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A Study to Evaluate the Effect of Ibrutinib on the Pharmacokinetics of Oral Contraceptives, CYP2B6, and CYP3A4 Substrates in Female Participants With B Cell Malignancy

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ClinicalTrials.gov Identifier: NCT03301207
Recruitment Status : Completed
First Posted : October 4, 2017
Last Update Posted : February 4, 2019
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Brief Summary:
The main purpose of this study is to evaluate the effects of repeat dosing of ibrutinib on the single-dose pharmacokinetics (PK) of oral contraceptives (OC - ethinylestradiol [EE] and levonorgestrel [LN]), the cytochrome P450 (CYP)2B6 probe bupropion and the CYP3A4 probe midazolam; and to evaluate the effects of single-dose ibrutinib on the single-dose PK of the CYP3A4 probe midazolam in female participants with B cell malignancy.

Condition or disease Intervention/treatment Phase
Leukemia, Lymphocytic, Chronic, B-Cell Drug: Ibrutinib Drug: OC: Ethinylestradiol (EE) 30 mcg and Levonorgestrel (LN) 150 mcg Drug: Bupropion Drug: Midazolam Phase 1

Detailed Description:
This is a multicenter study of ibrutinib (first-in-class, potent, covalently-binding inhibitor of Bruton's tyrosine kinase [BTK]) in female participants with B cell malignancy. The study consists of 3 phases: Screening Phase (up to 28 days), 7-day Pretreatment Phase (Days 1 to 7), Treatment Phase including PK assessment period (Days 8 to 26) and a Follow-up Phase (Day 27 to end of Cycle 6). The study procedures includes electrocardiogram (ECG), vital signs, blood samples withdrawal to evaluate PK and safety. The Antitumor activity will be assessed by means of computed tomography (CT) imaging and positron emission tomography (PET) scans. No formal statistical hypothesis will be tested. This is an estimation study designed to determine if an increase or decrease in exposure to OC or probe drugs occurs in the presence of ibrutinib.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Drug-Drug Interaction Study to Evaluate the Effect of Ibrutinib on the Pharmacokinetics of Oral Contraceptives, CYP2B6, and CYP3A4 Substrates in Female Subjects With B Cell Malignancy
Actual Study Start Date : October 20, 2017
Actual Primary Completion Date : July 17, 2018
Actual Study Completion Date : October 16, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Ibrutinib

Arm Intervention/treatment
Experimental: Ibrutinib + Oral Contraceptives + Probe Drugs (CYP)
Pre-treatment Phase: Participants will receive a single dose of oral contraceptive (OC) consisting of ethinylestradiol (EE) 30 microgram (mcg) and levonorgestrel (LN) 150 mcg on Study Day 1, and probe drugs (CYP) consisting of bupropion 75 milligram (mg) and midazolam 2 mg on Study Day 3, followed by a washout period from Study Days 4 to 7. Treatment Phase: Participants will receive ibrutinib 560 mg (4*140 mg capsules) once daily (QD) on Days 8 to 26 along with midazolam 2 mg once orally on Study Day 8 (Cycle 1 Day 1), OC once orally on Study Day 22 (Cycle 1 Day 15; EE and LN), and bupropion 75 mg and midazolam 2 mg once orally on Study Day 24 (Cycle 1 Day 17). From Study Day 27 (Cycle 1 Day 20) and onwards participants will continue oral treatment with ibrutinib 420 mg (3*140 mg capsules) or 560 mg QD (depending on the subtype of B-cell malignancy) up to the end of Cycle 6 (each cycle will consist of 28 days).
Drug: Ibrutinib
Ibrutinib capsule (at dose of 420 or 560 mg) will be taken orally QD.
Other Name: Imbruvica

Drug: OC: Ethinylestradiol (EE) 30 mcg and Levonorgestrel (LN) 150 mcg
Single dose of oral contraceptives (OC) (1 tablet containing 30 mcg EE and 150 mcg LN) will be taken orally on Study Days 1 and 22.
Other Name: Microgynon 30

Drug: Bupropion
Bupropion 75 mg tablet as a part of CYP cocktail will be taken on Study Days 3 and 24.

Drug: Midazolam
Midazolam 2 mg (1 milliliter [mL]) oral solution will be taken on Study Days 3 and 24 (as a part of CYP cocktail) and on Study Day 8 (alone).




Primary Outcome Measures :
  1. Maximum Observed Plasma Concentration (Cmax) of Ethinylestradiol (EE) and Levonorgestrel (LN) When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone [ Time Frame: Days 1 and 22: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 hours (h) post-dose ]
    The Cmax is the maximum observed plasma concentration.

  2. Maximum Observed Plasma Concentration (Cmax) of Bupropion and 4-Hydroxybupropion When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone [ Time Frame: Days 3 and 24: predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 34, 48, 58 h post-dose ]
    The Cmax is the maximum observed plasma concentration.

  3. Maximum Observed Plasma Concentration (Cmax) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Repeat Doses of Ibrutinib [ Time Frame: Day 3: predose, 15 minutes (min), and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 24: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 24 h post-dose ]
    The Cmax is the maximum observed plasma concentration.

  4. Maximum Observed Plasma Concentration (Cmax) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Single Dose of Ibrutinib [ Time Frame: Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 8: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 12 h post-dose ]
    The Cmax is the maximum observed plasma concentration.

