (PR): 
   At least a 30% decrease in the sum of the diameters of target    lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. (Note:  the appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD):  
 Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.6 
Radiologic Progression-Free Survival of Bony Metastasis 
 
Radiographic progression-free survival is based on parameters suggested by Prostate Cancer 
Working Group 2 [Scher, 2008].  A patient is considered to have progressed by bone scan if one of 
the following occurs after randomization: 
 
11.6.1 The first bone scan with ≥2 new lesions compared to baseline is observed <12 weeks from 
randomization and is confirmed by a second bone scan taken ≥6 weeks later showing ≥2 
additional new lesions (a total of ≥4 new lesions compared to baseline). 
 
11.6.2 The first bone scan with ≥2 new lesions compared to baseline is observed ≥12 weeks from 
randomization and the new lesions are verified on the next bone scan ≥6 weeks later (a total of 
≥2 new lesions compared to baseline).  
 

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11.7 
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.  
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesion
s 
Non-Target 
Lesions 
New 
Lesio
ns 
Overall 
Resp
onse 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript [16] for further details on what is evidence of a new 
lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 

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46 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 (Adverse 
Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
Data collection for this study will be done exclusively through Medidata Rave. Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
Rave roles in the CTSU Regulatory Support System (RSS). To access iMedidata/Rave the site 
user must have an active CTEP IAM account (https://eapps-ctep.nci.nih.gov/iam). In addition, 
site users that are members of the CITN must have the appropriate Rave roles (Rave CRA, Site 
PI, or Site co-PI) in RSS at the enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the CITN roster will be sent a study invitation e-mail from iMedidata. To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right corner of the iMedidata page. Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen. 
 
Users who have not previously activated their iMedidata/Rave accounts at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU website 
under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-
823-5923 or by e-mail at ctsucontact@westat.com. 
 
 

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47 
12.1.2 Responsibility for Data Submission 
 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis, either by FTP burst of data or via the CDS web application. This is the 
responsibility of the CITN COSC (Central Operating and Statistical Center). Reports are due 
January 31, April 30, July 31, and October 31.  Instructions for submitting data using the CDUS 
can be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 
 
 
The Coordinating Center is responsible for compiling and submitting CDUS data to CTEP for 
all participants and for providing the data to the Principal Investigator for review.   
 
When setting the dates, allow time for Coordinating Center compilation, Principal Investigator 
review, and timely submission to CTEP by the quarterly deadlines (see Section 13.1.1).   
12.2 
CTEP Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center and the 
procedures for auditing are presented in Appendix B. 
 The Coordinating Center is responsible for distributing all IND Action Letters or Safety Reports 
received from CTEP to all participating institutions for submission to their individual IRBs for 
action as required. 
 
12.3 
Collaborative Agreements Language: N/A 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
 Study Design/Endpoints 
 
The proposed clinical trial is a phase II, open-label, multicenter, randomized study of the 
administration of CYT107 after the completion of standard FDA-approved therapy with sipuleucel-
T for patients with asymptomatic or minimally symptomatic mCRPC. Patients who have completed 
a standard course of sipuleucel-T will be randomly assigned to either observation or 10 μg/kg of 
subcutaneous CYT107 every week for 4 doses beginning 3 to 7 days after completing sipuleucel-T 
therapy. Day 0 is the day of the first injection of CYT107.  
The first six patients randomly assigned to receive CYT107 will be followed for an additional 4 
weeks prior to the study expanding past six patients, as a lead-in phase to ensure safety and 
tolerability of the selected CYT107 dose. 
 
Treatment Schema 
Cohort 
CYT107 Dose 
Frequency 
1 - Observation 
No CYT107 dose 
-------- 
2 - CYT107  
10 μg/kg 
Days 0, 7, 14 and 21 

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48 
IL-7 is expected to increase the peak and the persistence of the immune response.  The persistence 
might be the most important for effective immunotherapy, i.e. increasing the “area under the 
curve”.  Thus, the primary endpoint for sizing the trial will be quantification of T-cell responses to 
PA2024 measured at day 70 (week 11), 7 weeks after the last CYT107 injection.  
 
