Trial of Indole-3-Carbinol and Silibinin

NCT03687073 | Completed Phase 1 FDA Drug

• 1 other identifier: 2017LS075
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

This is a non-therapeutic, Phase 1 clinical trial to examine the safety, pharmacokinetic (PK) characteristics, and pharmacodynamics (PD) effect of indole-3-carbinol (I3C) and silibinin (Sil) in healthy subjects.

Conditions

Smoking

Outcome Measures

Primary Outcomes (8)

• Safety of the combination of I3C + Sil

  Incidence of Dose Limiting Toxicities (DLTs)

  Week 8

• Pharmacokinetic profile of I3C + Sil

  AUC

  Week 8

• Pharmacokinetic profile of I3C + Sil

  Cmax

  Week 8

• Pharmacokinetic profile of I3C + Sil

  Half-life

  Week 8

• Pharmacokinetic profile of I3C + Sil

  Elimination rate

  Week 8

• Pharmacokinetic profile of I3C + Sil

  Plasma clearance

  Week 8

• Pharmacokinetic profile of I3C + Sil

  Renal clearance

  Week 8

• Pharmacokinetic profile of I3C + Sil

  Accumulation

  Week 8

Secondary Outcomes (13)

• Effect of I3C, Sil, or I3C + Sil on circulating inflammatory markers

  Week 8

• Effect of I3C, Sil, or I3C + Sil on circulating immunophenotype

  Week 8

• Effect of I3C, Sil, or I3C + Sil on protein expression of phosphorylated-Akt (pAkt), pERK, pSTAT3 and NF-kB from peripheral blood mononuclear cells (PBMC)

  Week 8

• Effect of I3C, Sil, or I3C + Sil on RNA sequencing from PBMC

  Week 8

• Effect of I3C, Sil, or I3C + Sil on PIK3CA pathway signaling in buccal cells

  Week 8

Study Arms (4)

Single-dose PK study

EXPERIMENTAL

Subjects will take the assigned dose of I3C, Sil, or I3C + Sil once at the study center. Ten mL of blood will be collected at the time points described in Section 9.14. Concurrently, urine will also be collected for 24 hours after the first dose of I3C, Sil or I3C + Sil, divided into the time intervals.

Drug: Indole-3-Carbinol; Drug: Silibinin; Drug: Silibin

Multi-dose PK Study

EXPERIMENTAL

Subjects will take the assigned dose of I3C, Sil, or I3C + Sil for 8 weeks. Ten mL of blood will be collected at the time points described in Section 9.14. Concurrently, urine will be collected for 24 hours after the first dose of I3C, Sil or I3C + Sil, divided into the time intervals.

Drug: Indole-3-Carbinol; Drug: Silibinin; Drug: Silibin

Safety Study

EXPERIMENTAL

Safety data will be generated during the multi-dose PK and PD study, as DLT is not anticipated in the single-dose PK study. Enrollment into dose cohorts 1 and 2 can occur on a continuous basis. Enrollment for dose cohorts 3 and 4 will be done sequentially using a modified 3+3 design (see Section 8.2). The first three subjects enrolled into a dose cohort must complete at least 21 days of the multi-dose PK/PD study without a DLT before the remaining 4 subjects in the cohort can be enrolled.

Drug: Indole-3-Carbinol; Drug: Silibinin; Drug: Silibin

Cohort 4 PD Study

EXPERIMENTAL

The effect of I3C, Sil, or I3C + Sil on the pharmacodynamic endpoints listed under the Secondary Objectives in Section 1.2 will be characterized. This PD study will be done concurrently with the multi-dose PK study. Subjects will take the assigned dose of I3C, Sil, or I3C + Sil for 8 weeks. Nasal epithelium, oral cavity cells, buccal cells, blood, and urine will be collected at the time points described in the study calendar in Section 4.0.

Drug: Indole-3-Carbinol; Drug: Silibinin; Drug: Silibin

Interventions

Indole-3-Carbinol DRUG

Cohorts 2, 3, \& 4: 400 mg PO BID

Also known as: 13C

Cohort 4 PD Study; Multi-dose PK Study; Safety Study; Single-dose PK study

Silibinin DRUG

Cohorts 1 \& 4: 720mg

Also known as: Sil

Cohort 4 PD Study; Multi-dose PK Study; Safety Study; Single-dose PK study

Silibin DRUG

Cohort 3: 360mg

Also known as: Sil

Cohort 4 PD Study; Multi-dose PK Study; Safety Study; Single-dose PK study

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult ≥ 18 years old
• Current smoker of ≥ 8 cigarettes per day for at least the last 6 months by self-report
• Adequate blood counts, and adequate liver and kidney function defined as follows:
• Hemoglobin ≥ 9 g/dL for women, ≥ 10 g/dL for men
• Platelet count ≥ 100 x 10\^9/L
• Total bilirubin ≤ Institutional upper limit of normal (≤ 1.3 mg/dL for UMMC)
• ALT ≤ 1.5 times institutional upper limit of normal
• Creatinine ≤ 1.4 g/dL and estimated GFR ≥ 80 mL/min/1.7m2
• Able to understand the experimental nature of the study and provide informed written consent

You may not qualify if:

• Chronic proton pump inhibitor, H2-blocker (i.e., ranitidine, famotidine), and/or calcium carbonate use
• History of gastric bypass surgery, gastric banding, bowel resection, malabsorption syndromes such as celiac sprue or pancreatic insufficiency, or other conditions that may affect gastric or intestinal absorption of nutrients
• Current use of tobacco products other than cigarettes (i.e. snuff, snuz, smokeless tobacco, cigars, pipes), or use of these products within 3 months of study registration
• Major or chronic medical disease, including heart disease, poorly controlled diabetes, etc., to be adjudicated by the principal investigator
• Known active malignancy
• History of aerodigestive malignancies
• Women who are pregnant, intend to become pregnant within 3 months of study registration, or who are lactating. Women of childbearing potential must have a negative urine pregnancy test within 14 days of starting the assigned intervention
• Antibiotic use within 2 months of study registration by self-report
• History of respiratory tract cancer
• Known allergy to I3C, Sil, or its components
• Psychiatric and/or social situations that would potentially limit compliance with study requirements

Sponsors & Collaborators

• Masonic Cancer Center, University of Minnesota: lead

Study Sites (1)

Masonic Cancer Center at University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

MeSH Terms

Conditions

Smoking

Interventions

indole-3-carbinol; Silybin; gp100 Melanoma Antigen

Condition Hierarchy (Ancestors)

Behavior

Intervention Hierarchy (Ancestors)

Silymarin; Flavonolignans; Flavonoids; Chromones; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Membrane Proteins; Proteins; Amino Acids, Peptides, and Proteins; Melanoma-Specific Antigens; Neoplasm Proteins; Antigens, Neoplasm; Antigens; Biological Factors

Study Officials

• Naomi Fujioka, MD

  Division of Hematology, Oncology and Transplantation, University of Minnesota

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 14, 2018
• First Posted: September 27, 2018
• Study Start: November 29, 2018
• Primary Completion: May 7, 2021
• Study Completion: May 7, 2021
• Last Updated: August 11, 2021

Record last verified: 2021-08

Locations

US (1)