Conditions: Anatomic Stage I Breast Cancer AJCC v8 Anatomic Stage IA Breast Cancer AJCC v8 Anatomic Stage IB Breast Cancer AJCC v8 Anatomic Stage II Breast Cancer AJCC v8 Anatomic Stage IIA Breast Cancer AJCC v8 Anatomic Stage IIB Breast Cancer AJCC v8 Breast Ductal Carcinoma In Situ Early Stage Breast Carcinoma Invasive Breast Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 27
Healthy volunteers: no

Brief summary:
This phase 1b trial studies the biologic effect of 9cUAB30 on early stage breast cancer. 9cUAB30 is a retinoid X receptor (RXR)-selective retinoid that acts in a tissue selective manner with the goal of minimizing side effects, a necessary feature of agents under development for cancer prevention.

Detailed description:
PRIMARY OBJECTIVE:

I. Compare molecular analysis of pre- and post-treatment tissue samples of breast cancers of patients treated with 14-28 days of oral retinoid X receptor (RXR)-selective retinoid 9cUAB30 (9 cUAB30) will demonstrate significantly reduced proliferation.

SECONDARY OBJECTIVES:

I. Determine if 14-28 days of oral RXR-selective 9c-UAB30 treatment increases apoptotic index, as measured by cleaved caspase 3 assay.

II. Examine the differences in gene expression from baseline to post-exposure breast cancer samples using a custom gene panel from Nanostring Technologies.

III. To examine if the maximum concentration (Cmax) and safety of 9cUAB30 in the first 5 participants is affected by reducing the number of capsules at the 240 mg dose level.

IV. To examine the Cmax of all participants at baseline and on the day of surgery.

V. Determine if treatment with 2-4 weeks of 9cUAB30 prior to surgery will increase gene expression of type I immune cells in the tumor immune environment of all participants except the first 5.

VI. Assess the overall safety of 9cUAB30 in comparison with known retinoid toxicity.

EXPLORATORY OBJECTIVE:

I. Determine if treatment with 2-4 weeks of 9cUAB30 prior to surgery will increase activated type I dendritic cells in peripheral blood.

OUTLINE:

Patients receive retinoid 9cUAB30 orally (PO) once daily (QD) for 14 to 28 days. Patients then undergo tumor resection surgery. Patients undergo blood and urine sample collection throughout the study.

After completion of study treatment, patients are followed up at 7 days and 4-5 weeks.

Arms:
arm 1: Patients receive retinoid 9cUAB30 PO QD for 14 to 28 days. Patients then undergo tumor resection surgery. Patients undergo blood and urine sample collection throughout the study.

Interventions: intervention 1: Biospecimen Collection intervention 2: Retinoid 9cUAB30 intervention 3: Therapeutic Conventional Surgery
Intervention descriptions: intervention 1: Undergo blood and urine sample collection intervention 2: Given PO intervention 3: Undergo tumor resection surgery

Protocol document:
Prot_SAP_000.pdf: 
DCP Protocol #:  UWI2015-05-01 
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DCP Protocol #: 
UWI2015-05-01  
Local Protocol #: UW16063 (UWI), XUAB1769 (UAB), 2017NTUC086 (UMN), 201909206 (UI) 
 
Phase Ib 9cUAB30 in Early Stage Breast Cancer to Evaluate Biologic Effect 
 
 
Consortium Name: 
 
 
University of Wisconsin Chemoprevention Consortium  
Name of Consortium Principal  
Howard H. Bailey, MD 
Investigator:  
 
 
K4/6 CSC 
 
 
 
 
 
600 Highland Ave 
 
 
 
 
 
Madison, WI 53792-6162 
Phone: (608)263-8624 
Fax: (608)265-3287 
E-mail address: hhb@medicine.wisc.edu 
 
Organization Name: 
 
 
University of Alabama at Birmingham  
Protocol Principal Investigator: 
Helen Krontiras, MD 
 
 
 
 
 
Professor of Surgery 
 
 
 
 
 
Division of Surgical Oncology 
 
 
 
 
 
510 20th St. S., FOT 1153 
 
 
 
 
 
Birmingham, AL 35243 
 
 
 
 
 
Phone: (205)934-3028 
 
 
 
 
 
Fax (205) 975-5971 
 
 
 
 
 
hkrontir@uabmc.edu 
 
Organization:  
 
 
University of Wisconsin 
Investigator:  
 
 
Lee Wilke, MD 
 
 
 
 
 
Professor School of Medicine and Public Health - Surgery 
 
 
 
 
 
H4/722 7375 Clinical Science Center 
 
 
 
 
 
600 Highland Avenue 
 
 
 
 
 
Madison, WI  53792-6162 
 
 
 
 
 
Phone:  608-265-5852 
 
 
 
 
 
Fax: 608-252-0944 
 
 
 
 
 
wilke@surgery.wisc.edu 
 
Organization:  
 
 
University of Alabama at Birmingham 
Biomarker Analysis:  
 
Sameer Al Diffalha, MD  
 
 
 
 
 
Director 
 
 
 
 
 
UAB Tissue Biorepository 
 
 
 
 
 
Ziegler Research Building, Room 449 
 
 
 
 
 
703 19th Street South 
 
 
 
 
 
Birmingham, AL 35294-0007 
 
 
 
 
 
saldiffalha@uabmc.edu 
 
 
 
 
 
 
Organization:   
 
 
University of Alabama at Birmingham 
Biomarker Analysis:  
 
Eddy S. Yang, MD, PhD 
 
 
 
 
 
Associate Professor 
 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
 
176F HSROC Rm 2232N 
 
 
 
 
 
1700 6th Avenue South 


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Birmingham, AL  35249-6832 
 
 
 
 
 
Phone: 205-934-2762 (Office) 
 
 
 
 
 
Fax: 205-975-0784 
 
 
 
 
 
eyang@uab.edu 
  
Organization:   
 
 
Providence Cancer Institute* 
Biomarker Analysis:   
 
Sasha E. Stanton, MD, PhD 
Earle A. Chiles Research Institute- Cancer Immunoprevention 
Laboratory 
4805 NE Glisan St.  
Suite 2N103  
Portland, OR 97213 
Phone: 503-215-2597 
Sasha.Stanton@providence.org 
 
 
Organization:   
 
 
University of Wisconsin 
Biomarker Analysis:  
 
Karla Esbona, PhD 
 
 
 
 
 
TRIP Laboratory Scientific Manager 
 
 
 
 
 
Translational Research Initiatives in Pathology (TRIP) 
 
 
 
 
 
Department of Pathology and Laboratory Medicine 
 
 
 
 
 
L5/143 CSC 8550 
 
 
 
 
 
600 Highland Ave 
 
 
 
 
 
Madison, WI 53792-8550 
 
 
 
 
 
Phone: 608-262-5136 
 
 
 
 
 
Fax: 608-263-3685 
 
 
 
 
 
kesbona@wisc.edu 
 
Organization:  
 
 
University of Minnesota 
Investigator:  
 
 
Jane Hui, MD 
 
 
 
 
 
Masonic Cancer Center 
 
 
 
 
 
195 Mayo Rm 11-142 PWB MCRB 
 
 
 
 
 
8195E, 420 Delaware St SE 
 
 
 
 
 
Minneapolis, MN  55455 
 
 
 
 
 
Phone:  612-625-2991 
 
 
 
 
 
Fax:  612-625-4406 
 
 
 
 
 
jhui@umn.edu 
 
Organization:  
 
 
University of Iowa 
Investigator:  
 
 
Sonia Sugg, MD 
 
 
 
 
 
Professor of Surgery 
 
 
 
 
 
University of Iowa Hospital and Clinics 
 
 
 
 
 
200 Hawkins Drive 
 
 
 
 
 
Iowa City, IA  52242 
 
 
 
 
 
Phone:  319-356-7675 
 
 
 
 
 
sonia-sugg@uiowa.edu 
 
Organization:  
 
 
Northwestern University 
Investigator:  
 
 
Seema Khan, MD 
Professor of Surgery 


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303 E. Superior, Suite 4-111 
Chicago, IL 60611 
Tel: (312) 503-4236 
Fax: (312) 503-2555 
skhan@nm.org 
 
Organization:  
 
 
University of Wisconsin 
Statistician: 
 
 
 
Richard Chappell, PhD  
 
 
 
 
 
610 Walnut St, WARF 207E  
 
 
 
 
 
Madison, WI 53726   
 
 
 
 
 
Telephone: 608-263-5572 or 608-229-6541 
 
 
 
 
 
No fax number 
 
 
 
 
 
chappell@biostat.wisc.edu 
 
Medical Monitor 
 
Edward Sauter, MD, PhD 
Breast and Gynecologic Cancer Research Group 
Division of Cancer Prevention 
9609 Medical Center Dr., Rm 5E326 
Bethesda, MD 20892-9783 
Phone: (240)276-7657 
Cell: (240)944-3279 
Email: edward.sauter@nih.gov  
 
Scientific Monitor: 
 
Brandy Heckman-Stoddard, PhD, MPH 
 
 
Breast and Gynecologic Cancer Research Group 
 
 
Division of Cancer Prevention 
 
 
9609 Medical Center Dr., Rm 5E344 
 
 
Bethesda, MD 20850-9783 
 
 
Phone: (240)276-7048 
 
 
Email: heckmanbm@mail.nih.gov    
 
*No participant accrual occurs at this site. 
 
IND Sponsor:  
NCI/Division of Cancer Prevention  
6130 Executive Blvd., Rm2117 
Bethesda, MD  20892 
(For FedEx use Rockville, MD  20852) 
 
IND#  
 
 
 
Agent(s)/Supplier: 
9cUAB30/NCI, DCP repository    
 
NCI Contract # 
HHSN261201200033I 
  
Protocol Version Date:  
28 January 2022 
 
Protocol Revision or 
Amendment #  
 
Version 20 
 


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SCHEMA 
Pilot Study of 9cUAB30 in Early Stage Breast Cancer to Evaluate Biologic Effect 
Up to 41 participants with early stage breast cancer – diagnosed by core biopsy 
↓ 
Invasive breast cancer between 0.5 cm and 5 cm in size 
Estrogen receptor positive (ER+) or estrogen receptor negative (ER–),  
Her2neu positive or Her2neu negative 
OR 
Ductal carcinoma in-situ (DCIS) at least 1.0 cm in size,  
ER+ DCIS that is Grade 3 or ER- DCIS of any grade  
 
*Beginning November 2021 only estrogen receptor negative (ER-) participants (12 participants) will be 
enrolled.  
↓ 
Administration of 9cUAB30 240 mg once daily in the evening on an empty stomach (take agent at least 2 
hours after last eating and wait at least 1 hour before eating again) for 14-28 days before surgery 
(First 5 participants enrolled N=5) 
First dose taken in clinic with 5 minute and 2hr. PK blood draws 
 
After interim analysis* 
➢ Administration of 9cUAB30 240 mg once daily in the evening  on an empty stomach (take agent 
at least 2 hours after last eating and wait at least 1 hour before eating again ) for 14-28 days 
before surgery (N=31)  
OR 
➢ Administration of 9cUAB30 160 mg once daily in the evening  on an empty stomach (take agent 
at least 2 hours after last eating and wait at least 1 hour before eating again ) for 14-28 days  
before surgery (N=36) 
↓ 
Home BP Check Day 7 
↓ 
Telephone Contact and Home BP Check Day 8 (+/-1 day) 
↓ 
Home BP Check Day before surgery 
↓  
Definitive Breast Surgery Day 15-29 
↓ 
Telephone Contact 7 days (+/-1 day) after surgery and 4-5wks after surgery 
  
Slides from core biopsy and surgical specimens will be obtained for each enrolled participant along with 
historical matched control tissues. 
Study Endpoints: 
Primary: Change in proliferation (Ki-67) 
Secondary:  
• 
Change in apoptosis (Cleaved Caspase 3) 
• 
Differences in gene expression from pre and post treatment samples using a custom gene panel from 
Nanostring Technologies 
• 
Examine Safety and PK drug levels in first 5 participants for interim analysis  
• 
PK drug levels 
• 
Increase gene expression of type I immune cells in the tumor immune environment 
• 
Examine safety in comparison to known Retinoid toxicity 
Exploratory: Increase activated type I dendritic cells in peripheral blood (participants 6-25) 


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*If the interim analysis for dose 240mg does not establish Cmax >957 ng/mL or has ≥ 2 subjects 
experience grade 2 hypertriglyceridemia of any attribution then the study dose will be changed to 160mg. 
 
TABLE OF CONTENTS 
 
 
SCHEMA ...................................................................................................................................................... 4 
1. 
OBJECTIVES ..................................................................................................................................... 7 
1.1   Primary Objective ........................................................................................................................................ 7 
1.2 
Secondary Objectives .................................................................................................................................. 7 
1.3  
Exploratory Objective .................................................................................................................................. 7 
2. 
BACKGROUND................................................................................................................................. 8 
2.1 
Study Disease .............................................................................................................................................. 8 
2.2 
Study Agent ................................................................................................................................................. 8 
2.3 
Rationale .................................................................................................................................................... 11 
3. 
SUMMARY OF STUDY PLAN ...................................................................................................... 13 
4. 
PARTICIPANT SELECTION .......................................................................................................... 15 
4.1 
Inclusion Criteria ....................................................................................................................................... 15 
4.2 
Exclusion Criteria ...................................................................................................................................... 16 
4.3 
Inclusion of Women and Minorities .......................................................................................................... 17 
4.4 
Recruitment and Retention Plan ................................................................................................................ 17 
5. 
AGENT ADMINISTRATION .......................................................................................................... 18 
5.1 
Dose Regimen and Dose Groups ............................................................................................................... 18 
5.2 
9cUAB30 Administration .......................................................................................................................... 18 
5.3 
Run-in Procedures ..................................................................................................................................... 18 
5.4 
Contraindications ....................................................................................................................................... 18 
5.5 
Concomitant Medications .......................................................................................................................... 19 
5.6 
Dose Modification ..................................................................................................................................... 19 
5.7 
Adherence/Compliance .............................................................................................................................. 19 
6. 
PHARMACEUTICAL INFORMATION ......................................................................................... 19 
6.1 
9cUAB30 (IND 101,064, NCI, DCP) ........................................................................................................ 19 
6.2 
Reported Adverse Events and Potential Risks ........................................................................................... 20 
6.3  
Availability ................................................................................................................................................ 24 
6.4 
Agent Distribution ..................................................................................................................................... 24 
6.5  
Agent Accountability ................................................................................................................................. 24 
6.6 
Packaging and Labeling ............................................................................................................................. 25 
6.7 
Storage ....................................................................................................................................................... 25 
6.8 
Registration/Randomization ...................................................................................................................... 25 
6.9 
Blinding and Unblinding Methods ............................................................................................................. 25 
6.10 Agent Destruction/Disposal ....................................................................................................................... 25 
7. 
CLINICAL EVALUATIONS AND PROCEDURES ...................................................................... 26 
7.1 
Schedule of Events .................................................................................................................................... 26 
7.2 
Baseline Testing/Prestudy Evaluation ....................................................................................................... 27 
7.3 
Evaluation During Study Intervention ....................................................................................................... 29 
7.4 
Evaluation at Completion of Study Intervention ....................................................................................... 30 
7.5 
Post-intervention Follow-up Period ........................................................................................................... 31 
7.6 
Methods for Clinical Procedures ............................................................................................................... 31 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION............................................... 31 
8.1 
Primary Endpoint ....................................................................................................................................... 31 
8.2 
Secondary Endpoints ................................................................................................................................. 32 
8.3 
Exploratory Endpoint ................................................................................................................................. 35 
8.4 
Off-Agent Criteria ..................................................................................................................................... 35 
8.5 
Off-Study Criteria ...................................................................................................................................... 36 


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Study Termination ..................................................................................................................................... 36 
9. 
CORRELATIVE/SPECIAL STUDIES ............................................................................................ 36 
9.1 
Rationale for Methodology Selection ........................................................................................................ 36 
9.2 
Comparable Methods ................................................................................................................................. 37 
10. 
SPECIMEN MANAGEMENT ......................................................................................................... 37 
10.1 Laboratories ............................................................................................................................................... 37 
10.2 Collection and Handling Procedures ......................................................................................................... 38 
10.3 Shipping Instructions ................................................................................................................................. 40 
10.4 BioBanking ................................................................................................................................................ 42 
11. 
REPORTING ADVERSE EVENTS ................................................................................................. 42 
11.1 Adverse Events .......................................................................................................................................... 43 
11.2 Serious Adverse Events ............................................................................................................................. 45 
12. 
STUDY MONITORING ................................................................................................................... 46 
12.1 Data Management ...................................................................................................................................... 46 
12.2 Case Report Forms .................................................................................................................................... 46 
12.3 Source Documents ..................................................................................................................................... 46 
12.4 Data and Safety Monitoring Plan ............................................................................................................... 47 
12.5 Sponsor or FDA Monitoring ...................................................................................................................... 47 
12.6 Record Retention ....................................................................................................................................... 47 
12.7 Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) ......... 47 
13. 
STATISTICAL CONSIDERATIONS .............................................................................................. 47 
13.1 Study Design/Description .......................................................................................................................... 47 
13.2 Randomization/Stratification ..................................................................................................................... 48 
13.3 Accrual and Feasibility .............................................................................................................................. 48 
13.4 Primary Objective, Endpoint(s), Analysis Plan ......................................................................................... 49 
13.5 Secondary Objectives, Endpoints, Analysis Plans ..................................................................................... 49 
13.6 Reporting and Exclusions .......................................................................................................................... 50 
13.7 Evaluation of Toxicity ............................................................................................................................... 50 
13.8 Evaluation of Response ............................................................................................................................. 50 
13.9 Interim Analysis......................................................................................................................................... 50 
13.10 Ancillary Studies ....................................................................................................................................... 50 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................ 50 
14.1 Form FDA 1572 ......................................................................................................................................... 51 
14.2 Other Required Documents ....................................................................................................................... 51 
14.3 Institutional Review Board Approval ........................................................................................................ 51 
14.4 Informed Consent ...................................................................................................................................... 51 
14.5 Submission of Regulatory Documents ....................................................................................................... 52 
14.6 Other .......................................................................................................................................................... 52 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE ...................................................................... 52 
REFERENCES ........................................................................................................................................... 53 
APPENDIX A ............................................................................................................................................. 56 
APPENDIX B ............................................................................................................................................. 57 
APPENDIX C ............................................................................................................................................. 61 


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1. 
OBJECTIVES 
 
The overall goal is to determine if 9cUAB30 can produce a potentially beneficial biologic effect on human 
breast cancer at a non-toxic dose.  We hypothesize that comparative molecular analysis of pre- and post-
treatment tissue samples of breast cancers of patients treated with 14-28 days of oral RXR-selective 
9cUAB30 will demonstrate significantly reduced proliferation, increased apoptosis and changes consistent 
with ligand-RXR binding, as reflected in downstream markers, evaluated at the mRNA level by Nanostring, 
with selective confirmation at the protein level by IHC. 
 
1.1   
Primary Objective 
 
We hypothesize that comparative molecular analysis of pre- and post-treatment tissue samples of breast 
cancers of participants treated with 14-28 days of oral RXR-selective 9cUAB30 will demonstrate 
significantly reduced proliferation.   
 
1.2 
Secondary Objectives  
 
1.2.1  Determine if 14-28 days of oral RXR-selective 9cUAB30 treatment increases apoptotic index, as 
measured by cleaved caspase 3 assay.  
 
1.2.2  Examine the differences in gene expression from baseline to post-exposure breast cancer samples 
using a custom gene panel from Nanostring Technologies. Examined genes will be selected as described 
below and will include up to 48 genes. Prospective biomarkers on the panel will include but are not limited 
to (A) biomarkers associated with cell proliferation or apoptosis: PCNA, p21, p27, TUNEL assay, caspase 
3; (B) potential biomarkers of rexinoid activity reported in published studies: ABCA1, ABCG1, RARβ, 
SREBP-1c, cyclin D1, IGFBP6; (C) potential biomarkers of response to 9cUAB30 as defined in our 
preliminary studies: RET, MEN1, mTOR, AKT1, AKT2, 4EBP1, eIF4G1, S6K, IGFBP5, TGFβR1, 
PPARα, PPARγ (D) housekeeping genes for normalization: GAPDH, TUBB, PGK1, GUSB, and CLTC. 
Additionally, as possible, we will perform IHC for a subset of 5 of the most differentially regulated genes 
found on Nanostring to verify that gene expression data also results in protein differences. 
 
1.2.3 
To examine if the Cmax and safety of 9cUAB30 in the first 5 participants is affected by reducing 
the number of capsules at the 240mg dose level. That is using 3 capsules of 80mg each instead of 12 capsules 
of 20mg each. 
 
