The following datasets contain the data available for EPPT UWI10-16-01R. The description and documentation for each file is listed below. SAS7bdat and CSV versions of the actual data will be available to CDAS projects approved to use this study's data.

Analysis Datasets

Raw Datasets

These 17 datasets contain the raw form data received, excluding PII.

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Trial Summary

This randomized phase I double blinded trial is a series of dose escalation studies that observe the frequency and severity of adverse events caused by escalating dose levels of the drug 9cUAB30 in healthy volunteers. The use of 9cUAB30 is suspected to prevent the growth of cancer. The protocol looks to find the recommended phase II dose of 9cUAB30, based on the maximum tolerated dose (the highest dose level with minimal adverse events) and pharmacokinetic measures from plasma and urine sampling. The study began with the UWI09-8-02 (c2003) protocol, which monitored the use of 20mg and 40mg of 9cUAB30. After a lack of unacceptable toxicity in participants, a second study was conducted (UWI10-16-01R (c2003)) which observed 9cUAB30 in amounts of 40mg, 80mg, and 160mg. After a lack of unacceptable toxicity was observed again, a third and final study (UWI10-16-01R (c2012)) was conducted which monitored participants taking 240mg of 9cUAB30.

The UWI10-16-01R (06/29/2015) trial contains randomized protocols with various treatment levels:

1. UWI09-8-02 (c2003)
   • Placebo (2 capsules once daily)
   • 9cUAB30 (2 x 10mg capsules (20mg) once daily)
   • 9cUAB30 (2 x 20mg capsules (40mg) once daily)
2. UWI10-16-01R (c2003)
   • Placebo (8 capsules once daily)
   • 9cUAB30 (8 x 5mg capsules (40mg) once daily)
   • 9cUAB30 (8 x 10mg capsules (80mg) once daily)
   • 9cUAB30 (8 x 20mg capsules (160mg) once daily)
3. UWI10-16-01R (c2012)
   • Placebo (12 capsules once daily)
   • 9cUAB30 (12 x 20mg capsules (240mg) once daily)

Target Enrollment: 33

Statistical Considerations:

The primary objective is to determine the recommended phase II dose of 9cUAB30. For our purposes, the maximally tolerated dose is defined as the highest dose level with < 25% (2 of 8) of treated participants experiencing a grade 3 toxicity that is possibly, probably or definitely related to study drug. The recommended phase II dose will be based on the MTD. The co-primary objective was to characterize the urine and plasma single dose and steady state pharmacokinetics of 9cUAB30 in normal volunteers. Eligible participants were to be randomized in groups of 10, with 8 participants receiving the appropriate dose level of drug and 2 participants receiving placebo, in a double-blind fashion for 28 days. If there was no dose-limiting toxicity and the difference between the AUCs on Day 1 and Day 36 is within tolerance limits, dose was to be escalated and the group with the subsequent drug dose treated. The groups received the following escalating doses: 20 mg, 40 mg, 80 mg, 160 mg, and 240mg.

The secondary objectives are to correlate the pharmacokinetics of 9cUAB30 with toxicity, to compare toxicity between placebo and controls at each dose level, and to assess changes in single dose pharmacokinetics from Day 1 to Day 36.

Enrollment Statistics

Total Enrollment: 54 Participants(35 Female, 19 Male)

• 46 participants completed study
• 7 participants did not complete study
  • 1 particpant ineligible continue
  • 2 due to adverse events
  • 4 due to "other" reasons

Protocol 1: UWI09-8-02 (C2003) - 19 Participants (10 Female, 9 Male)

• Placebo: 5 Participants
  • 4 participants completed study
  • 1 particpants did not complete study due to "other" reasons
• 9cUAB30 20 mg: 8 Participants
  • 8 participants completed study
• 9cUAB30 40 mg: 6 Participants
  • 5 participants completed study
  • 1 participant did not complete study due to "other" reasons

Protocol 2: UWI10-16-01R (C2003) - 24 Participants (17 Female, 8 Male)

• Placebo: 4 Participants
  • 4 participants completed study
• 9cUAB30 40 mg: 3 Participants
  • 3 participants completed study
• 9cUAB30 80 mg: 8 Participants
  • 8 participants completed study
• 9cUAB30 160 mg: 6 Participants
  • 5 participants completed study
  • 2 participants did not complete study
    • 1 ineligible to continue
    • 1 due to an adverse event

Protocol 3: UWI10-16-01R (C2012) - 10 Participants (8 Female, 2 Male)

• Placebo: 2 Participants
  • 1 participants completed study
  • 1 participant did not complete study due to concomitant medication usage
• 9cUAB30 240 mg: 8 Participants
  • 6 participants completed study
  • 2 participants did not complete study
    • 1 due to an adverse event
    • 1 due to inability to complete visit 6
• 9cUAB30 80 mg: 8 Participants
  • 8 participants completed study
• 9cUAB30 160 mg: 6 Participants
  • 5 participants completed study
  • 2 participants did not complete study
    • 1 ineligible to continue
    • 1 due to an adverse event