T cell responses will be measured by interferon-gamma ELISPOT as the most quantifiably and 
reproducible assay. In the IMPACT study, 2 weeks after last sipuleucel-T administration, the 
background-subtracted mean PA2024 ELISPOT was 40 SFC/ 3x105 PBMC with a standard 
deviation of 69 based on n = 63. At 10 weeks after the last administration the background-
subtracted mean PA2024 ELISPOT was 23 SFC/ 3x105  
PBMC with a standard deviation of 36 based on n = 42. Participant leukapheresis samples from pre-
and post-Provenge® vaccine will be used when possible to allow planned a more comprehensive 
evaluation of longitudinal vaccine responses.  
 
Primary Endpoint: 
With 38 patients per group with evaluable data (40 patients per group, assuming 5% missing 
immunogenicity data), there is 80% power to detect a difference between a mean of 47 in the 
sipuleucel-T plus CYT107 group and a mean of 23 in the sipuleucel-T alone group, assuming the 
same standard deviation of 36 in both groups. This calculation is based on a two-sided t-test with a 
significance level of 0.05. The presumption is that the effect of CYT107 will be positive on all of 
the immune parameters and that the effect on each assay will track with positive effects on the other 
immune assays such that there should be similar power to detect differences in the other endpoints. 
These, however, are not considered primary endpoints, and hence no multiplicity adjustment will be 
made. The Mann-Whitney-Wilcoxon (MWW) Test will be used as part of the statistical analysis; 
the power is roughly equivalent to that based on the t-test. The effect of CYT107 will also be 
positive on clinical activity, but the results are likely to be more variable. 
 
13.2 
Sample Size/Accrual Rate 
 
80 patients total will be enrolled in this study, 6-8 patients per month accrual total at approximately 
12 CITN sites.  Patients without adequate sampling for immune responses will be replaced.  
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
 
Males 
 
Total 
Hispanic or Latino 
+ 
15 
= 
15 
Not Hispanic or Latino 
+ 
65 
= 
65 
Ethnic Category: Total of all 
subjects 
+ 
80 
(B1) 
= 
80 
(C1) 
Racial Category 
American Indian or Alaskan Native 
+ 
12 
= 
12 
Asian 
+ 
 8 
= 
 8 
Black or African American 
+ 
31 
= 
31 
Native Hawaiian or other Pacific 
Islander 
+ 
 8 
= 
 8 
White 
+ 
21 
= 
21 
Racial Category: Total of all 
subjects 
+ 
80 
(B2) 
= 
80 
(C2) 

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49 
13.3 
Stratification Factors 
 
Patients will be stratified for prior abiraterone or neo-adjuvant chemotherapy with or without 
abiraterone in order to balance arms.   
 
13.4 
Analysis of Secondary Endpoints 
 
1. To determine whether CYT107 administration increases the vaccine-induced antigen-specific T-
cell immune response to PAP 
The effect on antigen-specific T-cell immune responses to PAP will be measured using the 
same assays and time points as for the primary endpoint, PA2024. 
 
2. To assess the character of the T-cell immune response to PAP and PA2024  
The effect on the number and percentage of PBMC subsets and T lymphocyte subsets (i.e., 
CD4+ and CD8+ T cell naïve, effector memory, and central memory subsets, CD4+ Treg and 
activated CD4+ and CD8+ T cells) will be assessed using multiparameter flow cytometric 
analysis of whole blood. The PBMC immunophenotyping assay will quantify the absolute 
number and proportion of T cells (both CD8+ and CD4+), NK cells (CD56+CD3-), NKT cells 
(CD56+CD3+), B cells (CD19+), monocytes (CD16+), dendritic cells (HLA-DR+ CD123+ or 
CD11c+), and CD122 (IL15R-beta)-expressing cells.  
An additional panel will quantify the absolute number and proportion of memory and naïve T 
cell subsets using antibodies to CD45RA, CCR7 and CD28 of regulatory T cells using 
antibodies to CD127 and CD25, and the activation state of T cells using antibodies to PD-1, 
ICOS, and HLA-DR, among others. The absolute change in each parameter as well as variance 
in change over time for each patient (mean, median, and SE/SD) will be evaluated. 
 
3. To determine whether CYT107 administration increases the vaccine-induced antigen-specific 
antibody immune responses to PAP and PA2024 
IgM and IgG response to PAP and PA2024 will be measured by standard ELISA. 
 
