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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03896737




Registration number
NCT03896737
Ethics application status
Date submitted
28/03/2019
Date registered
1/04/2019
Date last updated
1/10/2024

Titles & IDs
Public title
Daratumumab-bortezomib-dexamethasone (Dara-VCd) vs Bortezomib-Thalidomide-Dexamethasone (VTd), Then Maintenance With Ixazomib (IXA) or IXA-Dara
Scientific title
A Multicenter, Open Label, Randomized Phase II Study Comparing Daratumumab Combined With Bortezomib-Cyclophosphamide-dexamethasone (Dara-VCd) Versus the Association of Bortezomib-Thalidomide-dexamethasone (VTd) as Pre Transplant Induction and Post Transplant Consolidation, Both Followed by a Maintenance Phase With Ixazomib Alone or in Combination With Daratumumab, in Newly Diagnosed Multiple Myeloma (MM) Young Patients Eligible for Autologous Stem Cell Transplantation
Secondary ID [1] 0 0
EMN18
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Daratumumab plus Velcade Cyclophosphamide Dexamethasone
Treatment: Drugs - Velcade Thalidomide Dexamethasone

Experimental: Dara-VCd - treatment period includes administration of four 28-day cycles of induction with Dara- VCd; then patients will undergo transplant and finally they will receive two 28-day cycles of Dara-VCd consolidation treatment.

The response will be assessed after each cycle. Patients in the first randomization will be stratified according to FISH (standard/missing vs high risk,defined as del17, t 4;14, t 14;16) and ISS (I vs II and III).

TREATMENT SCHEMA - INDUCTION Daratumumab: 16 mg/Kg given by IV infusion on days 1, 8, 15, 22, on cycles 1-2 and on days 1, 15 on cycles 3-4.

Bortezomib: 1.3 mg/m2 given SC injection on days 1, 8,15, 22; Cyclophosphamide: 300 mg/ m2 given orally or IV infusion on days 1, 8, 15, 22; Dexamethasone: 40 mg given orally or by IV infusion on days 1, 8, 15,22 Repeat for four 4-week induction cycles.

Active comparator: VTd - treatment period includes administration of four 28-day cycles of induction with VTd; then patients will undergo transplant and finally they will receive two 28-day cycles of VTd consolidation treatment.

TREATMENT SCHEMA INDUCTION

ARM VTd:

Bortezomib: 1.3 mg/m2 given by SC injection on days 1, 4, 8, 11 of 28-day cycle; Thalidomide: 100 mg given orally on days 1-28. Dexamethasone: 20 mg given orally or by IV injection on days 1, 2, 3, 4, 8, 9, 10 and 11 of every 28-day cycle.

Repeat for four 4-week induction cycles.


Treatment: Drugs: Daratumumab plus Velcade Cyclophosphamide Dexamethasone
To compare Dara-VCd versus VTd as pre transplant induction and post transplant consolidation, both followed by a maintenance phase with Ixazomib alone or in combination with Daratumumab, in newly diagnosed Multiple Myeloma (MM) young patients eligible for autologous stem cell transplantation.

Treatment: Drugs: Velcade Thalidomide Dexamethasone
To compare Dara-VCd versus VTd as pre transplant induction and post transplant consolidation, both followed by a maintenance phase with Ixazomib alone or in combination with Daratumumab, in newly diagnosed Multiple Myeloma (MM) young patients eligible for autologous stem cell transplantation.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression free survival (PFS)
Timepoint [1] 0 0
5 years
Primary outcome [2] 0 0
MRD negativity
Timepoint [2] 0 0
5 years
Secondary outcome [1] 0 0
Overall response rate (ORR)
Timepoint [1] 0 0
5 years
Secondary outcome [2] 0 0
Progression free survival 2 (PFS2)
Timepoint [2] 0 0
5 years
Secondary outcome [3] 0 0
Duration of response (DoR)
Timepoint [3] 0 0
5 years
Secondary outcome [4] 0 0
Overall survival (OS):
Timepoint [4] 0 0
5 years
Secondary outcome [5] 0 0
Time to the next anti-myeloma therapy (TNT)
Timepoint [5] 0 0
5 years
Secondary outcome [6] 0 0
MRD by NGF and Positron Emission Tomography (PET)/CT
Timepoint [6] 0 0
5 years
Secondary outcome [7] 0 0
Definition of prognostic factors, as assessed by Next Generation Sequencing (NGS) (MM-panel)
Timepoint [7] 0 0
5 years

Eligibility
Key inclusion criteria
* Patient at least 18 years of age and = 65 years.
* Patient eligible for autologous stem cell transplantation (ASCT).
* Left Ventricular Ejection Fraction (LVEF) = 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available.
* Newly diagnosed multiple myeloma patient.
* Patient has given voluntary written informed consent before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
* Patient with documented multiple myeloma and measurable disease as defined by:
* Monoclonal plasma cells in the bone marrow =10% or presence of a biopsy proven plasmacytoma
* Measurable disease as defined by at least one of the following:

