Effect of P-glycoprotein Inhibition on Lenalidomide Pharmacokinetics in Healthy Males

This study has been completed.
Sponsor:
Collaborator:
Covance
Information provided by (Responsible Party):
Celgene Corporation
ClinicalTrials.gov Identifier:
NCT01712828
First received: October 22, 2012
Last updated: February 12, 2013
Last verified: January 2013
  Purpose

To find out if the blood level of lenalidomide can be changed when a drug that prevents p-glycoprotein (a protein naturally present in the body that helps carry substances across cell membranes that is found in many parts of the body like the intestines, liver, and kidneys) from working (called a P-gp inhibitor) when taken together with lenalidomide. The study is also trying to find out if blood level of temsirolimus can be changed when a subject takes lenalidomide together with temsirolimus.


Condition Intervention Phase
Healthy
Drug: Lenalidomide
Drug: Quinidine
Drug: Temsirolimus
Drug: Diphenhydramine
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Official Title: A Phase 1, Open-Label, Two-Part, Fixed-Sequence Crossover Study to Evaluate the Effect of P-glycoprotein Inhibition on Lenalidomide Pharmacokinetics in Healthy Male Subjects

Resource links provided by NLM:


Further study details as provided by Celgene Corporation:

Primary Outcome Measures:
  • Lenalidomide PK-AUC (0-24) [ Time Frame: Up to 21 days ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from time zero to 24 hours post dose

  • Lenalidomide PK-(Cmax) [ Time Frame: Up to 21 days (including washout phase) ] [ Designated as safety issue: No ]
    Maximum observed plasma concentration

  • Lenalidomide PK-(Tmax) [ Time Frame: Up to 21 days ] [ Designated as safety issue: No ]
    Time to maximum observed plasma concentration

  • Lenalidomide PK-AUC(0-t) [ Time Frame: Up to 21 days ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from time zero to time t, where t is the last measurable time point

  • Lenalidomide PK-AUC(0-∞) [ Time Frame: Up to 21 days ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from time zero extrapolated to infinity

  • Lenalidomide PK-(T1/2) [ Time Frame: Up to 21 days ] [ Designated as safety issue: No ]
    Estimate of the terminal elimination half-life in plasma

  • Temsirolimus and Sirolimus PK-AUC (0-24) [ Time Frame: Up to 38 days ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from time zero to 24 hours post dose

  • Temsirolimus and Sirolimus PK-(Cmax) [ Time Frame: Up to 38 days ] [ Designated as safety issue: No ]
    Maximum observed plasma concentration

  • Temsirolimus and Sirolimus PK-(Tmax) [ Time Frame: Up to 38 days ] [ Designated as safety issue: No ]
    Time to maximum observed plasma concentration

  • Temsirolimus and Sirolimus PK-(AUC 0-t) [ Time Frame: Up to 38 days ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from time zero to time t, where t is the last measurable time point


Secondary Outcome Measures:
  • Number of participants with adverse events [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: Yes ]
    Safety monitoring will be done by regular adverse event assessment, concomitant medication, clinical laboratory tests, physical exams, ECGs, and vital signs.


Enrollment: 31
Study Start Date: October 2012
Study Completion Date: January 2013
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lenalidomide plus Quinidine Drug: Lenalidomide
25 mg Lenalidomide capsule will be administered orally once in the first period, and once with Quinidine in the second period
Drug: Quinidine
300 mg of Quinidine will be administered orally every 12 hours for 1 day followed by 600 mg of Quinidine administered orally every 12 hours for the next 4 consecutive days
Experimental: Lenalidomide plusTemsirolimus and Diphenhydramine Drug: Lenalidomide
25 mg Lenalidomide capsule will be administered orally once in the first period, and once with Quinidine in the second period
Drug: Temsirolimus
25 mg/mL injection of Temsirolimus will be given directly into the vein over 30 minutes once in the second period and once with Lenalidomide in the third period.
Drug: Diphenhydramine
Just before Temsirolimus is given, 25 mg of Diphenhydramine (Benadryl) will be given directly into the vein to decrease chances of an allergic reaction to Temsirolimus.
Other Name: Benadryl

Detailed Description:

This will be a single-center, open label, 2-part study. Part 1 will be a two-period, fixed-sequence crossover study with lenalidomide alone in Period 1, followed by lenalidomide in combination with quinidine in Period 2. Part 2 will be a fixed-sequence, three-period, crossover study with lenalidomide alone in Period 1, temsirolimus (via direct intravenous infusion) in Period 2, and lenalidomide in combination with temsirolimus (via direct intravenous infusion) in Period 3. Diphenhydramine (given via intravenous injection) will be administered shortly before temsirolimus in order to decrease the chances of an allergic reaction to temsirolimus. Part 1 and Part 2 will be conducted at the same time. Subjects can only participate in either Part 1 or Part 2.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Must understand and voluntarily sign a written informed consent form prior to any study-related procedures being performed.
  • Must be able to communicate with the investigator, understand and comply with the requirements of the study, and agree to adhere to restrictions and examination schedules.
  • Healthy male volunteer of any race between 18 to 65 years of age (inclusive), and in good health as determined by a physical exam.
  • Agree to use barrier contraception (i.e., condoms not made of natural (animal) membrane [e.g., latex or polyurethane condoms are acceptable]) when engaging in sexual activity with a female of child-bearing potential while on study drug, and for at least 90 days after the last dose of study drug.
  • Must have a body mass index between 18 and 33 kg/m2 (inclusive).
  • Clinical laboratory tests must be within normal limits or acceptable to the principal investigator.
  • Must have confirmation of normal renal function (defined as an estimate glomerular filtration rate >90 mL/min).
  • Must be afebrile, with supine systolic blood pressure: 90 to 140 mmHg, supine diastolic blood pressure: 60 to 90 mmHg, and pulse rate: 40 to 110 bpm.
  • Must have a normal or clinically acceptable 12-lead electrocardiogram, with a QTcF (Fridericia's correction formula) value ≤ 430 msec.
  • Must refrain from sperm donations for the entire duration of the study, and for at least 90 days after the last dose of study drug.

Exclusion Criteria:

  • History of any clinically significant and relevant neurological, gastrointestinal, renal, hepatic, cardiovascular, psychological, pulmonary, metabolic, endocrine, hematological, allergic disease, drug allergies, known hypersensitivity to a member of the class of immunomodulatory drugs (IMiDs®), temosirolimus, sirolimus, polysorbate 80, diphenhydramine, or to any other component (or excipients) of Torisel®, or other major disorders.
  • Any condition which places the subject at unacceptable risk if he were to participate in the study, or confounds the ability to interpret data from the study.
  • Used any prescribed systemic or topical medication within 30 days of the first dose administration, unless Sponsor agreement is obtained.
  • Used any non-prescribed systemic or topical medication (including vitamin/mineral supplements, and herbal medicines) within 14 days of the first dose administration, unless Sponsor agreement is obtained.
  • Used any prescribed, or non-prescribed, systemic or topical medication that is a CYP3A inhibitor or inducer within 30 days of first dose administration. (refer to (http://medicine.iupui.edu/clinpharm/ddis/p450_Table_Oct_11_2009.pdf)
  • Has any surgical or medical conditions (excluding appendectomy) possibly affecting drug absorption, distribution, metabolism and excretion, e.g., bariatric procedure.
  • Donated blood or plasma within 8 weeks before the first dose administration to a blood bank or blood donation center.
  • History of drug abuse (as defined by the current version of the Diagnostic and Statistical Manual within 2 years before dosing, or positive drug screening test reflecting consumption of illicit drugs.
  • History of alcohol abuse (as defined by the current version of the Diagnostic and Statistical Manual) within 2 years before dosing, or positive alcohol screen.
  • Known to have serum hepatitis or known to be a carrier of the hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCVAb), or have a positive result to the test for HIV antibodies at Screening.
  • Exposed to an investigational drug (new chemical entity) within 30 days preceding the first dose administration, or 5 half-lives of that investigational drug, if known (whichever is longer).
  • For Part 2 only: has total bilirubin ≥ 1.5x upper limit of normal
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01712828

Locations
United States, Texas
Covance Clinical Research Unit Dallas
Dallas, Texas, United States, 75247
Sponsors and Collaborators
Celgene Corporation
Covance
Investigators
Study Director: Edward O'Mara, MD Celgene Corporation
  More Information

Additional Information:
No publications provided

Responsible Party: Celgene Corporation
ClinicalTrials.gov Identifier: NCT01712828     History of Changes
Other Study ID Numbers: CC-5013-CP-011
Study First Received: October 22, 2012
Last Updated: February 12, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Celgene Corporation:
Lenalidomide,
Revlimid,
pharmacokinetics,
healthy male subjects

Additional relevant MeSH terms:
Diphenhydramine
Promethazine
Quinidine
Krestin
Sirolimus
Everolimus
Thalidomide
Quinidine gluconate
Lenalidomide
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Gastrointestinal Agents
Histamine H1 Antagonists
Histamine Antagonists
Histamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Hypnotics and Sedatives
Central Nervous System Depressants
Anti-Allergic Agents
Anesthetics, Local
Anesthetics
Sensory System Agents
Antipruritics
Dermatologic Agents

ClinicalTrials.gov processed this record on April 14, 2014