Pharmacokinetic Study of Oral IXAZOMIB in Cancer Patients With Liver Dysfunction

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1 Pharmacokinetic Study of Oral IXAZOMIB (MLN9708) in Patients With Advanced Solid Tumors or Hematologic Malignancies With Varying Degrees of Liver Dysfunction

Conditions
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Advanced Solid Tumors, Hematologic Malignancies

Intervention / Treatment
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* Drug: IXAZOMIB


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IXAZOMIB Arm 1<br>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 | Drug: IXAZOMIB<br> <br> |
| Experimental: IXAZOMIB Arm 2<br>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 | Drug: IXAZOMIB<br> <br> |
| Experimental: IXAZOMIB Arm 3<br>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 | Drug: IXAZOMIB<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | 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. | 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]) | 
| Number of Participants Reporting Clinically Significant Change From Baseline in Laboratory Values | The number of participants with any markedly abnormal standard safety laboratory values collected throughout study. | Baseline up to Day 15 for each treatment cycle (28 days treatment cycle for up to a maximum of 12 cycles) | 
| Number of Participants Reporting Clinically Significant Change From Baseline in Vital Signs | 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). | Baseline up to Day 15 for each treatment cycle (28 days treatment cycle for up to a maximum of 12 cycles) |