4. To quantify the effects of CYT107  on T-cell diversity  
The T-cell repertoire will be characterized by T-cell receptor (TCR) deep sequencing and the 
analysis will be done with the Immunoseq Analyzer software (Harlan Robins, PhD, with 
Adaptive Biotechnologies, Seattle). 
 
5. To assess the effects of CYT107 on the immune competence of patients with advanced prostate 
cancer 
Bystander antigen specific immune responses will be assessed to other ongoing and nascent 
antitumor responses (e.g., PRAME, NY-ESO-1 and/or p53), additional tumor antigens specific 
to prostate cancer (e.g., PSA and/or PSMA), and memory viral responses (influenza A and 
CEF) using the IFNg ELISPOT assay.  
Thymic function will be assessed by measuring levels of T-cell receptor rearrangement DNA 
excision circles (TRECs). 
 

NCI Protocol #: CITN12-03 
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50 
6. To assess the clinical efficacy and tolerability of sipuleucel-T plus CYT107 compared with 
sipuleucel-T alone  
Adverse events will be graded and reported using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Clinical efficacy will be assess 
differences in (1) overall survival, (2) PSA kinetics (3) progression free survival and, (4) 
circulating tumor cells (CTC). Progression free survival will be assessed by RECIST criteria for 
measureable disease by bone scans and radiographic criteria for non-measurable bony 
metastasis.  
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with CYT107.  
 
13.5.2 Evaluation of Response 
 
All patients included in the study must 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).  [Note:  By arbitrary convention, 
category 9 usually designates the “unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  Patients 
in response categories 4-9 should be considered to have a treatment failure (disease progression).  
Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the 
analysis of the response rate.  Precise definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Sub analyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major protocol 
violations, etc.).  However, these sub analyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported.  The 95% confidence intervals should also be provided.  

NCI Protocol #: CITN12-03 
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51 
REFERENCES 
 
Arlen PM, Bianco F, Dahut WL, D’Amico A, Figg WD, Freedland SJ, Gulley JL, Kantoff PW, Kattan 
MW, Lee A, Regan MM, Sartor O. Prostate-Specific Antigen Working Group’s Guidelines on PSA 
Doubling Time. J. Urol. 2008 June; 179(6): 2181-2186.  
 
Beer TM, Bernstein GT, Corman JM, Glode LM, Hall S, Poll WL. Randomized trial of active cellular 
immunotherapy with sipuleucel-T in androgen dependent prostate cancer (ADPC) [abstract]. J Clin 
Oncol 25(June 20 Suppl), 5059 (2007). 
 
Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in 
metastatic prostate cancer before chemotherapy. N Engl J Med. 371:424-33 (2014). 
 
Beq S, Rozlan S, Gautier D, Parker R, Mersseman V, Schilte C, Assouline B, Rancé I, Lavedan P, 
Morre M, Cheynier R. Injection of glycosylated recombinant simian IL-7 provokes rapid and massive 
T-cell homing in rhesus macaques. Blood 114(4):816-25 (2009).  
 
Cheever MA, Higano CS. PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved 
therapeutic cancer vaccine. Clin Cancer Res 17, 3520-3527 (2011). 
 
Colombetti S, Levy F, Chapatte L. IL-7 adjuvant treatment enhances long-term tumor-antigen-specific 
CD8+ T-cell responses after immunization with recombinant lentivector. Blood 113, 6629–6637 (2009). 
 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
 
FDA.gov. [Homepage]. Clinical review—PROVENGE. Rockville, MD: US Food and Drug 
Administration Consumer Affairs Branch (CBER); 2010 [updated 2010 May 28; cited 2010 April]. 
Available from: http://www.fda.gov/BiologicsBloodVaccines/default.htm.  
 
Fong L, Weinberg VK, Chan SE, Corman JM, Amling CL, Stephenson RA, Formaker C, Simko J, 
Brownell Sims R, Carroll P, Small EJ. Neoadjuvant sipuleucel-T in localized prostate cancer: Effects 
on immune cells within the prostate tumor microenvironment. J Clin Oncol 30, 2012 (suppl; abstr 
2564) 
 
Fry TJ, Moniuszko M, Creekmore S, Donohue SJ, Douek DC, Giardina S, et al. IL-7 therapy 
dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates. 
Blood 101, 2294–2299 (2003).  
 