1.2.4  To examine the Cmax of all participants at baseline and on the day of surgery 
 
 
1.2.6 
Determine if treatment with 2-4 weeks of 9cUAB30 prior to surgery will increase gene expression 
of type I immune cells in the tumor immune environment of all participants except the first 5 
 
1.2.7    Assess the overall safety of 9cUAB30 in comparison with known retinoid toxicity.  
 
1.3  
Exploratory Objective 
1.3.1 
Determine if treatment with 2-4 weeks of 9cUAB30 prior to surgery will increase activated type I 
dendritic cells in peripheral blood. 
 
 
 
 


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2. 
BACKGROUND 
 
2.1 
Study Disease 
 
In 2019, an estimated 268,600 new cases of invasive breast cancer and 48,100 new cases of DCIS were 
diagnosed in women in the United States and approximately 41,760 women were expected to die from 
breast cancer.1 Prevention of breast cancer not only is key to reducing breast cancer mortality but also  to 
improving quality of life by reducing the number of patients who have to undergo surgery, chemotherapy 
and radiation therapy to treat their cancers.  
 
Women at increased risk for breast cancer are candidates for hormonal prevention strategies. Two selective 
estrogen modulators (SERMs), Tamoxifen or raloxifene, are highly effective ( 50%) in reducing risk of 
ER+ breast cancers.  Aromatase inhibitors (AIs) prevent the recurrence of invasive ER+ cancers as well as 
or better than SERMs. Currently, Exemestane, an AI, is included in management guidelines as an alternative 
to tamoxifen or raloxifene to reduce risk of invasive ER+ breast cancer in postmenopausal women at 
increased risk for breast cancer. However, because of the real and perceived risks of chemoprevention, 
patient uptake of current chemoprevention strategies remains low.2 3Studies show that only 12% of women 
at high risk for breast cancer opt for Tamoxifen as a preventive agent. The main reason women are declining 
Tamoxifen is due to concerns about toxicity.4 Moreover, a significant population of high-risk women will 
develop cancers that are not prevented by currently approved prevention strategies. For example, women 
with mutant BRCA-1 usually develop tumors that are ER-negative/PR-negative/Her2neu negative. 
Evidence is sparse that these patients will respond to traditional hormonal prevention.5 There is a need for 
an oral preventive agent with an attractive side effect profile that will prevent both ER-positive and more 
aggressive ER-negative breast cancers. 
 
2.2 
Study Agent 
 
Retinoids, which target the retinoic acid receptors (RARs), and rexinoids, which target the retinoid X 
receptors (RXRs), represent two classes of potential drugs with potent capacity to prevent breast cancers 
and have been studied extensively. 9-cis-Retinoic acid (9cRA) is a potent agonist for RXRs,6-10which 
activates RXR homodimer-mediated transcription or heterodimer-mediated transcription with other 
receptors of the steroid/thyroid superfamily (e.g. RARs, VDR, PPAR, TR and orphan receptors). These two 
pathways lead to activation of gene transcription that is responsible for the induction of differentiation and 
apoptosis. Thus, RXRs are the master regulators of gene expression of the RAR- and RXR-signaling 
pathways, and both pathways can be controlled by 9cRA.8-11 9-cis-retinoic acid has been shown to be 
effective in preventing mammary gland tumors in N-methyl-N-nitrosurea (MNU) animal models, 
unfortunately, the effective dose is near its maximally tolerated dose.12  
 
Targretin and other RXR-selective ligands, or rexinoids, have been developed in an effort to identify a 
rexinoid that will be safe for chronic human use. Targretin is the best studied rexinoid and FDA approved 
to treat cutaneous T-cell lymphoma. Targretin shares little structural similarity to 9cRA, and human clinical 
trials revealed it was better tolerated than 9cRA. Targretin did not produce many of the classic retinoic acid 
associated toxicities of 9cRA (bone fractures; skin lesions and redness; elevated serum calcium) but does 
produce dose-limiting hyperlipidemia (both elevated cholesterol and triglycerides) and hypothyroidism.13,14 
The lower toxicity of Targretin relative to 9cRA did not reduce potency of this rexinoid in cancer 
prevention. Several studies demonstrated Targretin was as effective as 9cRA in reducing the number and 
tumor burden of ER+ mammary cancers.12,15 Other groups established that the effects of combining 
Targretin or 9cRA with a SERM were additive and the combination regimen significantly decreased tumor 




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2.2.3 Preclinical toxicity studies 
 
In a series of preclinical studies conducted via the NCI DCP RAPID program, 9cUAB30 was found to have 
no lipid toxicity in two species (rat and dog), 28 and it had fewer side effects than Targretin. 9cUAB30 
displayed favorable pharmacology and was not mutagenic.29,30 
 
2.2.4 Human Studies 
 
After IND approval in 2009 (IND#101,604), DCP funded the first Phase 1 trial. Between November 2008 
and May 2009, 14 healthy volunteers at the University of Wisconsin (UW) were treated with single doses 
of 9cUAB30, 4 subjects at 5mg, 6 subjects at 10 mg, and 4 subjects at 20 mg.31 Subjects were 50% male 
and 50% female and all were white, non-Hispanic. Subjects were enrolled in groups of 4 sequentially into 
the progressively higher dose groups; a single dose of 5, 10, or 20 mg of 9cUAB30 was given orally in the 
morning on an empty stomach.  No subjects at dose level 5 mg or 20 mg experienced ≥grade 2 toxicity. 
There were few observed ≤ grade 1 laboratory abnormalities, including 2 subjects with grade 1 
hypertriglyceridemia After Tmax (2-3 hours after dose), 9cUAB30 levels declined steadily. Plasma half-
life increased in a dose dependent manner, averaging 2.79 hours in the 5-mg group, 5.76 hours in the 10-
mg group, and 7.21 hours for the 20-mg group. In regression analysis, AUC increased linearly across the 
examined dose range of 5 to 20 mg; a linear relationship between AUC and dose was found to be significant 
(β=38.7, p < 0.001). Cmax, increased with dose, but not in a linear fashion; it was found to be proportional 
to the log of dose (β= 4.43, p < 0.001). The average plasma clearance ranged from 25 to 39 L/h compared 
to the average renal clearance which ranged from 0.018 to 0.103 L/h.   
 
 
We initiated a double-blind, placebo-controlled single and multi-dose study of 9cUAB30 in healthy 
volunteers at 3 participating organizations (UW, UAB, and University of Iowa). Over the course of two 
different protocols (UWI09-8-02, UWI10-16-01R), 44 participants were enrolled into the study in cohorts 
of 10 (8 9cUAB30:2 placebo). The starting dose level was 20 mg followed by dose cohorts at 40 mg, 80 
mg, 160 mg, and 240mg daily. Subjects received a single, initial dose of study drug (fasting) on day 1 with 
full pharmacokinetic (PK) and safety monitoring for 24 hours and continued observation off study drug 
until returning the morning of day 8 for PK sampling and initiation of continuous daily dosing (day 8 -35) 
when they would return for full PK monitoring for 24 hours after their last dose. Summary PK parameters 
are presented in Table 1; we observed a linear to near linear increase in peak concentrations and AUC from 
20 to 160 mg per day of 9cUAB30. There was no further increase in 9cUAB30 concentrations (Cmax or 
AUC) from 160 to 240 mg dosing, in fact there was even some evidence to suggest a possible decline in 
drug levels raising the possibility of absorption issues/interference due to the large number of gelatin 
capsules at 240 mg (12 capsules). Comparison of baseline and day 36 pharmacokinetics parameters did not 
suggest drug accumulation or altered metabolism (whether an increase or decrease in absorption or 
clearance) with repeated dosing.  
 
Table 1:  AUC by Dose Level Cohorts 20mg-240mg Multi-day Study (UWI09-8-02, UWI10-16-01R) 
 
Parameter, 
Time 
0 mg 
(n=10) 
20 mg (n=8) 
40 mg (n=8) 
80 mg (n=8) 
160 mg (n=8) 
240 mg (n=8) 
Cmax* 
(ng/ml) 
 
 
 
 
 
 
Day 1 
0 (0-0) 128 
(41.0-252) 
176 
(19.8-430) 623 
(353-2620) 
975 
(348-1590) 
812 
(246-1830) 
Day 36 
0 (0-0) 122 
(54.8-143) 
201 
(54.5-247) 1060 
(220-1690) 
1420 
(486-5120) 
889 
(477-1370) 


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Change 
0 (0-0) -10.7 (-111-53.7) -47.8 
(-183-185) 492 
(-930-751) 
950 
(-1100-3990) 
186 
(-1290-623) 
AUC* 
 
 
 
 
 
 
Day 1 
0 (0-0) 1200 (304-3640) 1570 
(181-1900) 5710 (1850-12500) 13000 (2190-62000) 
8560 (2000-23400) 
Day 36 
0 (0-0) 1030 (529-2420) 2280 (865-16000) 8290 (3270-13500) 14400 (10700-40700) 12300 (4990-15400) 
Absolute 
Change 
0 (0-0) -86.3 (-2660-1280) 831 
(348-14400) 1730 (-3170-6510) 
5820 (-2250-27600) 2710 (-863-7310) 
*Data are presented as median (range) 
 
Subjects were followed for 30 days after their last study dose and escalation to the next dose cohort occurred 
after all 10 subjects at a dose level had completed the course with ≤1 subject experiencing unacceptable, 
attributable toxicity. Characteristics of the 44 subjects were; mean age - 40.9 (SD 13.5); ECOG performance 
status – all zero; 27 male; 17 female; 39 subjects - white, 5 - African American; all identified as not Hispanic 
or Latino. Early evaluation of observed toxicity did not reveal any consistency or pattern of toxicity 
normally seen with rexinoids. Reports of nausea or headache were rare and did not persist despite continued 
administration of study drug. Skin changes and fatigue were rarely reported. Serum lipid abnormalities 
were noted but rarely consistently elevated from baseline. 
 
 
Table 2: Percentage of subjects with worst grade of adverse event for CTCAE v4.0 category 
CTCAE 
Category 
Overall 
Grade 
0 mg 
(n=12) 
20 mg 
(n=8) 
40 mg 
(n=9) 
80 mg 
(n=8) 
160 mg 
(n=9) 
240 mg 
(n=8) 
0 
None 
2 
(17) 
2 
(25) 
0 
(0) 
2 
(25) 
1 
(11) 
0 
(0) 
1 
Mild 
5 
(42) 
2 
(25) 
5 
(56) 
2 
(25) 
3 
(33) 
3 
(38) 
2 
Moderate 
5 
(42) 
2 
(25) 
4 
(44) 
4 
(50) 
4 
(44) 
2 
(25) 
3 
Severe 
0 
(0) 
2 
(25) 
0 
(0) 
0 
(0) 
1 
(11) 
3* 
(38) 
*All grade 3 events were considered “Unlikely” to be related to treatment.  To be a dose-limiting toxicity, 
they would have had to be at least “Possibly” related. 
 
2.3 
Rationale 
 
The goal of this Phase 1b window trial is to ensure that 9cUAB30 produces a biological effect in humans 
and to identify candidate RXR signaling pathways that may play a role for cancer prevention. We believe 
the low toxicity of the rexinoid 9cUAB30 will be well-received for prevention of breast cancers in the high 
risk population, and potentially even better received for women who have had cancer and wish to prevent 
the occurrence of a second tumor. The results of this study will help to determine the suitability of continued 
study with 9cUAB30 as a chemoprevention drug in trials proposed by the NCI DCP in the Clinical 
Development Plan of 9cUAB30. 
 
Treatment with 9cUAB30 in animal models reduced proliferation and number of tumors in both ER+ and 
ER- breast cancer animal models, suggesting a chemopreventive effect of the drug. To evaluate the anti-
proliferative effect in humans, we chose the pre-surgical window trial design. The model of short-term 
administration of a drug between the window of diagnosis to operative intervention, allows for evaluation 
of biomarker response from baseline (core biopsy) to post-treatment (surgery). Several pre-surgical trials 


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have shown the ability of SERMs to reduce proliferation as measured by Ki67 after short-term 
administration. In these trials administration of tamoxifen or other SERM results in decrease of Ki67 by 
approximately 40% when surgical resection samples are compared with pretreatment core biopsy samples. 
32-35 We expect that 9cUAB30 will reduce proliferation and increase apoptosis.  
 
Because breast cancer prevention/therapy preclinical mouse model data with Targretin, 9cRA and 
9cUAB30 suggest a linear relationship between increasing dose/concentration and anti-cancer effects, it is 
important to explore the highest 9cUAB30 dose that pharmacodynamics suggest.  The new formulation of 
9cUAB30 will significantly lower the gelatin: active ingredient ratio (12 capsules vs 3 capsules) thus raising 
the potential of higher tissue exposure at 240 mg as compared to 160 mg.  Therefore, we plan to “pilot” the 
240 mg dose in initial participants with planned assessment of C2hr (Tmax usually at 2 hours) at 2 hours 
post initial dose. If real time assessment of 9cUAB30 concentrations observe a significant increase over 
957 ng/ml levels we will continue at 240 mg/day. If initial concentrations are not appreciably >957 ng/ml 
with 240 mg/day, participants will be treated at 160 mg/day.  
 
Further, we plan to evaluate the potential effect of 9cUAB30 on various breast cancer pathways, shedding 
light into the mechanism of action to help design future trials.  
 
Increasing evidence suggests that tobacco and alcohol use are risk factors in the development of 
intraepithelial neoplasia and cancer. In addition, tobacco and alcohol use may adversely affect agent 
intervention, for example by altering the safety profile or metabolism of a drug. Standardized assessments 
of tobacco and alcohol use during clinical trials will aid in understanding the potential relationship between 
the use of these products and clinical endpoints or cancer prevention biomarkers. Therefore, NCI, DCP is 
including assessment of tobacco and alcohol use at baseline and at surgery, to determine the potential impact 
of tobacco and alcohol use on 1) treatment toxicity and symptom burden, and 2) the efficacy of treatment 
intervention. 
 
The rexinoic acid receptor bexarotene decreases Th2 tumor immune environment and increases 
CD8+ T-cells in breast tumors of TgMMTV-neu transgenic mouse mammary tumor model. 
 
The rexinoic acid receptor (RXR) agonists bexarotene and 9cUAB30 have been shown to prevent breast 
cancer through inhibiting proliferation.,43,44,45 RXR has also been shown to have immune roles, although 
the effects vary depending on the immune environment, including preventing T-cell apoptosis and 
inhibiting the viral response to infection.46 47,48 The breast cancer tumor immune microenvironment can 
determine both whether a tumor will be responsive to therapy and predict a patient’s risk of relapse.49,50  A 
type I immune environment is essential both to recruit CD8+ T-cells to the tumor and to ensure that these 
CD8+ T-cells are active to destroy the tumor.51,52 On the other hand, Th2 regulatory T-cells induce a type II 
immune response which suppresses CD8+ T-cell activity.53 The majority of breast tumors develop an 
immunosuppressive immune environment which begins to develop in DCIS and increases as the tumor 
progresses to IBC.54 This immunosuppressive environment prevents the level of anti-tumor immune 
infiltration in the majority of breast tumors that is necessary for improved immune tumor destruction and 
better prognosis.55  
 
We have demonstrated that bexarotene can decrease both hyperplasia and invasive breast cancer while 
increasing CD8+ T-cells in the tumor in TgMMTV-neu mice. Furthermore, bexarotene was able to enhance 
the efficacy of a multi-antigen vaccine to prevent breast cancer in these mice suggesting an anti-tumor 
immune role for bexarotene.  When mice were vaccinated with the HER2-IGFBP2-IGF1R vaccine and 
concurrent bexarotene, the percent of mice that did not develop tumors increased from 65% to 87% (HR 
18.1 95% CI 6.4 to 63.2, p<0.0001).  Bexarotene alone only inhibited tumor development in 15% of the 
mice that was not significantly more than in the adjuvant controls (p=0.307).56 Similar to human breast 


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cancer, TgMMTV-neu mice develop a type II tumor immune environment.7 When treating TgMMTV-neu 
mice that had existing 100 mm3 tumors with bexarotene, we found the tumor immune environment became 
more type I with increased CD8+ T-cells in the tumor and decreasing GATA3+ cells (a marker of Th2 T-
cells) in the tumor (Fig. 3).  Because of bexarotene’s role in modulating the immune environment, we 
wanted to determine if the rexinoic acid receptor in human immune cells.   
 
In evaluating RXR expression in human peripheral blood mononuclear cells (PBMC), we found that RXR 
had the highest expression in antigen presenting cells (APC).  RXR is expressed in almost 30% of APC, 
24.9±13% of macrophages, 38.6±14% of plasmacytic dendritic cells (pDC), 33.1±16% of monocytic 
dendritic cells (mDC) (Fig. 4).  Further, when PBMC were treated with increasing doses of bexarotene for 
48 hours, there was increased co-stimulatory CD40 expression on mDC (indicating mDC activation, p=0.03 
between 0 and 20 uM bexarotene, Fig 5A) and pDC (indicating pDC activation, p=0.05 between 0 and 20 
uM bexarotene, Fig 5B).  There was also increased type I cytokine release including IL-1β (p=0.04 between 
0 and 20 uM bexarotene Fig 6A) and TNFα (p=0.03 between 0 and 20 uM bexarotene Fig 6B) but not type 
II cytokine release of IL-10 (p=0.99) and IL-4 (p=0.97) (Fig 6C and D).  Infiltration of activated dendritic 
cells has been associated with improved prognosis in multiple solid tumors.58,59  These data suggest that 
bexarotene can activate and bias DCs to develop into type I DCs and therefore may have an immune 
component of its anti-tumor activity. 
 
Activation of monocytic dendritic cells is conserved between RXR agonists bexarotene and 9cUAB30.  
While bexarotene may have both an anti-proliferative and immune anti-tumor role, it has been associated 
with significant toxicities including pancreatitis, hypertriglyceridemia, headache, and thyroid 
abnormalities.60 A second novel retinoid 9cUAB30 is much better tolerated, with only grade 1 and 2 
toxicities in an initial 14-person healthy volunteer dose escalation study.31  9cUAB30 has been shown to be 
effective with tamoxifen in hormone-induced mammary cancers in rats reducing tumor growth by 57%.61 
From preliminary experiments comparing the activation of dendritic cells by 9cUAB30 and bexarotene in 
parallel, 9cUAB30 can also increase CD40 expression on monocytic dendritic cells (p=0.05 at 20 uM as 
compared to 0 uM 9cUAB30, Fig 7D) and plasmacytic dendritic cells (p=0.02 at 20 uM as compared to 0 
uM 9Cuab30, fig 7E)  suggesting that this activity is conserved across RXR agonists.  We therefore aim to 
evaluate whether increasing doses of 9cUAB30 can activate type 1 dendritic cells and enhance the type I 
immune environment in women with early stage breast cancer.  We hypothesize that the activation of type 
I dendritic cells by the RXR agonist 9cUAB30 can contribute to its anti-cancer activity.  
 
3. 
SUMMARY OF STUDY PLAN 
 
Eligible participants will be ≥18 years of age and newly diagnosed pre- or post-menopausal patients with 
core biopsy proven invasive breast cancer between 0.5 cm and 5 cm in size or DCIS that is ≥ 1.0 cm in size 
and is either Grade 3 ER+ DCIS or ER- DCIS of any grade 
 
Patients agreeing to participate will take 9cUAB30 240 mg (160 mg contingent on interim analysis) by 
mouth daily for 14 – 28 days until the time of surgery. Tissue from the core biopsy will be used for the pre-
treatment biomarker analysis. The tissue obtained from the surgical excision will be used for post-treatment 
biomarker analysis. We plan to enroll ER+ participants and ER- participants for a total of up to 41 
participants undergoing intervention. We expect the study to be complete within 18-24 months. Beginning 
in November 2021, participants will be limited only to estrogen receptor negative status. 
 
At baseline all participants will have a complete medical history, physical examination and review of 
concomitant medications. Participants will undergo laboratory testing to determine eligibility within 30 
days prior to day 1 of the study. Baseline laboratory tests will include WBC, differential, hemoglobin, 


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hematocrit, platelets, INR, PTT, AST, ALT, total bilirubin, alkaline phosphatase, BUN, creatinine, calcium, 
glucose, albumin, electrolytes (Na, K, Co2, Cl), HDL, LDL, total cholesterol, triglycerides, thyroid 
stimulating hormone, FT3, and FT4 (may omit any if collected as part of initial cancer workup documented 
in the medical record within 30 days of study Day 1). A plasma and urine sample for pharmacokinetic (PK) 
analysis will also be obtained. An additional 30 ml blood sample will be obtained to evaluate and measure 
the immune response of 9cUAB30 in participants 6-25.  
 
For the first 5 participants, two extra plasma PK samples will be collected after administering the first dose 
of the study agent at 5 minutes and 2 hours post the drug administration to evaluate the Cmax. After the 
first 5 participants complete study participation, their PK samples will be evaluated to determine the Cmax 
and adverse events will be evaluated to determine safety of the 240mg dose. Based on this evaluation, it 
will be determined to continue study dose at 240mg or to reduce to 160mg (refer to section 13.9). 
 
For all study participants, 1 H&E stained slide, 5 unstained slides of 5µm thickness and 5 unstained slides 
of 10µm thickness will be requested from the diagnostic core biopsy formalin fixed paraffin embedded 
(FFPE) tissue block containing tumor using the existing diagnostic core biopsy material already collected. 
 
As part of the assessment of participant evaluability, a pathologist will examine the deepest level cut from 
blocks of the core biopsy and surgical resection specimens containing tumor. If the estimated residual tumor 
in the block is considered sufficient to enable cutting of at least 5 unstained slides at 5µm thickness, needed 
to support the future performance of Ki-67 and caspase 3 assays, the participant can be considered 
evaluable. 
 
Once a surgery date is scheduled, participants meeting eligibility requirements will begin oral 9cUAB30 
for daily treatment for at least 14 (but not longer than 28 days) days at the 240 mg/day dose level (160 mg 
contingent on interim analysis) prior to surgery. The day the participant begins taking 9cUAB30 is 
considered Day 1 of the study. Each participant will be provided with a blood pressure (BP) monitor to 
track the BP values at home. During the visit, participants will be instructed on how to use the monitor. The 
instructions are noted on the BP diary (Appendix C) for reference at home. Participants will be asked to 
measure and document the blood pressure values in the BP diary on Day 7, Day 8 (approximately 24 hours 
later) and the day prior to surgery. All BP readings should be taken in the morning. They will be instructed 
to notify the study team if the value of the reading is Systolic ≥160 and Diastolic ≥100. The study 
coordinator will contact the participant on Day 8 by telephone to assess adverse events and other symptoms, 
review medications and review the BP readings. Study team will also contact participants on the day before 
surgery to remind them to take last dose of medication, bring the pill diary and blood pressure monitors and 
bring all the pill bottles given to them. Participants will be encouraged to contact the investigator or study 
coordinator with any new symptoms or concerns at any time during the trial.  
 
Surgery must occur between Days 15 and 29 of the study. On the day of surgery or the day before surgery 
laboratory tests will be obtained and include WBC, differential, hemoglobin, hematocrit, platelets, INR, 
PTT, AST, ALT, total bilirubin, alkaline phosphatase, BUN, creatinine, calcium, glucose, albumin, 
electrolytes (Na, K, Co2, Cl), HDL, LDL, total cholesterol, triglycerides, thyroid stimulating hormone, FT3, 
FT4, as well as a plasma and urine sample for PK. The history and physical examination will be obtained 
and/or updated within 24 hours of the procedure. An additional 30 ml blood sample will be obtained during 
this visit to evaluate and measure the immune response of 9cUAB30 by comparing it to the sample obtained 
at baseline for participants 6-25.   
 
At the time of surgery, tissue samples will be obtained of remnant tumor and processed as is the usual 
standard at each institution. One H&E stained slide, 5 unstained slides of 5µm thickness and 5 unstained 


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slides of 10µm thickness will be requested from the formalin fixed paraffin embedded (FFPE) tissue 
blocks containing tumor as described in section 10.2.1 
 
The plasma and urine samples for PK will be sent to University of Wisconsin - CP lab for evaluation. The 
immunogenicity samples will be sent to University of Washington – Tumor Vaccine Group. All other 
baseline and pre-surgical laboratory studies will be performed at each participating institution.  
 
All participants will receive $30 for completing the screening visit, $70 for completing the surgery visit and 
returning the blood pressure machine as compensation towards the extra efforts taken such as travel 
expenses, parking, time missed from work or other expenses associated with the study visits. The first 5 
participants will be given additional $50 for the additional time required for the study visit. 
 
The study participants will be matched with historical nonrandomized controls from each site based on sex 
(female), pathologic stage, receptor status, grade, and menopausal status from each site. These samples will 
be obtained from blocks no more than 5 years old. The pre-surgical and post-surgical tissue samples (from 
the participants and matched controls) will be batched and analyzed concurrently utilizing 
immunohistochemistry and Nanostring to measure any effects of 9cUAB30 on tumor cell proliferation 
(Ki67) and activation of RXR downstream pathways (gene expression). Slides will be analyzed via 
immunohistochemistry at Wisconsin and via Nanostring at UAB per existing protocols. 
 
Seven days after surgery and 4-5 weeks after surgery a follow-up phone call will be performed for safety 
assessment.  
 
4. 
PARTICIPANT SELECTION 
 
Potential participants will be screened and recruited from the University of Alabama at Birmingham, 
University of Wisconsin, University of Minnesota, University of Iowa and Northwestern University. 
Beginning in November of 2021, study sites will be limited to University of Alabama at Birmingham, 
University of Wisconsin, and Northwestern University.  
 
4.1 
Inclusion Criteria 
 
1. Female only. The sample size of males affected by breast cancer is limited, hence we will not be able 
to collect significant data for analysis of the effect of study drug on breast cancer in males 
2. Age > 18 years. Because no dosing or adverse event data is currently available on the use of 9cUAB30 
in participants <18 years of age.  
3. ECOG performance status ≤ 1 or Karnofsky ≥ 70% (convert the Karnofsky score into the ECOG scale 
based on Appendix A).  
4. Invasive breast cancer diagnosed by needle core biopsy, between 0.5 cm and 5 cm in size based on 
imaging, that is ER+ or ER-, Her2neu positive or negative 
OR 
DCIS of the breast diagnosed by core needle biopsy and at least 1.0 cm in size based on imaging. Grade 
3 ER+ DCIS will be allowed as well as ER- DCIS of any grade.  For DCIS-only lesions, the imaging 
abnormality corresponding to the cancer must be at least 1.0 cm in size (i.e. calcifications, distortion or 
mass on mammogram, or mass or nonmass enhancement on MRI). 
5. Participants must have normal organ and marrow function as defined below:  
• WBC ≥3000/mm3;  
• Platelets ≥ 100,000/mm3,  


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• Hemoglobin >10 g/dL;  
• Bilirubin ≤ upper limit of institutional normal;  
• AST ≤ upper limit of institutional normal 
• Creatinine ≤ upper limit of institutional normal 
• Triglycerides ≤1.5xULN  
• Cholesterol ≤1.5xULN  
6. Participants must agree to discontinue all supplements containing vitamin A while taking study 
medication and for thirty days after the last dose of study medication.  
7. Have not been treated with chemotherapy, or biological therapy in the last 5 years. We do not know if 
the previous treatment will have an effect on the tissues to be examined.   
8. Have not used tamoxifen, raloxifene, or other antiestrogen compounds within 6 months of study entry. 
If used within 5 years of study entry, total duration of use must be less than 6 months. 
9. Have not used exogenous hormone replacement therapy or hormonal contraception in the year prior to 
diagnosis. The use of non-systemic estrogen (such as vaginal estrogen use) is allowed. 
10. The effects of 9cUAB30 on the developing human fetus are unknown. Since retinoids are known to be 
teratogenic, to avoid any complications due to unintentional pregnancies only postmenopausal women 
and some premenopausal women (as outlined below) will be eligible. Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she should inform her study 
physician immediately. 
• 
Women will be considered postmenopausal if one of the following is met: 
i. Prior bilateral oophorectomy 
ii. 60 years of age or older 
iii. Age less than 60 years; amenorrheic for 12 or more months; and follicle-stimulating hormone 
(FSH) in the postmenopausal range or had prior hysterectomy. 
• 
Premenopausal women without childbearing potential are eligible to participate if one of the 
following criteria is met: 
i. Prior hysterectomy  
ii. Prior fallopian tubal ligation (cut, tied, or sealed) 
iii. Prior placement of permanent intratubal contraceptive devices (e.g. Essure) 
iv. Partner with prior vasectomy and willing to use barrier method (e.g. condoms) 
11. Participants must have the ability to understand, and the willingness to sign, a written informed consent 
document.  
4.2 
Exclusion Criteria 
1. Participant taking medications that might interact with 9cUAB30; See section 5.4 for a detailed list of 
potentially interacting medications  
2. Participant who has started or increased dosage of lipid-lowering agents in the last 30 days of 
enrollment.  
3. Participant receiving any other investigational agents within 30-days of enrollment nor during study 
participation with the exception of 18F-FFNP investigational imaging agent. See section 5.4 for a 
detailed description of 18F-FFNP trial co-enrollment conditions.   
4. Participant with a history of allergic reactions attributed to compounds of similar chemical or biologic 
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5. Participant with an uncontrolled intercurrent illness including, but not limited to; 
a. ongoing or active infection,  
b. symptomatic congestive heart failure,  
c. unstable angina pectoris,  
d. cardiac arrhythmia,  
e. a persistent grade 3 hypertension***  
f. psychiatric illness/social situations that will limit compliance with study requirements.  
6. Participant who is breastfeeding or planning to breastfeed for a month post last dose of study agent   
7. Participant known to be HIV-positive, as we do not know the effects of study drug on suppression of 
the immune system.  
8. Participant with a history of a second cancer diagnosis or reoccurrence <2 years from study entry with 
the exception of a history of squamous or basal cell carcinoma of the skin <2 years from study entry 
will not be excluded from this study. This is to eliminate the residual effects of any previous treatments 
for those cancers.  
9. Participant with history of ipsilateral breast radiation.  
10. Participant’s core biopsy slides suggest that later re-sectioning will not contain sufficient tumor to allow 
for an adequate evaluation of Ki67 and caspase 3 assays, at a minimum. 
 
***To assess hypertension during eligibility verification, see below instructions: 
For grade 1, grade 2, and non-persistent grade 3 hypertension, repeat blood pressure reading after 5 minutes.   
If the average reading of the two measurements is grade 3 (systolic BP 160 mm Hg or diastolic BP 100 
mm Hg) the patient is not eligible. If the average reading of the two measurements is less than or equal to 
grade 2, then the participant is eligible.  If the average of the 2 readings is grade 1 or grade 2 hypertension, 
document the appropriate level hypertension on the baseline symptom form.  
 
4.3 
Inclusion of Women and Minorities 
 
Women of all races and ethnic groups are eligible for this trial.  
 
4.4 
Recruitment and Retention Plan 
 
Potential participants will be screened and recruited from the University of Alabama at Birmingham, 
University of Wisconsin, University of Minnesota, University of Iowa and Northwestern University. Breast 
cancer surgeon investigators at each site will be instrumental in achieving accrual targets. The duration of 
the accrual is expected to take 18- 24 months. Beginning in November of 2021, study sites will be limited 
to University of Alabama at Birmingham, University of Wisconsin, and Northwestern University. 
 
Each site will review the surgeon’s clinic patient list to identify potential participants. Through review of 
the medical record, the study team will determine if a patient is eligible and contact them for interest in the 
study. Review of medical records prior to consenting to the research study is very minimum risk of harm 
to the potential study participants and involves no study related procedures for which written consent is 
normally required outside of the research context.  
 
 
The potential participant may be initially approached by their physician and the study coordinator will then 
speak with them more in depth about the study. 
 
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and after analysis of the PK data collected from the first 5 participants, it will be determined whether to 
continue with 240mg dose level or to modify the dose to 160mg for rest of the study. If the study continues 
at 240mg dose level, the remaining 31 participants will be accrued. If the dose is determined to need to be 
reduced to 160mg, 36 participants will be accrued at 160mg. We expect a participant dropout rate of less 
than 5%.  
 
 
5. 
AGENT ADMINISTRATION 
 
Intervention will be administered on an outpatient basis. Reported AEs and potential risks are described in 
Section 6.2.  
 
5.1 
Dose Regimen and Dose Groups 
 
The study drug 9cUAB30 240 mg (3 capsules of 80 mg) or *160 mg (2 capsules of 80 mg) will be taken 
daily for a period of at least 14 days but not to exceed 28 days.   
 
*Depending on if interim dose modification rules are met.  
 
5.2 
9cUAB30 Administration 
 
All study drug will be dispensed by research pharmacies at the participating organizations. Three bottles 
(30 capsules per bottle) will be distributed to study participants at the 240mg dose level.  If the interim dose 
modification rules are met and the study is modified to 160mg daily, two bottles (30 capsules per bottle) 
will be distributed to the remaining participants. Individually labeled participant-specific bottles of 
9cUAB30 will be distributed to the investigational pharmacy at each site. The daily dose will be self-
administered at approximately the same time every evening on empty stomach (2 hours after eating and 
wait for 1 hour before eating again). The last dose will be the day before surgery.  
 
5.3 
Run-in Procedures  
 
Not applicable 
 
5.4 
Contraindications 
 
Due to the effects demonstrated in other Rexinoids, the following medications are contraindicated:  
• 
bile acid sequestrants (cholestyramine, colesevelam, colestipol)  
• 
ezetimibe 
• 
fibric acids (fenofibrate, gemfibrozil) 
• 
nicotinic acid (niacin) 
Because of potential effects on drug metabolism other contraindicated agents are:  
• 
St John’s Wort 
• 
oral ketoconazole 
• 
tetracycline 
• 
oral corticosteroids 
• 
CYP2B6 Substrates (Sensitive): Bupropion, cyclophosphamide (Activated to acrolein by 
CYP2B6), efavirenz, irinotecan, ketamine, promethazine, propofol, selegiline,  
 
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resume use on the day of surgery.  
 
Because of potential confounding effects on pharmacokinetics, participants may not take other topical or 
oral retinoids. These agents are:  
• 
retinol 
• 
Retinal 
• 
tretinoin (Retin-A)  
• 
isotretinoin  
• 
alitretinoin 
• 
etretinate  
• 
acitretin  
• 
Tazarotene  
• 
bexarotene  
• 
Adapalene 
 
For participants who choose to co-enroll in an 18F-FFNP PET/MRI trial, Day 1 of 9cUAB30 study drug 
administration must be at least 1 day after the FFNP administration to ensure the AE reporting period for 
the FFNP trial has concluded. 
 
5.5 
Concomitant Medications 
 
All medications (prescription and over-the-counter), vitamin and mineral supplements, and/or herbs taken 
by the participant will be documented on the concomitant medication CRF and will include: 1) start and 
stop date, dose and route of administration, and indication. Medications taken for a procedure (e.g., biopsy) 
should also be included. Medications given in the hospital as part of the standard surgical protocol will not 
be documented as concomitant medications. However, any medications given to treat an adverse or 
unexpected event following surgery will be documented. 
 
5.6 
Dose Modification 
 
No dose modifications will occur for an individual participant. The study dose may be reduced from 240 
mg/day to 160 mg/day if interim dose modification rules are met (see Section 13.9). No other dose 
modifications will be allowed.  
 
5.7 
Adherence/Compliance 
 
Subjects that maintain 90% compliance for the time period beginning day 1 of the trial and ending on the 
day before surgical intervention will be considered compliant. Compliance will be measured through pill 
counts conducted by the study coordinator or institutional pharmacy and recorded in the CRF.  
 
6. 
PHARMACEUTICAL INFORMATION 
 
6.1 
9cUAB30 (IND 101,064, NCI, DCP)   
 
This Phase Ib clinical study investigating the biologic effect of a novel retinoid 9- cis-UAB30 (9cUAB30) 
will be conducted under an IND sponsored by NCI, DCP. 9cUAB30 [8- (3’,4’-dihydro-1-(2’H)-naphthalen-
1’-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid], has been synthesized at the University of Alabama (D. 
Muccio) and is undergoing development through the NCI, DCP RAPID program. This new RXR-selective 
retinoid is a conformationally- constrained analogue of 9-cis-retinoic acid (9-cis-RA) (Muccio et al. 1998). 


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Evidence continues to accumulate from in vitro and in vivo studies, as well as from clinical trials, that 
retinoids have therapeutic effects in several neoplastic diseases. Several RXR agonists (rexinoids) have 
undergone clinical evaluation as potential chemopreventive compounds. 9cUAB30 is a yellow powder 
which will be formulated into capsules as subsequently described. Active capsules are size 1, Swedish 
orange, hard-gelatin capsules containing 80 mg 9cUAB30 plus pregelatinized starch, colloidal silicon 
dioxide, crospovidone and magnesium stearate. All capsules are manufactured under contract to NCI, DCP, 
and are packaged in 60 cc white HDPE bottles, 30 capsules per bottle, with 33/400 polypropylene caps. 
 
6.2 
Reported Adverse Events and Potential Risks 
 
Nonclinical PK evaluations show that 9cUAB30 is orally available in mice, rats, and dogs. In mice, plasma 
9cUAB30 levels were similar after one and seven days of dosing, indicating no drug accumulation. 
Increases in the area under the drug concentration curve (AUC) were less than proportional to dose possibly 
due to an increased rate of clearance (Cl) and decreased half-life (t½) seen at the same time. In rats, drug 
levels increased with dose. In dogs, the time to maximal drug concentration (tmax) was 2–3.5 hours and t½ 
was 2.7–4 hours. In vitro metabolic studies suggest that human metabolism may be similar to canine 
metabolism and differ significantly from murine (rat) metabolism. In isolated human liver microsomes, the 
major cytochrome P 450 (CYP) isozymes responsible for 9cUAB30 metabolism were CYP2C8, CYP2C9 
and CYP2C19; at 10 M, 9cUAB30 also induced CYP2B6. A 9cUAB30 glucuronide conjugate can be 
formed by uridine diphosphate (UDP) glucuronosyltransferase 1A9 (UGT1A9).  
 
9cUAB30 has been evaluated in multiple nonclinical toxicity and safety pharmacology studies sponsored 
by NCI, DCP. In a 28-day oral toxicity study of 9cUAB30 in rats, target organs were the liver and 
hematologic system. Dose-dependent increases in liver weight as a percent of brain weight, vacuolation in 
liver tissue consistent with glycogen deposition, and increased serum aspartate aminotransferase (AST) and 
alkaline phosphatase (ALP) levels were observed. Hematologic changes included dose-dependent 
decreases in prothrombin time (PT), increases in fibrinogen, and, at the highest dose (100 mg/kg-bw-day), 
eosinopenia and neutrophilia. The no observed adverse effect level (NOAEL) was considered to be 
3 mg/kg-bw/day. In a 28-day oral toxicity study of 9cUAB30 in female dogs, no treatment-related toxicities 
were observed even at the highest dose (100 mg/kg-bw/day), which was considered the no observed adverse 
effect level (NOAEL). In safety pharmacology studies, no cardiac effects were seen in female dogs treated 
with single doses of 9cUAB30 up to 300 mg/kg-bw/day. Additionally, in a functional observational battery 
(FOB) study in rats, no effects on central nervous system (CNS) or behavior were seen with single doses 
of 9cUAB30 up to 100 mg/kg-bw/day. In genotoxicity studies, 9cUAB30 was negative in the in vivo mouse 
bone marrow micronucleus assay and the bacterial reverse mutation test (Ames). In the Chinese hamster 
ovary (CHO) cell assay, 9cUAB30 did not increase chromosome aberrations or polyploidy after three-hour 
exposure to low levels of 9cUAB30 in the absence of metabolic activation. However, longer duration (24 
hours) in the presence or absence of metabolic activation, or higher doses of 9cUAB30 with metabolic 
activation, increased chromosome aberrations and polyploidy. Because of variable outcomes and lack of a 
dose response in the CHO cell assay, 28-day in vivo mutagenicity and six-month oncogenicity studies were 
undertaken in transgenic mice. In the Big Blue lacI/cII transgenic mouse mutagenicity study, no dose-
related increases in mutation frequency were found in the liver, kidney, or spleen. In addition, 9cUAB30 
was not oncogenic in p53+/– transgenic mice, and there was no evidence of vitamin A-like toxicity. These 
results, combined with the negative oncogenicity and mutagenicity data, suggest an acceptable toxicity 
profile for 9cUAB30.  
 
9cUAB30 has been tested in normal volunteers in a phase 1, first-in-human, open-label, single ascending 
dose study (UWI06-8-03) and in a 28-day double-blind, placebo-controlled, randomized, multiple 
ascending dose (MAD) study (under two protocols UWI09-8-02, UWI10-16-01R). In the first study, single 
doses of 5, 10, and 20 mg 9cUAB30 were well tolerated and orally available, with a tmax of 2.2–3.1 hours. 


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Most adverse events (AEs) were grade 1 in severity; Grade 3 AE’s were rare and likely unrelated to study 
agent. There were no grade 4, or serious AEs (SAEs), and no dropouts. The most common treatment-
emergent AE (TEAE) was headache with the first dose and little to no occurrence thereafter raising the 
possibility of caffeine withdrawal due to fasting as a potential cause. Another common TEAE was grade 1 
(1 grade 3 event on day 1 prior to initial dose) hypertension which was more frequently observed with 
higher doses (see Table 3). Because of this observation, we more closely examined Blood Pressure results 
throughout the study (see figure 2).  Based on absolute BP readings there is no evidence of increased BP 
during the first 24 hours after their initial dose (data not shown) and no evidence of an increase from 
baseline through day 36 (figure 2). The increase in numbers of TEAE’s implies participants entered the 
study with borderline hypertension and resultant repeated measurements led to sporadic BP elevations 
meeting CTCAE requirements across participants and sustained elevations within participants where not  
seen. 
 
 
 


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Figure 2: 
*Median and first and third quartiles are displayed  
 


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Other common TEAEs were increased blood chloride, decreased hemoglobin (anemia), and 
hypercholesterolemia. Rare events such as rash, dry skin, sweating, burping after meals, shaking, 
temperature of body feeling warmer, were also observed. Interestingly, commonly associated 
retinoid/rexinoid toxicities were not observed with any frequency or significant grade (skin changes, 
headache, hyperlipidemia, leukopenia, etc.), supporting the hypothesis that the conformational changes to 
9cUAB30 structure as compared to 9cRA result in less toxicity.  Our data supports that 9cUAB30 daily 
dosing of ≤240 mg/day for up to 28 days continuously is safe. 
 
Table 3: TEAEs by treatment Reported by ≥Three Subjects in UWI09-8-02, UWI10 16 01R  
System Organ Class 
Preferred Term 
0 mg 
(n=12) 
n(%) 
20 mg 
(n=8) 
n(%) 
40 mg 
(n=9) 
n(%) 
80 mg 
(n=8) 
n(%) 
160 mg 
(n=9) 
n(%) 
240 mg 
(n=8) 
n(%) 
Any TEAE 
10 (83) 
6 (75) 
9 (100) 
6 (75) 
8 (89) 
8 (100) 
Gastrointestinal Disorders 
1 (8) 
3 (38) 
2 (22) 
2 (25) 
2 (22) 
0 (0) 
   Nausea 
1 (8) 
1 (13) 
1 (11) 
0 (0) 
2 (22) 
0 (0) 
   Vomiting 
1 (8) 
1 (13) 
1 (11) 
0 (0) 
0 (0) 
0 (0) 
General Disorders and Administrative Site 
Conditions 
1 (8) 
3 (38) 
0 (0) 
1 (13) 
2 (22) 
0 (0) 
   Fatigue 
0 (0) 
2 (25) 
0 (0) 
0 (0) 
2 (22) 
0 (0) 
Infections and Infestations 
5 (42) 
0 (0) 
0 (0) 
2 (25) 
2 (22) 
2 (25) 
   Sinusitis 
2 (17) 
0 (0) 
0 (0) 
0 (0) 
1 (11) 
2 (25) 
Investigations 
4 (33) 
1 (13) 
5 (56) 
2 (25) 
2 (22) 
5 (63) 
   Blood Chloride Increased 
1 (8) 
0 (0) 
1 (11) 
2 (25) 
1 (11) 
0 (0) 
   Cholesterol High 
1 (8) 
1 (13) 
2 (22) 
1 (13) 
1 (11) 
1 (13) 
   Increased LDL Cholesterol 
1 (8) 
1(13) 
0 (0) 
1 (13) 
0 (0) 
0 (0) 
Metabolism and Nutrition Disorders 
3 (25) 
2 (25) 
2 (22) 
3 (38) 
1 (11) 
0 (0) 
   Hypertriglyceridemia 
2 (17) 
2 (25) 
2 (22) 
2 (25) 
1 (11) 
0 (0) 
Musculoskeletal And Connective Tissue 
Disorders 
1 (8) 
1 (13) 
0 (0) 
1 (13) 
1 (11) 
4 (50) 
   Back pain 
0 (0) 
1 (13) 
0 (0) 
0 (0) 
1 (11) 
1 (13) 
Nervous System Disorders 
4 (33) 
2 (25) 
3 (33) 
3 (38) 
3 (33) 
4 (50) 
   Headache 
3 (25) 
2 (25) 
3 (33) 
3 (38) 
2 (22) 
4 (50) 
Respiratory, Thoracic, and Mediastinal 
Disorders 
0 (0) 
1 (13) 
0 (0) 
2 (25) 
1 (11) 
2 (25) 
   Nasal Congestion 
0 (0) 
1 (13) 
0 (0) 
2 (25) 
0 (0) 
1 (13) 
Skin and Subcutaneous Tissue Disorders 
1 (8) 
1 (13) 
0 (0) 
3 (38) 
4 (44) 
4 (50) 
   Dry Skin 
0 (0) 
1 (13) 
0 (0) 
2 (25) 
0 (0) 
1 (13) 
   Pruritus 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (11) 
3 (38) 


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System Organ Class 
Preferred Term 
0 mg 
(n=12) 
n(%) 
20 mg 
(n=8) 
n(%) 
40 mg 
(n=9) 
n(%) 
80 mg 
(n=8) 
n(%) 
160 mg 
(n=9) 
n(%) 
240 mg 
(n=8) 
n(%) 
   Rash Acneiform 
1 (8) 
0 (0) 
0 (0) 
1 (13) 
1 (11) 
2 (25) 
Vascular Disorders 
5 (42) 
2 (25) 
7 (78) 
4 (50) 
7 (78) 
8 (100) 
   Hot Flashes 
2 (17) 
0 (0) 
0 (0) 
0 (0) 
1 (11) 
0 (0) 
   Hypertension 
5 (42) 
2 (25) 
7 (78) 
4 (50) 
7 (78) 
8 (100) 
 
6.3  
Availability 
 
9cUAB30 is an investigational agent supplied to investigators by the Division of Cancer Prevention (DCP), 
NCI. The agent is formulated into 80mg capsules.  
 
6.4 
Agent Distribution 
 
Agents will only be released by NCI, DCP after documentation of IRB approval of the DCP-approved 
protocol and consent is provided to DCP and the collection of all Essential Documents is complete (see 
DCP website for description of Essential Documents).  
 
DCP guidelines require that the agent be shipped directly to the institution or site where the agent will be 
prepared and administered. NCI, DCP-supplied agents are requested by Consortium Lead Organization 
(CLO), University of Wisconsin to be dispatched to Participating Organization (PO) by completing the 
DCP Clinical Drug Request form (NIH-986) (to include complete shipping contact information) and faxing 
or mailing the form to the DCP agent repository contractor: 
 
John Cookinham 
MRIGlobal 
DCP Repository 
1222 Ozark Street 
North Kansas City, MO 64116   
Phone: (816) 360-3805 
FAX: (816) 753-5359 
Emergency Telephone: (816) 360-3800 
 
DCP does not permit the transfer of agents between institutions (unless prior approval from DCP is 
obtained). DCP does not automatically ship agents; the site must make a request. 
 
6.5  
Agent Accountability 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful record of 
the inventory and disposition of all agents received from DCP using the NCI Drug Accountability Record 
Form (DARF). The Investigator is required to maintain adequate records of receipt, dispensing and final 
disposition of study agent. Include on receipt record from whom the agent was received and to whom study 
agent was shipped, date, quantity and batch or lot number. On dispensing record, note quantities and dates 
study agent was dispensed to and returned by each participant.  
DCP requirements for agent accountability and the required forms are available on the DCP website. 
 


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6.6 
Packaging and Labeling 
 
9cUAB30 capsules will be packaged by NCI, DCP. Each bottle will contain 30 capsules of 80mg 9cUAB30. 
Two-part labels will be placed on each bottle. One part stays on bottle, and one part goes into the participant 
chart or other designated research record as a source document. Sites will be responsible for recording the 
Participant ID (PID) number on the bottle once they are dispensed. The label remaining on the bottle will 
identify study specific information, such as Study title, DCP protocol number, dosing instructions, 
recommended storage conditions, the name and address of the distributor, and a caution statement 
indicating that the agent is limited by United States law to investigational use only and the agent should be 
kept out of reach of children. 
 
6.7 
Storage 
 
The agent should be stored at a temperature of between 2°and 8° C. Participants transporting study 
medication from clinic to home will be provided with a cold, but unfrozen, ice pack. Participants will be 
instructed to store study medication in the refrigerator.  
 
6.8 
Registration/Randomization 
 
CLO will be informed about the expected date and time of the scheduled screening visit as soon as it has 
been scheduled. 
 
PID will be assigned sequentially to all participants who sign consent form at the PO and will designate the 
recruitment site, the study and the participant. Once a participant has signed a consent form and has satisfied 
all eligibility criteria: 
 
• 
Fax (608-467-5900) or email (multisite_research@cancer.wisc.edu) the participant’s eligibility 
checklist signed by Investigator and copy of the signed consent form to CLO during normal business 
hours (M-F 8:00 am – 4:00 pm Central Time).  
• 
CLO will verify eligibility documents are complete and assign bottle numbers to dispense the study 
medication.  
• 
CLO will email a confirmation of accrual to the study coordinator at the participating institution 
including the bottle numbers to be assigned to the participant. If a confirmation is not received within 
two hours, the coordinator should contact the CLO to confirm that eligibility documents were received.  
• 
CLO will be responsible for tracking number of ER+ and ER- participants to ensure correct tracking of 
accrual. A notification of accrual will be sent to each PO after a participant has been assigned to 
treatment. 
• 
After receiving the confirmation from CLO, this information should be conveyed to the local site 
investigational pharmacist to process the study drug request. 
 
6.9 
Blinding and Unblinding Methods 
 
Not applicable 
 
6.10 
Agent Destruction/Disposal 
 
DCP-supplied agents: at the completion of investigation, all unused study agent will be returned to NCI, 
DCP Repository according to the DCP “Guidelines for AGENT RETURNS” and using the DCP form 
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9. Appendix D – administer the follow-up version of tobacco and alcohol assessments 
10. Blood pressure on Surgery Day 15-29 will only be obtained if the Day before Surgery average blood 
pressure is above Systolic ≥ 120 or Diastolic ≥ 80. 
 
7.2 
Baseline Testing/Prestudy Evaluation 
 
7.2.1  Screening Visit (within 30 days of Day 1) 
 
Newly diagnosed early stage breast cancer patients will be screened as potential participants from the 
University of Alabama at Birmingham, University of Wisconsin, University of Minnesota, University of 
Iowa, and Northwestern University. A history and physical examination will be performed as part of 
standard of care by providers at each institution.   
 
The procedures to be performed to evaluate eligibility are:  
 
• 
Invasive breast cancer or DCIS confirmed on pathology report; eligible participants must have invasive 
breast cancer between 0.5 cm and 5.0 cm in size based on imaging or for DCIS-only lesions, the imaging 
abnormality corresponding to the cancer must be at least 1.0 cm in size (i.e. calcifications, distortion or 
mass on mammogram, or mass or nonmass enhancement on MRI).  
• 
Estrogen receptor status must be confirmed on pathology report. Estrogen receptor positivity defined 
as per 2010 ASCO-CAP Guidelines36 – with at least 1% positive tumor nuclei in the sample on testing 
in the presence of expected reactivity of internal (normal epithelial elements) and external controls.  
o Eligible participants must have invasive breast cancer that is ER+ or ER-,  
OR 
o Eligible participants must have DCIS that is ER+ and grade 3, or that is ER- and any grade. 
 
*Beginning in November 2021, participants will be limited to estrogen receptor negative status. 
 
• 
Her2neu status must be confirmed on pathology report for those with invasive cancer.37 Her2neu status 
is defined as positive and negative based on the 2013 ASCO-CAP guideline. As recommended by the 
guideline, Her2neu equivocal results must have a reflex or new test to determine Her2neu status.  
• 
Review of the participant's medical history. 
• 
Measurement of height and weight.  
• 
Evaluation of vital signs including temperature, pulse, blood pressure, and respiration rate. 
• 
For grade 1, grade 2, and non-persistent grade 3 hypertension, repeat blood pressure reading 
after 5 minutes.  
• 
If the average reading of the two measurements is grade 3 (systolic BP 160 mm Hg or diastolic 
BP 100 mm Hg) the patient is not eligible.  
• 
If the average reading of the two measurements is less than or equal to grade 2, then the 
participant is eligible.   
• 
If the average of the 2 readings is grade 1 or grade 2 hypertension, document the appropriate 
level hypertension on the baseline symptom form.  
• 
A physical examination. A gynecologic examination may be waived. The physical examination may 
be performed by any healthcare professional (i.e. physician, nurse practitioner, physician assistant) who 
is allowed by local policy to perform physical examinations.  
• 
Assessment of Performance Status, using the ECOG method (convert a Karnofsky score into an ECOG 
score using the scale in Appendix A). 
• 
Review of concomitant medications including over the counter medications and nutrition supplements  
• 
Review and discussion of study including review of informed consent document. 


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• 
Patients agreeing to participate in the study will sign the informed consent document. 
 
After obtaining written informed consent, a participant is registered with CLO and assigned a unique PID 
number (see section 6.8) and eligibility evaluations may occur. Eligibility evaluations determine if the 
participant is a fit candidate for study participation. All eligibility evaluations (including labs) must be 
completed within 30 days of Day 1. The eligibility checklist is provided to each site to help determine if 
the participant is eligible for the trial.  
 
• 
Administer the baseline version of tobacco and alcohol assessment questionnaire – Appendix D 
• 
Perform the laboratory tests as outlined in section 7.1. Results from laboratory tests or physical 
examinations performed outside the context of the research study may be used to confirm eligibility, 
provided these procedures were conducted within 30 days of Day 1.  
• 
A fasting or non-fasting lipid panel may be obtained, if drawn within 30 days of Day 1. If non-fasting 
lipid levels are outside of the range for eligibility, a fasting lipid panel can be drawn. For the fasting 
lipid panel, participants should be fasting for at least 10 hours prior to this draw. 
• 
Collect urine and blood sample for baseline PK studies.  
• 
Collect 30 mL blood sample for immune studies for participants 6-25.  
 
If deemed eligible, follow the below mentioned procedures: 
 
For the first 5 participants:  
a. Since the participants will be fasting for the laboratory tests, they can have a meal after blood draw for 
laboratory tests while they wait to get their laboratory results.   
b. Once the lab results are obtained to determine eligibility, dispense the study agent in 3 bottles of 30 
capsules of 80mg each and administer the first dose of 240mg (3 capsules) at the clinic visit after 
minimum of 2 hours post their last meal.  The participant will be able to eat again after both PK blood 
draws are performed. This will be considered as Day 1. 
c. Document the date and time in the pill diary and provide the diary to participant with instructions on 
how to complete. 
d. First post-dose PK sample of 3mL blood will be collected within 5 minutes of drug administration.  
e. Second post-dose PK sample of 3 mL blood will be collected 2 hours from the time the drug was taken. 
Participants should not eat between the PK blood draws.  
f. The study dose has to be taken in the evening on empty stomach (2 hours after last eating and wait for 
1 hour before eating again), every day until the day before surgery.  
g. They will be provided with a BP monitor to measure BP at home. While they are in clinic, they will be 
instructed on how to use the monitor. The instructions are noted on the BP diary for reference at home 
(Appendix C).  Participants will be asked to measure and document the blood pressure values in the BP 
diary on Day 7, Day 8 (approximately 24 hours later) and day prior to surgery. All BP measurements 
should be taken in the morning. They will be instructed to notify the study team if the value of the 
reading is Systolic ≥160 or Diastolic ≥100 (grade 3). The study coordinator will contact the participants 
on Day 8 by telephone to assess adverse events and other symptoms, review medications and review 
the BP readings. 
 
For participants 6 onwards:  
a. Review guidelines for agent administration with the participant and provide the diary to participant 
with instructions on how to complete. 
b. Dispense study agent – 9cUAB30 based on the dose of the study determined by interim analysis. 
Participant will be given enough study drug for the duration of participation in the treatment phase of 
the study. 
• 
Dose 240mg (3 capsules) – dispense 3 bottles of 30 capsules each or  


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• 
Dose 160mg (2 capsules) – dispense 2 bottles of 30 capsules each.  
c. Participants may start taking the medication in the evening on the date of dispense, in the evening on 
empty stomach (2 hours after last eating and wait for 1 hour before eating again) until the day before 
surgery.  
d. They will be provided with a BP monitor to measure BP at home. While they are in clinic, they will be 
instructed on how to use the monitor.  The instructions are noted on the BP diary for reference at home 
(Appendix C). Participants will be asked to measure and document the blood pressure values in the BP 
diary on Day 7, Day 8 (approximately 24 hours later) and day prior to surgery. All BP measurements 
should be taken in the morning. They will be instructed to notify the study team if the value of the 
reading is Systolic ≥160 or Diastolic ≥100 (grade 3). The study coordinator will contact the participants 
on Day 8 by telephone to assess adverse events and other symptoms, review medications and review 
the BP readings. 
 
7.3 
Evaluation During Study Intervention 
 
7.3.1  Day 1 
 
Participant starts study medication. This day will be determined based on when the surgery will be 
scheduled for the participant. The study drug should be started at minimum 14 days before scheduled 
surgery and not more than 28 days before surgery. In order to avoid any further delay of surgery due to 
participation in the study, it will be recommended that the study medication be started as soon as the 
participant is deemed eligible.  For the first 5 participants this will be in clinic on the day of screening visit. 
 
7.3.2 
Day 7 
 
Home BP monitoring in the morning. They will note the BP value and time reading taken in the BP diary 
and call the study team if they see a value of systolic ≥160 or diastolic ≥100. Participants will be instructed 
to repeat the reading after 5 minutes if the value of the reading is Systolic ≥ 120 or Diastolic ≥ 80. The 
average reading of the two measurements will be noted in the database and used for adverse event 
determination. See section 11.1.1 Reportable AEs, for how the blood pressure should be obtained. 
 
7.3.3  Day 8 (telephone contact) 
 
• 
Home BP monitoring in the morning. They will note the BP value and time reading taken in the BP 
diary and call the study team if they see a value of systolic ≥160 or diastolic ≥100. Participants will be 
instructed to repeat the reading after 5 minutes if the value of the reading is Systolic ≥ 120 or Diastolic 
≥ 80. The average reading of the two measurements will be noted in the database and used for adverse 
event determination. See section 11.1.1 Reportable AEs, for how the blood pressure should be obtained. 
• 
Day 8 (+/- 1Day) is a telephone contact: the study coordinator will attempt to make contact with the 
participant at least two times.  
• 
If the coordinator is unable to reach the participant between Day 7 and 9 a protocol deviation is filed.  
• 
The coordinator will continue his/her attempts to reach the participant until contact is made; 
• 
Concomitant medication review 
• 
Review adverse events/symptom assessment  
• 
The coordinator will also review the blood pressure readings documented on the blood pressure diary 
and if the participant has missed taking their BP reading on both Day 7 and Day 8 then they should be 
encouraged to collect the missed readings on the following two consecutive days approximately 24 
hours apart from each other. If the participant has missed taking their BP reading on only Day 8 then 
they should be encouraged to collect the missed reading on the following morning. 


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• 
During this telephone contact if any adverse events are reported that require treatment or further 
evaluations, the participants will be asked to visit site for further evaluations of the symptoms.  
 
7.3.4 
Day before surgery (telephone contact) 
 
• 
Home BP monitoring in the morning. They will note the BP value and time reading taken in the BP 
diary and call the study team if they see a value of systolic ≥160 or diastolic ≥100. This has to be 
taken by participant day before surgery and not on the day the study coordinator calls participant. For 
grade 1, grade 2, and grade 3 hypertension blood pressure readings, repeat blood pressure reading 
after 5 minutes. The average reading of the two measurements will be noted in the database and used 
for adverse event determination. See section 11.1.1 Reportable AEs, for how the blood pressure 
should be obtained. 
• 
Day before surgery telephone contact (- 2 Days): the study coordinator will attempt to make contact 
with the participant at least two times. If the coordinator is unable to reach the participant before 
surgery, a protocol deviation is filed.  
• 
Concomitant medication review 
• 
Review adverse events/symptom assessment  
• 
Remind of the last dose of study medication. 
• 
Remind that a study team member will meet them the day of their surgery before surgery for study 
related procedures.  
• 
Remind to bring study medication bottles, blood pressure monitor and diary to the clinic visit on the 
day of surgery. 
 
7.4 
Evaluation at Completion of Study Intervention 
 
7.4.1  Day 15-29 (Pre-surgery – assessments must occur before surgery) 
 
• 
Pre-surgery assessments may be completed up to 1 day prior to scheduled surgery (if surgery is 
scheduled for Monday, then pre-surgery assessments may be completed on Friday of the prior week). 
If pre-surgery assessments are completed prior to the day of surgery, the participant should be reminded 
that their last dose of medication should be the day before surgery.  
o If visit occurs on the day prior to surgery, pill bottles and diaries should be collected on the 
Day of Surgery to allow participant to take the last dose and document it. 
• 
Evaluation of vital signs including temperature, pulse, and respiration rate.  
o Blood pressure on Surgery Day 15-29 will only be obtained if the average Day before Surgery 
blood pressure is above Systolic ≥ 120 or Diastolic ≥ 80. An assessment of blood pressure 
should be collected using the study-supplied wrist monitor. 
▪ 
For grade 1, grade 2, grade 3 hypertension blood pressure readings, repeat blood pressure 
after 5 minutes. The average reading of the two measurements will be noted in the 
database and used for adverse event determination. 
• 
A physical examination. A gynecologic examination may be waived. The physical examination may 
be performed by any healthcare professional (i.e. physician, nurse practitioner, physician assistant) who 
is allowed by local policy to perform physical examinations.  
• 
Assessment of Performance Status, using the ECOG method (convert a Karnofsky score into an ECOG 
score using the scale in Appendix A). 
• 
Administer the follow-up version of tobacco and alcohol assessment questionnaire – Appendix D 
• 
Review of concomitant medications including over the counter medications and nutrition supplements.  


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• 
Perform the laboratory tests as outlined in section 7.1. The lipid panel (cholesterol, HDL cholesterol, 
LDL cholesterol, triglycerides) must be drawn after the participant has fasted for 10 hours (water is 
OK). 
• 
Collect 10 mL urine and 3 mL blood for pharmacokinetic studies (prior to study medication dosing if 
the visit is 1 day prior to surgery) 
• 
Collect 30 ml blood sample for immune studies for participants 6-25. 
• 
Safety assessment and review of adverse events 
• 
Pill accountability by the coordinator 
• 
Blood pressure monitor will be collected from participant and all the documented readings will be 
checked for grades and documented in the adverse event log accordingly.  
 
7.5 
Post-intervention Follow-up Period 
 
7.5.1  7 days after surgery (+/- 1 Day) 
 
• 
Follow-up telephone contact: the study coordinator will attempt to make contact with the participant 
at least two times.  
• 
If the coordinator is unable to reach the participant within this time frame a protocol deviation is filed.  
• 
The coordinator will continue his/her attempts to reach the participant until contact is made; 
• 
Concomitant medication review; 
• 
Review adverse events/symptom assessment: if any AEs not related to surgery are concerning to either 
the participant or the study coordinator/nurse the participant will be scheduled for a clinic visit and 
evaluation.  
 
7.5.2  4-5 Weeks after Surgery 
 
• 
Follow-up telephone contact: the study coordinator will attempt to make contact with the participant 
at least two times.  
• 
If the coordinator is unable to reach the participant within this time frame a protocol deviation is filed.  
• 
The coordinator will continue his/her attempts to reach the participant until contact is made; 
• 
Concomitant medication review; 
• 
Review adverse events/symptom assessment: if any AEs not related to surgery are concerning to either 
the participant or the study coordinator/nurse the participant will be scheduled for a clinic visit and 
evaluation.  
 
All participants will receive $30 for completing the screening visit and $70 for completing the surgery and 
returning the blood pressure machine visit as compensation towards the extra efforts taken such as travel 
expenses, parking, time missed from work or other expenses associated with the study visits. The first 5 
participants will be given additional $50 for the additional time required for the study visit. 
 
7.6 
Methods for Clinical Procedures 
 
• 
Participants will be fasting for 10 hours prior to serum lipid evaluation for the Day 15-29 Visit. 
 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 
 
8.1 
Primary Endpoint 
 


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Our primary endpoint is that treatment with 9cUAB30 for 14-28 days will result in reduced proliferation as 
measured by Ki-67 expression in breast cancer tissue obtained at surgical resection compared with tissue 
obtained at diagnostic core biopsy/baseline.  
 
8.2 
Secondary Endpoints 
 
Our secondary endpoint is that treatment with 9cUAB30 for 14-28 days will result in increased apoptosis 
in breast cancer tissue obtained at surgical resection compared with tissue obtained at diagnostic core 
biopsy/baseline. Additionally, we plan to explore the effect of 9cUAB30 on a molecular level using 
Nanostring technology providing further insight into its mechanism of action. Examined genes will include 
up to 48 genes. Prospective biomarkers on the panel will include but are not limited to (A) biomarkers 
associated with cell proliferation or apoptosis: PCNA, p21, p27, TUNEL assay, caspase 3; (B) potential 
biomarkers of rexinoid activity reported in published studies: ABCA1, ABCG1, RARβ, SREBP-1c, cyclin 
D1, IGFBP6; (C) potential biomarkers of response to 9cUAB30 as defined in our preliminary studies: RET, 
MEN1, mTOR, AKT1, AKT2, 4EBP1, eIF4G1, S6K, IGFBP5, TGFβR1, PPARα, PPARγ (D) 
housekeeping genes for normalization: GAPDH, TUBB, PGK1, GUSB, and CLTC. Additionally, as 
possible, we will perform IHC for a subset of 5 of the most differentially regulated genes found on 
Nanostring to verify that gene expression data also results in protein differences. 
 
One of our secondary endpoint will be to examine if Cmax at Day 1 in the first 5 participants is increased 
from 957ng/ml by reducing the number of capsules for the 240mg dose level. Dose of each capsule has 
been changed from 20mg per capsule to 80 mg per capsule. We will examine if there is any difference in 
absorption of the study agent with this formulation. Additionally, we will examine adverse events in these 
participants for safety due to the change in formulation. 
 
In all of the participants we will examine the urine and plasma drug concentration levels of 9cUAB30 at 
baseline and on the day of surgery. 
 
Determine if treatment with 9cUAB30 modifies the tumor immune environment to a type I immune 
environment.  Tumor biopsy specimens collected prior to 9cUAB30 therapy and at the time of surgery will 
be tested as well as external comparator tumors before and after surgery untreated with 9cUAB30 and 
matched by site.  These tissues are being prepared for Nanostring to evaluate for expression of RXR genes.  
We propose to use these same RNA preparations to evaluate the Nanostring pan-cancer immune profiling 
panel on the tumor tissue.  We predict that there will be a shift to type I gene expression (including CD8, 
TBET, IFNG, and IL-1B included in the panel) and decrease in GATA3 and type II gene expression similar 
to what we have seen with bexarotene therapy in the TgMMTV-neu mouse (Fig 3). 
 
 


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.   
 
Figure 4. The rexinoic acid receptor is highly expressed on antigen presenting cells.  2X106 peripheral 
blood mononuclear cells from women without breast cancer were evaluated for expression of the rexinoic 
acid receptor (RXR) by flow cytometry.   CD4: RXR+CD3+ CD4+, CD8: RXR+ CD3+, CD8+, NK T-
cells: RXR+ CD56+, B-cells: RXR+ CD20+, Macrophages: RXR+ HLA DR+ CD14+, Plasmacytic 
dendritic cells: RXR+ LIN- HLA DR+ CD123+ (pDendritic), Monocytic dendritic cells: RXR+ LIN- HLA 
DR+ CD11c+ (mDendritic), and myeloid derived suppressor cells (MDSC) Monocytic MDSC (mMDSC) 
RXR+HLA DR- CD14+CD11b+ and plasmacytic MDSC (pMDSC) RXR+ HLA DR- LIN- 
CD33+CD11b+ 
 
 
 
 
Figure 3: Tumor immune environment with increased CD8+ T-cells and decreased immune 
suppressive GATA3 cells with bexarotene therapy. TgMMTV-neu mice (n=4) were treated with four 
weeks of either PBS and sesame oil (control) or 50 mg/m2 bexarotene for four weeks and their tumors 
were evaluated at sacrifice.  For each mouse the average of three independent high-powered fields (20X) 
were averaged.  (A) Percent of DAPI+ CD8+ cells (B) Percent of DAPI+GATA3+ cells 


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Figure 5. Rexinoic acid activation activates antigen presenting cells. 1.5X106 peripheral blood 
mononuclear cells from women without breast cancer (n=8) were stimulated by increasing concentrations 
of bexarotene for 48 hours.  Monocytic dendritic cells (CD11c+HLA DR+ LIN-) (A) and plasmacytic 
dendritic cells (CD123+ HLA DR+ LIN-) (B) have increased CD40+ expression suggesting increased 
Figure 6. Increasing concentration of bexarotene induces a type I immune environment. 1.5X106 
peripheral blood mononuclear cells from women without breast cancer (n=8) were stimulated by increasing 
concentrations of bexarotene for 48 hours.  PBMC released increased type I IL-1B (A) and TNF-a (B) but 
not type II IL-10 (C) or IL-4 (D) by Luminex assay.    * p<0.05 ** p<0.01. 


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8.3 
Exploratory Endpoint 
 
For participants 6-25, we will determine if 9cUAB30 increases activated dendritic cells in the peripheral 
blood.  Three 10 mL vials of whole blood drawn in sodium heparin tubes will be obtained and shipped fresh 
to the University of Washington prior to starting the 9cUAB30 therapy and at surgery.  The University of 
Washington Tumor Vaccine Group Immune Monitoring Laboratory has developed a flow cytometry panel 
that includes CD11c-AF700, CD14-V450, CD123-PE, and HLA-DR BV605 to evaluate for antigen 
presenting cells.  As immature dendritic cells activate and mature, they increase expression of co-
stimulatory molecules CD40 FITC and CD86 PECy7 as well as percent of MHC class II receptors on their 
cell surface.62,63  We will measure the expression of CD40, CD86, and MHC II on CD11c and CD123 
dendritic cells by FACS analysis.  We expect that there will be at least a doubling in the percent of CD11c 
dendritic cells that are expressing CD40 and CD86 activation markers as that has been what we have seen 
in vitro with increasing doses of 9cUAB30 (Fig 7). 
 
It has been found that use of some Retinoids have resulted in various toxicities such as, skin toxicity, angular 
chelitis, headache, hyperlipidemia, vision changes and elevations in hepatic transaminases.  During this 
study all safety information will be obtained for participants who have taken 9cUAB30 and we will compare 
this safety profile to that seen with other Retinoids.  
8.4 
Off-Agent Criteria  
 
Participants may stop taking study agent for the following reasons: completed the protocol-prescribed 
intervention, adverse event or serious adverse event that will compromise the surgery, inadequate agent 
supply, noncompliance, concomitant medications, lost to follow-up, pregnancy or medical contraindication. 
Figure 7. Both bexarotene and 9cUAB30 can activate monocytic dendritic cells. 1.5X106 PBMC cells 
from women without breast cancer (n=5) were stimulated by increasing concentrations of (A-C) bexarotene 
and (D-F) 9cUAB30 for 48 hours.  Monocytic dendritic cells (CD11c+HLA DR+ LIN-) (A and D) and 
plasmacytic dendritic cells (CD123+ HLA DR+ LIN-) (B but not D) have increased CD40+ expression 
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Participants will continue to be followed, if possible, for safety reasons and in order to collect endpoint data 
according to the schedule of events.  
 
8.5 
Off-Study Criteria 
 
Participants may go ‘off-study’ for the following reasons: the protocol intervention and any protocol-
required follow-up period is completed, adverse event/ serious adverse event, lost to follow-up, non-
compliance, concomitant medication, medical contraindication, withdraw consent, death, determination of 
ineligibility (including screen failure), pregnancy, or subject wishes.  
 
8.6 
Study Termination 
 
NCI, DCP as the study sponsor has the right to discontinue the study at any time. If not stopped early, the 
study will be considered terminated when the final report is written.   
 
9. 
CORRELATIVE/SPECIAL STUDIES 
 
9.1 
Rationale for Methodology Selection 
 
The primary goal of the study is to ensure that 9cUAB30 produces a biological effect in humans to justify 
pursuing more large-scale studies of 9cUAB30. To assess response to 9cUAB30, expression levels of 
biomarkers will be assessed pre and post treatment with immunohistochemistry (IHC) and Nanostring 
technology.  We have incorporated a nonrandomized matched “control” cohort to better understand baseline 
variability in biomarker analysis between diagnostic core biopsy and surgical resections.  
 
If the treatment agent 9cUAB30 is effective against breast cancer, it should reduce proliferation and/or kill 
breast cancer cells. In paraffin blocks, proliferation is assessed by immunohistochemistry via measuring 
changes in Ki67 and cell death is measured by the caspase 3 assay and routine histology. Another measure 
of proliferation is PCNA. However, all cells of breast cancer frequently stain with PCNA so it is not very 
useful. Paraffin embedded biopsy tissue will be compared with paraffin embedded tissue after definitive 
surgery following treatment with 9cUAB30.  These assays will be performed on 5 µm tissue sections from 
paraffin embedded tissues. Prior to analyzing treated cases, there will be a study of the variability of Ki67 
and caspase 3 between biopsies and definitive surgery (i.e., excision of any remaining tumor either in a 
lumpectomy or in a mastectomy). This study will be performed on retrospective samples which have not 
been treated between the biopsy and definitive surgery from each institution. Other than this, there will be 
no existing data with which to compare results of treatment with 9cUAB30 in this format of analysis. 
 
Specifically, at each institution, pretreatment core biopsy FFPE blocks containing breast cancer will be used 
to obtain 5 unstained slides of 5µm thickness for immunohistochemistry analysis to be performed at 
Wisconsin and 1 H&E stained slide, 5 unstained slides of 10µm thickness for Nanostring analysis to be 
performed at UAB. Post treatment, 1 H&E stained slide, 5 unstained slides of 5µm thickness and 5 
unstained slides of 10µm thickness will be prepared from diagnostic FFPE blocks from the definitive 
surgical resection for analysis also to be performed at Wisconsin and UAB.  
 
Additionally, each institution will provide matched samples (at the direction of UAB Pathology Core lab) 
from archival diagnostic core biopsy FFPE blocks containing breast cancer and archival FFPE blocks from 
the corresponding definitive surgical resection. Each matched case will be used to obtain 1 H&E stained 
slide, 5 unstained slides of 5µm thickness and 5 unstained slides of 10µm thickness from the archived core 
biopsy and 1 H&E stained slide, 5 unstained slides of 5µm thickness and 5 unstained slides of 10µm 


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thickness from the archived surgical specimen. These will be prepared and sent to Wisconsin and UAB as 
directed for analysis. 
 
9.2 
Comparable Methods 
 
Immunohistochemistry  
 
In paraffin sections, immunohistochemistry is the best assay for proliferation and activated caspases are the 
best assay for cell death by apoptosis. The antibody for Ki67 will be a rabbit monoclonal (SP6). We have 
experience with both SP6 and the mouse monoclonal MIB-1 antibodies and prefer SP6. The most important 
variable in measuring proliferation and apoptosis is probably the time between the end of treatment with 
9cUAB30 surgery and definitive surgery. This should be as constant as practicable. 
   
Similarly, the best time to measure changes in proliferation is a function of the time after therapy with 
9cUAB30 ends and the length of therapy with 9cUAB30. An answer to this will also require a pilot study. 
 
Nanostring 
 
Gene expression analysis will be performed using the Nanostring nCounter platform.  The Nanostring 
nCounter Dx Analysis System delivers direct, multiplexed measurements of gene expression through the 
digital readout of the relative abundance of mRNA transcripts isolated from formalin fixed paraffin 
embedded (FFPE) tissue.  Multiple validation studies of this technology compared q-PCR, microarray, and 
Nanostring techniques.   
 
Results showed that Nanostring technology achieved superior gene expression quantification results 
compared to arrays and/or IHC in archived FFPE samples.37 38-40 Furthermore, robust data could be obtained 
from RNA extracted from 30 year old archived FFPE tumors.41  These reports support the utility of the 
Nanostring nCounter platform to yield highly robust and reproducible data.      
 
Flow Cytometry (Exploratory only):  
 
Whole blood will be processed from baseline and prior to surgery and frozen for batch evaluation.  Dendritic 
cell activation will be evaluated by a dendritic cell antibody panel.  For evaluation of immune components 
in whole blood, 12 color flow cytometry will be performed using an LSR2 Flow Cytometer (BD 
Biosciences).  Batched flow cytometry using validated methods from the Cancer Immunotherapy Trials 
Network will allow for samples from both baseline and after treatment with 9cUAB30 to be run with the 
same controls and to allow direct comparison.  Flow cytometry is the best method to measure activation 
markers in the peripheral blood of individual dendritic cell populations (Autissier Cytometry 77A:410 
2010). 
 
10. 
SPECIMEN MANAGEMENT  
 
10.1 
Laboratories 
 
The University of Wisconsin will perform the immunohistochemistry analysis on the tissue provided from 
each of the sites, as well as pharmacokinetic urine and blood testing. The University of Alabama at 
Birmingham will perform the Nanostring analysis. 
 
Immunohistochemistry 


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Each institution will provide unstained slides from archival formalin-fixed paraffin embedded blocks 
containing malignant tissue that will support provision of ~ 100 mg, from both the pre-surgical core biopsy 
as well as the definitive surgical resection as detailed in section 10.2.1.  A total of 5 unstained slides of 5µm 
thickness (for the UWCCC TRIP lab) and 1 H&E stained slide, 5 unstained slides of 10µm thickness (for 
the Yang lab) will be required.  If the core biopsy will not support the preparation of the requested slides, 
alternatively, 1 H&E stained slide, and 5 unstained slides at 5 µm will be accepted.   The preparation of 
these slides will be coordinated with the UAB Tissue Biorepository Laboratory and UWCCC TRIP to 
assure the slides are prepared and submitted shortly before the analysis will occur.   
 
Nanostring analysis 
 
Using the Nanostring platform, the gene expression of the following genes will be assessed:  
- 
Potential biomarkers of rexinoid activity: ABCA1, ABCG1, RAR,  SREBP1c, cyclinD1, IGFBP6 
- 
Potential biomarkers of response to 9cUAB30: RET, MEN1, mTOR, AKT1, AKT2, 4EBP1, eIF4G1, 
S6K, IGFBP5, TGFbR1, PPAR, PPAR 
Additionally, 5 housekeeping genes (GAPDH, TUBB, PGK1, GUSB, and CLTC) will be used as 
internal controls. 
-   Pan-cancer immune profiling panel 
 
Slides will be processed with the same protocol designed by Nanostring for their FDA cleared Prosigna 
Breast Cancer Prognostic Gene Signature Assay.  Briefly, H&E stained slides will be examined by Dr. Al 
Diffalha, who will determine the tumor surface area and delineate the tumor.  Tumor surface area will be 
used to estimate the amount of tissue required. Sections will then be macrodissected and RNA is extracted 
using a commercially available FFPE kit from Roche (also used exclusively by Nanostring) and quantified.  
As little as 50ng of high quality RNA can be used to hybridize overnight with gene-specific probe pairs 
consisting of a Reporter and Capture probes.  The fluorescent Reporter probe consists of a 35-50 base probe 
sequence that is complementary to the mRNA target and a DNA sequence that hybridizes to a “color code” 
unique to each target. After hybridization, the samples are purified through a series of automated magnetic 
bead capture steps and washes on the nCounter Prep Station, bound to the surface of a nCounter Cartridge 
(via the Capture probe) and subjected to a high voltage to align and immobilize the Reporter probes to be 
read in the nCounter Digital Analyzer.    
 
Flow Cytometry Analysis: 
 
The blood for flow cytometry analysis of dendritic cell activation will be performed from SOPs form the 
University of Washington Tumor Vaccine Group.  In brief, 30 mL of blood will be collected at baseline 
and after 9cUAB30 therapy prior to surgery and sent directly to the University of Washington Immune 
Monitoring Laboratory where it will be frozen and stored in liquid nitrogen.  Samples will be thawed and 
evaluated in batches.  The samples will be stained with a cell surface marker dendritic cell panel including 
CD11c AF700, CD123 PE-Cy5, HLA-DR BV605, and activation markers CD40 FITC and CD86 BV650 
and fixed with 2% paraformaldehyde prior to evaluation.  The dendritic cell panel has been previously 
validated for use in clinical studies but the activation markers CD40 and CD86 will require further 
validation.  Flow cytometry will be performed on a BD Biosciences LSRII cytometer. 
 
 
10.2 
Collection and Handling Procedures 
 
 
The University of Wisconsin Comprehensive Cancer Center’s (UWCCC) CP Laboratory (Cancer 
Pharmacology Lab) will serve as the central repository for blood and urine specimens. The University of 
Alabama at Birmingham (UAB) Tissue Biorepository Laboratory and UWCCC TRIP will serve as the 
central repositories for tissue specimens. The UWCCC CP Laboratory will prepare sample kits for each 


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subject enrolled on the study – for both the slides being sent to UAB and UWCCC, and the blood and urine 
being sent to UWCCC. Each site will receive two kits as they activate the study. The CP lab will send 
additional kits to the sites as needed based on the rate of accrual.  
 
Each kit will be sent in a box to each site. Each box will contain: 
• 
Styrofoam cooler for blood and urine samples and airbill – which go to UWCCC  
• 
Slide mailers, shipping box and airbill for slides – which go to UWCCC and UAB 
 
The University of Washington will ship 2 kits for the 30 mL peripheral blood to each of the sites prior to 
start of the trial and then will ship further kits to the sites as needed based on recruitment.  The University 
of Washington will train the sites on packing and shipping the blood.  All blood processing and storage 
during the trial will be performed at the University of Washington and after analysis any remaining 
specimens will be returned to the Division of Cancer Prevention repository. 
 
