Isatuximab in Type I Cryoglobulinemia (ICE)
Primary Purpose
Multiple Myeloma, Monoclonal Gammopathy of Undetermined Significance, Cryoglobulinemic Vasculitis
Status
Not yet recruiting
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Isatuximab Injection
Sponsored by
About this trial
This is an interventional treatment trial for Multiple Myeloma
Eligibility Criteria
Inclusion Criteria:
- Age > 18 years
- Written informed consent
- Indolent Multiple myeloma or monoclonal gammopathy of unknown significance (MGUS) with monoclonal IgG component
- Active cryoglobulinemia vasculitis defined by positive type I IgG cryoglobulinemia and a clinically active cryoglobulinemia with skin, joint, renal, and/or peripheral involvement,
- Treated naïve or relapsers type I cryoglobulinemia patients
- Affiliated to National French social security system
Contraception :
- Male participants : A male participant must agree to use a highly effective method of contraception during the participation period and for at least 5 months after the last dose of study treatment and refrain from donating sperm during this period.
- Female participants : A female participant is eligible to participate if she is not pregnant, not breastfeeding, and with at least one of the following conditions:
- Not a female of childbearing potential (FCBP), OR
- A FCBP who must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 24 hours of starting study medication and must apply a highly effective method of contraception during the participation period and for at least 5 months after the last dose of study treatment and refrain from donating oocyte during this period
- HIV negative serology; negative HBs Ag test; HCV negative serology and/or negative HCV RNA if positive HCV serology
Exclusion Criteria:
- Patient with a vasculitis unrelated to cryoglobulinemia
- Patient with non-active cryoglobulinemia vasculitis,
- Patient with diagnosis of multiple myeloma
- Patient treated with immunosuppressant (e.g alkylating agent, Rituximab, chemotherapy for plasma-cell neoplasms) introduced or increased in the month prior to the inclusion,
- Live vaccines within 30 days prior to baseline or concurrently with Isatuximab
- Infection requiring hospitalization and/or use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 60 days of Day 0.
- Active tuberculosis
- HIV positive, positive Ag HbS, positive HCV RNA
- Any clinically significant, uncontrolled medical conditions that, in the Investigator's opinion, would expose excessive risk to the patient or may interfere with compliance or interpretation of the study results.
- Hypersensitivity or history of intolerance to steroids, mannitol, pregelatinized starch, sodium stearyl fumarate, histidine (as base and hydrochloride salt), arginine hydrochloride, poloxamer 188, sucrose or any of the other components of study therapy that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents.
- Hypersensitivity to the active substances (isatuximab and premedication) or to any of their excipients
- Received any investigational drug within 14 days prior to inclusion or within 5 half-lives of the investigational drug, whichever is longer.
- Participation in another interventional study or being in the exclusion period at the end of a previous study.
Vulnerable populations
- pregnant or breastfeeding women
- Persons deprived of liberty by judicial or administrative decision
- Persons under psychiatric care without their consent
- Adults subject to a legal protection measure
- Persons unable to express their consent
- Neutrophils < 1000/mm3
- Platelets < 75000/mm3
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Isatuximab
Arm Description
Isatuximab will be given intravenously.
Outcomes
Primary Outcome Measures
Clinical response W20
Complete clinical response rate of cryoglobulinemia vasculitis symptoms. The complete clinical response is defined by the remission of all affected organs involved at baseline and the absence of clinical relapse according to the international guidelines.
The skin and articular remissions are evaluated clinically (disappearance of purpura and/or ulcers, disappearance of arthritis).
Renal remission is evaluated biologically (proteinuria <0.5g/24h or proteinuria/creatinuria <50 mg/mmol).
Neurological remission is evaluated clinically (any improvement of pains and paresthesia by visual analogue scales, any improvement of muscular testing in case of motor impairment at baseline) and electrophysiologically (improvement of electromyogram abnormalities compared to baseline).
Secondary Outcome Measures
Adverse event
Frequency and severity of adverse clinical events
Response
Complete, partial and non-clinical response rates
Remission BVAS
Rate of patients remaining in remission with a Birmingham Vasculitis Activity Score (BVAS), BVAS=0
Early failures
Rate of early failures (non-clinical response)
Cryoglobulinemia
Rate of cryoglobulinemia clearance
Rheumatoid factor
Rate of negativation of rheumatoid factor activity
C4 complement
Rate of normalization of C4 complement level
Renal complete remission
Rate of renal complete remission defined as proteinuria <0.5g/24h or proteinuria/creatinuria <50 mg/mmol, disappearance of hematuria, and glomerular filtration rate ≥60ml/min/1.73m²
Clinical relapse
Clinical relapse rate defined by de novo appearance or reappearance of a manifestation attributable to cryoglobulinemia vasculitis
Relapse
Incidence of relapse
Gammaglobulin
Mean change of gammaglobulin level from baseline to Week 20
CD19+ B cells
Mean change of CD19+ B cells level from baseline to Week 20
Quality of life SF36
Quality of life assessed by the mean variation of the Short Form 36 Health Survey Questionnaire (SF-36) from baseline to Week 20 The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.
Infections
Rate of infections
Full Information
NCT ID
NCT05114109
First Posted
September 27, 2021
Last Updated
October 28, 2021
Sponsor
Assistance Publique - Hôpitaux de Paris
1. Study Identification
Unique Protocol Identification Number
NCT05114109
Brief Title
Isatuximab in Type I Cryoglobulinemia
Acronym
ICE
Official Title
Isatuximab in Type I Cryoglobulinemia: A Prospective Pilot Study
Study Type
Interventional
2. Study Status
Record Verification Date
September 2021
Overall Recruitment Status
Not yet recruiting
Study Start Date
November 1, 2021 (Anticipated)
Primary Completion Date
December 31, 2022 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Cryoglobulinaemia is defined as the presence of immunoglobulins in the serum, which reversibly precipitate and form a gel when the temperature drops below 37°C and redissolve upon re-warming. Classification includes three subgroups based on Immunoglobulin (Ig) composition. Type I cryoglobulinaemia consists of only one isotype or subclass of immunoglobulin. Types II and III are classified as mixed cryoglobulinaemia (MC) because they include both IgG and IgM components. Overall, cryoglobulinaemia is considered a rare disease (<5/10,000 in the general European and North American population), although prevalence is likely to be higher in some areas such as the Mediterranean Basin. MC vasculitis is a multi-organic disease involving kidneys, joints, skin, and peripheral nerves. In type I cryoglobulinaemic vasculitis, searching for an underlying plasma-cell neoplasms is mandatory. Cryoglobulinaemia composed of IgG is more often found in multiple myeloma or monoclonal gammapathy of unknown significance. The course of MC vasculitis varies widely, and the prognosis is influenced by both MC-induced damage to vital organs and co-morbidities associated with underlying diseases. Type I cryoglobulinaemic vasculitis is a plasma cell associated disorder at the crossroad between autoimmunity and plasma-cell neoplasm. Treatment should be modulated according to the underlying associated disease and the severity of internal organ involvement. The overall 10-year survival after a diagnosis of cryoglobulinaemic syndrome ranges from 50% to 90% in case of renal involvement. The main therapeutic goal must be the cure of the underlying haematological disease (overwhelmingly plasma-cell neoplasms). The most common neoplasias are multiple myeloma (predominantly associated with type I cryoglobulinaemia and hyper-viscosity) in more than 50% of cases. Treating the underlying monoclonal disorder has been associated with improvement/stabilization of cryoglobulinaemic symptoms in most patients with type I cryoglobulinemia, although negativation of serum cryoglobulins was achieved in only half the patients. Alkylating agents and bortezomib are the main therapeutic options, but are associated with side effects including neuropathy. Patients presenting with symptomatic hyperviscosity require urgent therapeutic intervention using plasma exchange or plasmapheresis to remove cryoglobulins from the circulation. There is no standard of care or international guidelines for treatment of type 1 cryoglobulinemia. Isatuximab is an anti-CD38 monoclonal antibody that has been effective to treat relapsed or refractory multiple myeloma. Autoreactive plasma cells represent a key player in autoimmune disorders and particularly in type I cryoglobulinemia. Type I cryoglobulinemia is a model of plasma cell associated disorder at the crossroad between autoimmunity and plasma-cell neoplasm. However, rituximab fails to target this population and is poorly effective in this condition. Thus, there is an unmeet need for plasma cell targeted therapy in type I cryoglobulinemia. Clonal plasma cells in type I cryoglobulinemia do express surface CD38, providing a rationale for the use of isatuximab in cryoglobulinemia. Although the biology of the clonal plasma cell in type I cryoglobulinemia is distinct from that of Amyloid light-chain (AL) amyloidosis, they are models of hematological diseases associated with monoclonal Ig and whose tumor mass is low. In AL amyloidosis anti-CD38 targeted therapy was highly efficient as monotherapy in treatment naïve patients and relapsers. Thus, Isatuximab represents a highly promising therapy in type I cryoglobulinemia that could be use as monotherapy.
This study is a Phase 2 pilot prospective study of 21 patients with type I cryoglobulinemia treated by Isatuximab. Isatuximab will be given intravenously at 10 mg/kg at day 0, week (W)1, W2, W3, and W4 then every 2 weeks for a total of 12 infusions.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma, Monoclonal Gammopathy of Undetermined Significance, Cryoglobulinemic Vasculitis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
21 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Isatuximab
Arm Type
Experimental
Arm Description
Isatuximab will be given intravenously.
Intervention Type
Drug
Intervention Name(s)
Isatuximab Injection
Intervention Description
Isatuximab will be given intravenously at 10mg/kg at day 0, week (W)1, W2, W3, and W4 then every 2 weeks for a total of 12 infusions.
Primary Outcome Measure Information:
Title
Clinical response W20
Description
Complete clinical response rate of cryoglobulinemia vasculitis symptoms. The complete clinical response is defined by the remission of all affected organs involved at baseline and the absence of clinical relapse according to the international guidelines.
The skin and articular remissions are evaluated clinically (disappearance of purpura and/or ulcers, disappearance of arthritis).
Renal remission is evaluated biologically (proteinuria <0.5g/24h or proteinuria/creatinuria <50 mg/mmol).
Neurological remission is evaluated clinically (any improvement of pains and paresthesia by visual analogue scales, any improvement of muscular testing in case of motor impairment at baseline) and electrophysiologically (improvement of electromyogram abnormalities compared to baseline).
Time Frame
20 Weeks
Secondary Outcome Measure Information:
Title
Adverse event
Description
Frequency and severity of adverse clinical events
Time Frame
20 Weeks
Title
Response
Description
Complete, partial and non-clinical response rates
Time Frame
12 and 20 weeks
Title
Remission BVAS
Description
Rate of patients remaining in remission with a Birmingham Vasculitis Activity Score (BVAS), BVAS=0
Time Frame
12 and 20 weeks
Title
Early failures
Description
Rate of early failures (non-clinical response)
Time Frame
4 weeks
Title
Cryoglobulinemia
Description
Rate of cryoglobulinemia clearance
Time Frame
12 and 20 weeks
Title
Rheumatoid factor
Description
Rate of negativation of rheumatoid factor activity
Time Frame
12 and 20 weeks
Title
C4 complement
Description
Rate of normalization of C4 complement level
Time Frame
12 and 20 weeks
Title
Renal complete remission
Description
Rate of renal complete remission defined as proteinuria <0.5g/24h or proteinuria/creatinuria <50 mg/mmol, disappearance of hematuria, and glomerular filtration rate ≥60ml/min/1.73m²
Time Frame
12 and 20 weeks
Title
Clinical relapse
Description
Clinical relapse rate defined by de novo appearance or reappearance of a manifestation attributable to cryoglobulinemia vasculitis
Time Frame
20 weeks
Title
Relapse
Description
Incidence of relapse
Time Frame
48 weeks
Title
Gammaglobulin
Description
Mean change of gammaglobulin level from baseline to Week 20
Time Frame
20 weeks
Title
CD19+ B cells
Description
Mean change of CD19+ B cells level from baseline to Week 20
Time Frame
20 weeks
Title
Quality of life SF36
Description
Quality of life assessed by the mean variation of the Short Form 36 Health Survey Questionnaire (SF-36) from baseline to Week 20 The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.
