Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615000934549
Ethics application status
Approved
Date submitted
16/07/2015
Date registered
8/09/2015
Date last updated
14/01/2021
Date data sharing statement initially provided
16/07/2019
Date results information initially provided
16/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A multicentre single arm study of carfilzomib-thalidomide-dexamethasone (CarTD) for newly diagnosed transplant-eligible multiple myeloma (MM) patients refractory to initial bortezomib-based induction therapy
Scientific title
A multicentre single arm study to evaluate the safety and efficacy of carfilzomib-thalidomide-dexamethasone (CarTD) for newly diagnosed transplant-eligible multiple myeloma (TE NDMM) patients refractory to initial bortezomib-based induction therapy
Secondary ID [1] 287098 0
ALLG MM17
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 295618 0
Condition category
Condition code
Cancer 295896 295896 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
SALVAGE: Carfilzomib will be given by IV infusion over 30 minutes on Days 1, 2, 8, 9, 15, 16 of each 4-week cycle for 4 cycles. Carfilzomib 20 mg/m2 will be delivered on Cycle 1 Day 1 and 2 and then escalated to 56 mg/m2 from Cycle 1 Day 8 onwards. Thalidomide will be given continuously at a starting dose of 100mg oral daily starting on Day 1, Cycle 1 for the duration of the cycle. Dexamethasone will be given at a dose of 20mg orally on days 1, 2, 8, 9, 15 and 16 of each 4 week cycle prior to carfilzomib dosing.

After 4 cycles of Car-TD Patients will undergo full disease re-evaluation and patients with less than stringent CR will receive an additional 2 cycles of car-TD and then proceed to a G-CSF stimulated PBSC collection. If <2million/kg CD34+ cells are available for ASCT the patient will be withdrawn from the study. Patients with sCR after 4 cycles of Car-TD will proceed directly to a G-CSF mobilised PBSC collection for ASCT, there is no time period intended prior to ASCT.

Patients will go to ASCT if eligible to do so with no time period prior to ASCT intended.

Autologous stem cell transplant (ASCT): All patients with >=2 million/kg CD34 cells available will then receive a melphalan 200mg/m2 conditioned ASCT as per standard institutional practice.

CONSOLIDATION: Commencing at 3 months post-ASCT patients without evidence of disease progression will receive a further 2 cycles of carfilzomib as described above. Thalidomide will be given continuously at a starting dose of 100mg daily starting on day 1 of the first cycle of carfilzomib consolidation and continued for a maximum of 12 months. Dexamethasone will be given at a dose of 20mg on days 1, 2, 8, 9, 15, 16 of each 4-week cycle of carfilzomib consolidation prior to carfilzomib dosing and then revert to a dose of 40mg weekly in combination with ongoing thalidomide to a maximum of 12 months.

All dosing is recorded by hospital staff. Drug accountability logs will be used by the hospital staff.
Intervention code [1] 292338 0
Treatment: Drugs
Comparator / control treatment
Single arm
Control group
Uncontrolled

Outcomes
Primary outcome [1] 295567 0
To determine the overall response rate (ORR) to treatment with Car-TD salvage therapy in TE NDMM patients who have had a sub-optimal response to a bortezomib-based induction therapy. The ORR will be calculated as the number of patients who have experienced at least a partial response prior to ASCT, divided by the number of patients registered on the trial.
Timepoint [1] 295567 0
The primary efficacy analyses will be conducted after all patients, have completed pre-ASCT salvage therapy (4 or 6 cycles of Car-TD).
Primary outcome [2] 295568 0
To evaluate the composite primary outcome of tolerability and safety profile of Car-TD salvage therapy when administered to TE NDMM patients who have had a sub-optimal response to a bortezomib-based induction therapy.
The co-primary outcome of the trial is to evaluate the tolerability and safety of Car-TD salvage therapy.
The co-primary objective of the trial is to evaluate the tolerability and safety of Car-TD salvage therapy. These evaluations will be conducted on the Safety Set. Treatment emergent adverse events will be defined as per the CTCAE v4.03 and will be summarised by system organ class and/or preferred term as counts and percentages of participants with further subdivision based on severity and relationship to Car-TD therapy. Particular attention will be given to (i) rates of peripheral neuropathy (either sensory and/or painful) and cardiac toxicities >=Grade 2, (ii) cessation of carfilzomib and/or thalidomide and/or dexamethasone due to unacceptable toxicity, and (iii) subject withdrawal due to unacceptable toxicity.
Timepoint [2] 295568 0
The primary safety analyses will be conducted after all patients, who are still receiving study treatment, have completed pre-ASCT salvage therapy (4 or 6 cycles of Car-TD). Adverse event data will be collected in relation to the salvage (Car-TD 4 or 6 cycles plus 30 days) and consolidation (Car-TD 2 cycles followed by ongoing TD plus 30 days) portions of the study.
Secondary outcome [1] 315864 0
To determine the maximal depth of response achieved with sequential treatment with Car-TD salvage therapy, autologous stem cell transplantation (ASCT) and post-ASCT consolidation with Car-TD/TD.For all patients in the Full Analysis Set (FAS), responses, as defined by the IMWG criteria and as assessed at the 4 major re-staging points after each phase of treatment will be tabulated and presented as shift tables to enable comparison of response status at the beginning and end of each phase.
Timepoint [1] 315864 0
For all patients in the full analysis set, responses, as defined by the IMWG criteria and as assessed at the 4 major re-staging points after each phase of treatment will be tabulated and presented as shift tables to enable comparison of response status at the beginning and end of each phase (Baseline, and Treatment is comprised of 3 phases – Car-TD salvage; ASCT; and, post-ASCT Car-TD/TD consolidation).
Secondary outcome [2] 315865 0
To determine the Progression Free Survival (PFS) and Overall Survival (OS) achieved with Car-TD salvage therapy, autologous stem cell transplantation (ASCT) and post-ASCT consolidation with Car-TD/TD. This is a composite outcome. PFS will be measured from the date of commencing Car-TD salvage therapy until the earlier of the dates of progression or death from any cause. OS will be measured from the date of registration until the date of death from any cause. This information will be collected on case report forms.
Timepoint [2] 315865 0
PFS will be measured from the date of commencing Car-TD salvage therapy until the earlier of the dates of progression or death from any cause. Patients who have not progressed or died at the time of analysis (i.e. on or before the study censor date for PFS) will have their PFS censored at the study censor date for PFS. The study censor date for PFS is the earliest of the last dates of disease response assessment of those patients who remain on study (i.e. those patients who have not withdrawn or have not been deemed to be lost-to-follow-up). Patients who have withdrawn or have been lost to follow-up before the censor date will have their PFS censored at the date of their last disease response assessment on study.
OS will be measured from the date of registration until the date of death from any cause. Patients who have not died at the time of analysis (i.e. on or before the study censor date for OS) will have their OS censored at the study censor date for OS. The study censor date for OS is the earliest of the last dates of vital status assessment of those patients who remain on study (i.e. those patients who have not withdrawn or have not been deemed to be lost-to-follow-up). Patients who have withdrawn or have been lost to follow-up before the censor date will have their OS censored at the date of their last contact on study. Follow up in the study will continue for 3 years following the completion of treatment.

Eligibility
Key inclusion criteria
Male and Female patients, >17 years of age.
Symptomatic NDMM as per IMWG criteria.
Eligible for high-dose melphalan conditioned ASCT.
Failed to achieve at least a minimal response (MR) with a minimum of 2 cycles of a prior bortezomib-based induction therapy or a partial response (PR) with a minimum of 4 cycles of a prior bortezomib-based induction therapy.
Adequate liver function (total bilirubin < 1.5 ULN, ALT < 2.5x ULN) unless considered secondary to MM.
Absolute neutrophil count > = 1.0 x 109/L within one week of starting therapy.
Platelet count > = 50 x 109/L (>= 30 x 109/L if MM involvement in the marrow is greater than 50%) within one week of starting therapy, patients should not have received platelet transfusions within one week of the screening platelet count.
Hb >= 80g/L, red cell transfusions as per institutional protocol are allowed.
Subject must have LVEF >= 50% determined by 2-D transthoracic echocardiogram (ECHO) or Multigated Acquisition Scan (MUGA).
Has provided written informed consent.
Women of childbearing potential must have a negative serum pregnancy test within the 72 hours prior to the first study drug administration.
Women of childbearing potential and male subjects who are sexually active with WOCBP must agree to use 2 highly effective methods of contraception during the study and for 30 days following the last dose of study treatment including a male condom.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients who have had myocardial infarction within 6 months prior to enrolment, or NYHA (New York Hospital Association) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia or active conduction system abnormalities
Other uncontrolled intercurrent illness including, but not limited to, severe active infection, or psychiatric illness/social situations that would limit compliance with study requirements
Patients with myelodysplastic syndrome.
Known history of allergy to Captisol (registered trademark) (a cyclodextrin derivative used to solubilise carfilzomib)
Patients with contraindication to dexamethasone.
Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to pre-existing pulmonary or cardiac impairment.
Women who are pregnant or lactating.
Active Hepatitis B or Hepatitis C.
HIV infection, other immunosuppressive therapy or autoimmune disease
Prior diagnosis of cancer that was:
more than 5 years prior to current diagnosis with subsequent evidence of disease recurrence or clinical expectation of recurrence is greater than 10%
within 5 years of current diagnosis with the exception of successfully treated basal cell or squamous cell skin carcinoma or carcinoma in situ of the cervix
Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. This condition must be discussed with the patient prior to signing consent and registration in the trial.

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
Active, not recruiting
Date of first participant enrolment
Anticipated
14/09/2015
Actual
28/09/2016
Date of last participant enrolment
Anticipated
17/08/2018
Actual
19/04/2018
Date of last data collection
Anticipated
17/07/2022
Actual
Sample size
Target
50
Accrual to date
Final
50
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,VIC
Recruitment hospital [1] 8055 0
The Alfred - Prahran
Recruitment hospital [2] 8056 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 8057 0
Icon Cancer Care South Brisbane - South Brisbane
Recruitment hospital [4] 8058 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [5] 8059 0
St Vincents & Mercy Private Hospital - Mercy campus - East Melbourne
Recruitment hospital [6] 8060 0
The Canberra Hospital - Garran
Recruitment postcode(s) [1] 16099 0
2065 - St Leonards
Recruitment postcode(s) [2] 16101 0
2605 - Garran
Recruitment postcode(s) [3] 16100 0
3002 - East Melbourne
Recruitment postcode(s) [4] 16096 0
3004 - Prahran
Recruitment postcode(s) [5] 16098 0
4101 - South Brisbane
Recruitment postcode(s) [6] 16097 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 291658 0
Commercial sector/Industry
Name [1] 291658 0
Onyx Pharmaceuticals Inc., a subsidiary of Amgen, Inc.
Country [1] 291658 0
United States of America
Primary sponsor type
Other Collaborative groups
Name
Australiasian Leukaemia and Lymphoma Group
Address
Ground Floor, 35 Elizabeth Street, Richmond 3121 Victoria
Country
Australia
Secondary sponsor category [1] 290332 0
None
Name [1] 290332 0
Address [1] 290332 0
Country [1] 290332 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293184 0
Alfred Health
Ethics committee address [1] 293184 0
55 Commercial Road, Melbourne, Victoria, 3004
Ethics committee country [1] 293184 0
Australia
Date submitted for ethics approval [1] 293184 0
28/04/2016
Approval date [1] 293184 0
16/05/2016
Ethics approval number [1] 293184 0

Summary
Brief summary
The primary purpose of this study is to determine the efficacy and safety of carfilzomib-thalidomide-dexamethasone (CarTD) therapy for newly diagnosed transplant-eligible multiple myeloma (NDMM) patients who did not respond adequately to initial bortezomib-based therapy.

Who is it for? You may be eligible to join this study if you are aged over 18 years, have been diagnosed with symptomatic NDMM as per International Myeloma Working Group (IMWG) criteria, are eligible for high-dose melphalan conditioned autologous stem cell transplant (ASCT) and failed to achieve a minimum response or partial response on 2 or 4 cycles of prior bortezomib-based induction therapy respectively.

Study details
Enrolled participants will first undergo 4 x 4-week cycles of salvage CarTD therapy, followed by an additional 2 cycles if they do not achieve a stringent complete response.

Participants will then receive melphalan-conditioned ASCT, followed by 2 cycles of consolidation CarTD therapy. Patients will be monitored for myeloma response and safety and tolerability of CarTD therapy using blood samples, and the assessment of toxicities (adverse event review) as well as for disease progression and survival information for up to 3 years following the completion of treatment.

It is hoped that the findings of this trial will provide an evaluation of the efficacy and safety of CarTD salvage and consolidation therapy in multiple myeloma patients who do not respond to the standard care bortezomib-based therapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 58814 0
Prof Andrew Spencer
Address 58814 0
Alfred Health, 55 Commercial Road, Melbourne, Victoria 3004
Country 58814 0
Australia
Phone 58814 0
+61 3 9076 3393
Fax 58814 0
Email 58814 0
aspencer@netspace.net.au
Contact person for public queries
Name 58815 0
Prof Andrew Spencer
Address 58815 0
Alfred Health, 55 Commercial Road, Melbourne, Victoria, 3004
Country 58815 0
Australia
Phone 58815 0
+61 3 9076 3393
Fax 58815 0
Email 58815 0
aspencer@netspace.net.au
Contact person for scientific queries
Name 58816 0
Prof Andrew Spencer
Address 58816 0
Alfred Health, 55 Commercial Road, Melbourne, Victoria 3004
Country 58816 0
Australia
Phone 58816 0
+61 3 9076 3393
Fax 58816 0
Email 58816 0
aspencer@netspace.net.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

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

Documents added automatically
No additional documents have been identified.