  5. Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of EE and LN When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone [ Time Frame: Days 1 and 22: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 h post-dose ]
    The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.

  6. Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of Bupropion and 4-Hydroxybupropion When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone [ Time Frame: Days 3 and 24: predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 34, 48, 58 h post-dose ]
    The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.

  7. Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Repeat Doses of Ibrutinib [ Time Frame: Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 24: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 24 h post-dose ]
    The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.

  8. Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Single Dose of Ibrutinib [ Time Frame: Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 8: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 12 h post-dose ]
    The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.

  9. Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of EE and LN When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone [ Time Frame: Days 1 and 22: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 h post-dose ]
    The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.

  10. Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Bupropion and 4-Hydroxybupropion When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone [ Time Frame: Days 3 and 24: predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 34, 48, 58 h post-dose ]
    The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.

  11. Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Repeat Doses of Ibrutinib [ Time Frame: Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 24: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 24 h post-dose ]
    The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.

  12. Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Single Dose of Ibrutinib [ Time Frame: Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 8: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 12 h post-dose ]
    The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.


Secondary Outcome Measures :
  1. Plasma Concentration of Ibrutinib and its Metabolite PCI-45227 [ Time Frame: Predose, 1, 2, 4, and 6 h post-dose on Days 8, 22, and 24 ]
    Plasma concentrations of Ibrutinib and its Metabolite PCI-45227 will be measured.

  2. Number of Participants With Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Screening up to end of the 6 month treatment or 30 days after the last dose of study drug for Participants discontinuing treatment before 6 months ]
    An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.

  3. Number of Participants With Laboratory Abnormalities as a Measure of Safety and Tolerability [ Time Frame: Screening, Days 8 and 36, and End of Treatment (approximately 7 months) ]
    Blood samples for serum chemistry and hematology will be collected at predefined time points for clinical laboratory testing.

  4. Number of Participants With Electrocardiogram (ECG) Abnormalities Findings as a Measure of Safety and Tolerability [ Time Frame: Screening and End of Treatment (approximately 7 months) ]
    Triplicate ECG will be performed at screening and a single time point ECG will be performed at end of treatment visit.

  5. Number of Participants With Vital Sign Abnormalities as a Measure of Safety and Tolerability [ Time Frame: Screening, Days 8 and 36, and End of Treatment (approximately 7 months) ]
    Vital signs includes Temperature, Heart Rate, Respiratory Rate and Blood Pressure.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), or Waldenstrom's macroglobulinemia (WM)

    1. Participants with MCL must have relapsed or refractory disease after at least 1 prior line of systemic therapy
    2. Participants with MZL must have failed an anti-cluster of differentiation (CD)20 monoclonal antibody-based therapy
  • Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
  • Adequate hematologic, hepatic, and renal functions
  • Before the first dose of oral contraceptive (OC), a woman must be either:

    1. Not of childbearing potential: postmenopausal (greater than [>]45 years of age with amenorrhea for at least 12 months and a serum follicle stimulating hormone level >40 international unit per Liter [IU/L] or milli international unit per milli Liter [mIU/mL]); permanently sterilized
    2. Of childbearing potential and practicing a highly effective non-hormonal method of birth control
  • Women of childbearing potential must have a negative serum (Beta-human chorionic gonadotropin [Beta-hCG]) or urine pregnancy test at screening

Exclusion Criteria:

  • Major surgery planned within 2 weeks of the first dose of ibrutinib or during study participation up to Cycle 2 Day 1
  • History of other malignancies, except:

    1. Malignancy treated with curative intent and with no known active disease present for greater than or equal to (>=)3 years before the first dose of ibrutinib and felt to be at low risk for recurrence by treating physician
    2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    3. Adequately treated in-situ cancer without evidence of disease
  • History of breast or endometrial cancer
  • Prior treatment/exposure with ibrutinib or other Bruton's tyrosine kinase (BTK) inhibitor
  • Requires ongoing anticoagulation treatment with warfarin or equivalent vitamin K antagonists (for example, phenprocoumon)
  • Requires therapies that must be discontinued or substituted 7 days prior to Study Day 1, or must be temporally interrupted during the course of the study, including the following:

    1. Medications known to induce or inhibit drug metabolizing enzymes (CYP3A4 and CYP2B6)
    2. Medication which are not allowed to be used in combination with EE, LN, bupropion, or midazolam

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03301207


Locations
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Poland
Pratia MCM Krakow
Krakow, Poland, 30-510
Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu
Wroclaw, Poland, 50-367
Spain
Hosp. Univ. Fund. Jimenez Diaz
Madrid, Spain, 28040
Clinica Univ. de Navarra
Pamplona, Spain, 31008
Sponsors and Collaborators
Janssen Research & Development, LLC
Investigators
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Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC

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Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT03301207     History of Changes
Other Study ID Numbers: CR108347
2017-000496-84 ( EudraCT Number )
54179060CLL1017 ( Other Identifier: Janssen Research & Development, LLC )
First Posted: October 4, 2017    Key Record Dates
Last Update Posted: February 4, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
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Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Midazolam
Bupropion
Contraceptive Agents
Levonorgestrel
Contraceptives, Oral
Ethinyl Estradiol
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action