Clinical trial NCT05114109: Isatuximab in Type I Cryoglobulinemia
Official title: Isatuximab in Type I Cryoglobulinemia: A Prospective Pilot Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Multiple Myeloma
Monoclonal Gammopathy of Undetermined Significance
Cryoglobulinemic Vasculitis
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2021-11-09
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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 :

  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

Primary outcomes:
measure: Clinical response W20
timeFrame: 20 Weeks
Secondary outcomes:
measure: Adverse event
timeFrame: 20 Weeks
measure: Response
timeFrame: 12 and 20 weeks
measure: Remission BVAS
timeFrame: 12 and 20 weeks
measure: Early failures
timeFrame: 4 weeks
measure: Cryoglobulinemia
timeFrame: 12 and 20 weeks
measure: Rheumatoid factor
timeFrame: 12 and 20 weeks
measure: C4 complement
timeFrame: 12 and 20 weeks
measure: Renal complete remission
timeFrame: 12 and 20 weeks
measure: Clinical relapse
timeFrame: 20 weeks
measure: Relapse
timeFrame: 48 weeks
measure: Gammaglobulin
timeFrame: 20 weeks
measure: CD19+ B cells
timeFrame: 20 weeks
measure: Quality of life SF36
timeFrame: 20 weeks
measure: Infections
timeFrame: 48 weeks
Other outcomes:
Locations:
Study officials:
References: