Conditions: Prostate Cancer
Keywords: prostatic neoplasms castration-resistant bone metastasis radium-223 sipuleucel-T
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: no

Brief summary:
This clinical trial studies the effect of radium-223 when added to sipuleucel-T for treating castrate-resistant prostate cancer that has spread to the bone. Sipuleucel-T is an autologous cellular immunotherapy designed to stimulate an immune response against prostate cancer. It has been suggested that the immune response may be strengthened by radiation therapy. Therefore this study is testing whether radium-223 added to sipuleucel-T increases the immune response and anti-tumor effect against prostate cancer.

Detailed description:
This is a randomized study designed to assess the antigen-specific immune response of sipuleucel-T with or without radium-223. Eligible subjects will be registered and randomly assigned in a 1:1 ratio to receive sipuleucel-T and radium-223 or sipuleucel-T alone.

Subjects in both arms (sipuleucel-T and radium) will undergo a standard 1.5 to 2.0 blood volume leukapheresis, followed approximately 3 days later by an IV infusion of sipuleucel-T. This process will occur a total of 3 times at approximately 2-week intervals. Subjects in Arm 1 will receive a total of 6 infusions of radium-223 at IV dose of 50 kBq/kg at 4-week interval.

All participants are allowed to receive the best supportive care which includes secondary hormonal manipulation as required. No chemotherapy, external-beam radiation, or other radionuclides are allowed while on active treatment but are permitted after completion of active treatment. Glucocorticoid-containing treatments should be minimized to less than the equivalent dose of prednisone 10mg daily if feasible for the 3 months following sipuleucel-T therapy. All patients continue medical or surgical castration during treatment.

Arms:
arm 1: Radium-223 will be administered by intravenous injection over 1 minute at 50kbq (1.35 microcurie) per kg body weight per standard of care every 4 weeks at weeks 0, 4, 8, 12, 16, and 20

Sipuleucel-T will be administered intravenously per standard of care every 2 weeks at weeks 6, 8, and 10 arm 2: Sipuleucel-T will be administered intravenously per standard of care every 2 weeks at weeks 6, 8, and 10

Interventions: intervention 1: Radium-223 intervention 2: Sipuleucel-T
Intervention descriptions: intervention 1: 6 infusions of radium-223 with 3 infusions of sipuleucel-T starting after second dose of radium-223 intervention 2: 3 infusions of sipuleucel-T alone

Protocol document:
Prot_SAP_000.pdf: 
1 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
STUDY PROTOCOL  
 
J1522-A RANDOMIZED PHASE 2 STUDY OF SIPULEUCEL-T WITH OR WITHOUT 
RADIUM-223 IN MEN WITH ASYMPTOMATIC OR MINIMALLY SYMPTOMATIC 
BONE-METASTATIC CASTRATE-RESISTANT PROSTATE CANCER 
 
Coordinating Center:                                               The Sidney Kimmel Comprehensive Cancer        
                                                                                    Center at Johns Hopkins 
 
Principal Investigator and IND Sponsor:  
Emmanuel Antonarakis, MD 
The Sidney Kimmel Comprehensive Cancer 
201 N. Broadway, RM 9129 
 
Baltimore, MD 21287 
Phone: 443-287-0553 
Fax: 410-367-2668 
Email: eantona1@jhmi.edu 
 
Co-PI: 
A. Oliver Sartor, MD 
Tulane Cancer Center 
1430 Tulane Ave., SL-42 
New Orleans, LA 70112                                                         
Phone: 504-988-7869 
Email: osartor@tulane.edu 
 
Statistician:                                                             Brandon Luber, ScM 
                                                                                    550 North Broadway  
                                                                                    550 Bldg. 1103  
                                                                                    Baltimore, MD 21205 
                                                                                    Phone: 443-287-2908 
                                                                                    Email: bluber1@jhmi.edu 
 
 
Lead Site Study Coordinator: 
                       Serina King 
                                                                                    201North Broadway, RM 9132  
                                                                                     
                                                                                    Baltimore, MD 21287 
                                                                                    Phone: 410-614-6139 
                                                                                    Email: sking18@jhmi.edu 
 
 
 
 


2 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
Lead Site Research Nurse:                                     Michaella Afful, RN 
                                                                                    201 North Broadway, 9th Floor  
                                                                                     
                                                                                    Baltimore, MD 21287 
                                                                                    Phone: 410-502-0017 
                                                                                    Email: mafful1@jhmi.edu 
 
 
Participating Site Specific Co-Investigator 
 
The Sidney Kimmel Comprehensive Cancer 
Emmanuel Antonarakis, MD 
201 N. Broadway, RM 9129 
 
Baltimore, MD 21231 
Phone: 443-287-0553 
Email: eantona1@jhmi.edu 
Tulane Cancer Center 
A. Oliver Sartor, MD 
1430 Tulane Ave., SL-
42 
New Orleans, LA 
70112                              
Phone: 504-988-7869 
Email: 
osartor@tulane.edu 
 
 
 
 
 
 
Statement about Proper Study Conduct 
 
This study will be conducted in compliance with Good Clinical Practices, according to ICH 
Harmonized Tripartite Guideline. 
 
 
Confidentiality Statement 
 
The information in this document is provided to you as an investigator, potential investigator, 
consultant, or contractor, for review by you, your staff, and the appropriate Institutional Review 
Board or Ethics Committee. By accepting this document, you agree that the information 
contained herein will not be disclosed to others without written authorization from the lead 
site/sponsor, except to the extent necessary to initiate the study or conduct study-related activities 
 
 
 


3 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
 
 
PROTOCOL SIGNATURE PAGE 
 
A RANDOMIZED PHASE 2 STUDY OF SIPULEUCEL-T WITH OR WITHOUT RADIUM-
223 IN MEN WITH ASYMPTOMATIC OR MINIMALLY SYMPTOMATIC BONE-
METASTATIC CASTRATE-RESISTANT PROSTATE CANCER 
 
 
 
Investigator Name:                 ______________________________________________  
 
Title:                                       ______________________________________________  
  
Address:                                  ______________________________________________  
 
Address:                                  ______________________________________________  
 
Address:                                  ______________________________________________  
 
Phone:                                     ______________________________________________  
 
Facsimile:                               ______________________________________________  
 
Signature:                               ______________________________________________  
 
Date:                                       ______________________________________________ 
 
 
 
 
 
 
 
 
 
 
 


4 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
Amendment Rationale 
The quantification of radium-223 radioactivity in Xofigo® is based on the primary 
standardization performed by the US National Institute of Standards and Technology (NIST).  
The NIST Standard Reference Material is used to calibrate the instruments in production and 
quality control of both the drug substance and drug product.  Additionally, the calibrated 
instruments in production at the Institute for Energy Technology (IFE, Norway) are used to 
prepare the NIST traceable radium-223 reference material, which are then sent to the treatment 
sites (e.g., nuclear medicine laboratory physicians or technicians) for dial setting of their dose 
calibrators, to allow verification of the patient dose.  A reassessment of the primary 
standardization was initiated by the NIST.  A discrepancy of approximately 10% between the 
published NIST primary standardization (Cessna, 2010, NIST 2010) and current measurements 
was confirmed and a revised NIST primary reference standard has been issued (Zimmerman, 
2015, NIST update).  As a result of the revised NIST primary standardization, an adaption of the 
numerical description of patient dose and the description of radioactive concentration of the drug 
product solution becomes necessary.  This concerns Xofigo® for commercial use and product 
used in clinical trials.   
After the implementation of the new standard (NIST update) the numerical description of the 
patient dose will be adjusted from 50 kBq/kg to 55 kBq/kg, and the numerical description of the 
radioactivity in the vial will be changed from 1,000 kBq/mL to 1,100 kBq/mL 
The values in this protocol have been revised as per the United States National Institute of 
Standards and Technology (NIST) standardization update. 
Bayer has submitted a variation application to the FDA.   The current standard (NIST 2010), dial 
setting and dose will remain in effect  for this study until  Bayer has confirmed  the unique 
implementation date in the 2nd quarter of  2016 as agreed with FDA and notified  the Principal 
Investigator and IND Sponsor: 
 
Emmanuel Antonarakis, MD 
The Sidney Kimmel Comprehensive Cancer 
201 N. Broadway, RM 9129  
Baltimore, MD 21287 
 
 
 
 


5 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
PROTOCOL SYNOPSIS 
 
Protocol Title: A Randomized Phase 2 Study of Sipuleucel-T With or Without Radium-223 IN 
Men With Asymptomztic or Minimally Symptomatic Bone-Metastatic Castrate-Resistant 
Prostate Cancer  
 
Protocol Number: 
 
Phase: II 
 
Study Centers: 4-5 centers in the U.S. 
 
Investigational Product, Dosage Form, Route, and Dose Regimen:  
 
Radium-223 (Xofigo®) is an alpha-emitting radioisotope developed by Algeta ASA. Radium-
223 is indicated for treatment of men with castrate-resistant prostate cancer (CRPC) with 
symptomatic bone metastases and no known visceral metastatic disease. The approved dose and 
schedule of radium-223 is 50 kBq (or 1.35 microcurie) (55 kBq/kg (or 1.49 microcurie)) after 
implementation of the NIST update) per kg body weight intravenous (IV) infused at 4 week 
interval for 6 injections. 
 
Sipuleucel-T (Provenge®) is an autologous cellular immunotherapy product designed to 
stimulate an immune response against prostate cancer. Sipuleucel-T is indicated for use in 
patients with asymptomatic or minimally symptomatic metastatic CRPC (mCRPC). A dose of 
sipuleucel-T is prepared using PBMCs from a single leukapheresis procedure. A minimum of 50 
million antigen presenting cells (APCs, the biologically active component of sipuleucel-T) are 
administered via a single IV infusion. A complete treatment of sipuleucel-T will include 3 doses 
of autologous cells, infused at approximately 2-week intervals.  
 
Primary Objective   
 
• To determine whether addition of radium-223 to sipuleucel-T enhances immune response 
to sipuleucel-T measured by peripheral PA2024-specific T-cell proliferation compared 
with sipuleucel-T alone in men asymptomatic or minimally symptomatic bone-metastatic 
CRPC 
 
Secondary Immune Objectives 
 
• To evaluate peripheral antigen-specific T-cell proliferation over time 
• To evaluate peripheral antigen specific T-cell activation to sipuleucel-T over time 


6 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
• To evaluate antigen specific antibody response to sipuleucel-T over time  
• To evaluate the sipuleucel-T product immune parameters 
 
Secondary Clinical Objectives 
 
• To evaluate safety of combined use of radium-223 and sipuleucel-T.  
• To evaluate PSA50 response (at least a 50% decline in PSA)   
• To evaluate time to radiographic or clinical progression.  
Study Design and Duration:  
 
This is a randomized study designed to assess the antigen-specific immune response of 
sipuleucel-T when administered with or without radium-223.   
 
Eligible subjects will be registered and randomly assigned in a 1:1 ratio to receive sipuleucel-T 
and radium-223 or sipuleucel-T alone; 
 
Arm 1: 6 infusions of radium-223 with 3 infusions of sipuleucel-T starting after second 
dose of radium-223 
 
Arm 2: 3 infusions of sipuleucel-T alone 
 
Subjects in both arms will undergo a standard 1.5 to 2.0 blood volume leukapheresis, followed 
approximately 3 days later by an IV infusion of sipuleucel-T. This process will occur a total of 3 
times at approximately 2-week intervals. Subjects in Arm 1 will receive a total of 6 infusions of 
radium-223 at IV dose of 50 kBq/kg (55 kBq/kg after implementation of the NIST update) at 4-
week interval 
  
Research visits will be scheduled at screening, at each  radium-223 infusion, prior to each 
leukapheresis (preleukapheresis visit), and week 32, 45 and 58 for Arm 1 (radium-223 and 
sipuleucel-T combination arm) and at screening, prior to each leukapheresis (preleukapheresis 
visit), and week 6, 10, 14, 26, 39, and 52 for Arm 2 (sipuleucel-T alone arm)  for physical 
examinations, vital signs, ECOG performance status, adverse event (AE) monitoring, anticancer 
therapies, first opioid use for cancer-related pain, and  laboratory tests. Serum PSA will be 
assessed at baseline, and week 16, 32, 45, and 58 for Arm 1 and at baseline, and week 10, 26, 39, 
and 52 for Arm 2. There is a ± 7 day window for each visit to accommodate holidays, vacations, 
etc. 
Imaging studies including bone scintigraphy test (bone scan) or Na-F PET or C11 acetate PET 
and abdomen/pelvis CT or MRI will be obtained at screening and week 16, 32, 45, and 58 for 
Arm 1 and at screening and week 10, 26, 39, and 52 for Arm 2. After the last study visit, imaging 
studies will be obtained according to the participating institution’s standard and/or at the 
investigator’s discretion. 


7 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
Immune monitoring blood samples will be drawn at screening and at 6, 10, 14, 26, 39, and 52 
weeks after the first infusion of sipuleucel-T in both arms. Additional blood samples will be 
obtained at baseline, first pre-leukapheresis visit (only in Arm 1), and weeks 14 and 52 post the 
first infusion of sipuleucel-T for exploratory antigen spread assessment. 
 
After last study research visit, safety, treatment-related AEs, survival status, PSA, first opioid use 
for cancer-related pain (if applicable), and anticancer therapies will be assessed every 3 months 
for additional 1 year or until the subject’s death.  
 
The study design is illustrated below. 
     
            
  
 
Study Population and Sample Size 


8 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
This study will enroll 30 evaluable patients with asymptomatic or minimally symptomatic 
mCRPC, 18 years of age or older. Up to 33 patients are estimated to be required to be enrolled to 
allow for drop-outs and subjects who may not receive 3 infusions of sipuleucel-T or 2 infusions 
of radium-223. 
 
Inclusion Criteria 
 
 
1. Written informed consent provided prior to the initiation of study procedures.  
 
2. Age ≥ 18 years.  
 
3. Histologically documented adenocarcinoma prostate cancer confirmed by a pathology 
report from prostate biopsy or a radical prostatectomy specimen. If prostatic tumor is of 
mixed histology, > 50% of the tumor must be adenocarcinoma.  
 
4. Bone metastases as manifested by one or more lesions on a bone scan performed within 2 
months of screening  
 
5. Castrate-resistant prostate cancer, in the setting of castrate levels of testosterone (≤ 50 
ng/dL), defined as current or historical evidence of disease progression concomitant with 
surgical castration or androgen deprivation therapy (ADT), as demonstrated by two 
consecutive rises in PSA OR new lesions on bone scan:  
 
• PSA progression will be defined as 2 rising PSA values compared to a reference 
value, measured at least 7 days apart and the second value is ≥ 2 ng/mL [1]. It must 
be documented within 2 months of screening. 
 
• Appearance of one or more new areas of abnormal uptake on bone scan when 
compared to imaging studies acquired during castration therapy or against the 
precastration studies if there was no response. Increased uptake of pre-existing lesions 
on bone scan does not constitute progression. It must be documented within 4 months 
of screening. 
 
6. Serum PSA ≥ 2.0 ng/mL.  
 
7. Screening ECOG performance status ≤ 1  
 
8. Asymptomatic or minimally symptomatic disease (no narcotic analgesic; other analgesics 
use is allowed). 
 


9 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
9. Prior abiraterone and enzalutamide are permitted, but not required. 
10. Concurrent osteoclast-inhibitory therapies (zoledronic acid, denosumab) are permitted if 
patients have been on a stable dose for at least 1 month. 
 
