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

Janssen (J&J Innovative Medicine)

Status and phase: Completed; Phase 1

Conditions: Leukemia, Lymphocytic, Chronic, B-Cell

Treatments: Drug: Ibrutinib; Drug: Bupropion; Drug: Midazolam; Drug: OC: Ethinylestradiol (EE) 30 mcg and Levonorgestrel (LN) 150 mcg

Study type: Interventional

Funder types: Industry

Identifiers

NCT03301207

CR108347

2017-000496-84 (EudraCT Number)

54179060CLL1017 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 25 patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Other

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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25 participants in 1 patient group

Ibrutinib + Oral Contraceptives + Probe Drugs (CYP)

Experimental group

Description:

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).

Treatment:

Drug: Midazolam

Drug: OC: Ethinylestradiol (EE) 30 mcg and Levonorgestrel (LN) 150 mcg

Drug: Bupropion

Drug: Ibrutinib