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Study of Oral Ixazomib in Adult Participants With Relapsed or Refractory Light Chain Amyloidosis

Primary Purpose

Light-Chain Amyloidosis

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Ixazomib
Dexamethasone
Sponsored by
Millennium Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Light-Chain Amyloidosis focused on measuring Drug therapy

Eligibility Criteria

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

Inclusion Criteria:

  • Male or female participants 18 years or older
  • Biopsy-proven systemic relapsed or refractory light-chain (AL) amyloidosis, which after at least 1 prior therapy, in the investigator's opinion, requires further treatment
  • If received stem cell transplant, must be at least 3 months posttransplantation and recovered from side effects
  • Must have measurable disease defined as serum differential free light chain concentration ≥ 40 mg/L
  • Must have objective measurable organ (heart or kidney) amyloid involvement
  • Must have cardiac biomarker risk stage I or II disease
  • Must have adequate hematologic, hepatic, and renal function
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
  • Female participants who are postmenopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse
  • Male participants who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse
  • Voluntary written consent

Exclusion Criteria

  • Peripheral neuropathy that is greater or equal to Grade 2
  • Cardiac status as described in protocol
  • Severe diarrhea (≥ Grade 3) not controllable with medication or requires administration of total parenteral nutrition
  • Known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption of tolerance of MLN9708
  • Uncontrolled infection requiring systematic antibiotics
  • Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
  • Presence of other active malignancy with the exception of nonmelanoma skin cancer, cervical cancer, treated early-stage prostate cancer provided that prostate-specific antigen is within normal limit, or any completely resected carcinoma in situ
  • Female participants who are lactating or pregnant
  • Major surgery within 14 days before the first dose of study drug
  • Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol

Sites / Locations

  • Tufts Medical Center
  • Boston Medical Center
  • Barbara Ann Karmanos Cancer Institute
  • Mayo Clinic
  • Mount Sinai Medical Center
  • Fox Chase Cancer Center
  • University Health Network
  • CHU Limoges, Department of Hematology and Cell Therapy, Reference Center for AL amyloidosis
  • Universitatsklinikum Heidelberg Innere Medizin V; Hamatologie, Onkologie und Rheumatologie
  • Amyloidosis Research & Treatment Center, Fondazione IRCCS Policlinico San Matteo

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Dose Escalation Cohort: Ixazomib 4.0 mg

Dose Escalation Cohort: Ixazomib 5.5 mg

Dose Expansion Cohort: Ixazomib 4.0 mg (PI Naive)

Dose Expansion Cohort: Ixazomib 4.0 mg (PI Exposed)

Arm Description

Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Ixazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were not treated with any other proteasome inhibitor (PI). Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.

Ixazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until PD or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were previously treated with any other PI. Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.

Outcomes

Primary Outcome Measures

Number of Participants With at Least One Treatment Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)
An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.
Number of Participants With Clinically Significant Abnormal Laboratory Values Reported as TEAE
The number of participants with any clinically significant abnormal standard safety laboratory values collected throughout the study reported as TEAEs. Parameters assessed were hematology, serum chemistry and urinalysis. Abnormal laboratory values were assessed as an AE if that value leads to discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered by the investigator to be a clinically significant change from baseline.
Number of Participants With Peripheral Neuropathy Reported as a TEAE
Neurotoxicity was assessed as the number of participants with the TEAE of peripheral neuropathy.
Maximum Tolerated Dose (MTD) of Ixazomib
MTD was highest dose of Ixazomib, at which <=1 of 6 participants experienced dose-limiting toxicity (DLT). DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events, v 4.03 as: Grade 4 neutropenia (absolute neutrophil count <500 cells/mm^3) for >7 days;Grade 3 neutropenia with fever or infection;Grade 4 thrombocytopenia (platelets < 25,000/mm^3) for >7 days;Grade 3 thrombocytopenia with clinically significant bleeding;platelet count <10,000/mm^3;Grade 2 peripheral neuropathy with pain or >=Grade 3 peripheral neuropathy; >=Grade 3 nausea/emesis, diarrhea controlled by supportive therapy;Grade 3 QTc prolongation (QTc >500 msec);any >=Grade 3 nonhematologic toxicity except Grade 3 arthralgia/myalgia;or <1 week Grade 3 fatigue;delay in initiation of the subsequent therapy cycle by >2 weeks;other >=Grade 2 study drug-related nonhematologic toxicities requiring therapy discontinuation, considered possibly related to therapy as assessed by Investigator.
Recommended Phase 2 Dose (RP2D) of Ixazomib
The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1). The RP2D of Ixazomib was determined in dose escalation group on the basis of the totality of safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) data observed in Cycle 1.

