Isa-RVD Study: Phase II, Multi-centre, Single-Arm, Open-Label Study to evaluate the efficacy and safety of the combination regimen Isatuximab, Lenalidomide, Bortezomib, and Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Cancer Trials Ireland

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

3 Mar 2022 → ongoing

Decision date (initial)

2024-09-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Aventis Pharma Limited, trading as Sanofi, 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PT

External identifiers

EU CT number

2024-512749-18-00

EudraCT number

2020-000946-32

ClinicalTrials.gov

NCT05123131

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy, Pharmacogenetic

To evaluate the Very Good Partial Response (VGPR) or better rate at the end of two cycles of induction treatment, defined as the proportion of patients who have achieved VGPR or better, according to IMWG criteria (Kumar et al. 2016), at the end of two cycles of induction treatment.

Secondary objectives 18

1. To evaluate CR and sCR rate following one year and two years of maintenance therapy.
2. To evaluate ORR and rate of VGPR, or better following one year of maintenance therapy. ORR will be defined as achieving a partial response or better.
3. To evaluate time to VGPR or better.
4. To assess negative MRD rate following induction, following ASCT and after 1 and 2 years of maintenance treatment.
5. To evaluate clinical outcomes including: TTP, PFS, OS, DOR.
6. To assess the safety and tolerability of Isa-RVD.
7. To evaluate stem cell yield after mobilization.
8. To evaluate sCR and CR in the subgroup of non-IgG kappa positive patients.
9. To evaluate time to sCR and CR in the subgroup of non-IgG kappa positive patients.
10. To evaluate the clinical efficacy of Isa-RVD in high-risk cytogenetic subgroups: del(1p), gain of 1q, del(17p), t(4;14), t(14;16), t(14;20).
11. To explore immune modulatory effects of Isa-RVD through immune profiling (NK, T, and B cells) and T-cell receptor sequencing.
12. To compare MRD detection performed by flow cytometry and next generation sequencing.
13. To assess the immunogenicity of Isatuximab.
14. To evaluate PROs.
15. To characterize somatic aberrations present in cfDNA and CTCs as biomarkers of response/resistance.
16. To define markers of the permissive BM microenvironment that characterize risks of progression in MM.
17. To define the immune-oncogenomic landscape of NDMM in response to therapy.
18. A subgroup analysis will be performed for all secondary efficacy endpoints (excluding stem cell yield) repeating the analyses on the subset of patients treated per protocol V7 to explore any impact in the change in frequency of maintenance therapy.

Conditions and MedDRA coding

Newly diagnosed Multiple Myeloma

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Previously diagnosed with MM based on standard IMWG criteria and currently requires treatment.
2. Provided voluntary written informed consent before performance of any study-related procedures not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
3. Age ≥18 years, ≤75 years, with patients over the age of 70 requiring CI approval.
4. Measurable disease defined as at least one of the following: • Serum M protein ≥0.5g/dL (≥5g/L) • Urine M protein ≥200 mg/24 hours • Serum FLC assay: Involved FLC assay ≥10 mg/dL (≥100 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65).
5. Screening laboratory evaluations within the following parameters: • ANC ≥ 1,000 cells/dL (1.0 x 109/L) (growth factors cannot be used within 14 days before first study treatment administration) • Platelet count ≥75,000 cells/dL (75 x 109/L) if <50% BM nucleated cells are plasma cells, ≥30,000 cells/dL (30 x 109/L) if ≥50% of BM nucleated cells are plasma cells (without transfusions required during the 3 days prior to the screening haematologic test) • Total bilirubin ≤2.0 X ULN (except patients with Gilbert Syndrome, who are eligible if total bilirubin <3.0 mg/dL) • AST (SGOT) and ALT (SGPT) ≤3.0 x ULN • Haemoglobin ≥8g/dL • Calculated CrCl ≥30 mL/min.
6. ECOG performance status ≤ 2.
7. Participant agrees to be registered into the mandatory Risk Management Programme for Lenalidomide and be willing and able to comply with the requirements of this programme.
8. Ability to understand and the willingness to sign a written informed consent document.
9. Participant is considered eligible for ASCT by the treating physician.