11. Adequate screening hematologic, renal, and liver function as evidenced by laboratory test 
results within the following ranges ≤ 28 days prior to registration:  
 
• Absolute neutrophil count (ANC) ≥ 1.5 x109/L 
• Platelet count ≥ 100 x109/L  
• Hemoglobin ≥ 10.0 g/dL  
• Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN) 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN  
• Creatinine ≤ 1.5 x ULN 
• Albumin > 2.5 g/L  
 
Exclusion Criteria 
 
1. The presence of known lung or liver metastases greater than 1.0 cm in the long axis 
diameter. 
 
2. The presence of lymphadenopathy greater than 3 cm in the short-axis diameter. 
 
3. The presence of known brain metastases. 
 
4. Spinal cord compression, imminent long bone fracture, or any other condition that, in the 
opinion of the investigator, is likely to require radiation therapy and/or steroids for pain 
control during the active phase. 
 
5. Previous treatment with chemotherapy for mCRPC, or chemotherapy for any reason 
within 6 months prior to registration. (Chemotherapy in the adjuvant setting or for 
hormone-sensitive prostate cancer is permitted, as long as it was completed more than 6 
months before registration). 
 
6. Intention to receive chemotherapy within 6 months after enrollment in protocol therapy. 
 
7. History of radiation therapy, either via external beam or brachytherapy within 28 days 
prior to registration. 
 
8. Systemic radiotherapy with strontium-89, samarium-153, rhenium-186 or rhenium-188 
for the treatment of bony metastases within previous 24 weeks 
 


10 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
9. Prior history of other cancers (except non-melanoma skin cancers or low-grade low-stage 
urothelial cancers), or other localized cancers without evidence of recurrence for at least 
3 years. 
 
10. Use of prednisone or equivalent systemic corticosteroid within 2 weeks of treatment. Use 
of inhaled, intranasal, intra-articular, and topical steroids is allowed. Oral or IV steroids 
to prevent or treat IV contrast reactions are allowed. 
 
11. Use of opioid analgesics for cancer-related pain  
 
12. Use of experimental drug within 4 weeks of treatment. 
 
13. Uncontrolled medical conditions including diabetes, heart failure, COPD, ulcerative 
colitis, or Crohn’s disease. 
 
14. Uncontrolled fecal incontinence. 
 
15. Any medical intervention, any other condition, or any other circumstance which, in the 
opinion of the investigator, could compromise adherence with study requirements or 
otherwise compromise the study’s objectives. 
 
Study Endpoints 
 
Primary Endpoint 
 
• Peripheral PA2024-specific T-cell proliferation using a tritiated thymidine (3H-
thymidine) incorporation assay at week 6 after the first sipuleucel-T infusion in each arm 
reported as stimulation index (SI), defined as 3H-thymidine incorporation in the presence 
of PA2024 antigen divided by 3H-thymidine incorporation with media alone.  
 
Secondary Endpoints 
 
Secondary Immune Endpoints 
 
• The mean peripheral PA2024-and PAP-specific T-cell proliferation using a 3H-thymidine 
incorporation assay reported as SI at baseline and 6, 10, 14, 26, 39, and 52 weeks after 
the first infusion of sipuleucel-T. 
• The mean peripheral PA2024-and PAP-specific T-cell activation to sipuleucel-T using 
interferon gamma (IFNγ) enzyme-linked immunosorbent spot (ELISPOT) at baseline and 
weeks 6, 10, 14, 26, 39, and 52 weeks after the first infusion of sipuleucel-T. 


11 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
• The mean PA2024-and PAP-specific antibody (IgM and IgG) response to sipuleucel-T 
using enzyme-linked immunosorbent assay (ELISA) at baseline and weeks 6, 10, 14, 26, 
39, and 52 weeks after the first infusion of sipuleucel-T. 
• Product immune parameters including CD54 + cell counts and upregulation and total 
nucleated cell (TNC) counts  
 
Secondary Clinical Endpoints 
 
• The frequency of the maximum observed grade of each toxicity. Incidence and severity 
of adverse events and laboratory abnormalities, graded according to CTCAE v4.0 [2].  
• To evaluate the PSA50 response 
- 
PSA50 response is defined as at least a 50% decline in PSA from baseline 
value 
 
• Median time to radiographic progression using (RECIST and PCWG2 criteria for soft 
tissue and bone lesions, respectively, as assessed by the investigator). 
 
Exploratory Objectives:  
• Median time to PSA progression based on Prostate Cancer Working Group 2 (PCWG2) 
criteria [1]: 
– in patients with no PSA decline from baseline as: ≥ 25% increase from the 
baseline value and an increase in absolute value of ≥ 2 ng/mL, at least 12 weeks 
from baseline  
– in patients with an initial PSA decline from baseline as: ≥ 25% increase and an 
absolute increase of ≥ 2 ng/mL above the nadir value, which is confirmed by a 
second value obtained three or more weeks later 
• Median time to ALP progression.  
– in patients with no ALP decline from baseline as: ≥ 25% increase from the 
baseline value, at least 12 weeks from baseline 
– in patients with an initial ALP decline from baseline as: ≥ 25% increase above the 
nadir value, which is confirmed by a second value obtained three or more weeks 
later. 
• Median time to pain progression defined as use of opioid analgesics for cancer-related 
pain. 
• Median time to occurrence of first skeletal related event (SRE): 
– the use of external beam radiotherapy to relieve skeletal symptoms or the 
occurrence of new symptomatic pathological bone fractures (vertebral or non-
vertebral) or the occurrence of spinal cord compression or a tumor related 
orthopedic surgical intervention. 
• Median time to occurrence of first start of chemotherapy use.  
 


12 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
Statistical Considerations  
 
The study is designed to test the null hypothesis of no difference in immune response to 
sipuleucel-T evaluated on the basis of PA2024-stimulated T cell proliferation via 3H-thymidine 
uptake between sipuleucel-T alone and sequential administration of radium-223.  
 
For primary endpoint, PA2024-specific 3H-thymidine uptake was selected because it has 
demonstrated the highest signal to noise ratio and showed the strongest correlation with OS of all 
cellular and humoral assays evaluated in prior studies of sipuleucel-T.  
 
With 15 subjects in each arm, we seek to detect a 3.6-fold difference between the arms with 80% 
power in mean SI of PA2024-specific 3H-thymidine uptake at week 6 after the first infusion of 
sipuleucel-T    
 
The immune response population will consist of all subjects who receive 3 infusions of 
sipuleucel-T and at least 4 infusions of radium-223.  
 
The intent-to-treat population is defined as all randomized subjects, regardless of whether they 
receive treatment. Analysis of non-immune response efficacy endpoints will be performed using 
this analysis population.  
 
The safety population will include all subjects who undergo at least 1 leukapheresis procedure or 
receive at least 1 dose of radium-223. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


13 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
 
 
Contents 
1.0   INTRODUCTION ................................................................................................................ 18 
1.1   Background and Rationale ................................................................................................ 18 
1.2   Study Agents ..................................................................................................................... 19 
1.2.1   Sipuleucel-T ............................................................................................................... 19 
1.2.2   Radium-223................................................................................................................ 20 
2.0   OBJECTIVES ....................................................................................................................... 21 
2.1   Primary Objective ............................................................................................................. 21 
2.2    Secondary Objectives ....................................................................................................... 21 
2.2.1    Secondary Immune Objectives ................................................................................. 21 
2.2.2    Secondary Clinical Objectives .................................................................................. 21 
3.0   STUDY DESIGN.................................................................................................................. 21 
4.0   STUDY POPULATION ....................................................................................................... 23 
4.1   Inclusion Criteria .............................................................................................................. 24 


14 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
4.2   Exclusion Criteria ............................................................................................................. 25 
5.0   STUDY TREATMENTS ...................................................................................................... 26 
5.1   Radium-223....................................................................................................................... 26 
5.2   Sipuleucel-T ...................................................................................................................... 30 
5.3   Treatment Compliance ...................................................................................................... 32 
5.4   Drug Accountability.......................................................................................................... 32 
5.5   Concomitant Medications ................................................................................................. 32 
5.6   Prohibited and/or Restricted Treatments .......................................................................... 32 
5.7   Discontinuation from Study Treatments or Assessments ................................................. 33 
5.7.1    Patient withdrawal .................................................................................................... 33 
5.7.2   Discontinuation from Sipuleucel-T Treatment .......................................................... 34 
5.7.3   Discontinuation from Radium-223 Treatment ........................................................... 34 
5.7.4   Study Termination ..................................................................................................... 34 
5.8.   Lost to Follow-Up ............................................................................................................ 35 
5.9   Disease Progression .......................................................................................................... 35 
6.0   STUDY ASSESSMENTS AND PROCEDURES ................................................................ 36 
6.1.   Schedule of Assessments ..................................................................................................... 36 
6.2   Registration ....................................................................................................................... 41 
6.3   Randomization .................................................................................................................. 41 
6.4   Demographics ................................................................................................................... 41 
6.5   Clinical Assessments ........................................................................................................ 41 
6.6    Safety Assessments .......................................................................................................... 43 
6.7   Concomitant Medications ................................................................................................. 43 
6.8   Survival Status .................................................................................................................. 44 
6.9   Laboratory Test Assessments ........................................................................................... 44 
6.10   Immune Assessments ...................................................................................................... 45 
6.10.1   Peripheral  Immune Response Assessments ............................................................ 45 
6.10.2   Antigen Spread Assessment ..................................................................................... 46 


15 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
6.10.3   Product Immune Parameter Assessments ................................................................ 47 
6.11   Study Materials ............................................................................................................... 47 
7.0   ADVERSE EVENTS ............................................................................................................ 47 
7.1   Categories for Ranking Severity of Adverse Events ........................................................ 47 
7.2   Relationship of Adverse Events to Study Treatments ...................................................... 48 
7.3   Adverse Events Reporting ................................................................................................ 48 
7.4   Serious Adverse Events .................................................................................................... 49 
7.5   Death Reports.................................................................................................................... 51 
7.6   Laboratory Test Result Abnormalities .............................................................................. 52 
8.0   STATISTICAL CONSIDERATIONS.................................................................................. 52 
8.1   General Considerations ..................................................................................................... 52 
8.2   Sample Size Determination............................................................................................... 52 
8.3   Populations for Analyses .................................................................................................. 52 
8.4   Study Termination ............................................................................................................ 53 
8.5   Endpoints .......................................................................................................................... 53 
8.5.1   Primary Endpoints ..................................................................................................... 53 
8.5.2   Secondary Endpoint(s) ............................................................................................... 53 
8.6   Analyses ............................................................................................................................ 54 
8.7   Interim Analyses ............................................................................................................... 57 
9.0   REGULATORY REQUIREMENTS ................................................................................... 58 
9.1   Investigator Responsibilities ............................................................................................. 58 
9.2.   Study Coordinator Responsibilities ................................................................................. 58 
9.3   Study Personnel Responsibilities ...................................................................................... 58 
9.4   Participating Sites Responsibilities ................................................................................... 59 
9.5   Patient Information and Informed Consent ....................................................................... 59 
9.6   Subject Confidentiality ..................................................................................................... 60 
9.7   Good Clinical Practice ...................................................................................................... 60 
9.8   Ethical Considerations ...................................................................................................... 60 


16 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
10.0   STUDY MANAGEMENT ................................................................................................. 60 
10.1   Clinical Trial Agreement ................................................................................................ 60 
10.2   Lead research program coordinators ............................................................................... 61 
10.3   Case report forms ............................................................................................................ 61 
10.4   Source documents ........................................................................................................... 61 
10.5   Study Monitoring and Quality Assurance....................................................................... 61 
10.6   Protocol Amendments ..................................................................................................... 62 
10.7   Record retention .............................................................................................................. 62 
10.8   Publication policy ........................................................................................................... 62 
10.8.1   Publications and NIST ............................................................................................. 62 
11.0   LIST OF ABBREVIATIONS ............................................................................................. 63 
APPENDIX 1: Investigator Initiated Trial Immune Monitoring Requisition Form ..................... 67 
APPENDIX 2: Dendreon Specimen Shipping Instructions .......................................................... 69 
APPENDIX 3: Dendreon SAE Form ............................................................................................ 72 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


17 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


18 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
1.0   INTRODUCTION 
 
1.1  Background and Rationale 
 
Prostate cancer is the most common malignancy in men in the United States, with estimated 238, 
590 new cases and 29,720 deaths in 2013 [3]. Approximately 80% of prostate cancer cases are 
diagnosed when the cancer is still confined to the primary site (localized prostate cancer). But 
12% prostate cancers are diagnosed as locally advanced stage and 4% as metastatic disease.  
 
Localized prostate cancer can be treated with various local therapies and some selected cases can 
be followed with active surveillance. However, approximately 20% to 40% of patients who have 
been treated with a curative intent develop disease recurrence [4]. While some selective patients 
with PSA-only recurrence with no evidence of disseminated disease can be treated with local 
salvage therapies, majority of patients with recurrent disease require systemic therapy such as 
ADT with or without concomitant antiandrogen agents. Despite high rate of initial response to 
ADT, virtually all patients will progress to metastatic disease, the disease condition called 
metastatic castrate-resistant prostate cancer (mCRPC). When patients develop mCRPC, the 
disease is considered noncurable and lethal with a median survival around 2 years.  
 
There has been tremendous advance in the treatment of mCRPC over the last decade since the 
approval of docetaxel in 2003. Currently 6 therapeutic agents with various mechanisms that have 
shown survival benefit have been approved by Food and Drug Administration (FDA) for the 
treatment of mCRPC. While the approval of multiple agents have resulted in increased overall 
survival and improved quality of life and provided wider therapeutic options for the patients, it 
has created challenges of establishing the optimal use of these therapeutics including the optimal 
sequence and possible combination of those agents.     
 
Sipuleucel-T is an autologous cellular immunotherapy product designed to stimulate an immune 
response against prostate cancer. Sipuleucel-T has improved survival in patients with 
asymptomatic or minimally symptomatic mCRPC in 3 phase III trials [5-7]. Despite the survival 
benefit, majority of patients treated with sipuleucel-T do not experience radiographic or PSA 
response, making the assessment of treatment response difficult. Furthermore, there is no 
established clinical or molecular marker to predict the response to sipuleucel-T immune therapy. 
However recently published analysis of immune responses from these 3 trials showed that 
antigen-specific immune responses to sipuleucel-T, both humoral and T-cell responses, correlate 
with survival benefit [8], confirming the immune-based mechanism of action of sipuleucel-T and 
also suggesting the possibility that producing a stronger immune response may translate to the 
better clinical outcome.  
 
It has been suggested that immune modulation can be enhanced by radiation therapy through a 
variety of mechanisms. Radiation-induced cell death has been shown to stimulate tumor-specific 


19 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
immune responses by enhanced display of tumor associated antigens and upregulation of tumor 
suppressive proteins and inflammatory cytokines [9]. This synergistic antitumor effect of 
combined immune therapy and radiation therapy has been evaluated in various cancer types. In 
prostate cancer, a phase I/II study of ipilimumab in combination with radiotherapy in mCRPC 
showed a promising antitumor effect including PSA decline and radiographic tumor reduction.  
 