Kaech SM, Tan JT, Wherry EJ, Konieczny BT, Surh CD, Ahmed R. Selective expression of the 
interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nature 
Immunol 4, 1191–1198 (2003). 
 
Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T 
immunotherapy for castration-resistant prostate cancer. N Engl J Med 363,411–22 (2010).  
 
Levy Y, Lacabaratz C, Weiss L, Viard JP, Goujard C, Lelièvre JD, et al. Enhanced T cell recovery in 
HIV-1-infected adults through IL-7 treatment. J Clin Invest 119, 997–1007 (2009).  

NCI Protocol #: CITN12-03 
Version Date: July 26, 2017 
52 
Levy Y, Sereti I, Tambussi G, Routy JP, Lelievre JD, Delfraissy JF, Molina JM, Fischl M, Goujard C, 
Rodriguez B, Rouzioux C, Avettand-Fenoel V, Croughs T, Beq S, Morre M, Poulin JF, Sekaly RP, 
Thiebaut R, Lederman MM.  Effects of rhIL-7 on T Cell Recovery and Thymic Output in HIV-infected 
Patients receiving antiretroviral therapy: results of a Phase I/IIa Randomized, Placebo Controlled, 
Multicenter Study. Clin Infect Dis. 2012 May 1. [Epub ahead of print]   
 
Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates 
with FoxP3 and suppressive function of human CD4+ TReg cells. J Exp Med 203, 1701–1711 (2006).  
 
Mackall CL, Fry TJ, Bare C, Morgan P, Galbraith A, Gress RE. IL-7 increases both thymic-dependent 
and thymic-independent T-cell regeneration after bone marrow transplantation. Blood 97, 1491–1497 
(2001).  
 
Mackall Cl, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nature Rev 
Immunol 11, 330-342 (2011).  
 
Melchionda F, Fry TJ, Milliron MJ, McKirdy MA, Tagaya Y, Mackall CL. Adjuvant IL-7 or IL-15 
overcomes immunodominance and improves survival of the CD8+ memory cell pool. J Clin Invest 115, 
1177–1187 (2005).   
 
Morrissey PJ, Conlon P, Braddy S, Williams DE, Namen AE, Mochizuki DY. Administration of IL-7 
to mice with cyclophosphamide-induced lymphopenia accelerates lymphocyte repopulation. J Immunol 
146, 1547–1552 (1991).   
 
Nanjappa SG, Walent JH, Morre M, Suresh M. Effects of IL-7 on memory CD8 T cell homeostasis are 
influenced by the timing of therapy in mice. J Clin Invest 118, 1027–1039 (2008).  
 
Park JH, Yu Q, Erman B, Appelbaum JS, Montoya-Durango D, Grimes HL, et al. Suppression of IL-
7Rα transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-
dependent T cell survival. Immunity 21, 289–302 (2004).   
 
Pellegrini M, Calzascia T, Elford AR, Shahinian A, Lin AE, Dissanayake D, et al. Adjuvant IL-7 
antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nature 
Med 15, 528–536 (2009).   
 
Perales M-A, Goldberg JD, Lechner L, Koehne G, Yuan J, Papadopoulos E, Young J, Jakubowski A, 
Zaidi B, Gallardo H, Kendle R, Liu C, Rasalan T, Xu Y, Wolchok J, Croughs T, Morre M, Maloy M, 
Heller G, Van den Brink, M. Recombinant human interleukin-7 (CYT107) enhances T-cell recovery 
without causing graft-versus-host disease following T-cell depleted allogeneic haematopoietic stem cell 
transplantation. Oral Session 5: Immunotherapy/Immune reconstitution, Annual Meeting of the 
European Group for Blood and Marrow Transplantation, Paris, France (April 2011). 
 
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic 
prostate cancer without previous chemotherapy.  N Engl J Med. 368:138-48 (2013). 
 
Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, et al. Expression of 
interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J 
Exp Med 203, 1693–1700 (2006).  

NCI Protocol #: CITN12-03 
Version Date: July 26, 2017 
53 
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points of 
clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: 
recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008; 26:1148-
59.  
 
Sereti I, Dunham RM, Spritzler J, Aga E, Proschan MA, Medvik K, et al. IL-7 administration drives T 
cell-cycle entry and expansion in HIV-1 infection. Blood 113, 6304–6314 (2009).   
 