10.2.1 Methods for preparing tissue specimens of participants and historical matched controls. 
 
NOTE:   
• 
Unstained sections are to be mounted on charged slides 
• 
Historical matched samples should be prepared at the same time as the participant tissue sample.  
 
From both the participant’s and historical matched sample of pre-surgical core biopsy and the definitive 
surgical resection: 
• 
A pathologist should identify, from each procedure, a FFPE archival block that contains an 
adequate amount of malignant tumor tissue to support the preparation of 11 slides (1 H&E stained 
slide, 5 unstained slides of 5µm thickness and 5 unstained slides of 10µm).  If the core biopsy will 
not support the preparation of 11 slides, 1 H&E stained slide, and 5 unstained slides at 5µm will be 
acceptable. 
• 
Samples that are considered adequate and eligible for analysis: 
• 
From the core biopsy – contain >20% malignant nuclei 
• 
From the surgical tumor sample – contain >10% malignant nuclei 
• 
After notification to the respective laboratory, the slides are to be labeled with the study number – 
UWI 2015-05-01, the PID # assigned to the participant, followed by a P (for pre-surgical core) or 
S (for surgical) to denote the time-point, followed by a 10 or a 5 (to denote the thickness of the 
cut), followed by the # of the cut (to denote the order in which the slides were cut from the block) 
as follows:  
• 
Labeling of Pre-Surgical Core Biopsy Slides 
• 
1 for H&E staining:  PID-P 
• 
5 unstained to be cut at 5 microns: PID-P5-1, PID-P5-2, … PID-P5-5 
• 
5 unstained to be cut at 10 microns: PID-P10-6, PID-P10-7, … PID-P10-10 
• 
Labeling of Surgical Slides:   
• 
1 for H&E staining:  PID-S 
• 
5 unstained to be cut at 5 microns: PID-S5-1, PID-S5-2, … PID-S5-5 
• 
5 unstained to be cut at 10 microns: PID-S10-6, PID-S10-7, …PID-S10-10 
For historical matched control samples – contact CLO to get the Sample ID (SID) 
• 
Labeling of Historical Matched Pre-Surgical Core Biopsy Slides 
• 
1 for H&E staining:  SID-HP 
• 
5 unstained to be cut at 5 microns: SID-HP5-1, SID-HP5-2, … SID-HP5-5 
• 
5 unstained to be cut at 10 microns: SID-HP10-6, SID-HP10-7, … SID-HP10-10 
• 
Labeling of Historical Matched Surgical Slides 


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1 for H&E staining:  SID-HS 
• 
5 unstained to be cut at 5 microns: SID-HS5-1, SID-HS5-2, … SID-HS5-5 
• 
5 unstained to be cut at 10 microns: SID-HS10-6, SID-HS10-7, … SID-HS10-10 
• 
Unstained sections are to be prepared as follows for participant’s samples as well as historical 
matched samples, cut and prepared in the order listed, placed on the labeled charged slides, and are 
NOT to be melted: 
• 
Core Biopsy   
• 
1 H&E stained slide 
• 
5 unstained at 5µm thickness (mounted on charged slides) 
• 
5 unstained at 10µm thickness (mounted on charged slides) 
• 
If core will not support the requested # of slides, prepare only the 5 unstained at 5µm 
thickness and do not prepare the 5 unstained at 10µm thickness 
• 
Surgical Resection 
• 
1 H&E stained slide 
• 
5 unstained at 5µm thickness (mounted on charged slides) 
• 
5 unstained at 10µm thickness (mounted on charged slides) 
• 
If core will not support the requested # of slides, prepare only the 5 unstained at 5µm 
thickness and do not prepare the 5 unstained at 10µm thickness 
• 
Complete the Slide Submission Form located in the lab manual. 
 
10.2.2 Methods for drawing and processing the pharmacokinetics of blood 
At each pharmacokinetic time point (baseline, 5 minutes post day 1 dose, 2 hours post day 1 dose and Day 
15-29 prior to surgery), draw one 3ml green top heparinized tube.  Centrifuge the tube for 10 minutes to 
separate plasma.  Divide the plasma into 2 cryovial tubes.  Label the 2 cryovial tubes with the labels 
provided in the kit.  Make sure to add the participant number, initials, and date of processing to the labels.  
Freeze the cryovial tubes at -70/ -80°C, and save for transport to the UWCCC CP Laboratory.   
10.2.3 Methods for processing the pharmacokinetics of urine  
Request the participant to void and record date and time.  Store samples immediately at 4°C.  Aliquot 
approximately 10ml of urine into a falcon tube for urine pharmacokinetics.  Freeze urine aliquot within 1-
4 hours at -70 / -80°C.  Discard any remaining urine. 
10.2.4 Methods for processing for whole blood. 
30 mL of blood will be collected from participants 6-25 at baseline and on day of surgery 
(Day 15-29) prior to surgery in green top sodium heparin tubes and shipped directly to the 
University of Washington.  Whole blood will cryopreserved in freezing media (10% 
dimethylsulfoxide and 90% media which includes 12.5% human serum albumin and 
RPMI-1640 with L-glutamine and 25 mM HEPES) and stored in liquid nitrogen until use 
in the assay.10.3 
Shipping Instructions 
All samples will be shipped in compliance with the International Air Transport Association (IATA) 
Dangerous Goods Regulations. 
 
10.3.1 Methods for shipping of tissue slides: 
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hours of preparation.  Slides should be prepared and shipped Monday – Wednesday.  They should not be 
shipped on a Thursday, Friday, on a holiday, or on the day prior to a holiday.   
 
Unstained slides are to be packaged securely in provided slide holders, and packaged carefully (they should 
not vibrate in the container) to avoid breakage of the slides.   
 
Although slides from more than one participant are encouraged to be prepared and shipped together, it is 
critical that slides from different participants be packaged in separate slide holders/mailers to avoid 
confusion.  
 
Slides are to be shipped via overnight delivery, at room temperature, with the Slide Submission Form(s) 
(Appendix B), and de-identified copies of the pathology reports (labeled with the PID only) using the 
provided pre-printed airbill to: 
 
1 H&E stained slide and 5 unstained slides cut at 10 microns: 
 
Deborah Della Manna 
1700 6th Ave South 
176F HSROC Room 2220B 
Birmingham, AL 35249-6832 
 
 
5 unstained slides cut at 5 microns: 
 
CP Lab K4/559 CSC 
600 Highland Avenue Madison 
WI 53792-5669 
 
Call the CP Lab to inform them of a shipment (608) 263-5369 or email the CP lab mailing list 
3plab@lists.medicine.wisc.edu.  
 
 
10.3.2.  Methods for shipping the plasma and urine pharmacokinetics samples: 
Once the participant has completed the study, ship the carton containing the pharmacokinetic samples for 
one participant to the address below. If multiple participants are completing the study, samples from 
multiple participants can be combined in one shipment.  
 
CP Lab K4/559 CSC 
600 Highland Avenue Madison 
WI 53792-5669 
 
Call the CP Lab to inform them of a shipment (608) 263-5369 or email the CP lab mailing list 
3plab@lists.medicine.wisc.edu  
 
Use the express courier service indicated by the shipping label contained in the kit. Closely follow all 
special shipping instructions outlined in the kit instruction packet.  
 
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not ship the day before a holiday.  
 
Fill the styrofoam cooler with dry ice and put all of the blood and urine samples into the cooler. Place the 
cooler into the shipping box in which you received the kit. 
 
 
10.3.3 Method for shipping blood samples for immunology 
 
For the 30 mL of peripheral blood for immune evaluation, blood will be packaged per protocol in the 
shipping box received in the kit and shipped FED-EX priority overnight for next day delivery.  The 
University of Washington Immune Monitoring Laboratory can receive blood shipped Monday through 
Thursday except the day prior to a national holiday.  Prior to shipment, the Immune Monitoring Laboratory 
must be contacted (contact uwiml@uw.edu to inform that samples are shipped).  Any remaining samples 
after evaluation for the trial will be returned to the Division of Cancer Prevention repository.  
 
UW IML CITN CENTRAL LAB 
Attention: Yi Yang  
850 Republican street 
Brotman 219 
Seattle WA 98109 
 
10.3.4 Sample Shipment Schedule:  
 
Sample Type 
Time Point 
Lab to send (see address 
above) 
Shipment 
Tissue Slides 
➢ Baseline 
➢ Surgery 
UAB Tissue Biorepository 
Laboratory – Alabama 
UWCCC CP Lab - 
Wisconsin 
Batch Shipment (Pre-surgical and 
surgical samples) 
Historical Tissue 
Slides 
➢ Baseline 
➢ Surgery 
UAB Tissue Biorepository 
Laboratory – Alabama 
UWCCC CP Lab - 
Wisconsin 
To be sent along with the participant 
that it matches. Batch shipment 
Plasma for PK 
 
➢ Baseline 
➢ Surgery 
UWCCC CP lab - Wisconsin Batch Shipment 
Urine for PK 
➢ Baseline 
➢ Surgery 
UWCCC CP lab - Wisconsin Batch Shipment 
Blood for 
immunology 
➢ Baseline 
➢ Surgery 
UW IML CITN CENTRAL 
LAB - Washington 
Same day shipment (ambient) 
 
10.4 
BioBanking 
 
Biologic specimens collected during the conduct of each clinical trial that are not used during the course of 
the study will be considered deliverables under the contract and thus the property of the NCI. At study 
completion, NCI reserves the option to either retain or relinquish ownership of the unused biologic 
specimens. If NCI retains ownership of specimens, the Contractor shall collect, verify and transfer the 
requested biologic specimens from the site to a NCI-specified repository or laboratory at NCI’s expense.  
 
11. 
REPORTING ADVERSE EVENTS  
 


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DEFINITION: AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign), 
symptom, or disease temporally associated with participation in a study, whether or not related to that 
participation. This includes all deaths that occur while a participant is on a study. 
 
Please note that all abnormal clinical laboratory values that are determined to be of clinical significance 
based on a physician’s assessment are to be reported as AEs. Those labs determined to be of no clinical 
significance or of unknown clinical significance (per the physician’s assessment) should not be reported as 
AEs. Any lab value of unknown clinical significance should continue to be investigated/followed-up further 
for a final determination, if possible. 
 
A list of AEs that have occurred or might occur  can be found in §6.2 Reported Adverse Events and Potential 
Risks, as well as the Investigator Brochure or package insert.  
 
 
 
11.1 
Adverse Events 
 
11.1.1 Reportable AEs 
 
11.1.1.1 All AEs that occur after the informed consent is signed and baseline assessments are completed 
(including run-in) must be recorded on the AE CRF (paper and/or electronic) whether or not related to study 
agent. 
 
How to obtain blood pressure for the study (for study team and participants) 
 
• 
Use the wrist blood pressure monitors provided for the study to record all readings for the study.  
• 
When the blood pressure is being obtained, the participant should sit for at least 5 minutes before 
taking the blood pressure.  
• 
Place the cuff on participant’s wrist as instructed in the wrist blood pressure monitor’s manual.  
• 
The arm used to measure blood pressure should be supported and ensure the arm is at heart level.  
• 
The participant should be instructed not to talk during this time, keep their back rested and legs 
uncrossed. 
In the case of an elevated blood pressure, in which it was repeated, the average of the values should be 
used for Adverse Event determination.  
 
11.1.1.2 AEs not related to surgery that occur from the time of surgery through the 4-5 week post surgery 
follow-up visit must be recorded on the AE CRF (paper and/or electronic) whether or not related to study 
agent.  
 
11.1.1.3 All SAEs, including all hospitalizations, during the study period will be reported as per DCP SAE 
reporting procedures, with the following exception:  
 
Hospitalization for planned surgery will not be reported. However, if this hospitalization event lasts longer 
than the usual period at the institution (as determined by the Site Principal Investigator or Sponsor), it will 
be reportable as an SAE. Adverse events (AEs) relevant to the prolongation of this hospitalization will also 
be collected and reported on AE CRFs. 
 
11.1.2 AE Data Elements: 
The following data elements are required for AE reporting. 


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AE verbatim term 
• 
NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) AE term 
(MedDRA lowest level term) 
• 
CTCAE (MedDRA) System Organ Class (SOC) 
• 
Event onset date and event ended date 
• 
Treatment assignment code (TAC) at time of AE onset 
• 
Severity grade 
• 
Attribution to study agent (relatedness) 
• 
Whether or not the event was reported as a SAE 
• 
Whether or not the subject dropped due to the event 
• 
Outcome of the event 
 
 
 
 
11.1.3  Severity of AEs 
11.1.3.1 
Identify the AE using the CTCAE version 4.0. The CTCAE provides descriptive 
terminology (MedDRA lowest level term) and a grading scale for each AE listed. A copy of the CTCAE 
can be found at http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
 
AEs will be assessed according to the grade associated with the CTCAE term. AEs that do not have a 
corresponding CTCAE term will be assessed according to the general guidelines for grading used in the 
CTCAE v4.0. as stated below.  
 
CTCAE v4.0 general severity guidelines:  
Grade 
Severity 
Description  
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
(ADL)*. 
3 
Severe 
Severe or medically significant but not immediately life-
threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL**. 
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Fatal 
Death related to AE. 
   
ADL 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
11.1.4 Assessment of relationship of AE to treatment 
 
The possibility that the AE is related to study agent will be classified as one of the following: not related, 
unlikely, possible, probable, definite. 
  
11.1.5 Follow-up of AEs 


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All AEs, including lab abnormalities that in the opinion of the investigator are clinically significant, will be 
followed according to good medical practices and documented as such. AEs with a “possibly”, “probably” 
or “definitely” attribution to study agent that have occurred prior to surgery will be monitored up to 4-5 
weeks after surgery via phone calls.   
 
Participants with AEs “possibly”, “probably” or “definitely” related to study agent that are not resolved at 
the 4 – 5 weeks post-surgery phone contact, should be referred to their primary care provider for follow-
up. 
 
 
11.2 
Serious Adverse Events  
 
11.2.1 DEFINITION: Regulations at 21 CFR §312.32 (revised April 1, 2014) defines an SAE as any 
untoward medical occurrence that at any dose has one or more of the following outcomes: 
 
• 
Death 
• 
A life-threatening AE 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to perform normal life 
functions 
• 
A congenital anomaly or birth defect 
• 
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization should also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the participant and may require intervention to 
prevent one of the other outcomes. 
 
11.2.2 Reporting SAEs to DCP 
 
11.2.2.1 
The Lead Organization and all Participating Organizations will report SAEs on the DCP SAE 
Report Form found at http://prevention.cancer.gov/clinical-trials/clinical-trials-management/protocol-
information-office/pio-instructions-and-tools/2012-consortia. 
 
11.2.2.2 
Contact the DCP Medical Monitor by phone or email (email preferred) within 24 hours of 
knowledge of the event.  
 
 
Edward Sauter, MD, PhD 
Breast and Gynecologic Cancer Research Group 
Division of Cancer Prevention 
9609 Medical Center Dr., Rm 5E326 
Rockville, MD 200850 
Office Tel (240)276-7657 
Cell: (240)944-3279 
Email: edward.sauter@nih.gov 
 
Include the following information when calling the Medical Monitor: 
• 
Date and time of the SAE 
• 
Date and time of the SAE report 
• 
Name of reporter 
• 
Call back phone number 


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• 
Affiliation/Institution conducting the study 
• 
DCP protocol number 
• 
Title of protocol 
• 
Description of the SAE, including attribution to drug 
 
11.2.2.3 
The Lead Organization and all Participating Organizations will email (do not FAX) written 
SAE reports to DCP’s Regulatory Contractor CCS Associates, Inc. (CCSA; phone: 650-691-4400) at 
safety@ccsainc.com within 48 hours of learning of the event using the fillable PDF SAE Report Form.    
  
11.2.2.4 
The DCP Medical Monitor and CCSA regulatory & safety staff will determine which SAEs 
require FDA submission as IND safety reports. 
 
11.2.2.5 
The Lead Organization and all Participating Organizations will comply with applicable 
regulatory requirements related to reporting SAEs to the IRB/IEC.  
 
11.2.3 Follow-up of SAE 
Site staff should send follow-up reports as requested when additional information is available. Additional 
information should be entered on the DCP SAE Report Form in the appropriate format. Follow-up 
information should be sent to DCP as soon as available SAE’s will be followed for 30 days after completion 
of treatment.  Any ongoing SAE’s will be referred to the primary care physician for follow-up.  
 
12. 
STUDY MONITORING 
 
12.1 
Data Management 
All of the procedures outlined in the University of Wisconsin Chemoprevention Consortium standardized 
Data Management Plan (approved 09/23/2019) will be followed in this protocol.  Please refer to this 
document for additional details on data management procedures.   
This study will report clinical data using the OnCore web-based application clinical trials/database.  OnCore 
will be the database of record for the protocol and is subject to NCI and FDA audit.  All OnCore data entry 
will be performed at the CLO where staff is trained in OnCore per our DMP and applicable regulatory 
requirements such as 21 CFR; Part 11. 
 
12.2 
Case Report Forms 
All data entry will be performed by the Consortium lead Organization (or CLO, the University of 
Wisconsin) staff.  Participant data will be entered into protocol-specific electronic case report forms 
(CRF’s), developed from the standard set of DCP Chemoprevention CRF Templates and utilizing NCI-
approved Common Data Elements (CDE).  PO’s will be required to submit data for quality assurance review 
and entry into the OnCore database within 10 business days of each study encounter.  All data entry will be 
completed by the CLO within 15 business days of the scheduled visit, as defined in the approved master 
Data Management Plan. Amended e-CRFs will be submitted to the DCP Protocol Information Office for 
review and approval. 
   
12.3 
Source Documents 
The CLO will provide participating sites with standardized, pre-printed source document forms that serve 
a dual role as source documents and as CRF’s, which may be used to ensure that all data items are collected.  
These pre-printed source document forms must be signed and dated by the person completing the form.  If 
the policy at the site mandates the use of an approved local institutional form or source documentation, the 
local institutional form may be submitted for the forms supplied by the CLO, as long as all required data 
points are included on the local institutional form.  All de-identified source documents will be sent 


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electronically or by mail to the CLO monitor.  All data is due at the CLO within 10 business days of each 
study visit. 
   
12.4 
Data and Safety Monitoring Plan 
The standard University of Wisconsin Chemoprevention Consortium DSMP was approved by the DCP on 
03/20/2018.  In addition to the standard procedures outlined in the consortium DSMP, we will be modifying 
the DMP and will perform additional monitoring of data for this trial.   
 
12.5 
Sponsor or FDA Monitoring 
The NCI, DCP (or their designee), pharmaceutical collaborator (or their designee), or FDA may 
monitor/audit various aspects of the study. These monitors will be given access to facilities, databases, 
supplies and records to review and verify data pertinent to the study.  
 
12.6 
Record Retention 
 
Clinical records for all participants, including CRFs, all source documentation (containing evidence to study 
eligibility, history and physical findings, laboratory data, results of consultations, etc.), as well as IRB 
records and other regulatory documentation will be retained by the Investigator in a secure storage facility 
in compliance with Health Insurance Portability and Accountability Act (HIPAA), Office of Human 
Research Protections (OHRP), Food and Drug Administration (FDA) regulations and guidances, and 
NCI/DCP requirements, unless the standard at the site is more stringent. The records for all studies 
performed under an IND will be maintained, at a minimum, for two years after the approval of a New Drug 
Application (NDA). For NCI/DCP, records will be retained for at least three years after the completion of 
the research. NCI will be notified prior to the planned destruction of any materials. The records should be 
accessible for inspection and copying by authorized persons of the Food and Drug Administration. If the 
study is done outside of the United States, applicable regulatory requirements for the specific country 
participating in the study also apply. 
 
12.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) 
 
Not Applicable  
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Description 
 
We aim to enroll 24 ER+ participants and 12 ER- participants for a total of 36 participants.  We plan to 
“pilot” the 240 mg dose in 5 initial participants with planned assessment of Cmax (Tmax usually at 2 hours) 
at 2 hours post initial dose (see section 2.3 for further information).  In the original 9cUAB30 Phase I study, 
we saw a flattening of the otherwise linear PK concentration curve; there was a mean Cmax of 957 ng/ml 
(SD 611) at the 240 mg dose level, similar to the mean Cmax of 983 (SD 434) for the 160 mg dose level.  
If Cmax had continued to be linear, we will have expected to see a Cmax of 1668 at the 240 mg dose level 
(calculated using linear regression with a forced intercept of 0, omitting the 240 mg level).  We will test the 
hypothesis H0: Cmax=957 (concentration curve is flat) vs the hypothesis HA:Cmax=1668 (concentration 
curve is linear) with a one-tailed one-sample Student t-test. Assuming a standard deviation of 611, we will 
have 0.69 power to reject H0: Cmax=957 given that the true mean Cmax is 1668 using a one-tailed one-
sample t-test of level 0.05.  Based on the results of this analysis, if we do not reject H0 and the dose gets 
changed to 160 mg after enrolling 5 participants, 36 additional participants will be enrolled to meet total of 
36 participants for data analysis on 160 mg dose and 41 participants total in the study. If we reject H0 we 


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will continue at 240 mg/day and enroll 31 more subjects. 
 
This is a single arm open label pre-surgical “window trial” of the novel rexinoid 9cUAB30.  The primary 
objective is to evaluate whether therapy with 9cUAB30 substantially reduces proliferation in breast cancer 
cells. To test the hypothesis that proliferation decreases in 9cUAB30 treated cases, we plan to examine 
Ki67 from newly diagnosed breast cancer patients. For each enrolled participant, we will obtain baseline 
core biopsy tissue samples and post-treatment definitive surgical tissue samples.  To account for potential 
confounding variability associated within the tumor as a result of core biopsy, we plan to include a matched 
historical nonrandomized “control” group which will have an initial sample as well as post-surgical sample. 
This matched group will come from archived tissue samples of core biopsy and definitive surgical tissue 
samples available at each participating Institution. The primary endpoint will be the absolute change in 
Ki67 expression in each treated participant and matched “control” pair.   
 
The primary analysis will compare the difference in absolute change in Ki67 between treatment and 
matched “control” group using a one-tailed paired t-test or Wilcoxon signed-rank test, as appropriate, at a 
significance level of 0.05.  We chose the one-tailed test as we are only interested in detecting the reduction 
in Ki67 expression level with 9cUAB30 as compared to controls. 
 
13.2 
Randomization/Stratification  
 
We aim to enroll 24 ER+ participants and 12 ER- participants for a total of 36 participants.  As this is a 
non-randomized trial, stratification for randomization is not applicable.  One of the analyses to be 
performed will be stratified by estrogen receptor status.  
 
13.3 
Accrual and Feasibility 
 
According to Dowsett et al., there was a mean decrease in Ki67 of 59.5% and an estimated standard 
deviation (SD) of 57.5% with tamoxifen, the least effective among tamoxifen alone, anastrozole alone, and 
tamoxifen/anastrozole combination.34As we do not know if 9cUAB30 will have as much of a decrease as 
tamoxifen, we will use a range of more conservative estimates, from 50-75% of 59.5%, or 29.8-44.6%. 
According to Chen et al., there was a mean increase in Ki67 of 1.7% with a SD of 7.6% based on three 
untreated observations with the time interval comparable to the proposed study.43 However, three 
observations for estimation of SD is not reliable.  Instead we used the widest interval-based SD estimate of 
14.8% (from the 2-4 day interval), to be conservative.   We also conservatively used an estimate of 0% for 
change in the control group instead of 1.7%, again, because of the sample size consideration.  
 
Since we are using matched pairs, we needed to estimate the mean and SD of the difference between the 
matched pair. With 0% as our control estimate, the estimate of the range of the mean difference is thus 
29.8-44.6%.  The SD is estimated using the equation √𝜎𝑇2 + 𝜎𝐶2 −2ρσ 𝑇σ 𝐶 where σ𝑇 is the SD of the 
treatment group, σ𝐶 is the SD of the control group, and ρ is the correlation between the matched pair.  The 
value of this equation increases as ρ decreases in value, so an estimate using a smaller correlation coefficient 
is more conservative.  This correlation is unlikely to be negative.  Also, if the effect on Ki67 is not dependent 
on the factors that will be used to choose the matched controls, the correlation is likely to be close to 0.   
For these reasons, we use 0 as the estimate of ρ; this gives an estimate of 59.4% for the SD of the difference 
between the matched pair.  
 
We will enroll 36 participants, and obtain 36 matched pairs.  Stratified analyses will be conducted if we 
reach a minimum of 12 participants (and matched pairs) with ER-.  Assuming 20% of the participants 
cannot be evaluated at the end of study due to dropout or unevaluable/unavailable specimen, we will have 
approximately 28 participants, with 9 participants with ER- and 19 with ER+.  The range of mean difference 


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in the change of 29.8-44.6% and the estimated SD of 59.4% result in an effect size ranging from 0.502-
0.751.  The table below shows the attainable power of a one-tailed level 0.05 paired test under various effect 
sizes.  With 32 participants, the study will have 0.82-0.98 power to detect the range of effect size of 0.502-
0.751. With the 9 participants and matched controls in the ER- group, there will be a power of 0.39-0.65 to 
detect an effect size range of 0.502 -0.751 between the treatment group and the matched controls.  With the 
19 participants and matched controls in the ER+ group there will be a power of 0.67-0.93 to detect the same 
effect size range. Because of the nature of the study being exploratory, we are not making adjustment for 
multiplicity of testing in subgroups defined by ER status. 
 
 
 
Subgroup 
 
Effect Size 
All (n=28) 
ER+ (n=19) 
ER- (n=9) 
0.751 
0.98 
0.93 
0.65 
0.626 
0.94 
0.83 
0.52 
0.502 
0.82 
0.67 
0.39 
Power for Different Estimated Effect Sizes 
 
 
13.4 
Primary Objective, Endpoint(s), Analysis Plan 
 
The primary objective will be to evaluate if there is a significant decrease in proliferation (Ki67) expression 
in breast cancer cells from baseline to post-exposure in participants treated with 9cUAB30 compared with 
matched controls. The primary endpoint is the absolute change from baseline to post-exposure in 9cUAB30 
treated and matched controls in Ki-67 in breast epithelial cells obtained by needle core biopsy.  The 
baseline, post-exposure, absolute change in Ki-67, and difference in absolute change between the treated 
and matched controls will all be summarized with descriptive statistics.  The primary analysis will compare 
the absolute change in Ki-67 between treatment and matched “control” group using a one-tailed paired t-
test or Wilcoxon signed-rank test, as appropriate, at a significance level of 0.05.   
 
13.5 
Secondary Objectives, Endpoints, Analysis Plans 
 
The first of secondary objectives is to evaluate if there is a difference in the change in apoptosis (caspase 
3) from baseline to post-exposure in breast cancer epithelial cells in participants treated with 9cUAB30 
compared with matched controls.  In the second of secondary objectives, we will examine the differences 
in gene expression from baseline to post-exposure breast cancer samples using a custom gene panel from 
Nanostring Technologies. Examined genes will be selected as described below and will include 23 genes. 
Prospective biomarkers on the panel will include (A) biomarkers associated with cell proliferation or 
apoptosis: PCNA, p21, p27, caspase 3;  (B) potential biomarkers of rexinoid activity reported in published 
studies: ABCA1, ABCG1, RARβ, SREBP-1c, cyclin D1, IGFBP6; (C) potential biomarkers of response to 
9cUAB30 as defined in our preliminary studies: RET, MEN1, mTOR, AKT1, AKT2, 4EBP1, eIF4G1, 
S6K, IGFBP5, TGFβR1, PPARα, PPARγ; and (D) housekeeping genes for normalization: GAPDH, TUBB, 
PGK1, GUSB, and CLTC. Additionally, as possible, we will perform IHC for a subset of 5 of the most 
differentially regulated genes found on Nanostring to verify that gene expression data also results in protein 
differences. 
 
One of the secondary objectives will be to examine if the Cmax at day 1 is increased from 957 ng/ml by 
reducing the number of capsules for the 240 mg dose level. The endpoint for this objective is Cmax 
measured at day 1.  This will be tested using a one-tailed one-sample Student t-test. 
 


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Observed toxicities seen in this study will be compared with those known to occur from retinoid use.  This 
comparison will be qualitative by necessity and descriptive in nature.  As such these will be described in 
descriptive statistics. 
  
13.6 
Reporting and Exclusions 
 
All participants who receive any 9cUAB30 will be analyzed for adverse events. Subjects that maintain 90% 
compliance for the time period beginning day 1 and ending on the day before surgical intervention will be 
considered compliant. Compliance will be measured though pill counts conducted by the study coordinator 
and recorded in the CRF. For biomarker modulation, all participants that have evaluable pre- and post-
treatment samples will be included in the analysis. Compliance and availability of evaluable samples for 
biomarker studies will be included in descriptive statistics.  
 
13.7 
Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first dose of 9cUAB30. The toxicity 
will be tabulated by severity with descriptive statistics.  
 
13.8 
Evaluation of Response 
 
All participants included in the study will be assessed for response to intervention with 9cUAB30, 
specifically decrease in proliferation and increase in apoptosis.  All of the participants who met the 
eligibility criteria will be included in the main analysis. All conclusions regarding efficacy will be based on 
all eligible participants. 
 
13.9 
Interim Analysis 
 
There is no planned interim analysis of the primary endpoint of the study. Safety data will be monitored by 
the consortium’s data monitoring committee.  
 
There will be an interim analysis after first 5 participants complete the study at dose 240 mg. This will be 
to analyze the Cmax and evaluate toxicity data collected for the first 5 participants. 
 
The dose of the study will be reduced to 160 mg if one of the following criteria is met:  
 
1. If the mean Cmax is not >957 ng/mL 
2. If ≥ 2 subjects experience grade 2 hypertriglyceridemia of any attribution 
 
If the study dose is reduced to 160mg due to the toxicity criteria at 240mg, then another cohort of 
5participants will be evaluated only for toxicity.  
 
If any subjects experience grade 4 or higher toxicity, the study will be suspended for accrual. The study 
chair will consult with the DSMC for study termination or other course of action.  The PI will work with 
the NCI DCP Investigators to make a decision in consideration of the DSMC’s recommendation. 
 
13.10 Ancillary Studies 
 
Not applicable  
 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 


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14.1 
Form FDA 1572 
Prior to initiating this study, the Protocol Lead Investigator at the Lead or Participating Organization(s) will 
provide a signed Form FDA 1572 stating that the study will be conducted in compliance with regulations 
for clinical investigations and listing the investigators, at each site that will participate in the protocol. All 
personnel directly involved in the performance of procedures required by the protocol and the collection of 
data should be listed on Form FDA 1572. 
 
14.2 
Other Required Documents 
 
14.2.1 Current (within two years) CV or biosketch for all study personnel listed on the Form FDA 1572 
and Delegation of Tasks form for the Lead Organization and all Participating Organizations.  
 
14.2.2 Current medical licenses (where applicable) for all study personnel listed on Form FDA 1572 and 
Delegation of Tasks form for the Lead Organization and all Participating Organizations. 
 
14.2.3 Lab certification (e.g., CLIA, CAP) and lab normal ranges for all labs listed on Form FDA 1572 
for the Lead Organization and all Participating Organizations. 
 
14.2.4 Documentation of training in “Protection of Human Research Subjects” for all study personnel 
listed on the FDA Form 1572 and Delegation of Tasks form for the Lead Organization and all Participating 
Organizations. 
 
14.2.5 Documentation of Federalwide Assurance (FWA) number for the Lead Organization and all 
Participating Organizations. 
 
14.2.6 Signed Investigator’s Brochure/Package Insert acknowledgement form 
 
14.2.7 Delegation of Tasks form for the Lead Organization and all Participating Organizations signed by 
the Principal Investigator for each site and initialed by all study personnel listed on the form 
 
14.2.8 Signed and dated NCI, DCP Financial Disclosure Form for all study personnel listed on Form FDA 
1572 for the Lead Organization and all Participating Organizations 
 
14.3 
Institutional Review Board Approval 
 
Prior to initiating the study and receiving agent, the Investigators at the Lead Organization and the 
Participating Organization(s) must obtain written approval to conduct the study from the appropriate IRB. 
Should changes to the study become necessary, protocol amendments will be submitted to the DCP PIO 
according to DCP Amendment Guidelines. The DCP-approved amended protocol must be approved by the 
IRB prior to implementation 
 
14.4 
Informed Consent 
 
All potential study participants will be given a copy of the IRB-approved Informed Consent to review. The 
investigator or designee will explain all aspects of the study in lay language and answer all questions 
regarding the study. If the participant decides to participate in the study, he/she will be asked to sign and 
date the Informed Consent document. The study agent(s) will not be released to a participant who has not 
signed the Informed Consent document. Subjects who refuse to participate or who withdraw from the study 
will be treated without prejudice. 


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Participants must be provided the option to allow the use of blood samples, other body fluids, and tissues 
obtained during testing, operative procedures, or other standard medical practices for further research 
purposes. If applicable, statement of this option may be included within the informed consent document or 
may be provided as an addendum to the consent. A Model Consent Form for Use of Tissue for Research is 
available through a link in the DCP website. 
 
Prior to study initiation, the informed consent document must be reviewed and approved by NCI, DCP, the 
Consortium Lead Organization, and the IRB at each Organization at which the protocol will be 
implemented. Any subsequent changes to the informed consent must be approved by NCI, DCP, the 
Consortium Lead Organization’s IRB, and then submitted to each organization’s IRB for approval prior to 
initiation. 
 
14.5 
Submission of Regulatory Documents 
 
All regulatory documents are collected by the Consortia Lead Organization and reviewed for completeness 
and accuracy. Once the Consortia Lead Organization has received complete and accurate documents from 
a participating organization, the Consortium Lead Organization will forward the regulatory documents to 
DCP’s Regulatory Contractor: 
 
 
Paper Document/CD-ROM Submissions: 
 
Regulatory Affairs Department 
 
CCS Associates, Inc. 
 
2001 Gateway Place, Suite 350 West 
             San Jose, CA 95110 
 
Phone : 650-691-4400 
 
Fax : 650-691-4410 
 
 
E-mail Submissions : 
 
regulatory@ccsainc.com 
 
Regulatory documents that do not require an original signature may be sent electronically to the Consortium 
Lead Organization for review, which will then be electronically forwarded to DCP’s Regulatory Contractor. 
 
14.6 
Other 
 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and the 
applicable regulatory requirements. 
 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE 
 
All laboratory tests and clinic visits required for study participation will be done at no cost to the 
participant or his/her insurance company. Although it is not expected, taking part in this study may lead to 
added costs to participants.  
All participants will receive $30 for completing the screening visit and $70 for completing the surgery 
visit and returning the blood pressure machine as compensation towards the extra efforts taken such as 
travel expenses, parking, time missed from work or other expenses associated with the study visits. The 
first 5 participants will be given additional $50 for the additional time required for the study visit. 
 
 
 


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22. Grubbs CJ, Lubet RA, Atigadda VR, et al: Efficacy of new retinoids in the prevention of mammary 
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23. Vedell PT, Lu Y, Grubbs CJ, et al: Effects on gene expression in rat liver after administration of RXR 
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24. Moon RC, Grubbs CJ, Sporn MB: Inhibition of 7,12-dimethylbenz(a)anthracene-induced mammary 
carcinogenesis by retinyl acetate. Cancer Res 36:2626-30, 1976 
25. Moon RC, Grubbs CJ, Sporn MB, et al: Retinyl acetate inhibits mammary carcinogenesis induced by 
N-methyl-N-nitrosourea. Nature 267:620-1, 1977 
26. Atigadda VR, Vines KK, Grubbs CJ, et al: Conformationally defined retinoic acid analogues. 5. Large-
scale synthesis and mammary cancer chemopreventive activity for (2E,4E,6Z,8E)-8-(3',4'-dihydro-
1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6- octatrienoic acid (9cUAB30). J Med Chem 
46:3766-9, 2003 
27. Hursting SD, Nunez NP, Patel AC, et al: The utility of genetically altered mouse models for nutrition 
and cancer chemoprevention research. Mutat Res 576:80-92, 2005 
28. Lindeblad M, Kapetanovic IM, Kabirov KK, et al: Assessment of oral toxicity and safety of 9-cis-
UAB30, a potential chemopreventive agent, in rat and dog studies. Drug Chem Toxicol 34:300-10, 
2011 
29. Jackson JP, Kabirov KK, Kapetanovic IM, et al: In vitro assessment of P450 induction potential of 
novel chemopreventive agents SR13668, 9-cis-UAB30, and pentamethychromanol in primary cultures 
of human hepatocytes. Chem Biol Interact 179:263-72, 2009 
30. Kapetanovic IM, Horn TL, Johnson WD, et al: Murine oncogenicity and pharmacokinetics studies of 
9-cis-UAB30, an RXR agonist, for breast cancer chemoprevention. Int J Toxicol 29:157-64, 2010 
31. Kolesar JM, Hoel R, Pomplun M, et al: A pilot, first-in-human, pharmacokinetic study of 9cUAB30 in 
healthy volunteers. Cancer Prev Res (Phila) 3:1565-70, 2010 
32. Dowsett M, Bundred NJ, Decensi A, et al: Effect of raloxifene on breast cancer cell Ki67 and apoptosis: 
a double-blind, placebo-controlled, randomized clinical trial in postmenopausal patients. Cancer 
Epidemiol Biomarkers Prev 10:961-6, 2001 
33. Dowsett M, Dixon JM, Horgan K, et al: Antiproliferative effects of idoxifene in a placebo-controlled 
trial in primary human breast cancer. Clin Cancer Res 6:2260-7, 2000 
34. Dowsett M, Smith IE, Ebbs SR, et al: Short-term changes in Ki-67 during neoadjuvant treatment of 
primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free 
survival. Clin Cancer Res 11:951s-8s, 2005 
35. Decensi A, Robertson C, Viale G, et al: A randomized trial of low-dose tamoxifen on breast cancer 
proliferation and blood estrogenic biomarkers. J Natl Cancer Inst 95:779-90, 2003 
36. Hammond ME, Hayes DF, Dowsett M, et al: American Society of Clinical Oncology/College Of 
American Pathologists guideline recommendations for immunohistochemical testing of estrogen and 
progesterone receptors in breast cancer. J Clin Oncol 28:2784-95, 2010 
37. Reis PP, Waldron L, Goswami RS, et al: mRNA transcript quantification in archival samples using 
multiplexed, color-coded probes. BMC Biotechnol 11:46, 2011 
38. Beard RE, Abate-Daga D, Rosati SF, et al: Gene expression profiling using nanostring digital RNA 
counting to identify potential target antigens for melanoma immunotherapy. Clin Cancer Res 19:4941-
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39. Masque-Soler N, Szczepanowski M, Kohler CW, et al: Molecular classification of mature aggressive 
B-cell lymphoma using digital multiplexed gene expression on formalin-fixed paraffin-embedded 
biopsy specimens. Blood 122:1985-6, 2013 
40. Russell JN, Clements JE, Gama L: Quantitation of gene expression in formaldehyde-fixed and 
fluorescence-activated sorted cells. PLoS One 8:e73849, 2013 
41. Balko JM, Cook RS, Vaught DB, et al: Profiling of residual breast cancers after neoadjuvant 
chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance. Nat Med 18:1052-9, 
2012 
42. Chen X, Zhu S, Fei X, et al: Surgery time interval and molecular subtype may influence Ki67 change 
after core needle biopsy in breast cancer patients. BMC Cancer 15:822, 2015 


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43. Li Y, Zhang Y, Hill J, et al: The rexinoid, bexarotene, prevents the development of premalignant lesions 
in MMTV-erbB2 mice. Br J Cancer 98:1380-8, 2008, 2361704 
44. Li Y, Shen Q, Kim HT, et al: The rexinoid bexarotene represses cyclin D1 transcription by inducing 
the DEC2 transcriptional repressor. Breast Cancer Res Treat 128:667-77, 2011, 3444826 
45. Love WK, Deangelis JT, Berletch JB, et al: The Novel Retinoid, 9cUAB30, Inhibits Telomerase and 
Induces Apoptosis in HL60 Cells. Transl Oncol 1:148-52, 2008, 2533143 
46. Larange A, Cheroutre H: Retinoic Acid and Retinoic Acid Receptors as Pleiotropic Modulators of the 
Immune System. Annu Rev Immunol 34:369-94, 2016,  
47. Yang Y, Minucci S, Ozato K, et al: Efficient inhibition of activation-induced Fas ligand up-regulation 
and T cell apoptosis by retinoids requires occupancy of both retinoid X receptors and retinoic acid 
receptors. J Biol Chem 270:18672-7, 1995,  
48. Ma F, Liu SY, Razani B, et al: Retinoid X receptor alpha attenuates host antiviral response by 
suppressing type I interferon. Nat Commun 5:5494, 2014, 4380327 
49. Denkert C, Loibl S, Noske A, et al: Tumor-associated lymphocytes as an independent predictor of 
response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28:105-13, 2010,  
50. Loi S, Sirtaine N, Piette F, et al: Prognostic and predictive value of tumor-infiltrating lymphocytes in a 
phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition 
of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol 31:860-7, 
2013,  
51. Melief CJ, van Hall T, Arens R, et al: Therapeutic cancer vaccines. J Clin Invest 125:3401-12, 2015, 
4588240 
52. Slingluff CL, Jr.: The present and future of peptide vaccines for cancer: single or multiple, long or 
short, alone or in combination? Cancer J 17:343-50, 2011, 3204371 
53. DeNardo DG, Coussens LM: Inflammation and breast cancer. Balancing immune response: crosstalk 
between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res 9:212, 
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54. Marquez JP, Stanton SE, Disis ML: The antigenic repertoire of premalignant and high-risk lesions. 
Cancer Prev Res (Phila) 8:266-70, 2015, 4383662 
55. Stanton SE, Disis ML: Clinical significance of tumor-infiltrating lymphocytes in breast cancer. J 
Immunother Cancer 4:59, 2016, 5067916 
56. Disis ML, Gad E, Herendeen DR, et al: A multiantigen vaccine targeting neu, IGFBP-2, and IGF-IR 
prevents tumor progression in mice with preinvasive breast disease. Cancer Prev Res (Phila) 6:1273-
82, 2013, 3864759 
57. Gad E, Rastetter L, Slota M, et al: Natural history of tumor growth and immune modulation in common 
spontaneous murine mammary tumor models. Breast Cancer Res Treat 148:501-10, 2014, 4280094 
58. Tran Janco JM, Lamichhane P, Karyampudi L, et al: Tumor-infiltrating dendritic cells in cancer 
pathogenesis. J Immunol 194:2985-91, 2015, 4369768 
59. Gabrilovich DI, Chen HL, Girgis KR, et al: Production of vascular endothelial growth factor by human 
tumors inhibits the functional maturation of dendritic cells. Nat Med 2:1096-103, 1996,  
60. Duvic M, Hymes K, Heald P, et al: Bexarotene is effective and safe for treatment of refractory 
advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol 
19:2456-71, 2001,  
61. Grubbs CJ, Hill DL, Bland KI, et al: 9cUAB30, an RXR specific retinoid, and/or tamoxifen in the 
prevention of methylnitrosourea-induced mammary cancers. Cancer Lett 201:17-24, 2003,  
62. Lanier LL, O'Fallon S, Somoza C, et al: CD80 (B7) and CD86 (B70) provide similar costimulatory 
signals for T cell proliferation, cytokine production, and generation of CTL. J Immunol 154:97-105, 
1995, 7527824 
63. Shin JS, Ebersold M, Pypaert M, et al: Surface expression of MHC class II in dendritic cells is 
controlled by regulated ubiquitination. Nature 444:115-8, 2006, 17051151 
 
 


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APPENDIX A 
Performance Status Criteria 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of 
a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and 
capable of all self-care, but unable to 
carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
0 
Dead. 


