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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

European Myeloma Network B.V., Ceska Myelomova Skupina z.s., Emn Trial Office S.r.l. Impresa Sociale

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

16 Apr 2019 → ongoing

Decision date (initial)

2024-06-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Millennium Pharmaceuticals Inc. · Janssen Pharmaceutica

External identifiers

EU CT number

2024-511781-37-00

EudraCT number

2018-002089-37

ClinicalTrials.gov

NCT03896737

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

- Determine the progression free survival (PFS) at 36 months from first randomization (24 months from second).
- Determine minimal residual disease (MRD) negativity rate after consolidation according to IMWG criteria, by means of next generation sequencing (NGS)
- Determine MRD negativity rate during maintenance according to IMWG criteria, by means of next generation sequencing (NGS)

Secondary objectives 19

1. Determine the overall response rate (ORR).
2. Determine the VGPR rate.
3. Determine the CR.
4. Determine the PFS2.
5. Determine the safety.
6. Determine the duration of response (DoR).
7. Determine the overall survival (OS).
8. Determine the time to progression (TTP).
9. Determine the time to next therapy (TNT)
10. Determine MRD negativity rate by next generation flow cytometry (NGF) and imaging negativity by PET/CT after induction, consolidation and during maintenance
11. Determine the role of MRD on OS
12. Determine the prognostic role of different sensitivity levels of MRD
13. Determine the MRD duration
14. Determine the conversion rate of MRD negativity in MRD positivity and viceversa
15. Determine whether tumor response and outcome may change in subgroups with different prognosis according to current prognostic factors.
16. Determine whether tumor response and outcome may change in subgroups with different prognosis according to new prognostic factors, as evaluated by NGS.
17. Determine the impact of maintenance treatment on MRD.
18. Definition of prognosis factors, as assessed by NGS
19. Evaluate QoL.

Conditions and MedDRA coding

YOUNG PATIENTS AFFECTED BY MULTIPLE MYELOMA (MM) TO THE DIAGNOSIS ELIGIBLE TO THE AUTOLOGOUS TRANSMISSION OF STEM CELLS

Study design 5 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Patient at least 18 years of age and ≤ 65 years.
2. Patient eligible for ASCT.
3. LVEF ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available.
4. Newly diagnosed multiple myeloma patient.
5. 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.
6. Patient with documented multiple myeloma and measurable disease as defined by: 1) Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma. 2) Measurable disease as defined by at least one of the following: 2.1) serum M-protein level ≥1 g/dL or urine M-protein level ≥200 mg/24 hours; or 2.2) Light chain multiple myeloma: involved serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
7. Evidence of end organ damage/presence of biomarkers of malignancies, specifically: 1) 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). 2) Renal insufficiency: creatinine clearance <40 mL per minute (measured or estimated by validated equations) or serum creatinine >177 μmol/L (>2 mg/dL). 3) Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or haemoglobin value <100 g/L. 4) 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.
8. Any one or more of the following biomarkers of malignancy: 1) Clonal bone marrow plasma cell percentage ≥ 60% (clonality should be established by showing κ/λ-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). 2) Involved/uninvolved serum free light chain ratio ≥100 (values based on the serum Freelite assay. The involved free light chain must be ≥100 mg/L). 3) or >1 focal lesion on MRI studies (each focal lesion must be 5 mm or more in size)
9. Patient is, in the investigator(s) opinion willing and able to comply with the protocol requirements.
10. 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 through a medical assessment of success of the procedure, according to local procedure) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin prior to dosing and for at least 4 weeks before starting thalidomide through 90 days after the last dose of study drugs and 6 months after the last dose of cyclophosphamide. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
11. 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 drugs and 6 months after the last dose of cyclophosphamide.
12. Patient with an ECOG performance status score of 0, 1, or 2 or Karnofsky performance status ≥ 60%.
13. Pretreatment clinical laboratory values within 30 days of enrolment: - Platelet count ≥75 x 10^9 /L; - Absolute neutrophil count (ANC) ≥ 1 x 10^9 /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
14. Patient has a life-expectancy >3 months.