Sereti I, Estes J, Thompson W, Fischl M, Croughs T, Beq S, Yao M, Boulassel MR, Lederman MM, 
Routy J-P. Gut Mucosa T Lymphocyte Restoration in Chronically HIV-Infected Patients Treated with 
Recombinant Huma Interleukin-7 (rhIL-7). Conference on Retrovirus and Opportunistic Infections, 
Seattle, WA (March 2012). 
 
Sheikh NA, De La Rosa CP, Kuan L, Stewart FP, Frohlich MW, Urdal DL, et al. Sipuleucel-T 
treatment results in sequential ex vivo activation of APCs and T cells during the culture step—evidence 
for in vivo immunological priming [abstract]. In: Proceedings of the 101st Annual Meeting of the 
American Association for Cancer Research; 2010 Apr 17–21; Washington, DC. Philadelphia (PA): 
AACR Abstract nr. 5608 (2010).    
 
Sheikh NA, Petrylak D, De La Rosa CP, Stewart FP, Kuan LY, Whitmore JB, Trager JB, Poehlein CH, 
Frohlich MW, Urdal DL.  Sipuleucel-T immune parameters correlate with survival: an integrated 
analysis of randomized Phase 3 clinical trials in men with castrate-resistant prostate cancer (2012).  
 
Sportes C, Hakim FT, Memon SA, Zhang H, Chua KS, Brown MR, et al. Administration of rhIL-7 in 
humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J 
Exp Med 205, 1701–1714 (2008).   
 
Swainson L, Kinet S, Mongellaz C, Sourisseau M, Henriques T, Taylor N. IL-7-induced proliferation 
of recent thymic emigrants requires activation of the PI3K pathway. Blood 109, 1034–1042 (2007). 
 
Takada K, Jameson SC. Naive T cell homeostasis: from awareness of space to a sense of place. Nature 
Rev Immunol 9, 823–832 (2009). 
 
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or 
mitoxantrone plus prednisone for advanced prostate cancer.  N Engl J Med. 351:1502-12 (2004). 
 
 
 

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54 
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. 
 
 
 

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55 
APPENDIX B 
CTEP MULTICENTER GUIDELINES 
 
If an institution wishes to collaborate with other participating institutions in performing a CTEP 
sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
 The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office 
(PIO).  The Protocol Chair is responsible for the coordination, development, submission, and 
approval of the protocol as well as its subsequent amendments.  The protocol must not be 
rewritten or modified by anyone other than the Protocol Chair.  There will be only one version 
of the protocol, and each participating institution will use that document.  The Protocol Chair is 
responsible for assuring that all participating institutions are using the correct version of the 
protocol. 
 The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
 The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure safety 
of the patients. 
 The Protocol Chair will be responsible for the review of and timely submission of data for study 
analysis. 
 
Responsibilities of the Coordinating Center 
 Each participating institution will have an appropriate assurance on file with the Office for 
Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible for assuring 
that each participating institution has an OHRP assurance and must maintain copies of IRB 
approvals from each participating site.  
 Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
 The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each participating site 
prior to the first patient registration from that site. 
 The Coordinating Center is responsible for the preparation of all submitted data for review by 
the Protocol Chair. 
 The Coordinating Center will maintain documentation of AE reports.  There are two options for 
AE reporting: (1) participating institutions may report directly to CTEP with a copy to the 
Coordinating Center, or (2) participating institutions report to the Coordinating Center who in 
turn report to CTEP.  The Coordinating Center will submit AE reports to the Protocol Chair for 
timely review. 
 Audits may be accomplished in one of two ways:  (1) source documents and research records 
for selected patients are brought from participating sites to the Coordinating Center for audit, or 
(2) selected patient records may be audited on-site at participating sites.  If the NCI chooses to 
have an audit at the Coordinating Center, then the Coordinating Center is responsible for having 
all source documents, research records, all IRB approval documents, NCI Drug Accountability 
Record forms, patient registration lists, response assessments scans, x-rays, etc. available for the 
audit. 
 
