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Mass Balance, Pharmacokinetics and Metabolism Study of IXAZOMIB

Primary Purpose

Advanced Solid Tumors, Lymphoma

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

IXAZOMIB

About this trial

This is an interventional treatment trial for Advanced Solid Tumors

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

IXAZOMIB

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

Secondary Outcome Measures

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".

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".

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".

Number of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Number of Participants With TEAEs Related to Investigations System Organ Class for Laboratory Values

Number of Participants With TEAEs Related to Vital Signs

Vital signs included oral body temperature, heart rate, and blood pressure.

Full Information

NCT ID

NCT01953783

First Posted

September 26, 2013

Last Updated

August 25, 2020

Sponsor

Millennium Pharmaceuticals, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT01953783

Brief Title

Mass Balance, Pharmacokinetics and Metabolism Study of IXAZOMIB

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2020

Overall Recruitment Status

Completed

Study Start Date

March 19, 2014 (Actual)

Primary Completion Date

December 17, 2014 (Actual)

Study Completion Date

February 9, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Millennium Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Advanced Solid Tumors, Lymphoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

7 (Actual)

8. Arms, Groups, and Interventions

Arm Title

IXAZOMIB

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

IXAZOMIB

Intervention Description

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.

Primary Outcome Measure Information:

Title

Part A: Cmax: Maximum Observed Plasma Concentration for Ixazomib

Description

Maximum observed plasma concentration (Cmax) is the peak plasma concentration of ixazomib, obtained directly from the plasma concentration-time curve.

Time Frame

Day 1 of Part A pre-dose and at multiple timepoints (up to Day 14) post-dose

Title

Part A: Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Ixazomib

Description

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.

Time Frame

Day 1 of Part A pre-dose and at multiple timepoints (up to Day 14) post-dose

Title

Part A: AUC(0-312): Area Under the Plasma Concentration-time Curve From Time 0 to 312 Hrs Post-dose for Ixazomib

Description

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.

Time Frame

Day 1 of Part A pre-dose and at multiple timepoints (up to 312 hrs) post-dose

Title

Part A: Cmax: Maximum Observed Plasma Concentration of TRA

Description

Maximum observed plasma concentration (Cmax) of TRA is the peak plasma concentration of TRA, obtained directly from the plasma TRA concentration-time curve.

Time Frame

Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose

Title

Part A: Tmax: Time to Reach the Cmax for TRA

Description

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.

Time Frame

Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose

Title

Part A: AUC(0-816): Area Under the Plasma Concentration-time Curve From Time 0 to 816 Hrs Post-dose for TRA

Description

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.

Time Frame

Day 1 of Part A pre-dose and at multiple timepoints (up to 816 hrs) post-dose

Title

Part A: Cmax: Maximum Observed Whole Blood Concentration of TRA

Description

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.

Time Frame

Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose

Title

Part A: Tmax: Time to Reach the Maximum Observed Whole Blood Concentration (Cmax) for TRA

Description

Time Frame

Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose

Title

Part A: AUC(0-816): Area Under the Whole Blood Concentration-time Curve From Time 0 to 816 Hrs Post-dose for TRA

Description

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.

Time Frame

Day 1 of Part A pre-dose and at multiple timepoints (up to 816 hrs) post-dose

Title

Part A: Cumulative Percentage of Ixazomib Dose Recovered in the Urine

Description

Percentage of the ixazomib dose excreted unchanged in the urine from 0 to 168 hrs post-dose.

Time Frame

Day 1 of Part A from 0 to pre-dose and at multiple timepoints (up to 168 hrs) post-dose

Title

Part A: Cumulative Percentage of the Total Radioactivity Dose Excreted in Feces

Description

Percentage of the TRA dose excreted in feces from Day 1 to Day 35 of Part A

Time Frame

Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose

Title

Part A: Cumulative Percentage of the Total Radioactivity Dose Excreted in Urine

Description

Percentage of the TRA dose excreted in urine from Day 1 to Day 35 of Part A.

Time Frame

Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose

Title

Part A: Renal Clearance of Ixazomib

Description

Time Frame

Day 1 pre-dose and at multiple timepoints (up to Day 14) post-dose

Secondary Outcome Measure Information:

Title

Ixazomib and Metabolites as Percent of Total Radioactivity in Plasma

Description

Time Frame

Day 1 pre-dose and at multiple time points (up to 816 hrs) post-dose

Title

Ixazomib and Metabolites as Percent of Total Dose Administered in Urine

Description

Time Frame

Day 1 pre-dose and at multiple time points (up to Day 35) post-dose

Title

Ixazomib and Metabolites as Percent of Total Dose Administered in Feces

Description

Time Frame

Day 1 pre-dose and at multiple time points (up to Day 35) post-dose

Title

Number of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Time Frame

Baseline up to Cycle 5 Day 45

Title

Number of Participants With TEAEs Related to Investigations System Organ Class for Laboratory Values

Time Frame

Baseline up to Cycle 5 Day 45

Title

Number of Participants With TEAEs Related to Vital Signs

Description

Vital signs included oral body temperature, heart rate, and blood pressure.

Time Frame

Baseline up to Cycle 5 Day 25

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Monitor

Organizational Affiliation

Millennium Pharmaceuticals, Inc.

Official's Role

Study Director

Facility Information:

City

Cleveland

State/Province

Ohio

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

28932928

Citation

Gupta N, Zhang S, Pusalkar S, Plesescu M, Chowdhury S, Hanley MJ, Wang B, Xia C, Zhang X, Venkatakrishnan K, Shepard DR. A phase I study to assess the mass balance, excretion, and pharmacokinetics of [14C]-ixazomib, an oral proteasome inhibitor, in patients with advanced solid tumors. Invest New Drugs. 2018 Jun;36(3):407-415. doi: 10.1007/s10637-017-0509-1. Epub 2017 Sep 21.

Results Reference

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Mass Balance, Pharmacokinetics and Metabolism Study of IXAZOMIB

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