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Trial registered on ANZCTR


Registration number
ACTRN12620000490976p
Ethics application status
Not yet submitted
Date submitted
12/03/2020
Date registered
20/04/2020
Date last updated
20/04/2020
Date data sharing statement initially provided
20/04/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase I/II single arm study of combination Belantamab Mafodotin, Carfilzomib, Dexamethasone in patients with early relapsed multiple myeloma
Scientific title
A phase I/II single arm study on the efficacy of combination Belantamab Mafodotin, Carfilzomib, Dexamethasone in patients with early relapsed multiple myeloma
Secondary ID [1] 300767 0
None
Universal Trial Number (UTN)
Trial acronym
BelaCarD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 316616 0
Condition category
Condition code
Cancer 314844 314844 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a phase I/II open label single arm clinical study. Patients with relapsed refractory multiple myeloma who have had 1 to 3 prior lines of treatment, will receive Belantamab Mafodotin in combination with carfilzomib and dexamethasone ("BelaMaf-Kd").
BelaMaf-Kd combination therapy will be given over treatment cycles of 28 days. Treatment will continue as long as tolerated, or until patient withdraws consent or disease progresses. If any of the treatments are stopped as intolerable, the other treatments may continue.
Belantamab mafodotin will be given intravenously over 30 minutes to 1 hour at 1.7mg/kg on days 1 and 8 of each cycle. It will be administered first (ahead of Carfilzomib) followed by a 1 hour rest period.
Carfilzomib will be infused in a 50-100ml intravenous bag over 30 minutes on day 1, cycle 1 at 20mg/m2, then at 70mg/m2 on days 1, 8 and 15 onwards. Carfilzomib will be administered after Belantamab Mafodotin provided the patient is clinically stable. The administration of carfilzomib is as per institutional guideline.
Dexamethasone 40mg (20mg for patients aged > 75) will be given orally weekly, on days 1, 8, 15 and 21.
Dose level reductions and delays in delivery apply for each therapy based on grade of symptoms and toxicities, and upon medical review.
Participants will be assessed within 7 days prior to starting each cycle for adverse events, according to CTCAE-NCI v5.0 and by physical examination, including weight and ECOG performance status, blood analysis, including myeloma markers and liver function, urinalysis, and evaluation of myeloma response according to the International Myeloma Working Group definition criteria.
Bone marrow biopsy will be performed at screening and within 2 weeks of completion of cycle 6, and to evaluate complete response or disease progression
Ocular examination will be performed at screening and day one of each cycle, at end of treatment and for > grade 2 symptoms)
Transthoracic Cardiac Echocardiogram will be performed to assess left ventricular ejection fraction at screening and within 2 weeks of completion of cycle 6, and upon grade 3 dyspnoea or at the investigators discretion during symptoms of cardiac failure.
Intervention code [1] 317093 0
Treatment: Drugs
Comparator / control treatment
There is no control group for this study.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 323195 0
Progression free survival, defined as the duration from the start of treatment (cycle 1, day 1) to disease progression or death from any cause whichever comes first.
Timepoint [1] 323195 0
Clinical examination and blood assay of myeloma markers will be performed ahead of each treatment cycle to evaluate myeloma response according to the International Myeloma Working Group definition criteria.
Bone marrow biopsy will be performed at screening and within 2 weeks of completion of cycle 6, and to evaluate complete response or PD (progressive disease).
Secondary outcome [1] 381131 0
To assess overall response rate (ORR) as defined by International Myeloma Working Group criteria
Timepoint [1] 381131 0
Assessed at 1 year following the completion of the last patient’s final cycle of treatment (i.e. at completion of the study)
Secondary outcome [2] 381132 0
To assess Minimal Residual Disease (MRD) negativity rate

Timepoint [2] 381132 0
Minimal residual disease negativity – or MRD negativity – is defined as the absence of myeloma tumour plasma cells within 1 million bone marrow cells, and is used as a highly sensitive measure of the effectiveness of therapy.
Bone marrow sampling and MRD negativity testing will be performed within 2 weeks of cycle 6 for patients who achieve serological complete response (CR) by paraprotein/light chain criteria.
MRD negativity rate will be evaluated across the cohort at one year following completion of the last patient's final cycle of treatment.

Secondary outcome [3] 381133 0
To assess Overall Survival (OS)
Timepoint [3] 381133 0
The close-out date for OS will be the earliest calendar date of the last date of contact for patients who have not withdrawn from the study, are not known to have died and have not been deemed to be lost to follow-up.
Secondary outcome [4] 381134 0
To document safety/toxicity profile of BelaMaf-Kd
Participants will be clinically assessed for any adverse events ahead of each treatment cycle and at end of treatment.
For instance, possible side effects of Belantamab mafodotin are changes affecting the eyes, including blurred vision, discomfort due to light, difficulty seeing at night and inflammation. An ocular examination will be performed on day one of every cycle, at end of treatment and as needed for patient reported visual disturbances.
Platelet levels will be reviewed ahead of each treatment cycle as thrombocytopaenia is a known side effect of both Belantamab mafodotin and Carfilzomib.
Participant reported changes in behaviour and personality such as nervousness, insomnia (a known side effect of high dose dexamethasone) will be assessed.
Timepoint [4] 381134 0
Participants will be clinically assessed at day 1 of each treatment cycle and at end of treatment..
In addition, an initial assessment of safety and dosing schedule will be conducted by the Data Safety Monitoring Committee after the 10th evaluable patient has completed the first cycle.
Subject to the Committee's advice re continuing/stopping, the efficacy of BelaMaf-Kd therapy will be assessed after the last of 70 participants recruited has been followed up for 12 months post completion of the last treatment cycle.
Secondary outcome [5] 381135 0
To assess change in global health status, as measured by the PRO instrument, EORTC QLQ-C30 during and after treatment.
Timepoint [5] 381135 0
The EORTC QLQ-C30 will be completed at screening, day 1 cycle 6 and end of treatment.
Secondary outcome [6] 381136 0
An exploratory investigation of immunologic and molecular predictors of response or resistance to BelaMaf-Kd via correlative translational studies
Timepoint [6] 381136 0
Bone marrow and peripheral blood sampling for correlative studies are done at screening, within 2 weeks after completion of cycle 6 and within 2 weeks after attainment of CR or confirmed PD.
Secondary outcome [7] 381137 0
An exploratory investigation of cardiac biomarkers that may predict for cardiovascular sequelae in patients treated with BelaMaf-Kd
Timepoint [7] 381137 0
Cardiac enzymes will be measured at the beginning of each cycle (D1), mid cycle (D8) and D15 in the first 6 treatment cycles. Baseline echocardiograms will be performed at screening and at the end of cycle 6 of treatment. Results will be correlated to cardiovascular adverse events.
ECG will be repeated upon new onset of grade 3 dyspnoea. Right heart catheterisation will be performed for confirmation of pulmonary hypertension.

Eligibility
Key inclusion criteria
Participants must have:
1. confirmed multiple myeloma as defined by the International Myeloma Working Group criteria
2. at least 1 and no more than 3 prior lines of therapy
3. measurable disease defined as at least one of:
a. Serum M-protein concentration of 5g/L or greater
b. Urine M-protein excretion of 200mg/24hr or greater OR
c. Serum free light chain (FLC) assay: involved FLC level of 100mg/L or greater and an abnormal serum free light chain ration (<0.26 or >1.65)
4. Adequate organ system function:
a. Haematological: Absolute neutrophil count of 1.0x109/L or greater, Haemoglobin of80g/L or greater, Platelet count of 50x109/L or greater
b. Hepatic: ALT < 2.5xULN and Bilirubin < 1.5xULN
c. Renal: eGFR > 20ml/min
d. Cardiac: LVEF > 45%
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants must not have had/be:
1. systemic anti-myeloma therapy within 14 days with the exception of corticosteroids equivalent to dexamethasone 160mg or greater within last 4 weeks
2. prior treatment with a monoclonal Antibody within 30 days of receiving first dose of study drugs
3. prior allogeneic stem cell transplant.
4. evidence of cardiovascular risk: QTc interval of 470msec or greater; uncontrolled arrhythmias; history of myocardial infarction or acute coronary syndrome within last 6 months; class II or IV heart failure defined by New York Heart Association functional classification system.
5. Pregnant or lactating females
6. Active infection requiring treatment
7. Known HIV infection
8. Hepatitis B surface Antigen (HbsAg) or Hepatitis B core Antibody (HBcAb) positivity
Positive hepatitis C antibody or positive hepatitis C RNA at screening or within 3 months prior to first dose of study treatment. (NOTE: participants with positive hepatitis C antibody due to prior resolved disease can be enrolled only if confirmatory negative hepatitis C RNA is obtained.)
9. Current corneal disease except for mild punctate keratopathy.
10. Known immediate or delayed hypersensitivity or unacceptable adverse effects from previous proteasome inhibitors.
11. Ongoing grade 2 or higher peripheral neuropathy
12. Known immediate or delayed hypersensitivity reaction to drugs chemically related to Belantamab Mafodotin

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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
After all patients enrolled on the study have had their 12-month assessment or withdrawn prior to this, the distribution of Progression Free Survival (PFS) will be estimated using the Kaplan-Meier (product-limit method). The calculation of 95% confidence intervals for quartiles of the time to a PFS event will be based on the complementary log-log transformation of the estimated PFS, and reported together with the Kaplan-Meier survival curve. Exploratory sub-group analyses will be performed as appropriate and will use the log-rank test to compare sub-groups.
Overall Survival and Time To Progression will be analysed in a similar way to PFS.

