Retinoid 9cUAB30 in Preventing Cancer in Healthy Volunteers

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01935960
First received: September 3, 2013
Last updated: September 16, 2014
Last verified: September 2014
  Purpose

This randomized phase I trial studies the side effects and best dose of retinoid 9cUAB30 in preventing cancer in healthy volunteers. The use of retinoid 9cUAB30 may keep cancer from forming in healthy volunteers.


Condition Intervention Phase
Healthy, no Evidence of Disease
Drug: retinoid 9cUAB30
Other: placebo
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
Official Title: A Randomized, Double-Blind, Phase I Dose-Escalation Study of the Novel Retinoid 9cUAB30

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Recommended phase II dose of retinoid 9cUAB30, based on maximum tolerated dose (MTD), defined as the highest dose level with < 25% of treated patients experiencing a grade 2 toxicity or any treated patients experiencing a grade 3 or higher toxicity [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
    Graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

  • Urine & plasma single dose & steady state PK of retinoid 9cUAB30, including maximum concentration (Cmax), time to peak concentration (Tmax), area under curve (AUC)0-least quantifiable concentration (lqc), AUC0-infinity, half-life (T½), and clearance (CL) [ Time Frame: Baseline; 30, 45, 60, and 90 minutes; 2, 4, 6, 8, 12, 16, 20, and 24 hours on day 1; and 8, 15, 22, 29, 36, and 43 days ] [ Designated as safety issue: No ]
    Basic pharmacokinetic and summary pharmacokinetic measures from the extensive plasma sampling on days 1 and 36, and levels obtained from single plasma and urine samples taken on days 8, 15, 22, and 29 will be summarized with basic statistics, including means, standard errors, medians, and interquartile ranges by dose, visit, and time point, as available.


Secondary Outcome Measures:
  • Incidence of toxicity, graded according to the CTCAE version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
    Patient toxicity will be summarized by the presence or absence of any toxicities, worst CTCAE grade, and strongest investigator defined relationship will all be examined and characterized by dose. Correlations between the different PK measures of retinoid 9cUAB30 and the different measures of toxicity will be estimated with polyserial correlation. To compare toxicities at each dose level to placebo, the Chi-square test will be used for the presence or absence of toxicities, and Wilcoxon rank-sum tests will be used for CTCAE grade and investigator defined relationship data.

  • Change in single dose pharmacokinetics,, including Cmax, Tmax, AUC0-lqc, AUC0-infinity, T1/2, and CL [ Time Frame: Day 1 to day 36 ] [ Designated as safety issue: No ]
    The pharmacokinetics of retinoid 9cUAB30 will be compared between day 1 and day 36 using one-sample t-tests, or Wilcoxon signed-rank tests as appropriate in order to evaluate the single vs. steady state levels. An appropriate regression model will be used to explore the relationship of dose with change in PK: logarithmic transformations will be used as necessary.

  • Level of retinoid 9cUA30 in skin biopsies [ Time Frame: Up to day 36 ] [ Designated as safety issue: No ]
    Will be summarized with descriptive statistics such as mean and standard deviation, and comparison of 9cUAB30 levels among placebo and the dose level cohorts will be made using analysis of variance.

  • Levels of blood and skin biomarkers, such as PCNA, apoptosis indices, differentiation markers, COX-2, ornithine decarboxylase, and matric metalloproteinases 2 and 9 [ Time Frame: Up to day 36 ] [ Designated as safety issue: No ]
    Will be compared among treatment groups and between in sun-exposed and non-sun-exposed skin (on upper arm) using ordinal regression models.


Enrollment: 40
Study Start Date: August 2013
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (retinoid 9cUAB30)
Participants receive retinoid 9cUAB30 PO QD on days 1 and 8-36. Treatment continues in the absence of unacceptable toxicity.
Drug: retinoid 9cUAB30
Given PO
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Placebo Comparator: Arm II (placebo)
Participants receive a placebo PO QD on days 1 and 8-36.
Other: placebo
Given PO
Other Name: PLCB
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the toxicities and recommended phase II dose of 9cUAB30 (retinoid 9cUAB30).

II. To characterize the urine and plasma single dose and steady state pharmacokinetics of 9cUAB30 in normal volunteers.

SECONDARY OBJECTIVES:

I. To correlate the pharmacokinetics of 9cUAB30 with toxicity. II. To compare observed toxicity between placebo controls and each dose level. III. To assess for any change in single dose pharmacokinetics (PK) after repeat dosing (day 1 vs. day 36).

IV. To assess the following potential biomarkers of UAB30: telomerase activity (measurement of telemetric repeats in peripheral blood mononuclear cells [PBMCs]); gene expression of deoxyribonucleic acid (DNA) methyltransferase in PBMCs; gene expression of cytochrome P450, family 2, subfamily B, polypeptide 6 (CYP2B6) in PBMCs.

V. To perform exploratory analysis of the following biomarkers in skin, in a subset of willing participants from University of Wisconsin (UWI) and University of Alabama at Birmingham (UAB): terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labeling (Tunel) assay; B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2 (Bcl2); proliferating cell nuclear antigen (PCNA); tumor protein p53 (p53); ornithine decarboxylase (ODC); cyclooxygenase-2 (cox-2); matrix metalloproteinase 2/matrix metalloproteinase 9; keratin 1/keratin 10; 9cUAB30 skin concentrations.

OUTLINE: This is a dose-escalation study. Participants are randomized to 1 of 2 treatment arms.

ARM I: Participants receive retinoid 9cUAB30 orally (PO) once daily (QD) on days 1 and 8-36. Treatment continues in the absence of unacceptable toxicity.

ARM II: Participants receive a placebo PO QD on days 1 and 8-36.

After completion of study treatment, patients are followed up at 7 and 30 days.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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 retinoids
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01935960

Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
United States, Iowa
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States, 52242
University of Iowa
Iowa City, Iowa, United States, 52242
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
Investigators
Principal Investigator: Howard Bailey University of Wisconsin Hospital and Clinics
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01935960     History of Changes
Obsolete Identifiers: NCT01999127
Other Study ID Numbers: NCI-2013-01655, NCI-2013-01655, UWI10-16-01R, UW13022, UWI10-16-01R, N01CN35153, P30CA014520
Study First Received: September 3, 2013
Last Updated: September 16, 2014
Health Authority: United States: Food and Drug Administration

ClinicalTrials.gov processed this record on October 19, 2014