Study of Dose Confirmation and Safety of Crizanlizumab in Pediatric Sickle Cell Disease Patients

Study Overview
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Brief Summary
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The purpose of the Phase 2 CSEG101B2201 study is to confirm and to establish appropriate dosing and to evaluate the safety in pediatric participants ages 6 months to <18 years with a history of VOC with or without HU/HC, receiving crizanlizumab for 2 years. The efficacy and safety of crizanlizumab was already demonstrated in adults with sickle cell disease. The approach is to extrapolate from the PK/pharmacodynamics (PD) already established in the adult population. The study is designed as a Phase II, multicenter, open-label study.

Official Title
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A Phase 2,Multicenter,Open-Label Study to Assess Appropriate Dosing and to Evaluate Safety of Crizanlizumab,With or Without Hydroxyurea/Hydroxycarbamide,in Sequential,Descending Age Groups of Pediatric Sickle Cell Disease 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 or female patients ages 2 to <18 years (Group 3 will be expanded to allow enrolment of patients ages 6 to <24 months (and at least 7 kg) in Part B once the appropriate dose is confirmed in 2 to <6 year old participants). Confirmed diagnosis of SCD (any genotype including HbSS, HbSC, HbSβ0-thalassemia, HbSβ+-thalassemia patients, and others) by hemoglobin electrophoresis or/and high-performance liquid chromatography (HPLC) [performed locally]. Confirmation of diagnosis by two accepted methods is recommended. Experienced at least 1 VOC within the preceding 12 months prior to screening, as determined by medical history. Prior VOC must have resolved at least 7 days prior to the first dose in the study and must include all the following: a.the occurrence of appropriate symptoms (see VOC definition in Section 7.2.1.1), b.either a visit to a medical facility or healthcare professional, c.receipt of oral/parenteral opioid or parenteral NSAIDs If receiving HU/HC, L-glutamine or erythropoietin stimulating agent, must have been receiving the drug consistently for at least 6 months prior to screening and plan to continue taking it at the same dose and schedule during the trial. Patients who have not been receiving such drugs must have been off them for at least 6 months prior to screening. . Dose alterations of HU/HC, L-glutamine or erythropoietin stimulating agent during Part A are not allowed, and if this occurs, the participant will enter directly to Part B. Received standard age-appropriate care for SCD, including penicillin prophylaxis, pneumococcal immunization, and parental education. Performance status: Karnofsky ≥ 50% for patients >10 years of age, and Lansky ≥ 50 for patients ≤ 10 years of age. Patient must meet the following laboratory values prior to Week 1 Day 1: Absolute Neutrophil Count ≥1.0 x 109/L , Platelets ≥75 x 109/L, Hemoglobin (Hgb) > 5.5 g/dL Patient must have adequate renal and hepatic function as defined:Estimated Glomerular filtration rate (eGFR) ≥ 75 mL/min/1.73 m2 using Schwartz formula, Direct (conjugated) bilirubin ≤ 2.0 x ULN, Alanine transaminase (ALT) ≤ 3.0 x ULN, Transcranial Doppler (TCD) for patients aged 2 to < 16 years at time of screening, with HbSS, HbSβ0-thalassemia, and HbSD disease indicating low risk for stroke (per investigator). Please refer to Section 7.2.2.6 for details Written informed consent/assent, according to local guidelines, signed by the patient and / or by the parents or legal guardian prior to any study related screening procedures are performed. Female of non-childbearing potential or with negative serum pregnancy test on Screening and a negative urine pregnancy test (dipstick) prior to dosing on Day 1. Exclusion Criteria: History of stem cell transplant. Received any blood products within 30 days prior to Week 1 Day 1 dosing. Plan to participate in a chronic transfusion program (pre-planned series of transfusions for prophylactic purposes) or undergo exchange transfusions/plasmapheresis during the study. Patients requiring episodic transfusion (simple or exchange) in response to worsened anemia or VOC are permitted. Patients with bleeding disorders 6.Contraindication or hypersensitivity to any drug from similar class as study drug or to any excipients of the study drug formulation. 7.History of severe hypersensitivity reaction to other monoclonal antibodies, which in the opinion of the investigator may pose an increased risk of serious infusion reaction 8.Received a monoclonal antibody or immunoglobulin-based therapy within 6 months of Screening, or has documented immunogenicity to a prior monoclonal antibody. 9.Received active treatment on another investigational trial within 30 days (or 5 half -lives of that agent, whichever is greater) prior to Screening or plans to participate in another investigational drug trial. 10.Pregnant females or females who have given birth within the past 90 days or who are breastfeeding. 11.Any documented history of a clinical stroke or intracranial hemorrhage, or an uninvestigated neurologic finding within the past 12 months. Silent infarcts (only present on imaging) are not excluding patients from study participation. 12.Any abnormal TCD within the past 12 months. 13.Use of therapeutic anticoagulation (prophylactic doses permitted) or antiplatelet therapy (other than aspirin) within the 10 days prior to Week 1 Day 1 dosing. 14.Hospitalized within 7 days prior to Week 1 Day 1 dosing. 15.Planning to undergo a major surgical procedure during the duration of the study. 16.Planning to initiate or terminate HU/HC or L-glutamine while on study (except if needed to terminate for safety reasons). 17.Patient with active human immunodeficiency virus (HIV) infection (detectable viral load). 18.Patients with known active Hepatitis B infection. 19.Patients with known Hepatitis C history. 20.Significant active infection or immune deficiency (including chronic use of immunosuppressive drugs) in the opinion of the investigator. 21.Malignant disease. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; any completely resected carcinoma in situ. 22.Has a serious mental or physical illness, which, in the opinion of the Investigator would compromise participation in the study. 23.Any condition which, in the opinion of the investigator, is likely to interfere with the successful collection of the measurements required for the study 24.Resting QTcF ≥450 msec at pretreatment (baseline) for patients under 12 years of age and ≥450 msec for males and ≥460 msec for female patients 12 years and older. 25.Cardiac or cardiac repolarization abnormality, including any of the following: a. History of myocardial infarction (MI), uncontrolled congestive heart failure, unstable angina, or coronary bypass graft (CABG) within 6 months prior to starting study treatment, b. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (bifascicular block, Mobitz Type II, and third degree AV block), c. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome ( Risk factors for Torsade de Pointes (TdP), including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/ symptomatic bradycardia, Inability to determine the QTcF). 26. Sexually active females who are unwilling to comply with reliable method of birth control until 15 weeks following last dose of study drug. 28.Not able to understand and to comply with study instructions and requirements. 29.Patients who are an employee of the sponsor or investigator or otherwise dependent on them. 30.Patients who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities. 31.Patients who received prior crizanlizumab treatment and/or other selectin targeting agents are not allowed 32.Patients having taken voxelotor less than 30 days prior to Screening, or planning to take voxelotor while on study are not allowed.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 17 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<br>SEG101 (crizanlizumab) administered on Week 1 Day 1, Week3 Day 1 and Day 1 of every 4-week cycle | Drug: Crizanlizumab<br>* Crizanlizumab (SEG101) is a concentrate for solution for infusion, i.v. use. Supplied in single use 10 mL vials at a concentration of 10 mg/mL. One vial contains 100 mg of crizanlizumab.<br>* Other names: SEG101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK (AUCd15) after 1st dose | Confirm appropriate dosing of crizanlizumab in participants aged 2 to < 18 years (Parts A) | Day 15 | 
| PD (AUCd15) after 1st dose | Confirm appropriate dosing of crizanlizumab in participants aged 2 to < 18 years (Parts A) | Day 15 | 
| PK (AUCtau) after multiple dose | Confirm appropriate dosing of Crizanlizumab in participants aged 2 to < 18 years old | Week 15 | 
| PD (AUCtau) after multiple dose | Confirm appropriate dosing of Crizanlizumab in participants aged 2 to < 18 years old | Week 15 | 
| PK (Cmax) after 1st dose and multiple dose | Confirm appropriate dosing of crizanlizumab in participants aged 2 to < 18 years (Parts A) | Week 1 and Week 15 | 
| PK pre-dose concentrations | Confirm appropriate dosing of crizanlizumab in participants aged 6 months to less than 24 months of age (Part B) | Week 1 to Week 19 | 
| Frequency of any adverse events (AEs) as a measure of safety and tolerability | Safety of crizanlizumab in participants aged 6 months to < 18 years (Parts A and B) | 6 months, 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized rate Vaso Occlusive Crisis (VOC) events leading to healthcare visit in clinic/ER/hospital | To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old participants at the time of study entry (Parts A and B) | 6 months, 2 years | 
| Annualized rate Vaso Occlusive Crisis (VOC) events treated at home (based on documentation by health care provider following phone contact with the patient) | To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old participants at the time of study entry (Parts A and B) | 6 months, 2 years | 
| Annualized rate each subcategory of VOC event (uncomplicated pain crisis, acute chest syndrome, hepatic sequestration, splenic sequestration, priapism) | To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old participants at the time of study entry (Parts A and B) | 6 months, 2 years | 
| Annualized rate hospitalizations and ER visits (both overall and VOC-related) | To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old participants at the time of study entry (Parts A and B) | 6 months, 2 years | 
| Annualized rate days of ER/hospitalization (both overall and VOC-related) | To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old participants at the time of study entry (Parts A and B) | 6 months, 2 years | 
| Annualized rate of dactylitis events | To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old participants at the time of study entry (Parts A and B) | 6 months, 2 years | 
| Number, seriousness, severity, and causality assessments of treatment emergent adverse events and other data as considered appropriate. | To assess other safety measures in participants aged 6 months to < 18 years at the time of study entry | 6 months, 2 years | 
| Absolute change from baseline in hemoglobin | To assess other safety measures in participants aged 6 months to < 18 years at the time of study entry | Baseline, 6 months, 2 years | 
| Immunogenicity: measurement of anti-drug antibodies (ADA) to crizanlizumab | To assess other safety measures in participants aged 6 months to < 18 years at the time of study entry | Week 1, Week 3, Week 15, Week 27, End of Treatment (EOT) (approx. 2 years) and Post-treatment follow-up (last infusion +105 days) | 
| Electrocardiogram (ECGs) at relevant PK time points | To assess other safety measures in participants aged 6 months to < 18 years at the time of study entry | Screening, Week 7, Week 11, week 15, week 27 and Week 51 | 
| Growth and sexual maturation assessments (Tanner stage) | To assess other safety measures in participants aged 6 months to < 18 years at the time of study entry | Screening, Week 51 and End of Treatment (EOT) | 
| PK pre-dose concentrations prior to each study drug dose. | Characterize long-term PK and PD of crizanlizumab in participants aged 6 months to >18 years | Week 1, Week 3, Week 7, Week 15, Week 19, Week 23, Week 27, Week 31, Week 35, Week 39, Week 43, Week 47 and Week 51 | 
| Percentage P-selectin inhibition prior to dosing | Characterize long-term PK and PD of crizanlizumab in participants aged 6 months to >18 years | Week 1, Week 3, Week 7, Week 15, Week 19, Week 23, Week 27, Week 31, Week 35, Week 39, Week 43, Week 47 and Week 51 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SEG101, Sickle cell disease, SCD, crizanlizumab, pediatric, pharmacokinetic, P-selectin, Covid-19, Coronavirus disease 2019