Total Study Population Demographics: (53 Randomized and Eligible People)

• Sex:
  • Female: 34 (64%)
  • Male: 19 (36%)
• Race:
  • White: 46(87%)
  • Black or African American: 7(13%)
• Age (years):
  • Mean: 42.8
  • Standard Deviation: ±14
• Weight (kg):
  • Mean: 83.7
  • Standard Deviation: ±18
• BMI (kg/m2):
  • Mean: 28.9
  • Standard Deviation: ±6.4
• Blood Pressure (mmHg):
  • Systolic:
    • Mean: 121
    • Standard Deviation: ±13
  • Diastolic:
    • Mean: 74.7
    • Standard Deviation: ±8.7

Final Analysis Population: 53

Eligibility Criteria

Inclusion Criteria

• Normal volunteers, either male or female
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 or Karnofsky >= 70%
• White blood cell (WBC) >= 3000/mm^3
• Platelets >= 100,000/mm^3
• Hemoglobin > 10 g/dL
• Bilirubin =< upper limit of institutional normal
• Aspartate aminotransferase (AST) =< upper limit of institutional normal
• Creatinine within institutional normal limits
• Sodium, potassium, chloride, bicarbonate: all =< upper limit of institutional normal
• Fasting triglycerides =< 1.5 x upper limit of normal (ULN)
• Fasting cholesterol =< 1.5 x ULN
• Participants must agree to discontinue all vitamin supplements while taking study medication and for thirty days past the last dose of study medication
• Heterosexual women and men must agree to use TWO effective forms of birth control for the duration of study participation and for 30 days following the last dose of study medication
  • Men must agree not to donate sperm during the study and for three months after receiving the last dose of study drug
  • The following persons are not considered to be able to father or bear children and therefore are eligible to participate without the use of concurrent birth control:
    • Female with bilateral oophorectomy and/or hysterectomy
    • Female with fallopian tubes cut, tied, or sealed
    • Female with sterilization implant (e.g. Adiana, Essure) placed > 3 months prior to randomization
    • Female post-menopausal (> 1 year since last menses)
    • Male with vasectomy > 3 months prior to randomization
  • One of the following methods of birth control must be used by women of childbearing potential:
    • Combined oral contraceptive pill in continuous use for > 30 days prior to study entry
    • Vaginal ring (e.g. NuvaRing) in continuous use for > 30 days prior to study entry
    • Skin patch (e.g. Ortho Evra) in continuous use for > 30 days prior to study entry
    • Injection (e.g. Depo-Provera, Noristerat) in continuous use for > 30 days prior to study entry
    • Copper intrauterine device (IUD) (e.g. ParaGard)
  • Note: The following hormonal methods are NOT acceptable:
    • Low dose progesterone only oral contraceptive pill ("mini pills" e.g. Micronor, Nor-Q.D., Ovrette)
    • Norplant subdermal implant
    • Mirena Hormonal Implanted Uterine Device (IUD)
  • In addition to the above method of contraception, one of the following methods of contraception will ALSO be used for the duration of study participation and for 30 days following the last dose of study medication:
    • Diaphragm, cervical cap, or cervical shield with spermicide
    • Contraceptive sponge (e.g. Today Sponge)
    • Condom (male or female type) plus spermicide
• Females of child-bearing potential must have a negative pregnancy test within the current menstrual cycle and within 7 days before starting drug
• Participants must have the ability to understand, and the willingness to sign, a written informed consent document

Exclusion Criteria

• Participants may not be taking medications that might interact with 9cUAB30
• Participants may not be taking lipid lowering agents
• Participants may not receive any other investigational agents within 30 days of enrollment nor during study participation
• Participants with a history of allergic reactions attributed to compounds of similar chemical or biologic composition of 9cUAB30s
• Participants with an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Breastfeeding must be discontinued for the duration of study participation and for one month after the last dose of the study agent if the mother is treated with 9cUAB30
• Individuals known to be human immunodeficiency virus (HIV)-positive may not participate in this study
• Individuals with a history of cancer diagnosis or reoccurrence < 5 years from study entry may not participate; however, individuals with a history of squamous or basal cell carcinoma of the skin < 5 years from study entry will not be excluded from this study

The Schema is a timeline of the study. It indicates start/end points, visits expected, major testing to be done, and any other information that is crucial to understanding how the study was completed.

Study Schema

Results/Findings:

This phase I dose escalation study of the novel retinoid 9cUAB30 determined 160mg per day as the recommend phase 2 dose based on concentrations well over those required for RXR activation in preclinical models and tolerability. Preliminary data suggest both a favorable toxicity profile as seen in the preclinical testing in animals and our prior pilot study with oral availability and linear pharmacokinetics.