Mass Balance, Pharmacokinetics and Metabolism Study of IXAZOMIB

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01953783
• Collaborator: (none)
• Enrollment: 7
• Location: 1
• Arm: 1
• Actual Duration (Months): 22.7
• Patients Per Site Per Month: 0.3

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Advanced Solid Tumors; Lymphoma	Drug: IXAZOMIB	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Mar 19, 2014
• Actual Primary Completion Date: Dec 17, 2014
• Actual Study Completion Date: Feb 9, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: IXAZOMIB 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; 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.

Outcome Measures

Primary Outcome Measures

1. Part A: Cmax: Maximum Observed Plasma Concentration for Ixazomib [Day 1 of Part A pre-dose and at multiple timepoints (up to Day 14) post-dose]

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

2. Part A: Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Ixazomib [Day 1 of Part A pre-dose and at multiple timepoints (up to Day 14) post-dose]

   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.

3. Part A: AUC(0-312): Area Under the Plasma Concentration-time Curve From Time 0 to 312 Hrs Post-dose for Ixazomib [Day 1 of Part A pre-dose and at multiple timepoints (up to 312 hrs) post-dose]

   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.

4. Part A: Cmax: Maximum Observed Plasma Concentration of TRA [Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose]

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

5. Part A: Tmax: Time to Reach the Cmax for TRA [Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose]

   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.

6. Part A: AUC(0-816): Area Under the Plasma Concentration-time Curve From Time 0 to 816 Hrs Post-dose for TRA [Day 1 of Part A pre-dose and at multiple timepoints (up to 816 hrs) post-dose]

   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.

7. Part A: Cmax: Maximum Observed Whole Blood Concentration of TRA [Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose]

   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.

8. Part A: Tmax: Time to Reach the Maximum Observed Whole Blood Concentration (Cmax) for TRA [Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose]

   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.

9. Part A: AUC(0-816): Area Under the Whole Blood Concentration-time Curve From Time 0 to 816 Hrs Post-dose for TRA [Day 1 of Part A pre-dose and at multiple timepoints (up to 816 hrs) post-dose]

   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.

10. Part A: Cumulative Percentage of Ixazomib Dose Recovered in the Urine [Day 1 of Part A from 0 to pre-dose and at multiple timepoints (up to 168 hrs) post-dose]

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

11. Part A: Cumulative Percentage of the Total Radioactivity Dose Excreted in Feces [Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose]

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

12. Part A: Cumulative Percentage of the Total Radioactivity Dose Excreted in Urine [Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose]

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

13. Part A: Renal Clearance of Ixazomib [Day 1 pre-dose and at multiple timepoints (up to Day 14) post-dose]

    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

1. Ixazomib and Metabolites as Percent of Total Radioactivity in Plasma [Day 1 pre-dose and at multiple time points (up to 816 hrs) post-dose]

   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".

2. Ixazomib and Metabolites as Percent of Total Dose Administered in Urine [Day 1 pre-dose and at multiple time points (up to Day 35) post-dose]

   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".

3. Ixazomib and Metabolites as Percent of Total Dose Administered in Feces [Day 1 pre-dose and at multiple time points (up to Day 35) post-dose]

   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".

4. Number of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Baseline up to Cycle 5 Day 45]

5. Number of Participants With TEAEs Related to Investigations System Organ Class for Laboratory Values [Baseline up to Cycle 5 Day 45]

6. Number of Participants With TEAEs Related to Vital Signs [Baseline up to Cycle 5 Day 25]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Cleveland	Ohio	United States

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Monitor, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01953783
• Other Study ID Numbers: C16016
• First Posted: Oct 1, 2013
• Last Update Posted: Aug 26, 2020
• Last Verified: Aug 1, 2020

• Additional relevant MeSH terms: Lymphoma; Ixazomib

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 1 investigative site in the United States from 19 March 2014 to 09 February 2016.
Pre-assignment Detail	Participants with a historical diagnosis of advanced solid tumors or lymphoma were enrolled in 1 treatment group of this 2-part study to receive ixazomib.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Period Title: Overall Study
STARTED	7
COMPLETED	5
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Overall Participants	7
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.6 (9.95)
Sex: Female, Male (Count of Participants)
Female	5 71.4%
Male	2 28.6%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	1 14.3%
Not Hispanic or Latino	6 85.7%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	1 14.3%
White	5 71.4%
Unknown or Not Reported	1 14.3%
Region of Enrollment (Count of Participants)
United States	7 100%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	164.4 (8.64)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	82.16 (16.772)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic(PK)-evaluable population included all participants who received protocol-specified single[14C]-ixazomib dose(Part A), did not receive any excluded concomitant medications till completion(Part A), had sufficient concentration-time and total radioactivity(TRA)-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	5
Geometric Mean (Standard Deviation) [nanogram per milliliter (ng/mL)]	89.06 (67.834)

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who received the protocol-specified single [14C]-ixazomib dose in Part A, did not receive any excluded concomitant medications through the completion of Part A, and had sufficient concentration-time and TRA-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	5
Median (Full Range) [hour (hr)]	0.5000 (0.044721)

3. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who received the protocol-specified single [14C]-ixazomib dose in Part A, did not receive any excluded concomitant medications through the completion of Part A, and had sufficient concentration-time and TRA-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	5
Geometric Mean (Standard Deviation) [nanogram*hour per milliliter (ng*hr/mL)]	1181 (600.53)

4. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who received the protocol-specified single [14C]-ixazomib dose in Part A, did not receive any excluded concomitant medications through the completion of Part A, and had sufficient concentration-time and TRA-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	5
Geometric Mean (Standard Deviation) [nanogram-equivalent per milliliter]	78.80 (48.814)

5. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who received the protocol-specified single [14C]-ixazomib dose in Part A, did not receive any excluded concomitant medications through the completion of Part A, and had sufficient concentration-time and TRA-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	5
Median (Full Range) [hr]	0.5000 (1.5547)

6. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who received the protocol-specified single [14C]-ixazomib dose in Part A, did not receive any excluded concomitant medications through the completion of Part A, and had sufficient concentration-time and TRA-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	5
Geometric Mean (Standard Deviation) [nanogram-equivalent*hour per milliliter]	2981 (1898.7)

7. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who received the protocol-specified single [14C]-ixazomib dose in Part A, did not receive any excluded concomitant medications through the completion of Part A, and had sufficient concentration-time and TRA-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	5
Geometric Mean (Standard Deviation) [nanogram-equivalent per milliliter]	181.6 (75.580)

8. Primary Outcome

Title	Part A: Tmax: Time to Reach the Maximum Observed Whole Blood Concentration (Cmax) for TRA
Description	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.
Time Frame	Day 1 of Part A pre-dose and at multiple timepoints (up to Day 35) post-dose

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who received the protocol-specified single [14C]-ixazomib dose in Part A, did not receive any excluded concomitant medications through the completion of Part A, and had sufficient concentration-time and TRA-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	5
Median (Full Range) [hr]	0.6000 (0.80436)

9. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who received the protocol-specified single [14C]-ixazomib dose in Part A, did not receive any excluded concomitant medications through the completion of Part A, and had sufficient concentration-time and TRA-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	5
Geometric Mean (Standard Deviation) [nanogram-equivalent* hour per milliliter]	29200 (4712.2)

10. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who received the protocol-specified single [14C]-ixazomib dose in Part A, did not receive any excluded concomitant medications through the completion of Part A, and had sufficient concentration-time and TRA-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	5
Mean (Standard Deviation) [percentage of dose]	3.226 (2.1274)

11. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who received the protocol-specified single [14C]-ixazomib dose in Part A, did not receive any excluded concomitant medications through the completion of Part A, and had sufficient concentration-time and TRA-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	5
Mean (Standard Deviation) [percentage of dose]	21.80 (3.4147)

12. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who received the protocol-specified single [14C]-ixazomib dose in Part A, did not receive any excluded concomitant medications through the completion of Part A, and had sufficient concentration-time and TRA-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	5
Mean (Standard Deviation) [percentage of dose]	62.06 (21.170)

13. Primary Outcome

Title	Part A: Renal Clearance of Ixazomib
Description	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.
Time Frame	Day 1 pre-dose and at multiple timepoints (up to Day 14) post-dose

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who received the protocol-specified single [14C]-ixazomib dose in Part A, did not receive any excluded concomitant medications through the completion of Part A, and had sufficient concentration-time and TRA-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	5
Geometric Mean (Standard Deviation) [liter per hour (L/hr)]	0.1191 (0.068763)

14. Secondary Outcome

Title	Ixazomib and Metabolites as Percent of Total Radioactivity in Plasma
Description	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".
Time Frame	Day 1 pre-dose and at multiple time points (up to 816 hrs) post-dose

Outcome Measure Data

Analysis Population Description

PK-evaluable population with acceptable excretion recovery included all participants who received protocol-specified single[14C]-ixazomib dose(Part A), did not receive any excluded concomitant medications till completion(Part A), and had sufficient concentration-time and TRA-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	4
P4, ixazomib	54.2
P2, ML00701258	7.91
P3, ML00701201	18.9
P6, ML00749506	10.6
P7, ML00752034	3.20

15. Secondary Outcome

Title	Ixazomib and Metabolites as Percent of Total Dose Administered in Urine
Description	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".
Time Frame	Day 1 pre-dose and at multiple time points (up to Day 35) post-dose

