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

Phase 2TerminatedNCT04661033

Sanofi8 enrolled

Overview

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

28 weeks (including screening)

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Warm Autoimmune Hemolytic Anemia (wAIHA)

Interventions

Pharmaceutical form:Solution for injection Route of administration: Subcutaneous

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (6)

Fox Chase Cancer Center Site Number : 8400004

Philadelphia, Pennsylvania, United States

Investigational Site Number : 2500001

Créteil, France

Investigational Site Number : 2760001

Essen, Germany

Investigational Site Number : 3800001

Milan, Italy

Investigational Site Number : 5280001

Leiden, Netherlands

Investigational Site Number : 8260001

London, London, City of, United Kingdom

Outcomes

Primary Outcomes

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.

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Day 85

Secondary Outcomes

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

Overall response rate was defined as the percentage of participants with a R or 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, LDH, haptoglobin, and reticulocytes), and absence of transfusion in the last 7 days and absence of rescue medication in the past 4 weeks

Time frame: Day 85 and Day 169

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

Durable response was defined as Hb level ≥10 g/dL with an increase from baseline of ≥2 g/dL on three consecutive evaluable visits during the study period; with absence of transfusion and no rescue medication during the period of 3 consecutive visits and for at least 7 days (transfusions) and 4 weeks (rescue medication) prior to the first consecutive visit.

Time frame: 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

The FACIT-Fatigue scale is a 13-item questionnaire assessing fatigue where participants scored each item on a 5-point scale (0 to 4): 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much. To score the FACIT-fatigue, all items are summed to create a single fatigue score with a range from 0 to 52, where higher score (and positive change scores) indicated better functioning. Baseline was defined as the Day 1 pre-dose value.

Time frame: 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

Blood samples were collected to evaluate the effect of Isatuximab on marker of hemolysis: LDH. Baseline is defined as the last assessment value before IMP.

Time frame: 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

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

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

Blood samples were collected to evaluate the effect of Isatuximab on marker of hemolysis: Haptoglobin. Baseline was defined as the last assessment value before IMP.

Time frame: 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 Reticulocytes at 1, 2, 4, 8, 12, and 24 Weeks

Blood samples were collected to evaluate the effect of Isatuximab on marker of hemolysis: Reticulocytes. Baseline was defined as the last assessment value before IMP.

Time frame: 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 Total Bilirubin at 1, 2, 4, 8, 12, and 24 Weeks

Blood samples were collected to evaluate the effect of Isatuximab on marker of hemolysis: Total Bilirubin. Baseline was defined as the last assessment value before IMP.

Time frame: 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: Maximum Observed Concentration (Cmax) Of Isatuximab

Blood samples were collected at the specified timepoints. Cmax was defined as maximum concentration observed after the first infusion. The non-compartmental pharmacokinetic (PK) analysis was performed.

Time frame: Post-dose on Day 1

Part A: Time to Reach Cmax (Tmax) of Isatuximab

Blood samples were collected at the specified timepoints. Tmax was defined as time to reach Cmax. The non-compartmental PK analysis was performed.

Time frame: Post-dose on Day 1

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

Blood samples were collected at the specified timepoints. AUClast was defined as area under the plasma concentration versus time curve calculated using the trapezoidal method from time zero to time of the Clast. The non-compartmental PK analysis was performed.

Time frame: Post-dose on Day 1

Part A: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval (AUCtau) of Isatuximab

Blood samples were collected at the specified timepoints. AUCtau was defined as area under the plasma concentration versus time curve over the dosing interval. The non-compartmental PK analysis was performed.

Time frame: Post-dose on Day 1

Part A: Mean Plasma Trough Concentration Of Isatuximab

Blood samples were collected at the specified timepoints. The non-compartmental Pharmacokinetic (PK) analysis was performed

Time frame: Post-dose on Days 15, 29, 43 and 57

Part A: Number Of Participants With Anti-Isatuximab Antibodies

Plasma samples were collected to evaluate antibodies to Isatuximab. Plasma samples were screened for antibodies binding to Isatuximab. Post-baseline positive, defined as Anti-drug antibody (ADA) that developed at any time during the ADA on-study observation period in participants without pre-existing ADA. Number of participants with positive ADA have been reported.

Time frame: Up to Days 169

Part B: Number of Participants With TEAEs And TESAEs

An 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 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.

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

Part B: Number of Participants With PCSA: Hematology

Blood samples were planned to be 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: Hb: ≤ 115 g/L (M); ≤ 95 g/L (F), ≥ 185 g/L (M); ≥ 165 g/L (F), Decrease from baseline ≥ 20 g/L; Hematocrit: ≤ 0.37 v/v (M); ≤ 0.32 v/v (F), ≥ 0.55 v/v (M); ≥ 0.5 v/v (F); Erythrocyte Count: ≥ 6 x 10\^12/L); Platelet count: \< 100 x 10\^9/L, ≥ 700 x 10\^9/L; Leukocytes: \< 3 x 10\^9/L (NB); \< 2 x 10\^9/L (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 \> ULN (if ULN ≥ 0.5 x 10\^9/L).

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

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

Blood samples were planned to be 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 mmol/L and \< LLN, ≥ 11.1 mmol/L (unfasted); ≥ 7 mmol/L (fasted); Creatinine: ≥ 150 µmol/L, ≥ 30% change from baseline, ≥ 100% change from baseline, ALT: \> 3 ULN, \> 5 ULN, \> 10 ULN; AST: \> 3 ULN; ALP: \> 1.5 ULN; Total Bilirubin: \> 1.5 ULN, \> 2 ULN; Sodium: ≤ 129 mmol/L; ≥ 160 mmol/L; Potassium: \< 3 mmol/L, ≥ 5.5 mmol/L and Calcium

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

Part B: Number of Participants With Potentially Clinically Significant Abnormality: Urinalysis

Urine samples were planned to be 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.

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

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

Vital signs were planned to be examined to determine the abnormalities. Vital signs included SSBP, SDBP, 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 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 bpm and decrease from baseline ≥ 20 bpm, ≥ 120 bpm and increase from baseline ≥ 20 bpm; Weight: ≥ 5% decrease from baseline, ≥5% increase from baseline.

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

Part B: Percentage Of Participants With Durable Hemoglobin Response By Day 169

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

Part B: Overall Response Rate (Response [R] Or Complete Response [CR]) At Day 169

Time frame: Day 169

Part B: Absolute Change From Baseline In FACIT-Fatigue Scale Score At Day 85 And Day 169

Time frame: Baseline (Day 1) and Day 85 and Day 169

Part B: Absolute Change From Baseline In LDH at 1, 2, 4, 8, 12, and 24 Weeks

Blood samples were planned to be collected to evaluate the effect of Isatuximab on marker of hemolysis: LDH. Baseline was defined as the last assessment value before IMP

Time frame: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24

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

Blood samples were planned to be collected to evaluate the effect of Isatuximab on marker of hemolysis: Haptoglobin. Baseline was defined as the last assessment value before IMP

Time frame: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24

Part B: Absolute Change From Baseline In Reticulocytes at 1, 2, 4, 8, 12, and 24 Weeks

Blood samples were planned to be collected to evaluate the effect of Isatuximab on marker of hemolysis: Reticulocytes. Baseline was defined as the last assessment value before IMP

Time frame: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24

Part B: Absolute Change From Baseline In Total Bilirubin at 1, 2, 4, 8, 12, and 24 Weeks

Blood samples were planned to be collected to evaluate the effect of Isatuximab on marker of hemolysis: Total Bilirubin. Baseline was defined as the last assessment value before IMP

Time frame: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24

Part B: Cmax Of Isatuximab

Blood samples were planned to be collected at the specified timepoints. Cmax was defined as maximum concentration observed after the first infusion.

Time frame: Post-dose on Day 1

Part B: AUCtau of Isatuximab

Blood samples were planned to be collected at the specified timepoints. AUCtau was defined as area under the plasma concentration versus time curve over the dosing interval.

Time frame: Post-dose on Day 1

Part B: Mean Plasma Trough Concentration Of Isatuximab

Blood samples were planned to be collected at the specified timepoints.

Time frame: Post-dose on Days 15, 29, 43 and 57

Part B: Number Of Participants With Anti-Isatuximab Antibodies

Plasma samples were planned to be collected to evaluate antibodies to Isatuximab. Plasma samples were planned to be screened for antibodies binding to Isatuximab. Post-baseline positive, defined as ADA that developed at any time during the ADA on-study observation period in participants without pre-existing ADA.

Time frame: Up to Days 169