A Pilot Study of Rituximab Neoadjuvant Therapy in Patients With High Risk Prostate Cancer Scheduled to Undergo Radical Prostatectomy
Phase: EARLY_PHASE1
Conditions: Prostate Cancer
Sponsor: Christopher Kane

A Pilot Study of Rituximab Neoadjuvant Therapy in 
Patients with High Risk Prostate Cancer Scheduled to 
Undergo Radical Prostactecomy
NCT01804712
Document Date: December 18, 2023

CONFIDENTIAL 
This material is the property of the Moores Cancer Center.  Do not disclose or use except as 
authorized in writing by the study sponsor. 
A Pilot Study of Rituximab Neoadjuvant Therapy in Patients with 
High Risk Prostate Cancer Scheduled to Undergo Radical 
Prostatectomy 
PRINCIPAL INVESTIGATOR 
Stephen B. Howell, M.D. 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0819 
La Jolla, CA 92093-0819 
Phone: (858) 822-1112 
Fax: (858) 822-1111 
Email: showell@ucsd.edu 
Study Drug:  
Rituximab (Rituxan®) 
Initial Version: 
February 27, 2013 
Amendment 1: 
July 1, 2013 
Amendment 2: 
December 18, 2013 

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Version Date December 18, 2013 
 
Page 2 of 43 
LIST OF INVESTIGATORS 
 
PRINCIPAL INVESTIGATOR 
Stephen B. Howell, M.D. 
Department of Medicine 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0819 
La Jolla, CA 92093-0819 
Phone: (858) 822-1112 
Fax: (858) 822-1111 
Email: showell@ucsd.edu 
 
BIOSTATISTICIAN 
Karen Messer, Ph.D. 
Department 
of 
Family 
& 
Preventative 
Medicine 
University of California, San Diego 
Moores UCSD Cancer Center 
3855 Health Sciences Drive #0901 
La Jolla CA, 92093-0901 
Phone: 858-822-6823 
E-mail: kmesser@ucsd.edu 
SUB-INVESTIGATORS 
Christopher Kane, M.D.  
Department of Surgery 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093-0987 
Phone: (858) 822-6187 
E-mail: ckane@ucsd.edu 
Christina Jamieson, Ph.D. 
Department of Surgery 
University of California, San Diego 
Moores UCSD Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla CA, 92093-0987 
Phone: (858)-822-2808 
E-mail:  camjamieson@ucsd.edu 
 
Ahmed Shabaik, M.D. 
Department of Pathology 
University of California, San Diego 
200 W. Arbor Drive #8720 
San Diego, CA 92103-8720 
Phone: (619) 543-6280 
E-mail: ashabaik@ucsd.edu 
Michael Karin, Ph.D. 
Department of Pharmacology 
University of California, San Diego 
9500 Gilman Drive #0723 
La Jolla, CA 92093 
Phone: (858) 534-0872 
E-mail: mkarin@ucsd.edu 
 
Frederick Millard, M.D. 
Department of Medicine 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093-0987 
Phone: (858) 822-6185 
Email: fmillard@ucsd.edu 
 
James Michael Randall, M.D. 
Department of Medicine 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093-0987 
Phone: (858) 822-5381 
Email: jrandall@ucsd.edu 
Michael Liss, M.D. 
Department of Surgery 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093-0987 
Phone: (858) 822-7874 
Email: mliss@ucsd.edu 
 
 
 
 

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Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Neoadjuvant rituximab for prostate cancer 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ........................................................................................................................................................ 5 
STUDY SUMMARY ...................................................................................................................................................................... 6 
1.0 
BACKGROUND AND RATIONALE ............................................................................................................................ 8 
1.1 
PROSTATE CANCER ......................................................................................................................................................................... 8 
1.2 
INFLAMMATION AND SIGNIFICANCE IN CANCER ......................................................................................................................... 8 
1.2.1 
Pre-Clinical Studies at UCSD ......................................................................................................................................... 9 
1.3 
RITUXIMAB ..................................................................................................................................................................................... 12 
1.4 
RATIONALE..................................................................................................................................................................................... 12 
2.0 
STUDY OBJECTIVES ................................................................................................................................................. 13 
2.1 
PRIMARY OBJECTIVES................................................................................................................................................................... 13 
2.2 
SECONDARY OBJECTIVES.............................................................................................................................................................. 13 
2.3 
ENDPOINTS ..................................................................................................................................................................................... 13 
3.0 
STUDY DESIGN........................................................................................................................................................... 14 
3.1 
DESCRIPTION OF THE STUDY ....................................................................................................................................................... 14 
3.2 
SAFETY PLAN.................................................................................................................................................................................. 15 
3.2.1 
Adverse Events Using Rituximab .............................................................................................................................. 15 
3.2.2 
General Plan to Manage Safety Concerns ............................................................................................................ 18 
4.0 
MATERIALS AND METHODS ................................................................................................................................. 18 
4.1 
PATIENTS ........................................................................................................................................................................................ 18 
4.1.1 
Inclusion Criteria .............................................................................................................................................................. 18 
4.1.2 
Exclusion Criteria ............................................................................................................................................................. 19 
4.2 
STUDY TREATMENT ....................................................................................................................................................................... 19 
4.2.1 
Rituximab Formulation ................................................................................................................................................. 19 
4.2.2 
Rituximab Dosage, Administration, and Storage............................................................................................ 19 
4.2.3 
Rituximab Dose Modifications ................................................................................................................................... 20 
4.3 
CONCOMITANT AND EXCLUDED MEDICATIONS ......................................................................................................................... 21 
4.3.1 
Supportive Care Guidelines ......................................................................................................................................... 21 
4.3.2 
Excluded Medications and Treatments................................................................................................................. 21 
4.4 
STUDY ASSESSMENTS .................................................................................................................................................................... 21 
4.4.1 
Definitions of Study Assessments ............................................................................................................................. 21 
4.4.2 
Screening and Pretreatment Assessments ......................................................................................................... 23 
4.4.3 
Evaluation and Procedures During Treatment ................................................................................................ 23 
4.4.4 
Surgery ................................................................................................................................................................................... 24 
4.4.5 
End of Treatment Visit ................................................................................................................................................... 24 
4.4.6 
Follow-up .............................................................................................................................................................................. 25 
4.5 
ASSAY METHODS ............................................................................................................................................................................ 25 
4.5.1 
Blood collection for research ..................................................................................................................................... 25 
4.5.2 
Tissue Procurement ........................................................................................................................................................ 25 
4.5.3 
Immunohistochemistry ................................................................................................................................................. 25 
4.6 
PATIENT DISCONTINUTATION ...................................................................................................................................................... 26 
4.7 
DATA QUALITY ASSURANCE .......................................................................................................................................................... 26 
5.0 
STATISTICAL METHODS ..................................................................................................................................... 26 
5.1.1 
Study Design and Justification of Sample Size .................................................................................................. 27 
5.1.2 
Analysis of the Study Conduct .................................................................................................................................... 27 
5.1.3 
Analysis of Demographic and Baseline Characteristics .............................................................................. 27 
5.1.4 
Primary Analysis .............................................................................................................................................................. 28 
5.1.5 
Secondary Analyses ......................................................................................................................................................... 28 

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6.0 
ASSESSMENT OF SAFETY ....................................................................................................................................... 29 
6.1 
SPECIFICATION OF SAFETY VARIABLES ..................................................................................................................................... 29 
6.1.1 
Adverse Events ................................................................................................................................................................... 29 
6.1.2 
Serious Adverse Events .................................................................................................................................................. 30 
6.2 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES .................................................................... 30 
6.2.1 
Adverse Event Reporting Period ............................................................................................................................... 30 
6.2.2 
Assessment of Adverse Events ................................................................................................................................... 31 
6.2.3 
Eliciting Adverse Events ................................................................................................................................................ 31 
6.2.5 
MedWatch 3500A Reporting Guidelines .............................................................................................................. 33 
6.3 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS .............................................................................................................. 34 
6.3.1 
Expedited Reporting of Serious Adverse Events............................................................................................... 34 
6.3.2 
Routine Reporting of Adverse Events .................................................................................................................... 35 
6.4 
TYPE AND DURATION OF FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS ................................................................ 35 
7.0 
INVESTIGATOR REQUIREMENTS ........................................................................................................................ 36 
7.1 
OBLIGATIONS OF INVESTIGATORS .............................................................................................................................................. 36 
7.2 
CONFLICT OF INTEREST ............................................................................................................................................................... 36 
7.3 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT ..................................................................................... 36 
7.4 
SUBJECT DATA PROTECTION ....................................................................................................................................................... 36 
7.5 
DATA AND SAFETY MONITORING/AUDITING .......................................................................................................................... 37 
7.6 
STUDY MEDICATION ACCOUNTABILITY ...................................................................................................................................... 37 
7.7 
RECORD RETENTION .................................................................................................................................................................... 37 
8.0 
REFERENCES .............................................................................................................................................................. 38 
9.0 
APPENDICES ............................................................................................................................................................... 40 
APPENDIX A. PERFORMANCE STATUS ....................................................................................................................................................... 40 
APPENDIX B. SCHEDULE OF EVENTS .............................................................................................................................................. 41 
APPENDIX C. GENENTECH SAFETY REPORTING FAX COVER SHEET..................................................................................................... 42 
 
 
 

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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CLL 
Chronic Lymphocytic Leukemia 
CMP 
Comprehensive Metabolic Panel 
CRPC 
Castration-resistant Prostate Cancer 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
HRPP 
Human Research Protections Program 
IHC 
Immunohistochemistry 
IRB 
Institutional Review Board 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin’s Lymphoma 
PSA 
Prostate-specific Antigen 
SAE 
Serious Adverse Event 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
TURP 
Transurethral resection of the prostate 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
 
 
 

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STUDY SUMMARY 
Title 
A Pilot Study of Rituximab Neoadjuvant Therapy in Patients with High 
Risk Prostate Cancer Scheduled to Undergo Radical Prostatectomy 
Short Title 
Neoadjuvant rituximab for prostate cancer 
Phase 
Pilot 
Methodology 
Open label, non-randomized, single arm 
Study Duration 
50 days + 3 years of follow-up 
Study Center(s) 
Single-center: UCSD 
Objectives 
Primary Objective 
To determine the histologic response rate in patients with high risk 
prostate cancer receiving one treatment cycle of neoadjuvant rituximab 
prior to radical prostatectomy, defined as an extent of B cell infiltration 
within the tumor region of the prostatectomy specimen of ≤ the 18.2 
percentile of the B cell content from 27 historical control samples. 
 
Secondary Objectives 
1. To determine the effectiveness of neoadjuvant rituximab in the 
treatment of prostate cancer as evaluated by the serum PSA. 
 
2. To determine the effect of neoadjuvant rituximab on the serum 
CXCL13 concentration.  
 
3. To determine the effect of neoadjuvant rituximab on peripheral 
blood B lymphocyte count. 
 
4. To assess the safety and tolerability of neoadjuvant rituximab. 
 
5. To explore the impact of neoadjuvant rituximab on 
immunohistochemical staining profiles of primary tumors including 
expression of: IKKα; BMI1; ubiquintinated histone 2A; B cell 
marker CD20; T cell markers CD3, CD4, and CD8; macrophage 
markers CD68 and CD11b; αSMA; CXCL13; LTα and LTβ, and 
LTβR. 
  
6.  To understand the long term impact of neoadjuvant rituximab in 
the treatment of prostate cancer on biochemical relapse based on 
PSA levels collected during standard of care follow-up. 
 
Number of Subjects 
18 
Patient Population 
Inclusion Criteria 
1. Ability to understand and provide written informed consent. 
 
2. Patient has EITHER: 
• 
A Kattan nomogram predicted probability of being disease free 5 
years after surgery of < 60%, OR 
• 
A Gleason sum ≥ 8. 
 
3. Indicated for radical prostatectomy. 
 
4. Eastern Cooperative Oncology Group (ECOG) performance status 
of 0-1. 
 

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5. Males aged ≥ 18 years. 
 
6. Adequate organ function as defined below measured within 21 days 
of study entry: 
Hematology: 
• 
Absolute Neutrophil Count (ANC) 
≥ 1.5 x 109/L 
• 
Platelet count   
 
 
≥ 100 x 109/L 
• 
Hemoglobin  
 
 
 
≥ 9.0 g/dL 
• 
White blood cell (WBC) count  
≥ 3.0 x 109/L 
 
Biochemistry: 
• 
AST/SGOT and ALT/SGPT  
≤ 2 x institution’s upper limit of  
 
 
 
 
normal (ULN)  
• 
Total bilirubin   
 
<1.5 times ULN 
• 
Serum creatinine  and BUN 
<1.5 times ULN 
• 
Na, K Cl, CO2, Ca, PO4  
within institutional limits 
 
Exclusion Criteria 
1. Received prior treatment for prostatic adenocarcinoma including prior 
surgery (excluding TURP), radiation therapy, or chemotherapy. 
 
2. Current or past use of investigational agents within 4 weeks of study 
enrollment. 
 
3. Use of erectile dysfunction drugs (e.g., Cialis, Viagra) within 14 days 
prior to treatment or during study. 
 
4. Evidence of metastatic disease on cross sectional imaging or bone 
scan. 
 
5. History of hepatitis B or C, HIV, tuberculosis or a chronic infection of 
any type. 
 
6.  Positive test results for chronic hepatitis B infection (defined as 
positive HBsAg serology) 
 
7. Positive test results for hepatitis C (hepatitis C virus [HCV] antibody 
serology testing). 
 
Study Product(s), Dose, 
Route, Regimen 
Rituximab: 375 mg/m2 intravenously once weekly. 
Duration of administration 
One cycle ( 1 cycle = 28 days) 
Reference therapy 
Historical response 
Statistical Methodology 
The null hypothesis is that a single cycle of rituximab will produce a 
histologic response in 20% or fewer   patients. The study will be powered 
to detect a true response rate of 50% or greater. This trial will use a 
Simon two stage design with an α of 0.05 and a β of 0.20 (power 0.8).  
The trial will enroll an initial cohort of 8 patients; if 3 or more have a 
histologic response the trial will continue and 10 more patients will be 
entered for a total of 18 patients. If 7 or more patients have a histologic 
response the null hypothesis will be rejected and it will be concluded that 
rituximab is associated with histologic response in more than 20% of 
patients.   
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
PROSTATE CANCER 
Prostate cancer is the most frequently diagnosed cancer in men and the second leading cause 
of cancer-related death in men in the United States. Hormonal ablation, with either surgical or 
medical castration, is the cornerstone of initial management of advanced prostate cancer. 
However, almost all patients with distant metastases will develop androgen-independent cancer 
within 18 to 24 months after castration and succumb to their disease (1, 2). Patients with 
metastatic castration-resistant prostate cancer (CRPC) have a median survival of 10 to 12 
months. Historically, chemotherapy was not considered to have significant activity in metastatic 
CRPC. However, practice patterns have altered during the last 10 years, in part due to the 
availability of prostate-specific antigen (PSA) measurements to monitor tumor burden and 
results of randomized trials. Recent studies have established roles for docetaxel, abiraterone, 
and the less cross-resistant taxane, cabazitaxel  (3). Nevertheless, the prognosis for men with 
CRPC remains poor and additional approaches to the management of this disease are needed. 
1.2 
INFLAMMATION AND SIGNIFICANCE IN CANCER 
A link between inflammation and cancer was proposed nearly 150 years ago (4).  In the past 
decade, studies using mouse models of human cancer have illustrated several key mechanisms 
that link inflammation to tumor development and progression (5).  Quite frequently, inflammatory 
signals, mainly cytokines, produced by immune cells within the tumor microenvironment lead to 
paracrine activation of transcription factors, such as NF-κB and STAT3, within pre-malignant 
cells, thereby enhancing survival and proliferation of cancer progenitors. Usually, this crosstalk 
does not involve irreversible genetic changes, although oncogenic mutations can result in up-
regulation of chemokine gene expression in malignant cells, thus promoting establishment of a 
pro-tumorigenic inflammatory microenvironment (6). Nonetheless, chronic inflammation may 
also enhance tumor initiation and/or malignant progression through induction of oncogenic 
mutations, chromosomal instability and epigenetic changes (7). The mechanisms and pathways 
through which inflammation elicits epigenetic changes that contribute to tumor development and 
progression are unknown.  
 
Inflammation is also of importance in wound repair and tissue regeneration and it has been 
pointed out that tumors are analogous to wounds that do not heal (8). Furthermore, signaling 
pathways that play a major role in tissue regeneration and stem cell renewal, namely the Wnt 
and Hedgehog pathways, are also key players in tumorigenesis (9).  However, it is unknown 
whether and how Wnt and Hedgehog signaling are activated in response to inflammatory 
signals generated by tissue injury. It is also not clear how tissue injury leads to stem cell 
activation.  
 
 
Another signaling pathway involved in inflammation, tissue repair and cancer is the NF-κB 
pathway (10). Recent studies of the roles of NF-κB transcription factors in cancer have focused 
on components of the IκB kinase (IKK) complex, namely the IKKα and IKKβ catalytic subunits 
(11).  While both kinases can activate NF-κB-mediated transcription, IKKα also has NF-κB-
independent functions in development (12-14) and tumorigenesis (15-17). NF-κB-independent 
activities of IKKα are particularly evident in prostate cancer.  The growth of CRPC depends on 
emergence of cancer stem-like cells that either do not require androgen signaling for growth and 
survival, are highly sensitive to castrate levels of androgens such that the low levels present in 
following castration are still sufficient to support growth  (18), or have an alteration in the 

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androgen receptor that render it constitutively active. Androgen ablation results in an 
inflammatory response, characterized by lymphocyte infiltration and production of cytokines that 
activate IKKα in surviving prostate cancer and this, in turn, accelerates the emergence of CRPC  
(15).  
 
 
The castration-induced inflammatory response is thought to be triggered by the death of 
androgen-deprived prostate cancer cells, which causes the release of signals that induce 
expression of inflammatory chemokines by components of the tumor stroma. This leads to 
recruitment of a heterogeneous collection of immune cells, of which B lymphocytes are 
particularly important as they serve as the main source of lymphotoxin, a heterodimeric member 
of the TNF family that activates IKKα (15).  Ablation of B cells or inhibition of their recruitment 
into the regressing tumors by neutralization of the B cell chemoattractant CXCL13 prevents 
IKKα activation and delays prostate cancer re-growth. IKKα is not required for primary tumor 
growth; however, it is required for metastatic spread, and lymphotoxin signaling leads to nuclear 
accumulation of IKKα (16). However, the molecular mechanisms by which nuclear IKKα 
enhances the survival and proliferation of progenitor cells that give rise to metastases and 
prostate cancer are not clear, although it was found that nuclear IKKα promotes metastasis 
through repression of the SBP5 gene, which codes for the metastasis inhibitor maspin (16). 
Previous studies suggested that nuclear IKKα acts as a histone H3 kinase (19, 20), whereas 
other reports have described an interaction between IKKα and the histone acetylase (HAT) 
CBP/p300 that results in phosphorylation of the latter (21). IKKα was also reported to regulate 
expression and activity of transcription factor E2F1 (22) and counteract SMRT repressor activity 
leading to acetylation of p65/RelA by p300 (23). 
 
1.2.1 Pre-Clinical Studies at UCSD 
Recent studies from Dr. Michael Karin’s laboratory at UCSD in both a syngeneic and xenograft 
mouse model of prostate cancer have demonstrated a key role for B cells in the growth of 
CRPC  (15).  B and T lymphocyte infiltration was detected in 100% of human prostate cancer 
samples, but B cells were undetectable in normal prostate or benign prostatic hyperplasia. In 
the mouse models, castration was found to result in an inflammatory response with infiltration of 
the tumor with T and B cells. B cell infiltration was in response to increased levels of CXCL13 
and resulted in the production of lymphotoxin. Antibody-mediated neutralization of CXCL13 
reduced lymphotoxin production.   
 
The re-growth of androgen-independent tumors following castration was found to be dependent 
on B cells.  As shown in Figure 1, reconstitution of host bone marrow with marrow from mice 
lacking B and T cells (Rag1) that had been supplemented with proficient B cells enhanced the 
re-growth of androgen-independent tumors, whereas reconstitution with marrow from mice 
lacking B cells but with added proficient T cells did not. Lymphotoxin expression in regressing 
tumors was absent unless mice were reconstituted with proficient B cells, and flow cytometry 
localized lymphotoxin to tumor infiltrating B cells. As shown in Figure 2, treatment of mice with 
anti-CD20 antibody significantly delayed tumor re-growth (15). 
 
 
 
 
 
 
 

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Figure 1. Role of B cells in development of androgen-independent prostate cancer. Myc-
CaP tumors were established in WT mice reconstituted with bone marrow from Rag1−/− males 
(n=10) or in Rag1−/− males. When tumors reached 1000 mm3, mice were castrated. Three days 
before castration, Rag1−/− mice (n=10 per group) received via the tail vein purified splenic B or 
T cells. Tumor volume was measured. Results are averages ± SEM. . Reproduced from 
reference (15). 
 
 
Figure 2.  The effect of anti-CD20 antibody 
treatment on the re-growth of AIPC following 
castration.  FVB mice (n=5 each group) were 
inoculated with myc-CaP cells, castrated as 
above and were given IgG2a or anti-CD20 (200 
μg) every 5 days by IP injection starting 4 days 
before castration. Tumor volume was measured 
as above. Results are averages ± SEM. (Karin, 
M, unpublished). 
 
 
 
 
Prostate cancer allografts from castrated, but not sham-operated, mice exhibited IKKα nuclear 
translocation. Silencing of IKKα in the tumor cells using siRNA delayed CRPC re-growth. 
Nuclear translocation of IKKα was dependent on IKKβ in bone marrow B cells.  IKKβ deletion 
abolished lymphotoxin expression by B cells (Figure 3A). To examine whether lymphotoxin 
production by tumor-infiltrating B lymphocytes stimulates CRPC re-growth, marrow from B-
Ltβ−/− or T-Ltβ−/− mice, which lack lymphotoxin-β, was transplanted into lethally irradiated 
mice. Lymphotoxin-β ablation in B cells, but not in T cells, delayed growth of CRPC and 
abolished lymphotoxin-β expression within tumors but did not prevent B cell or macrophage 
infiltration (Figure 3B). Treatment of mice with the lymphotoxin-βR-Ig decoy was as effective as 
B cell-specific lymphotoxin-β ablation in delaying CRPC re-growth and prevented IKKα and 
STAT3 activation (Figure 3C). Silencing of LTβR in Myc-CaP cells also delayed growth of 

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castration-resistant CaP (Figure 3D). Exogenous lymphotoxin maintained prostate cancer 
growth in the presence of flutamide in a manner dependent on IKKα whose nuclear 
translocation was lymphotoxin inducible.  
 
 
Figure 3. IKKβ-dependent lymphotoxin production by tumor-infiltrating B cells stimulates 
IKKα-dependent androgen-free survival.  A. RNA from splenic B cells of IkkβF/F and IkkβΔ/Δ 
mice was analyzed for LTα and LTβ expression as above. Results are averages ± SD (n=3).  B. 
Lethally irradiated FVB males were reconstituted with BM from B-Ltβ−/− or T-Ltβ−/− mice (n=6 
per group). After 8 weeks, myc-CaP tumors were established, mice were castrated and tumor 
volume was measured as above. Results are averages ± SEM.  C. FVB mice (n=6 each group) 
bearing myc-CaP tumors were castrated and given hIgG or LTβR-Ig (100 μg) every 5 days, 
starting 4 days before castration.  Tumor volume was measured as above. Results are 
averages ± SEM.  D. Tumors were established using myc-CaP cells transduced with 
lentiviruses expressing scrambled (sc) siRNA or LTβ-specific siRNA. Mice were castrated and 
tumor volume was measured. Results are averages ± s.e.m. (n=10).  
 
The results from these animal models suggest that an inflammatory response triggered by death 
of androgen-deprived primary cancer is an important contributor to emergence of CPRC.  
Tumor infiltrating B cells, which produce lymptoxin-α:β heterotrimers that stimulate the LTβR on 
prostate cancer cells to induce IKKα nuclear translocation and STAT3 activation, enhance 
androgen-independent growth.  Interference with any component of this response results in a 
significant and reproducible 3-4 week delay in appearance of CRPC in animal models. Although 
these inhibitory effects are not absolute, extrapolation from “mouse time” to “human time” 
suggests that interventions that prevent lymphotoxin production or signaling may delay 
appearance of CRPC in patients undergoing androgen ablation therapy by 2.3 to 3.1 years. 
Importantly, the available data suggest that, at least for prostate cancer, the inflammatory 

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response elicited by the dying primary tumor contributes to the failure rather than the previously 
proposed success of anti-cancer therapy (24).  
 
1.3 
RITUXIMAB 
Rituximab (Rituxan) is a genetically engineered chimeric murine/human monoclonal antibody 
against the CD20 antigen (human B-lymphocyte-restricted differentiation antigen, Bp35). Initial 
FDA approval was granted in 1997 for the treatment of patients with relapsed or refractory B-cell 
Non-Hodgkin’s Lymphoma (NHL). In the pivotal study, rituximab caused a rapid depletion of 
circulating and tissue-based B-cells generally within the first three doses, with sustained 
depletion for up to 6-9 months after treatment in about 83% of patients. Rituximab has 
subsequently been approved for several additional indications including  chronic lymphocytic 
leukemia (CLL), rheumatoid arthritis, Wegener’s granulomatosis and microscopic polyangiitis. 
Common adverse reactions observed in clinical trials of lymphoid malignancies were infusion 
reactions, fever, lymphopenia, neutropenia, chills, infection and asthenia; a more complete 
listing of adverse reactions are found in Section 3.2.1. 
 
Rituximab is prescribed for NHL patients at 375 mg/m2 intravenously (IV) once weekly. Four to 
eight doses are administered, depending on the indication, with a maximum of sixteen doses. 
For previously untreated and treated CD20-positive CLL, one dose of rituximab 375 mg/m2 is 
given prior to fludarabine and cyclophosphamide (FC), followed by  500 mg/m2 once monthly for 
5 months. For the treatment of rheumatoid arthritis 1000 mg rituximab is administered two 
weeks apart.  This study will utilize the schedule approved for the treatment of NHL of 375 
mg/m2 rituximab for 4 weekly doses which should allow for sufficient B cell depletion prior to 
surgery to detect changes in tumor B cell infiltration. 
 
1.4 
RATIONALE 
The data from the animal models focused on the emergence of CRPC following castration. 
Castration induces an inflammatory response that triggers B cell and lymphotoxin-mediated 
proliferation of androgen-independent cells that can be interrupted with an anti-CD20 antibody. 
While the optimal time to initiate rituximab therapy may be immediately after the institution of 
androgen deprivation therapy or cytotoxic chemotherapy due to the high level of inflammation 
produced by these treatments, it has now been well-documented that essentially all prostate 
cancers contain inflammatory cells irrespective of their androgen dependency.  Since some 
level of cell death and consequent inflammation is a constant ongoing process in human 
prostate cancers, treatment with rituximab may be effective when instituted at various stages 
during the tumor’s growth rather than just at the time of peak tumor cell death.  While it will 
eventually be important to determine whether the addition of rituximab to anti-androgen therapy 
can reduce the emergence of CRPC, there is no medical or ethical basis for doing serial 
biopsies on patients initiating anti-androgen therapy which precludes the opportunity to study 
pharmacodynamic endpoints of rituximab treatment. Instead, we will capitalize on the 
neoadjuvant setting to obtain initial pharmcodynamic evidence of rituximab effect in patients 
whose original diagnostic biopsy and subsequent radical prostatectomy sample are available for 
analysis. This is a uniquely appropriate population in which to address the question of whether 
rituximab can reduce B cell infiltration in prostate cancers and affect histologic markers 
reflecting B cell drive proliferation.  
 
 

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2.0 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
To determine the histologic response rate in patients with high risk prostate cancer 
receiving one treatment cycle of neoadjuvant rituximab prior to radical prostatectomy, 
defined as  an extent of B cell infiltration within the tumor region of the prostatectomy 
specimen of ≤ the 18.2 percentile of the B cell content from 27 historical control samples. 
 
2.2 
SECONDARY OBJECTIVES  
1.   To determine the effectiveness of neoadjuvant rituximab in the treatment of prostate 
cancer as evaluated by the serum PSA. 
 
2.   To determine the effect of neoadjuvant rituximab on the serum CXCL13 
concentration.  
 
3.   To determine the effect of neoadjuvant rituximab on peripheral blood B lymphocyte 
count. 
 
4.   To assess the safety and tolerability of neoadjuvant rituximab. 
 
5.   To explore the impact of neoadjuvant rituximab on immunohistochemical staining 
profiles of primary tumors including expression of: IKKα; BMI1; ubiquintinated 
histone 2A; B cell marker CD20; T cell markers CD3, CD4, and CD8; macrophage 
markers CD68 and CD11b; αSMA; CXCL13; LTα and LTβ, and LTβR.  
 
6.   To understand the long term impact of neoadjuvant rituximab in the treatment of 
prostate cancer on biochemical relapse based on PSA levels collected during 
standard of care follow-up. 
 
2.3 
ENDPOINTS 
Primary Endpoint: Histologic response rate after one cycle (28 days) of rituximab. Histologic 
response is defined as an extent of B cell infiltration within the tumor region of the prostatectomy 
specimen of ≤ the 18.2 percentile of the B cell content from 27 historical control samples. 
 
Secondary Endpoints: 
• 
Change in PSA from Day 1 to Day 29. 
• 
Change in peripheral blood B cell number from Day 1 to Day 29. 
• 
Change in serum CXCL13 level from screening or Day 1 (prior to drug administration) to 
Day 29. 
• 
Adverse events (description, timing, grade [CTCAE v4.03], severity, seriousness, and 
relatedness). 
• 
Change in staining of  markers of cell proliferation (Ki67) and apoptosis (TUNEL) 
between the radical prostatectomy specimen and historical control prostate cancer 
samples. 
• 
Staining of prostate cancer tissue for IKKα, BMI1, ubiquitinated histone 2A, B cell 
marker: CD20, T cell markers: CD3, CD4, and CD8, macrophage markers: CD68 and 

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CD11b, αSMA, CXCL13, RANK-L, LTα, LTβ, and LTβ receptor in radical prostatectomy 
specimen and historical control prostate cancer samples. 
• 
Time to biochemical progression, defined as a single PSA measurement of > 0.2 ng/mL, 
two PSA values of 0.2 ng/mL, or secondary treatment for increased PSA. 
3.0 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is an open label, single institution study of rituximab neoadjuvant therapy in patients with 
high risk prostate cancer scheduled to undergo radical prostatectomy. Prior to prostatectomy, 
patients will receive one treatment cycle (28 days) of rituximab 375 mg/m2 intravenously once 
weekly.  Patients will be scheduled to undergo radical prostatectomy within two weeks of 
completing study treatment. Tissue from prostatectomy will be used for immunohistochemistry 
(IHC) staining of pharmacodynamic markers. 
 
 
 
The null hypothesis is that a single cycle of rituximab will produce a histologic response in 20% 
or fewer patients. The study will be powered to detect a true response rate of 50% or greater. 
This trial will use a Simon two stage design with an α of 0.05 and a β of 0.20 (power 0.8).  The 
trial will enroll an initial cohort of 8 patients; if 3 or more have a histologic response the trial will 
continue and 10 more patients will be entered for a total of 18 patients. If 7 or more patients 
have a histologic response the null hypothesis will be rejected and it will be concluded that 
rituximab is associated with histologic response in more than 20% of patients.  Accrual is 
expected to occur at the rate of 1.5 patients per month over 12 months. 
 
Patients who are unable to undergo prostatectomy by 28 days after the last dose of rituximab 
(day 50), whose tumor tissue from radical prostatectomy is not evaluable, or who do not receive 
all 4 weekly doses of rituximab for reasons unrelated to study treatment or to disease 

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progression will continue to be followed for safety and for secondary endpoints, including 
biochemical progression, but will be replaced for the analysis of the primary endpoint. 
 
Patients will also be monitored for an additional 3 years as part of their standard-of-care follow-
up visits to determine time to biochemical relapse. Standard-of-care follow-up will include the 
measurement of PSA approximately every 3 months for the first two years, and then each 6 
months for the 3rd year.  Biochemical relapse is defined as a single PSA measurement of  
>0.2 ng/mL, two PSA values of 0.2 ng/mL, or secondary treatment for increased PSA (25).  
 
3.2 
SAFETY PLAN 
3.2.1 Adverse Events Using Rituximab 
Please refer to the package insert for more complete information.   
 
Adverse reactions of any grade have been observed in 99% of patients receiving rituximab for 
lymphoid malignancies. Severe and life-threatening (grade 3 and 4) events were reported in 
57% of these patients. 
 
Infusion reactions, which are sometimes severe and/or fatal, are associated with rituximab. 
Severe reactions typically occurred during the first infusion with time to onset of 30–120 
minutes. Rituximab-induced infusion reactions and sequelae include urticaria, hypotension, 
angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress 
syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid 
events, or death. 
 
General adverse events have been reported with rituximab, although it should be noted that 
fever, chills, rigors, flushing, and cytokine release syndrome have been associated with 
infusion-related reactions that can be severe and/or fatal. In clinical trials, general adverse 
events reported include fever (53%; 5 - 56% combination trials), chills (33%; 3 -13% 
combination trials), pain (12%), flushing (5%; 14% combination trials), night sweats (15%), 
peripheral edema (8 -16%), rigors (10% in combination trials), chest tightness (7% in 
combination trials), and fatigue (13%; 39% combination trials).  
 
Respiratory adverse events have been reported with rituximab, although it should be noted that 
hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome (ARDS), 
sneezing, cough, and throat irritation have been associated with infusion-related reactions that 
can be severe and/or fatal. In clinical trials, adverse events reported include throat irritation (9%; 
2% combination trials), increased cough (13%; 15% combination trials), bronchospasm (8%), 
dyspnea (7-10%), epistaxis (11%), and rhinitis (12%; 3% combination trials).  
 
Cardiovascular adverse events have been reported with rituximab, although it should be noted 
that hypotension, hypertension, myocardial infarction, ventricular fibrillation, and cardiogenic 
shock have been associated with infusion-related reactions that can be severe and/or fatal. 
Hypotension was reported in 10% (2% in combination trials) of patients and hypertension was 
noted in 6-12% (8% in combination trials) of patients during clinical trials.  
 
Tumor Lysis Syndrome: Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or 
hyperphosphatemia from tumor lysis, some fatal, can occur within 12−24 hours after the first 
infusion of Rituxan in patients with NHL.  A high number of circulating malignant cells 
(≥25,000/mm3) or high tumor burden confers a greater risk of TLS. 

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Hematologic adverse events have been reported with rituximab therapy. Lymphopenia (48%; 
40% Grade 3/4) is the most common hematologic reaction. Other hematologic adverse 
reactions include leukopenia (10-14%; 4% Grade 3/4), neutropenia (14%; 6% Grade 3/4), 
thrombocytopenia (12%; 2% Grade 3/4), and anemia (8 -16%; 3% Grade 3/4). In combination 
trials, cytopenias that had a higher incidence in therapy that included rituximab as compare to 
the comparator arms included neutropenia (4 -49%), anemia (35%), leukopenia (23%), 
pancytopenia (3%), thrombocytopenia (9 -11%), and febrile neutropenia (9 -15%). A single case 
of transient aplastic anemia (pure red cell aplasia) and 2 cases of hemolytic anemia were 
reported in patients with lymphoid malignancies. Cases of bone marrow aplasia, prolonged 
pancytopenia, late-onset neutropenia (defined as occurring 40 days after the last dose of 
rituximab), and hyperviscosity syndrome in patients with Waldenstrom's macroglobulinemia 
have been reported in post-marketing surveillance.  
 
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic 
failure, and death has occurred in patients treated with drugs classified as CD20-directed 
cytolytic antibodies, including rituximab. Cases have been reported in patients who are 
hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg 
negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has 
occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg 
negative, anti-HBc positive and hepatitis B surface antibody [anti-HBs] positive).  HBV 
reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid 
increase in serum HBV DNA level or detection of HBsAg in a person who was previously 
HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed 
by hepatitis. 
 
Rituximab-induced B-cell depletion is associated with decreased serum immunoglobulins in a 
minority of patients. Serious infections have been reported, including fatal bacterial, fungal, 
and new or reactivated viral infections (CMV, herpes simplex virus, parvovirus B19, varicella 
zoster virus, West Nile virus, hepatitis B and C virus). Onset can occur during therapy and up to 
one year after completion of rituximab-based treatment. In non-Hodgkin's lymphoma patients, 
the overall incidence of infection was 31%; 19% of patients had bacterial infections, 10% had 
viral infections, 1% had fungal infections, and 6% were unknown infections. Serious infection 
including sepsis has occurred in < 5% of these patients. In rheumatoid arthritis patients 39% of 
patients and 62% of Wegener's granulomatosis and microscopic polyangiitis patients 
experienced an infection of any type. Specific infections reported in clinical trials include 
nasopharyngitis/pharyngitis, upper respiratory tract infections, urinary tract infections, bronchitis, 
sinusitis (6%), pneumonia, lower respiratory tract infection, cellulitis, sepsis, and colitis. 
Infectious adverse event reported in post-marketing surveillance include an increase in fatal 
infections in HIV-associated lymphoma and an increased incidence of Grade 3/4 infections in 
patients with previously treated lymphoma without known HIV.  
 
Patients with hematologic malignancies or with autoimmune diseases who receive rituximab 
may develop potentially fatal progressive multifocal leukoencephalopathy (PML). 
Information suggests that patients with rheumatoid arthritis who receive rituximab have an 
increased risk of PML. PML is a white matter disease and is characterized by the onset of 
neurological signs and symptoms including weakness, sensory deficit, hemianopsia, cognitive 
dysfunction, aphasia, coordination or gait difficulties, and seizures, which progress over time.  
Mucocutaneous reactions, some with fatal outcomes have been reported with rituximab. These 
reports include bullous rash/vesicular rash, lichenoid dermatitis (lichen planus-like eruption), 

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paraneoplastic pemphigus (an uncommon disorder associated with the underlying malignancy), 
Stevens-Johnson syndrome, and toxic epidermal necrolysis.  
 
Abdominal pain, GI obstruction, and GI perforation, in some cases leading to death, were 
observed in patients receiving rituximab in combination with chemotherapy. Overall, abdominal 
pain has been reported in 14% of patients with lymphoid malignancies treated with rituximab 
and in 2% of rheumatoid arthritis patients treated with rituximab plus methotrexate. The 
incidence of abdominal pain was high in patients with bulky disease (i.e., a single lesion ≥ 10 
cm) than those with lesions < 10 cm in diameter. 
 
Nervous system or psychiatric events have been reported with rituximab, although it should 
be noted that headache, dizziness, and tremor have been associated with infusion-related 
reactions that can be severe and/or fatal. In clinical trials, adverse events reported include 
headache (17-19%), dizziness (10%), anxiety (5%; 2% combination trials), peripheral 
neuropathy (30% combination trials), paresthesias (2% combination trials), migraine (2% 
combination trials), and insomnia (14%). In post-marketing reports, Posterior Reversible 
Encephalopathy Syndrome (PRES) and Reversible Posterior Leukoencephalopathy Syndrome 
(RPLS) have been reported. 
 
Immune/autoimmune events have been reported with rituximab during post-marketing 
surveillance and include uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like 
symptoms, serum sickness, polyarticular arthritis, and vasculitis with rash. 
 
As with all therapeutic proteins, such as rituximab, there is potential for immunogenicity. One 
percent (4/356) of non-Hodgkin's lymphoma patients tested positive for human anti-chimeric 
antibody formation (HACA) and 3 patients had an objective clinical response. A total of 11% 
(273/2578) of rheumatoid arthritis patients tested positive for HACA any time after receiving 
rituximab and 23% (23/99) patients with Wegener's granulomatosis (WG) and microscopic 
polyangiitis (MPA) tested positive for HACA by 18 months.  
 
Skin/soft tissue or hypersensitivity adverse events have been reported with rituximab, although 
it should be noted that urticaria, angioedema, anaphylactoid reactions/anaphylactic shock, 
pruritus, rash (unspecified) have been associated with infusion-related reactions that can be 
severe and/or fatal. In clinical trials, adverse events reported include rash (10-15%; 17% 
combination trials), pruritus (14%; 5-17% combination trials), urticaria (8%; 2% combination 
trials), and angioedema (11%). 
 
Gastrointestinal adverse events have been reported with rituximab, although it should be 
noted that nausea and vomiting have been associated with infusion-related reactions that can 
be severe and/or fatal. In clinical trials, adverse events reported include nausea (18-23%; 8% 
combination trials), vomiting (10%), diarrhea (10-17%), dyspepsia (3% combination trials), and 
weight gain (11% combination trials).  
 
Musculoskeletal adverse events have been reported with rituximab, although it should be 
noted that myalgia has been associated with infusion-related reactions that can be severe 
and/or fatal. In clinical trials, adverse events reported include asthenia (26%; 2% combination 
trials), myalgia (10%), arthralgia (10-13%; 6-12% combination trials), and muscle spasms 
(17%). 
 
Metabolic adverse events reported with rituximab therapy include hyperglycemia (9%) and 
increased LDH (7%). 

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3.2.2 General Plan to Manage Safety Concerns 
A number of measures will be taken to ensure the safety of patients participating in this trial, 
addressed through exclusion criteria and routine monitoring.  Patients will be evaluated for 
adverse events at each study visit for the duration of their participation in the study and for 28 
days after the discontinuation of rituximab.  
 
At least 30 minutes before each rituximab infusion patients will be pre-medicated with 
diphenhydramine 25 mg intravenously (or another antihistamine) and acetaminophen 650 mg 
orally.  The infusion rate start at 50 mg/h and be advanced progressively (see section 4.2.2) to 
reduce the risk of infusion reaction.  Patients will be monitored closely during each study drug 
infusion for detection of symptoms or signs of infusion reactions and the infusion rate reduced or 
stopped based on changes in vital signs and patient appearance and response to treatment. 
Pre-medications and study drug administration have been specified to help minimize toxicity 
and guidelines are provided in Sections 4.2.2 and 4.2.3 for study drug modifications. 
 
Positive results of hepatitis B or C screen tests will be included in the patient’s electronic 
medical record at UCSD and will be brought to the attention of the primary UCSD physician for 
subsequent management. 
 
 
4.0 
MATERIALS AND METHODS 
 
4.1 
PATIENTS 
4.1.1 Inclusion Criteria 
Subjects must meet all of the inclusion criteria to participate in this study. 
 
1. Ability to understand and provide written informed consent. 
 
2. Patient has EITHER: 
• 
A Kattan nomogram predicted probability of being disease free 5 years after surgery 
of < 60%, OR 
• 
A Gleason sum ≥ 8. 
 
3. Indicated for radical prostatectomy. 
 
Note: candidates for radical prostatectomy are still eligible even if they have a history of 
deep venous thrombosis, pulmonary embolism, and/or cerebrovascular accident or 
currently requiring systemic anticoagulation. 
 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (Appendix A). 
 
5. Males aged ≥ 18 years. 
 
6. Adequate organ function as defined below measured within 21 days of study entry: 
 

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Hematology: 
o Absolute Neutrophil Count (ANC) 
≥ 1.5 x 109/L 
o Platelet count   
 
 
≥ 100 x 109/L 
o Hemoglobin   
 
 
≥ 9.0 g/dL 
o White blood cell (WBC) count 
≥ 3.0 x 109/L 
 
Biochemistry: 
o     AST/SGOT and ALT/SGPT  ≤ 2 x institution’s upper limit of normal (ULN)  
o     Total bilirubin  
 
<1.5 times ULN 
o Serum creatinine  and BUN <1.5 times ULN 
o Na, K Cl, CO2, Ca, PO4  
within institutional limits 
 
4.1.2 Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation. 
 
1. Received prior treatment for prostatic adenocarcinoma including prior surgery (excluding 
TURP), radiation therapy, or chemotherapy. 
 
2. Current or past use of investigational agents within 4 weeks of study enrollment. 
 
3. Use of erectile dysfunction drugs (e.g., Cialis, Viagra) within 14 days prior to treatment or 
during study. 
 
4. Evidence of metastatic disease on cross sectional imaging or bone scan. 
 
5. Receipt of a live vaccine within 4 weeks prior to rituximab administration. 
 
6. History of hepatitis B or C, HIV, tuberculosis or a chronic infection of any type. 
 
7. Positive test results for chronic hepatitis B infection (defined as positive HBsAg serology). 
 
8. Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing). 
 
4.2 
STUDY TREATMENT 
4.2.1 Rituximab Formulation 
Rituximab for injection is available in sterile, preservative-free single-use vials [100 mg/10 mL 
and 500 mg/50 mL]. 
 
4.2.2 Rituximab Dosage, Administration, and Storage 
Rituximab will be prepared for intravenous administration according to the package insert. 
 
Rituximab will be administered intravenously at a dose of 375 mg/m2 of body surface area once 
per week for 4 weeks (Days 1, 8, 15, and 22 of a 28-day cycle). The total dose to be infused on 
each treatment day will be based on the patient’s body surface area at the time of screening 
and will remain the same throughout the study. Patients that miss a dose for reasons unrelated 
to toxicity are expected to receive the next dose on schedule. 

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Rituximab should not be administered as an IV push or bolus. 
 
Premedicate before each infusion: 
 
Diphenhydramine 25 mg intravenously (or another antihistamine) and acetaminophen 650 mg 
orally should be administered at least 30 minutes prior to rituximab infusion.  
 
Since transient hypotension may occur during rituximab infusion, consideration should be given 
to withholding anti-hypertensive medications 12 hours prior to rituximab infusion. 
 
First Infusion  
Initiate infusion at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate 
by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.   
If an infusion reaction occurs, the infusion should be temporarily slowed or interrupted.  The 
infusion can continue at one-half the previous rate upon improvement of symptoms. 
Subsequent Infusions  
Initiate infusion at a rate of 100 mg/hr. In the absence of infusion toxicity, increase rate by 100 
mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr.  
If an infusion reaction occurs, the guidelines for the first infusion should be followed. 
 
Storage 
Unopened vials of rituximab are stable until the expiration date indicated on the package when 
stored at 2°C–8°C (36°F–46°F). Vials should be protected from direct sunlight and should not 
be frozen or shaken. 
 
When prepared as directed, rituximab solutions for infusion may be stored at 2°C–8°C (36°F–
46°F) for 24 hours. Rituximab solutions for infusion have been shown to be stable for an 
additional 24 hours at room temperature. However, since Rituximab solutions do not contain a 
preservative, diluted solutions should be stored refrigerated (2°C–8°C). No incompatibilities 
between Rituximab and polyvinylchloride or polyethylene bags have been observed. 
 
4.2.3 Rituximab Dose Modifications 
There will be no rituximab dosage modification in this study. 
 
Dose Discontinuation Guidelines 
 
Toxicity- NCI CTCAE Grade 
Dose Modifications 
Infusion Reactions 
Less severe allergic reactions 
(general itching or rash only) 
A. Stop infusion. 
B. Rapidly evaluate signs and symptoms 
C. Administer PRN medications (e.g., topical therapy for 
skin reactions, antipyretics, antihistamines). 
− 
If symptoms resolve, resume infusion at least one-
half the previous rate. 
 
Severe anaphylactic response 
A. Stop infusion IMMEDIATELY. 
B. Rapidly evaluate signs and symptoms. 
C. Administer emergency drugs (e.g., epinephrine, 
famotidine, diphenhydromine, hydrocortisone sodium 

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succinate). 
D. Maintain intravenous line with NS or Lactated Ringer’s to 
expand vascular space. 
E. Place patient in supine position and reassure 
patient/significant other. 
F. Monitor vital signs every 2 minutes until stable, then 
every 5 minutes for 30 minutes, then every 15 minutes as 
needed. 
G. Maintain patient’s airway, assessing for increasing 
edema of respiratory passage. (administer oxygen as 
needed, anticipate need for CPR). 
Discontinue study treatment. 
 
Hematologic and Non-Hematologic 
Grade  ≤ 1 
Continue study treatment without dose or schedule 
modification. 
Grade ≥ 2 
Discontinue study treatment. 
 
 
4.3 
CONCOMITANT AND EXCLUDED MEDICATIONS 
All concomitant medications and blood products, as well as interventions received by patients 
from the first dose of study drugs until the end of study visit should be recorded. 
 
4.3.1 Supportive Care Guidelines 
Patients should receive full supportive care for disease-related symptoms, including 
hematopoietic growth factors, anti-emetics, transfusion of blood products, fluid and electrolyte 
replacement, and antibiotics when appropriate. 
 
4.3.2 Excluded Medications and Treatments 
Use of anti-neoplastic or anti-tumor agents not part of the study therapy, including 
chemotherapy, radiation therapy, immunotherapy, and hormonal anticancer therapy, is not 
permitted while participating in this study. Concurrent use of investigational agents is not 
permitted. Concurrent use of erectile dysfunction drugs (Cialis, Viagra) is not permitted. 
4.4 
STUDY ASSESSMENTS 
A flowchart of scheduled study assessments is provided in Appendix B. 
 
All patients will be closely monitored for safety and tolerability during the study and the follow-up 
period. 
 
4.4.1 Definitions of Study Assessments 
a. Medical History 
Medical/Oncology history should include smoking history, surgeries, clinically significant 
diseases within the last 5 years, history of malignancy (date of first diagnosis, disease 
course, and prior therapies), and all medications taken over the 30 days prior to start of 

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study treatment (including prescriptions, over-the-counter, and herbal/homeopathic 
remedies). 
 
b. Demographics 
Demographics consist of age, gender, race, and ethnicity. 
 
c. Vital Signs 
Vital signs will include measurement of pulse rate, systolic and diastolic blood pressure 
while the patient is in a seated position, and temperature.  
 
d. Physical Measurements 
Physical measure will include body height and body weight. 
 
e. Physical Examination 
A complete physical examination should include the evaluation of general appearance; 
evaluation of head, eyes, ears, nose, and throat (HEENT); and cardiovascular, 
pulmonary, abdominal, musculoskeletal, skin, lymph nodes, neurological, and 
genitourinary systems. 
 
Changes from baseline abnormalities should be recorded at each subsequent physical 
examination. New or worsened abnormalities should be recorded as adverse events if 
appropriate. 
 
f. Performance Status 
Performance status will be evaluated according the ECOG criteria listed in Appendix A. 
 
g. Laboratory Assessments 
Laboratory assessments may include the following: 
 
• 
Hematology 
Including hemoglobin, hematocrit, platelet count, WBC count, and percentage or 
absolute differential count. 
 
• 
Comprehensive metabolic panel (CMP) 
Including sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
calcium, total protein, albumin, AST, ALT, total bilirubin, and alkaline 
phosphatase. 
 
• 
Prognostic marker 
Serum PSA. 
 
• 
Inflammatory marker 
 
Serum CXCL13. See Section 4.5.1. 
 
• 
Hepatitis B and C testing 
Hepatitis B testing includes HBsAg, anti-HBc, and anti-HBs. 
Hepatitis C testing includes antibody (HCV antibody). 
 
h. Pain assessment 
Patients should be asked to rate their current overall feeling of pain on a scale of 0-10. 

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i. Tumor Histology Assessment 
Assessment of prostate histology for diagnosis and staging will be performed according 
to standard institutional practices. 
 
4.4.2 Screening and Pretreatment Assessments 
Documentation of the informed consent for screening will be maintained in the patient’s 
research chart. Studies or procedures that were performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the studies 
were done before informed consent was obtained. 
 
The study population for this trial will consist of patients with high risk prostate cancer scheduled 
to undergo radical prostatectomy.  All patients who meet the inclusion and exclusion criteria will 
be offered enrollment into this study.  To confirm patient eligibility for study participation, the 
following assessments and procedures will be completed during the screening phase.  
 
All screening procedures must be performed within 21 days prior to registration unless 
otherwise stated. The screening procedures include: 
• 
Written informed consent (up to two months prior to study treatment) 
• 
Review of inclusion and exclusion criteria 
• 
Complete medical/oncology history 
• 
Documentation of concomitant medications 
• 
Demographics 
• 
Complete physical examination 
• 
Vital signs assessment 
• 
ECOG performance status assessment 
• 
Hematology and CMP 
• 
Assessment of PSA and CXCL13 serum levels (note: if collection of blood for 
CXCL13 is not performed in screening, it may be collected on Day 1) 
• 
Hepatitis B and C testing 
 
4.4.3 Evaluation and Procedures During Treatment 
During the treatment period, a window of +/- 1 days will apply to all visits and assessments, 
unless otherwise specified. Assessments scheduled on the day of study drug administration 
should be performed prior to study drug administration, unless otherwise noted. 
 
Day 1 
• 
Documentation of concomitant medications and adverse events 
• 
Physical exam and pain assessment* 
• 
Vital signs before and at the end of the  rituximab infusion 
• 
Weight and height 
• 
ECOG performance status* 
• 
Hematology*  
• 
CMP* 
• 
Serum PSA* 
• 
CXCL13* assessment 
• 
Rituximab administration 

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*note: If procedures performed during screening occur within 14 days of the first 
administration of study drug, these laboratory assessments do not need to be repeated 
on Day 1. 
 
Day 8 
• 
Documentation of concomitant medications and adverse events 
• 
Rituximab administration 
• 
Vitals signs before and at the end of the rituximab infusion 
 
Day 15 
• 
Documentation of concomitant medications and adverse events 
• 
Hematology 
• 
Serum PSA  
• 
CXCL13 assessment 
• 
Rituximab administration 
• 
Vitals signs before and at the end of the rituximab infusion 
 
Day 22 
• 
Documentation of concomitant medications and adverse events 
• 
Rituximab administration 
• 
Vitals signs before and at the end of the rituximab infusion 
 
Day 29 
• 
Documentation of concomitant medications and adverse events 
• 
Physical exam and pain assessment 
• 
Vital signs and pain assessment  
• 
Weight 
• 
ECOG performance status 
• 
Hematology  
• 
CMP 
• 
Serum PSA 
• 
CXCL13 assessment 
 
4.4.4 Surgery 
Patients will undergo radical prostatectomy according to standard institutional practices. 
Every attempt will be made to schedule surgery within 14 days after the last dose of 
rituximab (day 36-50).  If the surgery occurs >28 days after the last dose of rituximab 
(>day 50) the patient will be replaced for the primary outcome and histology based 
outcomes.  The patient will be included in the biochemical recurrence analysis. 
 
4.4.5 End of Treatment Visit 
The End of Treatment Visit will occur within 28 days of the last dose of study treatment. 
For patients completing the full cycle of study treatment, this visit will approximately 
occur on Day 50 and include the following assessments: 
• 
Documentation of concomitant medications and adverse events 
• 
Physical exam, vital signs, and weight 
• 
ECOG performance status 

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4.4.6 Follow-up 
Patients will be monitored for an additional 3 years as part of their standard-of-care follow-up 
visits to determine biochemical relapse. Standard-of-care follow-up will include the 
measurement of PSA every 3 months (+/- 1 month) for the first two years, and then each 6 
months (+/- 1 month) during the 3rd year.  Biochemical relapse is defined as a single PSA 
measurement of >0.2 ng/mL, two PSA values of 0.2 ng/mL, or secondary treatment for 
increased PSA.  PSA levels will be collected from patients’ medical records and will be entered 
into the study database. 
 
4.5 
ASSAY METHODS 
4.5.1 Blood collection for research 
Blood (approximately 8 ml) will be collected using 10 mL red top non-anti-coagulated tubes 
without gel and processed the day of collection for recovery of serum. Samples will be collected 
during screening (or Day 1), Day 15, and Day 29. Samples will be labeled with the subject’s de-
identified study number and collection date and delivered to the Moores Cancer Center 
Biorepository for storage until analysis of CXCL13 levels is performed. 
 
4.5.2 Tissue Procurement 
Dr. Ahmed Shabaik will be notified of upcoming prostatectomy of study patients. The entirety of 
the resected prostate tissue will be processed according to standard institutional procedures. 
Routine histological assessment for tumor staging will be performed and only then will excess 
tissue be made available for research purposes. 
 
Samples will be labeled with the subject’s de-identified study number and collection date. 
 
4.5.3 Immunohistochemistry 
Immunohistochemistry of tumor specimens from surgery and existing historical control prostate 
tissue will be performed in the laboratory of Christina Jamieson, Ph.D., in the UCSD Moores 
Cancer Center. 
 
Immunohistochemistry will be performed for the following markers: 
• 
IKKα,  
• 
BMI1,  
• 
Ubiquintinated histone 2A,  
• 
B cell marker: CD20,  
• 
T cell markers: CD3, CD4, and CD8,  
• 
Macrophage markers: CD68 and CD11b,  
• 
αSMA,  
• 
CXCL13,  
• 
RANK-L,  
• 
LTα,  
• 
LTβ, and  
• 
LTβ receptor. 
 

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4.6 
PATIENT DISCONTINUTATION 
Patients may discontinue study treatment at any time.  Any patient who discontinues treatment 
will be encouraged to return to the study center to undergo follow-up assessments.  The primary 
reason for discontinuation should be recorded.  Reasons for discontinuation of a patient by the 
investigator include, but are not limited to, the following: 
   
• 
Voluntary withdrawal from treatment (follow-up permitted), 
• 
Voluntary withdrawal of consent (termination of treatment and follow-up), 
• 
Patient noncompliance, 
• 
Investigator determination that it is not in the patient’s best interest to continue 
participation, 
• 
Lost to follow-up. 
 
4.7 
DATA QUALITY ASSURANCE 
Data will be collected via notes in the electronic medical record and outside reports (such as 
those for laboratory results) and entered into the appropriate Case Report Forms (CRFs) in an 
electronic database.  The study investigator will be responsible for sign off on the eCRFs in a 
timely fashion, in order that the database can be go live in time for the first patient registration.  
Data will be submitted within 1 month of completion of the appropriate tests.  Data will be 
monitored by the Moores Cancer Center Clinical Trials Office (CTO), within one month of the 
first patient completing cycle 1 and every 6 months thereafter, according to the Moores Cancer 
Center standard data monitoring plan. 
 
5.0 
STATISTICAL METHODS 
The primary goal of this trial is to determine the histologic response rate in patients with high 
risk prostate cancer receiving one treatment cycle (28 days) of neoadjuvant rituximab prior to 
radical prostatectomy. Patients will be considered to have a histologic response if the extent of 
B cell infiltration within the tumor region is ≤ the 18.2percentile of the B cell content from 27 
historical control samples. The threshold value of the 18.2 percentile for histologic response was 
chosen on the basis of analysis of B cell density in the prostatectomy specimens from 27 
untreated high-risk control samples, where high risk is defined as Gleason > 8 or PSA > 20 and 
more than 1 positive core, or intermediate risk and more than 50% positive cores.  The 
threshold was selected so as to be reasonably confident that the untreated population would 
have a histologic response rate of ≤20% by this definition.  This threshold is based on a 70% 
lower confidence limit on the 20th percentile of the distribution of B cell density in the 27 
untreated high-risk control samples. Note that while an unadjusted 20th percentile could have 
been used, 18.2 percentile was chosen to be more conservative. 
 
Secondary Endpoints include: 
• 
Change in PSA from Day 1 to Day 29. 
• 
Change in peripheral blood B cell number from Day 1 to Day 29. 
• 
Change in serum CXCL13 level from screening or Day 1 (prior to drug administration) to 
Day 29. 
• 
Adverse events (description, timing, grade [CTCAE v4.03], severity, seriousness, and 
relatedness). 
• 
Change in staining of markers of cell proliferation (Ki67) and apoptosis (TUNEL) 

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between the radical prostatectomy specimen and historical control prostate cancer 
samples. 
• 
Staining of IKKα, BMI1, ubiquitinated histone 2A, B cell marker: CD20, T cell markers: 
CD3, CD4, and CD8, macrophage markers: CD68 and CD11b, αSMA, CXCL13, RANK-
L, LTα, LTβ, and LTβ receptor in radical prostatectomy specimen and historical control 
prostate cancer samples. 
• 
Time to biochemical progression, defined as a single PSA measurement of > 0.2 ng/mL, 
two PSA values of 0.2 ng/mL, or secondary treatment for increased PSA. 
 
5.1.1 Study Design and Justification of Sample Size 
This is a single arm, non-randomized, open-label study and utilizes a Simon’s optimal 
two-stage design (26). Suppose 20% is the uninteresting level, i.e., if the histologic 
response rate is ≤ 20%, we will consider the treatment as not promising. We will test the 
null hypothesis H0: p≤20% against the alternative hypothesis H1: p>20%, where p is the 
histologic response rate after one treatment cycle of rituximab. The two stage design 
proposed below will have 80% power to reject the null and conclude that the true 
response rate is above 20%, if the true response rate is ≥50%, at 5% significance level. 
The study design is described in detail as follows: 
 
Stage 1: 8 subjects will be accrued; accrual will be held up until the response results for 
all the 8 subjects are known. The trial will be terminated at Stage 1 if ≤2 of the 8 subjects 
has a response; otherwise it continues to Stage 2.  
 
Stage 2: 10 more patients will be accrued. We will reject the therapy if among all the 18 
(8+10) subjects, the number of patients who have a defined response is ≤6. If 7 or more 
patients have a histologic response the null hypothesis will be rejected and it will be 
concluded that rituximab is associated with histologic response in more than 20% of 
patients.   
 
Early stopping probability: Under this design, if the null hypothesis is true, the probability 
of stopping the trial early will be 80%. 
 
The treatment/control status will be blinded to the operator in the response assessment 
procedure. At both interim and final analysis, the full set of 27 historical controls will be 
reassessed concurrently with the treated samples. Slides from the pre-existing historical 
control prostate tissue samples will be used for IHC. Please see the “PROTUX trial-
statistical plan for primary endpoint” document for details. 
 
5.1.2 Analysis of the Study Conduct 
Enrollment, eligibility violations, protocol deviations and reasons for patient 
discontinuation from the study will be summarized. 
 
5.1.3 Analysis of Demographic and Baseline Characteristics 
Demographic and baseline characteristics, such as age, race, disease stage, ECOG 
performance status, will be summarized with use of means, standard deviations, 
medians, and ranges for continuous variables and with use of proportions for categorical 
variables. 

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Study drug administration data will be listed and any dose modifications will be noted. 
Means and standard deviations will be used to summarize the length of time study drug 
was received. 
 
5.1.4 Primary Analysis 
The primary endpoint is the histologic response rate after one treatment cycle (28 days) of 
rituximab 375 mg/m2 intravenously once weekly for 4 weeks.  The primary analysis is described 
in section 5.1.1. The histologic response rate and its associated 95% confidence interval will be 
estimated.  
 
5.1.5 Secondary Analyses 
The analysis for PSA changes from day 1 to day 29 will use all patients that received at least 
one dose of rituximab. The analysis for peripheral blood B cell number changes from day 1 to 
day 29 and the analysis for serum CXCL13 level changes from screening or day 1 to day 29 will 
only use patients who received the full 4 doses of rituximab. Appropriate test (Paired T test or 
nonparametric Wilcoxon test) will be used to test if there are significant changes before and 
after the rituximab treatment.   
 
Staining of tissue for IKKα, BMI1, ubiquitinated histone 2A, B cell marker: CD20, T cell markers: 
CD3, CD4, and CD8, macrophage markers: CD68 and CD11b, αSMA, CXCL13, RANK-L, LTα, 
LTβ, and LTβ receptor will also be compared between the historical control prostate samples 
and radical prostatectomy specimen, and appropriate two sided tests at 5% significance level 
(e.g. nonparametric tests if data are not normally distributed) will be performed to see if the 
changes are significant or not. 
 
Patients will also be monitored for an additional 3 years as part of their standard-of-care follow-
up visits to determine biochemical relapse.  They will be monitored every 3 months for the first 
two years, and then each 6 months up to 3 years, as in our preliminary data (Figure 5). All 
patients who received a least one dose of rituximab will be included in this analysis. We expect 
the median time to biochemical relapse for this group of high risk patients to be approximately 
36 months (Kane, C, unpublished UCSD data, Figure 6).  Time to biochemical relapse will be 
analyzed using a Cox Proportional Hazards model with time to median relapse compared 
against an expected value of 36 months.  At three years of follow-up, with 18 subjects, this 
study has 71% power using a one sided, exponential MLE test with α = 10% to detect a 
doubling of median survival from 36 months to 72 months (27). This assumes uniform accrual 
over one year, no loss to follow-up, and exponentially distributed time to relapse. 
 

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Figure 6. Biochemical relapse following prostatectomy using standard versus extended LND. 
 
 
Details of any adverse events will be documented. The timing, grade (CTCAE v4.03), 
seriousness, duration, relatedness to study agent of adverse events will be summarized in a 
table. 
 
6.0 
ASSESSMENT OF SAFETY  
The safety of rituximab will be assessed through collection and analyses of adverse events 
(AEs) and laboratory tests. 
 
6.1 
SPECIFICATION OF SAFETY VARIABLES  
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) that are considered related to rituximab, all events of death, and any 
study specific issue of concern. 
 
6.1.1 Adverse Events 
An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other protocol-imposed 
intervention, regardless of attribution. 
 
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with Prostate Cancer that 
were not present prior to the AE reporting period. 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations). 

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• 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period. 
 
6.1.2 Serious Adverse Events 
An AE should be classified as an SAE if: 
• 
It results in death (i.e., the AE actually causes or leads to death).  
• 
It is life threatening (i.e., the AE, in the view of the investigator, places the patient 
at immediate risk of death.  It does not include an AE that, had it occurred in a 
more severe form, might have caused death.). 
• 
It requires or prolongs inpatient hospitalization. 
• 
It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the investigational product. 
• 
It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above). 
 
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs. 
 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to the grade 
of a specific AE, e.g., mild (Grade 1), moderate (Grade 2), or severe (Grade 3) myocardial 
infarction.  “Serious” is a regulatory definition (see previous definition) and is based on patient or 
event outcome or action criteria usually associated with events that pose a threat to a patient’s 
life or functioning.  Seriousness (not severity) serves as the guide for defining regulatory 
reporting obligations from the Sponsor to applicable regulatory authorities.  
 
Severity and seriousness should be independently assessed when recording AEs and SAEs on 
the CRF. 
The AE grading (severity) scale found in the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE), Version 4.03, will be used for AE reporting. The 
CTCAE v4.03 is available at http://ctep.cancer.gov/reporting/ctc.html 
6.2 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, as outlined in Section 5.1.1, are collected and reported to the FDA, UCSD IRB, 
and Genentech, Inc. in accordance with CFR 312.32 (IND Safety reporting). 
 
6.2.1 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of any study procedures and ends 30 days following 
the last administration of study treatment or study discontinuation/termination, whichever 
is earlier.  After this period, investigators should only report SAEs that are attributed to 
prior study treatment. 
 

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6.2.2 Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, 
suspected relationship to the rituximab (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should 
apply the following general guideline: 
 
Yes 
There is a plausible temporal relationship between the onset of the AE and 
administration of rituximab, and the AE cannot be readily explained by the subject’s 
clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a 
known pattern of response to rituximab; and/or the AE abates or resolves upon 
discontinuation of rituximab or dose reduction and, if applicable, reappears upon re-
challenge. 
 
No 
Evidence exists that the AE has an etiology other than the rituximab (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to rituximab administration (e.g., 
cancer diagnosed 2 days after first dose of rituximab). 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert or current Investigator Brochure. 
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current 
Investigator Brochure (I.B.) or not identified. This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. or I.B. For example, 
under this definition, hepatic necrosis would be unexpected if the P.I. or I.B. only referred 
to elevated hepatic enzymes or hepatitis. 
 
6.2.3 Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation timepoints should be 
adopted. Examples of non-directive questions include:  
“How have you felt since your last clinical visit?” 
“Have you had any new or changed health problems since you were last here?”  
 
6.2.4 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
 
a. Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or 
syndrome at the time of reporting, it is ok to report the information that is currently 

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available. If a diagnosis is subsequently established, it should be reported as follow-
up information. 
 
b. Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 
5.1.2), regardless of attribution, will be reported to the appropriate parties. When 
recording a death, the event or condition that caused or contributed to the fatal 
outcome should be reported as the single medical concept. If the cause of death is 
unknown and cannot be ascertained at the time of reporting, report “Unexplained 
Death”. 
 
c. Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE 
only if the frequency, severity, or character of the condition worsens during the study. 
When reporting such events, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., “more 
frequent headaches”). 
 
d. Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE. If a subject is hospitalized to undergo a 
medical or surgical procedure as a result of an AE, the event responsible for the 
procedure, not the procedure itself, should be reported as the SAE. For example, if a 
subject is hospitalized to undergo coronary bypass surgery, record the heart 
condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
Hospitalization or prolonged hospitalization required to allow efficacy measurement 
for the study or 
Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
 
e. Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy or 
within 90 days after the last dose of study drug, a report should be completed and 
expeditiously submitted to the Genentech, Inc. Follow-up to obtain the outcome of 
the pregnancy should also occur. Abortion, whether accidental, therapeutic, or 
spontaneous, should always be classified as serious, and expeditiously reported as 
an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female 
subject exposed to the investigational product should be reported as an SAE. 
 
f. Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if attributed to prior investigational 
product exposure. If the investigator should become aware of the development of 
cancer or a congenital anomaly in a subsequently conceived offspring of a female 
subject who participated in the study, this should be reported as an SAE. 

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g. Reconciliation 
h. The Sponsor (principal investigator) agrees to conduct reconciliation for the product. 
Genentech and the Sponsor will agree to the reconciliation periodicity and format, 
but agree at minimum to exchange monthly line listings of cases received by the 
other party. If discrepancies are identified, the Sponsor and Genentech will 
cooperate in resolving the discrepancies. The responsible individuals for each party 
shall handle the matter on a case-by-case basis until satisfactory resolution.  
i. 
Non-Serious AE Reporting 
All Non-serious Adverse Events originating from the Study will be forwarded, in a 
quarterly report to Genentech.  
 
6.2.5 MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the MedWatch 3500A form 
(http://www.fda.gov/medwatch/index.html): 
• 
Treatment regimen (dosing frequency, combination therapy) 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome, if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
Follow-up information 
Additional information may be added to a previously submitted report by any of the 
following methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
• 
Summarizing new information and faxing it with a cover letter including subject 
identifiers (i.e. D.O.B., initials, subject number), protocol description and number, 
if assigned, suspect drug, brief adverse event description, and notation that 
additional or follow-up information is being submitted  (The subject identifiers are 
important so that the new information is added to the correct initial report.) 
 
Occasionally, Genentech may contact the reporter for additional information, clarification 
or current status of the subject for whom an adverse event was reported.  For questions 
regarding STEAE reporting, you may contact the Genentech Drug Safety representative 
noted below. 
 
MedWatch 3500A form is available at 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 

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6.3 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS 
6.3.1 Expedited Reporting of Serious Adverse Events 
• 
The Principal Investigator must be notified within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study or 
within 30 days of the last administration of the study drug.  
 
• 
Investigators must report all SAEs to Genentech within the timelines described 
below. The completed Medwatch/case report should be faxed immediately 
upon completion to Genentech Drug Safety at: 
 
(650) 225-4682 
OR 
(650) 225-5288 
 
The Safety Reporting Fax Cover Sheet is found in Appendix C. 
 
Relevant follow-up information should be submitted to Genentech Drug Safety 
as soon as it becomes available. 
 
o Serious AE reports that are related to the investigational product will be 
transmitted to Genentech within fifteen (15) calendar days of the 
Awareness Date. 
o Serious AE reports that are unrelated to the investigational product will 
be transmitted to Genentech within thirty (30) calendar days of the 
Awareness Date. 
o Any reports of pregnancy following the start of administration with the 
investigational product will be transmitted to Genentech within thirty (30) 
calendar days of the Awareness Date. 
 
• 
The UCSD Human Research Protections Program (HRPP) must be notified 
within 10 business days of “any unanticipated problems involving risk to 
subjects or others” (UPR). 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), which in 
the opinion of the Principal Investigator was unanticipated, involved risk to 
subjects or others, and was possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved 
protocol that alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, updated 
sponsor safety report), interim result or other finding that indicates an 
unexpected change to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or others. 
6. Any complaint of a subject that indicates an unanticipated risk or that 
cannot be resolved by the Principal Investigator. 

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• 
Post-marketing 15-Day “Alert Report” 
The Principal Investigator is required to notify the FDA of any fatal or life-
threatening adverse event that is unexpected and assessed by the 
investigator to be possibly related to the use of Rituximab. An unexpected 
adverse event is one that is not already described in the Investigator Brochure. 
Such reports are to be submitted to the FDA (2 copies) at the following address: 
Central Document Room, 12229 Wilkins Avenue, Rockville, MD 20852. 
 
All Postmarketing 15-Day “Alert Reports” submitted to the FDA by the Sponsor-
Investigator must also be faxed to:  
Genentech Drug Safety  
Fax: 
(650) 225-4682 or (650) 225-4683  
(Please use the Genentech safety reporting fax cover sheet for the fax 
transmission) 
 
For questions related to safety reporting, contact: 
Genentech Drug Safety 
Tel: 
1-888-835-2555 
           
Or 
Fax: 
(650) 225-4682 or (650) 225-4683 
(Please use the Genentech safety reporting fax cover sheet for the fax 
transmission) 
 
6.3.2 Routine Reporting of Adverse Events 
• 
The UCSD HRPP will be notified of any adverse events that are not 
unanticipated problems involving risk to subjects or other (non-UPRs) at the time 
of the annual Continuing Review. 
6.4 
TYPE AND DURATION OF FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period should 
be followed to their resolutions, or until the investigator assesses them as stable, or the patient 
is lost to follow-up.  Resolution of AEs and SAEs (with dates) should be documented on the 
appropriate AE or SAE CRF page and in the patient’s medical record to facilitate source data 
verification. 
 
For some SAEs, follow-up may occur by telephone, fax, electronic mail, and/or a monitoring visit 
to obtain additional case details deemed necessary to appropriately evaluate the SAE report 
(e.g., hospital discharge summary, consultant report, or autopsy report). 
 
 

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7.0 
INVESTIGATOR REQUIREMENTS 
7.1 
OBLIGATIONS OF INVESTIGATORS 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to his/her 
original records to permit verification of proper entry of data. At the completion of the study, all 
case report forms will be reviewed by the Principal Investigator and will require his/her final 
signature to verify the accuracy of the data. 
7.2 
CONFLICT OF INTEREST 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed according to UCSD conflict of interest policy. 
7.3 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT  
The IRB should approve the consent form and protocol prior to any study-related activities.  It is 
expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the study, 
the patient will be asked to give consent to participate in the study by signing an IRB-approved 
consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 
7.4 
SUBJECT DATA PROTECTION 
In accordance with the Health Information Portability and Accountability Act (HIPAA), subjects 
who have provided written informed consent must also sign a subject authorization to release 
medical information to the study Sponsor and allow a regulatory authority, or Institutional 
Review Board access to subject’s medical information relevant to the study. 

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7.5 
DATA AND SAFETY MONITORING/AUDITING 
In addition to adverse event monitoring and clinical oversight by the principal investigator and 
co-investigators, quality assurance of the study will be performed by the clinical trials office 
internal monitor. Standard monitoring reports will be generated by the Biostatistics Shared 
Resource at two weeks after the first patient visit, and every 3 months or 6 months thereafter. 
 
This study will also use the UCSD Moores Cancer Center Data Safety and Monitoring Board 
(DSMB) to provide oversight in the event that this treatment approach leads to unforeseen 
toxicities.  
 
Data from this study will be reported to the DSMB after the first stage of the study (after 8 
subjects) or annually, whichever comes first. If the study proceeds to the second stage, reports 
to the DSMB will be made annually. 
 
If data capture is at UCSD, statisticians from the Biostatistics Shared Resource will prepare 
reports for data monitoring and DSMB review. The report will include following components:  
• 
accrual summary by month and by treatment group (if any);  
• 
study status summary including total number of accrual as of date, numbers of subjects 
who are on/off study, on study treatment(s), on study but off study treatment(s); 
• 
summary statistics for baseline variables that are crucial to study design and analysis;  
• 
data completeness report that summarizes number of observed data points vs. number 
of expected data points;  
• 
name, grade, onset date and relation to study treatment of adverse events, including all 
laboratory tests and hematological abnormalities, signs and symptoms from physical 
examination findings, and spontaneous reports of adverse events reported to the 
investigator by participants;  
• 
listings of study treatment (s) and their corresponding dosages, including treatment start 
date, treatment modification reasons, dates and off treatment date.  
• 
In addition, treatment response will be reported by presenting number of the cases 
exhibiting a partial response or complete response, number of progressive diseases and 
deaths.  
 
7.6 
STUDY MEDICATION ACCOUNTABILITY 
All study drug required for completion of this study will be commercially supplied. 
 
Study drug accountability records will be maintained in accordance with the regulations and 
institutional practices. 
7.7 
RECORD RETENTION 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, monitoring logs/letters, and regulatory documents (e.g., protocol and amendments, 
IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 
Study documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
 

Neoadjuvant rituximab for prostate cancer 
Version Date December 18, 2013 
 
Page 38 of 43 
 
8.0 
REFERENCES 
 
1. 
Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al. A 
controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J 
Med. 1989;321:419-24. 
2. 
Eisenberger MA, Blumenstein BA, Crawford ED, Miller G, McLeod DG, Loehrer PJ, et al. 
Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J 
Med. 1998;339:1036-42. 
3. 
Seruga B, Tannock IF. Chemotherapy-based treatment for castration-resistant prostate 
cancer. J Clin Oncol. 2011;29:3686-94. 
4. 
Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 
2001;357:539-45. 
5. 
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 
2010;140:883-99. 
6. 
Karin M. Inflammation and cancer: the long reach of Ras. Nat Med. 2005;11:20-1. 
7. 
Hussain SP, Harris CC. Inflammation and cancer: an ancient link with novel potentials. 
Int J Cancer. 2007;121:2373-80. 
8. 
Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma 
generation and wound healing. N Engl J Med. 1986;315:1650-9. 
9. 
Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in 
carcinogenesis. Nature. 2004;432:324-31. 
10. 
Ben-Neriah Y, Karin M. Inflammation meets cancer, with NF-kappaB as the 
matchmaker. Nature immunology. 2011;12:715-23. 
11. 
Karin M. NF-kappaB as a critical link between inflammation and cancer. Cold Spring 
Harbor perspectives in biology. 2009;1:a000141. 
12. 
Hu Y, Baud V, Delhase M, Zhang P, Deerinck T, Ellisman M, et al. Abnormal 
morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB 
kinase. Science. 1999;284:316-20. 
13. 
Hu Y, Baud V, Oga T, Kim KI, Yoshida K, Karin M. IKKalpha controls formation of the 
epidermis independently of NF-kappaB. Nature. 2001;410:710-4. 
14. 
Descargues P, Sil AK, Sano Y, Korchynskyi O, Han G, Owens P, et al. IKKalpha is a 
critical coregulator of a Smad4-independent TGFbeta-Smad2/3 signaling pathway that 
controls keratinocyte differentiation. Proc Natl Acad Sci U S A. 2008;105:2487-92. 
15. 
Ammirante M, Luo JL, Grivennikov S, Nedospasov S, Karin M. B-cell-derived 
lymphotoxin promotes castration-resistant prostate cancer. Nature. 2010;464:302-5. 
16. 
Luo JL, Tan W, Ricono JM, Korchynskyi O, Zhang M, Gonias SL, et al. Nuclear cytokine-
activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature. 
2007;446:690-4. 
17. 
Marinari B, Moretti F, Botti E, Giustizieri ML, Descargues P, Giunta A, et al. The tumor 
suppressor activity of IKKalpha in stratified epithelia is exerted in part via the TGF-beta 
antiproliferative pathway. Proc Natl Acad Sci U S A. 2008;105:17091-6. 
18. 
Maitland NJ, Collins AT. Prostate cancer stem cells: a new target for therapy. J Clin 
Oncol. 2008;26:2862-70. 
19. 
Anest V, Hanson JL, Cogswell PC, Steinbrecher KA, Strahl BD, Baldwin AS. A 
nucleosomal function for IkappaB kinase-alpha in NF-kappaB-dependent gene 
expression. Nature. 2003;423:659-63. 

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20. 
Yamamoto Y, Verma UN, Prajapati S, Kwak YT, Gaynor RB. Histone H3 
phosphorylation by IKK-alpha is critical for cytokine-induced gene expression. Nature. 
2003;423:655-9. 
21. 
Huang WC, Ju TK, Hung MC, Chen CC. Phosphorylation of CBP by IKKalpha promotes 
cell growth by switching the binding preference of CBP from p53 to NF-kappaB. Mol 
Cell. 2007;26:75-87. 
22. 
Tu Z, Prajapati S, Park KJ, Kelly NJ, Yamamoto Y, Gaynor RB. IKK alpha regulates 
estrogen-induced cell cycle progression by modulating E2F1 expression. J Biol Chem. 
2006;281:6699-706. 
23. 
Hoberg JE, Popko AE, Ramsey CS, Mayo MW. IkappaB kinase alpha-mediated 
derepression of SMRT potentiates acetylation of RelA/p65 by p300. Mol Cell Biol. 
2006;26:457-71. 
24. 
Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, et al. Activation of the 
NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity 
against tumors. Nat Med. 2009;15:1170-8. 
25. 
Kane CJ, Presti JC, Jr., Amling CL, Aronson WJ, Terris MK, Freedland SJ. Changing 
nature of high risk patients undergoing radical prostatectomy. J Urol. 2007;177:113-7. 
26. 
Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clinical trials. 
1989;10:1-10. 
27. 
Lawless J. Statistical Models and Methods for Lifetime Data: John Wiley and Sons; 
1982. 
 
 

Neoadjuvant rituximab for prostate cancer 
Version Date December 18, 2013 
 
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9.0 
APPENDICES 
APPENDIX A. PERFORMANCE STATUS 
 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance 
without restriction 
1 
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature, 
e.g., light housework or office work 
2 
Ambulatory and capable of all self-care but unable to 
carry out any work activities.  Up and about >50% of 
waking hours 
3 
Capable of only limited self-care, confined to a bed or 
chair >50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care.   
Totally confined to bed or chair 
5 
Dead 
 
 

Neoadjuvant rituximab for prostate cancer 
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APPENDIX B. SCHEDULE OF EVENTS 
Procedure 
Screen 
Day -21 
to Day -
1 
Study Treatment 
Surgery 
 
End of 
Treatment 
Visit  
Follow- 
Up # 
Day 1 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36* 
Day 50^ 
 
Informed consent 
Xg 
  
  
  
  
  
  
  
 
Medical history 
X 
  
  
  
  
  
  
  
 
Demographics 
X 
  
  
  
  
  
  
  
 
Eligibility criteria 
X 
  
  
  
  
  
  
  
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
  
X 
 
Adverse Events 
  
X 
X 
X 
X 
X 
  
X 
 
Vital signs a 
X 
Xb 
Xb 
Xb  
Xb   
X 
  
X 
 
Weight and Height  
X 
  
  
  
X 
  
X 
 
Physical Exam 
X 
X¥ 
  
  
  
X 
  
X 
 
ECOG Performance 
Status 
X 
X¥ 
  
  
  
X 
  
X 
 
Hematology c 
X 
X¥ 
  
X 
  
X 
  
  
 
Serum chemistries d 
X 
X¥ 
  
  
  
X 
  
  
 
Hepatitis B and C testing e 
X 
 
PSA assessment  
X 
X¥ 
  
X 
  
X 
  
  
X 
CXCL13 assessment 
X 
X¥ 
  
X 
  
X 
 
Pain assessment 
 X 
  
  
  
X 
  
  
 
Histology assessment f 
  
  
  
  
  
X 
  
 
Rituximab Administration 
  
X 
X 
X 
X 
  
  
  
 
Prostatectomy 
  
  
  
  
  
  
X 
  
 
 
Procedures should be performed on schedule +/- 1 day unless otherwise indicated. 
* 
Radical prostatectomy should be performed as close to day 36 as possible but in any case before day 50. 
^  End of treatment visit to occur within 28 days of the last dose of study drug. Patients who discontinue study drug early 
should be seen within 28 days, which will be earlier than Day 50. 
# 
Follow-up consisting of PSA assessment will occur during routine office visits every 3 months (+/- 1 month) for the first 
two years then every 6 months (+/- 1 month) during the third year. 
¥ 
If hematology, serum chemistries, PSA assessments, physical exam, and ECOG performed during screening occur 
within 14 days of the first administration of study drug, these procedures do not need to be repeated on Day 1. If 
research blood collection for CXCL13 assessment occurred during screening, then it need not be repeated on Day 1 
(alternatively- if blood not collected during screening then it should be collected on Day 1). 
a. Vital signs to include heart rate, blood pressure, and temperature.  
b. On infusion days, vital signs to be recorded both before and at the end of rituximab infusion. 
c. Hematology: hemoglobin, platelets, total white blood cell count, and differential. 
d. Complete Metabolic Panel (CMP) to include: glucose, BUN, creatinine, sodium, potassium, chloride, bicarbonate, 
calcium, total protein, albumin, AST/SGOT, ALT/SGPT, alkaline phosphatase and total bilirubin. 
e. Hepatitis B and C testing: Screen all patients for HBV infection by measuring HBsAg, anti-HBc, and anti-HBs before 
initiating treatment with rituximab  and HCV antibody. 
f. 
Histology assessment: to include routine analysis for tumor diagnosis and staging, plus assessment of 
pharmacodynamic markers specified in Section 4.5.3 for research. 
g. Informed consent may be obtained up to two months prior to study treatment. 

Neoadjuvant rituximab for prostate cancer 
Version Date December 18, 2013 
 
Page 42 of 43 
APPENDIX C. GENENTECH SAFETY REPORTING FAX COVER SHEET 
 
 
SAFETY REPORTING FAX COVER SHEET 
GENENTECH SUPPORTED RESEARCH 
 
AE / SAE FAX No: (650) 225-4682 
Alternate Fax No: (650) 225-5288 
 
Genentech Study 
Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
 
Subject Initials 
(Enter a dash if patient 
has no middle name) 
[ ] - [ ] - [ ] 
 
 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET