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Trial registered on ANZCTR


Registration number
ACTRN12617000202369
Ethics application status
Approved
Date submitted
2/02/2017
Date registered
7/02/2017
Date last updated
30/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomized phase 2 study of bortezomib, cyclophosphamide and dexamethasone induction (VCD) compared with VCD and daratumumab induction followed by daratumumab maintenance (VCDD) for the initial treatment of transplant ineligible patients with multiple myeloma.
Scientific title
A randomized phase 2 study of bortezomib, cyclophosphamide and dexamethasone induction (VCD) compared with VCD and daratumumab induction followed by daratumumab maintenance (VCDD) for the initial treatment of transplant ineligible patients with multiple myeloma.
Secondary ID [1] 291042 0
None
Universal Trial Number (UTN)
U1111-1192-2799
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 301834 0
Condition category
Condition code
Cancer 301511 301511 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Daratumumab at a dose of 16 milligrams per kilogram intravenously day 1,8,15,22 of each 35 day cycle for cycles 1 & 2, then day 1 and 15 for cycles 3-6, thereafter day 1 for cycles 7-9, (Daratumumab cycles concurrent with Bortezomib, Cyclophosphamide and Dexamethasone treatment for 9 cycles).
Bortezomib 1.3 milligrams per metre squared subcutaneously days 1,8,15,22 of each 35 day cycle.
Cyclophosphamide 300 milligrams per metre squared by mouth day 1 of each 35 day cycle.
Dexamethasone 20mg by mouth day 1,8,15,22 of each 35 day cycle.

Following 9 cycles of treatment subjects will receive maintenance treatment of Daratumumab 16mg per kg intravenously once every 4 weeks until disease progression, unacceptable toxicity, or withdrawal of consent..

Adherence monitored through hospital drug administration records and tablet adherence through drug packet return.
Intervention code [1] 297018 0
Treatment: Drugs
Comparator / control treatment
Velcade 1.3 milligrams per metre squared subcutaneously day 1,8,15,22 each 35 day cycle for 9 cycles.
Cyclophosphamide 300 milligrams per metre squared by mouth on day 1 of each 35 day cycle for 9 cycles.
Dexamethasone 20mg by mouth day 1,8,15,22 each 35 day cycle for 9 cycles.
Control group
Active

Outcomes
Primary outcome [1] 300908 0
To assess, through monoclonal protein serum assay, progression free survival of patients with newly diagnosed multiple myeloma who are not candidates for high dose chemotherapy and autologous stem cell transplantation on a Bortezomib, Cyclophosphamide , Dexamethasone and Daratumumab treatment regime in comparison to those on a Bortezomib, Cyclophosphamide and Dexamethasone regime.
Timepoint [1] 300908 0
Assessments at the end of every 35 day cycle for 9 cycles and thereafter follow-up at 3 monthly intervals until study closure or until all patients on study have been followed for at least 24 months.
Secondary outcome [1] 331170 0
To compare response rates to Velcade, Cyclophosphamide and Dexamethasone (VCD) and Velcade, Cyclophosphamide, Dexamethasone and Daratumumab (VCDD) therapy as measured by IMWG criteria
Timepoint [1] 331170 0
Assessments at the end of every 35 day cycle for 9 cycles and thereafter follow-up at 3 monthly intervals until study closure or until all patients on study have been followed for at least 24 months.
Secondary outcome [2] 331171 0
To assess Minimal Residual Disease as determined by multiparameter 8 colour flow cytometry from a bone marrow sample at the end of VCD(D) induction for all patients who have achieved Very Good Partial Response or better
Timepoint [2] 331171 0
At completion of induction therapy (i.e. after 9 cycles of treatment)
Secondary outcome [3] 331172 0
To assess overall survival following the addition of daratumumab to VCD compared to VCD
Timepoint [3] 331172 0
At 24 months post commencement of therapy.
Secondary outcome [4] 331173 0
To document the safety/toxicity profile of VCDD through biochemistry assay and medical examination.
Timepoint [4] 331173 0
Assessments at the end of every 35 day cycle for 9 cycles and thereafter follow-up at 3 monthly intervals until study closure or until all patients on study have been followed for at least 24 months.
Secondary outcome [5] 331174 0
Change in global health status, as measured by the EORTC QLQ-C30 questionnaire
Timepoint [5] 331174 0
Assessments at the end of every 35 day cycle for 9 cycles.
Secondary outcome [6] 331175 0
To evaluate quantitative and qualitative immunological changes in peripheral blood by flow cytometry and their associations with disease response using sequential flow cytometric peripheral blood immune panel (NK/T-cell activation).

