Pharmacokinetics and Pharmacodynamics Study of SEG101 (Crizanlizumab) in Sickle Cell Disease (SCD) Patients With Vaso- Occlusive Crisis (VOC)

Study Overview
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Brief Summary
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The purpose of the CSEG101A2202 study was to characterize the PK and PD of SEG101/crizanlizumab at 5 mg/kg and to evaluate the safety and efficacy of SEG101/crizanlizumab in SCD patients.

Detailed Description
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Study CSEG101A2202 was designed as a Phase II, multicenter, open-label study. The first 45 patients (to identify 27 evaluable patients) were enrolled to the treatment group crizanlizumab 5.0 mg/kg to complete full PK/PD sampling at week 1 and week 15. In all patients, trough PK/PD samples was collected prior to each dose. In addition, throughout the study (and when possible), all patients had blood drawn for serum to assess PK and PD drawn at times of onset and resolution of each VOC event, fever, or infection. Once the up to 45 patients were enrolled, 12 additional patients were enrolled to the exploratory treatment group and begin at 7.5 mg/kg of crizanlizumab.

Official Title
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A Phase 2, Multicenter, Open-Label Study to Assess PK/PD of SEG101 (Crizanlizumab), With or Without Hydroxyurea/Hydroxycarbamide, in Sickle Cell Patients With Vaso-Occlusive Crisis

Conditions
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Sickle Cell Disease (SCD)

Intervention / Treatment
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* Drug: crizanlizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and non-pregnant female patients 16-70 years of age (inclusive) Confirmed diagnosis of sickle cell disease by hemoglobin electrophoresis or high-performance liquid chromatography (HPLC) [performed locally]. All sickle cell disease genotypes are eligible. Experienced at least 1 VOC within the preceding 12 months prior to Screening, as determined by medical history. If receiving HU/HC or erythropoietin stimulating agent, must have been receiving the drug for at least 6 months prior to Screening Hemoglobin ≥4.0 g/dL. Absolute neutrophil count ≥1.0 x 109/L and platelet count ≥75 x 109/L Adequate renal and hepatic function as defined: GFR ≥45 mL/min/1.73 m2 calculated by CKD-EPI ALT ≤3 x ULN Direct (conjugated) bilirubin ≤2 x ULN ECOG performance status ≤2 Written informed consent (or assent/ parental consent for minor subjects) prior to any screening procedures Exclusion Criteria: History of stem cell transplant. Acute VOC ending 7 days prior to first dosing Ongoing hospitalization prior to Screening Received blood products within 30 days to first dosing Participating in a chronic transfusion program (pre-planned series of transfusions for prophylactic purposes) History of severe hypersensitivity reactions to other monoclonal antibodies Received a monoclonal antibody or immunoglobulin -based agent within 1 year of Screening, or has documented immunogenicity to a prior biologic. Received active treatment on another investigational trial within 30 days (or 5 half-lives of that agent, whichever is greater) prior to Screening Significant active infection or immune deficiency (including chronic use of immunosuppressive drugs) Resting QTcF ≥470 msec at pretreatment (baseline) or other cardiac or cardiac repolarization abnormality

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: crizanlizumab 5 mg/kg<br>SEG101 (crizanlizumab) drug at a dose of 5.0 mg/kg (or 7.5 mg/kg for exploratory group) by IV infusion. | Drug: crizanlizumab<br>* SEG101 (crizanlizumab) drug at a dose of 5.0 mg/kg (or 7.5 mg/kg for exploratory group) by IV infusion<br>* Other names: SEG101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize PK (AUC) of crizanlizumab at 5.0 mg/kg in SCD patients. | PK (AUC) | Week1 Day 1 Pre-dose, 0.5hr, 1hr, 2hr, 4hr, 6hr, 24hr; 72hr; Week2 Day 1; Week3 Day 1; Week15 Day1 Pre-dose, 0.5hr, 1hr, 2hr, 4hr, 6hr, 24hr; 72hr; Week16 Day1; Week17 Day1; Week18 Day1; Week19 Day1 | 
| To characterize PK (Ctrough) of crizanlizumab at 5.0 mg/kg in SCD patients. | PK (Ctrough) | Week 1 Day1; Week3 Day1; Week7 Day1; Week11 Day1; Week15 Day1; Week19 Day1; Week23 Day1; Week27 Day1; Week31 Day1; Week35 Day1; Week39 Day1; Week43 Day1; Week47 Day1; Week51 Day1, W75 Day1, W99 Day 1, W123 Day 1, W147 Day 1, W171 Day 1, Safety FU | 
| To characterize PK (Cmax) of crizanlizumab at 5.0 mg/kg in SCD patients. | PK (Cmax) | Week1 Day1 Pre-dose, 0.5hr, 1hr, 2hr, 4hr, 6hr, 24hr; Week15 Day1 Pre-dose, 0.5hr, 1hr, 2hr, 4hr, 6hr, 24hr | 
| Pharmacodynamics (PD): Percentage of P-selectin inhibition and PD-AUC inhibition of crizanlizumab at 5.0 mg/kg in SCD patients | P-selectin inhibition percentage & PD AUC inhibition after the starting dose, after multiple doses and prior to each study drug dose | Week1 Day1 Pre-dose, 2hr, 24hr; 72hr; Week2 Day1; Week3 Day1; Week15 Day1 Pre-dose, 2hr, 24hr; 72hr; Week16 Day1; Week17 Day1; Week18 Day1; Week19 Day1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized rate of VOC events leading to healthcare visit in clinic/ER/hospital over time. | Assess efficacy of crizanlizumab (VOC leading to healthcare visits) | Week 1 through end of treatment (approximately 24 months) | 
| Annualized rate of VOC events treated at home (based on documentation by health care provider following phone contact with patient) over time. | Assess efficacy of crizanlizumab (VOC treated at home) | Week 1 through end of treatment (approximately 24 months) | 
| Annualized rate of VOC events (including both healthcare visit and home treatment). | Assess efficacy of crizanlizumab (VOC events) | Week 1 through end of treatment (approximately 24 months) | 
| Annualized rate of each subcategory of all VOC events (uncomplicated pain crisis, acute chest syndrome, hepatic sequestration, splenic sequestration, priapism) over time. | Assess efficacy of crizanlizumab (subcategory of VOC events) | Week 1 through end of treatment (approximately 24 months) | 
| Annualized rate of hospitalizations and ER visits (both total and VOC-related) over time. | Assess efficacy of crizanlizumab (hospitalizations and ER visits) | Week 1 through end of treatment (approximately 24 months) | 
| Annualized days of ER/hospitalization (both total and VOC-related) over time. | Assess efficacy of crizanlizumab (Days of ER/hospitalizations) | Week 1 through end of treatment (approximately 24 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SCD, Sickle cell disease, sickle cell anemia, vaso-occlusive crisis, P-selectin, SEG101, crizanlizumab, monoclonal antibody, Anemia, Sickle Cell, HbS Disease, Hemoglobin SC Disease, Sickle Cell Disorders, Sickling Disorder Due to Hemoglobin S