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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
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Myeloma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 :

    1. 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.
    2. 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

    First Posted
    September 27, 2021
    Last Updated
    October 28, 2021
    Sponsor
    Assistance Publique - Hôpitaux de Paris
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    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

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    Isatuximab in Type I Cryoglobulinemia

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