Extended VRD plus Early Rescue vs Isatuximab-VRD vs Isatuximab-VIberdomide-D for NDMM patients who are candidates for ASCT

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion PETHEMA

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

14 Oct 2022 → ongoing

Decision date (initial)

2024-10-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

FUNDACION PETHEMA

External identifiers

EU CT number

2024-517008-12-00

EudraCT number

2021-004130-11

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To compare the efficacy of extended VRD# + ASCT plus ERI& (Arm B) vs. Isatuximab-VRD# + ASCT (Arm A) in terms of proportion of patients who are MRD-negative by next-generation flow cytometry (NGF) after 18 cycles + ASCT*
#VRD: Lenalidomide-Bortezomib-Dex;
&ERI: Early Rescue Intervention with Iberdomide-Isatuximab.
* 18 cycles would be:
- Arms A & C: Induction x4 + ASCT + Consolidation x2 + Continuous x12
- Arm B: Induction x6 + ASCT + Consolidation x2 + Extended x10

Secondary objectives 4

1. Safety secondary objective 2.1: To assess the safety of Isatuximab-VID* + ASCT (Arm C). *VID: Iberdomide-Bortezomib-Dex.
2. Key secondary efficacy objective 2.2: To explore preliminary efficacy comparison of Arm C (Isatuximab-VID* + ASCT) vs. Arm A (Isatuximab-VRD# + ASCT) in terms of proportion of patients who reach NGF MRD-negative after Induction (4 cycles) + ASCT+ consolidation (two cycles) and 12 continuous treatment cycles.
3. Key secondary efficacy objective 2.3: To explore preliminary efficacy comparison of Arm C (Isatuximab- VID*ASCT) vs. Arm B (VRD extended plus ERI) in terms of proportion of patients who reach NGF MRD-negative.
4. Other secondary objectives 2.4 Progression-Free Survival (PFS) 2.5 Overall Response Rate (ORR): PR or better (PR, VGPR, CR, sCR). 2.6 Complete Response Rate (CRR): CR or better (CR, sCR). 2.7 Time to Response (TTR), among participants who achieve confirmed PR or better. 2.8 Duration of Response (DoR) among participants who achieved PR or better. 2.9 PFS2 2.10 Overall Survival (OS)

Conditions and MedDRA coding

Newly-diagnosed multiple myeloma (NDMM)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Patient is, in the investigator’s opinion, willing and able to comply with the protocol requirements.
2. Patient must be able to understand the study procedures.
3. Patient has given voluntary written informed consent before performance of any study-related procedure non 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.
4. Newly diagnosed multiple myeloma patient who requires start active treatment according to the 2014 IMWG criteria, namely clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events: evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: Hypercalcaemia, Anaemia, Renal Insufficiency, or Bone lesions (one or more osteolytic lesions on skeletal radiography, CT, or PET-CT), and any one or more of the following biomarkers: clonal BMPC% ≥60%, i/u free light ratio ≥100 or > 1 focal lesions on MRI or PET/CT) [Lancet Oncol. 2014;15(12): e538-e548]
5. Patient must have a measurable secretory disease defined as either serum monoclonal protein of ≥ 0,5 g/dl or urine monoclonal (light chain) protein ≥ 200 mg/24 h. For patients whose disease is only measurable by serum FLC, the involved FLC should be ≥ 10mg/dL (100 mg/L), with an abnormal serum FLC ratio.
6. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
7. Patient must be ≤ 65 years of age.
8. Patient must have adequate organ function, defined as table 2 in protocol.
9. Female patient: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
10. Male patient: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
11. All prior treatment-related toxicities (defined by National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0 must be ≤ Grade 1 at the time of enrolment except for alopecia.

Exclusion criteria 29

1. Patient has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), plasma cell leukemia or active POEMS syndrome at the time of screening.
2. Patient has had clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS multiple myeloma.
3. Prior history of malignancies, other than multiple myeloma (except for basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or the breast), unless the patient has been free of the disease for ≥ 5 years.
4. Any serious medical condition that places the subject at an unacceptable risk if he or she participates in this study; subjects with conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and/or lupus, that likely need additional steroid or immunosuppressive treatments in addition to the study treatment.
5. Pregnant or breastfeeding females.
6. Men and women of reproductive potential who are not using effective contraceptive methods (double barrier method, intrauterine device, oral contraception).
7. Patient is simultaneously enrolled in other interventional clinical trial.
8. Patient has used an investigational drug within 28 days or five half-lives, whichever is longer, preceding the first dose of study drug.
9. Patient must not have received prior radiotherapy (except localized palliative radiotherapy for pain, palliation or fracture) within 2 weeks of start of study therapy. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
10. Major surgery (except kyphoplasty) ≤ 4 weeks prior to initiating protocol therapy.
11. Patient has peripheral neuropathy or neuropathic pain grade 1 with pain or ≥2, as defined by the National Cancer Institute Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0
12. Patient evidence of cardiovascular risk including any of the following: • Myocardial infarction within 6 months before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV). • Uncontrolled cardiac arrhythmia. • Screening 12-lead ECG showing a baseline interval QTcF> 470 msec (exception: subjects with pacemaker). • Patients with uncontrolled hypertension.
13. Patients who have current unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
14. Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect patient’s safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfil inclusion criteria.
15. Evidence of active mucosal or internal bleeding.
16. Any serious medical condition or psychiatric illness that would interfere in understanding of the informed consent form.
17. Uncontrolled endocrine diseases (i.e. diabetes mellitus, hypothyroidism or hyperthyroidism) (i.e. requiring relevant changes in medication within the last month, or hospital admission within the last 3 months).
18. Patient with acute diffuse infiltrative pulmonary disease and/or pericardial disease.
19. Patient with severe chronic obstructive pulmonary disease (COPD) or asthma with forced expiratory volume in the first minute (FEV1) less than 50%.
20. History of interstitial lung disease or ongoing interstitial lung disease.
21. Subject has gastrointestinal disease that may significantly alter the absorption of iberdomide and/or other oral study treatment.
22. Patient has an active infection requiring systemic antibiotic, antiviral, or antifungal treatment at the time of starting treatment.
23. Patient has known HIV infection.
24. Patient seropositive for hepatitis B defined by a positive test for hepatitis B surface antigen (HBsAg). Subjects with resolved infection (i.e., 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 PCR measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Subjects who were positive only for HBsAg and had a valid vaccination certificate for hepatitis B could be included in the stutjdy, without the need to determine an undetectable HBV viral load.
25. Patient has positive hepatitis C antibody test result or positive hepatitis C RNA test result 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 a confirmatory negative Hepatitis C RNA test is obtained.
26. Hepatitis RNA testing is optional and participants with negative Hepatitis C antibody test are not required Patient require concurrent administration of a strong inhibitor or inducer of cytochrome P450 (CYP3A4/5) (including within 14 days of initiating study treatment)
27. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to iberdomide or drugs chemically related to iberdomide.
28. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to isatuximab or drugs chemically related to isatuximab, hypersensitivity reactions, or idiosyncratic reactions to other molecular antibodies.
29. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to lenalidomide or dexamethasone or drugs chemically related to lenalidomide or dexamethasone.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Improvement in the percentage of patients MRD-negative in Arm A vs. Arm B when considering B1 endpoint. B1 endpoint: VRD extended impact only, without considering ERI impact: any patient that require an ERI per protocol before finishing the 18 cycles + ASCT, will be considered MRD-positive at that time, independently of the ERI impact
2. Non-inferiority in the percentage of patients MRD-negative in Arm A vs. Arm B when considering B2 endpoint. B2 endpoint: VRD extended plus ERI impact: any patient who achieves MRD negativity with ERI before finishing the 18 cycles + ASCT will be considered MRD-negative at that time.

Investigational products

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

Test 5

Comparator 5

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion PETHEMA

Sponsor organisation

Fundacion PETHEMA

Address

Calle Del Professor Martin Lagos Sn

City

Madrid

Postcode

28040

Country

Spain

Scientific contact point

Organisation

Fundacion PETHEMA

Contact name

Dr Juan José Lahuerta

Public contact point

Organisation

Fundacion PETHEMA

Contact name

Dr Juan José Lahuerta

Third parties 3

Locations

1 EU/EEA country · 69 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 9 files

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

Application history

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