Secondary Outcome Measures

Cmax: Maximum Observed Plasma Concentration for Ixazomib
Tmax: Time of First Occurrence of Cmax for Ixazomib
Ctrough: Plasma Concentration Immediately Prior to Dosing for Ixazomib
AUC0-168: Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Post-dose for Ixazomib
Emax: Maximum Observed Percent Inhibition of Whole Blood 20S Proteasome
TEmax: Time to Maximum Observed Effect (Emax) of Whole Blood 20S Proteasome Inhibition for Ixazomib
AUE0-168: Area Under Effect Curve of Whole Blood 20S Proteasome Inhibition From Zero to Concentration at 168 Hours for Ixazomib
Number of Participants With Best Organ Response to Treatment Based on Investigators Assessment
Organ response rate was estimated as the number of participants with documented organ response (ie. Heart or kidney ). Treatment response of amyloid-related organs were identified based on national cancer institute, common terminology criteria for adverse events (NCI CTCAE) Version 4.02 criteria.
Number of Participants With Best Hematologic Response to Treatment Based on Investigators Assessment
The overall hematologic response rate is defined as number of participants with complete response (CR) or partial response (PR) or very good partial response (VGPR) as assessed by the investigator. Response is determined according to standardized criteria using a central laboratory. CR=serum and urine negative for monoclonal protein by immunofixation; or free light chain ratio normal; < 5% plasma cells in bone marrow without clonal dominance. PR=reduction in dFLC > 50%. VGPR= dFLC < 40 mg/L.
Time to First Hematologic Response
Time to first hematologic response, measured as the time from the first dose of ixazomib to the date of first documentation of a hematologic response.
Time to First Organ Response
Time to first organ response, measured as the time from the first dose of ixazomib to the date of first documentation of a organ response.
Duration of Hematologic Response
Duration of hematologic response, measured as the time from the date of first documentation of a hematologic response to the date of hematologic disease progression.
Duration of Organ Response
Duration of organ response, measured as the time from the date of first documentation of a organ response to the date of organ disease progression.
Time to Hematologic Disease Progression
Time to hematologic progression, measured as the time from the date of the first dose of ixazomib to the date of first documented hematologic disease progression.
Time to Organ Disease Progression
Time to organ disease progression, measured as the time from the date of the first dose of ixazomib to the date of first documented organ disease progression.
Hematologic Disease Progression-Free Survival (PFS)
Hematologic disease PFS, measured as the time from the date of the first dose of ixazomib to the date of hematologic disease progression or death.
Organ Disease Progression-Free Survival (PFS)
Organ disease PFS, measured as the time from the date of the first dose of ixazomib to the date of organ disease progression or death.
Percentage of Participants With One Year Hematologic Disease PFS
One-year survival, defined as the patient survival probability at 1 year after the date of first dose of ixazomib.

Full Information

First Posted
March 15, 2011
Last Updated
March 18, 2020
Sponsor
Millennium Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01318902
Brief Title
Study of Oral Ixazomib in Adult Participants With Relapsed or Refractory Light Chain Amyloidosis
Official Title
An Open-Label, Dose-Escalation, Phase 1 Study of the Oral Formulation of MLN9708 Administered Weekly in Adult Patients With Relapsed or Refractory Light-Chain (AL) Amyloidosis Who Require Further Treatment
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
April 27, 2011 (Actual)
Primary Completion Date
November 13, 2018 (Actual)
Study Completion Date
November 13, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Millennium Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This study will include participants with previously treated systemic relapsed or refractory light-chain (AL) amyloidosis who require further therapy and will be aimed at determining the safety profile and the maximum tolerated dose/recommended phase 2 dose of MLN9078 (Ixazomib) administered orally.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Light-Chain Amyloidosis
Keywords
Drug therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
27 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dose Escalation Cohort: Ixazomib 4.0 mg
Arm Type
Experimental
Arm Description
Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
Arm Title
Dose Escalation Cohort: Ixazomib 5.5 mg
Arm Type
Experimental
Arm Description
Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
Arm Title
Dose Expansion Cohort: Ixazomib 4.0 mg (PI Naive)
Arm Type
Experimental
Arm Description
Ixazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were not treated with any other proteasome inhibitor (PI). Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.
Arm Title
Dose Expansion Cohort: Ixazomib 4.0 mg (PI Exposed)
Arm Type
Experimental
Arm Description
Ixazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until PD or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were previously treated with any other PI. Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.
Intervention Type
Drug
Intervention Name(s)
Ixazomib
Other Intervention Name(s)
MLN9708
Intervention Description
Ixazomib capsules.
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Intervention Description
Dexamethasone tablets.
Primary Outcome Measure Information:
Title
Number of Participants With at Least One Treatment Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)
Description
An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.
Time Frame
From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)
Title
Number of Participants With Clinically Significant Abnormal Laboratory Values Reported as TEAE
Description
The number of participants with any clinically significant abnormal standard safety laboratory values collected throughout the study reported as TEAEs. Parameters assessed were hematology, serum chemistry and urinalysis. Abnormal laboratory values were assessed as an AE if that value leads to discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered by the investigator to be a clinically significant change from baseline.
Time Frame
From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)
Title
Number of Participants With Peripheral Neuropathy Reported as a TEAE
Description
Neurotoxicity was assessed as the number of participants with the TEAE of peripheral neuropathy.
Time Frame
From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)
Title
Maximum Tolerated Dose (MTD) of Ixazomib
Description
MTD was highest dose of Ixazomib, at which <=1 of 6 participants experienced dose-limiting toxicity (DLT). DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events, v 4.03 as: Grade 4 neutropenia (absolute neutrophil count <500 cells/mm^3) for >7 days;Grade 3 neutropenia with fever or infection;Grade 4 thrombocytopenia (platelets < 25,000/mm^3) for >7 days;Grade 3 thrombocytopenia with clinically significant bleeding;platelet count <10,000/mm^3;Grade 2 peripheral neuropathy with pain or >=Grade 3 peripheral neuropathy; >=Grade 3 nausea/emesis, diarrhea controlled by supportive therapy;Grade 3 QTc prolongation (QTc >500 msec);any >=Grade 3 nonhematologic toxicity except Grade 3 arthralgia/myalgia;or <1 week Grade 3 fatigue;delay in initiation of the subsequent therapy cycle by >2 weeks;other >=Grade 2 study drug-related nonhematologic toxicities requiring therapy discontinuation, considered possibly related to therapy as assessed by Investigator.
Time Frame
Cycle 1 (28 days)
Title
Recommended Phase 2 Dose (RP2D) of Ixazomib
Description
The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1). The RP2D of Ixazomib was determined in dose escalation group on the basis of the totality of safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) data observed in Cycle 1.
Time Frame
Cycle 1 (28 days)
Secondary Outcome Measure Information:
Title
Cmax: Maximum Observed Plasma Concentration for Ixazomib
Time Frame
Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Title
Tmax: Time of First Occurrence of Cmax for Ixazomib
Time Frame
Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Title
Ctrough: Plasma Concentration Immediately Prior to Dosing for Ixazomib
Time Frame
Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Title
AUC0-168: Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Post-dose for Ixazomib
Time Frame
Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Title
Emax: Maximum Observed Percent Inhibition of Whole Blood 20S Proteasome
Time Frame
Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Title
TEmax: Time to Maximum Observed Effect (Emax) of Whole Blood 20S Proteasome Inhibition for Ixazomib
Time Frame
Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Title
AUE0-168: Area Under Effect Curve of Whole Blood 20S Proteasome Inhibition From Zero to Concentration at 168 Hours for Ixazomib
Time Frame
Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Title
Number of Participants With Best Organ Response to Treatment Based on Investigators Assessment
Description
Organ response rate was estimated as the number of participants with documented organ response (ie. Heart or kidney ). Treatment response of amyloid-related organs were identified based on national cancer institute, common terminology criteria for adverse events (NCI CTCAE) Version 4.02 criteria.
Time Frame
At Cycles 3, 6, 9, and 12; every 6 months thereafter until disease progression or the initiation of subsequent antineoplastic therapy and at end of treatment (EOT) visit (Up to approximately 12 months)
Title
Number of Participants With Best Hematologic Response to Treatment Based on Investigators Assessment
Description
The overall hematologic response rate is defined as number of participants with complete response (CR) or partial response (PR) or very good partial response (VGPR) as assessed by the investigator. Response is determined according to standardized criteria using a central laboratory. CR=serum and urine negative for monoclonal protein by immunofixation; or free light chain ratio normal; < 5% plasma cells in bone marrow without clonal dominance. PR=reduction in dFLC > 50%. VGPR= dFLC < 40 mg/L.
Time Frame
Day 22 to 28 in each cycle and end of treatment visit; then every 6 weeks thereafter until disease progression or initiation of subsequent antineoplastic therapy (Up to approximately 12 months)
Title
Time to First Hematologic Response
Description
Time to first hematologic response, measured as the time from the first dose of ixazomib to the date of first documentation of a hematologic response.
Time Frame
From the date of the first dose of ixazomib to the date of first documentation of a hematologic response (Up to approximately 12 months)
Title
Time to First Organ Response
Description
Time to first organ response, measured as the time from the first dose of ixazomib to the date of first documentation of a organ response.
Time Frame
From the date of the first dose of ixazomib to the date of first documentation of a organ response (Up to approximately 12 months)
Title
Duration of Hematologic Response
Description
Duration of hematologic response, measured as the time from the date of first documentation of a hematologic response to the date of hematologic disease progression.
Time Frame
From the date of first documentation of a hematologic response to the date of hematologic disease progression (Up to approximately 12 months)
Title
Duration of Organ Response
Description
Duration of organ response, measured as the time from the date of first documentation of a organ response to the date of organ disease progression.
Time Frame
From the date of first documentation of a organ response to the date of organ disease progression (Up to approximately 12 months)
Title
Time to Hematologic Disease Progression
Description
Time to hematologic progression, measured as the time from the date of the first dose of ixazomib to the date of first documented hematologic disease progression.
Time Frame
From the date of the first dose of ixazomib to the date of first documented hematologic disease progression (Up to approximately 12 months)
Title
Time to Organ Disease Progression
Description
Time to organ disease progression, measured as the time from the date of the first dose of ixazomib to the date of first documented organ disease progression.
Time Frame
From the date of the first dose of ixazomib to the date of first documented organ disease progression (Up to approximately 12 months)
Title
Hematologic Disease Progression-Free Survival (PFS)
Description
Hematologic disease PFS, measured as the time from the date of the first dose of ixazomib to the date of hematologic disease progression or death.
Time Frame
From the date of the first dose of ixazomib to the date of hematologic disease progression or death (Up to approximately 12 months)
Title
Organ Disease Progression-Free Survival (PFS)
Description
Organ disease PFS, measured as the time from the date of the first dose of ixazomib to the date of organ disease progression or death.
Time Frame
From the date of the first dose of ixazomib to the date of organ disease progression or death (Up to approximately 12 months)
Title
Percentage of Participants With One Year Hematologic Disease PFS
Description
One-year survival, defined as the patient survival probability at 1 year after the date of first dose of ixazomib.
Time Frame
From the date of the first dose of ixazomib to the date of hematologic disease progression or death (Up to 1 year)

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 Biopsy-proven systemic relapsed or refractory light-chain (AL) amyloidosis, which after at least 1 prior therapy, in the investigator's opinion, requires further treatment If received stem cell transplant, must be at least 3 months posttransplantation and recovered from side effects Must have measurable disease defined as serum differential free light chain concentration ≥ 40 mg/L Must have objective measurable organ (heart or kidney) amyloid involvement Must have cardiac biomarker risk stage I or II disease Must have adequate hematologic, hepatic, and renal function Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Female participants who are postmenopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse Male participants who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse Voluntary written consent Exclusion Criteria Peripheral neuropathy that is greater or equal to Grade 2 Cardiac status as described in protocol Severe diarrhea (≥ Grade 3) not controllable with medication or requires administration of total parenteral nutrition Known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption of tolerance of MLN9708 Uncontrolled infection requiring systematic antibiotics Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection Presence of other active malignancy with the exception of nonmelanoma skin cancer, cervical cancer, treated early-stage prostate cancer provided that prostate-specific antigen is within normal limit, or any completely resected carcinoma in situ Female participants who are lactating or pregnant Major surgery within 14 days before the first dose of study drug Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol
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
Tufts Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02111
Country
United States
Facility Name
Boston Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02118
Country
United States
Facility Name
Barbara Ann Karmanos Cancer Institute
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Mount Sinai Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Fox Chase Cancer Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19111
Country
United States
Facility Name
University Health Network
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
Facility Name
CHU Limoges, Department of Hematology and Cell Therapy, Reference Center for AL amyloidosis
City
Limoges Cedex
ZIP/Postal Code
87042
Country
France
Facility Name
Universitatsklinikum Heidelberg Innere Medizin V; Hamatologie, Onkologie und Rheumatologie
City
Heidelberg
ZIP/Postal Code
D-69120
Country
Germany
Facility Name
Amyloidosis Research & Treatment Center, Fondazione IRCCS Policlinico San Matteo
City
Pavia
ZIP/Postal Code
27100
Country
Italy

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.
Citations:
Citation
Sanchorawala V, Comenzo R, Zonder J, Kukreti V, Cohen A, Dispenzieri A, et al. MLN9708, an investigational oral proteasome inhibitor (PI), in relapsed or refractory lightchain (AL) amyloidosis. Clinical Lymphoma Myeloma and Leukemia 2013;13(suppl 1):S153-4; abstr P-229.
Results Reference
result
Citation
Sanchorawala V, Zonder J, Comenzo R, Schönland S, Dispenzieri A, Berg D, et al. Poster Presentation: Phase 1 study of MLN9708, a novel, investigational oral proteasome inhibitor, in patients with relapsed or refractory light-chain amyloidosis. XIII International Symposium on Amyloidosis, Groningen, The Netherlands 2012.
Results Reference
result
Citation
Merlini G, Sanchorawala V, Zonder J, Kukreti V, Schonland S, Jaccard A, et al. MLN9708, a novel, investigational oral proteasome inhibitor, in patients with relapsed or refractory light-chain amyloidosis (AL): results of a phase 1 study. In: 54th ASH Annual Meeting and Exposition; 2012 8-11 December; Atlanta, GA; p. abstr 731.
Results Reference
result
PubMed Identifier
28550039
Citation
Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schonland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. doi: 10.1182/blood-2017-03-771220. Epub 2017 May 26. Erratum In: Blood. 2020 Mar 26;135(13):1071.
Results Reference
derived

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Study of Oral Ixazomib in Adult Participants With Relapsed or Refractory Light Chain Amyloidosis

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