 

NCI Protocol #: CITN12-03 
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56 
 
Inclusion of Multicenter Guidelines in the Protocol 
 The protocol must include the following minimum information:  
 The title page must include the name and address of each participating institution and the 
name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
 The Coordinating Center must be designated on the title page. 
 Central registration of patients is required.  The procedures for registration must be stated in 
the protocol. 
 Data collection forms should be of a common format.  Sample forms should be submitted 
with the protocol.  The frequency and timing of data submission forms to the Coordinating 
Center should be stated. 
 Describe how AEs will be reported from the participating institutions, either directly to 
CTEP or through the Coordinating Center. 
 Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
 
Agent Ordering 
 Except in very unusual circumstances, each participating institution will order DCTD-supplied 
investigational agents directly from CTEP.  Investigational agents may be ordered by a 
participating site only after the initial IRB approval for the site has been forwarded by the 
Coordinating Center to the CTEP PIO.  
 
 
 

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57 
APPENDIX C 
COCKCROFT-GAULT FORMULA FOR CALCULATED CREATININE 
CLEARANCE 
 
 
This formula expects weight to be measured in kilograms and creatinine to be measured in mg/dL, as is 
standard in the USA.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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58 
APPENDIX D 
DOSE ADJUSTMENT FOR OBESE PATIENTS 
 
Obesity is defined as a BMI > 30 (NHLBI Class 1 Obesity.)  
 
In order to determine the proper dose for patients classified as obese, an adjusted body weight is calculated.  The following steps are provided to assist 
with the process:  
BMI Chart 
BMI 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
35 
40 
Ht 
Wt (lbs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
4'10" 
91 
96 
100 
105 
110 
115 
119 
124 
129 
134 
138 
143 
167 
191 
4'11" 
94 
99 
104 
109 
114 
119 
124 
128 
133 
138 
143 
148 
173 
198 
5'0" 
97 
102 
107 
112 
118 
123 
128 
133 
138 
143 
148 
153 
179 
204 
5'1" 
100 
106 
111 
116 
122 
127 
132 
137 
143 
148 
153 
158 
185 
211 
5'2" 
104 
109 
115 
120 
126 
131 
136 
142 
147 
153 
158 
164 
191 
218 
5'3" 
107 
113 
118 
124 
130 
135 
141 
146 
152 
158 
163 
169 
197 
225 
5'4" 
110 
116 
122 
128 
134 
140 
145 
151 
157 
163 
169 
174 
204 
232 
5'5" 
114 
120 
126 
132 
138 
144 
150 
156 
162 
168 
174 
180 
210 
240 
5'6" 
118 
124 
130 
136 
142 
148 
155 
161 
167 
173 
179 
186 
216 
247 
5'7" 
121 
127 
134 
140 
146 
153 
159 
166 
172 
178 
185 
191 
223 
255 
5'8" 
125 
131 
138 
144 
151 
158 
164 
171 
177 
184 
190 
197 
230 
262 
5'9" 
128 
135 
142 
149 
155 
162 
169 
176 
182 
189 
196 
203 
236 
270 
5'10" 
132 
139 
146 
153 
160 
167 
174 
181 
188 
195 
202 
207 
243 
278 
5'11" 
136 
143 
150 
157 
165 
172 
179 
186 
193 
200 
208 
215 
250 
286 
6'0" 
140 
147 
154 
162 
169 
177 
184 
191 
199 
206 
213 
221 
258 
294 
6'1" 
144 
151 
159 
166 
174 
182 
189 
197 
204 
212 
219 
227 
265 
302 
6'2" 
148 
155 
163 
171 
179 
186 
194 
202 
210 
218 
225 
233 
272 
311 
6'3" 
152 
160 
168 
176 
184 
192 
200 
208 
216 
224 
232 
240 
279 
319 
6.4” 
156 
164 
172 
180 
189 
197 
205 
213 
221 
230 
238 
246 
287 
328 

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59 
If BMI > 30, proceed with the following steps:  
 
1. Determine Ideal Weight (1 kg = 2.2 lbs):  
Males: 50 kg + (2.3 kg/inch over 5 feet)  
Females: 45.5 kg + (2.3 kg/inch over 5 feet) 
 (Patients less than 5 feet: subtract 2.3 kg/inch) 
 
2. Determine Adjusted Body Weight:  
Ideal Weight + 0.25 (actual weight – ideal weight) = Adjusted Body Weight 
 
Dose of CYT107 is 10 µg/kg. Vial is 1mg/0.5cc.