Clinical trial NCT03301207: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Leukemia, Lymphocytic, Chronic, B-Cell
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2017-10-04
Enrollment: 25
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.

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.

Eligibility 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

Primary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of Ethinylestradiol (EE) and Levonorgestrel (LN) When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone
timeFrame: Days 1 and 22: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 hours (h) post-dose
measure: Maximum Observed Plasma Concentration (Cmax) of Bupropion and 4-Hydroxybupropion When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone
timeFrame: Days 3 and 24: predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 34, 48, 58 h post-dose
measure: Maximum Observed Plasma Concentration (Cmax) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Repeat Doses of Ibrutinib
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Single Dose of Ibrutinib
timeFrame: 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
measure: 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
timeFrame: Days 1 and 22: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 h post-dose
measure: 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
timeFrame: Days 3 and 24: predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 34, 48, 58 h post-dose
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: 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
timeFrame: Days 1 and 22: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 h post-dose
measure: 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
timeFrame: Days 3 and 24: predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 34, 48, 58 h post-dose
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
Secondary outcomes:
measure: Plasma Concentration of Ibrutinib and its Metabolite PCI-45227
timeFrame: Predose, 1, 2, 4, and 6 h post-dose on Days 8, 22, and 24
measure: Number of Participants With Adverse Events as a Measure of Safety and Tolerability
timeFrame: 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
measure: Number of Participants With Laboratory Abnormalities as a Measure of Safety and Tolerability
timeFrame: Screening, Days 8 and 36, and End of Treatment (approximately 7 months)
measure: Number of Participants With Electrocardiogram (ECG) Abnormalities Findings as a Measure of Safety and Tolerability
timeFrame: Screening and End of Treatment (approximately 7 months)
measure: Number of Participants With Vital Sign Abnormalities as a Measure of Safety and Tolerability
timeFrame: Screening, Days 8 and 36, and End of Treatment (approximately 7 months)
Other outcomes:
Locations:
city: Krakow
country: Poland
facility: Pratia MCM Krakow
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu
city: Madrid
country: Spain
facility: Hosp. Univ. Fund. Jimenez Diaz
city: Pamplona
country: Spain
facility: Clinica Univ. de Navarra
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: de Jong J, Mitselos A, Jurczak W, Cordoba R, Panizo C, Wrobel T, Dlugosz-Danecka M, Jiao J, Sukbuntherng J, Ouellet D, Hellemans P. Ibrutinib does not have clinically relevant interactions with oral contraceptives or substrates of CYP3A and CYP2B6. Pharmacol Res Perspect. 2020 Oct;8(5):e00649. doi: 10.1002/prp2.649.