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Trial registered on ANZCTR


Registration number
ACTRN12611000561987
Ethics application status
Approved
Date submitted
11/03/2011
Date registered
1/06/2011
Date last updated
10/05/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
An international trial with a new standard of care for patients with AL amyloidosis.
Scientific title
A randomized open-label multicenter phase III trial of Melphalan and Dexamethasone (MDex) versus Bortezomib, Melphalan and Dexamethasone (BMDex), investigating the haematologic response after 3 cycles of therapy, in untreated patients with systemic light-chain (AL) amyloidosis
Secondary ID [1] 259754 0
NCT01277016
Universal Trial Number (UTN)
U1111-1119-8036
Trial acronym
ALLG MM13
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Untreated systemic light chain amyloidosis 261333 0
Amyloid 261354 0
Condition category
Condition code
Cancer 259513 259513 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
After stratification, patients will be randomized to receive either:

MDex: Patients will take oral melphalan at a dose of 0.22 mg/kg and oral dexamethasone at 40 mg daily for four consecutive days at the beginning of each cycle (days 1-4)every 28 days (MDex).

or

BMDex: cycles 1 and 2 = MDex (as above) with bortezomib at 1.3 mg/m2 i.v. on days 1, 4, 8 and 11 of a 28 day cycle,
cycles 3 – 8 = MDex with bortezomib at 1.3 mg/m2 i.v. on days 1, 8, 15 and 22 of a 35 day cycle.
(Experimental Arm: The combination of Bortezomib, Melphalan and Dexamethasone (BMDex))
Intervention code [1] 264179 0
Treatment: Drugs
Comparator / control treatment
The melphalan and dexamethasone (MDex) arm will be used as the control.

MDex: oral melphalan at 0.22 mg/kg and oral dexamethasone at 40 mg daily for 4 consecutive days every 28 days
Control group
Active

Outcomes
Primary outcome [1] 262290 0
To compare in patients treated with melphalan and dexamethasone or bortezomib, melphalan and dexamethasone: the hematologic response after 3 cycles.This will be scored as improved, stable or worsened after 3, 6 and 9 cycles of therapy, then every 6 weeks until disease progression or until 2 years after randomization. After disease progression the patients will be followed for survival and subsequent therapy at least every 3 months for at least 2 years.
Timepoint [1] 262290 0
The hematologic response after 3 cycles.
Secondary outcome [1] 273470 0
Hematological response at completion of therapy;

The hematologic response will be scored as improved, stable or worsened after 3, 6 and 9 cycles of therapy, then every 6 weeks until disease progression or until 2 years after randomization. After disease progression the patients will be followed for survival and subsequent therapy at least every 3 months for at least 2 years. Secondary endpoints include hematologic and amyloid disease responses, and overall survival at 12 and 24 months. Patients will be followed until death and the date of death must be recorded.
Timepoint [1] 273470 0
Completion of therapy;
Secondary outcome [2] 273527 0
organ response rates at 3, 6, 9 and 12 months;

Amyloid-related organ response will be evaluated on the basis of the accepted criteria described below:

An improvement of one or more affected organ(s) is defined by:
For the Kidneys: a 50% reduction in 24-hour urine protein excretion in the absence of progressive renal insufficiency (creatinine clearance decreased by a minimum of 25% over baseline).

For the Heart (echocardiograms must be performed at the same institution): a minimum of 2 mm reduction in the mean left ventricular thickness (average of posterior wall and septal thickness) by echocardiogram,

or improvement of ejection fraction (EF) by at least 20%,

or reduction of NT-proBNP of 30% and more than 300 ng/L over the starting value.
For the Liver:
a minimum of 50% decrease of an initially elevated alkaline phosphatase level,

or reduction in the size of the liver by at least 2 cm (determined by physical exam, US, CT or MRI).

Improvement in organ function must be confirmed at the next visit, in the absence of worsening of any other organs unless worsening is considered a treatment adverse event.
The Investigators may elect to repeat seemingly spurious results.


amyloid-related organ involvement will be scored as improved, stable or worsened after 3, 6 and 9 cycles of therapy, then every 6 weeks until disease progression or until 2 years after randomization. After disease progression the patients will be followed for survival and subsequent therapy at least every 3 months for at least 2 years. Secondary endpoints include hematologic and amyloid disease responses, and overall survival at 12 and 24 months. Patients will be followed until death and the date of death must be recorded.
Timepoint [2] 273527 0
3, 6, 9 and 12 months;
Secondary outcome [3] 273528 0
treatment-related mortality;

Patients will be followed until death and the date of death must be recorded.
Timepoint [3] 273528 0
end of study
Secondary outcome [4] 273529 0
toxicity.

Toxicities are to be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0
Timepoint [4] 273529 0
Before each cycle, at the end of treatment, every 6 weeks before progression, and then every 3 months after progression.
Secondary outcome [5] 273530 0
overall survival;

Secondary endpoints include hematologic and amyloid disease responses, and overall survival at 12 and 24 months. Patients will be followed until death and the date of death must be recorded.
Timepoint [5] 273530 0
end of study
Secondary outcome [6] 273531 0
progression-free survival;

Secondary endpoints include hematologic and amyloid disease responses, and overall survival at 12 and 24 months. Patients will be followed until death and the date of death must be recorded.
Timepoint [6] 273531 0
end of study
Secondary outcome [7] 273532 0
time to hematologic response;

The hematologic response will be scored as improved, stable or worsened after 3, 6 and 9 cycles of therapy, then every 6 weeks until disease progression or until 2 years after randomization.
Timepoint [7] 273532 0
before each cycle
Secondary outcome [8] 273533 0
time to organ response;

amyloid-related organ involvement will be scored as improved, stable or worsened after 3, 6 and 9 cycles of therapy, then every 6 weeks until disease progression or until 2 years after randomization. After disease progression the patients will be followed for survival and subsequent therapy at least every 3 months for at least 2 years.
Timepoint [8] 273533 0
before each cycle
Secondary outcome [9] 273534 0
quality of life;

Quality of Life QoL questionnaires will be administered to patients at each visit. The SF-36 and QLQ-C30 surveys will be used to register patient-reported outcomes.
Timepoint [9] 273534 0
before each cycle and every 3 months after progression;

Eligibility
Key inclusion criteria
Histologic diagnosis of amyloidosis.
Genetic testing must be negative for transthyretin mutations associated with hereditary amyloidosis or immunohistochemistry of amyloid deposits must provide clear evidence of kappa or lambda light chains in those who present with peripheral neuropathy or heart as the dominant organ involvement.
Not eligible for transplant with melphalan 200 mg/m2. Patients who are eligible for transplant with melphalan 200 mg/m2 but decline the procedure, can be enrolled in the study, but are stratified in a separate stratum before randomization.
Eastern Cooperative Oncology Group performance status 0, 1 or 2.
Measurable disease; at least one of the following criteria:
Monoclonal protein more than 10 g/L in serum,
Amyloid-forming (involved) free light chains greater than 75 mg/L with an abnormal kappa-lambda ratio,
Difference between involved and uninvolved free light chains grater than 50 mg/L
Bone marrow with a clonal predominance.
Symptomatic organ involvement (heart, kidney, liver/Gastrointestinal tract, peripheral nervous system).
Hemoglobin of 11 g/dL, absolute neutrophil count of 1500/microL, platelets of 140,000/microL.
Total bilirubin less than 2.5 mg/dL, alkaline phosphatase less than 5 times the upper limit of normal, Alanine transaminase 3 times the upper limit of normal (patients with a documented history of Gilbert’s disease who have a total bilirubin (predominantly unconjugated) greater than 2.5mg/L without any other liver function test abnormalities are still eligible)
Estimated glomerular filtration rate by the modification of diet in renal disease formula greater than 30 ml/min.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Amyloid-specific syndrome, such as carpal tunnel syndrome or skin purpura as the only evidence of disease. The finding of isolated vascular amyloid in a bone marrow biopsy specimen or in a plasmacytoma is not indicative of systemic amyloidosis.
Isolated soft tissue involvement.
Presence of non-AL amyloidosis.
Previous treatment for plasma cell disease. A single previous cycle of dexamethasone or steroid equivalent (maximum cumulative dexamethasone dose 160 mg) is allowed; in this case baseline data must be obtained after steroid administration. Previous stem cell harvest is allowed, provided that mobilization is performed with granulocyte colony stimulating factor only.
Bone marrow plasma cells greater than 30 percent.
Cardiac stage three disease
Chronic atrial fibrillation
Supine systolic blood pressure less than 100mmHg or symptomatic orthostatic hypotension or clinically important autonomic disease
Grade 3 sensory or grade 1 painful peripheral neuropathy.
Clinically overt multiple myeloma with lytic bone lesions
Patients with uncontrolled infection or active malignancy with the exception of adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years.
Patients with hypersensitivity to bortezomib, boron or mannitol.

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)
The patients will be screened and enrolled by their treating physician.
The patients will be randomized according to their fulfilment of the stratification criteria.

Randomization will be centralized at the Biometry & Clinical Epidemiology Service of the Coordinating Center (Fondazione IRCCS Policlinico San Matteo, Pavia, Italy). Random 1:1 allocation of treatments, balanced in blocks of different size, will be performed, while stratifying on cardiac stage, with the use of the Stata software.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
will be preformed electronically. Random 1:1 allocation of treatments, balanced in blocks of different size, will be performed, while stratifying on cardiac stage, with the use of the Stata software.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



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

Recruitment
Recruitment status
Active, not recruiting
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,SA,WA
Recruitment hospital [1] 8213 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 8214 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [3] 8215 0
The Alfred - Prahran
Recruitment hospital [4] 8216 0
Gosford Hospital - Gosford
Recruitment hospital [5] 8217 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [6] 8218 0
Westmead Hospital - Westmead
Recruitment hospital [7] 8219 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 16272 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 16273 0
3065 - Fitzroy
Recruitment postcode(s) [3] 16274 0
3004 - Prahran
Recruitment postcode(s) [4] 16275 0
2250 - Gosford
Recruitment postcode(s) [5] 16276 0
5000 - Adelaide
Recruitment postcode(s) [6] 16277 0
2145 - Westmead
Recruitment postcode(s) [7] 16278 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 3251 0
Italy
State/province [1] 3251 0
Pavia
Country [2] 3252 0
United Kingdom
State/province [2] 3252 0
London
Country [3] 3253 0
Netherlands
State/province [3] 3253 0
Groeningen
Country [4] 3254 0
Germany
State/province [4] 3254 0
Heidelberg
Country [5] 3255 0
Spain
State/province [5] 3255 0
Salamanca
Country [6] 3256 0
Greece
State/province [6] 3256 0
Athens
Country [7] 3257 0
Denmark
State/province [7] 3257 0
Copenhagen
Country [8] 3258 0
France
State/province [8] 3258 0
Paris
Country [9] 3259 0
France
State/province [9] 3259 0
Nantes
Country [10] 3260 0
France
State/province [10] 3260 0
Limoges
Country [11] 3261 0
Sweden
State/province [11] 3261 0
Stockholm
Country [12] 3262 0
Sweden
State/province [12] 3262 0
Gothenburg
Country [13] 3263 0
Norway
State/province [13] 3263 0
Oslo
Country [14] 3264 0
Norway
State/province [14] 3264 0
Trondheim

