Study Description
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.
Interventions
Crizanlizumab
Eligibility Criteria
Inclusion Criteria:
1. 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).
2. 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.
3. 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
4. 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.
5. Received standard age-appropriate care for SCD, including penicillin prophylaxis,
pneumococcal immunization, and parental education.
6. Performance status: Karnofsky ≥ 50% for patients >10 years of age, and Lansky ≥ 50
for patients ≤ 10 years of age.
7. 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
8. 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,
9. 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
10. 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.
11. 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:
1. History of stem cell transplant.
2. Received any blood products within 30 days prior to Week 1 Day 1 dosing.
3. 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.
4. 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.
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