Mass Balance, Pharmacokinetics and Metabolism Study of IXAZOMIB

Study Overview
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Brief Summary
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This is a phase 1, 2-part, open-label study in 4 to 6 pharmacokinetic-evaluable participants with advanced solid tumors or lymphoma.

Official Title
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A Phase 1 Study of [ 14 C]-Ixazomib to Assess Mass Balance, Pharmacokinetics, and Metabolism in Patients With Advanced Solid Tumors or Lymphoma

Conditions
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Advanced Solid Tumors, Lymphoma

Intervention / Treatment
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* Drug: IXAZOMIB


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each participant must meet all of the following inclusion criteria to be enrolled in the study: 18 years or older Histologic or cytologic diagnosis of advanced or metastatic solid tumor or lymphoma for which no standard, curative, or life-prolonging therapies exist or are effective Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 Female participants 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 participants 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 Recovered from the reversible effects of prior anticancer therapy Exclusion Criteria: Participants meeting any of the following exclusion criteria are not to be enrolled in the study: Female participants who are lactating or breastfeeding or have a positive serum pregnancy test Serious medical or psychiatric illness that could interfere with the study Treatment with any investigational products or radiotherapy within 21 days before the first dose of study drug Peripheral neuropathy greater than (>) Grade 2 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 Symptomatic brain metastasis. Participants 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 adverse events (AEs) Ongoing treatment with corticosteroids 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 Known hepatitis B surface antigen -positive, or known or suspected active hepatitis C infection or human immunodeficiency virus (HIV) positive Diagnosed or treated for another malignancy within 2 years before the first dose, OR previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection Any cardiovascular condition specified in the study protocol Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of IXAZOMIB History of urinary and/or fecal incontinence Inability to comply with study procedures or visit schedule including the requirement for inpatient confinement

