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Trial registered on ANZCTR


Registration number
ACTRN12618001085268
Ethics application status
Approved
Date submitted
21/06/2018
Date registered
28/06/2018
Date last updated
23/04/2019
Date data sharing statement initially provided
23/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A trial of Venetoclax in combination with Bortezomib-Cyclophosphamide-Dexamethasone (VCD) as induction therapy for newly diagnosed myeloma patients
Scientific title
An exploratory study of Venetoclax in combination with Bortezomib-Cyclophosphamide-Dexamethasone (VCD) induction therapy in newly diagnosed transplant eligible (NDTE MM) multiple myeloma with proteomic correlative studies
Secondary ID [1] 295278 0
Nil known
Universal Trial Number (UTN)
U1111-1216-0528
Trial acronym
V-VCD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
multiple myeloma 308455 0
Condition category
Condition code
Cancer 307437 307437 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Bortezomib 1.3mg/m2 subcutaneous injection days 1, 8, 15, 22 (4x 35 day cycles)
Cyclophosphamide 500mg single dose orally days 1, 8, 15, 22
Dexamethasone 40mg single dose orally days 1, 8, 15, 22
Venetoclax 800mg single dose orally taken daily on days 1 – 35
Upon completion of the four cycles of induction treatment patients then undergo high-dose (200mg/m2) melphalan conditioned autologous stem cell transplant (ASCT ), a procedure removing healthy stem cells followed by chemotherapy and then followed by the transfusion of the healthy cells back into the patient, carried out as per standard of care at the participating hospital.
Intervention code [1] 301610 0
Treatment: Drugs
Intervention code [2] 301632 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 306402 0
To determine the complete response rate measured by serum assay (CRR- = minimal response + partial response + very good partial response + complete response as defined by International Myeloma Working Group response criteria) achieved with the combination of Venetoclax and Bortezomib-Cyclophosphamide-Dexamethasone (V-VCD) in treatment naïve transplant eligible NDMM
Timepoint [1] 306402 0
Response assessment performed at the end of every cycle of treatment and 100 days post autologous stem cell transplant
Secondary outcome [1] 348399 0
To investigate the safety of therapy with V-VCD for the treatment of NDMM patients by recording the incidence and severity of adverse events (CTCAE Version 5).
Timepoint [1] 348399 0
Throughout study until 100 days post-ASCT
Secondary outcome [2] 348400 0
An exploratory investigation of the kinetics of complete response attainment with V-VCD through analysis of monoclonal proteins and light chains in the blood
Timepoint [2] 348400 0
At attainment of CR until 100 days post ASCT
Secondary outcome [3] 348401 0
To investigate the overall response rate by serum assay analysis (ORR: complete response, very good partial response, partial response) achieved with V-VCD
Timepoint [3] 348401 0
assessment at the end of each cycle of treatment and at 100 days post ASCT
Secondary outcome [4] 348402 0
Determine the clinical benefit rate (CBR) by serum assay analysis (ORR + minimal response) achieved with V-VCD
Timepoint [4] 348402 0
assessment at the end of each cycle of treatment and at 100 days post ASCT
Secondary outcome [5] 348403 0
Determine the rate of minimal residual disease (MRD) negativity achieved with V-VCD and subsequent high-dose chemotherapy conditioned ASCT using 8-colopur multi-parameter flow cytometry (MFC – EuroFlow).
Timepoint [5] 348403 0
MRD will be assessed in the bone marrow between days 90 to 100 post-ASCT

Eligibility
Key inclusion criteria
1.Male or female patients aged 18 years or older.
2.Patient has newly diagnosed treatment naïve MM as per the IMWG criteria and is planned to proceed to high-dose chemotherapy conditioned ASCT as part of first-line treatment.
3.Treatment naïve apart from a limited exposure to corticosteroids and/or radiotherapy for urgent symptom control.
4.No contraindication to the use of any of the study drugs.
5.Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
6.Subject has measurable disease at screening, defined as at least one of the following:
- Serum M-protein >= 5 g/L, OR
- Urine M-protein >= 200 mg in 24-hours, OR
- Serum immunoglobulin free light chain (FLC) >= 100 mg/L provided serum FLC ratio abnormal.
7.Subject must meet the following laboratory parameters, per laboratory reference range:
- Absolute neutrophil count (ANC) >= 1 x 10^9/L within 2 weeks prior to starting induction. Subjects may use growth factor support to achieve ANC eligibility criteria.
- Platelet count >= 50 x 109/L, within 2 weeks prior to starting induction. For subjects with > 50% myeloma involvement in the bone marrow, a platelet count of >= 30 x10^9/L within 2 weeks prior to starting induction is allowed. Subjects cannot receive a platelet transfusion within 72 hours prior to the platelet count used for eligibility.
- Haemoglobin >= 80 g/L, within 2 weeks prior to starting induction. Subjects may receive RBC transfusions in accordance with institutional guidelines to meet this criterion.
- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) <= 3 × upper limit of normal range (ULN).
- Total bilirubin <= 1.5 x ULN (unless bilirubin rise is due to Gilbert syndrome or of non-hepatic origin).
- CrCl >= 30 mL/minute (min), measured by 24-hour urine collection or calculated using Cockcroft-Gault formula:
CrCl = ((140 – age in years) × weight in kg × 0.85 if female) / (72 × serum creatinine in mg/dL)
8.Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC) prior to the initiation of any screening or study-specific procedures.
9.If female, subject is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation at least 3 months before study participation, bilateral oophorectomy and/or hysterectomy) or is of childbearing potential and is practicing an approved method of birth control throughout the study and 90 days after last dose of study drug.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.Subject has any of the following conditions:
- Non-secretory or oligo-secretory MM.
- Active plasma cell leukemia i.e., either 20% of peripheral white blood cells comprised of plasma cells or > 2.0 × 109/L) circulating plasma cells by standard differential.
- Waldenström's macroglobulinemia.
- Amyloidosis.
- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
- Subject is known to be positive for Human Immunodeficiency Virus (HIV)
- Significant cardiovascular disease, including uncontrolled angina, severe or uncontrolled arrhythmia, recent myocardial infarction within 6 months of induction, or congestive heart failure New York Heart Association (NYHA) Class >= 3.
- Major surgery within 4 weeks prior to starting induction.
- Uncontrolled and/or active systemic infections (viral, bacterial or fungal).
- Chronic hepatitis B (HBV) or hepatitis C (HCV) requiring treatment.
- Peripheral neuropathy >= Grade 3 or >= Grade 2 with pain within 2 weeks prior to starting induction.
- Uncontrolled diabetes or uncontrolled hypertension within 14 days prior to starting induction.
- Any other medical condition that, in the opinion of the Investigator, would adversely affect the subject's participation in the study.
2.Subject has a history of other active malignancies, including myelodysplastic syndrome (MDS), within the past 3 years prior to study entry, with the following exceptions:
- Adequately treated in situ carcinoma of the cervix uteri or the breast
- Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
- Prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels off treatment
- Previous malignancy with no evidence of disease, confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study
3.Subject has a hypersensitivity or allergy to any of the components of study therapy including Venetoclax, Bortezomib, boron, mannitol, or Dexamethasone.
4.Subject has received any prior anti-MM with the exception of Dexamethasone (total dose not exceeding 160mg) or localized radiotherapy for the emergency management of newly diagnosed MM.
5.Subject has received a strong or moderate CYP3A inhibitor or inducer within 1 week prior to commencing study treatment.
6.Administration or consumption of grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville orange) or star fruit within 3 days prior to the first dose of study drug.

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 2
Type of endpoint(s)
Safety/efficacy
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)
QLD,TAS,VIC
Recruitment hospital [1] 11204 0
The Alfred - Prahran
Recruitment hospital [2] 11205 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [3] 11206 0
St George Hospital (QLD) - St George
Recruitment hospital [4] 11207 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [5] 11208 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [6] 11209 0
Royal Hobart Hospital - Hobart
Recruitment postcode(s) [1] 23078 0
3004 - Prahran
Recruitment postcode(s) [2] 23079 0
3084 - Heidelberg
Recruitment postcode(s) [3] 23080 0
4487 - St George
Recruitment postcode(s) [4] 23081 0
3168 - Clayton
Recruitment postcode(s) [5] 23082 0
3000 - Melbourne
Recruitment postcode(s) [6] 23083 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 299869 0
Commercial sector/Industry
Name [1] 299869 0
Abbvie
Address [1] 299869 0
AbbVie Inc. Headquarters
1 N. Waukegan Road
North Chicago, Illinois 60064
Country [1] 299869 0
United States of America
Primary sponsor type
Hospital
Name
Alfred Health
Address
Alfred Hospital, 55 Commercial Road, Melbourne, VIC, 3004
Country
Australia
Secondary sponsor category [1] 299220 0
None
Name [1] 299220 0
Address [1] 299220 0
Country [1] 299220 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300741 0
Alfred Hospital Ethics Committee EC00315
Ethics committee address [1] 300741 0
Alfred Hospital, 55 Commercial Road, Melbourne, VIC, 3004
Ethics committee country [1] 300741 0
Australia
Date submitted for ethics approval [1] 300741 0
26/07/2018
Approval date [1] 300741 0
23/08/2018
Ethics approval number [1] 300741 0

Summary
Brief summary
The primary purpose of this trial is to assess whether the addition of venetoclax to a velcade (bortezomib), cyclophosphamide and dexamethasone treatment regime will cause an improvement in disease progression free survival.

Who is it for?
You may be eligible to participate in this trial if you are aged 18 years or over, have been newly diagnosed with multiple myeloma and are a candidate for chemotherapy and autologous stem cell transplant.

Study details
Eligible participants will be treated with 4 35 day cycles of venetoclax, velcade, cyclophosphamide and dexamethasone (V-VCD) followed by a high-dose melphalan conditioned autologous stem cell transplant (ASCT) with residual disease evaluation at day 100 post-ASCT. Participants will be required to have blood samples taken at the beginning of each cycle along with a medical exam in order for researchers to monitor whether the treatment is safe and whether it is effectively treating the myeloma.
It is hoped that the findings of this trial will establish the benefits of venetoclax in combination with VCD for the treatment of multiple myeloma patients early in the course of their disease.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84658 0
Prof Andrew Spencer
Address 84658 0
Alfred Health, 55 Commercial Road, Melbourne, Victoria, 3004
Country 84658 0
Australia
Phone 84658 0
+61 3 90763393
Fax 84658 0
+61 3 90762298
Email 84658 0
aspencer@netspace.net.au
Contact person for public queries
Name 84659 0
Ms Flora Yuen
Address 84659 0
Alfred Health, 55 Commercial Road, Melbourne, Victoria, 3004
Country 84659 0
Australia
Phone 84659 0
+61 3 90765407
Fax 84659 0
+61 3 90765531
Email 84659 0
F.Yuen2@alfred.org.au
Contact person for scientific queries
Name 84660 0
Ms Flora Yuen
Address 84660 0
Alfred Health, 55 Commercial Road, Melbourne, Victoria, 3004
Country 84660 0
Australia
Phone 84660 0
+61 3 90765407
Fax 84660 0
+61 3 90765531
Email 84660 0
F.Yuen2@alfred.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
What supporting documents are/will be available?
No other documents available
Summary results
No Results