| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Smoldering Multiple Myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10035226 |
| E.1.2 | Term | Plasma cell myeloma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- Safety run-in: To confirm the recommended dose of isatuximab when combined with lenalidomide and dexamethasone in participants with high-risk smoldering multiple myeloma (SMM)
- Randomized Phase 3: To demonstrate the clinical benefit of isatuximab in combination with lenalidomide and dexamethasone in the prolongation of progression free survival when compared to lenalidomide and dexamethasone in subjects with high-risk SMM |
|
| E.2.2 | Secondary objectives of the trial |
Safety run-in:
- To assess overall response rate (ORR)
- To assess duration of response (DOR)
- To assess minimal residual disease (MRD) negativity in participants achieving very good partial response (VGPR) or complete response (CR)
- To assess time to diagnostic (SLiM CRAB) progression or death
- To assess time to first-line treatment for multiple myeloma (MM)
- To assess the potential immunogenicity of isatuximab
- Impact of abnormal cytogenetic subtype
Randomized Phase 3 - Key Secondary Objectives:
- To compare between the arms:
* MRD negativity
* Sustained MRD negativity
* Second progression-free survival (PFS2)
* Overall survival
Other Secondary Objectives:
- To evaluate in both arms:
* CR rate
* ORR
* DOR
* Time to diagnostic (SLiM CRAB) progression
* Time to first-line treatment for MM
* Safety and tolerability
* Pharmacokinetics (PK)
* Potential of isatuximab immunogenicity
* Clinical outcome assessments (COAs) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Participants who are diagnosed within 5 years with SMM (per International Myeloma Working Group [IMWG] criteria), defined as serum M-protein ≥30 g/L or urinary M-protein ≥500 mg per 24 hour or both, and/or clonal bone marrow plasma cells (BMPCs) 10% to <60%, and absence of myeloma defining events or other related conditions and with high-risk SMM
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 or 2
- Capable of giving voluntary written informed consent |
|
| E.4 | Principal exclusion criteria |
- Evidence of any of the following calcium, renal failure, anemia, bone
lesions (CRAB) criteria or Myeloma Defining Events (SLiM CRAB) detailed
below (attributable to the participants SMM involvement):
*Increased calcium levels: Corrected serum calcium >1 mg/dL above
the ULN or >11 mg/dL
*Renal insufficiency: Determined by glomerular filtration rate (GFR)
<40 mL/min/1.73 m² (Modification of Diet in Renal Disease [MDRD]
Formula) or serum creatinine >2 mg/dL
*Anemia (hemoglobin 2 g/dL below lower limit of normal or <10
g/dL or both) transfusion support or concurrent treatment with
erythropoietin stimulating agents is not permitted
*≥ 1 bone lytic lesion
*BMPCs ≥60%
*Serum involved/uninvolved FLC ratio ≥100
*Whole body magnetic resonance imaging (WB-MRI) or positron
emission tomography-computed tomography (PET-CT) with more than 1
focal lesion (≥5 mm in diameter by MRI)
- Primary systemic amyloid light-chain (amyloid light chain) amyloidosis,
monoclonal gammopathy of undetermined significance (MGUS), standard
risk smoldering myeloma, soft-tissue plasmacytoma, and symptomatic
myeloma
- Uncontrolled infection within 28 days prior to randomization in Phase 3
or first study intervention administration in safety run-in
- Clinically significant cardiac or vascular disease within 3 months prior
to randomization, e.g. Myocardial Infarction; Unstable Angina; Coronary
(e.g. Coronary Artery Bypass Graft, Percutaneous Coronary Intervention)
or peripheral artery revascularization, Left Ventricular Ejection Fraction
<40%, Heart Failure NYHA III-IV, Stroke, Transient Ischemic Attack,
Pulmonary Embolism, other thromboembolic event, cardiac arrhythmia
(Grade 3 or higher by NCI-CTCAE Version 5.0)
- Known acquired immunodeficiency syndrome (AIDS)-related illness or
known human immunodeficiency virus (HIV) disease requiring antiviral
treatment or active hepatitis A (defined as positive hepatitis A antigen or
positive IgM). HIV serology at screening will be tested for German
participants and any other country where required as per local
regulations and serology hepatitis B and C at screening will be tested for
all participants.
-Uncontrolled or active HBV infection: Patients with positive HBsAg
and/or HBV DNA
Of note:
· Patient can be eligible if anti-HBc IgG positive (with or without positive
anti-HBs) but HBsAg and HBV DNA are negative. If anti-HBV therapy in
relation with prior infection was started before initiation of IMP, the
anti-HBV therapy and monitoring should continue throughout the study
treatment period.
· Patients with negative HBsAg and positive HBV DNA observed during
screening period will be evaluated by a specialist for start of anti-viral
treatment: study treatment could be proposed if HBV DNA becomes
negative and all the other study criteria are still met.
- Active HCV infection: positive HCV RNA and negative anti-HCV
Of note:
- Patients with antiviral therapy for HCV started before initiation of IMP
and positive HCV antibodies are eligible. The antiviral therapy for HCV
should continue throughout the treatment period until seroconversion.
- Patients with positive anti-HCV and undetectable HCV RNA without
antiviral therapy for HCV are eligible
- Malabsorption syndrome or any condition that can significantly impact
the absorption of lenalidomide
- Any of the following within 3 months prior to randomization (or first
study intervention administration in safety run-in cohort): treatment
resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious
or inflammatory bowel disease, diverticulitis.
- Received treatment (eg surgery, radiotherapy, medication) for a
malignancy within 3 years of randomization (or first study intervention
administration in safety run-in cohort)
- Prior exposure to approved or investigational treatments for SMM or
MM (including but not limited to conventional chemotherapies,
immunomodulatory imid drugs, or Proteasome inhibitors); concurrent
use of bisphosphonates or receptor activator of nuclear factor kappa-B
ligand (RANKL) inhibitor denosumab is not permitted; however, prior
bisphosphonates or once-a-year intravenous bisphosphonate given for
the treatment of osteoporosis is permitted
- Ongoing treatment with corticosteroids with a dose >10 mg prednisone
or equivalent per day at the time of randomization (or first study
intervention administration in safety run-in cohort)
- Women of childbearing potential or male participant with women of
childbearing potential who do not agree to use a highly effective method
of birth control
- Vaccination with a live vaccine 4 weeks before the start of the study
drug. Seasonal flu vaccines that do not contain live virus are permitted
Note: Other Inclusion/Exclusion criteria may apply. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Safety assessment: adverse events (AEs): Number of participants with AEs
2. Plasma concentration of isatuximab (Cmax): Maximum concentration observed after the first infusion
3. Receptor density/receptor occupancy (safety run-in): Change in CD38 receptor occupancy from baseline
4. Progression-free survival (PFS) (Randomized Phase 3): Time from randomization to MM (SLiM CRAB criteria) or other related conditions based on independent review committee assessment according to 2014 International Myeloma Working Group criteria or death from any cause, whichever happens first |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Baseline to 30 days after last study treatment administration (up to approximately 100 months after first study treatment)
2. Up to approximately 24 months
3. Baseline to Cycle 2 Day 1 (each cycle is 28 days)
4. Up to approximately 85 months |
|
| E.5.2 | Secondary end point(s) |
1. Overall response rate (ORR): Proportion of participants with best overall response recorded as partial response or better according to 2016 IMWG criteria
2. Duration of response (DOR): Time from the date of the first response to date of progressive disease or death, whichever happens first
3. Minimal residual disease (MRD) negativity: Number of participants for whom MRD is negative
4. Time to diagnostic (SLiM CRAB) progression or death: Time from randomization to diagnosis of SLiM-CRAB or other related conditions, progression, or death from any cause
5. Time to first-line treatment for multiple myeloma (MM): Time from randomization to first-line treatment for MM
6. Immunogenicity: Incidence of anti-drug antibodies (ADA): Number of participants with anti-drug antibodies against isatuximab
7. Sustained MRD negativity: Number of participants with sustained MRD negativity (sample is still negative at least 1 year after the first negativity assessment)
8. Second PFS (PFS2): Time from randomization to date of second objective progressive disease or death from any cause
9. Overall survival: Time from date of randomization to death from any cause
10. Complete response rate: Percentage of particpants with a CR as defined by 2016 IMWG response criteria
11. Safety assessment: adverse events (AEs): Number of participants with AEs
12. Plasma concentration of isatuximab: Maximum concentration observed after the first infusion (Cmax)
13. European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30: Mean change from baseline scores will be assessed, with responses ranging from 1=not at all to 4=very much or 1=very poor to 7=excellent; higher scores represent a better level of physical functioning
14. EORTC QLQ-MY20: Mean change from baseline in scores will be assessed using a 4-point scale, with responses ranging from 1=not at all to 4=very much; higher scores represent better perspectives of the future and higher level of symptomatology
15. EQ-5D-5L: Mean change from baseline scores will be assessed from 5 items, with responses ranging from 'no' to 'extreme problems'; health state utility values (HSUVs) are generated by multiplying the item scores by country specific value sets; health status is assessed via a VAS; higher scores = higher HSUV/health status
16. Economic questionnaire: Mean change from baseline scores will assess work productivity, resource utilization and working days missed by a caregiver; higher scores = greater impact on work/productivity, resources
17. Patient's Qualitative Assessment of Treatment Version 2 (PQAT-v2): Patient's qualitative assessment of treatment will be assessed using a 10 point VAS/NRS scale with response anchors of 'not beneficial at all' to 'extremely beneficial'; higher scores represent greater patient-perceived benefits of treatment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1, 2, 3, 4, 5, 7, 10: Up to approximately 85 months
6, 12: Up to approximately 24 months
8: Up to approximately 120 months
9: Up to approximately 144 months
11: Baseline to 30 days after last study treatment administration (up to approximately 100 months after first study treatment)
13, 14, 15, 16: Baseline to follow-up (up to approximately 10 years)
17: End of treatment (up to approximately 10 years) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 62 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Canada |
| China |
| Czechia |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Lithuania |
| New Zealand |
| Norway |
| Poland |
| Spain |
| Sweden |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 13 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 13 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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