Pilot Study Using Propranolol To Promote Prenylation Of The Gtpase Rap1b In Hematopoietic Stem Cell Transplant Recipients
Conditions: Hematopoietic Stem Cell Transplantation
Sponsor: Medical College of Wisconsin

Propranolol and Gene Expression in HCT                                                 Protocol v2.0, October 20, 2015 
 
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PILOT STUDY USING PROPRANOLOL TO PROMOTE PRENYLATION OF 
THE GTPASE RAP1B IN HEMATOPOIETIC STEM CELL TRANSPLANT 
RECIPIENTS 
 
 
 
Version 2.0 
 
Principal Investigator: 
Jennifer M. Knight, MD 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
Telephone: 414-955-8908 
Fax: 414-955-6285 
Email: jmknight@mcw.edu 
 
Co-Investigator: 
 
J. Douglas Rizzo, MD, MS 
CIBMTR 
 
Froedtert and the Medical College of Wisconsin 
Clinical Cancer Center 
9200 W. Wisconsin Avenue Suite C5500 
Milwaukee, WI 53226 
Telephone: 414-805-0700 
Fax: 414-805-0714 
Email: drizzo@mcw.edu 
 
Co-Investigator: 
 
Parameswaran Hari, MD, MS 
Froedtert and the Medical College of Wisconsin 
Clinical Cancer Center 
9200 W. Wisconsin Avenue Suite C5500 
Milwaukee, WI 53226 
Telephone: 414-805-4600 
Fax: 414-805-4606 
 
 
 
 
Email: phari@mcw.edu 
 
Co-Investigator: 
 
Carol L. Williams PhD 
Medical College of Wisconsin 
Basic Sciences Building 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
Telephone: 414-456-5640 
Fax: 414-955-6545 
 
 
 
 
Email: williams@mcw.edu 
 
Consultant 
 
 
Steve W. Cole, PhD 
and Statistician: 
 
UCLA-David Geffen School of Medicine 

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10833 LeConte Ave 
 
 
 
 
11-934 Factor Bldg 
 
 
 
 
Los Angeles, CA 90095-1678 
 
 
 
 
Telephone: 310-267-4243 
 
 
 
 
Email: coles@ucla.edu 
 
Sponsor: 
 
 
Medical College of Wisconsin 
 
 
 
 
 
 

Propranolol and Gene Expression in HCT                                                 Protocol v2.0, October 20, 2015 
 
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PROTOCOL SYNOPSIS 
 
Randomized Controlled Pilot Study Using Propranolol to Promote Prenylation of 
the GTPase Rap1 in Hematopoietic Stem Cell Transplant Recipients 
 
Principal Investigator: 
 
Jennifer M. Knight, MD 
 
Study Design: 
This is a an ancillary study designed to explore 
whether an additional cell signaling pathway 
(prenylation of Rap1) that was recently identified as 
being under beta-adrenergic control may be affected 
by beta-blocker use  
 
Primary Objective: 
The primary objective of this ancillary study is to 
explore whether beta-blocker administration will 
promote prenylation and membrane localization of 
Rap1 in peripheral blood mononuclear cells 
(PBMCs).   
 
Eligibility:  
Patients who are enrolled in the parent study are 
eligible for this ancillary study. 
  
Treatment Description: 
N/A – Patients are treated on the parent protocol 
. 
Accrual Objective: 
 
40 patients will be enrolled to the clinical trial. 
 
Accrual Period: 
 
The estimated accrual period is 9 months. 
 
Study Duration: 
It is estimated that the entire duration of the study 
will not exceed one year as follow-up is 30-45 days. 

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Glossary of Study Abbreviations 
AE:  
 
adverse events 
ANC:   
absolute neutrophil count 
CC:  
 
Cancer Center 
CR:  
 
complete response 
CRC:  
clinical research coordinator 
CTCAE:  
Common Terminology Criteria for Adverse Events  
CTRA: 
conserved transcriptional response to adversity 
DSM:  
Data and Safety Monitoring 
DSMC:  
Data and Safety Monitoring Committee 
ECOG: 
Eastern Cooperative Oncology Group 
G-CSF:  
granulocyte-colony stimulating factor 
HADS:  
Hospital Anxiety and Depression Scale 
HCT:   
hematopoietic stem cell transplantation  
HED:   
human equivalent dose 
ICSR:  
Individual Case Safety Reports 
IMWG:  
International Myeloma Working Group 
IRB: 
 
Institutional Review Board 
MCW:  
Medical College of Wisconsin 
MM:   
multiple myeloma 
nCR:   
near complete response 
OS:  
 
overall survival 
PFS:   
progression-free survival 
PI: 
 
Principal Investigator 
SES:   
socioeconomic status 
sCR:   
stringent complete response 
SNS:   
sympathetic nervous system 
TRM:   
treatment-related mortality 
UCLA: 
University of California Los Angeles 
VGPR:  
very good partial response 

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Table of Contents 
 
1.0 BACKGROUND AND RATIONALE  .................................................6 
     1.1 Rap1 in the tumor microenvironment  ..............................................6 
     1.2 Beta-blockade and cancer  ................................................................6 
     1.3 Propranolol dosing for cancer control ..............................................7 
     1.4 Rationale  ..........................................................................................7 
2.0 STUDY DESIGN ..................................................................................8 
     2.1 Primary objective  .............................................................................8 
     2.2 Patient eligibility  ..............................................................................8  
     2.3 Treatment plan  .................................................................................8 
     
   3.0 STUDY ENDPOINTS  .......................................................................8 
4.0 ENROLLMENT PROCEDURES  ........................................................8 
     4.1 Patient enrollment  ............................................................................8 
     4.2 Baseline demographic-, disease-, and treatment-related variables  ..9 
     4.3 Data and safety monitoring plan  ......................................................9 
     4.4 Specimen collection  .........................................................................9 
     4.5 Rap1 Prenylation  ..............................................................................9 
     4.6 Study monitoring  .............................................................................9  
5.0 STATISTICAL ANALYSIS  ..............................................................12 
     5.1 Study design  ...................................................................................12 
     5.2 Sample size and power calculation  ................................................12 
     5.3 Analysis of primary endpoints  .......................................................12 
 

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1.0 BACKGROUND AND RATIONALE: 
 
1.1 Rap1 in the tumor microenvironment 
 
Rap1, a small GTPase, suppresses metastasis by localizing at the plasma membrane of 
tumor cells through the process of prenylation, the post-translational attachment of a lipid 
tail. When Rap1 is localized at the plasma membrane of tumor cells, Rap1 promotes 
adhesion of the tumor cells and inhibits their metastatic spread. In contrast, when Rap1 
prenylation is inhibited, Rap1 cannot anchor at tumor cell membranes, resulting in loss of 
cell-cell adhesion and increased metastasis of tumor cells.  
 
Recently, it was discovered that prenylation of Rap1 is inhibited by activating adenosine 
receptors on tumor cells.
1, 2 This was the first demonstration that Rap1 prenylation can be 
regulated by receptor activation. 3, 4 Researchers subsequently discovered that prenylation 
of Rap1 is inhibited by activating 
eta
-adrenergic receptors (unpublished data). This 
discovery supports the novel model that beta-blockers will promote prenylation and 
membrane localization of Rap1, decreasing tumor aggressiveness. The demonstration that 
beta-blockers increase the prenylation of Rap1 will support future studies testing the 
effects of beta-blockers on the prenylation of Rap1 in patients’ tumors. The aim of this 
study is to assess whether beta-blocker administration promotes Rap1 prenylation and 
membrane localization. 
 
1.2 Beta-blockade and cancer 
 
Retrospective epidemiologic studies have linked the use of beta-blockers to reduced rates 
of progression for several solid tumors.
5-9 Recently, a retrospective case-control study of 
MM patients identified that concurrent use of any beta-blocker is associated with more 
favorable 5-year overall and disease-specific survival.
10 Preclinical pharmacologic and 
biomarker studies in animals are now laying the groundwork for translation of beta-
blockade as a novel adjuvant to existing therapeutic strategies in clinical oncology, 
linking the use of beta-adrenergic antagonists (beta-blockers) with reduced disease 
progression in humans.5-9, 11-18 Further, propranolol, a non-selective beta-adrenergic 
receptor blocker, has apoptotic and anti-proliferative effects on multiple myeloma (MM) 
cells.
19 Propranolol is the most studied nonselective beta-blocker;20 this, along with its 
safe side effect profile, cost-effectiveness, and efficacy in vitro in preventing tumor 
progression as compared to selective beta-antagonists
16, 21, 22 make it our preferred beta-
blocker for use in the current proposal. Propranolol does not have any significant drug 
interactions with the more common antineoplastic (melphalan) and infection-related 
drugs utilized to treat MM. 
 
The first 30 days following autologous hematopoietic stem cell transplantation (HCT) 
generally constitute the time period around transplantation of greatest psychological and 
physiological stress and inflammatory processes.23, 24 Psychosocial stress gradually 
improves over time with a return to pre-transplant psychosocial functioning by about one 
year post-transplant.25, 26 Therefore, it follows that the first 30 days may also be the time 

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period of highest beta-adrenergic signaling due to increased stress response. Further, data 
from mouse models have demonstrated that beta-blockade with propranolol 8 days prior 
to exogenous stress exposure is effective in blocking beta-adrenergic signaling at the 
tumor level.17 Tumor metastasis in mouse models is increased 30-fold as compared to the 
control group after 20 days of exposure to chronic stress.27 
 
 
1.3 Propranolol dosing for cancer control 
 
Murine models have demonstrated propranolol serum concentrations of 20 ng/ml (range 
0.16-0.26 ng/ml) (Sloan, personal communication) with sustained-release propranolol 
0.5mg over 21 days to be effective in beta-blockade mediated mitigation of stress-
induced tumor progression/metastases.27 Animal to human dosing may be converted 
using the dose translation formula based on body surface area where human equivalent 
dose (HED) (mg/kg) = animal dose (mg/kg) multiplied by Animal Km/Human Km 
(where animal Km = 3, human Km = 37).28 The HED is 122 mg/day or 142 mg/day for a 
60 kg and 70 kg human, respectively. However, the 0.5 mg dose is not a single-dose; 
therefore, with the sustained-release formulation the HED could be as low as 6 mg/day or 
7 mg/day, respectively. The actual HED is likely near the midpoint of the low and high 
values calculated, which would be 60 to 80 mg per day. Therefore, a goal dose of 40mg 
orally twice daily in humans should achieve similar serum concentrations as that 
demonstrated in mice to affect cancer progression. Both 20mg and 40mg of propranolol 
(one administration of a twice daily administration regimen) are effective for anxiolysis.29  
Given this as well as the variable pharmacokinetic profile of propranolol,30-32 it is also 
feasible that 20mg bid may affect prenylation of Rap1. 
 
1.4 Rationale 
 
This study will explore whether prenylation of Rap1 - recently identified as being under 
beta-adrenergic control - may be affected by beta-blocker use. Further, the proposed 
study addresses a major goal of the MCW Cancer Center; it promotes collaborative 
interactions between basic science researchers and clinicians at the Medical College. The 
proposed investigation of Rap1 prenylation will enhance the translational significance of 
Dr. Carol Williams’s studies of Rap1 and may lead to future clinical trials of beta-
blockers as novel therapeutic regulators of Rap1 in cancer. 
 
2.0 STUDY DESIGN 
 
This is a proof of concept randomized controlled pilot study assessing whether 
prenylation and membrane localization of Rap1 in PBMCs can be altered in individuals 
undergoing autologous HCT for MM by administering a daily beta-blocker (propranolol) 
to 20 participants. Outcomes of patients on this clinical trial will be compared to 20 
participants in a control arm. Study assessment time points are detailed in Table 4.7a. 
 
 
 

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2.1 Primary Objective 
 
The primary objective of this ancillary study is to explore whether beta-blocker 
administration will promote prenylation and membrane localization of Rap1 in peripheral 
blood mononuclear cells (PBMCs).   
 
2.2 Patient Eligibility 
 
Patients who are eligible for enrollment in the parent study. 
 
2.3 Treatment Plan 
 
Patients will be treated per the parent protocol. 
 
3.0 STUDY ENDPOINTS 
 
Western blotting on the cytosolic and membrane fractions of isolated PBMCs will 
determine the distribution of Rap1 in the different fractions as well as the status of Rap1 
prenylation in the cells exposed vs. not exposed to beta-blocker therapy. 
 
4.0 ENROLLMENT PROCEDURES 
 
4.1 Patient Enrollment 
 
Patients will be approached for this study during the pre-transplant evaluation phase. 
Transplant physicians will evaluate the patient eligibility onto the parent study and this 
ancillary study. Eligible patients willing to participate in the trial will sign an MCW IRB 
approved informed consent form. A Clinical Trials Office CRC will record the 
documentation of patient consent and proceed with registration procedures. All source 
documents that support eligibility including a signed informed consent/HIPAA and 
signed eligibility checklist, will be available, reviewed and eligibility verified. At the 
point of registration, a member of the study team will register the patient in the electronic 
database, including demographics, consent and on-study information. The patient will be 
assigned a unique sequence number for the study. The principal investigator (PI) of the 
study, Dr. Knight, will be notified prior to enrollment.  If at any point in time a patient 
wishes to withdraw from the study, they may notify Dr. Knight verbally or in writing. 
There will be no further data collection for participants who elect to withdraw from the 
study. 
 
