Safety, Pharmacokinetics, and Efficacy of Subcutaneous Isatuximab in Adults With Warm Autoimmune Hemolytic Anemia (wAIHA)

NCT04661033 | Terminated Phase 2 Results FDA Drug

• 3 other identifiers: ACT16832U1111-1255-53502020-003880-24
• Study Type: interventional
• Target: 8
• Locations: 6 countries
• Sites: 6

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

Conditions

Warm Autoimmune Hemolytic Anemia (wAIHA)

Keywords

(wAIHA)

Outcome Measures

Primary Outcomes (6)

• Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs) And Treatment Emergent Serious Adverse Events (TESAEs)

  An adverse event (AE) is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAE is defined as an AE that occurred from the time of the first IMP administration up to 30 days (included) after the last IMP administration. A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, was a medically important event.

  From first dose of study drug (Day 1) up to 30 days after last study intervention administration, approximately 101 days

• Part A: Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology

  Blood samples were collected to determine the hematology laboratory significant abnormalities. PCSA values: abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: Hemoglobin (Hb): ≤ 115 grams per Liter (g/L) (Male\[M\]); ≤ 95 g/L (Female\[F\]), ≥ 185 g/L (M); ≥ 165 g/L (F), Decrease from baseline ≥ 20 g/L; Hematocrit: ≤ 0.37 volume per volume (v/v) (M); ≤ 0.32 v/v (F), ≥ 0.55 v/v (M); ≥ 0.5 v/v (F); Erythrocyte Count: ≥ 6 x 10\^12 per Liter (/L); Platelet count: \< 100 x 10\^9/L, ≥ 700 x 10\^9/L; Leukocytes: \< 3 x 10\^9/L (Non-Black \[NB\]); \< 2 x 10\^9/L (Black \[B\]), ≥ 16 x 10\^9/L; Neutrophils: \< 1.5 x 10\^9/L (B); \< 1 x 10\^9/L (B); Lymphocytes: \> 4 x 10\^9/L; Monocytes: \> 0.7 x 10\^9/L; Basophils: \> 0.1 x 10\^9/L; Eosinophils: \> 0.5 x 10\^9/L or \> Upper limit of Normal (ULN) (if ULN ≥ 0.5 x 10\^9/L).

  From first dose of study drug (Day 1) up to end of study, approximately 169 days

• Part A: Number of Participants With PCSA: Clinical Chemistry And Electrolyte Parameters

  Blood samples were collected to determine the clinical chemistry laboratory and electrolyte parameters significant abnormalities. PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: Glucose: ≤ 3.9 millimoles per Liter (mmol/L) and \< Lower limit of normal (LLN), ≥ 11.1 mmol/L (unfasted); ≥ 7 mmol/L (fasted); Creatinine: ≥ 150 micromoles (µmol)/L, ≥ 30% change from baseline, ≥ 100% change from baseline, Alanine Aminotransferase (ALT): \> 3 ULN, \> 5 ULN, \> 10 ULN; Aspartate Aminotransferase (AST): \> 3 ULN; Alkaline Phosphatase (ALP): \> 1.5 ULN; Total Bilirubin: \> 1.5 ULN, \> 2 ULN; Sodium: ≤ 129 mmol/L, ≥ 160 mmol/L and Potassium: \< 3 mmol/L, ≥ 5.5 mmol/L.

  From first dose of study drug (Day 1) up to end of study, approximately 169 days

• Part A: Number of Participants With Potentially Clinically Significant Abnormality: Urinalysis

  Urine samples were collected to determine the urinalysis parameter significant abnormalities. PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: pH: ≤ 4.6 or ≥ 8.

  From first dose of study drug (Day 1) up to end of study, approximately 169 days

• Part A: Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs

  Vital signs were examined to determine the abnormalities. Vital signs included Sitting systolic blood pressure (SSBP), Sitting diastolic blood pressure (SDBP), Sitting heart rate (SHR) and weight. PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: SSBP: ≤95 millimeters of mercury (mmHg) and decrease from baseline ≥20 mmHg; ≥160 mmHg and increase from baseline ≥20 mmHg; SDBP: ≤45 mmHg and decrease from baseline ≥10 mmHg, ≥ 110 mmHg and increase from baseline ≥ 10 mmHg; SHR: ≤ 50 beats per minute (bpm) and decrease from baseline ≥ 20 bpm, ≥120 bpm and increase from baseline ≥ 20 bpm; Weight: ≥ 5% decrease from baseline, ≥5% increase from baseline.

  From first dose of study drug (Day 1) up to end of study, approximately 169 days

• Part B: Overall Response Rate (Response [R] Or Complete Response [CR]) At Day 85

  Overall response rate was defined as the percentage of participants with a response (R) or complete response (CR) over the evaluable participants. R was defined as an increase in Hb by ≥2 g/dL from baseline and an absence of transfusion in the last 7 days and absence of rescue medications in the past 4 weeks. Biochemical evidence of hemolysis might still be present. CR was defined as Hb ≥11 g/dL (women) or ≥12 g/dL (men), no evidence of hemolysis (normal bilirubin, Lactate dehydrogenase \[LDH\], haptoglobin, and reticulocytes), and absence of transfusion in the last 7 days and absence of rescue medication in the past 4 weeks.

  Day 85

Secondary Outcomes (29)

• Part A: Cohorts 2 and 3: Overall Response Rate (Response [R] Or Complete Response [CR]) At Day 85 And Day 169

  Day 85 and Day 169

• Part A: Cohorts 2 and 3: Percentage Of Participants With Durable Hemoglobin (Hb) Response By Day 169

  From first dose of study drug (Day 1) up to end of study (Day 169)

• 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

  Baseline (Day 1), Day 85 and Day 169

• Part A: Absolute Change From Baseline In Lactate Dehydrogenase (LDH) at 1, 2, 4, 8, 12, and 24 Weeks

  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

• Part A: Absolute Change From Baseline In Haptoglobin at 1, 2, 4, 8, 12, and 24 Weeks

  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

Study Arms (4)

Part A: Cohort 1: Isatuximab 140 mg SC Q2W x2

EXPERIMENTAL

Participants received 2 doses of Isatuximab 140 milligrams (mg) (1 milliliter \[mL\]) via subcutaneous (SC) injection every 2 weeks (Q2W) on Day 1 and Day 15.

Drug: Isatuximab SAR650984

Part A: Cohort 2: Isatuximab 280 mg SC Q2W x6

EXPERIMENTAL

Participants received 6 doses of Isatuximab 280 mg (2 mL) via SC injection Q2W through Day 71.

Drug: Isatuximab SAR650984

Part A: Cohort 3: Isatuximab 560 mg SC Q2W x6

EXPERIMENTAL

Participants received 6 doses of Isatuximab 560 mg (4 mL) via SC injection Q2W through Day 71.

Drug: Isatuximab SAR650984

Part B: Isatuximab up to 560 mg SC Q2W x6

EXPERIMENTAL

Participants were planned to receive 6 doses of Isatuximab up to 560 mg (4 mL) via SC injection Q2W through Day 71

Drug: Isatuximab SAR650984

Interventions

Isatuximab SAR650984 DRUG

Pharmaceutical form:Solution for injection Route of administration: Subcutaneous

Part A: Cohort 1: Isatuximab 140 mg SC Q2W x2; Part A: Cohort 2: Isatuximab 280 mg SC Q2W x6; Part A: Cohort 3: Isatuximab 560 mg SC Q2W x6; Part B: Isatuximab up to 560 mg SC Q2W x6

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Hemoglobin level \<10 g/dL at screening.
• Hemolysis (haptoglobin ≤40 mg/dL and total or indirect/unconjugated bilirubin above the upper limit of normal).
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sanofi: lead

Study Sites (6)

Fox Chase Cancer Center Site Number : 8400004

Philadelphia, Pennsylvania, 19111, United States

Location

Investigational Site Number : 2500001

Créteil, 94010, France

Location

Investigational Site Number : 2760001

Essen, 45147, Germany

Location

Investigational Site Number : 3800001

Milan, 20122, Italy

Location

Investigational Site Number : 5280001

Leiden, 2333 ZA, Netherlands

Location

Investigational Site Number : 8260001

London, London, City of, NW1 2PG, United Kingdom

Location

Related Links

• ACT16832 Plain language Results Summary

MeSH Terms

Interventions

isatuximab

Limitations and Caveats

The study was prematurely terminated based on strategic sponsor decision during Part A; not driven by any safety concerns, hence Part B was not conducted, and no analysis was performed.

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement

Contact-US@sanofi.com

800-633-1610 ext 6#

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2020
• First Posted: December 9, 2020
• Study Start: September 9, 2021
• Primary Completion: June 26, 2023
• Study Completion: June 26, 2023
• Last Updated: December 5, 2024
• Results First Posted: August 27, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will share

Locations

US (1); GB (1); IT (1); FR (1); DE (1); NL (1)