* serum M-protein level =1 g/dL or urine M-protein level =200 mg/24 hours; or
* Light chain multiple myeloma: Serum immunoglobulin free light chain =10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
* Evidence of end organ damage/presence of biomarkers of malignancies, specifically:
* Hypercalcaemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
* Renal insufficiency: creatinine clearance (CLcr)<40 mL per minute (measured or estimated by validated equations) or serum creatinine >177 µmol/L (>2 mg/dL)
* Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or haemoglobin value <100 g/L
* Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT. If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement
* Any one or more of the following biomarkers of malignancy:
* Clonal bone marrow plasma cell percentage = 60% (clonality should be established by showing ?/?-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used)
* Involved:uninvolved serum free light chain ration = 100 (values based on the serum Free light assay. The involved free light chain must be =100 mg/L)

-> 1 focal lesion on MRI (magnetic resonance imaging) studies (each focal lesion must be 5 mm or more in size) Patient is, in the investigator(s) opinion willing and able to comply with the protocol requirements.
* Women of childbearing potential must commit to either abstain continuously from heterosexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin prior to dosing through 90 days after the last dose of study drug. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
* Male patient agrees to use an acceptable method for contraception (i.e., condom or abstinence) during study drug therapy (including dose interruption) and for 90 days after the last dose of study drug.
* Patient with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 or Karnofsky performance status = 60%.
* Pretreatment clinical laboratory values within 30 days of enrolment:
* Platelet count =75 x 109/L;
* Absolute neutrophil count (ANC) = 1 x 109/L (G-CSF use is permitted);
* Corrected serum calcium <14 mg/dL (<3.5 mmol/L);
* Aspartate transaminase (AST) = 2.5 x the upper limit of normal (ULN);
* Alanine transaminase (ALT) = 2.5 x the ULN;
* Total bilirubin = 1.5 x the ULN;
* Calculated or measured creatinine clearance = 30 mL/minute.
* Patient has a life-expectancy >3 months.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Patient with a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, smoldering MM or Plasma Cell Leukemia (PCL). Monoclonal gammopathy of undetermined significance is defined by presence of serum M-protein <3 g/dL, clonal bone marrow plasma cells <10%, and absence of end-organ damage or amyloidosis that can be attributed to the plasma cell proliferative disorder. Smoldering multiple myeloma is defined as serum monoclonal protein = 30 g/L or urinary monoclonal protein = 500 mg per 24 h and/or clonal bone marrow plasma cell 10-60% with absence of related organ or tissue impairment or end-organ damage or amyloidosis. Plasma cell leukemia is defined as presence of circulating plasmacells (PCs) >2×109/L in peripheral blood or a peripheral blood plasmacytosis >20%
* Patient with a diagnosis of Waldenström's disease, or other conditions in which immunoglobulin M (IgM) M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
* Patient has prior or current systemic therapy or SCT for multiple myeloma, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.
* Patient has peripheral neuropathy of grade 2 or higher as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 4.0.
* Patient is exhibiting clinical signs of meningeal involvement of multiple myeloma.
* Clinical active infectious hepatitis type A, B, C or HIV.
* Subject has known chronic obstructive pulmonary disease (COPD) (defined as a Forced Expiratory Volume In 1 second (FEV1) <60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years. Subjects with known or suspected COPD or asthma must have a FEV1 test during screening.
* Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
* Known allergy to any of the study medications, their analogues, or excipients in the various formulations.
* Contraindication to any of the required concomitant drugs or supportive treatments.
* Pregnant or lactating females.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled 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
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
16/04/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/02/2026
Actual
Sample size
Target
Accrual to date
Final
401
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
Czechia
State/province [1] 0 0
Ostrava
Country [2] 0 0
Greece
State/province [2] 0 0
Athens
Country [3] 0 0
Italy
State/province [3] 0 0
Novara

Funding & Sponsors
Primary sponsor type
Other
Name
Stichting European Myeloma Network
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
EMN Trial Office S.r.l. Impresa Sociale
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This protocol is a phase II multicenter, randomized, open label study designed to assess the efficacy and safety of daratumumab combined with bortezomib, cyclophosphamide and dexamethasone (Dara-VCd) versus the association of bortezomib, thalidomide and dexamethasone (VTd) as pre transplant induction and post transplant consolidation, followed by maintenance with ixazomib alone or in combination with daratumumab, in newly diagnosed multiple myeloma (MM) patients eligible for autologous stem cell transplantation.

Patients enrolled in the Dara-VCd arm will receive: 4 cycles of daratumumab-bortezomib-cyclophosphamide-dexamethasone induction, followed by transplantation and 2 cycles of daratumumab-bortezomib-cyclophosphamide-dexamethasone consolidation. The choice of cyclophosphamide in combination with bortezomib and dexamethasone is suggested by the better safety profile of cyclophosphamide, in comparison with thalidomide and the efficacy of the alkylator agent, when combined with bortezomib.

Once-weekly bortezomib seems to be equally effective and better tolerated than the standard twice weekly schedule. The outcomes and response rate did not appear to be affected by the bortezomib dosing schedule.

Patients enrolled in the VTd arm will receive: 4 cycles of bortezomib-thalidomide-dexamethasone induction, followed by autologous transplantation and 2 cycles of bortezomib-thalidomide dexamethasone as consolidation. The VTd drug association is the current standard first line induction therapy for multiple myeloma patients who are eligible to stem cell transplantation.

At the end of consolidation phase patients with at least a partial response (= PR) will be rerandomized (assigned by chance) to one of 2 treatment groups to receive maintenance treatment with ixazomib alone or in combination with daratumumab. Patients will receive treatment until any sign of progression or intolerance, up to 24 months.
Trial website
https://clinicaltrials.gov/study/NCT03896737
Trial related presentations / publications
Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT03896737