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APPENDIX B 
UWI2015-05-01: Pilot Study of 9cUAB30 in Early Stage Breast 
Cancer to Evaluate Biologic Effect 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
PILL DIARY 
 
 
INSTRUCTIONS 
 
Please read the instructions noted below before you start taking the study medication. 
 
You have been given ___ pill bottles containing the study agent. (30 capsules of 80mg in each bottle)  
Please keep your study agent in the refrigerator. 
 
• Take 
 capsules (_____mg dose) by mouth in the evening on an empty stomach (at least two 
hours after last meal). After taking your study medication, you must wait for 1 hour before eating 
or drinking anything.   
• The number of doses you take depends on the number of days until your surgery. Therefore, you 
may or may not have leftover study medication in the bottles.  
• Do NOT take study medications on the day of surgery. 
• Please complete this Pill Diary daily using black or blue pen only. 
• Record the time, number of capsules, any symptoms or side effects that you notice and initial 
the line. 
• If you miss a dose or lose any capsule, please note this in the comments section of the table. 
• Return this Pill Diary at your next visit. 
• Return the pill bottles and any unused capsules at your next visit. 
• Return the pill bottles even if it is empty. 
 
In case you have any questions or concerns, please feel free to call the study team 
at________________  
 
Initial and Date (person explaining the instructions): 
 
 
Dose 
Date  
Time 
# of 
capsules 
taken 
Comments (symptoms or side effects noticed, reason for 
missed dose, etc.) 
Initials 
Day 1.  
 
 
 
 
 
Day 2.  
 
 
 
 
 
Day 3.  
 
 
 
 
 


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Dose 
Date  
Time 
# of 
capsules 
taken 
Comments (symptoms or side effects noticed, reason for 
missed dose, etc.) 
Initials 
Day 4.  
 
 
 
 
 
Day 5.  
 
 
 
 
 
Day 6.  
 
 
 
 
 
Day 7.  
 
 
 
 
 
Day 8.  
 
 
 
 
 
Day 9.  
 
 
 
 
 
Day 10. 
 
 
 
 
 
Day 11. 
 
 
 
 
 
Day 12. 
 
 
 
 
 
Day 13. 
 
 
 
 
 
Day 14. 
 
 
 
 
 
Day 15. 
 
 
 
 
 
Day 16. 
 
 
 
 
 
Day 17. 
 
 
 
 
 
Day 18. 
 
 
 
 
 
Day 19. 
 
 
 
 
 
Day 20. 
 
 
 
 
 
Day 21. 
 
 
 
 
 
Day 22. 
 
 
 
 
 
Day 23. 
 
 
 
 
 


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Dose 
Date  
Time 
# of 
capsules 
taken 
Comments (symptoms or side effects noticed, reason for 
missed dose, etc.) 
Initials 
Day 24. 
 
 
 
 
 
Day 25. 
 
 
 
 
 
Day 26. 
 
 
 
 
 
Day 27.  
 
 
 
 
Day 28.  
 
 
 
 
 
Participant Signature: __________________________________________ Date: ________________ 
Reviewer Signature: ___________________________________________ Date: _________________ 


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Blood Pressure Diary 
 
Instructions for taking blood pressure reading using the Monitor provided:  
 
• 
Put on cuff and place that arm comfortably on top of the table.  
• 
Sit in a sturdy chair with both feet on ground and apart from each other; do not cross your legs while 
sitting.  
• 
Wait in this position for 5 minutes and relax while taking normal breaths. After 5 minutes press the start 
button on the monitor.  
• 
The monitor reads and records the blood pressure and pulse. Please note the values for blood pressure 
on the pill diary along with the time.  
• 
Enter the value noted beside SYS under the column Systolic and the value noted beside DIA under 
diastolic column in the table below.  
• 
The reading should to be taken in the morning on Day 7, Day 8 and on the day before surgery.  
• 
If the value of the reading is Systolic ≥ 120 or Diastolic ≥ 80 the blood pressure should be repeated after 
5 minutes 
• 
Please notify the study team if the value of the reading is Systolic ≥160 or Diastolic ≥100. 
 
In case you have any questions or concerns, please feel free to call the study team at ______________.  
 
Initial and Date (person explaining the instructions): _______________________________ 
 
Dose Day 
Date 
Time 
Systolic 
Diastolic 
Initials 
Day 7 
 
 
 
 
 
Day 7 (after 5 mins) 
 
 
 
 
 
Day 8 
 
 
 
 
 
Day 8 (after 5 mins) 
 
 
 
 
 
Day before Surgery 
 
 
 
 
 
Day before Surgery 
(after 5 mins) 
 
 
 
 
 
 
Participant Signature: __________________________________________ Date: _________________ 
Reviewer Signature: ___________________________________________ Date: _________________ 
 


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APPENDIX C 
UWI2015-05-01: Pilot Study of 9cUAB30 in Early Stage Breast Cancer to 
Evaluate Biologic Effect 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
TOBACCO ASSESSMENT – BASELINE 
Instructions:  
When a number is requested in the response, please enter a whole number (i.e. “4”) and not a 
range or fraction of a number. 
 
Section A. Basic Cigarette Use Information 
 
1. Have you smoked at least 100 cigarettes (5 packs = 100 cigarettes) in your entire life? 
 
 Yes  
 
 No → Skip to Section B 
 Don’t know/Not sure → Skip to Section B 
 
2. How old were you when you first smoked a cigarette (even one or two puffs)? 
 
_______ Years old 
 
 
3. How old were you when you first began smoking cigarettes regularly?   
 
 
_______ Years old 
 
 
 Check here if you have never smoked cigarettes regularly. 
 
4. How many total years have you smoked (or did you smoke) cigarettes? Do not count any time you 
may have stayed off cigarettes. 
 
 
______ Years (If you smoked less than one year, write “1.”) 
 
 
5. On average when you have smoked, about how many cigarettes do you (or did you) smoke a day? 
(A pack usually has 20 cigarettes in it).  
 
_____ Number of cigarettes per day 
 
6. Do you NOW smoke cigarettes?  
 
 Everyday 
 Some days 
 Not at all → Skip to question 8 
 
7.  How soon after you wake up do you smoke your first cigarette?  
 
 Within 30 minutes 
 After 30 minutes 
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Evaluate Biologic Effect 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
8. How long has it been since you last smoked a cigarette (even one or two puffs)? 
 
First check which one of the following choices applies to you. Then, if applicable, write a number on the 
line for how many days, weeks, months, or years it has been since your last cigarette. 
 
 I smoked a cigarette today (at least one puff) 
 1-7 days → Number of days since last cigarette ________ 
 Less than 1 month → Number of weeks since last cigarette _________ 
 Less than 1 year → Number of months since last cigarette __________ 
 More than 1 year → Number of years since last cigarette ___________ 
 Don’t know/Don’t remember 
 
Section B. Use of Other Forms of Tobacco 
 
9.  Have you ever used other forms of tobacco, not including cigarettes? 
  
 Yes  
 No → Skip to Section C 
 
10. How often do you/did you use other forms of tobacco?  
 
 Every day → Number of times per day ________ 
 Some days → Number of days _______ per 
 Week 
 Month 
 Year 
 
11. Which of the following products have you ever used regularly? 
 Check all that apply  
 
 Cigarettes 
 E-cigarettes or other electronic nicotine delivery system 
 Traditional cigars, cigarillos or filtered cigars 
 Pipes 
 Waterpipe 
 Hookah 
 Clove cigarettes or kreteks 
 Bidis  
 Smokeless tobacco, like dip, chew, or snuff 
 Snus 
 Paan with tobacco, gutka, zarda, khaini 
 Other, Please specify:___________________________ 
 
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Evaluate Biologic Effect 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
12. If you do not currently use other forms of tobacco, but did in the past, how long has it been since 
you last used other forms of tobacco regularly?  
 
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago 
 Don’t know/Not sure 
 Never used other forms of tobacco regularly 
 
Section C. Second-Hand Smoke Exposure 
 
13. Are you currently living with a smoker?   
 
 Yes  
 No  
 
14. In the past 30 days, have you lived in a place where other people smoked cigarettes indoors?  
 
 Yes  
 No  
 
15. In the past 30 days, have you worked in a place where other people smoked cigarettes indoors? 
 
 Yes  
 No  
 
16. Thinking of all your childhood and adult years, have you ever lived in a place where other people 
smoked cigarettes indoors? 
 
 Yes → In total, for about how many years? _______ If less than 1, write “1.”   
 No  
 
 
 
 
 
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PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
17. Thinking of all the years you have worked, have you ever worked in a place where other people 
smoked cigarettes indoors?    
 
 Yes → In total, for about how many years? ______ If less than 1, write “1.”    
 No 
 
This assessment was completed by:  
 Study Team Member    
 Participant 
 
Completed By: _______________________________________________   Date __ __ / __ __ / __ __ __ __ 
                                                          (Signature of person completing)                                         (MM/DD/YYYY) 
Completed By: _______________________________________________ 
                                                          (Printed name of person completing) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Evaluate Biologic Effect 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
TOBACCO ASSESSMENT - FOLLOW-UP 
Instructions:  
When a number is requested in the response, please enter a whole number (i.e. “4”) and not a 
range or fraction of a number.  
1. Do you NOW smoke cigarettes?  
 
 Everyday 
 Some days 
 Not at all → Skip to Question 3. 
 Never smoked → Skip to Question 4 
 
 
2. On average, when you smoked, about how many cigarettes do you (or did you) smoke a day? (A 
pack usually has 20 cigarettes in it).    
 
 
 
_____ Number of cigarettes per day 
 
3. How long has it been since you last smoked a cigarette (even one or two puffs)?    
 
First check which one of the following choices applies to you. Then, if applicable, write a number on the 
line for how many days, weeks, months, or years it has been since your last cigarette. 
 
 I smoked a cigarette today (at least one puff) 
 1-7 days → Number of days since last cigarette ________ 
 Less than 1 month → Number of weeks since last cigarette _________ 
 Less than 1 year → Number of months since last cigarette __________ 
 More than 1 year → Number of years since last cigarette ___________ 
 Don’t know/Don’t remember 
 
4. Since your last visit, have you used other forms of tobacco, not including cigarettes?  
 
 Yes 
 No (End) 
 
5. How often do you/did you use other forms of tobacco?  
 
 Every day → Number of times per day ________ 
 Some days → Number of days _______ per 
 Week 
 Month 
 Year 
 
FUTOBAS Page 1 of 3 
DCP Consortia 2012 Template110/03/2018 


DCP Protocol #:  UWI2015-05-01 
Protocol Version: 20 
01/28/2022 
DCP Protocol Template Version 8.4 
–66– 
10/29/2015 
UWI2015-05-01: Pilot Study of 9cUAB30 in Early Stage Breast Cancer to 
Evaluate Biologic Effect 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
6. Since your last visit, which of the following products have you used?  Check all that apply 
 
 Cigarettes 
 E-cigarettes or other electronic nicotine delivery system 
 Traditional cigars, cigarillos or filtered cigars 
 Pipes 
 Waterpipe 
 Hookah 
 Clove cigarettes or kreteks 
 Bidis  
 Smokeless tobacco, like dip, chew, or snuff 
 Snus 
 Paan with tobacco, gutka, zarda, khaini 
 Other, Specify ______________________________________________________________ 
 
7. If you do not currently use other forms of tobacco, but did in the past, how long has it been since you 
last used other forms of tobacco regularly?  
 
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago 
 Don’t know/Not sure 
 Never used other forms of tobacco regularly 
 
The following instructions pertain to questions 8 - 10.  During each of the following time frames, please 
indicate whether you smoked cigarettes every day, some days, or not at all. 
 
8.  During study treatment 
 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 Not applicable  
FUTOBAS Page 2 of 3 
DCP Consortia 2012 Template 10/03/2018 


DCP Protocol #:  UWI2015-05-01 
Protocol Version: 20 
01/28/2022 
DCP Protocol Template Version 8.4 
–67– 
10/29/2015 
UWI2015-05-01: Pilot Study of 9cUAB30 in Early Stage Breast Cancer to 
Evaluate Biologic Effect 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
9.  After the end of study treatment 
 
 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 Not applicable (I have not completed the study treatment) 
 
10.  Since your last visit to this clinic 
 
 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 
 
This assessment was completed by:  
 Study Team Member    
 Participant 
 
Completed By: _______________________________________________   Date __ __ / __ __ / __ __ __ __ 
                                                          (Signature of person completing)                                                       (MM/DD/YYYY) 
Completed By: _______________________________________________ 
                                                          (Printed name of person completing) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FUTOBAS Page 3 of 3 
DCP Consortia 2012 Template 10/03/2018 
 


DCP Protocol #:  UWI2015-05-01 
Protocol Version: 20 
01/28/2022 
DCP Protocol Template Version 8.4 
–68– 
10/29/2015 
UWI2015-05-01: Pilot Study of 9cUAB30 in Early Stage Breast Cancer to 
Evaluate Biologic Effect 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
ALCOHOL ASSESSMENT – BASELINE 
Instructions: 
For the following questions about drinking alcoholic beverages, a drink means a 12 oz. beer, a 5 
oz. glass of wine, or one and a half ounces of liquor. 
 
When a number is requested in the response, please enter a whole number (i.e. “4”) and not a 
range or fraction of a number.  
 
1. In your entire life, have you had at least 12 drinks of any kind of alcoholic beverage?  
 
 Yes 
 No (End) 
 Refused (End) 
 Don’t know/Not sure 
 
2. In the past 12 months, on average, how often did you drink any type of alcoholic beverage?  
 
 
________ (Enter the number of days you drank based on the timeframe checked below.  Enter 0 
if you never drank and skip to Question 6.) 
  
 Week  
 Month 
 Year 
 Refused 
 Don’t know/Not sure 
 
3. In the past 12 months, on those days that you drank alcoholic beverages, on average, how many 
drinks did you have per day?  
 
 
________ (Enter the average number of drinks per day) 
 
 Refused 
 Don’t know/Not sure 
 
4. In the past 12 months, on how many days did you have 5 or more drinks of any alcoholic beverage?  
 
 
 
_________ (Enter the number of days you had 5 or more drinks, or enter 0 if none.) 
 
 Refused 
 Don’t know/Not sure 
 
ALCAS Page 1 of 3 
DCP Consortia 2012 Template 10/03/2018 


DCP Protocol #:  UWI2015-05-01 
Protocol Version: 20 
01/28/2022 
DCP Protocol Template Version 8.4 
–69– 
10/29/2015 
UWI2015-05-01: Pilot Study of 9cUAB30 in Early Stage Breast Cancer to 
Evaluate Biologic Effect 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
5. Was there ever a time or times in your life when you drank 5 or more drinks of any kind of alcoholic 
beverage almost every day?  
 
 Yes 
 No  
 Refused 
 Don’t know/Not sure 
 
6. If you do not currently drink alcoholic beverages, but did in the past, how long has it been since 
 
you last drank regularly?  
 
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago  
 Don’t know/Not sure 
 Never drank regularly 
 
7. At the heaviest point, either now or in the past, on the days when you drank, about how many drinks 
did you drink a day on the average?  
 
 
 
__________ (Enter the number of drinks a day) 
  
 Refused 
 Don’t know/Not sure 
 
8. How many years have you been drinking (or did drink) regularly?  
 
 
 
______ years 
 
 Refused 
 Don’t know/Not sure  
 
 
 
 
 
ALCAS Page 2 of 3 
DCP Consortia 2012 Template10/03/2018 


DCP Protocol #:  UWI2015-05-01 
Protocol Version: 20 
01/28/2022 
DCP Protocol Template Version 8.4 
–70– 
10/29/2015 
UWI2015-05-01: Pilot Study of 9cUAB30 in Early Stage Breast Cancer to 
Evaluate Biologic Effect 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
9. At what age did you begin drinking regularly?  
 
 
______ years of age 
 
 
 Refused 
 Don’t know/Not sure  
 
10. What type(s) of alcohol do you drink? (Mark ALL that apply) 
 
 Wine 
 Liquor 
 Beer 
 Wine cooler 
 
This assessment was completed by:  
 Study Team Member    
 Participant 
 
Completed By: __________________________________________________   Date __ __ / __ __ / __ __ __ __ 
                                                          (Signature of person completing)                                              (MM/DD/YYYY) 
Completed By: __________________________________________________ 
                                                          (Printed name of person completing) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALCAS Page 3 of 3 
DCP Consortia 2012 Template 10/03/2018 


DCP Protocol #:  UWI2015-05-01 
Protocol Version: 20 
01/28/2022 
DCP Protocol Template Version 8.4 
–71– 
10/29/2015 
UWI2015-05-01: Pilot Study of 9cUAB30 in Early Stage Breast Cancer to 
Evaluate Biologic Effect 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
ALCOHOL ASSESSMENT - FOLLOW-UP 
Instructions:For the following questions about drinking alcoholic beverages, a drink means a   
12 oz. beer, a 5 oz. glass of wine, or one and a half ounces of liquor. 
 
1. During the past 30 days, did you drink any alcoholic beverages?  
 
 Yes 
 No (End) 
 Refused (End) 
 Don’t know/Not sure 
 
2. During the past 30 days, how many days per week or per month did you drink any alcoholic beverages, 
on the average?  
  ________ (Enter number of days you drank based on the timeframe checked below.  Enter 0 if you 
did not drink.)  
 
 Week  
 Month 
 Refused 
 Don’t know/Not sure 
 
3. On the days when you drank, on average, about how many drinks did you have?  
 
________ (Enter the average number of drinks you had per day.) 
 
 Refused 
 Don’t know/Not sure 
 
4. In the past 30 days, on how many days did you have 5 or more drinks per day?  
________ (Enter the number of days you had 5 or more drinks, or enter 0 if none.) 
 
 Refused 
 Do not know/Not sure 
This assessment was completed by:  
 Study Team Member    
 Participant 
 
Completed By: _____________________________________________   Date __ __ / __ __ / __ __ __ __ 
                                                    (Signature of person completing)                                    (MM/DD/YYYY) 
Completed By: _____________________________________________ 
  
 
       
 
                                            (Printed name of person completing) 
 
 
 
 
FUALCAS Page 1 of 1 
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