Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12612000419864
Ethics application status
Approved
Date submitted
10/04/2012
Date registered
13/04/2012
Date last updated
26/08/2019
Date data sharing statement initially provided
26/08/2019
Date results information initially provided
26/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomized phase III study to compare Bortezomib, Melphalan, Prednisone (VMP) with High Dose Melphalan followed by Bortezomib, Lenalidomide, Dexamethasone
(VRD) consolidation and Lenalidomide maintenance in patients with newly diagnosed multiple myeloma
Scientific title
A double randomized phase III study in patients with newly diagnosed multiple myeloma to compare progression free survival (PFS) following treatment with either Bortezomib, Melphalan, Prednisone (VMP) or High Dose Melphalan followed by either Bortezomib, Lenalidomide, Dexamethasone (VRD) consolidation or no consolidation treatment, and Lenalidomide maintenance.
Secondary ID [1] 280291 0
ALLG MM15
Secondary ID [2] 280324 0
HOVON 95 MM
Secondary ID [3] 280326 0
www.clinicaltrials.gov NCT01208766
Universal Trial Number (UTN)
Trial acronym
ALLG MM15
Linked study record

Health condition
Health condition(s) or problem(s) studied:
newly diagnosed mutiple myeloma 286248 0
Condition category
Condition code
Cancer 286465 286465 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Numbers 1-4 are different treatment stages of this trial. The trial is a two arm controlled randomised trial with two subsequent randomisations.
1. 3 by 21 day cycles of: Bortezomib (1.3mg/m^2 i.v days 1,4,8,11), cyclophosphamide (500mg/m^2 i.v days 1,8), dexamethasone (40mg orally days 1,2,4,5,8,9,11,12) then cyclophosphamide mobilisation and collection of stem cells (non randomised)
2. Starting 4-6 weeks after stem cell mobilisation, 4 by 42 day cycles of VMP (Bortezomib (1.3mg/m^2 i.v days 1,4,8,11, 22,25,29,32), Melphalan (9mg/m^2 orally days1-4), Prednisolone 60mg/m^2 orally days 1-4)
3. Beginning 8 weeks after the last dose of VMP (or High Dose Melphalan from corresponding arm below) consolidation therapy of VRD consisting of 2 by 28 day cycles of Bortezomib (1.3mg/m^2 i.v days 1,4,8,11), Lenalidomide (25mg orally on days 1-21), Dexamethasone (20mg orally on days 1,2,4,5,8,9,11,12). Lenalidomide maintenenace will start immdeiately after the completion of this phase of treatment.
4. Lenalidomide maintenance (non-randomised) 10mg daily orally days 1-28 until relapse or progression
Intervention code [1] 284645 0
Treatment: Drugs
Comparator / control treatment
Numbers in this section describe the 2nd arm of treatment corresponding to the treatment phases described above. There are two subsequent randomisations both consisting of two arms.
2. High dose Melphalan (HDM; 100mg/m^2 intravenously day-3,-2 prior to transplant) beginning 4-6 weeks after stem cell collection and autologous stem cell transplantation (ASCT) according to local protocol.
3. no consolidation. Lenalidomide maintenance (described above) will start 8 weeks after the completion of the end of the last dose of HDM.
Control group
Active