Similar to external radiotherapy, radiopharmaceutical agent also has shown to upregulate tumor 
antigens in prostate cancer models. In a study by Chakraborty et, al., the exposure to beta particle 
emitting radiopharmaceutical, samarium-153-ethylenediaminetetrame-thylenephosphonate 
(153Sm-EDTMP), resulted in upregulation of the prostate cancer antigens, such as PSMA and 
PAP [10]. Such 153Sm-EDTMP-induced phenotypic changes in tumor cells rendered these tumor 
cells more susceptible to T cell–mediated killing.  
 
Radium-223 is an alpha-emitting radioisotope which is a bone-seeking calcium mimetic. It 
selectively targets the area with increased bone turnover, especially within the microenvironment 
of osteoblastic or sclerotic metastases [11]. It has been approved by FDA for the treatment of 
mCRPC with symptomatic bone metastases and without known visceral disease based on its 
ability to extend overall survival as shown its pivotal phase III trial [12]. Unlike beta particle 
emitting radiopharmaceuticals, radium-223 emits high-energy alpha particles of short range 
(<100 μm) thus saving the surrounding healthy tissues and significantly reducing unwanted 
myelotoxicity [13]. 
 
Based on the immune-modulatory effects of radiotherapy and radiopharmaceutical shown in the 
previous studies, we hypothesized that combined use of radium-223 and sipuleucel-T can 
enhance the sipuleucel-T-induced immune response, which translates to better clinical outcome. 
Since more than 90% of patients with mCRPC have bone metastases [14], this approach can be 
widely applied to early stage of mCRPC when patients are asymptomatic or minimally 
symptomatic from the bone lesions when the greatest clinical benefit can be obtained with 
immune-based therapies [15]. 
1.2   Study Agents 
 
1.2.1   Sipuleucel-T 
 
Sipuleucel-T is an autologous cellular immunotherapy product designed to stimulate an immune 
response against prostate cancer. It consists of autologous peripheral blood mononuclear cells 
(PBMCs), including antigen presenting cells (APCs, defined as large CD54-positive PBMCs) 
that have been activated in vitro with prostate antigen PA2024, a recombinant fusion protein 
composed of prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony-
stimulating factor (GM-CSF). 
 


20 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
Sipuleucel-T was approved in the United States in 2013 for the treatment of men with 
asymptomatic or minimally symptomatic mCRPC. In the pivotal trial D9902B (IMPACT), 512 
patients were randomized 2:1 to receive sipuleucel-T (N=341) or control (N=171) [7]. Overall 
survival was longer in the sipuleucel-T group (median of 25.8 months versus 21.7 months; 
hazard ratio (HR) =0.78; 95% confidence interval (CI): 0.62, 0.98; P=0.03). More than 3,339 
infusions of sipuleucel-T and control (a product manufactured from PBMCs without activation 
with the PA2024 antigen), have been administered to men with prostate cancer in clinical trials. 
 
Clinical data to support the safety of sipuleucel-T are provided from 904 subjects (sipuleucel-T, 
N=601; control, N=303) who participated in 4 multicenter, randomized, double-blind, controlled 
Phase 3 studies. Three of these studies were conducted in men with mCRPC (studies D9902B, 
D9901, and D9902A), and 1 study was conducted in men with androgen dependent prostate 
cancer (ADPC) [5-7;16]. In the 4 randomized Phase 3 studies, AEs reported in ≥ 20% of all 
subjects were chills, fatigue, pyrexia, and back pain. The most common AEs (observed in ≥ 5% 
of sipuleucel-T subjects as well as at least twice the rate of that in control subjects) included 
chills, pyrexia, headache, myalgia, influenza-like illness, and hyperhidrosis. The majority of 
these events occurred within 1 day of infusion; were grade 1 or 2 in severity; and were generally 
of short duration (i.e., resolved in ≤ 2 days). Grade 3 or 4 events were reported in 27.6% of 
subjects in the sipuleucel-T group, compared with 28.4% in the control group.  
 
1.2.2   Radium-223 
 
Radium-223 (Bayer Pharmaceuticals, NJ) is a calcium mimetic which localizes to bone at areas 
with increased bone turnover. Radium-223 decays via a chain of short-lived daughter nuclides to 
lead, producing four alpha-particles [13]. The high energy of alpha particle induces effective 
double stranded DNA breaks with short range of less than 100 μm, minimizing 
myelosuppression and causing limited effects on normal tissue. 
 
Radium-223 was approved by the US FDA on May 15, 2013 based on the interim results from a 
Phase III randomized trial, the ALSYMPCA study (Alpharadin in the treatment of patients with 
symptomatic bone metastases in castration-resistant prostate cancer). In this trial, 921 patients 
who had received, were not eligible to receive, or declined docetaxel were randomly assigned in 
a 2:1 ratio to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body 
weight intravenously (55 kBq/kg after implementation of NIST standard update) every 4 weeks 
or matching placebo. At the interim analysis, which involved 809 patients, radium-223, as 
compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 
months; HR=0.70; 95% CI, 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 
921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; 
HR=0.70; 95% CI, 0.58 to 0.83; P<0.001). The rate of AEs was consistently lower in the radium-
223 group than in the placebo group for all AEs (93% vs. 96%), grade 3 or 4 AEs (56% vs. 


21 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
62%), and serious AEs (47% vs. 60%). There were no clinically meaningful differences in the 
frequency of grade 3 and 4 hematologic AEs. Only one 
 patient developed grade 3 febrile neutropenia in the radium-223 group. For serious AEs that 
occurred in at least 5% of patients in the radium-223 group or the placebo group, the respective 
frequencies were as follows: disease progression (11% and 12%), bone pain (10% and 16%), 
anemia (8% and 9%), and spinal cord compression (4% and 5%). Also a significantly higher 
percentage of patients who received radium-223 had a meaningful improvement in the quality of 
life according to the Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score 
during the period of study-drug administration (25% vs. 16%, P=0.02). 
 
2.0   OBJECTIVES 
 
2.1   Primary Objective 
 
• To determine whether radium-223 in combination with sipuleucel-T enhances immune 
response to sipuleucel-T measured by peripheral PA2024-specific T-cell proliferation 
compared with sipuleucel-T alone in men asymptomatic or minimally symptomatic bone-
metastatic CRPC 
 
2.2    Secondary Objectives 
 
2.2.1    Secondary Immune Objectives 
 
• To evaluate peripheral antigen-specific T-cell proliferation over time. 
• To evaluate peripheral antigen specific T-cell activation to sipuleucel-T over time. 
• To evaluate antigen specific antibody response to sipuleucel-T over time.  
• To evaluate the sipuleucel-T product immune parameters. 
 
2.2.2    Secondary Clinical Objectives 
 
• To investigate safety of combined use of radium-223 and sipuleucel-T.  
• To evaluate PSA50 response (at least a 50% decline in PSA)   
• To evaluate time to radiographic or clinical progression.  
 
3.0   STUDY DESIGN  
 
This is a randomized study designed to assess the antigen-specific immune response of 
sipuleucel-T with or without radium-223.   
 
Eligible subjects will be registered and randomly assigned in a 1:1 ratio to receive sipuleucel-T 
and radium-223 or sipuleucel-T alone; 


22 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
Arm 1: 6 infusions of radium-223 with 3 infusions of sipuleucel-T starting after second 
dose of radium-223 
 
Arm 2: 3 infusions of sipuleucel-T alone 
 
Subjects in both arms will undergo a standard 1.5 to 2.0 blood volume leukapheresis, followed 
approximately 3 days later by an IV infusion of sipuleucel-T. This process will occur a total of 3 
times at approximately 2-week intervals. Subjects in Arm 1 will receive a total of 6 infusions of 
radium-223 at IV dose of 50 kBq/kg (55 kBq/kg after implementation of the NIST update) at 4-
week interval. 
  
All participants are allowed to receive the best supportive care which includes secondary 
hormonal manipulation (including flutamide, bicalutamide or nilutamide-but not abiraterone or 
enzalutamide) as required. No chemotherapy, external-beam radiation, or other radionuclides are 
allowed while on active treatment but are permitted after completion of active treatment. 
Glucocorticoid-containing treatments should be minimized to less than the equivalent dose of 
prednisone 10mg daily if feasible for the 3 months following sipuleucel-T therapy. All patients 
continue medical or surgical castration during treatment.  
 
Research visits will be scheduled at screening, at each radium-223 infusion, prior to each 
leukapheresis (preleukapheresis visit), and week 32, 45 and 58 for Arm 1 (radium-223 and 
sipuleucel-T combination arm) and at screening, prior to each leukapheresis (preleukapheresis 
visit), and week 6, 10, 14, 26, 39, and 52 for Arm 2 (sipuleucel-T alone arm)  for physical 
examinations, vital signs, ECOG performance status, adverse event (AE) monitoring, anticancer 
therapies, first opioid use for cancer-related pain, and laboratory tests. Serum PSA will be 
assessed at baseline, and week 16, 32, 45, and 58 for Arm 1 and at baseline, and week 10, 26, 39, 
and 52 for Arm 2. There is a ±7 day window for each visit to accommodate holidays, vacations, 
etc. 
 
Imaging studies including bone scintigraphy test (bone scan) or Na-F PET or C11 acetate PET 
and abdomen/pelvis CT or MRI will be obtained at screening and week 16, 32, 45, and 58 for 
Arm 1 and at screening and week 10, 26, 39, and 52 for Arm 2. After the last study visit, imaging 
studies will be obtained according to the participating institution’s standard and/or at the 
investigator’s discretion. 
 
Immune monitoring blood samples will be drawn at screening and at 6, 10, 14, 26, 39, and 52 
weeks after the first infusion of sipuleucel-T in both arms. Additional blood samples will be 
obtained at baseline, first pre-leukapheresis visit (only in Arm 1), and weeks 14 and 52 post the 
first infusion of sipuleucel-T for exploratory antigen spread assessment. 
 


23 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
After last study research visit at week 58, safety, treatment-related AEs, survival status, PSA, 
first opioid use for cancer-related pain (if applicable), and anticancer therapies will be assessed 
every 3 months for additional 1 year or until the subject’s death.  
 
The study design is illustrated in Figure 1.  
 
 
            
  
 
 
 
 
4.0   STUDY POPULATION 
 


24 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
To participate in this study, subjects must meet all inclusion criteria and none of the exclusion 
criteria. 
 
4.1   Inclusion Criteria 
 
 
4.1.1   Written informed consent provided prior to the initiation of study procedures.  
 
4.1.2   Age ≥ 18 years.  
 
4.1.3   Histologically documented adenocarcinoma prostate cancer confirmed by a pathology 
report from prostate biopsy or a radical prostatectomy specimen. If prostatic tumor is of mixed 
histology, > 50% of the tumor must be adenocarcinoma.  
 
4.1.4   Bone metastases as manifested by one or more lesions on a bone scan performed within 2 
months of screening  
 
4.1.5   Castrate-resistant prostate cancer, in the setting of castrate levels of testosterone (≤ 50 
ng/dL), defined as current or historical evidence of disease progression concomitant with 
surgical castration or ADT, as demonstrated by two consecutive rises in PSA OR new lesions on 
bone scan:  
 
PSA progression will be defined as 2 rising PSA values compared to a reference value, 
measured at least 7 days apart and the second value is ≥ 2 ng/mL [1]. It must be 
documented within 2 months of screening. 
 
Appearance of one or more new areas of abnormal uptake on bone scan when compared 
to imaging studies acquired during castration therapy or against the precastration studies 
if there was no response. Increased uptake of pre-existing lesions on bone scan does not 
constitute progression. It must be documented within 4 months of screening. 
 
4.1.6   Serum PSA ≥ 2.0 ng/mL.  
 
4.1.7   Screening ECOG performance status ≤ 1. 
 
4.1.8   Asymptomatic or minimally symptomatic disease (no narcotic analgesic; other analgesics 
use is allowed) 
 
4.1.9   Prior abiraterone and enzalutamide are permitted, but not required. 
 
4.1.10   Concurrent osteoclast-inhibitory therapies (zoledronic acid, denosumab) are permitted if 
patients have been on a stable dose for at least 1 month 


25 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
4.1.11   Adequate screening hematologic, renal, and liver function as evidenced by laboratory 
test results within the following ranges ≤ 28 days prior to registration:  
 
• Absolute neutrophil count (ANC) ≥ 1.5 x109/L 
• Platelet count ≥ 100 x109/L  
• Hemoglobin ≥ 10.0 g/dL  
• Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN) 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN  
• Creatinine ≤ 1.5 x ULN 
• Albumin > 25 g/L  
 
4.2   Exclusion Criteria 
 
4.2.1   The presence of known lung or liver metastases greater than 1.0 cm in long-axis diameter. 
 
4.2.2   The presence of lymphadenopathy greater than 3 cm in the short-axis diameter 
 
4.2.3   The presence of known brain metastases. 
 
4.2.4   Spinal cord compression, imminent long bone fracture, or any other condition that, in the 
opinion of the investigator, is likely to require radiation therapy and/or steroids for pain control 
during the active phase. 
 
4.2.5   Previous treatment with chemotherapy for mCRPC  or chemotherapy for any reason 
within 6 months prior to registration. (Chemotherapy in the adjuvant setting or for hormone-
sensitive prostate cancer is permitted, as long as it was completed more than 6 months before 
registration). 
 
 
4.2.6   Intention to receive chemotherapy within 6 months after enrollment in protocol therapy. 
 
4.2.7   History of radiation therapy, either via external beam or brachytherapy within 28 days 
prior to registration. 
 
4.2.8   Systemic radiotherapy with strontium-89, samarium-153, rhenium-186 or rhenium- 
188 for the treatment of bony metastases within previous 24 weeks 
 
4.2.9   Prior history of other cancers (except non-melanoma skin cancers or low-grade low-stage 
urothelial cancers), or other localized cancers without evidence of recurrence for at least 3 years. 
 


26 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
4.2.10   Use of prednisone or equivalent systemic corticosteroid within 2 weeks of sipuleucel-T. 
Use of inhaled, intranasal, intra-articular, and topical steroids is allowed. Oral or IV steroids to 
prevent or treat IV contrast reactions are allowed. 
 
4.2.11    Use of opioid analgesics for cancer-related pain  
 
4.2.12   Use of experimental drug within 4 weeks of treatment. 
 
4.2.13   Uncontrolled medical conditions including diabetes, heart failure, COPD, ulcerative 
colitis, or Crohn’s disease. 
 
4.2.14   Uncontrolled fecal incontinence. 
 
4.2.15   Any medical intervention, any other condition, or any other circumstance which, in the 
opinion of the investigator, could compromise adherence with study requirements or otherwise 
compromise the study’s objectives. 
 
5.0   STUDY TREATMENTS 
 
5.1   Radium-223 
 
5.1.1   Dosage Forms and Strength 
 
Radium-223 is available in single-use vials containing 6 mL of solution at a concentration of 
1,000 kBq/mL (27 microcurie/mL)  (1,100 kBq/mL  (29.7 microcurie/mL)after implementation 
of the NIST update) at the reference date with a total radioactivity of 6,000kBq/vial (162 
microcurie/vial) (6,600 kBq/vial (178 microcurie/vial) after implementation of the NIST update)  
at the reference date. 
 
5.1.2   Preparation  
 
Radium-223 is a ready-to-use solution and should not be diluted or mixed with any solutions. 
Each vial is for single use only. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration, whenever solution and container 
permit. 
 
