Back to resultsPharmacokinetics Study of Oral Ixazomib (MLN9708) in Relapsed/Refractory Multiple Myeloma and Advanced Solid Tumors Participants With Normal Renal Function or Severe Renal Impairment
Primary Purpose
Multiple Myeloma, Advanced Solid Tumors
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Ixazomib
Sponsored by
About this trial
This is an interventional treatment trial for Multiple Myeloma focused on measuring Drug Therapy
Eligibility Criteria
Inclusion Criteria:
- Male or female participants 18 years or older
- Participants with multiple myeloma (MM) diagnosed according to standard criteria or participants with a diagnosis of an advanced malignant solid tumor for which standard, curative, or life prolonging treatment does not exist or is no longer effective. Participants with multiple myeloma must have had at least 1 prior therapy
- A calculated creatinine clearance (CrCl) that meets entry criteria for enrollment (i.e., calculated CrCl either ≥ 90 mL/min for normal renal function or < 30 mL/min for severe renal impairment)
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception 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 through 90 after the last dose of study drug or agree to practice true abstinence
- Voluntary written informed consent
- Suitable venous access
Exclusion Criteria:
- Female participants who are pregnant or lactating and breastfeeding
- Failure to have recovered from clinically significant effects of prior chemotherapy (defined as toxicity greater than Grade 1 with the exception of alopecia)
- Major surgery or radiotherapy within 14 days before study drug administration
- Dexamethasone (or equivalent systemic steroid) higher than physiologic dosing within 7 days before study drug administration
- Central nervous system involvement
- Infection requiring IV antibiotic therapy or other serious infection within 14 days prior to first dose of study drug
- Diagnosis of Waldenstrom's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, myeloproliferative syndrome, or primary amyloidosis (with the exception of patients in whom amyloidosis has been documented as a complication of MM, who will be evaluated on a case-by-case basis for trial participation)
- Systemic treatment with strong and moderate inhibitors of Cytochrome P1A2 (CYP1A2), strong and moderate inhibitors of Cytochrome P3A (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
- Evidence of uncontrolled cardiovascular conditions
- Ongoing or active infection, or known human immunodeficiency virus (HIV) positive
- Comorbid systemic illness or psychiatric illness that could interfere with study completion
- Known allergy to study medications
- Inability to swallow oral medication or condition that could interfere with oral absorption or tolerance of treatment
Sites / Locations
- Winship Cancer Institute, Emory University
- Illinois Cancer Care
- University of Kansas Cancer Center, Clinical Research Center
- University of Maryland
- Mount Sinai Medical Center
- University of Oklahoma Peggy and Charles Stephenson Cancer Center
- Sarah Cannon Cancer Center
- Mary Crowley Cancer Research Centers Medical City
- Institute of Oncology Hematology Biomedical Research
- University of Texas Health Science Center San Antonio
- University Health Network
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
Normal Renal Function: Ixazomib
Severe Renal Impairment: Ixazomib
End-stage Renal Disease: Ixazomib
Arm Description
In the 15 day period that constitutes Part A of the trial, participants received a single oral dose of ixazomib 3.0 mg capsules. Participants from Part A had the option of continuing the study by participating in Part B, where they received ixazomib (4, 3, or 2.3 mg per protocol) capsules, orally on Days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity.
In the 15 day period that constitutes Part A of the trial, participants received a single oral dose of ixazomib 3.0 mg capsules. Participants from Part A had the option of continuing the study by participating in Part B, where they received ixazomib (4, 3, or 2.3 mg per protocol) capsules, orally on Days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity.
In the 15 day period that constitutes Part A of the trial, participants received a single oral dose of ixazomib 3.0 mg capsules. Participants from Part A had the option of continuing the study by participating in Part B, where they received ixazomib (4, 3, or 2.3 mg per protocol) capsules, orally on Days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity.
Outcomes
Primary Outcome Measures
Unbound Cmax: Unbound Maximum Observed Plasma Concentration for Ixazomib
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
Unbound AUClast: Unbound Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib
Secondary Outcome Measures
Number of Participants With Adverse Events
Adverse Event 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.
Percentage of Participants With Overall Response (OR) in Relapsed/Refractory Multiple Myeloma (RRMM) Participants
Overall response rate defined as percentage of relapsed/refractory multiple myeloma participants who achieved partial response (PR), complete response (CR) and very good partial response (VGPR) according to International Myeloma Working Group Criteria. PR=>50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >90% or <200 mg/24 h. If serum and urine M-protein are unmeasurable, >50% decrease in difference between involved and uninvolved free light chain levels in place of M-protein criteria. If serum and urine M-protein and serum free light assay are not measurable, >50% reduction in plasma cells in place of M-protein, provided baseline bone marrow plasma cell >0%; CR=negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow; VGPR=serum and urine M-protein detectable by immunofixation but not on electrophoresis or > 90% reduction in serum M-protein plus urine M-protein level <100 mg/24 h.