Target enrollment is 40 (20 per group) and includes patients undergoing autologous HCT 
for MM at MCW. Half of the participants in the parent study will be randomized via 
permuted block assignment with random block sizes to receive propranolol upon study 
entry. Informed consent will be obtained to access participants’ full medical records to 
ascertain relevant demographic and medical data as outlined in Section 4.2. The patient 
must have signed informed consent prior to registration on both studies. Due to the pilot 
and feasibility nature of this study, the need to monitor response to prophylactic beta-

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blocker usage in a medically ill population, as well as the objective nature of Western 
blot analysis, this pilot study will not be blinded. Patients will be enrolled by Day -7.. 
Total study duration will be up to 7 weeks for participants assigned to the intervention 
group (1 week pre-transplant through 6 weeks post-transplant) and 5 weeks for those in 
the control arm (1 week pre-transplant through 4 weeks post-transplant). Additional 
clinical information will be collected for 100 days post-transplant as identified in section 
3.2.2.2. 
 
4.2 Baseline Demographic-, Disease-, and Treatment-Related Variables 
 
Same as the parent study 
 
4.3 Data and Safety Monitoring Plan 
 
Same as parent study. 
 
4.4 Specimen Collection 
 
The Cancer Center Lab will draw one tube of blood to be stored in 8 mL BD Vacutainer 
CPT tubes at three study time points as described in Table 4.7b. These time points 
include baseline (Day -7), Day -2 (immediately prior to transplant, central line placement, 
or administration of any conditioning regimen), and Day +28. Blood will be drawn at one 
of two locations: in the hospital (if participants are immediately post-transplant and/or 
still or re-hospitalized) or in the transplant clinic during their regular visits. These 8 mL 
BD Vacutainer CPT  tubes will be transferred to Dr. Williams' lab at MCW for Western 
blot analysis. Before being transferred they will be assigned a dummy ID that will be the 
sole identifier of the samples. The linked identifiers will be stored on a secure computer 
network through the Clinical Trials Office under the PI’s name.  
 
4.5 Rap1 prenylation 
 
Peripheral blood mononuclear cells (PBMCs) will be isolated from the whole blood 
samples collected from patients at the three designated time points (Baseline, Day -2, and 
Day +28). Members of Dr. Carol Williams’ laboratory (Professor, Pharmacology and 
Toxicology, MCW) will conduct western blotting on the cytosolic and membrane 
fractions of isolated PBMCs to determine the distribution of Rap1 in the different 
fractions, and the status of Rap1 prenylation in the cells.  
 
 
4.6 Study Monitoring  
 
The follow-up schedule for scheduled study visits is outlined in Table 4.7a with study 
assessment time points described in Table 4.7b.  
 
 
 

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TABLE 4.7a. FOLLOW-UP SCHEDULE 
 
Study 
Assessment Time 
Point 
Target Day  
Baseline 
Day -7 ± 2 days   
Pre-Transplant 
Day -2 ± 1 day1 
4 weeks 
28 ± 2 days 
 
 
1Assessment must occur prior to any conditioning regimen 
 
 
 
 

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TABLE 4.7b. PATIENT CLINICAL ASSESSMENTS 
 
 
Study Assessments/  
Testing 
Baseline 
 
-2 
7 
14 
21 
28 
35 
42 
100 
Blood draw for Western blot analysis 
X 
X 
 
 
 
X 
 
 
 
 

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5.0 STATISTICAL ANALYSIS 
 
5.1 Study Design 
 
5.1.1 Accrual 
 
It is estimated that 9 months – 1 year will be necessary to enroll the targeted sample size. 
 
5.1.2 Primary Endpoint 
 
The primary endpoint is Day +28 (4 weeks) following HCT for MM, with intervention 
arm patients followed for an additional 1-2 weeks until they are weaned from beta-
blocker therapy. 
 
5.2 Sample Size and Power Calculation 
 
We will enroll 40 participants undergoing autologous HCT for MM at MCW. Accounting 
for study attrition and beta-blocker intolerance, we aim to have 30 patients with a 
complete set of prenylation data. A targeted final sample of 15 participants in the 
intervention group will be sufficient for Western blot analysis. This sample size is 
established for the purpose of the parent study and should be sufficient to describe 
prenylation. 
 
5.3 Analysis of Primary Endpoints 
  
5.3.1 Rap1 prenylation by beta-blocker exposure 
 
Western blotting on the cytosolic and membrane fractions of isolated PBMCs will 
determine the distribution of Rap1 in the different fractions as well as the status of Rap1 
prenylation in the cells exposed vs. not exposed to beta-blocker therapy. The statistical 
difference between cells from patients exposed to beta-blocker therapy (intervention arm) 
vs. those not exposed to beta-blocker therapy (control arm) will be determined by 
repeated-measures of analysis of variance (ANOVA) individually at the two blood 
assessment time points on beta-blocker therapy (Day -2, and Day +30). Baseline Rap1 
prenylation will also be assessed by the first blood draw and may be compared to later 
time points. Patients will be included in final analyses if and only if they have been 
adherent to the study drug during the designated time period as described in the parent 
protocol. 
 
 
 
 
 
 
 

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