Clinical trial NCT03474965: Study of Dose Confirmation and Safety of Crizanlizumab in Pediatric Sickle Cell Disease Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Sickle Cell Disease (SCD)
Keywords: SEG101
Sickle cell disease
SCD
crizanlizumab
pediatric
pharmacokinetic
P-selectin
Covid-19
Coronavirus disease 2019
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-03-23
Enrollment: 118
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


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.

Primary outcomes:
measure: PK (AUCd15) after 1st dose
timeFrame: Day 15
measure: PD (AUCd15) after 1st dose
timeFrame: Day 15
measure: PK (AUCtau) after multiple dose
timeFrame: Week 15
measure: PD (AUCtau) after multiple dose
timeFrame: Week 15
measure: PK (Cmax) after 1st dose and multiple dose
timeFrame: Week 1 and Week 15
measure: PK pre-dose concentrations
timeFrame: Week 1 to Week 19
measure: Frequency of any adverse events (AEs) as a measure of safety and tolerability
timeFrame: 6 months, 2 years
Secondary outcomes:
measure: Annualized rate Vaso Occlusive Crisis (VOC) events leading to healthcare visit in clinic/ER/hospital
timeFrame: 6 months, 2 years
measure: Annualized rate Vaso Occlusive Crisis (VOC) events treated at home (based on documentation by health care provider following phone contact with the patient)
timeFrame: 6 months, 2 years
measure: Annualized rate each subcategory of VOC event (uncomplicated pain crisis, acute chest syndrome, hepatic sequestration, splenic sequestration, priapism)
timeFrame: 6 months, 2 years
measure: Annualized rate hospitalizations and ER visits (both overall and VOC-related)
timeFrame: 6 months, 2 years
measure: Annualized rate days of ER/hospitalization (both overall and VOC-related)
timeFrame: 6 months, 2 years
measure: Annualized rate of dactylitis events
timeFrame: 6 months, 2 years
measure: Number, seriousness, severity, and causality assessments of treatment emergent adverse events and other data as considered appropriate.
timeFrame: 6 months, 2 years
measure: Absolute change from baseline in hemoglobin
timeFrame: Baseline, 6 months, 2 years
measure: Immunogenicity: measurement of anti-drug antibodies (ADA) to crizanlizumab
timeFrame: Week 1, Week 3, Week 15, Week 27, End of Treatment (EOT) (approx. 2 years) and Post-treatment follow-up (last infusion +105 days)
measure: Electrocardiogram (ECGs) at relevant PK time points
timeFrame: Screening, Week 7, Week 11, week 15, week 27 and Week 51
measure: Growth and sexual maturation assessments (Tanner stage)
timeFrame: Screening, Week 51 and End of Treatment (EOT)
measure: PK pre-dose concentrations prior to each study drug dose.
timeFrame: 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
measure: Percentage P-selectin inhibition prior to dosing
timeFrame: 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
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University Of Alabama
state: Alabama
city: Washington
country: United States
facility: Childrens National Hospital
state: District of Columbia
city: Gainesville
country: United States
facility: Univ of Florida College of Medicine
state: Florida
city: Hollywood
country: United States
facility: Joe DiMaggio Childrens Hospital
state: Florida
city: Atlanta
country: United States
facility: Childrens Healthcare of Atlanta
state: Georgia
city: Boston
country: United States
facility: Childrens Hosp Boston Dept of Hematology
state: Massachusetts
city: Bronx
country: United States
facility: Childrens Hospital at Montefiore
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Philadelphia
country: United States
facility: Childrens Hospital Of Philadelphia
state: Pennsylvania
city: Charleston
country: United States
facility: Medical Uni of South Carolina
state: South Carolina
city: Fort Worth
country: United States
facility: Cook Childrens Medical Center
state: Texas
city: Brussel
country: Belgium
facility: Novartis Investigative Site
city: Laeken
country: Belgium
facility: Novartis Investigative Site
city: Liege
country: Belgium
facility: Novartis Investigative Site
city: Salvador
country: Brazil
facility: Novartis Investigative Site
state: BA
city: Ribeirao Preto
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Cali
country: Colombia
facility: Novartis Investigative Site
state: Valle Del Cauca
city: Monteria
country: Colombia
facility: Novartis Investigative Site
city: Paris 15
country: France
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Nagpur
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Padova
country: Italy
facility: Novartis Investigative Site
state: PD
city: Orbassano
country: Italy
facility: Novartis Investigative Site
state: TO
city: Beirut
country: Lebanon
facility: Novartis Investigative Site
city: Tripoli
country: Lebanon
facility: Novartis Investigative Site
city: Muscat
country: Oman
facility: Novartis Investigative Site
city: Esplugues De Llobregat
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Palma De Mallorca
country: Spain
facility: Novartis Investigative Site
state: Islas Baleares
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Adana
country: Turkey
facility: Novartis Investigative Site
city: Mersin
country: Turkey
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Del Pozo Martin Y. 2021 ASH annual meeting. Lancet Haematol. 2022 Feb;9(2):e92-e93. doi: 10.1016/S2352-3026(21)00384-7. Epub 2021 Dec 16. No abstract available.