ANZCTR - Registration

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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

7/04/2024

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]

ALLG MM18

Universal Trial Number (UTN)

Trial acronym

ALLG MM18

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Multiple Myeloma

Condition category

Condition code

Cancer

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]

Treatment: Drugs

Comparator / control treatment

None-single arm

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

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]

Time to progression

Timepoint [1]

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]

Overall survival

Timepoint [2]

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]

Response and best overall response by IMWG criteria. Composite outcome.

Timepoint [3]

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]

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]

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]

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]

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]

Health Related Quality of Life as measured by the European standardized instrument EQ-5D-5L

Timepoint [6]

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

Sex

Both males and females

Can healthy volunteers participate?

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

Completed

Date of first participant enrolment

Anticipated

30/09/2015

Actual

17/03/2017

Date of last participant enrolment

Anticipated

Actual

14/05/2020

Date of last data collection

Anticipated

Actual

14/08/2023

Sample size

Target

100

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,NT,QLD,SA,TAS,WA,VIC

Recruitment hospital [1]

Sir Charles Gairdner Hospital - Nedlands

Recruitment hospital [2]

Concord Repatriation Hospital - Concord

Recruitment hospital [3]

Peter MacCallum Cancer Centre - Melbourne

Recruitment hospital [4]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [5]

Royal Hobart Hospital - Hobart

Recruitment hospital [6]

St Vincents & Mercy Private Hospital - Mercy campus - East Melbourne

Recruitment hospital [7]

Border Medical Oncology - Albury

Recruitment hospital [8]

Royal Darwin Hospital - Tiwi

Recruitment postcode(s) [1]

6009 - Nedlands

Recruitment postcode(s) [2]

2139 - Concord

Recruitment postcode(s) [3]

3000 - Melbourne

Recruitment postcode(s) [4]

5000 - Adelaide

Recruitment postcode(s) [5]

7000 - Hobart

Recruitment postcode(s) [6]

2640 - Albury

Recruitment postcode(s) [7]

0810 - Tiwi

Recruitment outside Australia

Country [1]

Singapore

State/province [1]

Country [2]

Korea, Democratic People's Republic Of

State/province [2]

Country [3]

Taiwan, Province Of China

State/province [3]

Taiwan

Country [4]

New Zealand

State/province [4]

New Zealand

Funding & Sponsors

Funding source category [1]

Other Collaborative groups

Name [1]

Australasian Leukaemia and Lymphoma Group

Address [1]

35 Elizabeth Street, Richmond VIC 3121

Country [1]

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]

Charities/Societies/Foundations

Name [1]

International Myeloma Foundation

Address [1]

IMF International Headquarters:
12650 Riverside Drive, Suite 206
North Hollywood, CA 91607

Country [1]

United States of America

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

St. Vincent's Hospital

Ethics committee address [1]

41 Victoria Parade, Fitzroy VIC 3065

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

28/08/2015

Approval date [1]

01/04/2016

Ethics approval number [1]

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

Dr Hang Quach

Address

Department of Haematology, St. Vincent’s Hospital Melbourne
41 Victoria Parade, Fitzroy VIC 3065

Country

Australia

Phone

+61 3 9288 2030

Fax

[email protected]

Contact person for public queries

Name

Hang Quach

Address

Department of Haematology, St. Vincent’s Hospital Melbourne
41 Victoria Parade, Fitzroy VIC 3065

Country

Australia

Phone

+61 3 9288 2030

Fax

[email protected]

Contact person for scientific queries

Name

Hang Quach

Address

Department of Haematology, St. Vincent’s Hospital Melbourne
41 Victoria Parade, Fitzroy VIC 3065

Country

Australia

Phone

+61 3 9288 2030

Fax

[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.	Type	Citation	Link	Email	Other Details	Attachment
22125	Study protocol			[email protected]	Access can be requested via the Health Data Austra... [More Details]

Results publications and other study-related documents

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Trial Review

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