Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001030460
Ethics application status
Approved
Date submitted
15/06/2016
Date registered
4/08/2016
Date last updated
4/08/2023
Date data sharing statement initially provided
26/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Multicentre Phase 3 Trial Comparing Elotuzumab-Cyclophosphamide-Thalidomide-Dexamethasone (E-CTD) with Cyclophosphamide-Thalidomide-Dexamethasone (CTD) for the Treatment of Relapsed and/or Refractory Multiple Myeloma (RRMM)
Scientific title
A Multicentre Phase 3 Trial Comparing Elotuzumab-Cyclophosphamide-Thalidomide-Dexamethasone (E-CTD) with Cyclophosphamide-Thalidomide-Dexamethasone (CTD) for the Treatment of Relapsed and/or Refractory Multiple Myeloma (RRMM)
Secondary ID [1] 289340 0
ALLG MM20
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 298960 0
Condition category
Condition code
Cancer 299029 299029 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a prospective, multi-centre, open-label study, randomised controlled trial of elotuzumab-cyclosphamide-thalidomide-dexamethasone (E-CTD) compared with cyclophosphamide-thalidomide-dexamethasone (CTD). All patients will meet the eligibility criteria at registration and recruitment will continue until 300 patients have been randomised. Randomisation will occur in a 2:1 ratio with 2 patients randomised to the E-CTD arm for every 1 patient randomised to the CTD arm. Patients will not be replaced after randomisation occurs.

Treatment is as follows, with cycle durations of 28 days:

EXPERIMENTAL ARM (E-CTD):
Cycle 1 and Cycle 2 = Elotuzumab (10mg/kg IV weekly) + Cyclophosphamide (500mg oral tablet weekly) + Thalidomide (100mg oral capsule, once daily at night-time) + Dexamethasone (28 mg oral tablet weekly AND 8 mg IV weekly);
Cycle 3 and beyond = Elotuzumab (20mg/kg IV day 1) + Cyclophosphamide (500mg oral tablet weekly) + Thalidomide (100mg oral capsule, once daily at night-time) + Dexamethasone (28 mg oral tablet AND 8 mg IV on day 1; 40 mg oral tablet on days 8, 15, and 22).
To be repeated every 28 days, with tumour assessment every 4 weeks until disease progression, and then for overall survival every 12 weeks.

CONTROL ARM (CTD)
Cyclophosphamide (500mg oral tablet weekly) + Thalidomide (100mg oral capsule, once daily at night-time) + Dexamethasone (40 mg oral tablet weekly).
To be repeated every 28 days, with tumour assessment every 4 weeks until disease progression, and then for survival every 12 weeks.

Median expected duration of treatment is 12 months in the experimental arm, and 8 months in the control arm.
Except for an emergency situation in which proper care for the protection, safety and well-being of the trial participant requires that an alternative treatment be used, the trial shall be conducted exactly as described in the approved protocol. It is the responsibility of the investigator to document any protocol deviations in the appropriate log and the subject’s case report form (CRF), accompanied by a suitable explanation and to satisfy any reporting requirements of their local Human Research Ethics Committee (HREC).

The choice of agents for venous thromboembolism, anti-viral, acid reflux and bisphosphonate prophylaxis will be as per institutional protocol. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of patient consent or study closure.
Intervention code [1] 294903 0
Treatment: Drugs
Comparator / control treatment
ACTIVE CONTROL ARM (CTD)
Cyclophosphamide (500mg oral tablet weekly) + Thalidomide (100mg oral capsule, once daily at night) + Dexamethasone (40mg oral tablet weekly).
Control group
Active

Outcomes
Primary outcome [1] 298491 0
To determine the progression free survival (PFS) with E-CTD when compared to CTD for the treatment of RRMM
Timepoint [1] 298491 0
PFS will be measured from the date of randomisation to the date of the first documented progression, according to International Myeloma Working Group (IMWG) criteria, or the date of death. At the time of analysis, patients not deemed lost-to-follow-up, will have their PFS censored at the study censor date for PFS (the earliest of the last dates of assessment of patients not known to have died and not deemed lost to follow up). Patients deemed lost-to-follow up will have their PFS censored at the earlier of their last date of assessment or the study censor date for PFS.

Patients will be assessed for survival every 3 months after documentation of progression or the initiation of a new anti-cancer therapy, until the median follow up has reached 48 months or when all patients have either withdrawn, died, or been deemed lost to follow up.
Secondary outcome [1] 324359 0
To compare the overall response rate (ORR) and clinical benefit rate (CBR) (ORR + minimal response) achieved with E-CTD when compared with CTD for the treatment of RRMM. These are composite outcomes.
Timepoint [1] 324359 0
Analysis of ORR will take place when all patients remaining on the study have been assessed for objective response as per IMWG response criteria. The ORR will be calculated as the proportion of randomised patients in each arm who achieve a partial response or better. The same approach will also be used to investigate the CBR in each arm (the proportion of randomised patients in each arm who achieve an MR or better).
Secondary outcome [2] 324841 0
To determine the overall survival (OS) with E-CTD when compared with CTD for the treatment of RRMM.
Timepoint [2] 324841 0
OS will be measured from the date of randomisation to the date of death. Patients not deemed lost-to-follow-up will have their OS censored at the study censor date for OS (the earliest of the last dates of contact of patients not known to have died and not deemed lost to follow up). Patients deemed lost to follow up will have their OS censored at the earlier of their date of last contact or the study censor date for OS.
Secondary outcome [3] 324843 0
To determine the rate of minimal residual disease (MRD) negativity in patients achieving serological CR, and the impact of MRD on PFS. These are composite outcomes.
Timepoint [3] 324843 0
Euroflow 8 colour multiparameter flow cytometry (MFC) will be performed on bone marrow aspirate samples taken at suspected CR. MRD negativity in patients achieving serological CR will be summarised by treatment arm, as proportions will be reported. The impact of MRD negativity on PFS will be investigated by fitting time to MRD negativity as an additional time-varying covariate in the Cox PH model that also includes covariates for treatment arm and the randomisation strata.

Eligibility
Key inclusion criteria
1. Male or female patients 18 years or older.
2. 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 patient at any time without prejudice to future medical care.
3. 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 the time of signing the informed consent form through 120 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.)
4. Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following:
- Agree to practice effective barrier contraception during the entire study treatment period and through 120 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. Patients must abide by thalidomide pregnancy prevention programme
6. Patients must have a diagnosis of a relapsed/refractory multiple myeloma as per IMWG criteria
7. Patients have had between 1-3 prior lines of therapy
- May include autologous or allogeneic stem cell transplant (induction followed by ASCT and maintenance is one line of therapy)
8. No contraindication to the use of any of the study drugs
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
10. Patient must be greater or equal to 2 weeks from prior chemotherapy, radiotherapy, biological therapy, immunotherapy, major surgery or any other investigational anti-cancer therapy prior to the first dose of study drug
11. Patients must meet the following clinical laboratory criteria:
- Absolute neutrophil count (ANC) greater than or equal to 1,000/mm3 and platelet count greater than or equal to 75,000/mm3. Subjects who fail screening due to neutropenia or anaemia will not be permitted to use growth factors to become eligible. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrolment.
- Total bilirubin less than or equal to 1.5 x the upper limit of the normal range (ULN).
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than or equal to 3 x ULN.
- Calculated creatinine clearance greater than or equal to 30 mL/min
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known thalidomide refractory disease or intolerance
2. Patients with monoclonal gammopathy of uncertain significance or smouldering MM.
3. Patients with primary amyloidosis
4. Patients who have had a prior allogeneic transplantation that requires ongoing immunosuppressive therapy
5. Female patients who are lactating or have a positive serum pregnancy test during the screening period.
6. Failure to have fully recovered (i.e. less than or equal to Grade 1 toxicity) from the reversible effects of prior chemotherapy.
7. Major surgery or radiotherapy within 14 days before enrolment.
8. Central nervous system involvement.
9. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrolment.
10. Patients who are either contraindicated or unwilling to receive anticoagulation therapy
11. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, New York Heart Association (NYHA) class 3 or 4 heart failure symptoms, unstable angina, or myocardial infarction within the past 6 months.
12. Known ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive, other immunosuppressive therapy or autoimmune disease.
13. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
14. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
15. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of the oral study medications including difficulty swallowing.
16. 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.
17. Patient has greater than or equal to Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period.
18. Participation in other clinical trials for the treatment of multiple myeloma, 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.