5.1.3   Dosage  
 
The dose regimen of radium-223 is 50 kBq (1.35 microcurie) (55 kBq/kg (1.49 microcurie/kg) 
after implementation of the NIST update) per kg body weight, given at 4 week intervals for 6 
injections. 


27 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
The volume to be administered to a given patient should be calculated using the: 
 
– Patient’s body weight (kg) 
– Dosage level 50 kBq/kg body weight (55 kBq/kg after implementation of the NIST 
update) or 1.35 microcurie/kg body weight (1.49 microcurie after implementation of the 
NIST update) 
– Radioactivity concentration of the product (1,000 kBq/mL; 27 microcurie/mL (1,100 
kBq/mL after implementation of the NIST update;29.7 microcurie/mL) at the reference 
date 
– Decay correction factor to correct for physical decay of radium-223. 
 
The total amount (volume to be drawn into the syringe) to be administered to a patient should be 
calculated as follows:  
 
Volume to be administered (mL) = Body weight (kg) x dose (50 kBq/kg b.w)a 
                                                          DK factor x 1,000 kBq (0.027 mCi)/mLb 
 
a 55 kBq/kg after implantation of the NIST update 
b 1,100 kBq (29.7 microcuriei)/mL after implantation of the NIST update 
 
Decay Correction Factor Table 
 
 
 
The Decay Correction Factor Table is corrected to 12 noon Central Standard Time (CST). To 
determine the decay correction factor, count the number of days before or after the reference 
date. The Decay Correction Factor Table includes a correction to account for the 7 hour time 


28 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
difference between 12 noon Central European Time (CET) at the site of manufacture and 12 
noon US CST, which is 7 hours earlier than CET. 
 
Immediately before and after administration, the net patient dose of administered radium-223 
should be determined by measurement in an appropriate radioisotope dose calibrator that has 
been calibrated with a National Institute of Standards and Technology (NIST) traceable radium-
223 standard (a new reference vial will be sent to each center corresponding to the updated NIST 
reference material) and corrected for decay using the date and time of calibration. The dose 
calibrator must be calibrated with nationally recognized standards, carried out at the time of 
commissioning, after any maintenance procedure that could affect the dosimetry and at intervals 
not to exceed one year. 
 
Each center must perform the Radium Ra 223 dichloride dial setting on their relevant dose 
calibrator(s) (upon notification by Bayer each center is required to update the dial setting to 
correspond to the new NIST standard). The current dial settings are to remain in effect until 
Bayer obtains FULL approval from the FDA for implementation. In preparation for 
implementation of the NEW dial setting, the clinical study center will receive a sealed vial 
labeled NIST standard containing a Radium Ra 223 dichloride solution for calibration only. The 
vial is identical to the vials used for study treatment. The amount of Radium Ra 223 dichloride in 
the vial will be stated on the label. Instructions for the dial setting, including the calibration log 
form, will be enclosed with the dispatch of the calibration sample.  
 
All sites will be notified by Bayer when FINAL regulatory approval from the FDA is in place 
and the updated NIST standardization is to be implemented.  
 
5.1.4   NIST Standardization Update 
 
The qualification of radium-223 radioactive in Xofigo (radium-223 dichloride; BAY 88-8223) is 
based on the primary standardization performed by the US NIST. National Institute of Standards 
and Technology prepares the standard reference material (SRM) using an official dial setting 
(primary standardization) as published [20]. The NIST SRM is used to calibrate the instruments 
in production and quality control for both the drug substance and drug product. Additionally, the 
NIST SRM is used to prepare the NIST traceable Ra-223 reference materials which are then sent 
to the end-users (e.g., nuclear medicine laboratory physicians or technicians) for dial-setting of 
their dose calibrators, to allow verification of the patient dose.  
 
In 2014, NIST performed a re-assessment of the primary standardization based on preliminary 
information suggesting a potential discrepancy of approximately 8-10% between the published 
NIST primary standardization [20] and results obtained by other national metrology institutes 
(United Kingdom, Germany, Japan). After completion of the re-assessment, NIST reported their 
findings [21] and had issued a revised NIST SRM in 2015. The discrepancy in the NIST 


29 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
standardization was determined to be -9.5% between activity values obtained using the old 
reference standard relative to the new primary standardization. Consequently, the current 
numerical values need to be corrected by approximately +10.5% 
 
The current NIST standard for radium-223 dichloride will remain in effect until the FDA has 
fully approved the regulatory variation submitted for Xofigo and is anticipated in the 2nd quarter 
of 2016. All sites are expected to begin preparation for the updated NIST standardization and 
obtain all necessary IRB approvals. Bayer will continue to notify sites about the status of the 
regulatory approval and the date that the updated NIST standardization is to be implemented. 
Upon notification, and prior to the implementation, all sites are expected to add a new dial 
setting to their dose calibrators for the new NIST standardization for radium-223 dichloride, 
which should be documented on the appropriate study forms.  
 
The change in the numerical description of the patient’s dose, product strength and labeled vial 
activity does not impact the safety or efficacy of Xofigo. The change in the NIST radium-223 
standard has no impact on subjects; dose subjects are receiving, and will continue to receive. 
Subjects will receive the same actual dose and volume that was studied in Study 15245 (BCI-06 
dosimetry study) and is associated with the proven safety and efficacy of radium-223 dichloride, 
though the stated nominal radiation dose received is being updated to reflect the new standard. 
The formula for the calculation of the volume to be administered has to be changed respectively. 
(see dose section) Subjects who are on-treatment at the time the new NIST reference standard 
goes into effect should be notified of this change and should be required to sign a Patient 
Information Sheet to acknowledge that they have received information on the updated NIST 
standard calibration. All patients randomized after the new reference standard is in effect should 
sign a revised Informed Consent Form that contains the updated NIST standardization. 
 
5.1.5   Administration 
 
Radium-223 should be administered by slow IV injection over 1 minute. The IV access line or 
cannula should be flushed with isotonic saline before and after injection of radium-223. 
 
5.1.6   Handling and Patient Protection 
 
Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-
particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-
radiation is 1.1%. The external radiation exposure associated with handling of patient doses is 
expected to be low, because the typical treatment activity will be below 8,000 kBq (216 
microcurie).  (8,800 kBq (238 microcurie) after implementation of the NIST update) In keeping 
with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation 
exposure, it is recommended to minimize the time spent in radiation areas, to maximize the 
distance to radiation sources, and to use adequate shielding. Any unused product or materials 


30 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
used in connection with the preparation or administration are to be treated as radioactive waste 
and should be disposed of in accordance with local regulations. The gamma radiation associated 
with the decay of radium-223 and its daughters allows for the radioactivity measurement of 
radium-223 and the detection of contamination with standard instruments. 
 
General warning 
 
Radium-223 should be received, used and administered only by authorized persons in designated 
clinical settings. The receipt, storage, use, transfer and disposal of radium-223 are subject to the 
regulations and/or appropriate licenses of the competent official organization. 
 
Radium-223 should be handled by the user in a manner which satisfies both radiation safety and 
pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. 
 
Radiation protection 
 
The administration of radium-223 is associated with potential risks to other persons (e.g., 
medical staff, caregivers and patient’s household members) from radiation or contamination 
from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection 
precautions must be taken in accordance with national and local regulations. 
 
For drug handling 
 
Follow the normal working procedures for the handling of radiopharmaceuticals and use 
universal precautions for handling and administration such as gloves and barrier gowns when 
handling blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the 
affected area should be flushed immediately with water. In the event of spillage of radium-223, 
the local radiation safety officer should be contacted immediately to initiate the necessary 
measurements and required procedures to decontaminate the area. A complexing agent such as 
0.01 M ethylene-diaminetetraacetic acid (EDTA) solution is recommended to remove 
contamination. 
 
For patient care 
 
Whenever possible, patients should use a toilet and the toilet should be flushed several times 
after each use. When handling bodily fluids, simply wearing gloves and hand washing will 
protect caregivers. Clothing soiled with radium-223 or patient fecal matter or urine should be 
washed promptly and separately from other clothing.  
 
5.2   Sipuleucel-T 
 


31 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
The patients included in the study are scheduled for standard treatment with commercially 
available sipuleucel-T according to institutional practice and the approved product information 
(available at; http://www.dendreon.com/prescribing-information.pdf). 
 
5.2.1   Leukapheresis and Infusion Scheduling  
 
Leukapheresis appointments will be scheduled at approximately 2-week intervals. The clinical 
trial site will schedule the subject’s infusion appointments based on this schedule. If the subject 
is subsequently deemed ineligible, the clinical trial site will be informed and the leukapheresis 
and infusion appointments will be canceled.  
 
5.2.2   Leukapheresis  
 
The collection of blood cells to manufacture sipuleucel-T is analogous to that for autologous 
blood transfusions. Subjects undergo a standard 1.5 to 2.0 blood volume leukapheresis to harvest 
PBMCs (primarily lymphocytes and monocytes).  
 
5.2.3   Product Quality assessment  
 
Prior to infusion, small samples (3% to 4%) of cellular components from pre and post-culture 
(PA2024) cells will be used to assess product potency as part of the normal sipuleucel-T 
manufacturing process. Sipuleucel-T quality assessments include total TNC count, CD54+ cell 
count and CD54 upregulation. 
 
5.2.4   Sipuleucel-T Infusion  
 
Each sipuleucel-T dose is released for infusion approximately 3 days following the leukapheresis 
procedure. Subjects will be infused according to the infusion guidelines (available at; 
http://www.dendreon.com/prescribing-information.pdf). 
 
5.2.5   Sipuleucel-T Product Failures and Leukapheresis Rescheduling  
 
In the event that a subject’s leukapheresis procedure fails, sipuleucel-T does not meet quality 
release specifications, or infusion is not possible for any other reason, the subject may be 
scheduled to undergo a repeat leukapheresis procedure. A minimum of 2 days must have elapsed 
since the last leukapheresis procedure. Scheduling will depend upon capacity of the 
leukapheresis and Dendreon manufacturing facilities. If the second or third leukapheresis 
appointment is delayed or rescheduled for any reason, a physical examination and all other pre-
leukapheresis procedures must be repeated within the 5 days prior to the next leukapheresis 
procedure.   
 


32 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
5.3   Treatment Compliance 
 
Study drugs will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified sub-investigator(s).  The appropriate study personnel will maintain 
records of study drug receipt and dispensing. 
 
5.4   Drug Accountability 
 
Study drugs should be kept in a secure place and must be administered only to patients in the 
trial. A log of study drug (received, administered to patients and destroyed) must be maintained 
and signed by the person responsible for drug handling at each center. Study site/institution 
personnel will record all study drug administered during this trial on the drug-dispensing log. 
Description of monitoring of the overall drug accountability will be detailed in study and site 
specific procedures. 
 
The nuclear medicine specialist or radiation oncologist at the center is responsible for drug 
accountability for radium-223. When the drug accountability has been monitored, the vials can 
be destroyed in accordance with hospital procedure for the handling of radioactive material, 
normally after storage for 4 months from date of receipt (>10 half-lives) before disposal; they 
may then be disposed as non-radioactive waste 
 
5.5   Concomitant Medications  
 
Subjects should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, or other therapies, in accordance with standard practice at the clinical 
trial site. Subjects receiving ADT, bisphosphonate therapy such as zoledronic acid (Zometa®), or 
denosumab (Xgeva®) at the time of registration should continue the therapy at a stable dose 
during radium-223 treatment.  
 
All concomitant medications administered from screening through the last research visit at week 
58, including indication, dose, route, frequency and treatment dates, will be recorded in the 
subject’s medical record and on the CRF. After the last research visit at week 58, only anticancer 
therapies will be recorded. The first opioid taken for cancer-related pain will be recorded, 
regardless of when it is started.  
 
5.6   Prohibited and/or Restricted Treatments  
 
Subjects on ADT must continue this therapy until the post-treatment visit or disease progression, 
whichever occurs first.  
 


33 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
The following medications and interventions must not be initiated until the completion of 
radium-223 treatment or disease progression, whichever occurs first:  
 
• Investigational vaccines or other investigational products. 
• Ipilimumab or nivolumab.  
• Hemibody radiation 
 
Glucocorticoid-containing treatments should be minimized to the equivalent dose of prednisone 
10mg daily or less if feasible for the 3 months following sipuleucel-T. Use of inhaled, intranasal, 
intra-articular, and topical steroids is acceptable, as well as a short course (i.e., ≤ 1 day) of 
prophylactic steroid therapy prior to administration of IV contrast for CT imaging.  
 
5.7   Discontinuation from Study Treatments or Assessments 
 
5.7.1    Patient withdrawal 
 
In accordance with the Declaration of Helsinki, patients have the right to withdraw from the 
study at any time for any reason, without prejudice to their medical care.  The investigator also 
has the right to withdraw patients from the study for any of the following reasons: 
 
• Consent withdrawal by the subject for any reason.  
• Occurrence of AEs, if discontinuation of study medication is considered necessary by 
the Investigator and/or patient. 
• The subject develops any condition requiring a prohibited treatment (Section 5.6).  
• Lack of patient compliance 
• Protocol violation. 
• Study termination. 
• The subject is lost to follow-up.  
• Progressive disease (patients will only come off study after meeting PCWG2 and/or 
RECIST criteria for radiographic progression and not for PSA) 
 
Subjects who withdraw consent, or lose the ability to freely provide consent, will be followed by 
the investigator for survival every 3 months using the Social Security Death Index (SSDI) and 
National Death Index (NDI). Date of death, where available, will be recorded in the subject’s 
medical record and on the CRF. 
 
Whenever possible, subjects discontinuing from the study will undergo a post-treatment visit. All 
AEs considered by the investigator to be related to study treatment(s) that are ongoing at the time 
of discontinuation will be followed by the investigator until resolution or until the subject returns 
to baseline. The investigator should make every reasonable attempt to ensure that the subject is 


34 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
contacted (via telephone or during a post-treatment visit) to obtain the final status of any AEs 
and concomitant medications.  
 
5.7.2   Discontinuation from Sipuleucel-T Treatment  
 
Subjects who are unable to, or refuse to, undergo leukapheresis or receive at least 1 partial 
sipuleucel-T infusion should discontinue sipuleucel-T treatment. 
 
Subjects who have received at least 1 partial (> 0 mL) infusion of sipuleucel-T may discontinue 
sipuleucel-T without the requirement to discontinue radium-223. These subjects will continue all 
protocol-specified assessments in the active phase.  
 
Any toxicity requiring sipuleucel-T discontinuation will be recorded as an AE in the subject’s 
medical record and on the CRF. 
 
5.7.3   Discontinuation from Radium-223 Treatment  
 
Radium-223 administration may be delayed by no more than four weeks for recovery of adverse 
events. In case of a treatment delay greater than four weeks, treatment should be discontinued. It 
is important to note that in general (unless otherwise agreed), in cases where study drug has been 
ordered, the time window is reduced to -3 days to + 3 days, due to decay. If administration has to 
be postponed more than 3 days after drug has been ordered, replacement of the drug order is 
required. Dose reduction for radium-223 will not be permitted and subjects with any toxicity 
requiring radium-223 dose reduction must discontinue radium-223 treatment. 
 
Any toxicity requiring radium-223 discontinuation will be recorded as an AE in the subject’s 
medical record and on the CRF. 
 
5.7.4   Study Termination 
 
The whole study may be discontinued at the discretion of the investigator in the event of any of 
the following: 
 
• Occurrence of AEs not seen previously which by virtue of their nature, severity and 
duration are considered to necessitate study termination. 
• Hematologic adverse events criteria for study termination 
– >2 events of grade ≥ 3 thrombocytopenia or neutropenia in the first 10 subjects 
– >3 events of grade ≥ 3 anemia in the first 10 subjects 
• Medical or ethical reasons affecting the continued performance of the study. 
• Bayer is unable to provide radium-223 for the subject.  
• Dendreon is unable to manufacture siptuleucel-T in > 2 of first 10 patients. 


35 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
• Difficulties in the recruitment of patients. 
 
5.8.   Lost to Follow-Up  
 
If the subject fails to respond to requests for follow-up, the clinical trial site will send a registered 
letter, at a minimum, to the subject requesting contact with the clinic. All attempts to resume 
contact (including copies of written correspondence) will be included in the source 
documentation. Subjects who do not respond to requests for follow-up after all reasonable 
attempts to establish contact will be considered “lost to follow-up”. Subjects who are lost to 
follow-up will be followed by the investigator for survival every 3 months using the SSDI and 
the NDI. Date of death, where available, will be recorded in the subject’s medical record and on 
the CRF. 
 
5.9   Disease Progression 
 
Disease progression is determined by the investigator per the definition below. The earliest date 
of disease progression will be recorded in the subject’s medical record and on the CRF. 
Following disease progression, all study treatments will cease, the subject will undergo a post-
treatment visit and will be treated at the investigator’s discretion.  
 
5.9.1   PSA Progression 
 
Any 1 or more of the following events constitutes PSA progression:  
 
• PSA Progression based on Prostate Cancer Working Group 2 (PCWG2) criteria [1]:  
 
– Decline from baseline: the first PSA increase that is ≥ 25% and ≥ 2 ng/mL above the 
nadir, and which is confirmed by a second value 3 or more weeks later (i.e., a 
confirmed rising trend).  
– No decline from baseline: PSA progression ≥ 25% and ≥ 2 ng/mL after 12 weeks 
from baseline.  
 
PSA measurements obtained during the treatment should not be used as the sole criterion for 
determining progression. Study treatments may be continued in equivocal cases where there is 
PSA progression but no clear evidence of disease progression or clinical deterioration, and where 
the investigator feels the subject is deriving clinical benefit from the study treatments and subject 
safety is not compromised.  
 
5.9.2   Clinical and Radiographic Progression 
 
5.9.2.1   Clinical Progression 


36 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
– New spinal cord or nerve root compression.  
– New pathologic fracture.  
– Use of opioid analgesics for cancer-related pain 
 
5.9.2.2    Radiographic Progression 
 
– Disease progression based on radiographic imaging based on RECIST and PCWG2 
criteria for soft tissue and bone, respectively. 
 
6.0   STUDY ASSESSMENTS AND PROCEDURES 
  
 
6.1.   Schedule of Assessments  


37 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization update (agreed on 17 Mar 2015) 
 
a. Arm 1: sipuleucel-T and radium-223 
 
 
Screena 
Rad-1b 
Rad-2 
 
 
Rad-3 
 
 
 
 
Rad-4 
 
Rad-5 
 
Rad-6 
 
 
 
 
 
F/Ue 
 
 
PreL-1c 
Sip-1 
 
PreL-2c 
Sip-2 
PreL-3c 
Sip-3 
 
 
 
 
 
 
 
 
 
Im-1 
 
 
 
 
 
 
 
 
 
 
Im-2d 
 
Im-3 d 
 
Im-4 d 
Im-5 d 
Im-6 d 
Im-7 d 
Week 
0 
4 
6 c 
6 
8 
8 c 
8 
10 c 
10 
12 
12 d 
16 
16 d 
20 
20 d 
32 d 
45 d 
58 d 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration/ 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pathology  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rad-223 infusion 
 
x 
x 
 
 
x 
 
 
 
 
x 
 
x 
 
x 
 
 
 
 
 
Sip-T infusion 
 
 
 
 
x 
 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   P/E 
x 
x 
x 
x 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
   Vital Signs 
x 
x 
x 
x 
xf 
x 
x 
xf 
x 
xf 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
   ECOG PS 
x 
x 
x 
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Imagingg 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
xh 
Safety Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    AEs/SAEs 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xi 
Medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Anticancer Tx 
x 
x 
x 
x 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
 1st Opioid use               
x 
x 
x 
x 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lab Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematology 
x 
x 
x 
x 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
Chemistry/ LDH/ 
magnesium/phosphorus 
x 
x 
x 
x 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
   Testosterone 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   PSA 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
 
   CoagulationL 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immune Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dendreonj  
x 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
x 
x 
x 
x 
 
JH Labk 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
 


38 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization update (agreed on 17 Mar 2015) 
 
Abbreviations: AE = adverse event; A/P = abdomen/pelvis; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; F/U = follow up visit; 
Im = Immune assessment visit; JH = Johns Hopkins; MRI = magnetic resonance imaging; PAP = prostatic acid phosphatase; P/E = physical exam; PET = 
positron emission tomography; Sip = sipuleucel-T infusion visit; PS = performance status; PreL = preleukapheresis visit; PSA = prostatic specific antigen; Rad = 
radium-223 infusion visit; SAE = serious adverse event; Tx = treatment 
 
a. 
All screening procedures must occur within 28 calendar days prior to registration, with the exception of written informed consent, histological 
documentation of prostate cancer with Gleason grading, and imaging for confirmation of metastatic disease  
b. Radium-223 visits will occur 6 times at weeks 0, 4, 8, 12, 16, and 20                                                                      
c. 
Applies to all leukapheresis; pre-leukapheresis visits will occur ≤ 5 days prior to each leukapheresis. First sipuleucel-T infusion may occur any time 
between the second and third radium-223 infusion.  
d.  At baseline, week 6, 10, 14, 26, 39, and 52 post-first sipuleucel-T infusion  
e. 
Follow-up visits will occur at every 3 months after week 58 visit for additional 1 year or until the subject’s death  
f. 
Vital signs will be measured 1 to 30 minutes prior to, and at 30 minutes (± 10 min) following each infusion 
g. Bone scan and CT or MRI abdomen/pelvis 
h. Per institution’s standard procedure/at the investigator’s discretion  
i. 
Only treatment-related events will be collected  
j. 
Baseline sample can be drawn at subject’s “day one visit” (prior to dosing). See Appendix 1 for sample preparation instructions.  
k. Blood samples for antigen spread analysis will be collected at baseline (can be drawn at subject’s “day one visit” (prior to dosing) , 1st pre-leukapheresis 
visit, and weeks 14 and 52 post-first sipuleucel-T infusion. 
l. 
PTT, PT/INR 
 
 
 
 
 
 
 
 
 


39 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization update (agreed on 17 Mar 2015) 
 
b. Arm 2: sipuleucel-T alone 
 
 
Screena 
Im-1 
PreL-1b 
Sip-1 
PreL-2b 
Sip-2 
PreL-3b 
Sip-3 
 
 
 
 
 
 
 
F/Ud 
 
 
 
 
 
 
Im-2c 
Im-3 c 
Im-4 c 
Im-5 c 
Im-6 c 
Im-7 c 
Week 
0 
0 
2 
2 
4 
4 
6 c 
10 c 
14 c 
26 c 
39 c 
52 c 
 
Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration/ 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pathology  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sip-T infusion 
 
 
x 
 
x 
 
x 
 
 
 
 
 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
   P/E 
x 
x 
 
x 
 
x 
 
 
 
 
 
 
 
 
   Vital Signs 
x 
x 
xe 
x 
xe 
x 
xe 
x 
x 
x 
x 
x 
x 
 
   ECOG PS 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
Imagingf 
x 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
xg 
Safety Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   AEs/SAEs 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xh 
Medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Anticancer Tx 
x 
x 
 
x 
 
x 
 
 
 
 
 
 
 
x 
 1st Opioid use                  
x 
x 
 
x 
 
x 
 
 
 
 
 
 
 
x 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lab Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematology 
x 
x 
 
x 
 
x 
 
 
 
 
 
 
 
 
Chemistry/ LDH/ 
magnesium / phosphorus 
x 
x 
 
x 
 
x 
 
 
 
 
 
 
 
 
   Testosterone 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
   PSA 
x 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
 
   CoagulationK 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immune Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dendreoni  
x 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
 
JH Labj 
x 
 
 
 
 
 
 
 
 
x 
 
 
x 
 


40 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization update (agreed on 17 Mar 2015) 
 
Abbreviations: AE = adverse event; A/P = abdomen/pelvis; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; F/U = follow up visit; 
Im = Immune assessment visit; JH = Johns Hopkins; MRI = magnetic resonance imaging; PAP = prostatic acid phosphatase; P/E = physical exam; PET = 
positron emission tomography; Sip = sipuleucel-T infusion visit; PS = performance status; PreL = preleukapheresis visit; PSA = prostatic specific antigen; SAE = 
serious adverse event; Tx = treatment 
 
a. 
All screening procedures must occur within 28 calendar days prior to registration, with the exception of written informed consent, histological 
documentation of prostate cancer with Gleason grading, and imaging for confirmation of metastatic disease  
b. Applies to all leukapheresis; pre-leukapheresis visits will occur ≤ 5 days prior to each leukapheresis  
c. 
At baseline, week 6, 10, 14, 26, 39, and 52 post-first sipuleucel-T infusion  
d. Follow-up visits will occur at every 3 months after week 58 visit for additional 1 year or until the subject’s death  
e. 
Vital signs will be measured 1 to 30 minutes prior to, and at 30 minutes (± 10 min) following each infusion 
f. 
Bone scan and CT or MRI abdomen/pelvis 
g. Per institution’s standard procedure/at the investigator’s discretion  
h. Only treatment-related events will be collected  
i. 
Baseline sample can be drawn at subject’s “day one visit” (prior to dosing). See Appendix 1 for sample preparation instructions.  
j. 
Blood samples for antigen spread analysis will be collected at baseline (can be drawn at subject’s “day one visit” (prior to dosing), and weeks 14 and 52 
post-first sipuleucel-T infusion. 
k. PTT, PT/INR 
 
 
 
 
 
 
 
 
 


41 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
6.2   Registration 
 
After eligibility screening, patients who are selected to participate will be registered with the 
study site/institution. A record of patients who fail to meet entry criteria (ie, screen failures) will 
be maintained by each individual site. Patient registration must be complete before beginning 
any treatment or study activities. 
 
Prior to protocol enrollment and initiation of treatment, subjects must sign and date an IRB-
approved consent form.  To register a patient, the following documents must be completed and 
faxed or emailed to the Lead Center Program Coordinator: 
 
• Signed patient consent form 
• Registration Form 
• Copies of the prostate cancer pathology report, baseline laboratory studies including CBC 
with differential, liver and kidney function tests, testosterone, PSA, and CT/bone scan.  
Other materials may also be sent if considered pertinent for confirming patient eligibility. 
 
The Lead Center will review the documents to confirm eligibility.  To complete the registration 
process the Lead Center will: 
 
• Assign a patient study number 
• Register the patient on the study with SKCCC’s Clinical Research Office 
• Fax or e-mail the patient study number to the participating site 
 
6.3   Randomization 
 
Eligible subjects will be registered and randomly assigned in a 1:1 ratio to receive 6 infusions of 
radium-223 and 3 infusions of sipuleucel-T starting after second dose of radium-223 (Arm 1) or 
3 infusions of sipuleucel-T alone (Arm 2). 
 
Arm 1: 6 infusions of radium-223 with 3 infusions of sipuleucel-T starting after second 
dose of radium-223 
 
Arm 2: 3 infusions of sipuleucel-T  
 
6.4   Demographics  
 
Demographic information, including birth date, race and ethnicity will be recorded in the 
subject’s medical record and on the CRF.  
 
6.5   Clinical Assessments  


42 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
Clinical assessments will be performed at the times noted in Table 1. 
 
6.5.1   Medical History  
 
Significant historic and current medical conditions or illness, allergies to medications, and prior 
surgical interventions will be recorded in the subject’s medical record and on the CRF. 
Information regarding the subject’s history of smoking and other risk factors for CVEs will also 
be recorded.  
 
Symptoms that are ongoing at the time of, or that develop after the subject provides informed 
consent and before registration, will also be considered medical history.  
 
Medical history will include the subject’s 6 most recent PSA values, vaccinations in the two 
years prior to registration, and all prior anticancer therapies. 
 
6.5.2   Physical Examination  
 
Physical examinations will be performed at the times noted in Table 1 and must be conducted by 
an appropriately qualified investigator listed on the Form FDA 1572.  
 
The physical examinations conducted at screening and at pre-leukapheresis visits will include a 
review of the skin, pulmonary, cardiovascular, and neurologic systems, abdomen, and 
extremities. A review of additional body systems will be at the discretion of the investigator.  
 
For all other visits that call for a physical examination, the body systems reviewed will be at the 
discretion of the investigator.  
 
Each physical examination will include weight measurement. Height will be measured at 
screening only.  
 
Abnormal physical examination findings at screening will be considered part of the medical 
history and will be recorded on the Medical History CRF. Any new or worsening physical 
examination findings identified after the subject’s registration will be considered AEs and will be 
recorded in the subject’s medical record and on the CRF.  
 
6.5.3   Vital Signs  
 
Vital signs (respiration rate, temperature, heart rate, and blood pressure) will be measured at the 
times noted in Table 1. Vital signs will be recorded in the subject’s medical record and on the 
CRF. 


43 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
6.5.4   ECOG Performance Status  
 
Eastern Cooperative Oncology Group performance status will be assessed at the times noted in 
Table 1. The assessment must be conducted by an appropriately qualified investigator listed on 
the Form FDA 1572. The ECOG performance status will be recorded in the subject’s medical 
record and on the CRF.  
 
6.5.5   Imaging  
 
Subjects must have a bone scintigraphy test (bone scan) or Na-F PET or C11-acetate PET and 
CT or MRI scan of the abdomen and pelvis within 56 days prior to registration. If a bone scan is 
used, solitary lesions or lesions which could be attributed to causes other than metastatic prostate 
cancer must be confirmed with a second modality (i.e., CT or MRI).  
 
When available, standard of care scans will be used to demonstrate metastatic disease at 
screening. If scans meeting the eligibility criteria are not available, scans may be obtained during 
the screening phase. If post-screening radiographic imaging is performed per standard of care to 
assess disease progression, the same modalities used at screening should be used.  
 
6.6    Safety Assessments  
 
Safety assessments will be performed in conjunction with all visits as indicated in Table 1.  
 
6.6.1   Adverse Events and Serious Adverse Events  
 
Adverse events, including serious AEs (SAEs) will be assessed at all visits and as needed during 
the course of the study.  
 
All non-serious AEs and SAEs, regardless of relationship to study treatment, will be collected 
from registration through the week 20 and will be recorded in the subject’s medical record and 
on the CRF. Following week 20, only new treatment-related AEs and SAEs will be recorded.   
 
Only treatment-related AEs and SAEs ongoing at week 20 visit will be followed by the 
investigator until resolution, return to baseline, or a determination by the investigator that no 
further improvement is expected.  
 
See Section 7.0 for information regarding AE and SAE reporting. 
 
6.7   Concomitant Medications  
 


44 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
The subject’s current prescription and nonprescription medications will be reviewed at the 
screening visit and recorded in the subject’s medical record and on the CRF. Medications taken 
from registration through the week 20 will also be recorded. Any medications associated with a 
possible or probable treatment-related AE will be recorded on the CRF, regardless of when they 
are taken. The concomitant medication administered, indication, dose, route, frequency, and start 
and stop dates will be recorded in the subject’s medical record and on the CRF.  
 
