Study Design and Initial Baseline Characteristics in Solace-Kids: Crizanlizumab in Pediatric Patients with Sickle Cell Disease
Authors: Heeney Matthew M. , Rees David C. , de Montalembert Mariane , Odame Isaac , Brown R. Clark , Wali Yasser , Nguyen Thu Thuy , Lam Du , Herranz Raquel Merino , Kanter Julie 
Published: November 2020

Background: Sickle cell disease (SCD) is a group of genetic blood disorders characterized by hemolytic anemia, multi-organ damage and acutely painful events (vaso-occlusive crises [VOCs]) that can cause life-threatening complications. Vaso-occlusion is mediated, in part, by P-selectin, an adhesion molecule expressed on endothelial cells and platelets. Adults and children with SCD have similar P-selectin expression levels; however, disease severity worsens with increasing age because of cumulative endothelial damage caused by repeated vaso-occlusion events. Crizanlizumab is a humanized anti-P-selectin monoclonal antibody that binds P-selectin and blocks its interaction with its ligands. SUSTAIN, a Phase 2 study in adults with SCD, has shown that crizanlizumab, compared with placebo, is well tolerated and significantly decreases the number of VOCs requiring a healthcare visit (Ataga et al. N Engl J Med 2017).
Aim: To describe the design of the first crizanlizumab study in pediatric patients (pts) with SCD and report demographics and baseline characteristics of a subset of enrolled pts (aged 6 to &lt;18 yr) (ClinicalTrials.gov: NCT03474965).
Methods: Primary objectives of this Phase 2, multicenter, open-label study are to confirm crizanlizumab dosing and assess safety. Pts aged 6 mo to &lt;18 yr with a confirmed SCD diagnosis (any genotype) and ≥1 VOC within the preceding 12 mo are included. The study will enroll ≥100 pts in 3 age groups: Group 1 (G1; 12 to &lt;18 yr), 2 (G2; 6 to &lt;12 yr), and 3 (G3; 6 mo to &lt;6 yr). Crizanlizumab is administered intravenously on weeks 1 and 3, and every 4 weeks thereafter for up to 2 years. Dose confirmation is being determined by single- and multiple-dose pharmacokinetic (PK) data and key safety data. Steady state PK, pharmacodynamic (PD) and safety data are used to validate the confirmed dose or prompt modifications, if required.
Secondary objectives include assessment of crizanlizumab efficacy, measured by annualized rate of VOCs leading to a healthcare visit (clinic, emergency room [ER] or hospital), and annualized rate of VOCs managed at home. VOC subcategories (uncomplicated pain crisis, acute chest syndrome, hepatic and splenic sequestration, and priapism), overall hospitalizations and ER visits and dactylitis events are also assessed. Safety measures include frequency and severity of adverse events. Long-term PK and PD will also be characterized by measuring pre-dose concentrations and percentage of P-selectin inhibition prior to each study drug dose.
Part A in each age group will confirm PK dose, beginning with ≥8 pts in G1. If unconfirmed, dose will be adjusted based on population PK model, and ≥8 additional pts enrolled. Once dose is confirmed, recruitment will be expanded for long-term safety and efficacy evaluation of the PK confirmed dose (Part B). This process will then repeat for G2 then G3 (2 to &lt;6 yr). Subsequently, ≥6 G3 pts aged 6 mo to &lt;2 yr will be enrolled, with only pre-dose PK/PD samples collected. Pts on hydroxyurea, L-glutamine or an erythropoietin-stimulating agent must have received the treatment for ≥6 mo prior to screening with no dosage or schedule adjustments during the study. Pts not currently on such drugs must have been off them for ≥6 mo prior to screening. Pts who have received prior crizanlizumab treatment are excluded from the trial.
Results: As of January 28, 2020, 59 pts were enrolled: 46 pts in G1 (11 pts in Part A and 35 pts Part B) and 13 pts in G2 Part A. Pt demographics are available for Part A in G1 and 2 (Table), based on 2 Data Monitoring Committee analyses. The median age of G1 was 17.0 yr (range 13-17), 6 (54.5%) were male and 11 (100%) were Black/African American. 9 (81.8%) had HbSS disease, 1 (9.1%) HbSC and 1 (9.1%) HbSβ0. The median age of G2 was 9.0 yr (range 6-11), 8 (61.5%) were male, 7 (53.8%) were Black/African American, 4 (30.8%) were White, and 2 were of multiple race, specifically 'White, Asian' (n=1, 7.7%) and 'White, Black/African American' (n=1, 7.7%). 12 (92.3%) pts had HbSS disease and 1 (7.7%) had HbSC.
Conclusions: This study aims to address an unmet treatment need in pediatric pts, exploring appropriate dosing and the safety of crizanlizumab. The annualized rates of VOCs, hospitalizations and ER visits will be assessed as secondary objectives. The primary analyses for Parts A and B of G1 and 2, and then G3, will occur consecutively when all pts enrolled in each group have either completed 26 weeks of treatment or discontinued the study treatment.

Disclosures
Heeney: UpToDate: Patents & Royalties: Author royalties; Micelle: Consultancy, Other; Keros: Consultancy; Novartis: Consultancy, Other; AstraZeneca: Consultancy, Other; Cyclerion: Consultancy, Other; Forma Therapeutics: Consultancy; Dova: Consultancy; Global Blood Therapeutics: Consultancy; Emerging Therapy Solutions (ETS): Consultancy. Rees:Alnylam Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AstraZeneca: Other: Data monitoring committee membership; Emmanus Medical: Consultancy, Honoraria; TauRx: Other: Data And Safety Monitoring. de Montalembert:Vertex: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Addmedica: Honoraria, Membership on an entity's Board of Directors or advisory committees. Odame:Novo Nordisk: Other: Study Advisory Board; Global Blood Therapeutics: Other: Study Data Safety Monitoring Board; Novartis: Other: Study Steering Committee. Wali:Novartis: Research Funding. Nguyen:Novartis: Current Employment. Lam:Novartis: Current Employment. Herranz:Novartis: Current Employment. Kanter:NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; bluebird bio, inc: Consultancy, Honoraria; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Guidepoint Global: Honoraria; Cowen: Honoraria; Jeffries: Honoraria; Wells Fargo: Honoraria; Medscape: Honoraria; GLG: Honoraria; Sanofi: Consultancy.

OffLabel Disclosure:
Crizanlizumab is a monoclonal antibody to P-selectin indicated in the USA for the prevention of vaso-occlusive crises in patients aged 16 years and over with sickle cell disease. This abstract described the new pediatric trial of crizanlizumab, which is not indicated for patients aged less than 16 years of age