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Trial registered on ANZCTR


Registration number
ACTRN12620000490976
Ethics application status
Approved
Date submitted
12/03/2020
Date registered
20/04/2020
Date last updated
22/04/2024
Date data sharing statement initially provided
20/04/2020
Date results provided
22/04/2024
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") over alternating treatment cycles of 28 days as follows:
Belantamab mafodotin will be given intravenously over 30 minutes to 1 hour at 2.5mg/kg on day 1 of cycle 1, then on day 1 of every second cycle, i.e. 8 weekly. 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 each cycle onwards.
The administration of carfilzomib is as per institutional guideline. Carfilzomib will be administered after Belantamab Mafodotin provided the patient is clinically stable.
Dexamethasone 40mg (20mg for patients aged > 75) will be given orally weekly, on days 1, 8, 15 and 22.
There will be two phases in the study. The first, safety, run-in phase will consist of 10 patients. After the 10th evaluable patient has completed the 1st cycle, all toxicities that occur will be summarised by worst grade and association with the study treatment. The trial management committee (TMC) will hold a meeting to assess whether or not there are any safety concerns at that dosing schedule. Provided that no more than 3 patients experience a grade 4, treatment-emergent toxicity, and subject to the confirmatory advice from the Data and Safety Monitoring Committee (DSMC), the expansion phase will commence at the same treatment dose and schedule. If 4 or more patients experience grade 4 toxicities, accrual will be paused and the safety ‘run in’ phase repeated at a dose reduction, with the same guidelines for expansion applied.

In the expansion phase, alternating BelaMaf-Kd and Kd treatment will continue as long as tolerated, or until patient withdraws consent or disease progresses.
Dose level reductions and delays in delivery apply for each therapy based on grade of symptoms and toxicities, and upon medical review. If any of the treatments are stopped as intolerable, the other treatments may continue.
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
To assess the preliminary efficacy of BelaMaf-Kd combination therapy in patients with relapsed refractory multiple myeloma via clinical examination and blood assay of myeloma markers.
Timepoint [1] 323195 0
At the completion of at least 12 months follow up for all patients.
Secondary outcome [1] 381136 0
An exploratory investigation of immunologic and molecular predictors of response or resistance to BelaMaf-Kd via correlative translational studies
Timepoint [1] 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 [2] 381137 0
An exploratory investigation of cardiac biomarkers that may predict for cardiovascular sequelae in patients treated with BelaMaf-Kd
Timepoint [2] 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.
Secondary outcome [3] 381131 0
To assess overall response rate (ORR) as defined by International Myeloma Working Group criteria
Timepoint [3] 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 [4] 381133 0
To assess Overall Survival (OS)
Timepoint [4] 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 [5] 381132 0
To assess Minimal Residual Disease (MRD) negativity rate

Timepoint [5] 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 [6] 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 [6] 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 [7] 381135 0
To assess change in global health status, as measured by the PRO instrument, EORTC QLQ-C30 during and after treatment.
Timepoint [7] 381135 0
The EORTC QLQ-C30 will be completed at screening, day 1 cycle 6 and end of treatment.

Eligibility
Key inclusion criteria
Participants must have:
1. Male or female, 18 years or older, capable of giving consent.
2. Have confirmed MM as defined by IMWG criteria.
3. ECOG Performance Status 0-2.
4. Have had at least 1 and no more than 3 prior lines of therapy.
5. Must have measurable disease defined as at least one of:
o Serum M-protein concentration of greater than or equal to 5g/L
o Urine M-protein excretion greater than or equal to 200mg/24hr or
o Serum free light chain (FLC) assay: involved FLC level greater than or equal to 100mg/L and an abnormal serum free light chain ration (less than 0.26 or greater than 1.65)
6. Adequate organ system function:
o Haematological (transfusion and/or growth factor support within 2 weeks are not permitted for the purpose of meeting eligibility criteria):
- Absolute neutrophil greater than or equal to 1.0x10^9/L
- Haemoglobin greater than or equal to 80g/L
- Platelet greater than or equal to 50x10^9/L
o Hepatic:
- ALT less than 2.5xULN
- Bilirubin unless than 1.5xULN (Isolated bilirubin greater than or equal to 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35%)
o Renal:
- eGFR greater than 30ml/min
- Spot urine (albumin/creatinine ratios) less than 500 mg/g (56 mg/mmol)
o Cardiac:
- LVEF greater than 45%
7. Female participants: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Is not a woman of childbearing potential (WOCBP)
OR
- Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of less than 1% per year), preferably with low user dependency (as described in Appendix 6), during the intervention period and for at least 4 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. A WOCBP must have a negative highly sensitive serum pregnancy test (as required by local regulations) within 72 hours before the first dose of study intervention.

The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with a nearly undetected pregnancy.
Non-childbearing potential is defined as follows (by other than medical reasons):
- greater than or equal to 45 years of age and has not had menses for greater than 1 year.
- Patients who have been amenorrhoeic for less than 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation.
? - Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.
8. Male participants: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Male participants are eligible to participate if they agree to the following during the intervention period and for 6 months after the last dose of study treatment to allow for clearance of any altered sperm:
- Refrain from donating sperm.
PLUS either:
- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent.
OR
- Must agree to use contraception/barrier as detailed below:
Agree to use a male condom, even if they have undergone a successful vasectomy, and female partner to use an additional highly effective contraceptive method with a failure rate of less than 1% per year as when having sexual intercourse with a woman of childbearing potential (including pregnant females).
9. All prior treatment-related toxicities (defined by National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0) must be equal to Grade 1 at the time of enrolment except for alopecia.
10. Participant must be able to understand the study procedures and agree to participate in the study by providing written informed consent.
Minimum age
18 Years
Maximum age
No limit
Sex
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 in total within last 4 weeks.
2. Prior treatment with mAb (except for mAb for COVID-19 prophylaxis or management) within 30 days of receiving first dose of study drugs
3. Evidence of cardiovascular risk:
- Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities such as 2nd degree (Mobitz Type II) or 3rd degree atrioventricular (AV) block; Clinically significant, uncontrolled arrhythmias
- History of myocardial infarction, acute coronary syndrome (including unstable angina), coronary angioplasty, or stenting or bypass grafting within last 6 months;
- Class III or IV heart failure defined by New York Heart Association functional classification system.
- Uncontrolled hypertension
4. Pregnant or lactating females.
5. Active infection requiring treatment.
6. Known HIV infection.
7. Active Hepatitis B infection. Patients with positive HBcAB and negative HBsAg are eligible provided HBV DNA is negative.
8. Positive hepatitis C antibody and 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 epithelial disease except for mild changes in corneal epithelium
10. Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to belantamab mafodotin..
11. Ongoing grade 2 or higher peripheral neuropathy.
12. Known immediate or delayed hypersensitivity reaction to proteasome inhibitors, or unacceptable adverse effects from previous proteasome inhibitors.
13. Participant must not have current unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if otherwise meets entry criteria.
14. Participant must not have presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant’s safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfil inclusion criteria.
15. Participant must not use contact lenses while participating in this study.
16. Participant must not be simultaneously enrolled in any interventional clinical trial.
17. Participant must not have used an investigational drug or approved systemic anti-myeloma therapy (including systemic steroids) within 14 days or five half-lives, whichever is shorter, preceding the first dose of study drug.
18. Participant must not have had plasmapheresis within 7 days prior to first dose of study treatment.
19. Participant must not have had major surgery = 4 weeks prior to initiating study treatment.
20. Participant must not have any evidence of active mucosal or internal bleeding.
21. Participant must not have invasive malignancies other than disease under study, unless the second malignancy has been medically stable for at least 2 years and, in the opinion of the principal investigators, will not affect the evaluation of the effects of clinical trial treatments on the currently targeted malignancy. Participants with curatively treated non-melanoma skin cancer may be enrolled without a 2-year restriction.
22. Participant must not have any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions (including lab abnormalities) that could interfere with participant’s safety, obtaining informed consent or compliance to the study procedures.

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
Analysis of the primary and secondary efficacy endpoint variables will be performed on an intention-to-treat basis and will include all patients enrolled on the study who commenced therapy with the study drugs.
The analysis sets for the safety and tolerability endpoints will be all patients who received at least one dose of belantamab mafodotin, carfilzomib or dexamethasone on the clinical study. In the case of safety endpoints (incidence and severity of AEs) patients must also have had at least one safety assessment on or after C1D1.

68 patients is considered to be feasible and will provide a preliminary estimate of the distribution of PFS. This sample size will also enable informal comparisons, with published PFS results from trials of single-agent therapy, to have 80% power.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
31/12/2020
Actual
12/01/2021
Date of last participant enrolment
Anticipated
31/12/2023
Actual
7/08/2023
Date of last data collection
Anticipated
31/12/2025
Actual
Sample size
Target
68
Accrual to date
Final
70
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 22297 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [2] 26460 0
Toowoomba Hospital - Toowoomba
Recruitment hospital [3] 16109 0
The Alfred - Melbourne
Recruitment hospital [4] 22305 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [5] 22304 0
The Townsville Hospital - Douglas
Recruitment hospital [6] 22299 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [7] 22300 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [8] 22303 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [9] 24213 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [10] 22298 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [11] 22301 0
Concord Repatriation Hospital - Concord
Recruitment hospital [12] 22302 0
Border Medical Oncology - Albury
Recruitment postcode(s) [1] 29625 0
3004 - Melbourne
Recruitment postcode(s) [2] 37459 0
3065 - Fitzroy
Recruitment postcode(s) [3] 37463 0
2139 - Concord
Recruitment postcode(s) [4] 37460 0
3220 - Geelong
Recruitment postcode(s) [5] 37461 0
5000 - Adelaide
Recruitment postcode(s) [6] 37465 0
5042 - Bedford Park
Recruitment postcode(s) [7] 39746 0
2010 - Darlinghurst
Recruitment postcode(s) [8] 37464 0
2640 - Albury
Recruitment postcode(s) [9] 37462 0
2298 - Waratah
Recruitment postcode(s) [10] 37466 0
4814 - Douglas
Recruitment postcode(s) [11] 37467 0
4029 - Herston
Recruitment postcode(s) [12] 42440 0
4350 - Toowoomba

Funding & Sponsors
Funding source category [1] 305225 0
Commercial sector/Industry
Name [1] 305225 0
GlaxoSmithKline Australia Pty Ltd
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
Approved
Ethics committee name [1] 305572 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 305572 0
Ethics committee country [1] 305572 0
Australia
Date submitted for ethics approval [1] 305572 0
24/08/2020
Approval date [1] 305572 0
30/10/2020
Ethics approval number [1] 305572 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 100818 0
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
Khoa Le
Address 100819 0
Alfred Hospital
55 Commercial Rd
Melbourne VIC 3004
Country 100819 0
Australia
Phone 100819 0
+61390767851
Fax 100819 0
Email 100819 0
khoa.le@alfred.org.au
Contact person for scientific queries
Name 100820 0
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 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.