Pharmacokinetic Study of Oral IXAZOMIB in Cancer Patients With Liver Dysfunction

Phase 1

Completed

• Conditions: Hematologic Malignancies; Advanced Solid Tumors
• Interventions: Drug: IXAZOMIB

• Registration Number: NCT01912222
• Lead Sponsor: Millennium Pharmaceuticals, Inc.

Brief Summary

This is a phase 1, 2-part, pharmacokinetic study in patients with advanced solid tumors or hematologic malignancies and varying degrees of liver dysfunction (normal function, moderate hepatic impairement or severe hepatic impairment) as defined by the National Cancer Institute (NCI) Organ Dysfunction Working Group.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2013-07-26
• Study First Submitted QC: 2013-07-26
• Study First Posted: 2013-07-31
• Study Start: 2013-08
• Primary Completion: 2015-03
• Study Completion: 2015-03
• Status Verified: 2016-02
• Results First Submitted: 2016-02-24
• Results First Submitted QC: 2016-02-24
• Results First Posted: 2016-03-25
• Last Update Submitted: 2016-05-03
• Last Update Posted: 2016-06-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 48

Inclusion Criteria

• 18 years or older
• Patients must have a diagnosis of an advanced malignant solid tumor or hematologic malignancy for which standard, curative, or life-prolonging treatment does not exist or is no longer effective
• Total bilirubin and aspartate aminotransferase (AST) levels consistent with normal hepatic function (total bilirubin and AST ≤ the upper limit of normal), moderate hepatic impairment (total bilirubin > 1.5 to 3x the upper limit of normal with any AST level) or severe hepatic impairment (total bilirubin > 3x the upper limit of normal with any AST level)
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
• Female patients who are postmenopausal for at least 1 year OR are surgically sterile OR if of childbearing potential, agree to practice 2 effective methods of contraception at the same time during the entire study through 90 days after the last dose of study drug OR agree to practice true abstinence
• Male patients who agree to practice effective barrier contraception during the entire study and through 90 days after the last dose of study drug OR agree to practice true abstinence
• Voluntary written consent
• Suitable venous access for the conduct of blood sampling
• Appropriate clinical laboratory values as specified in the protocol

Exclusion Criteria

• Systemic treatment with strong and moderate inhibitors of CYP1A2, strong and moderate inhibitors of CYP3A, or clinically significant CYP3A inducers or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of study drug
• Use of any nicotine-containing products within 14 days before the first dose of study drug
• Central Nervous System Involvement or Symptomatic brain metastasis. Patients with brain metastases: must have stable neurologic status following local therapy (surgery or radiation) for at least 2 weeks after completion of the definitive therapy; and must be without neurologic dysfunction that would confound the evaluation of neurologic and other AEs
• Female patients who are lactating or breastfeeding or have a positive serum pregnancy test
• Serious medical or psychiatric illness that could interfere with participation in the study
• Treatment with any investigational products or radiotherapy within 21 days before the first dose of study drug
• Systemic anticancer therapy within 14 days before the first dose of study drug
• Exposure to nitrosoureas or mitomycin C within 6 weeks before the first dose of study drug
• Treatment with therapeutic monoclonal antibodies or antibody-drug conjugates within 60 days before the first dose of study drug
• Radiotherapy or major surgery within the 14 days preceding the first dose of study drug
• Infection requiring systemic intravenous antibiotic therapy or other serious infection within 14 days before the first dose of study drug
• Life-threatening illness unrelated to cancer
• Severe CNS, pulmonary, or renal disease not related to the patient's cancer
• Known human immunodeficiency virus (HIV) positive
• Evidence of uncontrolled cardiovascular conditions
• QTc > 500 milliseconds (msec) on a 12-lead ECG obtained during the Screening period
• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of IXAZOMIB
• Known allergy to the study medication, its analogues, or excipients in the formulation

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
IXAZOMIB Arm 2	IXAZOMIB	Experimental: Arm 2 (Moderate hepatic impairment) In the 15 day period that constitutes Part A of the trial, patients will receive a single oral 2.3 mg dose of IXAZOMIB capsule on Day 1. Patients from Part A will then have the option of continuing the study by participating in Part B, starting immediately after Part A, where they will receive IXAZOMIB on Days 1, 8, and 15 of a 28-day cycle
IXAZOMIB Arm 1	IXAZOMIB	Experimental: Arm 1 (Normal hepatic function) In the 15 day period that constitutes Part A of the trial, patients will receive a single oral 4 mg dose of IXAZOMIB capsule on Day 1. Patients from Part A will then have the option of continuing the study by participating in Part B, starting immediately after Part A, where they will receive IXAZOMIB on Days 1, 8, and 15 of a 28-day cycle
IXAZOMIB Arm 3	IXAZOMIB	Experimental: Arm 3 (Severe hepatic impairment) In the 15 day period that constitutes Part A of the trial, patients will receive a single oral 1.5 mg dose of IXAZOMIB capsule on Day 1. Patients from Part A will then have the option of continuing the study by participating in Part B, starting immediately after Part A, where they will receive IXAZOMIB on Days 1, 8, and 15 of a 28-day cycle

Primary Outcome Measures

Name	Time	Method
Tmax- Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib	Part A, Day 1: Pre-dose and at multiple timepoints (up to 336 hours) post-dose
Unbound Cmax: Unbound Maximum Observed Plasma Concentration for Ixazomib	Part A, Day 1: Pre-dose and at multiple timepoints (up to 336 hours) post-dose
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) and Serious Adverse Events (SAE)	Baseline up to 30 days after last dose of study drug (Day 45 for each treatment cycle for up to a maximum of 12 cycles [28 days treatment cycles])	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Number of Participants Reporting Clinically Significant Change From Baseline in Vital Signs	Baseline up to Day 15 for each treatment cycle (28 days treatment cycle for up to a maximum of 12 cycles)	Vital signs included body temperature (oral or tympanic measurement), sitting blood pressure (after the participant has rested for at least 5 minutes), and pulse (bpm).
Unbound AUC(0-last): Unbound Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib	Part A, Day 1: Pre-dose and at multiple timepoints (up to 336 hours) post-dose
Number of Participants Reporting Clinically Significant Change From Baseline in Laboratory Values	Baseline up to Day 15 for each treatment cycle (28 days treatment cycle for up to a maximum of 12 cycles)	The number of participants with any markedly abnormal standard safety laboratory values collected throughout study.