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IXAZOMIB<br>Part A: Participants will receive a single dose of 4.1-milligram (mg) [14C]-IXAZOMIB oral solution containing approximately 500-nCurie (nCi) of total radioactivity on Day 1 and remain at the clinic for 8 days. On Days 14 and 21, participants may be administered a single 4.0-mg capsule of IXAZOMIB. Participants will return to the clinic in the evening before Days 14, 21, 28, and 35 for a 24-hour overnight clinic visit. Part B: Eligible participants from Part A may continue into Part B once they have completed their Day 35 assessments in Part A. Participants may receive IXAZOMIB capsules administered orally at a dose of 4.0-mg once weekly on Days 1, 8, and 15 of 28-day cycles. Participants will continue in this study until disease progression or unacceptable toxicity. | Drug: IXAZOMIB<br>* Part A: Ixazomib 4.1 mg containing approximately 500-nCi [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21. Part B: Ixazomib 4 mg, capsule, orally, once weekly, on Days 1, 8 and 15 in 28-day cycles until disease progression or unacceptable toxicity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Cmax: Maximum Observed Plasma Concentration for Ixazomib | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of ixazomib, obtained directly from the plasma concentration-time curve. | Day 1 of Part A pre-dose and at multiple timepoints (up to Day 14) post-dose | 
| Part A: Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Ixazomib | Time to reach the maximum observed plasma concentration (Cmax), equal to time (hours) to Cmax of ixazomib after administration, obtained directly from the plasma concentration-time curve. | Day 1 of Part A pre-dose and at multiple timepoints (up to Day 14) post-dose | 
| Part A: AUC(0-312): Area Under the Plasma Concentration-time Curve From Time 0 to 312 Hrs Post-dose for Ixazomib | AUC(0-312) is a measure of the area under the plasma concentration time-curve from time zero to 312 hrs post-dose for ixazomib. | Day 1 of Part A pre-dose and at multiple timepoints (up to 312 hrs) post-dose | 
| Part A: Cmax: Maximum Observed Plasma Concentration of TRA | Maximum observed plasma concentration (Cmax) of TRA is the peak plasma concentration of TRA, obtained directly from the plasma TRA concentration-time curve. | Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose | 
| Part A: Tmax: Time to Reach the Cmax for TRA | Time to reach the maximum observed plasma concentration (Cmax) for TRA, equal to time (hours) to Cmax for TRA after administration, obtained directly from the plasma TRA concentration-time curve. | Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose | 
| Part A: AUC(0-816): Area Under the Plasma Concentration-time Curve From Time 0 to 816 Hrs Post-dose for TRA | AUC(0-816) is a measure of the area under the plasma concentration time-curve from time zero to 816 hrs post-dose for TRA. | Day 1 of Part A pre-dose and at multiple timepoints (up to 816 hrs) post-dose | 
| Part A: Cmax: Maximum Observed Whole Blood Concentration of TRA | Maximum observed whole blood concentration (Cmax) of a TRA is the peak whole blood concentration of TRA, obtained directly from the whole blood TRA concentration-time curve. | Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose | 
| Part A: Tmax: Time to Reach the Maximum Observed Whole Blood Concentration (Cmax) for TRA | Time to reach the maximum observed whole blood concentration (Cmax) for TRA, equal to time (hours) to Cmax for TRA after administration, obtained directly from the whole blood TRA concentration-time curve. | Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose | 
| Part A: AUC(0-816): Area Under the Whole Blood Concentration-time Curve From Time 0 to 816 Hrs Post-dose for TRA | AUC(0-816) is a measure of the area under the whole blood concentration time-curve from time zero to 816 hrs post-dose for TRA. | Day 1 of Part A pre-dose and at multiple timepoints (up to 816 hrs) post-dose | 
| Part A: Cumulative Percentage of Ixazomib Dose Recovered in the Urine | Percentage of the ixazomib dose excreted unchanged in the urine from 0 to 168 hrs post-dose. | Day 1 of Part A from 0 to pre-dose and at multiple timepoints (up to 168 hrs) post-dose | 
| Part A: Cumulative Percentage of the Total Radioactivity Dose Excreted in Feces | Percentage of the TRA dose excreted in feces from Day 1 to Day 35 of Part A | Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose | 
| Part A: Cumulative Percentage of the Total Radioactivity Dose Excreted in Urine | Percentage of the TRA dose excreted in urine from Day 1 to Day 35 of Part A. | Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose | 
| Part A: Renal Clearance of Ixazomib | Renal clearance is the volume of plasma from which ixazomib is completely removed by the kidney in a given amount of time, calculated as the amount of ixazomib excreted in the urine divided by the area under the plasma ixazomib concentration-time curve. | Day 1 pre-dose and at multiple timepoints (up to Day 14) post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ixazomib and Metabolites as Percent of Total Radioactivity in Plasma | The plasma samples were pooled for participants over 816 hrs post-dose, and data was analysed using the Hamilton method time-proportional pooling, and therefore the data is reported as percent of total radioactivity in plasma with measure type as number and measure dispersion as Not applicable, NA. | Day 1 pre-dose and at multiple time points (up to 816 hrs) post-dose | 
| Ixazomib and Metabolites as Percent of Total Dose Administered in Urine | The 35-day post-dose data is extrapolated from the average of four participant data from 0-168-hr pooled urine. The data is therefore reported as percentage of dose with measure type as number and measure dispersion as NA. | Day 1 pre-dose and at multiple time points (up to Day 35) post-dose | 
| Ixazomib and Metabolites as Percent of Total Dose Administered in Feces | The 35-day post-dose data is extrapolated from the average of four participant data from 0-168-hr pooled feces. The data is therefore reported as percentage of dose with measure type as number and measure dispersion as NA. | Day 1 pre-dose and at multiple time points (up to Day 35) post-dose | 
| Number of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | Baseline up to Cycle 5 Day 45 | 
| Number of Participants With TEAEs Related to Investigations System Organ Class for Laboratory Values |  | Baseline up to Cycle 5 Day 45 | 
| Number of Participants With TEAEs Related to Vital Signs | Vital signs included oral body temperature, heart rate, and blood pressure. | Baseline up to Cycle 5 Day 25 |