6.7.1   Anticancer Therapies  
 
All anticancer therapies received prior to screening and through the end of the follow-up will be 
recorded in the subject’s medical record and on the CRF. Anticancer therapies include, but are 
not limited to, radiation, chemotherapy, hormone therapy, investigational cancer therapies, all 
other systemic therapies, and surgery. The start/stop date and dose of anticancer therapies will be 
recorded. 
 
6.7.2   First Cancer-Related Opioid Use  
 
Each subject’s first cancer-related opioid use, as determined by the investigator, will be recorded 
in the subject’s medical record and on the CRF. Cancer-related opioid use is defined as use for 
cancer-related pain that is of at least 2 consecutive days in duration.  
 
Opioid analgesic use for treatment or prevention of infusion reactions, such as chills or rigors, 
post-procedural pain, or for indications clearly unrelated to cancer pain (e.g., cough, pain due to 
an injury or accident) should NOT be considered cancer related. 
 
6.8   Survival Status  
 
Confirmation of survival status will be obtained by speaking directly with the subject on the 
telephone or in person. Death certificates will be obtained as a source document for the date and 
cause of death recorded on the CRF.  
 
If a death certificate cannot be obtained, one or more of the following documents (in preferential 
order) will be the source document for the date and cause of death:  
 
1. SSDI/NDI (date of death only).  
2. Hospital report.  
3. Hospice report.  
4. Clinical chart note. 
5. Other medical records.  
 
6.9   Laboratory Test Assessments  


45 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
At the times noted in Table 1, blood samples will be obtained for assessment of the parameters 
presented in Table 2. 
 
Table 2:   Clinical Laboratory Tests 
 
Hematology 
Chemistry  
hemoglobin  
sodium  
hematocrit  
potassium  
platelets  
bicarbonate  
mean corpuscular volume  
chloride  
mean corpuscular hemoglobin  
lactate dehydrogenase  
mean corpuscular hemoglobin concentration  
blood urea nitrogen  
leukocytes  
creatinine  
neutrophils  
phosphorus  
lymphocytes  
calcium 
monocytes  
magnesium 
eosinophils  
glucose 
basophils  
albumin 
  
total protein 
 
total bilirubin 
 
alkaline phosphatase 
 
alanine aminotransferase 
 
aspartate aminotransferase 
 
 
Other Assessments  
total testosterone  
prostatic specific antigen  
Coagulation  
prothrombin time  
Partial thromboplastin time 
international normalized ratio 
 
6.10   Immune Assessments  
 
6.10.1   Peripheral Immune Response Assessments 
 
Cellular and humoral immune responses will be assessed from 100 mL blood samples (9x10 mL 
heparin whole blood tubes and 1x10 mL serum tube) collected at the times noted in the Schedule 
of Assessments (Table 1).  
 
Immune response assessments will include T-cell activation to PA2024 and PAP using IFN-γ 
ELISPOT assay, T-cell proliferation response to PA2024 and PAP by 3H-thymidine uptake, and 
humoral (IgG and IgM) response to PA2024 and PAP by ELISA. 
 


46 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
The following research blood samples should be collected and processed as instructed in 
Immune Monitoring Requisition Form (Appendix 1): 
 
Ship the specimen as instructed in Immune Monitoring Shipping Instructions (Appendix 2) 
 
6.10.2   Antigen Spread Assessment 
 
Antigen spread induced by sipuleucel-T treatment will be evaluated by measuring humoral (IgG) 
response to 10 off-target antigens which were previously identified from subjects in the 
sipuleucel-T arm of IMPACT study using protein microarrays (ProtoArrays) [17]. Serum IgG 
level against each antigen will be measured using Luminex xMAP.     
 
Exploration of new secondary antigens will also be performed by detecting significant IgG 
responses using the protein microarray.     
 
At each time points (baseline, 1st pre-leukapheresis visit (only in Arm 1), and weeks 14 and 52 
post-first sipuleucel-T infusion), the following research blood samples should be collected and 
processed as outlined below: 
 
• Draw approximately 10 mL of peripheral blood into 2 plain (red top) or SST (gold top) 
tubes, each containing ≥ 5 mL of blood per vacutainer. 
• Allow blood to coagulate for 20 minutes, then centrifuge at 250C, 1500 x g (2700-3000 
rpm), for 15 minutes. 
• Pipette the serum into 10 cryotubes (about 0.5 mL/tubs). 
• Store cryotubes frozen, at - 80 0C , until the time of analysis 
 
Antigen Spread analysis will be performed in the Laboratory of Charles Drake MD/PhD at 
Johns Hopkins. Plasma pharmacokinetic samples collected at outside institutions should be 
shipped on dry ice (a minimum of 5 kg) to laboratory at Johns Hopkins, at the address below. 
Overnight shipments should occur on Monday–Thursday, except when the following day is a 
holiday. A fax or call should be placed to the laboratory prior to shipment, providing the tracking 
information. 
 
Charles Drake, MD/PhD 
Johns Hopkins Hospital 
Attn: Thomas Nirschl and Brian Francica 
 
CRB1, 4th floor, Room 416. 
1650 Orleans Street 
Baltimore, MD 21231 
Phone number:  
Lab phone: 410-502-9778  


47 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
Cell phone: 703-635-9449 or 256-975-1661  
Email: tnirsch1@jhmi.edu or bfranci3@jhmi.edu 
 
6.10.3   Product Immune Parameter Assessments 
 
Prior to infusion, small samples (3% to 4%) of cellular components from pre and post-culture 
(PA2024) cells will be used to assess product potency as part of the normal sipuleucel-T 
manufacturing process. The data of the product immune parameters will be obtained for analysis 
for correlation with clinical outcome.   
 
6.11   Study Materials  
 
The clinical trial site will have a calibrated scale for recording body weight and a calibrated 
sphygmomanometer and thermometer for vital signs assessments. A current and fully stocked 
advanced cardiac life support cart will be immediately available on the premises. The clinical 
trial site will also have a refrigerated centrifuge, a monitored and alarmed refrigerator, and a 
freezer (-20°C or below) as well as containers and dry ice for shipment of blood samples.  
 
The clinical trial site will provide all materials required for accurate documentation of subject 
visits and study activities.  
 
Materials needed for the collection of laboratory samples, including immune monitoring 
samples, will be provided by Dendreon.  
 
7.0   ADVERSE EVENTS  
 
An AE is defined as any untoward medical occurrence in a subject while on study that does not 
necessarily have a causal relationship with the treatment. An AE can, therefore, be any 
unfavorable and unintended sign (e.g., abnormal laboratory finding), symptom, or disease 
temporally associated with the treatment, whether or not considered related to the treatment. 
Adverse events include exacerbation of a pre-existing illness, an increase in frequency or 
intensity of a pre-existing episodic event or condition, a condition detected or diagnosed after 
product administration (even though it may have been present prior to the start of the study) or a 
continuous persistent disease or symptoms present at screening that worsen following the start of 
the study. 
 
7.1   Categories for Ranking Severity of Adverse Events  
 
The NCI CTCAE [2] will be used to score AE severity. In general, the following general severity 
definitions apply:  
 


48 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
Mild (Grade 1): 
The AE results in mild, easily tolerated symptoms, or is asymptomatic 
with clinical or diagnostic observations only. Intervention is not 
usually indicated. 
Moderate (Grade 2): 
The AE produces moderate symptoms with discomfort sufficient to 
interfere with some aspect of the subject’s normal daily activity. 
Minimal, local, or noninvasive intervention is required.  
Severe (Grade 3): 
The AE is medically significant but not immediately life threatening, 
results in discomfort or disability which is incapacitating and prevents 
most normal daily activities, clearly damaging to the health, requiring 
hospitalization, prolongation of existing hospitalization or 
complicated treatment.  
Life Threatening  
(Grade 4): 
The AE could reasonably result in death unless immediate medical 
intervention is undertaken.  
Fatal (Grade 5): 
The AE results in death. 
 
7.2   Relationship of Adverse Events to Study Treatments  
 
The following categories will be used to determine relatedness of AEs to study treatments:  
 
None: 
The AE is clearly related to other factors, such as the subject’s clinical 
state, environmental factors, or other modes of therapy or concomitant 
medications administered to the subject.  
Possible: 
The AE follows a reasonable temporal sequence from administration 
of study treatment, but could readily have been produced by the 
subject’s clinical state, environmental factors, or other modes of 
therapy or concomitant medications administered to the subject.  
Probable: 
The AE follows a reasonable temporal sequence from administration 
of study treatment and cannot readily have been produced by the 
subject’s clinical state, environmental factors, or other modes of 
therapy or concomitant medications administered to the subject. 
 
7.3   Adverse Events Reporting   
 
The principal investigator will notify the appropriate regulatory agencies of any SAEs occurring 
during the study period, regardless of causality. These agencies include the Sidney Kimmel 
Comprehensive Cancer Center (SKCCC) Data and Safety Monitoring Committee (DSMC), and 
the Institutional Review Board (IRB) and the Institutional Biosafety Committee (IBC) of the 
Johns Hopkins Medical Institutions (JHMI). The representatives of Dendreon will also be 
notified. Expedited reporting to the PI within 24 hours is required for all SAEs (see Section 
7.4.1). For SAEs that are fatal, life-threatening, or treatment-related but non-life threatening: 
IRB/IBC reporting by the PI is required within 3 days. For unrelated SAEs, IRB/IBC reporting 


49 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
by the PI is required within 15 days. All other AEs should be documented on CRFs and 
submitted according to the standard data management guidelines.  
 
Adverse event information will be collected continuously throughout the duration of the study. 
Participants will be instructed to notify their treating provider of any new signs or symptoms, and 
providers will actively assess patients for adverse events at each visit (including by evaluation of 
laboratory studies). The investigator will assess each AE for its severity and for its relationship to 
the study drug, and all events Grade 1 or higher will be documented on CRFs and then reported 
as described above within the required time frame. Any AE occurring while a patient is on study 
(i.e. after informed consent has been signed) or within 30 days of study termination requires 
reporting. AEs occurring later than this must still be reported if a causal relationship with the 
study drug is suspected. 
 
For all AEs, the investigator must pursue and obtain information to adequately determine the 
causality and outcome of the event, and to assess whether it meets criteria for a SAE. In addition, 
follow-up of an AE is required until the event either resolves or stabilizes.  
 
The principal investigator must keep copies of all CRFs and other AE information, including 
correspondence with the IRB and/or FDA, for as long as required to comply with national and 
international regulations. 
 
7.4   Serious Adverse Events  
 
An SAE is defined as any adverse drug experience occurring at any dose that results in any of the 
following outcomes: death, a life threatening adverse drug experience, subject hospitalization or 
prolongation of an existing hospitalization, a persistent or significant disability/incapacity, or a 
congenital anomaly/birth defect. An important medical event that may not result in death, be life 
threatening, or require hospitalization may be considered a SAE when, based upon appropriate 
medical judgment, it may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in subject hospitalization, or the development of drug 
dependency or drug abuse.  
 
7.4.1   Serious Adverse Event Collection and Reporting 
 
All SAEs and unknown/unexpected reactions that occur from the signing of the study-specific 
consent through the duration of the post-therapy adverse event collection should be reported to 
the Study Coordinator, Dendreon Safety Manager, and Bayer Global Pharmacovigilance within 
24 hours of being made aware of the SAE. If the Study Coordinator cannot be reached within 24 


50 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
hours, the PI (Emmanuel Antonarakis MD) should be contacted at 443-287-0553 or at 
eantona1@jhmi.edu. Notification can be made via phone or telefacsimile or email. 
  
Study Coordinator 
Attn:                          Serina King 
Facsimile:                  410-614-7287 
Phone:                        410-614-6139 
 
Dendreon Corporation 
Attn:                           Safety Manager 
Facsimile:                  206-829-1647 
Phone:                        206-219-7899 
After Hours:               206-274-6774 
Bayer 
Attn:                           Global Pharmacovigilance - USA  
Email                          DrugSafery.GPV.US@bayer.com 
Facsimile:                   973-709-2185 
Address: 
Mail only: 
 
Bayer HealthCare  
P.O. Box 915Whippany, NJ 07981-0915 
Address:   
 
100 Bayer Blvd., Whippany, NJ 07981  
FDX or UPS only   
67 Whippany Road, Whippany, NJ 07981 for UPS  
 
Reports for all Bayer products can also be phoned in via our Clinical Communications Dept:  
Phone:  
 
1-888-842-2937 
 
The initial report for each SAE or death to the Study Coordinator should include the following 
information:  
 
• name and contact information of the reporter 
• protocol # and title  
• patient identified by one or more of the following: 
• patient initial 
• patient identification number 
• knowledge that a patient who experienced the adverse event exists 
• age 
• sex 
• date the event occurred  
• description of the SAE  


51 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
• investigational agent(s) received (and dose level) at the time the SAE occurred  
• time from administration of the investigational agent(s) to start of the event 
• description of the patient’s condition  
 
Follow-up information including severity, causality, action taken, concomitant medications, and 
outcome should be communicated to the principal investigator as soon as possible with an 
indication whether an amendment will need to be made to the protocol, the consent form, or 
both, as a result of this event. 
 
The Investigator may report serious adverse drug reactions (SADRs) using either: 
 
An ADEERS form (Adverse Event Expedited Reporting System) available at 
http://ctep.cancer.gov/reporting/adeers.html   
 
OR 
  
 A MedWatch form available at http://www.fda.gov/medwatch/  
 
The report of SAE to Dendreon should be made using an SAE Report Form provided by 
Dendreon (Appendix 3). Significant new information regarding an ongoing SAE and the 
resolution must be sent to Dendreon within 3 business days of awareness of the new information 
to Dendreon on the SAE Report Form. 
 
Sponsor investigator shall notify institution, co-investigators and IRB immediately during the 
conduct of the study and/or after the study is completed should it become aware of information 
related to the study that would impact participant safety or clinical care. Institution shall 
promptly disclose such information to study participants. 
 
7.5   Death Reports  
 
Death is an expected outcome of this study. Deaths that meet any of the following criteria must 
be reported as an SAE:  
 
• Deaths that occur within 30 days of receiving the last study treatment.  
• Deaths that are the outcome of a SAE that occurs within 30 days from the last study 
treatment and are not due to disease recurrence.  
• Deaths that occur at any time during the study and are considered by the investigator to 
be possibly or probably related to the study treatment.  
 
Deaths that do not meet these criteria will not be reported as an SAE, but will be recorded on the 
CRF. 


52 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
7.6   Laboratory Test Result Abnormalities  
 
The following laboratory abnormalities should be captured on the AE CRF or SAE Report Form 
as appropriate: 
 
• Any clinically significant result that is not part of another reported clinical diagnosis.  
• Any result that meets the definition of an SAE.  
• Any result leading to study drug discontinuation or interruption.  
• Any result that required therapeutic intervention or a change in subject management.  
 
Laboratory abnormalities not meeting the above conditions will not be reported on the AE CRF 
or SAE report form.  
 
8.0   STATISTICAL CONSIDERATIONS  
 
8.1   General Considerations  
 
This randomized phase 2 study is designed to test the null hypothesis of no difference in immune 
response to sipuleucel-T based on PA2024-stimulated T cell proliferation via tritiated-thymidine 
uptake between sipuleucel-T alone and sequential administration of radium-223  
 
8.2   Sample Size Determination  
 
The study is designed to test the null hypothesis of no difference in the stimulation index (SI) 6 
weeks after the first vaccination with sipuleucel-T between sipuleucel-T alone and sequential 
administration of radium-223 and sipuleucel-T using PA2024-stimulated T cell proliferation via 
3H-thymidine uptake as the assay. With 15 patients per treatment group, there is 80% power to 
detect a 3.6-fold increase in mean SI between the sequential radium-223 and sipuleucel-T and 
sipuleucel-T alone (data from OpenACT trial) at 6 weeks after the first sipuleucel-T infusion 
[18]. These power calculations are based on one-sided tests at the 0.05 level.  The calculations 
assume that SI values are lognormally distributed with the same SD in each group, namely 1.4. 
The value of 1.4 comes from the P09-1 (OpenACT) trial.  
 
To allow for drop-outs and subjects who may not receive 3 infusions of sipuleucel-T or 4 
infusions of radium-223, 34 subjects will be enrolled.   
 
8.3   Populations for Analyses  
 
The immune response population will be defined as subjects who receive 3 infusions of 
sipuleucel-T and 2 infusions of radium-223. Analysis of immune response endpoints, including 


53 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
the primary endpoint, will be performed using this population. This population will also be used 
to perform supplementary analyses of non-immune response efficacy endpoints.  
 
The safety population will include all subjects who receive at least 1 leukapheresis procedure or 
receive at least 1 dose of radium-223. All safety variables (e.g., AEs, laboratory data, and vital 
sign data) will be analyzed based on the safety population. 
 
8.4   Study Termination  
 
The whole study may be discontinued at the discretion of the investigator in the event of any of 
the following: 
 
• Occurrence of AEs not seen previously which by virtue of their nature, severity and 
duration are considered to necessitate study termination. 
• Hematologic adverse events criteria for study termination 
– >2 events of grade ≥ 3 thrombocytopenia or neutropenia in the first 10 subjects 
– >3 events of grade ≥ 3 anemia in the first 10 subjects 
            Medical or ethical reasons affecting the continued performance of the study. 
• Bayer is unable to provide radium-223 for the subject.  
• Dendreon is unable to manufacture siptuleucel-T in >2 of first 10 patients. 
• Difficulties in the recruitment of patients. 
 
8.5   Endpoints  
 
8.5.1   Primary Endpoints  
 
• Peripheral PA2024-specific T-cell proliferation using a tritiated thymidine (3H-
thymidine) incorporation assay at week 6 after the first sipuleucel-T infusion in each arm 
reported as stimulation index (SI), defined as 3H-thymidine incorporation in the presence 
of PA2024 antigen divided by 3H-thymidine incorporation with media alone.   
 
8.5.2   Secondary Endpoint(s)  
 
8.5.2.1   Secondary Immune Endpoint(s)  
 
• The mean peripheral PA2024-and PAP-specific T-cell proliferation using a 3H-thymidine 
incorporation assay reported as SI at baseline and 6, 10, 14, 26, 39, and 52 weeks after 
the first infusion of sipuleucel-T. 
• The mean peripheral PA2024-and PAP-specific T-cell activation to sipuleucel-T using 
interferon gamma (IFNγ) enzyme-linked immunosorbent spot (ELISPOT) at baseline and 
weeks 6, 10, 14, 26, 39, and 52 weeks after the first infusion of sipuleucel-T. 


54 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
• The mean PA2024-and PAP-specific antibody (IgM and IgG) response to sipuleucel-T 
using enzyme-linked immunosorbent assay (ELISA) at baseline and weeks 6, 10, 14, 26, 
39, and 52 weeks after the first infusion of sipuleucel-T. 
• Product immune parameters including CD54 + cell counts and upregulation and total 
nucleated cell (TNC) counts. 
 
8.5.2.1   Secondary Clinical Endpoint(s)  
 
• The frequency of the maximum observed grade of each toxicity. Incidence and severity 
of adverse events and laboratory abnormalities, graded according to CTCAE v4.0 [2].  
• To evaluate the PSA50 response 
- 
PSA50 response is defined as at least a 50% decline in PSA from baseline 
value 
• Median time to radiographic progression using (RECIST and PCWG2 criteria for soft 
tissue and bone lesions, respectively, as assessed by the investigator). 
 
Exploratory Objectives:  
• Median time to PSA progression based on Prostate Cancer Working Group 2 (PCWG2) 
criteria [1]: 
– in patients with no PSA decline from baseline as: ≥ 25% increase from the 
baseline value and an increase in absolute value of ≥ 2 ng/mL, at least 12 weeks 
from baseline  
– in patients with an initial PSA decline from baseline as: ≥ 25% increase and an 
absolute increase of ≥ 2 ng/mL above the nadir value, which is confirmed by a 
second value obtained three or more weeks later 
• Median time to ALP progression.  
– in patients with no ALP decline from baseline as: ≥ 25% increase from the 
baseline value, at least 12 weeks from baseline 
– in patients with an initial ALP decline from baseline as: ≥ 25% increase above the 
nadir value, which is confirmed by a second value obtained three or more weeks 
later. 
• Median time to pain progression defined as use of opioid analgesics for cancer-related 
pain. 
• Median time to occurrence of first skeletal related event (SRE): 
– the use of external beam radiotherapy to relieve skeletal symptoms or the 
occurrence of new symptomatic pathological bone fractures (vertebral or non-
vertebral) or the occurrence of spinal cord compression or a tumor related 
orthopedic surgical intervention. 
• Median time to occurrence of first start of chemotherapy use.  
 
8.6   Analyses  


55 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
8.6.1   Subject Disposition  
 
Subject disposition will include, but will not be limited to, the following:  
 
• Number of subjects registered.  
• Number of subjects infused.  
• Number of subjects who prematurely discontinued the study (i.e., refused further study 
assessments [with the possible exception of survival status]).  
• Reason(s) for premature discontinuation from the study.  
• Number of subjects who died.  
• Cause of death summary.  
• Number of subjects in the immune response and safety analysis sets.  
 
In addition, the number of subjects screened for the trial will be summarized for the overall study 
population.  
 
8.6.2   Demographics and Baseline Characteristics  
 
Demographic information and baseline disease information and characteristics will be 
summarized with descriptive statistics for all analysis populations.  
 
8.6.3   Efficacy Analyses  
 
The primary efficacy analysis will compare the two randomized groups in terms of SI measured 
6 weeks after the first infusion ofsipuleucel-T. We will compute the logarithms of each patient’s 
SI and use these data in a t test to compare the two groups.   
 
A secondary analysis will look at the trends in SI over time.  This analysis will consist of a 
repeated measurement analysis of immune response over time evaluated using PA2024-
stimulated T cell proliferation via 3H-thymidine uptake based on the immune response 
population. The logarithm of response will be used for analysis. Fixed-effect terms in the model 
will include treatment arm, visit as a class effect, and a treatment-by-visit interaction. The 
correlation of responses across time within a subject will be modeled using several candidate 
variance-covariance structures including unstructured, compound symmetry, heterogeneous 
compound symmetry, autoregressive, and heterogeneous autoregressive. The variance-
covariance structure providing the smallest Bayesian information criteria will be selected for the 
final model. Fixed-effect terms in the model will be tested for significance using type III sums of 
squares. The formal test for difference between the studies will be based on the p-value for the 
treatment effect unless we find a significant treatment-by-visit interaction (p < 0.05), in which 
case by-visit treatment comparisons will be made using appropriate contrast statements. 


56 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
Estimates of treatment effect and corresponding 95% CIs will be provided on the ratio scale 
obtained by exponentiation of the model derived treatment effect and CI on the logarithm scale.   
 
Immune responses over time for other assays will be analyzed using identical methods described 
for the primary efficacy analysis, except for the IFNγ ELISPOT which we will analyze using 
ranks instead of on the logarithm scale.  
 
Because PSA and imaging scans are conducted at different time points across the two groups, the 
time-to-event secondary clinical endpoints will be summarized using generalized Kaplan-Meier 
methods for interval censored data and displayed graphically where appropriate 
 
8.6.4   Safety Analyses  
 
Safety data will be summarized descriptively in aggregate within the safety population. No 
formal statistical testing is planned for the safety data. 
 
8.6.4.1   Adverse Events  
 
Adverse events will be summarized and listed by the Medical Dictionary for Regulatory 
Activities (MedDRA) terms, by preferred term within each system organ class. Summary tables 
will include all AEs reported from the first radium-223 infusion.  
 
Summaries to be produced include the following:  
 
• Incidence within system organ class (MedDRA).  
• Incidence by decreasing frequency.  
• Incidence by NCI CTCAE severity grade, by decreasing frequency.  
• Incidence of Grade ≥ 3 AEs, by decreasing frequency.  
• Incidence of SAEs.  
• Incidence of AEs within 1 day of infusion.  
• Incidence of AEs that resulted in premature discontinuation of study treatments.  
 
Adverse events that occur multiple times for a subject will be counted only once per subject in 
incidence summary tables. In tables that enumerate AEs by severity, only the greatest severity 
for an AE occurring multiple times for a subject will be counted. 
 
8.6.4.2   Laboratory Data  
 
Summaries of laboratory data collected from baseline until study completion will include: 
 


57 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
• Incidence of clinically significant laboratory abnormalities by NCI CTCAE v4 [2]. A 
clinically significant laboratory toxicity is defined as a post-baseline grade 3 or higher 
toxicity where the baseline value was grade 2 or lower.  
• Summary statistics (mean, median, standard deviation, minimum, and maximum) for 
laboratory values and their change from baseline by time point.  
 
Baseline results will be defined as the most recent nonmissing value obtained on or prior to the 
randomization date.  
 
8.6.4.3   Vital Signs  
 
Vital sign data (blood pressure, respiration rate, heart rate, and body temperature) will be 
summarized descriptively by time point.  
 
8.6.5   Study Treatment Administration  
 
Leukapheresis and sipuleucel-T infusion information will be summarized.  
 
This will include the following:  
 
• Number of subjects who received a total of 0, 1, 2, or 3 infusions.  
• Reason(s) for not completing 3 infusions.  
• Number of subjects who receive a total of 0, 1, 2, 3, 4, or 5 or more leukaphereses.  
• Number of subjects who receive a total of 3 leukaphereses and 3 infusions of sipuleucel-
T  
 
The duration of treatment with radium-223 will be summarized. 
 
This will include the following:  
 
• Number of subjects who received a total of 0, 1, 2, 3, 4, 5, or 6 infusions.  
• Reason(s) for not completing 6 infusions.  
 
8.6.6   Concomitant Medications and Procedures  
 
Concomitant medications and procedures will be presented in data listings and will be coded 
using the World Health Organization Drug Dictionary. Separate summaries will be provided for 
medications that were started prior to registration and for medications started after registration. 
 
8.7   Interim Analyses  
 


58 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
We will carry out interim safety assessments with statistical monitoring.  We will monitor 
patients in groups of 10 (5 per treatment arm).  The formal monitoring rule relates to the risk of 
hematologic adverse events.  Specifically, we will monitor thrombocytopenia, neutropenia, and 
anemia. 
 
 
>2 events of grade ≥ 3 thrombocytopenia or neutropenia in the first 10 subjects 
 
>3 events of grade ≥ 3 anemia in the first 10 subjects 
 
9.0   REGULATORY REQUIREMENTS   
 
9.1   Investigator Responsibilities  
 
The Principal Investigator is responsible for performing the following tasks: 
 
• Coordinating, developing, writing, submitting, and obtaining IRB-approval for the 
protocol as well as its subsequent amendments.  
• Assuring that all study personnel are using the correct version of the protocol.  
• Taking responsibility for the overall conduct of the study and for monitoring the progress 
of the study.  
• Reviewing and ensuring reporting of serious adverse events (SAEs).  
• Reviewing data from all patients.  
9.2.   Study Coordinator Responsibilities 
 
The study coordinator is responsible for performing the following tasks: 
 
• Ensuring that IRB approval has been obtained prior to patient registration, and 
maintaining copies of IRB approvals (including approval of amendments).  
• Managing patient registration.  
• Collecting and compiling data from each patient.  
• Establishing procedures for documentation, reporting, and submission of AEs/ SAEs to 
the principal investigator (Emmanuel Antonarakis, MD) and other applicable parties.  
• Data entry and query answering. 
• Facilitating audits by securing selected source documents and research records from 
participating patients for audit.  
 
9.3   Study Personnel Responsibilities 
 
Study personnel (co-investigators, research nurses) are responsible for these tasks:  
 
• 
Following the protocol as written, and Good Clinical Practice (GCP) guidelines.  


59 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
• 
Submitting data to the project manager.  
• 
Registering all patients by submitting the patient registration form and signed informed 
consent form promptly.  
• 
Providing sufficient experienced clinical and administrative staff and adequate facilities 
and equipment to conduct the trial according to the protocol.  
• 
Maintaining regulatory binders and providing copies of all required documents to the 
project manager.  
• 
Collecting/submitting data according to the schedule specified by the protocol.  
 
9.4   Participating Sites Responsibilities 
 
Participating sites are responsible for performing the following tasks: 
• Following the protocol as written, and the guidelines of GCP. 
• Submitting data to the Lead Center (SKCCC) 
• Registering all patients with the Lead Center (SKCCC) by submitting patient registration 
form, and signed informed consent promptly 
• Providing sufficient experienced clinical and administrative staff and adequate facilities 
and equipment to conduct a collaborative trial according to the protocol 
• Maintaining regulatory binders on site and providing copies of all required documents to 
the Lead Center (SKCCC) 
• Collecting and submitting data according to the schedule specified by the protocol 
• Query resolving 
9.5   Patient Information and Informed Consent 
 
Before obtaining consent, members of the study team will review the rationale for the treatment 
program with the patient. The discussion will review the alternatives available (including 
hormonal therapy, chemotherapy, or supportive care as appropriate), the potential benefits of this 
program, the risks and the probability of their occurrence, and the procedures to minimize these 
risks. Should an adverse event occur, the provisions available to ensure medical intervention will 
also be reviewed. Why the risks are reasonable in relation to the anticipated benefits, incentives, 
or costs that will or may be incurred as a result of participating in the study, as well as the efforts 
to maintain confidentiality, will also be discussed with the patient. 
Patients will be required to sign and date (in triplicate) a statement of informed consent that 
meets the requirements of the Code of Federal Regulations (Federal Register Vol. 46, No. 17, 
January 27, 1981, part 50) and the IRB. The medical record will include a statement that written 
informed consent was obtained (and document the date that it was obtained) before the patient is 
enrolled in the study. The original signed document will become part of the patient’s medical 
record and a copy will be sent home with each patient. 
The consent form will include the following: 
 


60 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
• the nature and objectives, potential toxicities, and benefits of the intended study 
• the length of therapy and likely follow-up required 
• alternatives to the proposed therapy (standard and investigational therapies) 
• the name of the investigator(s) responsible for the protocol 
• the right of the patient to accept or refuse treatment and to withdraw from the study 
 
Subjects who are on-treatment at the time the new NIST reference standard goes into effect 
should be notified of this change and should be required to sign a Patient Information Sheet to 
acknowledge that they have received information on the updated NIST standard calibration. All 
patients randomized after the new reference standard is in effect should sign a revised Informed 
Consent Form that contains the updated NIST standardization. 
 
