A Phase 3 randomized, open label, multicenter study of isatuximab (SAR650984) in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with high-risk smoldering multiple myeloma
Isatuximab in combination with lenalidomide and dexamethasone in high-risk smoldering multiple myeloma (ITHACA)
Tanaka Tomoyuki
Sanofi K.K.
Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan
+81-3-6301-3670
clinical-trials-jp@sanofi.com
Clinical Study Unit
Sanofi K.K.
Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan
+81-3-6301-3670
clinical-trials-jp@sanofi.com
Not Recruiting
April. 16, 2021
Aug. 24, 2021
300
Interventional
randomized controlled trial
open(masking not used)
active control
parallel assignment
treatment purpose
- 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
Participants are excluded from the study if any of the following criteria apply:
- 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):
a) Increased calcium levels: Corrected serum calcium >1 mg/dL above the ULN or >11 mg/dL
b) 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
c) 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
d) >=1 bone lytic lesion
e) BMPCs >=60%
f) Serum involved/uninvolved FLC ratio >=100 and an involved FLC >= 100mg/L
g) Whole body magnetic resonance imaging (WB-MRI) or positron emission tomography-computed tomography (PET-CT) with more than 1 bone focal lesion (>=5 mm in diameter by MRI)
- Primary systemic amyloid light-chain (AL) 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.
18age old over
No limit
Both
Plasma cell myeloma
Drug: Isatuximab (SAR650984)
Pharmaceutical for: Solution for infusion, Route of administration: Intravenous
Drug: Lenalidomide
Pharmaceutical form: Capsules, Route of administration: Oral
Drug: Dexamethasone
Pharmaceutical form: Tablets and solution for injection, Route of administration: Oral and intravenous
1. Safety assessment: adverse events (AEs) - Safety Run-in Part [ Time Frame: Up to approximately 63 months ]
Number of participants with AEs
2. Plasma concentration of isatuximab: Cmax - Safety Run-in Part [ Time Frame: After first infusion in Cycle 1 in safety run-in part. 1 cycle = 28 days ]
Maximum concentration observed after the first infusion (Cmax)
3. Receptor density/receptor occupancy Safety Run-in Part [ Time Frame: Baseline to Cycle 2 Day 1 (each cycle is 28 days) ]
Change in CD38 receptor occupancy from baseline
4. Progression-free survival (PFS) Randomized Phase 3 [ Time Frame: Up to approximately 114 months ]
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 (IMWG) criteria or death from any cause, whichever happens first
1. Overall response rate (ORR) - Safety Run-in Part and Randomized Phase 3 [ Time Frame: Up to approximately 63 and 114 months for Safety Run-in Part and Randomized Phase 3, respectively ]
Proportion of participants with best overall response recorded as partial response or better according to 2016 IMWG criteria
2. Duration of response (DOR) - Safety Run-in Part and Randomized Phase 3 [ Time Frame: Up to approximately 63 and 114 months for Safety Run-in Part and Randomized Phase 3, respectively ]
Time from the date of the first response to date of progressive disease or death, whichever happens first
3. Minimal residual disease (MRD) negativity - Safety Run-in Part and Randomized Phase 3 [ Time Frame: Up to approximately 65 months ]
Number of participants for whom MRD is negative
4. Time to diagnostic (SLiM CRAB) progression or death - Safety Run-in Part and Randomized Phase 3 [ Time Frame: Up to approximately 63 and 114 months for Safety Run-in Part and Randomized Phase 3, respectively ]
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) - Safety Run-in Part and Randomized Phase 3 [ Time Frame: Up to approximately 63 and 114 months for Safety Run-in Part and Randomized Phase 3, respectively ]
Time from randomization to first-line treatment for MM
6. Immunogenicity: Incidence of anti-drug antibodies (ADA) - Safety Run-in Part [ Time Frame: Up to approximately 27 months ]
Number of participants with anti-drug antibodies against isatuximab
7. Sustained MRD negativity - Randomized Phase 3 [ Time Frame: Up to approximately 65 months ]
Number of participants with sustained MRD negativity (sample is still negative at least 1 year after the first negativity assessment)
8. Second PFS (PFS2) Randomized Phase 3 [ Time Frame: Up to approximately 144 months ]
Time from randomization to date of second objective progressive disease or death from any cause
9. Overall survivall - Randomized Phase 3 [ Time Frame: Up to approximately 144 months ]
Time from date of randomization to death from any cause
10. PFS and OS in participants with cytogenetic abnormalities - Safety Run-In and Randomized Part
[ Time Frame: Up to approximately 63 and 114 months for Safety Run-in Part and Randomized Phase 3, respectively ]
11. Complete response rate - Randomized Phase 3 [ Time Frame: Up to approximately 114 months ]
Percentage of participants with a CR as defined by 2016 IMWG response criteria
12. Time to biochemical progression - Randomized Phase 3
[ Time Frame: Up to approximately 114 months ]
13. Safety assessment: adverse events (AEs) - Randomized Phase 3 [ Time Frame: Up to approximately 144 months ]
Number of participants with AEs
14. Plasma concentration of isatuximab - Randomized Phase 3 [ Time Frame: At predose of Cycle 2 Day 1 and Cycle 6 Day 1 ]
Maximum concentration observed after the first infusion (Cmax)
15. European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 - Randomized Phase 3 [ Time Frame: Baseline to follow-up (up to approximately 7 years) ]
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
16. EORTC QLQ-MY20 - Randomized Phase 3 [ Time Frame: Baseline to follow-up (up to approximately 7 years) ]
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
17. EQ-5D-5L - Randomized Phase 3 [ Time Frame: Baseline to follow-up (up to approximately 7 years) ]
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
18. Randomized Phase 3: HRUPQ - Randomized Phase 3 [ Time Frame: Baseline to follow-up (up to approximately 7 years) ]
Mean change from baseline in Health resource utilization and productivity questionnaire (HRUPQ) scores. HRUPQ will assess health care resource utilization of high risk smoldering multiple myeloma (HR SMM) and the impact of HR SMM on employment/work higher scores = greater impact on work/productivity, resources
19. Patient's Qualitative Assessment of Treatment Version 2 (PQAT-v2) - Randomized Phase 3 [ Time Frame: End of treatment (up to approximately 5 years) ]
Patient's qualitative assessment of treatment will be assessed using a 10 point visual analogue/numeric rating scale with response anchors of 'not beneficial at all' to 'extremely beneficial'; higher scores represent greater patient-perceived benefits of treatment
Sanofi K.K.
National hospital Organization Mito Medical Center Institution Review Board
Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org/
NCT04270409
ClinicalTrials.gov
2019-003139-47
EudraCT
Australia/Brazil/Czechia/Denmark/France/Hungary/Israel/Republic of Korea/Lithuania/Norway/Spain/Turkey/Canada/Germany/Greece/Italy/New Zealand/United Kingdom/China/Poland/Sweden/United States
