Study of Dexamethasone Plus IXAZOMIB (MLN9708) or Physicians Choice of Treatment in Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
NCT ID: NCT01659658
Last Updated: 2025-09-02
Study Results
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View full resultsBasic Information
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TERMINATED
PHASE3
177 participants
INTERVENTIONAL
2012-12-26
2022-07-11
Brief Summary
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Detailed Description
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The study will enroll approximately 177 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:
* IXAZOMIB 4 mg plus Dexamethasone 20 mg
* Physician's choice: Participants will receive one of the following treatment options as selected by the physician:
1. Dexamethasone 20 mg
2. Dexamethasone 20 mg + Melphalan 0.22 mg/kg
3. Dexamethasone 20 mg + Cyclophosphamide 500 mg
4. Dexamethasone 20 mg + Thalidomide 200 mg
5. Dexamethasone 20 mg + Lenalidomide 15 mg
6. All participants will be asked to take oral formulation of the drugs. In both treatment arms, each participant will continue to receive sequential cycles of therapy until disease progression, unacceptable toxicity, or until the study is terminated, whichever occurs first. Participants in Arm B receiving melphalan and dexamethasone will be treated to best response plus 2 additional cycles.
This multi-center trial will be conducted worldwide. The overall time to participate in this study is 120 months (10 years), including 84 months of enrollment and 36 months of follow-up after the last participant is enrolled.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Arm A: Ixazomib + Dexamethasone
Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 and dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle for up to a maximum of 95.2 months. Dexamethasone was increased up to 40 mg/day after 4 weeks, if tolerated.
IXAZOMIB
IXAZOMIB capsules
Dexamethasone
Dexamethasone tablets
Arm B: Dexamethasone + Melphalan
Participants received dexamethasone 20 mg, orally, and melphalan 0.22 mg/kg, orally once on Days 1 through 4 of each 28-day cycle, for up to a maximum of 72.4 months.
Dexamethasone
Dexamethasone tablets
Melphalan
Melphalan tablets
Arm B: Dexamethasone + Cyclophosphamide
Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22, and cyclophosphamide 500 mg, orally, on Days 1, 8 and 15 of each 28-day cycle for up to a maximum of 72.4 months.
Dexamethasone
Dexamethasone tablets
Cyclophosphamide
Cyclophosphamide tablets
Arm B: Dexamethasone + Thalidomide
Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle, and thalidomide daily at a starting dose of 50 mg and increased, as tolerated, to a maximum of 200 mg, orally for up to a maximum of 72.4 months.
Dexamethasone
Dexamethasone tablets
Thalidomide
Thalidomide capsules
Arm B: Dexamethasone + Lenalidomide
Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle and lenalidomide 15 mg, orally, once on Days 1 through 21 every 28 days for up to a maximum of 72.4 months.
Dexamethasone
Dexamethasone tablets
Lenalidomide
Lenalidomide capsules
Interventions
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IXAZOMIB
IXAZOMIB capsules
Dexamethasone
Dexamethasone tablets
Melphalan
Melphalan tablets
Cyclophosphamide
Cyclophosphamide tablets
Thalidomide
Thalidomide capsules
Lenalidomide
Lenalidomide capsules
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Biopsy-proven diagnosis of primary systemic light chain amyloidosis (AL amyloidosis) according to the following standard criteria:
1. Histochemical diagnosis of amyloidosis, as based on tissue specimens with Congo red staining with exhibition of an apple-green birefringence
2. If clinical and laboratory parameters insufficient to establish AL amyloidosis or in cases of doubt, amyloid typing may be necessary.
3. Measurable disease as defined by serum differential free light chain concentration (dFLC, difference between amyloid forming \[involved\] and nonamyloid forming \[uninvolved\] free light chain \[FLC\]) ≥ 50 mg/L.
4. Objective, measurable major (cardiac or renal) organ amyloid involvement as defined as follows (amyloid involvement of at least 1 required):
1. Cardiac involvement is defined as the presence of a mean left ventricular wall thickness on echocardiogram greater than 12 mm in the absence of other potential causes of left ventricular hypertrophy (controlled hypertension is allowed) with a noncardiac biopsy showing amyloid, or a positive cardiac biopsy in the presence of clinical or laboratory evidence of involvement. If there is isolated cardiac involvement, then typing of amyloid deposits is recommended.
2. Renal involvement is defined as proteinuria (predominantly albumin) \>0.5 g/day in a 24-hour urine collection.
Note: Amyloid involvement of other organ systems is allowed, but not required.
5. Must be relapsed or refractory after 1 or 2 prior therapies. For this protocol, relapsed is defined as progressive disease (PD) documented more than 60 days after last dose; refractory is defined as documented absence of hematologic response or hematologic progression on or within 60 days after last dose of prior therapy.
1. Participant must not have been previously treated with proteasome inhibitors. (The sponsor reserves the right to open the study to proteasome inhibitor-exposed participants in the future, at some time point after the first interim analysis (IA). In that case, the participant may not be refractory to proteasome inhibitor therapy.)
2. Given that the physician may select from an offered list of regimens to treat a specific participant, the participant may be refractory to an agent/s listed within the list of offered treatment choices
3. Must have recovered (ie, ≤ Grade 1 toxicity or participant's baseline status) from the reversible effects of prior therapy
4. If a participant has received a transplant as his/her first-line therapy, he/she must be at least 3 months post transplantation and recovered from the side effects of the stem cell transplant.
6. Must meet criteria for 1 of the following AL Amyloidosis Risk Stages (as defined by N-terminal proBNP \[NT-proBNP\] cut-off of \< 332 pg/mL and troponin T cut-off of 0.035 ng/mL as thresholds):
1. Stage 1: both NT-proBNP and troponin T under threshold
2. Stage 2: either NT-proBNP or troponin T (but not both) over threshold;
3. Stage 3: both NT-proBNP and troponin T over threshold (but NT-proBNP \< 8000 pg/mL)
7. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.
8. Clinical laboratory values:
1. Absolute neutrophil count ≥ 1000/µL
2. Platelet count ≥ 75,000/µL
3. Total bilirubin ≤ 1.5 upper limit of normal (ULN), except for participants with Gilbert's syndrome as defined by \> 80% unconjugated bilirubin and total bilirubin ≤ 6 mg/dL
4. Alkaline phosphatase ≤ 5 x ULN
5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3 x ULN
6. Calculated creatinine clearance ≥ 30 mL/min
9. Female participants who:
1. If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study treatment, AND
2. Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
3. Agree to practice true abstinence when this is line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.).
Male participants, even if surgically sterilized (ie, status post vasectomy), who:
1. Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, AND
2. Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
3. Agree to practice true abstinence when this is line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.)
10. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
Exclusion Criteria
2. Female participants who are lactating, breast feeding, or pregnant.
3. Medically documented cardiac syncope, uncompensated New York Heart Association (NYHA) Class 3 or 4 congestive heart failure, myocardial infarction within the previous 6 months, unstable angina pectoris, clinically significant repetitive ventricular arrhythmias despite antiarrhythmic treatment, or severe orthostatic hypotension or clinically important autonomic disease.
4. Clinically overt multiple myeloma, according to the International Myeloma Working Group (IMWG) criteria with at least 1 of the following:
1. Bone lesions
2. Hypercalcemia, defined as a calcium of \> 11 mg/dL
5. Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or gastrointestinal (GI) procedure that could interfere with the oral absorption or tolerance of treatment.
6. Requirement for other concomitant chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered to be investigational or which would be considered as a treatment of AL amyloidosis. However, participants may be on chronic steroids (maximum dose 20 mg/day prednisone or equivalent) if they are being given for disorders other than amyloidosis (eg, adrenal insufficiency, rheumatoid arthritis, etc.).
7. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the participant inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
8. Ongoing or active infection, known human immunodeficiency virus (HIV) positive, active hepatitis B or C infection.
9. Psychiatric illness/social situations that would limit compliance with study requirements.
10. Known allergy to boron, MLN9708, any of the study treatments, their analogues, or excipients.
11. Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of study treatment.
12. Diagnosed or treated for another malignancy within 3 years (or 5 years for participants in France) before study enrollment 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.
18 Years
ALL
No
Sponsors
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Millennium Pharmaceuticals, Inc.