The effect of therapy on NK-cell mediated antibody dependent cellular cytotoxicity and direct cytotoxicity (using functional and imaging assays) as well as alterations in novel pathway signaling will be compared between paired pre and post therapy patient peripheral blood samples
Timepoint [6] 331175 0
At baseline and at the end of 4 cycles of induction.
Secondary outcome [7] 331298 0
To assess next therapy and next therapy response where relevant.
Timepoint [7] 331298 0
From end of study treatment until study closure or until all patients on study have been followed for at least 24 months.

Eligibility
Key inclusion criteria
1. Male or female patients 18 years or older.
2. Patients must have a diagnosis of symptomatic multiple myeloma as per IMWG criteria
3. Measureable disease
4. Newly diagnosed and not considered candidate for high-dose chemotherapy with autologous stem cell transplantation
5. Patients must be untreated apart from a brief course of corticosteroids or radiotherapy
6. No contraindication to the use of any of the study drugs
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
8. Patients must meet the following clinical laboratory criteria:
a. ANC greater than or equal to 1.0 times 10 to the power of 9 per litre (G-CSF use is permitted)
b. Platelet count greater than or equal to 70 times 10 to the power of 9 per litre for subjects in whom less than 50 percent of bone marrow nucleated cells are plasma cells; otherwise platelet count greater than 50 times 10 to the power of 9 per litre
c. Total bilirubin less than or equal to 2 times upper limit of normal (ULN), except in subjects with Gilbert syndrome, then direct bilirubin less than or equal to 2 times ULN
d. ALT and AST less than or equal to 5 times ULN
9. Voluntary written consent
10. Female patients who are postmenopausal or agree to use effective contraception
11. Male patients who agree to use effective contraception
12. Study site must be able to get correlative samples to the Alfred Hospital, Melbourne, Australia, within 24 hours of collection
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients with Amyloid light-chain (AL) amyloidosis, monoclonal gammopathy of uncertain significance or smouldering MM.
2. Female patients who are lactating or have a positive serum pregnancy test during the screening period.
3. Patient has greater than or equal to Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period.
4. Subject has significant airways disease according to the following definitions:
a. Subject has known chronic obstructive pulmonary disease (COPD) with an Forced Expiratory Volume in 1 second (FEV1) less than 50 percent of predicted normal.
b. Subject has had known moderate or severe persistent asthma within the last 2 years, or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
5. 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.
6. Known ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive
7. Active malignancy with the exception of any of the following:
a. Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer
b. Adequately treated Stage I cancer from which the subject is currently in remission and has been in remission for 2 years
c. Stage I prostate cancer that does not require treatment
d. Any other cancer from which the subject has been disease-free for greater than or equal to 2 years
8. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
9. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
10. 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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
After a “burn-in” period of 1:1 randomized allocation of the first 30 patients to the two study arms, a response adaptive randomization (RAR) will be used to preferentially assign patients to the study arm that appears to be superior.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
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] 7401 0
The Alfred - Prahran
Recruitment hospital [2] 7405 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [3] 7412 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [4] 7413 0
Gold Coast Hospital - Southport
Recruitment hospital [5] 7415 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [6] 9224 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [7] 9225 0
Box Hill Hospital - Box Hill
Recruitment hospital [8] 9226 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [9] 9227 0
St Vincent's Private Hospital - Fitzroy
Recruitment hospital [10] 9228 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [11] 9229 0
The Canberra Hospital - Garran
Recruitment hospital [12] 9230 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [13] 9231 0
Icon Cancer Care South Brisbane - South Brisbane
Recruitment hospital [14] 9232 0
Icon Cancer Care Wesley - Auchenflower
Recruitment hospital [15] 9233 0
Icon Cancer Care Chermside - Chermside
Recruitment hospital [16] 9234 0
Icon Cancer Care Southport - Southport
Recruitment hospital [17] 9235 0
Icon Cancer Care Townsville - Hyde Park
Recruitment hospital [18] 9236 0
Icon Integrated Cancer Centre North Lakes - North Lakes
Recruitment hospital [19] 9237 0
Icon Cancer Care Adelaide - Kurralta Park
Recruitment hospital [20] 9238 0
Blacktown Hospital - Blacktown
Recruitment postcode(s) [1] 15203 0
3004 - Prahran
Recruitment postcode(s) [2] 15207 0
4102 - Woolloongabba
Recruitment postcode(s) [3] 15214 0
2065 - St Leonards
Recruitment postcode(s) [4] 15215 0
4215 - Southport
Recruitment postcode(s) [5] 15217 0
5000 - Adelaide
Recruitment postcode(s) [6] 17880 0
2298 - Waratah
Recruitment postcode(s) [7] 17881 0
3128 - Box Hill
Recruitment postcode(s) [8] 17882 0
5042 - Bedford Park
Recruitment postcode(s) [9] 17883 0
3065 - Fitzroy
Recruitment postcode(s) [10] 17884 0
3220 - Geelong
Recruitment postcode(s) [11] 17885 0
2605 - Garran
Recruitment postcode(s) [12] 17886 0
4029 - Herston
Recruitment postcode(s) [13] 17887 0
4101 - South Brisbane
Recruitment postcode(s) [14] 17888 0
4066 - Auchenflower
Recruitment postcode(s) [15] 17889 0
4032 - Chermside
Recruitment postcode(s) [16] 17890 0
4812 - Hyde Park
Recruitment postcode(s) [17] 17891 0
4509 - North Lakes
Recruitment postcode(s) [18] 17892 0
5037 - Kurralta Park
Recruitment postcode(s) [19] 17893 0
2148 - Blacktown

Funding & Sponsors
Funding source category [1] 295472 0
Commercial sector/Industry
Name [1] 295472 0
Janssen Pharmaceuticals
Address [1] 295472 0
1125 Trenton-Harbourton Road P.O. Box 200 Titusville, NJ 08560
Country [1] 295472 0
United States of America
Primary sponsor type
Hospital
Name
Alfred Health
Address
Alfred Hospital, 55 Commercial Road, Melbourne, VIC, 3004
Country
Australia
Secondary sponsor category [1] 294293 0
None
Name [1] 294293 0
Address [1] 294293 0
Country [1] 294293 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296803 0
Alfred Health Human Research Ethics Committee
Ethics committee address [1] 296803 0
Alfred Hospital, 55 Commercial Road, Melbourne, VIC, 3004
Ethics committee country [1] 296803 0
Australia
Date submitted for ethics approval [1] 296803 0
30/01/2017
Approval date [1] 296803 0
28/04/2017
Ethics approval number [1] 296803 0

Summary
Brief summary
The primary purpose of this trial is to assess whether the addition of datatumumab to a velcade, cyclophosphamide and dexamethasone treatment regime will cause an improvement in disease progression free survival.
Who is it for?
You may be eligible to participate in this trial if you are aged 18 years or over, have been newly diagnosed with multiple myeloma and are not a candidate for high dose chemotherapy and autologous stem cell transplant.
Study details
Eligible participants will be assigned to either a velcade, cyclophosphamide and dexamethasone (VCD) or velcade, cyclophosphamide, dexamethasone and daratumumab (VCDD) treatment arm. Both arms will receive 9 35 day cycles of treatment with the VCDD arm continuing on daratumumab maintenance monthly until disease progression, unacceptable toxicity, or withdrawal of consent. Paricipants will be required to have blood samples taken at the beginning of each cycle along with a medical exam in order for researchers to monitor whether the treatment is safe and whether it is effectively treating the myeloma.
It is hoped that the findings of this trial will establish the benefits of daratumumab in combination with VCD for the treatment of multiple myeloma patients early in the course of their disease.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 72098 0
A/Prof Peter Mollee
Address 72098 0
Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, QLD 4102
Country 72098 0
Australia
Phone 72098 0
+61 7 3176 2111
Fax 72098 0
Email 72098 0
Peter.Mollee@health.qld.gov.au
Contact person for public queries
Name 72099 0
Ms Nola Kennedy
Address 72099 0
Alfred Health, Commercial Road, Melbourne, Victoria, 3004
Country 72099 0
Australia
Phone 72099 0
+61 3 90762217
Fax 72099 0
+61 3 90765531
Email 72099 0
n.kennedy@alfred.org.au
Contact person for scientific queries
Name 72100 0
A/Prof Peter Mollee
Address 72100 0
Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, QLD 4102
Country 72100 0
Australia
Phone 72100 0
+61 7 3176 2111
Fax 72100 0
Email 72100 0
Peter.Mollee@health.qld.gov.au

No information has been provided regarding IPD availability
Summary results
No Results