9.6   Subject Confidentiality  
 
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. After this discussion, they will be asked to 
sign a Notice of Privacy Practice research authorization/HIPAA form. The original signed 
documents will become part of the patient’s medical records, and each patient will receive a copy 
of the signed documents. The use and disclosure of protected health information will be limited 
to the individuals described in the research authorization form. The research authorization form 
must be completed by the Principal Investigator and approved by the IRB. 
 
9.7   Good Clinical Practice 
 
The study will be conducted in accordance with the ICH for GCP and the appropriate regulatory 
requirement(s).  The investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and Investigator’s Brochure.  Essential clinical 
documents will be maintained to demonstrate the validity of the study and the integrity of the 
data collected.  Master files should be established at the beginning of the study, maintained for 
the duration of the study and retained according to appropriate regulations.   
 
9.8   Ethical Considerations 
 
This study will be conducted in compliance with the protocol, GCP guidelines established by the 
International Conference on Harmonization, and the ethical standards set forth in the Declaration 
of Helsinki 2004 (available at: www.laakariliitto.fi/e/ethics/helsinki.html). 
 
10.0   STUDY MANAGEMENT  
10.1   Clinical Trial Agreement 
 


61 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
This trial is being conducted under one or more clinical trial agreements that contain, among 
other terms, the publication policy, indemnity agreements, and financial arrangements for the 
study. 
 
10.2   Lead research program coordinators 
 
A Lead Research Program Coordinator at the SKCCC coordinating center will be assigned to the 
study. A Lead Research Program Coordinator will manage the study activities at each of the 
participating sites. The responsibilities of the Lead Research Program Coordinator include 
project compliance, data collection, data entry, data reporting, regulatory monitoring, problem 
resolution and prioritization, and coordination of the activities of the protocol team. 
 
10.3   Case report forms 
 
Case report forms will be generated by Staff at the Lead Site Coordinating Center at SKCCC for 
the collection of all study data. The data should be entered in a timely manner, (within 2 weeks 
of the visit). Investigators will be responsible for ensuring that the CRFs are kept up-to-date. 
 
10.4   Source documents 
 
Study personnel will record clinical data in each patient’s source documents (ie, the patient’s 
medical record). Source documentation will be made available to support the patient research 
record. Study monitors will review entries on the CRFs at regular intervals, comparing the 
content with source documents. 
 
10.5   Study Monitoring and Quality Assurance 
 
This is a DSMP Level I study under the SKCCC Data Safety Monitoring Plan (12/6/2012). The 
SKCCC Compliance Monitoring Program will provide external monitoring for JHU-affiliated 
sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019). The SMC Subcommittee will 
determine the level of patient safety risk and level/frequency of monitoring. 
The Clinical Research Office will perform an audit after the first subject has been treated and 
then periodically depending on the rate of accrual and prior audit results. All trial monitoring and 
reporting will be reviewed annually by the SKCCC Safety Monitoring Committee.  
 
The PI is responsible for internally monitoring the study. Data must be reviewed to assure the 
validity of data, as well as, the safety of the subjects. The PI will also monitor the progress of the 
trial, review safety reports, and clinical trial efficacy endpoints and to confirm that the safety 
outcomes favor continuation of the study.”  
 
Contact the CRO QA Office (croqaoffice@jhmi.edu) with questions. 


62 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
10.6   Protocol Amendments 
 
Before starting the study, the protocol must be approved by each institution’s IRB or 
Independent Ethics Committee (IEC). Any changes to the protocol or discontinuation of the trial 
require a written protocol amendment or statement, respectively. The Investigators and IEC/IRB 
must approve the protocol amendment or statement. The Principal Investigator(s) will sign the 
protocol amendment.  
 
10.7   Record retention 
 
The investigator will maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. After study closure, the 
investigator will maintain all source documents, study-related documents, and the CRFs.  
 
Because the length of time required for retaining records depends upon a number of regulatory 
and legal factors, documents should be stored until the investigator is notified that the documents 
may be destroyed. In this study, records are to be retained and securely stored for a minimum of 
7 years after the completion of all study activities. 
 
10.8   Publication policy 
 
Bayer recognizes the right of the investigator to publish results upon completion of the 
study.  All Investigator Initiated studies are the property of the investigator and publications 
generated from such studies are at the discretion of the investigator. Bayer strongly encourages 
investigators to publish the results of all studies supported through the Investigator Initiated 
Research (IIR) Program.  
As an important milestone to the IIR, we encourage all investigators to submit a draft manuscript 
of the supporting publication(s) or abstract to submission for a courtesy review prior to 
submission of the final version for publication or congress presentation.  This will be reviewed 
promptly and will not be withheld unreasonably. All relevant aspects regarding data reporting 
and publication will be part of the contract between Bayer and the investigator/institution 
The Principal Investigator should ensure that the information regarding the study be publicly 
available on the internet at www.clinicaltrials.gov. 
 
10.8.1   Publications and NIST 
 
Bayer recommends inclusion of the new NIST standard in abstracts/ publications submitted OR 
pending publication January 2016 onwards from IIRs and other non- Bayer supported 
abstracts/publications for consistency. Investigators may choose to add a footnote to the 
publication or within the body of the publication include the new NIST standard. 


63 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
11.0   LIST OF ABBREVIATIONS 
 
Abbreviation  
Definition  
153Sm-EDTMP 
samarium-153-ethylenediaminetetrame-
thylenephosphonate 
3H-thymidine 
tritiated thymidine 
AE  
adverse event  
ADT  
androgen deprivation therapy  
ALT 
APC 
alanine aminotransferase 
antigen presenting cell 
AST 
CI 
aspartate aminotransferase 
confidence interval  
COPD 
chronic obstructive pulmonary disease 
CRF  
case report form  
CRPC  
castrate-resistant prostate cancer  
CT  
computed tomography  
DK 
decay correction factor 
DMC  
Data Monitoring Committee  
DNA  
deoxyribonucleic acid  
ECOG  
Eastern Cooperative Oncology Group  
ELISA  
enzyme-linked immunosorbent assay  
ELISPOT  
enzyme-linked immunospot assay  
FACT-P 
Functional Assessment of Cancer Therapy-Prostate 
FDA  
Food and Drug Administration  
GCP  
Good Clinical Practice  
GM-CSF  
granulocyte-macrophage colony-stimulating factor  
HR  
hazard ratio  
IB  
investigator’s brochure  
ICF  
informed consent form  
ICH  
International Conference on Harmonisation  
IEC 
IND  
Independent Ethics Committee 
Investigational New Drug  
IFNγ 
Interferon γ 
IRB  
Institutional Review Board  
IV  
intravenous  
LDH  
lactate dehydrogenase  
mCRPC  
metastatic castrate-resistant prostate cancer  
MedDRA  
Medical Dictionary for Regulatory Activities  
MRI  
magnetic resonance imaging  
NCI CTCAE  
National Cancer Institute Common Terminology 
Criteria for Adverse Events  


64 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
Abbreviation  
Definition  
NDI  
National Death Index  
NIST 
National Institute of Standards and Technology 
PAP  
prostatic acid phosphatase  
PBMC  
peripheral blood mononuclear cell  
PET  
positron emission tomography  
PSA  
prostate specific antigen  
QC 
quality control 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA  
ribonucleic acid  
SAE  
serious adverse event  
SKCCC 
SRE 
Sidney Kimmel Comprehensive Cancer Center 
skeletal related event 
SRM 
Standard Reference Material 
SSDI  
Social Security Death Index  
TNC  
total nucleated cells  
ULN  
upper limit of normal  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference List 
1. 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(7):1148-1159. 
2. NCI. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. National 
Cancer Institute; 14 Jun 2010.   2010.  
3. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63(1):11-
30. 


65 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
4. Ward JF, Moul JW. Rising prostate-specific antigen after primary prostate cancer therapy. Nat 
Clin Pract Urol 2005; 2(4):174-182. 
5. Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH et al. 
Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in 
patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006; 
24(19):3089-3094. 
6. Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L et al. Integrated data 
from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular 
immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 2009; 115(16):3670-
3679. 
7. 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 2010; 363(5):411-422. 
8. Sheikh NA, Petrylak D, Kantoff PW, Dela RC, Stewart FP, Kuan LY et al. Sipuleucel-T 
immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials 
in men with castration-resistant prostate cancer. Cancer Immunol Immunother 2013; 62(1):137-
147. 
9. Shore ND, Mantz CA, Dosoretz DE, Fernandez E, Myslicki FA, McCoy C et al. Building on 
sipuleucel-T for immunologic treatment of castration-resistant prostate cancer. Cancer Control 
2013; 20(1):7-16. 
10. Chakraborty M, Wansley EK, Carrasquillo JA, Yu S, Paik CH, Camphausen K et al. The use 
of chelated radionuclide (samarium-153-ethylenediaminetetramethylenephosphonate) to 
modulate phenotype of tumor cells and enhance T cell-mediated killing. Clin Cancer Res 2008; 
14(13):4241-4249. 
11. Henriksen G, Breistol K, Bruland OS, Fodstad O, Larsen RH. Significant antitumor effect 
from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental skeletal 
metastases model. Cancer Res 2002; 62(11):3120-3125. 
12. Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fossa SD et al. Alpha emitter 
radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369(3):213-223. 
13. Bruland OS, Nilsson S, Fisher DR, Larsen RH. High-linear energy transfer irradiation 
targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to 
conventional modalities? Clin Cancer Res 2006; 12(20 Pt 2):6250s-6257s. 
14. Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004; 350(16):1655-1664. 
15. Gulley JL, Madan RA, Schlom J. Impact of tumour volume on the potential efficacy of 
therapeutic vaccines. Curr Oncol 2011; 18(3):e150-e157. 
16. Beer TM, Bernstein GT, Corman JM, Glode LM, Hall SJ, Poll WL et al. Randomized trial of 
autologous cellular immunotherapy with sipuleucel-T in androgen-dependent prostate cancer. 
Clin Cancer Res 2011; 17(13):4558-4567. 
17. Debraj GuhaThakurta. Induction of antigen spread after sipuleucel-T treatment and its 
association with improved clinical outcome. 1(Suppl 1):P101[Journal for ImmunoTherapy of 
Cancer]. 2013.  


66 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
18. van Belle G, Martin DC. Sample-Size as a Function of Coefficient of Variation and Ratio of 
Means. American Statistician 1993; 47:165-167. 
19. Pocock SJ. The combination of randomized and historical controls in clinical trials. J Chronic 
Dis 1976; 29(3):175-188. 
20. Cessna JT, Zimmerman BE. Standardization of radium-223 by liquid scintillation counting. 
Appl. Radiat. Isot. 2010; 68(7-8):1523-1528. 
21. Zimmerman BE, Bergeron DE, Cessna JT, Fitzgerald R. Revision of the NIST standard for 
223Ra: New measurements and review of 2008 data. J Res Natl InstStand Technol. 2015; 
120:37-57.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


67 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
APPENDIX 1: Investigator Initiated Trial Immune Monitoring Requisition Form 
 
Sample Draw Instructions     
 
1.  There is an expiry limit on samples.  Schedule blood draws in the afternoon if possible.     
 
2.  Prepare 10 immune monitoring tubes from the Dendreon immune monitoring kit:     
• 1 red-top/no additive tube and 9 green-tops/sodium heparin vacutainer tubes 
• Complete subject initials, date, and time-point on the labels affixed to each vacutainer 
tube      
 
3.  Draw blood using a 21G needle into the immune monitoring tubes: 
• Draw the red-top first, followed by the green-top tubes.   
• Make sure to completely fill the vacutainer tubes (10mL per tube). Mix the tubes at least 
5 times by gentle inversion. 
• Do NOT centrifuge the immune monitoring samples. 
• Keep the immune monitoring samples at ambient temperature. No gel packs are 
required.     
 
4.  Fill out form completely, then photocopy and retain a copy with the appropriate patient 
records.     
 
5.  Notify Clinical Immunology at clinicalimmunology@dendreon.com when samples are 
shipped. 
 
 
 
 
 
 
 
 
 
 
 


68 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
Site and Subject Information 
Sponsor Investigator Name:                                            
Institution Name:    
Patient Identification:  
Subject Number:   
 
Subject Initial:
 
Subject Date of Birth:  
 
Sample Collection Information 
Immune Monitoring Time-point (check the corresponding box):   
     
Baseline           Imm-1             Imm-2            Imm-3             Imm-4                Imm-5           Imm-6 
Time Samples 
Drawn: 
 
Date Samples 
Drawn:   
Time Zone (Circle One):    
ET 
CT 
MT 
PT 
 
 
Sample Collected By:  
 
 
 
 
 
Signature 
 
 
 
Full Name (Capitals) 
 
 
 
 
 
 
 
 
 


69 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
APPENDIX 2: Dendreon Specimen Shipping Instructions 
 
 


70 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
 
 
 
 
Immune Monitoring Shipping Instructions for Sponsor Investigators 
 
Notifying Dendreon of specimen collection: 
 
1. Dendreon requires a minimum of 24 hours notice before the specimens arrive at 
Dendreon. 
2. At least 24 hours prior to Dendreon receiving the specimens:  
a. Contact Dendreon by e-mail at: clinicalimmunology@dendreon.com.   
b. Provide the following information: 
i. Complete subject number 
ii. Date of specimen collection 
iii. FedEx air bill number 
 3.   If the specimen is not collected as planned, contact Dendreon right away by email. 
 
Shipping the specimen: 
 
1. After the subject’s blood draw is complete, wrap specimen tubes in the absorbent cloth 
provided and place into the main pouch of the 95 kPA flexible envelope. 
2. Remove the adhesive backing from the flexible envelope and seal by folding along the 
“FOLD HERE” slit at the opening of the envelope. 
3. Press very firmly at the middle of the slit, working outward to achieve a complete seal. 
4. Make a photocopy of the completed Investigator Initiated Trial Immune Monitoring 
Requisition Form and include in the blood shipping box. 
5. Keep the original Investigator Initiated Trial Immune Monitoring Requisition Form with 
the subject’s medical record. 
6. Wrap one bubble-wrap sheet around the sealed flexible envelope to provide additional 
protection for the specimen tubes.  The bubble-wrap should be secured around the 
flexible envelope with adhesive tape. 
7. Place the bubble-wrapped, sealed flexible envelope containing the specimens inside the 
shipping carton and tape the carton closed with 2-inch wide packing tape. 
8. Place the sealed carton inside the UN3373 pak orange bag, remove the adhesive 
backing and completely seal the bag.   
9. Fill out the FedEx billable stamp with your information and attach label to the package.  
Do not cover the UN3373 orange label. 


71 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization 
update (agreed on 17 Mar 2015) 
 
10. Saturday, Sunday, and holiday deliveries are not acceptable.  A list of holidays has been 
provided. 
11. Send the sample(s) priority overnight via FedEx Next Day to: 
 
Dendreon Corporation 
Attention: Clinical Immunology 
1208 Eastlake Avenue E, Seattle, WA   98102 
Phone: 206-829-1639 
 
 


72 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization update (agreed on 17 Mar 2015) 
 
APPENDIX 3: Dendreon SAE Form 
 
 


73 
 
Version 4.0 Date: 08/21/2020                                                             NCT02463799 
The values for radium-223 in this protocol has been revised as per the US NIST standardization update (agreed on 17 Mar 2015)