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
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
24/10/2016
Actual
16/01/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
300
Accrual to date
23
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 8229 0
The Alfred - Prahran
Recruitment hospital [2] 10903 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [3] 10904 0
The Canberra Hospital - Garran
Recruitment hospital [4] 10905 0
The Tweed Hospital - Tweed Heads
Recruitment hospital [5] 10906 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [6] 10907 0
Tamworth Rural Referral Hospital - Tamworth
Recruitment hospital [7] 10908 0
Calvary Mater Newcastle - Waratah
Recruitment postcode(s) [1] 16287 0
3004 - Prahran
Recruitment postcode(s) [2] 22669 0
2485 - Tweed Heads
Recruitment postcode(s) [3] 22670 0
2340 - Tamworth
Recruitment postcode(s) [4] 22671 0
2298 - Waratah
Recruitment outside Australia
Country [1] 7959 0
New Zealand
State/province [1] 7959 0

Funding & Sponsors
Funding source category [1] 293830 0
Other Collaborative groups
Name [1] 293830 0
Bristol-Myers Squibb
Country [1] 293830 0
United States of America
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group (ALLG)
Address
Ground Floor, 35 Elizabeth Street
North Richmond, VIC, 3121
Country
Australia
Secondary sponsor category [1] 292659 0
None
Name [1] 292659 0
Address [1] 292659 0
Country [1] 292659 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295257 0
Alfred Health
Ethics committee address [1] 295257 0
Ethics committee country [1] 295257 0
Australia
Date submitted for ethics approval [1] 295257 0
01/09/2016
Approval date [1] 295257 0
17/11/2016
Ethics approval number [1] 295257 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 66314 0
Prof Andrew Spencer
Address 66314 0
Department of clinical haematology
Alfred Health
55 Commercial Road
Melbourne VIC 3004
Country 66314 0
Australia
Phone 66314 0
+61390763393
Fax 66314 0
Email 66314 0
[email protected]
Contact person for public queries
Name 66315 0
Delaine Smith
Address 66315 0
Australasian Leukaemia and Lymphoma Group (ALLG)
Ground Floor, 35 Elizabeth Street,
North Richmond, VIC, 3121
Country 66315 0
Australia
Phone 66315 0
+613 8373 9701
Fax 66315 0
+613 9429 8277
Email 66315 0
[email protected]
Contact person for scientific queries
Name 66316 0
Andrew Spencer
Address 66316 0
Department of clinical haematology
Alfred Health
55 Commercial Road
Melbourne VIC 3004
Country 66316 0
Australia
Phone 66316 0
+61390763393
Fax 66316 0
Email 66316 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified IPD data, for all data collected during the trial
When will data be available (start and end dates)?
Data available 3 months following publication, for an indefinite period
Available to whom?
Data are potentially available to:
• Researchers from not-for-profit organisations
• Commercial organisations
• Other
Based in:
• Any location
Further information:
All data requests will be considered by the primary sponsor on a case by case basis. Requests must include a methodologically sound proposal. Specific conditions of use may apply and will be specified in a data sharing agreement (or similar) that the requester must agree to before access is granted.
Available for what types of analyses?
Any type of analysis
Assessed on a case-by-case basis
How or where can data be obtained?
Access can be requested via the Health Data Australia catalogue (https://researchdata.edu.au/health/). Search for the ACTRN number in the catalogue to find datasets associated with this trial or email enquiries to [email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
19921Study protocol  [email protected] Access can be requested via the Health Data Austra... [More Details]



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIImmunotherapeutics in Multiple Myeloma: How Can Translational Mouse Models Help?2019https://doi.org/10.1155/2019/2186494
N.B. These documents automatically identified may not have been verified by the study sponsor.