Leukemia, Lymphocytic, Chronic, B-Cell
Conditions
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.
Interventions
DRUGIbrutinib
Ibrutinib capsule (at dose of 420 or 560 mg) will be taken orally QD.
DRUGOC: 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.
DRUGBupropion
Bupropion 75 mg tablet as a part of CYP cocktail will be taken on Study Days 3 and 24.
DRUGMidazolam
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).
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. |
| 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 | 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'. |
| 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 | 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'. |
| 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 | 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. |
| 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 | 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. |
| 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 | 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. |
| Maximum Observed Plasma Concentration (Cmax) of Ethinylestradiol (EE) and Levonorgestrel (LN) When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone | 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. |
| Maximum Observed Plasma Concentration (Cmax) of Bupropion and 4-Hydroxybupropion When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone | 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. |
| Maximum Observed Plasma Concentration (Cmax) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Repeat Doses of Ibrutinib | 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. |
| Maximum Observed Plasma Concentration (Cmax) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Single Dose of Ibrutinib | 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. |
| 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 | 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'. |
| 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 | 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'. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentration of Ibrutinib and its Metabolite PCI-45227 | 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. |
| Number of Participants With Laboratory Abnormalities as a Measure of Safety and Tolerability | 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. |
| Number of Participants With Electrocardiogram (ECG) Abnormalities Findings as a Measure of Safety and Tolerability | 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. |
| Number of Participants With Vital Sign Abnormalities as a Measure of Safety and Tolerability | Screening, Days 8 and 36, and End of Treatment (approximately 7 months) | Vital signs includes Temperature, Heart Rate, Respiratory Rate and Blood Pressure. |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 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. |
Countries
Poland, Spain
Outcome results
None listed