INDUSTRY
Responsible Party
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Principal Investigators
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Medical Director
Role: STUDY_DIRECTOR
Takeda
Locations
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Cedars Sinai Medical Center
Los Angeles, California, United States
University of Chicago
Chicago, Illinois, United States
Indiana University School of Medicine
Indianapolis, Indiana, United States
Tufts Medical Center
Boston, Massachusetts, United States
Boston Medical Center
Boston, Massachusetts, United States
Karmanos Cancer Institute
Detroit, Michigan, United States
Mayo Clinic
Rochester, Minnesota, United States
Washington University
St Louis, Missouri, United States
Columbia University Medical Center
New York, New York, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
University of Cincinnati
Cincinnati, Ohio, United States
Cleveland Clinic
Cleveland, Ohio, United States
Vanderbilt University Medical Center
Nashville, Tennessee, United States
University of Texas Southwestern Medical Center
Dallas, Texas, United States
Froedtert and The Medical College of Wisconsin
Milwaukee, Wisconsin, United States
Westmead Hospital
Westmead, New South Wales, Australia
Princess Alexandra Hospital
Woolloongabba, Queensland, Australia
Box Hill Hospital
Box Hill, Victoria, Australia
Sir Charles Gairdner Hospital
Nedlands, Western Australia, Australia
Centro de Pesquisas Oncologicas
Florianópolis, Santa Catarina, Brazil
Hospital Universitario Clementino Fraga Filho (UFRJ)
Rio de Janeiro, , Brazil
Irmandade Da Santa Casa de Misericordia de Sao Paulo
São Paulo, , Brazil
Hospital Israelita Albert Einstein
São Paulo, , Brazil
Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo
São Paulo, , Brazil
Tom Baker Cancer Centre
Calgary, Alberta, Canada
Cross Cancer Institute
Edmonton, Alberta, Canada
Vancouver General Hospital
Vancouver, British Columbia, Canada
Princess Margaret Hospital
Toronto, Ontario, Canada
Fakultni nemocnice Ostrava
Ostrava, Moravskoslezsk Kraj, Czechia
Vseobecna fakultni nemocnice v Praze
Prague, Praha, Hlavni Mesto, Czechia
Arhus Universitetshospital Arhus Sygehus
Aahus, , Denmark
Rigshospitalet
Copenhagen, , Denmark
Hotel Dieu
Nantes, Loire-Atlantique, France
Hopital Claude Huriez
Lille, , France
Centre Hospitalier et Universitaire de Limoges
Limoges, , France
Hopital Saint Louis
Paris, , France
Hopital de Rangueil
Toulouse, , France
Charite - Universitatsmedizin Berlin
Berlin, , Germany
Universitatsklinikum Hamburg Eppendorf
Hamburg, , Germany
Universitat Heidelberg
Heidelberg, , Germany
University General Hospital of Patras
Pátrai, Achaia, Greece
Alexandra Hospital
Athens, , Greece
Rambam Health Corporation
Haifa, , Israel
Hadasit Medical Research Services and Development Ltd
Jerusalem, , Israel
Meir Medical Center
Kfar Saba, , Israel
Rabin Medical Center - PPDS
Petah Tikva, , Israel
Chaim Sheba Medical Center
Ramat Gan, , Israel
Institute of Hematology "Seragnoli" University of Bologna
Bologna, , Italy
Fondazione IRCCS Policlinico San Matteo di Pavia
Pavia, , Italy
VU Medisch Centrum
Amsterdam, North Holland, Netherlands
Maastricht University Medical Center
AZ Maastricht, , Netherlands
Universitair Medisch Centrum Utrecht
Utrecht, , Netherlands
Gachon University Gil Medical Center
Incheon, , South Korea
Seoul National University Hospital
Seoul, , South Korea
Severance Hospital at Yonsei University Health System - PPDS
Seoul, , South Korea
Samsung Medical Center - PPDS
Seoul, , South Korea
The Catholic University of Korea, Seoul St Mary's Hospital
Seoul, , South Korea
Clinica Universidad de Navarra
Pamplona, Navarre, Spain
Hospital Clinic de Barcelona
Barcelona, , Spain
Hospital Universitario de La Princesa
Madrid, , Spain
Hospital Universitario Puerta de Hierro - Majadahonda
Majadahonda, , Spain
Hospital Universitario de Salamanca
Salamanca, , Spain
Queen Elizabeth Hospital
Birmingham, , United Kingdom
Royal Free and University College Medical School
London, , United Kingdom
Manchester Royal Infirmary
Manchester, , United Kingdom
Oxford University Hospitals NHS Trust
Oxford, , United Kingdom
Countries
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References
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Sanchorawala V, Wechalekar AD, Kim K, Schonland SO, Landau HJ, Kwok F, Suzuki K, Dispenzieri A, Merlini G, Comenzo RL, Cherepanov D, Hayden VC, Kumar A, Labotka R, Faller DV, Kastritis E. Quality of life and symptoms among patients with relapsed/refractory AL amyloidosis treated with ixazomib-dexamethasone versus physician's choice. Am J Hematol. 2023 May;98(5):720-729. doi: 10.1002/ajh.26866. Epub 2023 Feb 14.
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.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Related Links
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To obtain more information on the study, click this link.
Other Identifiers
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2011-005468-10
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
U1111-1164-7621
Identifier Type: REGISTRY
Identifier Source: secondary_id
C16011-CTIL
Identifier Type: OTHER
Identifier Source: secondary_id
NL41603.028.12
Identifier Type: REGISTRY
Identifier Source: secondary_id
12/LO/1771
Identifier Type: REGISTRY
Identifier Source: secondary_id
MOH_2017-05-07_000374
Identifier Type: OTHER
Identifier Source: secondary_id
C16011
Identifier Type: -
Identifier Source: org_study_id
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