Time Frame
20 weeks
Title
Infections
Description
Rate of infections
Time Frame
48 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age > 18 years
Written informed consent
Indolent Multiple myeloma or monoclonal gammopathy of unknown significance (MGUS) with monoclonal IgG component
Active cryoglobulinemia vasculitis defined by positive type I IgG cryoglobulinemia and a clinically active cryoglobulinemia with skin, joint, renal, and/or peripheral involvement,
Treated naïve or relapsers type I cryoglobulinemia patients
Affiliated to National French social security system
Contraception :
Male participants : A male participant must agree to use a highly effective method of contraception during the participation period and for at least 5 months after the last dose of study treatment and refrain from donating sperm during this period.
Female participants : A female participant is eligible to participate if she is not pregnant, not breastfeeding, and with at least one of the following conditions:
Not a female of childbearing potential (FCBP), OR
A FCBP who must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 24 hours of starting study medication and must apply a highly effective method of contraception during the participation period and for at least 5 months after the last dose of study treatment and refrain from donating oocyte during this period
HIV negative serology; negative HBs Ag test; HCV negative serology and/or negative HCV RNA if positive HCV serology
Exclusion Criteria:
Patient with a vasculitis unrelated to cryoglobulinemia
Patient with non-active cryoglobulinemia vasculitis,
Patient with diagnosis of multiple myeloma
Patient treated with immunosuppressant (e.g alkylating agent, Rituximab, chemotherapy for plasma-cell neoplasms) introduced or increased in the month prior to the inclusion,
Live vaccines within 30 days prior to baseline or concurrently with Isatuximab
Infection requiring hospitalization and/or use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 60 days of Day 0.
Active tuberculosis
HIV positive, positive Ag HbS, positive HCV RNA
Any clinically significant, uncontrolled medical conditions that, in the Investigator's opinion, would expose excessive risk to the patient or may interfere with compliance or interpretation of the study results.
Hypersensitivity or history of intolerance to steroids, mannitol, pregelatinized starch, sodium stearyl fumarate, histidine (as base and hydrochloride salt), arginine hydrochloride, poloxamer 188, sucrose or any of the other components of study therapy that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents.
Hypersensitivity to the active substances (isatuximab and premedication) or to any of their excipients
Received any investigational drug within 14 days prior to inclusion or within 5 half-lives of the investigational drug, whichever is longer.
Participation in another interventional study or being in the exclusion period at the end of a previous study.
Vulnerable populations
pregnant or breastfeeding women
Persons deprived of liberty by judicial or administrative decision
Persons under psychiatric care without their consent
Adults subject to a legal protection measure
Persons unable to express their consent
Neutrophils < 1000/mm3
Platelets < 75000/mm3
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
David Saadoun, Pr
Phone
673081143
Ext
+33
Email
david.saadoun@aphp.fr
First Name & Middle Initial & Last Name or Official Title & Degree
matthieu Resche-Rigon
Phone
142499742
Ext
+33
Email
matthieu.resche-rigon@u-paris.fr
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Learn more about this trial
Isatuximab in Type I Cryoglobulinemia
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