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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01659658




Registration number
NCT01659658
Ethics application status
Date submitted
2/08/2012
Date registered
8/08/2012
Date last updated
25/04/2024

Titles & IDs
Public title
Study of Dexamethasone Plus IXAZOMIB (MLN9708) or Physicians Choice of Treatment in Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
Scientific title
A Phase 3, Randomized, Controlled, Open-label, Multicenter, Safety and Efficacy Study of Dexamethasone Plus MLN9708 or Physicians Choice of Treatment Administered to Patients With Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
Secondary ID [1] 0 0
2011-005468-10
Secondary ID [2] 0 0
C16011
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Relapsed or Refractory Systemic Light Chain Amyloidosis 0 0
Condition category
Condition code
Metabolic and Endocrine 0 0 0 0
Metabolic disorders
Metabolic and Endocrine 0 0 0 0
Other metabolic disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - IXAZOMIB
Treatment: Drugs - Dexamethasone
Treatment: Drugs - Melphalan
Treatment: Drugs - Cyclophosphamide
Treatment: Drugs - Thalidomide
Treatment: Drugs - Lenalidomide

Experimental: 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.

Active Comparator: 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.

Active Comparator: 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.

Active Comparator: 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.

Active Comparator: 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.


Treatment: Drugs: IXAZOMIB
IXAZOMIB capsules

Treatment: Drugs: Dexamethasone
Dexamethasone tablets

Treatment: Drugs: Melphalan
Melphalan tablets

Treatment: Drugs: Cyclophosphamide
Cyclophosphamide tablets

Treatment: Drugs: Thalidomide
Thalidomide capsules

Treatment: Drugs: Lenalidomide
Lenalidomide capsules

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants With Overall Hematologic Response
Timepoint [1] 0 0
From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Primary outcome [2] 0 0
2-Year Vital Organ (Heart or Kidney) Deterioration and Mortality Rate
Timepoint [2] 0 0
Up to 2 years
Secondary outcome [1] 0 0
Percentage of Participants With Complete Hematologic Response
Timepoint [1] 0 0
From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Secondary outcome [2] 0 0
Overall Survival
Timepoint [2] 0 0
From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Secondary outcome [3] 0 0
Progression Free Survival (PFS)
Timepoint [3] 0 0
From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Secondary outcome [4] 0 0
Hematologic Disease Progression Free Survival
Timepoint [4] 0 0
From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Secondary outcome [5] 0 0
Time to Vital Organ (Heart or Kidney) Deterioration and Mortality Rate
Timepoint [5] 0 0
From randomization to time of vital organ deterioration or death (up to 115 months)
Secondary outcome [6] 0 0
Percentage of Participants With Best Vital Organ (Cardiac and/or Kidney) Response
Timepoint [6] 0 0
From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Secondary outcome [7] 0 0
Vital Organ Progression Free Survival
Timepoint [7] 0 0
From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Secondary outcome [8] 0 0
Duration of Hematologic Response
Timepoint [8] 0 0
From time of first documented response to disease progression (up to 115 months)
Secondary outcome [9] 0 0
Number of Participants With Serious Adverse Events (SAEs)
Timepoint [9] 0 0
From first dose of study drug through 30 days after administration of the last dose of study drug (up to 115 months)
Secondary outcome [10] 0 0
Time To Treatment Failure (TTF)
Timepoint [10] 0 0
From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Secondary outcome [11] 0 0
Time To Subsequent Anticancer Treatment
Timepoint [11] 0 0
From first dose of study drug until subsequent anticancer treatment (up to 115 months)
Secondary outcome [12] 0 0
Change From Baseline in 36-item Short Form General Health Survey (SF-36) Mental Component Summary Score at Week 28 of the PFS Follow-up
Timepoint [12] 0 0
Baseline, Week 28 of the PFS Follow-up
Secondary outcome [13] 0 0
Change From Baseline in SF-36 Physical Component Summary Score at Week 28 of the PFS Follow-up
Timepoint [13] 0 0
Baseline, Week 28 of the PFS Follow-up
Secondary outcome [14] 0 0
Change From Baseline in Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) Score at Week 28 of the PFS Follow-up
Timepoint [14] 0 0
Baseline, Week 28 of the PFS Follow-up
Secondary outcome [15] 0 0
Change From Baseline in Amyloidosis Symptom Scale Total Score at Week 28 of the PFS Follow-up
Timepoint [15] 0 0
Baseline, Week 28 of the PFS Follow-up
Secondary outcome [16] 0 0
Number of Participants in Each Category of the EuroQol 5-Dimensional (EQ-5D) Questionnaire Score
Timepoint [16] 0 0
At Week 28 of the OS follow-up
Secondary outcome [17] 0 0
EuroQol 5-Dimension 3-Level (EQ-5D-3L) Visual Analogue Scale Score
Timepoint [17] 0 0
At Week 28 of the OS follow-up
Secondary outcome [18] 0 0
Plasma Concentration of Ixazomib
Timepoint [18] 0 0
Cycle 1, Day 1: 1, 4 hours postdose, Day 14: 144 hours postdose; Cycle 2, Day 1: predose, Day 14: 144 hours postdose; Cycles 3 to 10, Day 1: predose (cycle length=28 days)
Secondary outcome [19] 0 0
Number of Hospitalizations
Timepoint [19] 0 0
From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)