Funding & Sponsors
Funding source category [1] 264646 0
Other Collaborative groups
Name [1] 264646 0
Australasian Leukaemia and Lymphoma Group
Address [1] 264646 0
Level 6, 372 Albert St
East Melbourne, Victoria
Australia. 3002
Country [1] 264646 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group (ALLG)
Address
Level 6, 372 Albert St
East Melbourne, Victoria
Australia. 3002
Country
Australia
Secondary sponsor category [1] 263789 0
None
Name [1] 263789 0
Address [1] 263789 0
Country [1] 263789 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 266645 0
The Alfred Ethics Committee
Ethics committee address [1] 266645 0
55 Commercial Rd
Melbourne
Vic 3004
Ethics committee country [1] 266645 0
Australia
Date submitted for ethics approval [1] 266645 0
20/03/2011
Approval date [1] 266645 0
24/04/2013
Ethics approval number [1] 266645 0
Ethics committee name [2] 297844 0
Metro South Hospital and Health Service HREC
Ethics committee address [2] 297844 0
Centre for Health Research
Princess Alexandra Hospital
Woolloongabba
QLD 4102
Ethics committee country [2] 297844 0
Australia
Date submitted for ethics approval [2] 297844 0
Approval date [2] 297844 0
Ethics approval number [2] 297844 0
Ethics committee name [3] 297845 0
Royal Adelaide Hospital Research Ethics Committee
Ethics committee address [3] 297845 0
Level 3 Hanson Institute
Royal Adelaide Hospital
North Terrace
Adelaide
SA 5000
Ethics committee country [3] 297845 0
Australia
Date submitted for ethics approval [3] 297845 0
Approval date [3] 297845 0
04/05/2012
Ethics approval number [3] 297845 0
Ethics committee name [4] 297846 0
Sir Charles Gairdner Group HREC
Ethics committee address [4] 297846 0
Level 2 A Block,
Hospital Ave
Nedlands
WA 6009
Ethics committee country [4] 297846 0
Australia
Date submitted for ethics approval [4] 297846 0
Approval date [4] 297846 0
11/05/2012
Ethics approval number [4] 297846 0
Ethics committee name [5] 297847 0
St Vincent's HREC Melbourne
Ethics committee address [5] 297847 0
PO Box 2900
Fitzroy
Melbourne
Vic 3065
Ethics committee country [5] 297847 0
Australia
Date submitted for ethics approval [5] 297847 0
Approval date [5] 297847 0
30/03/2012
Ethics approval number [5] 297847 0

Summary
Brief summary
We propose to test in a phase III study (oral melphalan and dexamethasone (MDex), the standard therapy for AL patients who are not autologous candidates for stem cell transplant (ASCT), against bortezomib added to MDex (BMDex). The hematologic response rate with MDex is 60% with 30% complete responses. The median overall survival with MDex is 5.1 years and the median progression free survival is 3.8 years. The basis for the combination of BMDex includes the high activity of bortezomib in AL, particularly the high complete response rate and the rapidity of hematologic response to bortezomib and dexamethasone, and the large clinical experience in phase II and phase III studies with bortezomib, melphalan and prednisone in myeloma.

Untreated patients diagnosed with AL who are not candidates for stem cell transplant with melphalan 200 mg/m2 are the target population. Patients who are eligible for SCT with melphalan 200 mg/m2 but who decline the procedure can be enrolled in the study as a subgroup with stratified randomization. Because many newly diagnosed AL patients present with limited organ reserve, the eligibility criteria take into consideration the impact of cardiac involvement on overall survival using cardiac biomarker staging. Stage I and II patients will be eligible and stage III patients will be enrolled in an ancillary phase II study.
Trial website
www.allg.org
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 32297 0
A/Prof Peter Mollee
Address 32297 0
Australasian Leukaemia and Lymphoma Group
35 Elizabeth Street
Richmond
VIC 3121
Country 32297 0
Australia
Phone 32297 0
+61 7 3240 2396
Fax 32297 0
Email 32297 0
Peter_Mollee@health.qld.gov.au
Contact person for public queries
Name 15544 0
Ms Delaine Smith
Address 15544 0
Australasian Leukaemia and Lymphoma Group
35 Elizabeth Street
Richmond
VIC 3121
Country 15544 0
Australia
Phone 15544 0
+61 3 8373 9701
Fax 15544 0
Email 15544 0
delaine.smith@allg.org.au
Contact person for scientific queries
Name 6472 0
A/Prof Peter Mollee
Address 6472 0
Australasian Leukaemia and Lymphoma Group
35 Elizabeth Street
Richmond
VIC 3121
Country 6472 0
Australia
Phone 6472 0
61 7 3240 2396
Fax 6472 0
Email 6472 0
Peter_Mollee@health.qld.gov.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 2166 0
Kastritis E, Leleu X, Arnulf B, et al. A randomized phase III trial of Melphalan and Dexamethasone (MDex) versus Bortezomib, Melphalan and Dexamethasone (BMDex) for untreated patients with AL Amyloidosis. Blood. 2016;128:abstr 646. doi: 10.1182/blood-2016-02-702696.
Attachments [1] 2166 0
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary