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Trial registered on ANZCTR


Registration number
ACTRN12615000818538
Ethics application status
Approved
Date submitted
17/07/2015
Date registered
10/08/2015
Date last updated
1/05/2019
Date data sharing statement initially provided
1/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Single arm, multicentre study of Carfilzomib in combination with Thalidomide and Dexamethasone (CaTD) in patients with relapsed and/or refractory multiple myeloma (RRMM).
Scientific title
Single arm, multicentre study evaluating the safety and efficacy of Carfilzomib in combination with Thalidomide and Dexamethasone (CaTD) in patients with relapsed and/or refractory multiple myeloma (RRMM).
Secondary ID [1] 287101 0
ALLG MM18
Universal Trial Number (UTN)
Trial acronym
ALLG MM18
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 295623 0
Condition category
Condition code
Cancer 295902 295902 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Carfilzomib will be given in the following schedules, on Days 1,2,8,9,15,16 of a 4-week cycle for cycles 1 to 12 then on days 1,2,15,16 in a 4-week cycle during cycles 13-18. For the first 10 patients from each of Australia and Asia, the dose of carfilzomib will be 20/27 per m^2 (i.e. 20mg/m^2 on Cycle 1 Day 1, escalated to 27mg/m^2 from Cycle 1 Day 8). Safety data will be analysed from each of the cohort of 10 patients from Australia and Asia by the respective sponsor’s trial management committee, after the 10th patient has completed cycle 2 of treatment. Provided no more than 4 of the first 10 patients from each of Australia or Asia, experiencing Grade 4 toxicities as defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE v4.03) in the first 2 cycles, the subsequent patients will be started at a higher dose escalation of carfilzomib, 20/56 per m^2 (i.e. 20mg/m^2 on Cycle 1 Day 1, escalated to 56mg/m^2 from Cycle 1 Day 8) in combination with thalidomide and dexamethasone. Enrolment of patient 11 onwards will be halted until safety assessment has been done on the first 10 patients after their completion of 2 cycles of treatment. Safety reviews of the first cohort of 10 patient on carfilzomib dose 20/27mg per m^2 from each of Australia and Asia are to be done separately by the respective sponsor’s trial management committee, and will determine the dose schedule only for the respective patient cohorts.

For patients who were initially commenced on carfilzomib 20/27mg per m^2, dose escalation to 56mg/m^2 from Cycle 4 onwards is permitted if the patient has not achieved at least a PR after the second cycle of treatment and provided that the patient has not had grade > or = 3 carfilzomib-related toxicities in the previous cycles. This is allowed prior to and irrespective of the assessment of grade 4 toxicities in the first cohort of 10 patients from each country.
As there is evidence that a slower 30-minute infusion is better tolerated, all infusions of carfilzomib will be administered over 30 minutes.
Thalidomide will be given at a dose of 100 mg oral tablet daily from cycles 1 to 12. Dexamethasone will be given at a dose of 20 mg oral tablet on Days 1, 8, 9, 15, 16, 22, 23 of a 4-week cycle from cycles 1 to 12, then 20 mg oral tablet on Days 1, 8, 15, 16 of a 4-week cycle from cycles 13-18. For patients aged above 75 years, a lower starting dose of dexamethasone of 12mg will be used and escalated to 20mg at the investigators discretion. A log of administration will be maintained at the hospital.
Intervention code [1] 292344 0
Treatment: Drugs
Comparator / control treatment
None-single arm
Control group
Uncontrolled

Outcomes
Primary outcome [1] 295576 0
To assess the progression free survival (PFS) with combination carfilzomib, thalidomide and dexamethasone (CaTD) in patients with RRMM who have had 1 to 3 prior therapies.

PFS measured as per IMWG criteria:

Increase of >= 25% from lowest response value in any one or more of the following:

Serum M-component and/or (the absolute increase must be >= 0.5 g/dL)
Urine M-component and/or (the absolute increase must be >= 200 mg/24 h)

Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be > 10 mg/dL

Bone marrow plasma cell percentage; the absolute percentage must be >=10%

Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas

Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder
Timepoint [1] 295576 0
Progression free survival, defined as the duration from the start of treatment (C1D1) to disease progression or death from any cause whichever comes first. PFS will be censored by the closeout date and the date of last follow-up for patients lost to follow-up.
Secondary outcome [1] 315874 0
Time to progression
Timepoint [1] 315874 0
Time to progression, defined as the duration from the start of treatment (C1D1) to disease progression or relapse based upon IMWG criteria, with deaths due to causes other than progression censored. TTP will be censored by the closeout date and the date of last follow-up for patients lost to follow-up.
When all patients have either completed the final cycle of maintenance therapy on trial or come off trial (due to death, progression, intolerance or patient choice)
Secondary outcome [2] 315875 0
Overall survival
Timepoint [2] 315875 0
Overall survival defined as the duration from the start of treatment (C1D1) to death from any cause. OS will be censored by the closeout date and the date of last follow-up for patients lost to follow-up
When all patients have either completed the final cycle of maintenance therapy on trial or come off trial (due to death, progression, intolerance or patient choice)
Secondary outcome [3] 315876 0
Response and best overall response by IMWG criteria. Composite outcome.
Timepoint [3] 315876 0
When all patients have either completed the final cycle of maintenance therapy on trial or come off trial (due to death, progression, intolerance or patient choice)
Secondary outcome [4] 315877 0
Duration of response. Assessed by IMWG criteria.
Progressive disease assessed as;
Increase of >= 25% from lowest response value in any one or more of the following:

Serum M-component and/or (the absolute increase must be >= 0.5 g/dL)
Urine M-component and/or (the absolute increase must be >= 200 mg/24 h)

Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be > 10 mg/dL

Bone marrow plasma cell percentage; the absolute percentage must be >=10%

Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas

Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder
Timepoint [4] 315877 0
Duration of response is defined as the duration from the first response to the time of progression. Duration of response will be censored by deaths due to causes other than progression, the closeout date and the date of last follow-up for patients lost to follow-up.

When all patients have either completed the final cycle of maintenance therapy on trial or come off trial (due to death, progression, intolerance or patient choice)
Secondary outcome [5] 315878 0
Toxicity and tolerability, composite outcome.
Worst NCI-CTCAE V4.03 grade of adverse events.
Incidence of serious adverse events
Treatment breaks due to toxicity
Dose reductions due to toxicity
Number of and reasons for patient withdrawal
When all patients have either completed the final cycle of maintenance therapy on trial or come off trial (due to death, progression, intolerance or patient choice)
Timepoint [5] 315878 0
Worst NCI-CTCAE V4.03 grade of adverse events.
Incidence of serious adverse events
Treatment breaks due to toxicity
Dose reductions due to toxicity
Number of and reasons for patient withdrawal
When all patients have either completed the final cycle of maintenance therapy on trial or come off trial (due to death, progression, intolerance or patient choice)
Secondary outcome [6] 315879 0
Health Related Quality of Life as measured by the European standardized instrument EQ-5D-5L
Timepoint [6] 315879 0
When all patients have either completed the final cycle of maintenance therapy on trial (end of cycle 18) or come off trial (due to death, progression, intolerance or patient choice)

Eligibility
Key inclusion criteria
1. Male and female patients, > or =18 years of age
2. Relapsed and/or refractory multiple myeloma at study entry.
3. Patients must have evaluable multiple myeloma with at least one of the following (assessed within 21 days prior to registration):
a. Serum M-protein > or = 5 g/L, or
b. Urine M-protein > or = 200 mg/24 hour, or
In patients without detectable serum or urine M-protein, serum free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal serum k/l ratio or
For IgA patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) > or = 7500 mg/L (7.5 g/L).
4. Received at least one, but no more than three prior treatment regimens or lines of therapy for multiple myeloma. (Induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as one line of therapy).
5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2.
6. Adequate hepatic function within 28 days prior to registration with bilirubin < 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times the ULN.
7. Left Ventricular Ejection Fraction (LVEF) > or = 40%.
8. Absolute neutrophil count (ANC) > or = 1000/mm3 (or 1000 cells/microL) within 21 days prior to registration. Screening ANC should be independent of growth factor support for > or = 1 week.
9. Platelet count > or = 50,000 cells/mm^3 (> or = 30,000 cells/mm3 if myeloma involvement in the bone marrow is > 50%) within 21 days prior to registration. Patients should not have received platelet transfusions for at least 1 week prior to obtaining the screening platelet count.
10. Calculated or measured creatinine clearance (CrCl) of > or =15 mL/min within 21 days prior to registration. Calculation should be based on the Cockcroft and Gault formula
11. Written informed consent in accordance with federal, local, and institutional guidelines.
12. Female patients of child-bearing potential (FCBP) must have negative serum pregnancy test within 21 days prior to registration and agree to use an effective method of contraception during and for 3 months following last dose of drug.
13. Male patients must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a FCBP.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Chemotherapy with approved or investigational anticancer therapeutics within 21 days prior to registration, with the exception of dexamethasone up to 160mg or equivalent every 4 weeks.
2. Previous treatment with carfilzomib.
3. Focal radiation therapy within 7 days prior to registration. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to registration (i.e., prior radiation must have been to less than 30% of the bone marrow).
4. Active congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within four months prior to registration.
5. Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents within 14 days prior to registration.
6. Known HIV seropositive and/or untreated hepatitis B (patients with hepatitis B surface antigen [HBsAg] and core antibody [HBcAb] are eligible if receiving adequate antiviral therapy directed at hepatitis B).
7. Patients with known cirrhosis.
8. Active malignancy, that is expected to require treatment with chemotherapy within one year, or results in a life expectancy less than one year.
9. Female patients who are pregnant or lactating.
10. Known history of allergy to Captisol (registered trademark) (a cyclodextrin derivative used to solubilise carfilzomib)
11. Patients with hypersensitivity to carfilzomib, velcade, boron, or mannitol.
12. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to registration.
13. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to registration.
14. Any other clinically significant medical disease or psychiatric condition that, in the Investigator’s opinion, may interfere with protocol adherence or a patient’s ability to give informed consent.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint(s)
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)
NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 10693 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [2] 10695 0
Concord Repatriation Hospital - Concord
Recruitment hospital [3] 10698 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [4] 10699 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [5] 10700 0
Royal Hobart Hospital - Hobart
Recruitment hospital [6] 10701 0
St Vincents & Mercy Private Hospital - Mercy campus - East Melbourne
Recruitment hospital [7] 10702 0
Border Medical Oncology - Albury
Recruitment hospital [8] 10703 0
Royal Darwin Hospital - Tiwi
Recruitment postcode(s) [1] 22424 0
0810 - Tiwi
Recruitment postcode(s) [2] 22417 0
2139 - Concord
Recruitment postcode(s) [3] 22423 0
2640 - Albury
Recruitment postcode(s) [4] 22420 0
3000 - Melbourne
Recruitment postcode(s) [5] 22421 0
5000 - Adelaide
Recruitment postcode(s) [6] 22415 0
6009 - Nedlands
Recruitment postcode(s) [7] 22422 0
7000 - Hobart
Recruitment outside Australia
Country [1] 7035 0
Singapore
State/province [1] 7035 0
Country [2] 21446 0
Korea, Democratic People's Republic Of
State/province [2] 21446 0

Funding & Sponsors
Funding source category [1] 291662 0
Other Collaborative groups
Name [1] 291662 0
Australasian Leukaemia and Lymphoma Group
Address [1] 291662 0
35 Elizabeth Street, Richmond VIC 3121
Country [1] 291662 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australiasian Leukaemia and Lymphoma Group
Address
Ground Floor, 35 Elizabeth Street, North Richmond, Victoria, 3121
Country
Australia
Secondary sponsor category [1] 290336 0
Charities/Societies/Foundations
Name [1] 290336 0
International Myeloma Foundation
Address [1] 290336 0
IMF International Headquarters:
12650 Riverside Drive, Suite 206
North Hollywood, CA 91607
Country [1] 290336 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293188 0
St. Vincent's Hospital
Ethics committee address [1] 293188 0
41 Victoria Parade, Fitzroy VIC 3065

Ethics committee country [1] 293188 0
Australia
Date submitted for ethics approval [1] 293188 0
28/08/2015
Approval date [1] 293188 0
01/04/2016
Ethics approval number [1] 293188 0
HREC/16/SVHM/19

Summary
Brief summary
The primary purpose of this study is to determine the efficacy and safety of carfilzomib-thalidomide-dexamethasone (CarTD) therapy for relapsed and/or refractory multiple myeloma (RRMM) patients. Who is it for? You may be eligible to join this study if you are aged over 18 years, have RRMM and have received between one and three lines of therapy previously. Study details The study will recruit participants in Australia and Singapore. All participants will receive 12 x 4-week cycles of CarTD therapy followed by 6 cycles of carfilzomib-dexamethasone only. The first 10 participants recruited in each country will receive a low dose for their first 3 cycles. Depending on the toxicity observed in these participants' first 2 cycles, a higher dose may then be used for their remaining cycles (cycle 4 onwards) and for all cycles in newly recruited participants. Patients will be monitored for myeloma response and safety and tolerability of CarTD therapy using blood samples and by reviewing adverse events that occur as well as for disease progression and survival information for 1 year following the last patients final cycle of treatment. It is hoped that the findings of this trial will provide an evaluation of the efficacy and safety of CarTD therapy in RRMM patients who have relapsed after prior treatment for multiple myeloma.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 58834 0
Dr Hang Quach
Address 58834 0
Department of Haematology, St. Vincent’s Hospital Melbourne
41 Victoria Parade, Fitzroy VIC 3065
Country 58834 0
Australia
Phone 58834 0
+61 3 9288 2030
Fax 58834 0
Email 58834 0
HANG.QUACH@svha.org.au
Contact person for public queries
Name 58835 0
Dr Hang Quach
Address 58835 0
Department of Haematology, St. Vincent’s Hospital Melbourne
41 Victoria Parade, Fitzroy VIC 3065
Country 58835 0
Australia
Phone 58835 0
+61 3 9288 2030
Fax 58835 0
Email 58835 0
HANG.QUACH@svha.org.au
Contact person for scientific queries
Name 58836 0
Dr Hang Quach
Address 58836 0
Department of Haematology, St. Vincent’s Hospital Melbourne
41 Victoria Parade, Fitzroy VIC 3065
Country 58836 0
Australia
Phone 58836 0
+61 3 9288 2030
Fax 58836 0
Email 58836 0
HANG.QUACH@svha.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
No individual participant data will be publicly available as it is the aggregate data that is under investigation.
What supporting documents are/will be available?
No other documents available
Summary results
No Results