Eligibility
Key inclusion criteria
1. Male or female participants 18 years or older.

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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Amyloidosis due to mutations of the transthyretin gene or presence of other non-AL
amyloidosis.

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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC,WA
Recruitment hospital [1] 0 0
Westmead Hospital - Westmead
Recruitment hospital [2] 0 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [3] 0 0
Box Hill Hospital - Box Hill
Recruitment hospital [4] 0 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 0 0
214 - Westmead
Recruitment postcode(s) [2] 0 0
4102 - Woolloongabba
Recruitment postcode(s) [3] 0 0
3128 - Box Hill
Recruitment postcode(s) [4] 0 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Illinois
Country [3] 0 0
United States of America
State/province [3] 0 0
Indiana
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
Michigan
Country [6] 0 0
United States of America
State/province [6] 0 0
Minnesota
Country [7] 0 0
United States of America
State/province [7] 0 0
Missouri
Country [8] 0 0
United States of America
State/province [8] 0 0
New York
Country [9] 0 0
United States of America
State/province [9] 0 0
Ohio
Country [10] 0 0
United States of America
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Tennessee
Country [11] 0 0
United States of America
State/province [11] 0 0
Texas
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United States of America
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Wisconsin
Country [13] 0 0
Brazil
State/province [13] 0 0
Santa Catarina
Country [14] 0 0
Brazil
State/province [14] 0 0
Rio de Janeiro
Country [15] 0 0
Brazil
State/province [15] 0 0
Sao Paulo
Country [16] 0 0
Canada
State/province [16] 0 0
Alberta
Country [17] 0 0
Canada
State/province [17] 0 0
British Columbia
Country [18] 0 0
Canada
State/province [18] 0 0
Ontario
Country [19] 0 0
Czechia
State/province [19] 0 0
Moravskoslezsk Kraj
Country [20] 0 0
Czechia
State/province [20] 0 0
Praha, Hlavni Mesto
Country [21] 0 0
Denmark
State/province [21] 0 0
Aahus
Country [22] 0 0
Denmark
State/province [22] 0 0
Copenhagen
Country [23] 0 0
France
State/province [23] 0 0
Loire-Atlantique
Country [24] 0 0
France
State/province [24] 0 0
Lille
Country [25] 0 0
France
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Limoges
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France
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Paris
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France
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Toulouse
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Germany
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Berlin
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Germany
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Hamburg
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Germany
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Heidelberg
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Greece
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Achaia
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Greece
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Athens
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Israel
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Haifa
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Israel
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Jerusalem
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Israel
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Kfar Saba
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Israel
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Petach Tikva
Country [37] 0 0
Israel
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Ramat-Gan
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Italy
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Bologna
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Italy
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Pavia
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Korea, Republic of
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Incheon
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Korea, Republic of
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Seoul
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Netherlands
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Noord-Holland
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Netherlands
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AZ Maastricht
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Netherlands
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Utrecht
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Spain
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Navarra
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Spain
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Barcelona
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Spain
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Madrid
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Spain
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Majadahonda
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Spain
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Salamanca
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United Kingdom
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Birmingham
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United Kingdom
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London
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United Kingdom
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Manchester
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United Kingdom
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Oxford

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Millennium Pharmaceuticals, Inc.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The purpose of this study is to provide continued access of ixazomib and/or other study
medications and to continue collecting relevant safety data to monitor participant's safety,
determine whether dexamethasone plus IXAZOMIB improves hematologic response, 2-year vital
organ (that is, heart or kidney) deterioration and mortality rate versus a physician's choice
of a chemotherapy regimen in participants diagnosed with relapsed or refractory systemic
light chain (AL) amyloidosis.
Trial website
https://clinicaltrials.gov/ct2/show/NCT01659658
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Takeda
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT01659658