PB2304 CRIZANLIZUMAB DOSE CONFIRMATION IN PEDIATRIC PATIENTS WITH SICKLE CELL DISEASE: SOLACE‐KIDS TRIAL DESIGN
Authors: M. Heeney, D. Rees, M. de Montalembert, I. Odame, R. Merino, B. Elliott, S. Bodla, J. Kanter
Journal: HemaSphere (2019)

Background: Sickle cell disease (SCD) is the most common serious single‐gene disorder in the world and can lead to complications, including acute pain and acute/chronic organ damage. Episodes of vaso‐occlusion are a hallmark of SCD. P‐selectin, an adhesion molecule expressed primarily on endothelial cells and platelets, plays a key role in the initiation of leukocyte rolling along the blood vessel wall (leading to inflammation propagation) and contributes to multicellular adhesion and microvascular occlusion in SCD. Although children and adults with SCD have similar P‐selectin expression, SCD worsens with advancing age as repeated vascular occlusion results in cumulative endothelial damage. Crizanlizumab, a humanized monoclonal antibody that binds P‐selectin and blocks interaction with its ligands (including leukocyte PSGL‐1), significantly decreased vaso‐occlusive crises (VOCs) leading to healthcare visit vs placebo and was well tolerated in SUSTAIN, a phase 2 study in adults with SCD. Aims: To report the design of the first crizanlizumab study in pediatric patients with SCD. Methods: Primary objectives of this phase 2, multicenter, open‐label study are to confirm appropriate dosing and safety of crizanlizumab therapy in patients &gt;6mo – &lt;18yrs, using sequential, descending age groups of pediatric SCD patients. Secondary objectives include assessing number of VOCs and number/duration of hospitalizations and emergency room visits. Planned enrollment is ≥100 patients with confirmed SCD diagnosis (all genotypes), who experienced ≥1 VOC within the preceding 12mo, in 3 sequential descending age groups: Group 1 (≥26 patients; 12yr‐&lt;18yr), Group 2 (≥26 patients; 6yr – &lt;12yr), and Group 3 (≥8 patients; 2yr – &lt;6yr) and (≥6 patients; 6mo – &lt;2yr). First, the dose will be confirmed (Part A) by ≥8 patients in Group 1. If not confirmed, the dose will be adjusted based on observed pharmacokinetics/pharmacodynamics, and ≥8 additional patients will be enrolled in Group 1 (Part A) to confirm the new dose. Once the dose is confirmed, Group 1 will be expanded (Part B), and ≥8 patients will be enrolled to Group 2 for dose confirmation. This schema will continue until dose confirmed in Group 3, which will then be expanded for enrollment of an exploratory group of ≥6 patients ages 6mo‐&lt;24mo. Patients being treated with hydroxyurea/hydroxycarbamide must have been taking it for ≥6mo prior to study entry with no planned dose adjustments other than accounting for weight changes. Crizanlizumab (5.0 mg/kg intravenously) will be administered on week 1, week 3, and every 4 weeks thereafter for 2 years. Results: Trial ongoing (ClinicalTrials.gov: NCT03474965). Summary/Conclusion: This study aims to address the unmet treatment need in pediatric patients with SCD by establishing pharmacokinetics/pharmacodynamics and confirming appropriate dose in different age groups. Safety will be assessed as a primary objective. Additionally, the number of VOCs and number/duration of hospitalizations and emergency room visits will be assessed as a secondary objective. Sponsored by Novartis.