Outcome Measure Data

Analysis Population Description

PK-evaluable population with acceptable excretion recovery included all participants who received protocol-specified single[14C]-ixazomib dose(Part A), did not receive any excluded concomitant medications till completion(Part A), and had sufficient concentration-time and TRA-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	4
U9, ixazomib	1.30
U1	0.391
U2	0.926
U3	1.61
U4	1.33
U5, ML00701258	2.72
U6, ML00701201	30.2
U7	2.75
U8	0.695
U10, ML00751996	5.93
U11, ML00749506	1.28
U12, ML00752034	0.069
U13	0.974

16. Secondary Outcome

Title	Ixazomib and Metabolites as Percent of Total Dose Administered in Feces
Description	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".
Time Frame	Day 1 pre-dose and at multiple time points (up to Day 35) post-dose

Outcome Measure Data

Analysis Population Description

PK-evaluable population with acceptable excretion recovery included all participants who received protocol-specified single[14C]-ixazomib dose(Part A), did not receive any excluded concomitant medications till completion(Part A), and had sufficient concentration-time and TRA-time data to permit reliable estimation of PK parameters and mass balance.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	4
FH6, ixazomib	13.8
FH1	0.900
FH2	0.111
FH3, ML00701258	0.620
FH4, ML00701201	0.901
FH5	1.14
FH7, ML00752034	1.58
FH8	0.502
FH9	0.112

17. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least 1 dose of ixazomib.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	7
TEAEs	7 100%
SAEs	1 14.3%

18. Secondary Outcome

Title	Number of Participants With TEAEs Related to Investigations System Organ Class for Laboratory Values
Time Frame	Baseline up to Cycle 5 Day 45

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least 1 dose of ixazomib.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	7
Blood bilirubin increased	1 (9.90) 14.3%
Platelet count decreased	1 (25.53) 14.3%
Lymphocyte count decreased	1 (117.64) 14.3%

19. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least 1 dose of ixazomib.

Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
Measure Participants	7
Number [participants]	0 0%

Adverse Events

Time Frame	Treatment-emergent adverse events are adverse events that started after the first dose of study drug and no more than 30 days after the last dose of study drug (Cycle 5 Day 45).
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Ixazomib
Arm/Group Description	Ixazomib 4.1 milligram (mg) containing approximately 500-nCurie (nCi) of total radioactivity [14C]-ixazomib, solution, orally on Day 1 and ixazomib 4 mg, capsule, orally on Days 14 and 21 in Part A. Participants who had completed their Day 35 assessments in Part A were eligible to continue in 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 in Part B.
All Cause Mortality
	Ixazomib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ixazomib
	Affected / at Risk (%)	# Events
Total	1/7 (14.3%)
Infections and infestations
Influenza	1/7 (14.3%)
Other (Not Including Serious) Adverse Events
	Ixazomib
	Affected / at Risk (%)	# Events
Total	7/7 (100%)
Gastrointestinal disorders
Diarrhoea	5/7 (71.4%)
Abdominal pain upper	2/7 (28.6%)
Constipation	2/7 (28.6%)
Nausea	2/7 (28.6%)
Vomiting	2/7 (28.6%)
Abdominal pain	1/7 (14.3%)
Dry mouth	1/7 (14.3%)
General disorders
Catheter site erythema	1/7 (14.3%)
Fatigue	1/7 (14.3%)
Gait disturbance	1/7 (14.3%)
Influenza like illness	1/7 (14.3%)
Malaise	1/7 (14.3%)
Medical device complication	1/7 (14.3%)
Immune system disorders
Drug hypersensitivity	1/7 (14.3%)
Infections and infestations
Urinary tract infection	1/7 (14.3%)
Viral infection	1/7 (14.3%)
Investigations
Blood bilirubin increased	1/7 (14.3%)
Lymphocyte count decreased	1/7 (14.3%)
Platelet count decreased	1/7 (14.3%)
Weight decreased	1/7 (14.3%)
Metabolism and nutrition disorders
Decreased appetite	3/7 (42.9%)
Hyperuricaemia	1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Back pain	2/7 (28.6%)
Muscle spasms	1/7 (14.3%)
Neck pain	1/7 (14.3%)
Pain in extremity	1/7 (14.3%)
Nervous system disorders
Headache	3/7 (42.9%)
Dizziness	2/7 (28.6%)
Dysgeusia	1/7 (14.3%)
Peripheral sensory neuropathy	1/7 (14.3%)
Renal and urinary disorders
Bladder spasm	1/7 (14.3%)
Respiratory, thoracic and mediastinal disorders
Cough	2/7 (28.6%)
Dyspnoea	1/7 (14.3%)
Dyspnoea exertional	1/7 (14.3%)
Skin and subcutaneous tissue disorders
Pruritus	2/7 (28.6%)
Rash maculo-papular	2/7 (28.6%)
Skin discolouration	1/7 (14.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.