Recruitment
Recruitment status
Not yet 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)
VIC
Recruitment hospital [1] 16109 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 29625 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 305225 0
Commercial sector/Industry
Name [1] 305225 0
GlaxoSmithKline Australia Pty Ltd
Address [1] 305225 0
GSK Australia Pty Ltd (Head office)
Level 3, 436 Johnston Street
Abbotsford VIC 3067
Country [1] 305225 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Myeloma Research Consortium
Address
Australasian Myeloma Research Consortium
Alfred Hospital
55 Commercial Rd
Melbourne VIC 3004
Country
Australia
Secondary sponsor category [1] 305586 0
None
Name [1] 305586 0
Address [1] 305586 0

Country [1] 305586 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 305572 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 305572 0
The Alfred Hospital Ethics Committee
Alfred Hospital
55 Commercial Rd
Melbourne VIC 3004
Ethics committee country [1] 305572 0
Australia
Date submitted for ethics approval [1] 305572 0
22/06/2020
Approval date [1] 305572 0
Ethics approval number [1] 305572 0

Summary
Brief summary
The study aims to determine the efficacy of combination therapy with Carfilzomib and Dexamethasone and Belantamab mafodotin (BelaMaf-Kd) for patients with relapsed refractory multiple myeloma. Belantamab mafodotin is a new drug which has not been approved for use by the Therapeutic Goods Administration and so this combination is considered an experimental treatment.

Who is it for?
You may be eligible to participate in this trial if you are aged 18 years or over, and have received between 1 to 3 prior lines of therapy for multiple myeloma but have not undergone allogeneic stem cell transplantation.

Study Details
Eligible participants will receive 6 cycles of combination BelaMafKd with treatment given over a 28 day cycle as tolerated. Belantamab mafodotin and Carfilzomib will be delivered by IV infusion on days 1 and 8 and days 1, 8 and 15 respectively. Dexamethasone will be given orally weekly.

Participants will be required to have blood samples taken and medical reviews (including ophthalmic examination) at the beginning of each cycle. An ultrasound test of cardiac function will be performed at screening and within 2 weeks of completion of cycle 6. A bone marrow biopsy will be performed at screening, at cycle 6 and to confirm a complete response or disease progression. These assessments will enable researchers to monitor whether the treatment is safe and whether it is effectively treating the myeloma.
Study treatments will be halted if participants show disease progression, unacceptable toxicity, or upon withdrawal of consent.
A final medical assessment and ophthalmic exam will be performed at end of treatment, with follow up to continue every 12 weeks until one year after the final cycle of treatment.

Follow up assessments will continue every 12 weeks until one year after the final cycle of treatment.

It is hoped that the findings of this trial will establish the benefits of Belantamab mafodotin in combination with Carfilzomib and Dexamethasone for the treatment of patients with early relapsed multiple myeloma.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 100818 0
A/Prof Hang Quach
Address 100818 0
St. Vincent's Hospital Melbourne
41 Victoria Pde,
Fitzroy, VIC 3065
Country 100818 0
Australia
Phone 100818 0
+61396548906
Fax 100818 0
Email 100818 0
hang.quach@svhm.org.au
Contact person for public queries
Name 100819 0
Ms Robyn Secomb
Address 100819 0
Alfred Hospital
55 Commercial Rd
Melbourne VIC 3004
Country 100819 0
Australia
Phone 100819 0
+61390765407
Fax 100819 0
Email 100819 0
r.secomb@alfred.org.au
Contact person for scientific queries
Name 100820 0
A/Prof Hang Quach
Address 100820 0
St. Vincent's Hospital Melbourne
41 Victoria Pde,
Fitzroy, VIC 3065
Country 100820 0
Australia
Phone 100820 0
+61396548906
Fax 100820 0
Email 100820 0
hang.quach@svhm.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
Results of this study will be pooled and anonymous.
What supporting documents are/will be available?
No other documents available
Summary results
No Results