Exclusion criteria 18

1. Prior therapy for multiple myeloma. Participants who received smouldering treatment qualify to participate as long as the prior treatment was not a CD38 therapy.
2. Diagnosed or treated for another malignancy within 3 years prior to enrolment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in-situ malignancy, or low risk prostate cancer after curative therapy.
3. Central nervous system involvement.
4. Peripheral neuropathy ≥ Grade 3, or Grade 2 with pain on clinical examination during the screening period.
5. Any medical or psychiatric illness that, in the Investigator’s opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study.
6. Concurrent uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, Grade 3 thromboembolic event or myocardial infarction within 6 months prior to enrolment
7. Prior major surgical procedure or radiation therapy within 4 weeks of initiation of study treatment (this does not include limited course of radiation used for management of bone pain within 7 days of study treatment).
8. Daily requirement for corticosteroids (equivalent to >10 mg/day prednisone for more than 7 days (except for inhalation corticosteroids). Patients may receive corticosteroids for the management of their MM that should not exceed the equivalent of 160mg of dexamethasone in a 2-week period and should be stable for at least 7 days prior to the initiation of study treatment.
9. Concurrent symptomatic amyloidosis or plasma cell leukaemia.
10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes).
11. Known active infection requiring parenteral or oral anti-infective treatment within 7 days of start of study treatment.
12. Active hepatitis B or hepatitis C viral infection.
13. Pregnant or breastfeeding female or female who intends to become pregnant during the participation in the study. FCBP unwilling to prevent pregnancy by the use of a highly effective method of contraception for ≥4 weeks before the start of study treatment, during treatment (including dose interruptions) and up to 5 months following the last dose of study treatment and/or who are unwilling or unable to be tested for pregnancy before study treatment initiation (2 negative tests) and then monthly up to 5 months following the last dose of study treatment.
14. Male participants who disagree to practice true abstinence or disagree to use highly effective contraception during sexual contact with a pregnant female or FCBP while participating in the study during dose interruptions and at least 3 months following study treatment discontinuation, even if he has undergone a successful vasectomy.
15. Receiving any other investigational agents.
16. Hypersensitivity to steroids, or H2 blockers that would prohibit further treatment with these agents.
17. Inability to tolerate thromboprophylaxis.
18. Hypersensitivity (or contraindication) to dexamethasone, sucrose histidine (as base and hydrochloride salt), boron, mannitol, and polysorbate 80, or to any of the components of the study therapy.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. VGPR or better rate at the end of two cycles of induction treatment, defined as the proportion of patients who have achieved VGPR or better, according IMWG criteria (Kumar et al. 2016), at the end of two cycles of induction treatment.

Secondary endpoints 15

1. CR and sCR rate after one year and two years of maintenance therapy.
2. ORR and rate of VGPR or better following one year of maintenance therapy. ORR will be defined as achieving a partial response or better.
3. Time to VGPR or better.
4. Negative MRD rate following induction, ASCT and after 1 and 2 years of maintenance treatment.
5. Clinical outcomes including: TTP, PFS, OS, DOR.
6. Safety and tolerability of Isa-RVD.
7. Stem cell yield after mobilization.
8. CR and sCR rate following induction, ASCT and maintenance treatment in the subgroup of non-IgG kappa positive patients.
9. Duration of and time to sCR and time to CR in the subgroup of non-IgG kappa positive patients.
10. Clinical efficacy in high-risk cytogenetic subgroups: del(1p), gain of 1q, del(17p), t(4;14), t(14;16), t(14;20).
11. Immune profiling (NK, T, and B cells) and T-cell receptor sequencing.
12. MRD detection performed by flow cytometry and NGS.
13. Immunogenicity of Isatuximab.
14. PROs.
15. Stem cell yield after mobilization (number of CD34+ cells)

Investigational products

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

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Cancer Trials Ireland

Sponsor organisation

Cancer Trials Ireland

Address

Rcsi House, 121 Saint Stephen's Green 121 Saint Stephen's Green

City

Dublin 2

Postcode

D02 H903

Country

Ireland

Scientific contact point

Organisation

Cancer Trials Ireland

Contact name

Head of Operations

Public contact point

Organisation

Cancer Trials Ireland

Contact name

Head of Operations

Third parties 6

Locations

2 EU/EEA countries · 8 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 13 files

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

Application history

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