Outcomes
Primary outcome [1] 286916 0
PFS from randomisation to compare the efficacy of VMP versus high dose therapy (HDT) and stem cell transplantation. Disease progression will be determined by physician using results from clinical tests applied to a standard and protocol-defined definition of progression.
Timepoint [1] 286916 0
Following treatment in randomisation 1.
Primary outcome [2] 286917 0
To evaluate the effect of consolidation with VRD followed by Lenalidomide maintenance with no consolidation but Lenalidomide maintenance alone on progression free survival.
Disease progression will be determined by physician using results from clinical tests applied to a standard and protocol-defined definition of progression.
Timepoint [2] 286917 0
Following conclusion of maintenance therapy
Secondary outcome [1] 296980 0
To compare PFS in patients undergoing VMP versus single HDT+ ASCT; or VMP versus tandem HDT + ASCT; or single versus tandem HDT + ASCT.
Disease progression will be determined by physician using results from clinical tests applied to a standard and protocol-defined definition of progression.
The protocol allows for Australian sites to not be randomised to tandem transplant arm.
Timepoint [1] 296980 0
Following treatment in randomisation 1.
Secondary outcome [2] 296981 0
To assess safety and toxicity by tabulation of adverse events using CTCAE v4
Timepoint [2] 296981 0
duration of study treatment
Secondary outcome [3] 296982 0
To assess the prognostic value of risk factors at diagnosis on PFS
Timepoint [3] 296982 0
duration of trial
Secondary outcome [4] 296985 0
To compare overall response rate and complete and very good partial response (CR + VGPR)
Response will be determined by physician using results from clinical tests applied to standard and protocol-defined definitions of CR and VGPR.
Timepoint [4] 296985 0
after induction therapy
Secondary outcome [5] 296986 0
To compare overall response rate and complete and very good partial response (CR + VGPR)
Response will be determined by physician using results from clinical tests applied to standard and protocol-defined definitions of CR and VGPR.
Timepoint [5] 296986 0
after VMP or HDT
Secondary outcome [6] 296987 0
To compare overall response rate and complete and very good partial response (CR + VGPR)
Response will be determined by physician using results from clinical tests applied to standard and protocol-defined definitions of CR and VGPR.
Timepoint [6] 296987 0
after consolidation
Secondary outcome [7] 296988 0
To compare overall response rate and complete and very good partial response (CR + VGPR)
Response will be determined by physician using results from routine clinical tests applied to standard and protocol-defined definitions of CR and VGPR.
Timepoint [7] 296988 0
during maintenance therapy

Eligibility
Key inclusion criteria
-Patients with a confirmed diagnosis of symptomatic multiple myeloma stage I to III according to the International Staging System (ISS)
-Measurable disease as defined by the presence of M-protein in serum or urine (serum Mprotein > 10 g/l or urine M-protein > 200 mg/24 hours), or abnormal free light chain ratio;
-Age 18-65 years inclusive;
-World Health Organisation (WHO) performance status 0-3 (WHO=3 is allowed only when caused by MM and not by comorbid conditions)
-Negative pregnancy test at inclusion if applicable;
-Written informed consent.

Randomization 1
-WHO performance 0-2;
-Bilirubin and transaminases < 2.5 times the upper limit of normal values;
-A suitable stem cell graft containing at least 4 x 10^6 CD34+ cells/kg (or according to national guidelines).

Randomization 2
-Bilirubin and transaminases < 2.5 times the upper limit of normal values;
-Absolute Neutrophil Count >= 0.5 x 10^9/l and platelets > 20 x 10^9/l;
-Patient is able to adhere to the requirements of the Lenalidomide Pregnancy Prevention Risk Management Plan.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Known intolerance of Boron;
-Systemic light chain (AL) amyloidosis;
-Primary Plasmacell Leukemia;
-Non-secretory multiple myeloma (MM);
-Previous chemotherapy or radiotherapy except local radiotherapy in case of local myeloma progression or corticosteroids maximum 5 days for symptom control;
-Severe cardiac dysfunction (NYHA classification II-IV);
-Significant hepatic dysfunction (serum bilirubin >= 30 mmol/l or transaminases >= 2.5 times normal level), unless related to myeloma;
-Patients with glomerular filtration rate (GFR) <15 ml/min,
-Patients known to be Human immunodeficiency virus (HIV)-positive;
-Patients with active, uncontrolled infections;
-Patients with neuropathy, Common Toxicity Criteria for Adverse Events (CTCAE) grade 2 or higher;
-Patients with a history of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma;
-Patients who are not willing or capable to use adequate contraception during the therapy (all men, all pre-menopausal women);
-Lactating women.

Randomization 1
-Severe pulmonary, neurologic, or psychiatric disease;
CTCAE grade 3-4 polyneuropathy during Bortezomib treatment;
-Allogeneic Stem Cell Transplantation (Allo SCT) planned;
-Progressive disease.

Randomization 2
-Progressive disease;
-Neuropathy, except CTCAE grade 1;
-CTCAE grade 3-4 polyneuropathy during Bortezomib treatment

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)
patient will be registered and randomisation will be allocated from central trial coordinating centre.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised random number generation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Trial employs 2 subsequent randomisations. Only patients participating in first rnadomisation will be eligible for subsequent second randomisation.
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
21/01/2011
Actual
2/09/2013
Date of last participant enrolment
Anticipated
Actual
15/04/2014
Date of last data collection
Anticipated
Actual
15/04/2016
Sample size
Target
1500
Accrual to date
Final
1500
Recruitment in Australia
Recruitment state(s)
NSW,VIC,ACT,QLD,SA,WA,TAS

Funding & Sponsors
Funding source category [1] 285066 0
Other Collaborative groups
Name [1] 285066 0
Australasian Leukaemia and Lymphoma Group
Country [1] 285066 0
Australia
Primary sponsor type
Other Collaborative groups
Name
HOVON
Address
VU University Medical Center,
P.O.Box 7057
1007 MB Amsterdam
The Netherlands
Country
Netherlands
Secondary sponsor category [1] 283927 0
Other Collaborative groups
Name [1] 283927 0
Fonesa Onlus
Address [1] 283927 0
c/o Divisione Universitaria di Ematologia
Via Genova 3
10129 Turin, Italy
Country [1] 283927 0
Italy
Secondary sponsor category [2] 283928 0
Other Collaborative groups
Name [2] 283928 0
Australasian Leukaemia and Lymphoma Group
Address [2] 283928 0
Level 6, 372 Albert St.
East Melbourne, Vic., 3002.
Country [2] 283928 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287069 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 287069 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 287069 0
Australia
Date submitted for ethics approval [1] 287069 0
01/07/2012
Approval date [1] 287069 0
01/08/2013
Ethics approval number [1] 287069 0

Summary
Brief summary
Despite the use of high dose chemotherapy and ASCT (a procedure where the patient's own cells are collected, high dose therapy eliminates patient's cancer cells and patient's collected cells are reinfused), multiple myeloma remains incurable. This study aims to:
1.compare induction therapy employing either a chemotherapy regimen employing Bortezomib, melphalan and prednisolone or high dose therapy and ASCT
2. compare consolidation therapy employing either a chemotherapy regimen of bortezomib, lenalidomide and dexamethasone or no treatment
3. investigate maintenance therapy employing lenalidomide
The study plans to treat 1500 patients worldwide.

Trial details

In this study you will receive the drug bortezomib delivered intravenously (i.v) on days 1,4,8 and 11, the drug cyclophosphamide delivered i.v on days 1 and 8, and dexamethasone delivered orally on days 1,2,4,5,8,9,11 and 12 of a 21 day treatment cycle

you will then be allocated to receive either option in 1. and either option in 2. below
1. either 4 cycles of the drug bortezomib delivered intravenously (i.v) on days 1,4,8, 11, 22, 25, 29 and 32, the drug melphalan delivered orally on days 1 -4 and prednisolone delivered orally on days 1-4 of a 6 week cycle;or high dose melphalan i.v 3 and 2 days before reinfusion of patient's own stem cells
2. either 2 cycles of consolidation treatment consisting of the drug bortezomib delivered intravenously (i.v) on days 1,4,8 and 11, the drug lenalidomide delivered orally on days 1-21, and dexamethasone delivered orally on days 1,2,4,5,8,9,11 and 12 of a 28 day treatment cycle or no consolidation treatment

All patients will then receive repeating 28 day cycles of daily oral lenalidomide therapy as long as the therapy continues to fight the myeloma.

Your response to the treatment will be assessed at routine clinical visits using the usual clinical investigations that would monitor the status of your disease.

Who is it for?

This study is open to male or female patients aged 18-65 with a diagnosis of multiple myeloma. The full details of this study's inclusion and exclusion criteria can be found in the relevant sections within this record.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34037 0
Prof Andrew Spencer
Address 34037 0
Alfred Hospital
55 Commercial Rd, Melbourne VIC 3004
Country 34037 0
Australia
Phone 34037 0
+61 03 9076 2000
Fax 34037 0
Email 34037 0
[email protected]
Contact person for public queries
Name 17284 0
Ms Delaine Smith
Address 17284 0
Australasian Leukaemia and Lymphoma Group
Level 6, 372 Albert St.,
East Melbourne, Vic., 3002
Australia
Country 17284 0
Australia
Phone 17284 0
+61 3 96562760
Fax 17284 0
Email 17284 0
[email protected]
Contact person for scientific queries
Name 8212 0
Prof Andrew Spencer
Address 8212 0
Alfred Hospital
Commercial Road
Prahran
Melbourne, Victoria, 3004
Country 8212 0
Australia
Phone 8212 0
+61 3 9076 3393
Fax 8212 0
Email 8212 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
aggregate data is shared


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.