Exclusion criteria 21

1. Patient with a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, plasma cell leukemia or smoldering multiple myeloma. 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 endorgan damage or amyloidosis. Plasma cell leukemia is defined as the presence of circulating plasmacells (PCs) >2×10^9 /L in peripheral blood or a peripheral blood plasmacytosis >20%.
2. Patient with a diagnosis of Waldenström’s disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
3. 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.
4. Patient has peripheral neuropathy of grade 2 or higher as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 5.0.
5. Patient is exhibiting clinical signs of meningeal involvement of multiple myeloma.
6. Known to be: - seropositive for human immunodeficiency virus (HIV) - seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. - seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
7. Subject has known chronic obstructive pulmonary disease (COPD), persistent asthma, or a history of asthma within the last 2 years with a forced expiratory volume in 1 second [FEV1] <60%. Subjects with known or suspected COPD or asthma must have a FEV1 test during screening.
8. 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.
9. Known allergy to any of the study medications, their analogues, or excipients in the various formulations.
10. Contraindication to any of the required concomitant drugs or supportive treatments.
11. Pregnant or lactating females.
12. Acute active infection requiring antibiotics or infiltrative pulmonary disease.
13. Serious medical condition, laboratory abnormality or psychiatric illness that prevented the subject from the enrolment or place the subject at unacceptable risk, including acute diffuse infiltrative pericardial and pulmonary disease.
14. Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.
15. Invasive malignancy within the past 5 years.
16. Major surgery within 14 days before enrollment.
17. Radiotherapy within 14 days before enrollment.
18. Live vaccine 30 days before start of treatment and 90 days after the end of study treatment
19. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.
20. Participation in other clinical trials with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial.
21. Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Progression free survival (PFS): PFS in part 1 and part 2 of the study will be measured from the date of first or second randomization to the date of first observation of disease progression or death to any cause as an event. In the first part the efficacy of Dara VCd will be compared with VTd at 3 years from the first randomization; in the second part the efficacy of daratumumab-ixazomib will be compared with ixazomib at 2 years from the second randomization.
2. MRD negativity: MRD evaluation by clonotypic analysis of immunoglobulin heavy chain (IgH) VDJ gene rearrangement will be performed on bone marrow samples obtained by the end of induction and consolidation therapy and thereafter every 6 months after the first maintenance treatment dose. For this purpose, the ClonoSEQ TM assay (Adaptive Biotechnologies, Seattle) will be used at sensitivity thresholds of 10 -3 (1 cancer cell per 1,000 nucleated cells), 10 -4 and ≥10 –5 .

Secondary endpoints 8

1. Overall response rate (ORR): ORR will include at least PR using the International Response Criteria reported by Durie et al. Categories of response will include stringent Complete Response (sCR), CR, VGPR, PR, SD and PD. If, during the course of the study, other relevant categories are identified in the literature, then these categories may be added. Responders are defined as subjects with at least a PR.
2. Progression free survival 2 (PFS2): PFS2 will be measured from the date of first randomization to the date of observation of second disease progression (i.e. progression after the second line of therapy) or death to any cause as an event.
3. Duration of response (DoR): Time between first documentation of response and PD.
4. Overall survival (OS): OS is defined as the time between the date of first randomization and death.
5. Time to progression (TTP): TTP will be measured from the date of randomization to the date of first observation of PD, or deaths due to PD.
6. Time to the next anti-myeloma therapy (TNT): TNT will be measured from the date of first randomization to the date of next anti-myeloma therapy.
7. MRD by NGF and PET/CT ✓ Immunophenotypic CR is defined as CR plus absence of phenotypically aberrant PCs (clonal) in bone marrow with a minimum of 1 million total bone marrow cells analyzed by multiparametric flow cytometry (with 2 tubes of 8 colors) ✓ PET/CT negativity is defined as the complete disappearance of any area of FDG uptake, according to the IMWG criteria.
8. Definition of prognostic factors, as assessed by NGS (MM-panel): NGS will be employed to deeply characterize MM CD138+ clone(s) both at diagnosis and at time of first progression. NGS data will be analyzed to describe patients genomic profile at baseline and to identify prognostic factors related to disease progression. A stratification of patients will be performed according to the evolution patterns, and eventual clinical correlations will be searched.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 15

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

European Myeloma Network B.V.

Sponsor organisation

European Myeloma Network B.V.

Address

Blaak 555

City

Rotterdam

Postcode

3011 GB

Country

Netherlands

Scientific contact point

Organisation

European Myeloma Network B.V.

Contact name

Mario Boccadoro

Public contact point

Organisation

European Myeloma Network B.V.

Contact name

Pieter Sonneveld

Third parties 8

Ceska Myelomova Skupina z.s.

Sponsor organisation

Ceska Myelomova Skupina z.s.

Address

Jihlavska 340/20, Bohunice Bohunice

City

Brno-Bohunice

Postcode

625 00

Country

Czechia

Scientific contact point

Organisation

Ceska Myelomova Skupina z.s.

Contact name

Roman Hajek

Public contact point

Organisation

Ceska Myelomova Skupina z.s.

Contact name

Roman Hajek

Third parties 3

Emn Trial Office S.r.l. Impresa Sociale

Sponsor organisation

Emn Trial Office S.r.l. Impresa Sociale

Address

Via Saluzzo 1/a, TO

City

Turin

Postcode

10125

Country

Italy

Scientific contact point

Organisation

Emn Trial Office S.r.l. Impresa Sociale

Contact name

Mario Boccadoro

Public contact point

Organisation

Emn Trial Office S.r.l. Impresa Sociale

Contact name

Mario Boccadoro

Third parties 2

Sponsor responsibilities

Article 77 compliance

European Myeloma Network B.V.

Contact point sponsor

European Myeloma Network B.V.

Article 77 implementation

European Myeloma Network B.V.

Locations

3 EU/EEA countries · 24 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 42 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications