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Trial registered on ANZCTR


Registration number
ACTRN12616000772448
Ethics application status
Approved
Date submitted
30/05/2016
Date registered
14/06/2016
Date last updated
1/05/2019
Date data sharing statement initially provided
1/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 3 trial of thalidomide-dexamethasone consolidation versus thalidomide-dexamethasone-Ixazomib consolidation for transplant eligible multiple myeloma patients undergoing a single autologous stem cell transplantation as part of front-line therapy
Scientific title
A Phase 3 trial of thalidomide-dexamethasone consolidation versus thalidomide-dexamethasone-Ixazomib consolidation for transplant eligible multiple myeloma patients undergoing a single ASCT as part of front-line therapy
Secondary ID [1] 289239 0
ALLG MM19
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 298812 0
Condition category
Condition code
Cancer 298866 298866 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomised, multi-centre, open label phase 3 trial, with the primary objective to determine whether the addition of ixazomib to thalidomide and low dose dexamethasone maintenance therapy post-ASCT for MM patients improves progression free survival (PFS) and/or overall survival (OS).

Patients with symptomatic MM who are transplant eligibile will be registered prior to undergoing ASCT. Patients who have achieved clinical and haematologic recovery following ASCT will initiate screening for study eligibility no earlier than 75 days following ASCT, complete screening within 15 days, and be randomised no later than 115 days after ASCT.

Patients are randomised 1:1 to receive either:
Arm 1 (Control)- 12 cycles of thalidomide (100mg/day- oral tablet), dexamethasone (40mg/week- oral tablet); or
Arm 2 (Experimental): 12 cycles of thalidomide (100mg/day- oral tablet), dexamethasone (40mg/week-oral tablet), plus ixazomib therapy (4mg, on day 1, day 8, and day15 of each cycle- oral capsule);
for a maximum of 12 months.

A treatment cycle is defined as 28 days. Cycle 13 is the time-point at the end of consolidation treatment (cycles 1-12)

The study drugs will be administered or dispensed only to eligible patients under the supervision of the investigator or identified sub-investigator(s). The appropriate study personnel will maintain records of study drug receipt and dispensing.
Intervention code [1] 294783 0
Treatment: Drugs
Comparator / control treatment
Thalidomide (100mg/day- oral tablet) + Dexamethasone (40mg/week- oral tablet), for a maximum of 12 months
Control group
Active

Outcomes
Primary outcome [1] 298350 0
To determine whether the addition of ixazomib to thalidomide and low dose dexamethasone consolidation therapy post-ASCT for MM patients, improves progression free survival (PFS).
Timepoint [1] 298350 0
Progression free survival (PFS) is measured from the date of randomisation until the earliest date of relapse, progression, or death from any cause. Patients who have not relapsed, progressed or died by the study close-out date will have their PFS censored at the study close-out date for PFS, unless they are deemed lost to follow up before that date, in which case their PFS will be censored at the date that they were last known to be alive and progression-free. The study close-out date for PFS is the earliest of the last dates of disease assessment for patients who are alive, progression-free and on-study. Missing disease assessments will be handled as follows: if disease progression or death is documented after one single missing assessment, the actual event date of the progression or death will be used for the PFS date. If disease progression is documented after two or more missing assessments, the PFS time of these patients will be censored at the date of the last assessment as per the International Myeloma Working Group (IMWG) response criteria for MM.

Disease outcome measures are based on high vs standard risk disease (as defined by Revised International Staging System R-ISS for Multiple Myeloma) and as per the IMWG response criteria for MM.
Secondary outcome [1] 323911 0
To determine whether the addition of ixazomib to thalidomide and low dose dexamethasone improves overall survival (OS).
Timepoint [1] 323911 0
Patients will be assessed for OS (vital status) monthly during consolidation treatment, then cycle 13 onwards. OS is measured from the date of randomisation until the date of death from any cause. Patients who are not known to have died by the study close-out date will have their OS censored at the study close-out date for OS unless they are deemed lost to follow-up before that date, in which case their OS will be censored at the date they were last known to be alive. The study close-out date for OS is the earliest of the last dates of assessment of vital status for patients remaining on the study.
Secondary outcome [2] 323913 0
To determine salvageability at time of relapse, "PFS2", which is the time from randomisation to progression on first salvage (second line) treatment.
Timepoint [2] 323913 0
Following progression, patients will be followed up every 3 months to document disease outcome measures, as defined by the Revised International Staging System R-ISS for Multiple Myeloma and the IMWG response criteria for MM.
Secondary outcome [3] 323914 0
To determine the safety ixazomib in combination with thalidomide and low dose dexamethasone consolidation therapy post-ASCT in Multiple Myeloma patients.
Timepoint [3] 323914 0
Ongoing analysis from registration to end of follow up period (60 months). Study parameters include documentation of medication administered, adverse events (as per the Common Terminology Criteria for Adverse Events, CTCAE v4.0), and dose adjustments.
Secondary outcome [4] 323915 0
To assess the impact of the addition of ixazomib on Quality of Life (QoL)/Patient reported health outcomes (PRO).
Timepoint [4] 323915 0
Ongoing analysis from registration to the end of the follow up period (60 months). The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life - Core questionairre (QLQ-C30) version 3, and MM module (QLQ-MY20) will be used to assess PROs in the MM19 trial.
Questionnaires are to be completed at the following time points- Registration, 75-115 days post ASCT, day 1 of every 28 day cycle (cycle 1-cycle 12), day 1 of every month in the follow up period post- cycle 12, at disease progression, and every 3 months following progression in the overall survival follow up period.
Secondary outcome [5] 323918 0
To assess the cost-effectiveness of ixazomib in combination with thalidomide low and dose dexamethasone compared with thalidomide and low dose dexamethasone as consolidation therapy post-ASCT in Multiple Myeloma patients
Timepoint [5] 323918 0
Ongoing analysis from registration to end of follow up (60 months). Health economics data will include the following documentation: EUROQoL EQ-5D-5L questionnaire; hospitalisations; concomitant medications; AE/SAE treatment; protocol drug use.

Questionnaires are to be completed at the following time points- Registration, 75-115 days post ASCT, day 1 of every 28 day cycle (cycle 1-cycle 12), day 1 of every month in the follow up period post- cycle 12, at disease progression, and every 3 months following progression in the overall survival follow up period.
Secondary outcome [6] 324608 0
To determine whether the addition of ixazomib to thalidomide and low dose dexamethasone improves overall response rate (ORR), including MRD negativity
Timepoint [6] 324608 0
Patients will be assessed for ORR monthly during consolidation treatment, then every 3 months following disease progression or C13 onwards. ORR will be determined by tabulating each patient's disease response according to the IMWG uniform response criteria. OR is defined as the achievement of a partial response (PR) or better on study.
Secondary outcome [7] 324612 0
To determine the tolerability (measured by performance status (Eastern Cooperative Oncology Group scale)) of ixazomib in combination with thalidomide and low dose dexamethasone consolidation therapy post-ASCT in MM patients.

Timepoint [7] 324612 0
Ongoing analysis from registration to end of follow up period (60 months). Study parameters include documentation of medication administered, adverse events (as per the Common Terminology Criteria for Adverse Events, CTCAE v4.0), and dose adjustments.

Eligibility
Key inclusion criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Male or female patients 18 years or older.
2. Voluntary written informed 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 patient at any time without prejudice to future medical care.
3. Patients must have a diagnosis of a symptomatic MM as per IMWG criteria and be eligible for front-line melphalan conditioned ASCT, with > 2x 10^6 CD34/Kg available for ASCT.
4. Female patients who:
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from 4 weeks before the start of study treatment and during the entire study treatment period and through 90 days after the last dose of the study drugs, OR
- Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).
Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following:
- Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
- Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).
5. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.
6. Patients must meet the following clinical laboratory criteria:
- Absolute neutrophil count (ANC) >= 1,000/mm^3 and platelet count >= 75,000/mm^3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.
- Total bilirubin <= 1.5 x the upper limit of the normal range (ULN).
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3 x ULN.
- Calculated creatinine clearance >= 30 mL/min per Cockcroft-Gault equation.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Female patients who are lactating or have a positive serum pregnancy test during the screening period.
2. Failure to have fully recovered (i.e., <= Grade 1 toxicity) from the reversible effects of prior chemotherapy.
3. Progressive disease post-ASCT
4. Failure of haemopoietic recovery post-ASCT
5. Major surgery within 14 days before enrolment.
6. Radiotherapy within 14 days before enrolment. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the ixazomib.
7. Central nervous system involvement with the disease under study (myeloma).
8. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrolment.
9. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
10. Systemic treatment, within 14 days before the first dose of ixazomib, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort.
11. Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.
12. Any serious medical or psychiatric condition (including uncontrolled infection) that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol or would be a contraindication to consolidation/maintenance therapy
13. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
14. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing.
15. Diagnosed or treated for another malignancy within 2 years before study enrolment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
16. Patient has >= Grade 2 peripheral neuropathy, or Grade 1 with pain on clinical examination during the screening period.
17. Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial.
18. Contraindication to the use of either thalidomide, ixazomib or dexamethasone

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)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
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)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 8230 0
The Alfred - Prahran
Recruitment hospital [2] 10838 0
Box Hill Hospital - Box Hill
Recruitment hospital [3] 10839 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [4] 10840 0
The Tweed Hospital - Tweed Heads
Recruitment hospital [5] 10841 0
Royal Hobart Hospital - Hobart
Recruitment hospital [6] 10842 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 16288 0
3004 - Prahran
Recruitment postcode(s) [2] 22582 0
3128 - Box Hill
Recruitment postcode(s) [3] 22583 0
4102 - Woolloongabba
Recruitment postcode(s) [4] 22584 0
2485 - Tweed Heads
Recruitment postcode(s) [5] 22585 0
7000 - Hobart
Recruitment postcode(s) [6] 22586 0
2010 - Darlinghurst
Recruitment outside Australia
Country [1] 7906 0
New Zealand
State/province [1] 7906 0

Funding & Sponsors
Funding source category [1] 293630 0
Commercial sector/Industry
Name [1] 293630 0
Takeda Pharmaceuticals U.S.A. Inc.
Address [1] 293630 0
One Takeda Parkway
Deerfield, IL 60015
Country [1] 293630 0
United States of America
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group (ALLG)
Address
Ground Floor, 35 Elizabeth Street,
Richmond
Melbourne, Victoria, 3121
Country
Australia
Secondary sponsor category [1] 292465 0
None
Name [1] 292465 0
Address [1] 292465 0
Country [1] 292465 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295125 0
Alfred Health
Ethics committee address [1] 295125 0
The Alfred Hospital
55 Commercial Road,
Prahran VIC 3181
Ethics committee country [1] 295125 0
Australia
Date submitted for ethics approval [1] 295125 0
01/07/2016
Approval date [1] 295125 0
15/12/2016
Ethics approval number [1] 295125 0

Summary
Brief summary
PURPOSE
The primary purpose of this study is to determine the efficacy and safety of the addition of ixazomib and low dose dexamethasone maintenance therapy for transplant-eligible multiple myeloma (MM) patients who are undergoing single autologous stem cell transplantation (ASCT) as part of front-line therapy.

WHO IS IT FOR?
You may be eligible to join this study if you are aged over 18 years, have been diagnosed with symptomatic MM as per International Myeloma Working Group (IMWG) criteria, are eligible for front-line melphalan conditioned autologous stem cell transplant (ASCT), and do not have central nervous system involvement with the disease (MM).

STUDY DETAILS
Enrolled participants who have achieved clinical and haematological recovery following ASCT will undergo screening for study eligibility no earlier than 75 days following ASCT, complete screening within 15 days, and be randomised into treatment arms no later than 115 days after ASCT.

Participants will then be randomised 1:1 to the control arm (thalidomide + dexamethasone), or the experimental arm (thalidomide + dexamethasone + ixazomib), for a maximum of 12 months or until the disease progresses, whichever occurs first.

Outcomes
It is hoped that the findings of this trial will provide information on:
1. Whether the addition of ixazomib to standard maintenance therapy will improve progression free survival in multiple myeloma patients who have undergone ASCT as part of front-line therapy; and
2. Provide information on the safety and efficacy of ixazomib addition to standard maintenance therapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 65926 0
Prof Andrew Spencer
Address 65926 0
Department of Clinical Haematology
Alfred Health
55 Commercial Road
Melbourne Victoria 3004
Country 65926 0
Australia
Phone 65926 0
+61390763393
Fax 65926 0
Email 65926 0
aspencer@netspace.net.au
Contact person for public queries
Name 65927 0
Prof Andrew Spencer
Address 65927 0
Department of Clinical Haematology
Alfred Health
55 Commercial Road
Melbourne Victoria 3004
Country 65927 0
Australia
Phone 65927 0
+61390763393
Fax 65927 0
Email 65927 0
aspencer@netspace.net.au
Contact person for scientific queries
Name 65928 0
Prof Andrew Spencer
Address 65928 0
Department of Clinical Haematology
Alfred Health
55 Commercial Road
Melbourne Victoria 3004
Country 65928 0
Australia
Phone 65928 0
+61390763393
Fax 65928 0
Email 65928 0
aspencer@netspace.net.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
No Results