Duration of Response (DOR) in RRMM Participants
DOR was defined as time from date of first documentation of a PR or better to date of first documentation of progressive disease (PD) for responders. Increase of >25% from lowest response value in any one or more of following: Serum M-component and/or (absolute increase must be >0.5 g/dL); Urine M-component and/or (the absolute increase must be >200 mg/24 h); difference between involved and uninvolved free light chain (FLC) levels and the absolute increase must be > 10 mg/dL; Bone marrow plasma cell percentage; absolute percentage must be > 5%; Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder. Responders without PD were censored at the date of the last response assessment that was stable disease (SD) or better.
Full Information
NCT ID
NCT01830816
First Posted
April 4, 2013
Last Updated
March 8, 2019
Sponsor
Millennium Pharmaceuticals, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT01830816
Brief Title
Pharmacokinetics Study of Oral Ixazomib (MLN9708) in Relapsed/Refractory Multiple Myeloma and Advanced Solid Tumors Participants With Normal Renal Function or Severe Renal Impairment
Official Title
Phase 1/1b Pharmacokinetics Study of Oral MLN9708 in Patients With Relapsed/Refractory Multiple Myeloma and Advanced Solid Tumors With Normal Renal Function or Severe Renal Impairment
Study Type
Interventional
2. Study Status
Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
September 16, 2013 (Actual)
Primary Completion Date
March 3, 2015 (Actual)
Study Completion Date
November 18, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Millennium Pharmaceuticals, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study is to characterize the single-dose pharmacokinetic (PK) parameters of ixazomib (MLN9708) in cancer participants with either normal renal function or severe renal impairment (RI), including participants with end-stage renal disease (ESRD).
Detailed Description
The drug tested in this study was called ixazomib (MLN9708). Ixazomib was administered to participants with cancer and either normal renal function or severe renal impairment, including end-stage renal disease (ESRD) requiring hemodialysis. This study characterized the PK, safety and efficacy of ixazomib.
The study enrolled 41 participants (37 multiple myeloma and 4 advanced solid tumor). The study was conducted in 2 parts, Part A and Part B. Participants were enrolled to receive:
Ixazomib 3.0 mg
In Part A, all participants were asked to take one 3 mg ixazomib capsule, orally on Day 1. Participants who tolerated ixazomib in Part A had the option of continuing the study by participating in Part B. In Part B, participants received ixazomib (4, 3, or 2.3 mg per protocol) on Days 1, 8, and 15 of each 28-day cycle until participants experienced disease progression or unacceptable toxicity.
This multicenter trial was conducted at 6 study sites in the United States and Canada. The overall time to participate in this study was 435 days. Participants made multiple scheduled visits to the clinic.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma, Advanced Solid Tumors
Keywords
Drug Therapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
41 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Normal Renal Function: Ixazomib
Arm Type
Experimental
Arm Description
In the 15 day period that constitutes Part A of the trial, participants received a single oral dose of ixazomib 3.0 mg capsules. Participants from Part A had the option of continuing the study by participating in Part B, where they received ixazomib (4, 3, or 2.3 mg per protocol) capsules, orally on Days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity.
Arm Title
Severe Renal Impairment: Ixazomib
Arm Type
Experimental
Arm Description
In the 15 day period that constitutes Part A of the trial, participants received a single oral dose of ixazomib 3.0 mg capsules. Participants from Part A had the option of continuing the study by participating in Part B, where they received ixazomib (4, 3, or 2.3 mg per protocol) capsules, orally on Days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity.
Arm Title
End-stage Renal Disease: Ixazomib
Arm Type
Experimental
Arm Description
In the 15 day period that constitutes Part A of the trial, participants received a single oral dose of ixazomib 3.0 mg capsules. Participants from Part A had the option of continuing the study by participating in Part B, where they received ixazomib (4, 3, or 2.3 mg per protocol) capsules, orally on Days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Ixazomib
Other Intervention Name(s)
MLN9708
Intervention Description
Ixazomib capsules
Primary Outcome Measure Information:
Title
Unbound Cmax: Unbound Maximum Observed Plasma Concentration for Ixazomib
Time Frame
Part A, Day 1: Predose and at multiple timepoints (up to 336 hours) post-dose
Title
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
Time Frame
Part A, Day 1: Predose and at multiple timepoints (up to 336 hours) post-dose
Title
Unbound AUClast: Unbound Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib
Time Frame
Part A, Day 1: Predose and at multiple timepoints (up to 336 hours) post-dose
Secondary Outcome Measure Information:
Title
Number of Participants With Adverse Events
Description
Adverse Event 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.
Time Frame
From signing of first dose of study drug up to the 30 days after the last dose of study drug (approximately up to 885 days)
Title
Percentage of Participants With Overall Response (OR) in Relapsed/Refractory Multiple Myeloma (RRMM) Participants
Description
Overall response rate defined as percentage of relapsed/refractory multiple myeloma participants who achieved partial response (PR), complete response (CR) and very good partial response (VGPR) according to International Myeloma Working Group Criteria. PR=>50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >90% or <200 mg/24 h. If serum and urine M-protein are unmeasurable, >50% decrease in difference between involved and uninvolved free light chain levels in place of M-protein criteria. If serum and urine M-protein and serum free light assay are not measurable, >50% reduction in plasma cells in place of M-protein, provided baseline bone marrow plasma cell >0%; CR=negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow; VGPR=serum and urine M-protein detectable by immunofixation but not on electrophoresis or > 90% reduction in serum M-protein plus urine M-protein level <100 mg/24 h.
Time Frame
Day 1 of every other cycle from cycle 1 (each cycle of 28 days) up to progression of disease (approximately up to 855 days)
Title
Duration of Response (DOR) in RRMM Participants
Description
DOR was defined as time from date of first documentation of a PR or better to date of first documentation of progressive disease (PD) for responders. Increase of >25% from lowest response value in any one or more of following: Serum M-component and/or (absolute increase must be >0.5 g/dL); Urine M-component and/or (the absolute increase must be >200 mg/24 h); difference between involved and uninvolved free light chain (FLC) levels and the absolute increase must be > 10 mg/dL; Bone marrow plasma cell percentage; absolute percentage must be > 5%; Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder. Responders without PD were censored at the date of the last response assessment that was stable disease (SD) or better.
Time Frame
Day 1 of every other cycle from cycle 1 (each cycle of 28 days) up to progression of disease (approximately up to 855 days)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male or female participants 18 years or older
Participants with multiple myeloma (MM) diagnosed according to standard criteria or participants with a diagnosis of an advanced malignant solid tumor for which standard, curative, or life prolonging treatment does not exist or is no longer effective. Participants with multiple myeloma must have had at least 1 prior therapy
A calculated creatinine clearance (CrCl) that meets entry criteria for enrollment (i.e., calculated CrCl either ≥ 90 mL/min for normal renal function or < 30 mL/min for severe renal impairment)
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception 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 through 90 after the last dose of study drug or agree to practice true abstinence
Voluntary written informed consent
Suitable venous access
Exclusion Criteria:
Female participants who are pregnant or lactating and breastfeeding
Failure to have recovered from clinically significant effects of prior chemotherapy (defined as toxicity greater than Grade 1 with the exception of alopecia)
Major surgery or radiotherapy within 14 days before study drug administration
Dexamethasone (or equivalent systemic steroid) higher than physiologic dosing within 7 days before study drug administration
Central nervous system involvement
Infection requiring IV antibiotic therapy or other serious infection within 14 days prior to first dose of study drug
Diagnosis of Waldenstrom's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, myeloproliferative syndrome, or primary amyloidosis (with the exception of patients in whom amyloidosis has been documented as a complication of MM, who will be evaluated on a case-by-case basis for trial participation)
Systemic treatment with strong and moderate inhibitors of Cytochrome P1A2 (CYP1A2), strong and moderate inhibitors of Cytochrome P3A (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
Evidence of uncontrolled cardiovascular conditions
Ongoing or active infection, or known human immunodeficiency virus (HIV) positive
Comorbid systemic illness or psychiatric illness that could interfere with study completion
Known allergy to study medications
Inability to swallow oral medication or condition that could interfere with oral absorption or tolerance of treatment
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Millennium Pharmaceuticals, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Winship Cancer Institute, Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Illinois Cancer Care
City
Peoria
State/Province
Illinois
ZIP/Postal Code
61615
Country
United States
Facility Name
University of Kansas Cancer Center, Clinical Research Center
City
Fairway
State/Province
Kansas
ZIP/Postal Code
66205
Country
United States
Facility Name
University of Maryland
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Mount Sinai Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
31406
Country
United States
Facility Name
University of Oklahoma Peggy and Charles Stephenson Cancer Center
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
Sarah Cannon Cancer Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
Mary Crowley Cancer Research Centers Medical City
City
Dallas
State/Province
Texas
ZIP/Postal Code
75201
Country
United States
Facility Name
Institute of Oncology Hematology Biomedical Research
City
Laredo
State/Province
Texas
ZIP/Postal Code
78041
Country
United States
Facility Name
University of Texas Health Science Center San Antonio
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
University Health Network
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
12. IPD Sharing Statement
Learn more about this trial
Pharmacokinetics Study of Oral Ixazomib (MLN9708) in Relapsed/Refractory Multiple Myeloma and Advanced Solid Tumors Participants With Normal Renal Function or Severe Renal Impairment
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