Clinical trial NCT04661033: Safety, Pharmacokinetics, and Efficacy of Subcutaneous Isatuximab in Adults With Warm Autoimmune Hemolytic Anemia (wAIHA)
Official title: A Multicenter, Open-label, Non-randomized, Phase 1b/2 Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Subcutaneous Isatuximab in Adults With Warm Autoimmune Hemolytic Anemia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Warm Autoimmune Hemolytic Anemia (wAIHA)
Keywords: (wAIHA)
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2020-12-09
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Primary Objectives:

* Part A: To evaluate the safety and tolerability of subcutaneous injections of isatuximab in adults with wAIHA
* Part B: To evaluate the efficacy of the selected dose in adults with wAIHA

Secondary Objectives:

* Part A (Cohorts 2 and 3 only)
* To evaluate the efficacy of isatuximab in adults with wAIHA
* To evaluate the durability of response to isatuximab and time to response
* To evaluate the impact of isatuximab treatment on fatigue

Part B

* To evaluate the safety and tolerability of isatuximab in adults with wAIHA
* To evaluate the durability of response to isatuximab and time to response
* To evaluate the impact of isatuximab treatment on fatigue

Parts A (all Cohorts) and B

* To evaluate the effect of isatuximab on markers of hemolysis
* To characterize the pharmacokinetic profile of isatuximab in adults with wAIHA
* To evaluate the immunogenicity of isatuximab

Detailed description: 28 weeks (including screening)

Eligibility criteria: Inclusion criteria :

* Participant must be ≥18 to years of age, inclusive, at the time of signing the informed consent.

  - Males and females with a confirmed diagnosis of primary w AIHA or systemic lupus erythematosus (SLE)-associated w AIHA (without other SLE-related manifestations apart from cutaneous and musculoskeletal manifestations) who meet the following criteria:
  1. Hemoglobin level \<10 g/dL at screening.
  2. Hemolysis (haptoglobin ≤40 mg/dL and total or indirect/unconjugated bilirubin above the upper limit of normal).
  3. Positive direct antiglobulin test (DAT) (IgG or IgG + complement C3d pattern or IgM warm autoantibodies (positive dual DAT)).

     * Participants who have previously failed to maintain a sustained response after treatment with corticosteroids (corticosteroid-refractory or corticosteroid-dependent primary wAIHA).
     * Part A only: Participants who have previously failed to maintain a sustained response after treatment with rituximab (or other anti-CD20 monoclonal antibodies). The last dose of the anti-CD20 antibody must have been administered at least 12 weeks before enrollment.
     * Part B: Participants who have had an insufficient response to at least 1 prior therapy in addition to corticosteroids (splenectomy is regarded as a prior therapy).
     * Contraceptive use by men and women

     Exclusion criteria:
* Clinically significant medical history or ongoing chronic illness that would jeopardize the safety of the participant or compromise the quality of the data derived from his or her participation in the study as determined by the Investigator.

  * Serious infection that required hospitalization within 3 months prior to enrollment.
  * Secondary wAIHA from any cause including drugs, lymphoproliferative disorders, infectious or autoimmune disease (SLE without other SLE-related manifestations apart from cutaneous and musculoskeletal manifestations is allowed), or active hematologic malignancies. Participants with positive antinuclear antibodies but without a definitive diagnosis of an autoimmune disease are allowed.
  * History of coagulation or bleeding disorders (Evans Syndrome is allowed).
  * Uncontrolled or active HBV or HCV infection
  * HIV infection.
  * Serum gammaglobulin levels \<3 g/L.
  * Females who are pregnant, lactating, or considered unreliable with respect to contraceptive practice.
  * Concurrent treatment with corticosteroids, unless the participant has been on a stable daily dose for ≥ 15 days prior to enrollment.
  * Treatment with cyclophosphamide within 4 weeks prior to enrollment.
  * Treatment with cytotoxic drugs (other than cyclophosphamide) within 12 weeks prior to enrollment.
  * Treatment with non-cytotoxic, immunomodulatory drugs (including but not limited to Cyclosporine, Sirolimus, Tacrolimus, Idelalisib, Ibrutinib), excluding biologic agents, within 4 weeks prior to enrollment.
  * Treatment with any biologic agent within 12 weeks prior to enrollment.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Primary outcomes:
measure: Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs) And Treatment Emergent Serious Adverse Events (TESAEs)
timeFrame: From first dose of study drug (Day 1) up to 30 days after last study intervention administration, approximately 101 days
measure: Part A: Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology
timeFrame: From first dose of study drug (Day 1) up to end of study, approximately 169 days
measure: Part A: Number of Participants With PCSA: Clinical Chemistry And Electrolyte Parameters
timeFrame: From first dose of study drug (Day 1) up to end of study, approximately 169 days
measure: Part A: Number of Participants With Potentially Clinically Significant Abnormality: Urinalysis
timeFrame: From first dose of study drug (Day 1) up to end of study, approximately 169 days
measure: Part A: Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs
timeFrame: From first dose of study drug (Day 1) up to end of study, approximately 169 days
measure: Part B: Overall Response Rate (Response [R] Or Complete Response [CR]) At Day 85
timeFrame: Day 85
Secondary outcomes:
measure: Part A: Cohorts 2 and 3: Overall Response Rate (Response [R] Or Complete Response [CR]) At Day 85 And Day 169
timeFrame: Day 85 and Day 169
measure: Part A: Cohorts 2 and 3: Percentage Of Participants With Durable Hemoglobin (Hb) Response By Day 169
timeFrame: From first dose of study drug (Day 1) up to end of study (Day 169)
measure: Part A: Cohorts 2 and 3: Absolute Change From Baseline in Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Scale Score At Day 85 and Day 169
timeFrame: Baseline (Day 1), Day 85 and Day 169
measure: Part A: Absolute Change From Baseline In Lactate Dehydrogenase (LDH) at 1, 2, 4, 8, 12, and 24 Weeks
timeFrame: Cohort 1 : Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, and 12; Cohorts 2 and 3: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24
measure: Part A: Absolute Change From Baseline In Haptoglobin at 1, 2, 4, 8, 12, and 24 Weeks
timeFrame: Cohort 1 : Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, and 12; Cohorts 2 and 3: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24
measure: Part A: Absolute Change From Baseline In Reticulocytes at 1, 2, 4, 8, 12, and 24 Weeks
timeFrame: Cohort 1 : Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, and 12; Cohorts 2 and 3: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24
measure: Part A: Absolute Change From Baseline In Total Bilirubin at 1, 2, 4, 8, 12, and 24 Weeks
timeFrame: Cohort 1 : Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, and 12; Cohorts 2 and 3: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24
measure: Part A: Maximum Observed Concentration (Cmax) Of Isatuximab
timeFrame: Post-dose on Day 1
measure: Part A: Time to Reach Cmax (Tmax) of Isatuximab
timeFrame: Post-dose on Day 1
measure: Part A: Area Under the Plasma Concentration Versus Time Curve Calculated Using the Trapezoidal Method From Time Zero to Time of the Last Concentration Observed Above the Lower Limit of Quantification (Clast) (AUClast) of Isatuximab
timeFrame: Post-dose on Day 1
measure: Part A: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval (AUCtau) of Isatuximab
timeFrame: Post-dose on Day 1
measure: Part A: Mean Plasma Trough Concentration Of Isatuximab
timeFrame: Post-dose on Days 15, 29, 43 and 57
measure: Part A: Number Of Participants With Anti-Isatuximab Antibodies
timeFrame: Up to Days 169
measure: Part B: Number of Participants With TEAEs And TESAEs
timeFrame: From first dose of study drug (Day 1) up to end of study, approximately 169 days
measure: Part B: Number of Participants With PCSA: Hematology
timeFrame: From first dose of study drug (Day 1) up to end of study, approximately 169 days
measure: Part B: Number of Participants With PCSA: Clinical Chemistry And Electrolyte Parameters
timeFrame: From first dose of study drug (Day 1) up to end of study, approximately 169 days
measure: Part B: Number of Participants With Potentially Clinically Significant Abnormality: Urinalysis
timeFrame: From first dose of study drug (Day 1) up to end of study, approximately 169 days
measure: Part B: Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs
timeFrame: From first dose of study drug (Day 1) up to end of study, approximately 169 days
measure: Part B: Percentage Of Participants With Durable Hemoglobin Response By Day 169
timeFrame: From first dose of study drug (Day 1) up to end of study (Day 169)
measure: Part B: Overall Response Rate (Response [R] Or Complete Response [CR]) At Day 169
timeFrame: Day 169
measure: Part B: Absolute Change From Baseline In FACIT-Fatigue Scale Score At Day 85 And Day 169
timeFrame: Baseline (Day 1) and Day 85 and Day 169
measure: Part B: Absolute Change From Baseline In LDH at 1, 2, 4, 8, 12, and 24 Weeks
timeFrame: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24
measure: Part B: Absolute Change From Baseline In Haptoglobin at 1, 2, 4, 8, 12, and 24 Weeks
timeFrame: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24
measure: Part B: Absolute Change From Baseline In Reticulocytes at 1, 2, 4, 8, 12, and 24 Weeks
timeFrame: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24
measure: Part B: Absolute Change From Baseline In Total Bilirubin at 1, 2, 4, 8, 12, and 24 Weeks
timeFrame: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24
measure: Part B: Cmax Of Isatuximab
timeFrame: Post-dose on Day 1
measure: Part B: AUCtau of Isatuximab
timeFrame: Post-dose on Day 1
measure: Part B: Mean Plasma Trough Concentration Of Isatuximab
timeFrame: Post-dose on Days 15, 29, 43 and 57
measure: Part B: Number Of Participants With Anti-Isatuximab Antibodies
timeFrame: Up to Days 169
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center Site Number : 8400004
state: Pennsylvania
city: Creteil Cedex
country: France
facility: Investigational Site Number : 2500001
city: Essen
country: Germany
facility: Investigational Site Number : 2760001
city: Milano
country: Italy
facility: Investigational Site Number : 3800001
city: Leiden
country: Netherlands
facility: Investigational Site Number : 5280001
city: London
country: United Kingdom
facility: Investigational Site Number : 8260001
state: London, City Of
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: