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Trial registered on ANZCTR


Registration number
ACTRN12613000283774
Ethics application status
Approved
Date submitted
1/03/2013
Date registered
8/03/2013
Date last updated
17/12/2018
Date data sharing statement initially provided
17/12/2018
Date results information initially provided
17/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Oral Azacitidine, Lenalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma
Scientific title
A Phase Ib trial of oral azacitidine in combination with lenalidomide and dexamethasone (Rd) for myeloma patients with relapsed and/or refractory multiple myeloma who have failed a prior lenalidomide-containing regimen
Secondary ID [1] 282046 0
NONE
Universal Trial Number (UTN)
Trial acronym
ROAR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 288520 0
Condition category
Condition code
Cancer 288851 288851 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Oral azacitadine will be administered at escalating dosing schedules in the dose escalation phase:
1 (A) 100mg for days 1-14 of 28 day cycle
2 (B) 100mg for days 1-21 of 28 day cycle
3 (C) 150mg for days 1-14 of 28 day cycle
4 (D) 150mg for days 1-21 of 28 day cycle
5 (E) 200mg for days 1-14 of 28 day cycle
6 (F) 200mg for days 1-21 of 28 day cycle

Oral azacitidine will be administered in conjunction with 25mg oral lenalidomide on day 1-21 for each 28-day cycle and 40mg oral dexamethasone at Day 1, 8, 15, 22 of each 28-day cycle.

At least three patients per dosing schedule will be treated. The first patients will start at the lowest dose level and be assessed for their tolerabilty of the combination of drugs at the end of cycle one. If there are no dose limiting toxicites observed, the following three patients will be commenced on the next dose level. This will continue until a dose level is reached in which patients begin to experience toxicities. The dose level below that level will be deemed the Maximum Tolerated Dose (MTD) . In the Dose Expansion phase all future patients, and up to 20, will be treated at the MTD.
Intervention code [1] 286638 0
Treatment: Drugs
Comparator / control treatment
uncontrolled
Control group
Uncontrolled

Outcomes
Primary outcome [1] 288979 0
To examine the safety and tolerability, and determine the maximum tolerated dose of azacitidine when administered orally in combination with fixed dose lenalidomide and dexamethasone in patients with relapsed/refractory myeloma who have a history of lenalidomide failure.
Timepoint [1] 288979 0
During the trial treatment at the completion of each dose level
Secondary outcome [1] 301486 0
To characterise the safety and tolerability of the study treatment.
This will be assessed by the use of physical examination including assessment for signs and symtoms of venous thromboembolism and the ongoing assessment of adverse events. Regular blood tests will be used to assess bone marrow, kidney and liver function.
Timepoint [1] 301486 0
Safety and tolerability will be assessed on a continuous basis with the mionitoring of adverse events.
Physical examintations and blood tests to assesss safety and tolerability will be conducted at the beginning of each cycle and on day 15 of the first cycle, and whenever it is clinical required.
Secondary outcome [2] 301499 0
To characterise the immunophenotype of the myeloma cells by multi-parameter flow cytometry (minimum 7 colour) and correlate with methylation studies and levels of chemokines/chemokine receptors/ligands (see below)

Timepoint [2] 301499 0
To be assessed at screening, cycle 1 day 5 and end of cycles 3 and 6.
Secondary outcome [3] 301639 0
To assess the methylation status of multiple genes (such as p15, p16, CD9, BAX, SOCS-1, SOCS-3 and p21) using genomic DNA extracted from CD138 isolated plasma cells (bone marrow aspirate)
Timepoint [3] 301639 0
To be assessed at screening, cycle 1 day 5 and end of cycles 3 and 6.
Secondary outcome [4] 301640 0
To measure the sequential levels of chemokine/chemokine receptors/ligands by ELISA (may include but not restricted to: IL6, IL6R, TNFa, bFGF, VEGF, IL-1b, IL-2, CXCR4, RANKL and MCP-1) in plasma collected from both bone marrow and peripheral blood
Timepoint [4] 301640 0
To be assessed at screening, cycle 1 day 5 and 15, cycle 2 onwards on day 1 and at replase or progression. Also at the time of BMAT at the end of cycle 3 and 6.
Secondary outcome [5] 301641 0
Sequential analysis of circulating proteasome (cProteasome) levels and correlation with disease response.
Timepoint [5] 301641 0
To be assessed at screening, day 1 of each cycle and replase or progression.

Eligibility
Key inclusion criteria
1. Age 18 years and above
2. Confirmed diagnosis of MM as per IMWG criteria
3. ECOG performance status 0-2
4. Relapsed and/or refractory MM with a history of lenalidomide failure where lenalidomide failure is defined as
a) Progressive disease while on a lenalidomide containing regimen OR b) Progressive disease within 60 days of completing a lenalidomide containing regimen OR c)Failure to achieve at least a minimal response (MR) with 4 cycles of lenalidomide containing therapy when such therapy was administered either as part of initial therapy for newly diagnosed MM or as salvage therapy for the treatment of relapsed/refractory MM.
5. Adequate liver and kidney function (<2 x institutional upper limit of normal)
6. Platelet count > 75 x 109/L, absolute neutrophil count > 1.0 x 109/L
7. No contraindication to the use of azacitidine, lenalidomide or dexamethasone
8. Patient has voluntarily agreed and has given written informed consent.
9. Life expectancy of > 8 weeks
10. Patient must be >4 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. All females of childbearing potential (FOCBP)** must agree to have two negative pregnancy tests in the 24hrs before commencing lenalidomide and use two reliable methods of contraception simultaneously or to practice complete abstinence from any sexual contact during the following time periods related to this study: 1) for at least 28 days before starting study; 2) while participating in the study; 3) dose interruptions; and 4) for at least 28 days after study treatment discontinuation. The two methods of reliable contraception must include one highly effective method and one additional effective method to prevent pregnancy, not plan on conceiving children during or within 6 months following lenalidomide
12. All male participants must practice complete abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 28 days following study drug discontinuation, even if he has undergone a successful vasectomy.

** A female of childbearing potential is defined as a sexually mature woman who: 1 has not undergone a hysterectomy or bilateral oophorectomy or 2, has not been naturally post-menopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (I.e, has had menses at any time in the preceding 24 consecutive months).

Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients with monoclonal gammopathy of uncertain significance.
2. Primary amyloidosis
3. Patients who have received prior allogeneic transplantation < 12 months prior to entering study
4. Patients who have had prior allogeneic transplantation and show evidence of active graft-versus-host disease that requires immunosuppressive therapy
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
6. Patients with a prior malignancy within the last 5 years (except for basal or squamous cell carcimnoma or in situ cancer of the cervix).
7. Pregnant or lactating women.
8. Known hepatitis B, Hepatitis C, HIV infection, other immunosuppressive therapy or autoimmune disease


Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The first patients enrolled will receive a lower dose of azacitidine (100mg for Days 1-14 of each 28-day cycle). If that dose is found to be safe, the next patients will receive a higher dose. The doses will increase for each new group of patients as long as it remains safe to do so. The highest safe dose will be established this way. The azacitidine dose levels are:

1 (A) 100mg for Days 1-14 of each 28-day cycle
2 (B) 100mg for Days 1-21 of each 28-day cycle
3 (C) 150mg for Days 1-14 of each 28-day cycle
4 (D) 150mg for Days 1-21 of each 28-day cycle
5 (E) 200mg for Days 1-14 of each 28-day cycle
6 (F) 200mg for Days 1-21 of each 28-day cycle


Approximately 3 participants will be enrolled into the first dose level, and then another 3 participants will be enrolled into the next dose level of and so on. If too many participants are experiencing too many side effects of the study medications then that dose level will be closed and participants will be enrolled into the dose level below it. For example, if too many participants experience toxicity with the dose level of 150mg of azacitidine for Days 1-21 of each 28-day cycle then that level will be stopped and participants will be enrolled into lower dose level of 150 mg of azacitidine for Days 1-14 of each 28-day cycle instead.
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
Single group
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Phase Ib 3 x 3 paradigm with expansion to 22 patients at maximum tolarated dose enabling the >90% chance of detecting any AE with a >10% incidence. Preliminary analysis of safety will occur in real-time as part of the dose escalation phase of the trial and be summarised upon determination of the MTD. A final analysis will be planned to be completed 12 months following the recruitment of the final patient and include all subsequent safety data (recorded and tabulated) from all patients.

Similarly, preliminary efficacy data including all patients will be determined by assignment of response (MR/PR/CR) as per the IMWG International Uniform Response Criteria. Exploratory measures of response including progression free survival (PFS) time to progression (TTP) and overall survival (OS) will be determined by the method of Kaplan-Meier.


Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Participant recruitment difficulties
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)
VIC
Recruitment hospital [1] 702 0
The Alfred - Prahran
Recruitment hospital [2] 9309 0
St Vincent's Private Hospital - Fitzroy
Recruitment hospital [3] 9310 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [4] 9311 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [5] 9312 0
Box Hill Hospital - Box Hill
Recruitment postcode(s) [1] 6445 0
3004 - Melbourne
Recruitment postcode(s) [2] 17975 0
3065 - Fitzroy
Recruitment postcode(s) [3] 17976 0
3220 - Geelong
Recruitment postcode(s) [4] 17977 0
3168 - Clayton
Recruitment postcode(s) [5] 17978 0
3128 - Box Hill

Funding & Sponsors
Funding source category [1] 286823 0
Hospital
Name [1] 286823 0
The Alfred Hospital
Address [1] 286823 0
Malignant Haematolgy and Stem Cell Transplantation Service,
Level 1, South Block
The Alfred
Commercial Road, Melbourne
VICTORIA 3004
Country [1] 286823 0
Australia
Primary sponsor type
Hospital
Name
The Alfred Hospital
Address
Malignant Heamatology and Stem Cell Transplantation Service
Level 1, South Block
The Alfred
Commercial Road
Melbourne
VICTORIA 3004
Country
Australia
Secondary sponsor category [1] 285610 0
Commercial sector/Industry
Name [1] 285610 0
Clegene Pty. Ltd.
Address [1] 285610 0
Celgene Pty. Ltd.
Level 7, 607 St Kilda Rd
Melbourne VIC 3004, Australia
Country [1] 285610 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288888 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 288888 0
Ground Floor, Linay Pavilion
The Alfred
Commercial Road, Melbourne
VICTORIA 3004
Ethics committee country [1] 288888 0
Australia
Date submitted for ethics approval [1] 288888 0
22/02/2013
Approval date [1] 288888 0
18/04/2013
Ethics approval number [1] 288888 0
106/13

Summary
Brief summary
This study will investigate the safety and tolerabilty of escalating doses of oral azacitadine in combination with a fixed dose of lenalidominde and dexamethasone in patients with relapased/refractory multiple myeloma. This study is for patients who have previously been diagnosed with multiple myeloma and who have previously been treated unsuccessfully with lenalidomide.

The dose levels of oral azacitadine are:
1 (A) 100mg for days 1-14 of 28 day cycle
2 (B) 100mg for days 1-21 of 28 day cycle
3 (C) 150mg for days 1-14 of 28 day cycle
4 (D) 150mg for days 1-21 of 28 day cycle
5 (E) 200mg for days 1-14 of 28 day cycle
6 (F) 200mg for days 1-21 of 28 day cycle

The fixed dose of lenalidomide is 25mg on Day 1 to 21 of each 28-day cycle.
The fixed dose of dexamethasone is 40mg on Day 1, 8, 15 and 22 or each 28-day cycle.

A total of up to 30 patients may take part in this trial. The first 3 patients will be enrolled in the lowest dose level 1(A). If this dose level is tolerated well by these patients, the next 3 patients will be enrolled in the next dose level 2(B), and so on until a dose level is reached where too many side effects are experienced. The dose level below the one with too many side effects will be declared the Maximum Tolerated Dose (MTD) and patients will drop back to this dose level and continue at this dose. This MTD dose level will be expanded to allow up to 22 patients to receive this dose.

You may be eligible to join this study is you are above 18 years of age and have adequate liver, kidney and bone marrow function; have no contrainidications to the use of azacitidine, lenalidomide or dexamethasone; you provide consent; you have not had therapy for your multiple myeloma in the last 4 weeks and agree to practise abstinence or use contraception for the specified time period.


Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 38230 0
Prof Andrew Spencer
Address 38230 0
Malignant Heamatolgy and Stem Cell Transplantation Service
Ground Floor, South Block
The Alfred
Commercial Road, Melbourne
VICTORIA 3004
Country 38230 0
Australia
Phone 38230 0
+61 3 9076 393
Fax 38230 0
+61 3 9076 298
Email 38230 0
a.spencer@alfred.org.au
Contact person for public queries
Name 38231 0
Dr Anna Kalff
Address 38231 0
Malignant Heamatolgy and Stem Cell Transplantation Service
1st Floor, South Block
The Alfred
Commercial Road, Melbourne
VICTORIA 3004
Country 38231 0
Australia
Phone 38231 0
+61 3 9076 7152
Fax 38231 0
+61 3 9076 5531
Email 38231 0
a.kalff@alfred.org.au
Contact person for scientific queries
Name 38232 0
Dr Anna Kalff
Address 38232 0
Malignant Heamatolgy and Stem Cell Transplantation Service
1st Floor, South Block
The Alfred
Commercial Road, Melbourne
VICTORIA 3004
Country 38232 0
Australia
Phone 38232 0
+61 3 9076 7152
Fax 38232 0
+61 3 9076 5531
Email 38232 0
a.kalff@alfred.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Will not be shared
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary