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

Novartis Pharmaceuticals117 enrolled

Overview

The purpose of this study was to confirm and to establish appropriate dosing and to evaluate the safety in pediatric participants ages 2 to \<18 years with a history of Vaso-Occlusive Crisis (VOC) with or without Hydroxyurea/Hydroxycarbamide (HU/HC), receiving crizanlizumab for 2 years. The efficacy and safety of crizanlizumab was previously demonstrated in adults with sickle cell disease. The approach was to extrapolate from the pharmacokinetics (PK)/pharmacodynamics (PD) already established in the adult population. The study was designed as a Phase II, multicenter, open-label study.

This was an open-label, single-arm study of crizanlizumab in sickle-cell disease (SCD) pediatric participants. This study consisted of 2 parts, Part A and Part B. In Part A, the dose for 3 age groups (see groups below), was first confirmed on the basis of single and multiple dose (steady state) PK data and key safety data from an initial subgroup of participants. In Part B, safety and efficacy were collected from additional participants from 6 to \<18 years (Groups 1 and 2, only). At least 100 participants were planned to be enrolled in the trial in total, split in 3 age groups: * Group 1 (age 12 to \<18 years): at least 26 participants (≥8 in Part A and ≥18 in Part B), * Group 2 (age 6 to \<12 years): at least 26 participants (≥8 in Part A and ≥18 in Part B), * Group 3 (age 2 to \<6 years): at least 8 participants (≥8 Part A). Crizanlizumab was administered every 4 weeks with a loading dose 2 weeks after the first dosing (i.e., by i.v. infusion) on Week 1 Day 1, Week 3 Day 1, and then day 1 of every fourth week) for up to 2 years. The initial dose of crizanlizumab was 5 mg/kg dose for Group 1 and Group 2 Part A. It was later adjusted to 8.5 mg/kg for Group 2 and 3 based on final dose confirmation from emerging PK data analysis and safety considerations determined in Part A of the study.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Interventions

CrizanlizumabDRUG

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.

Eligibility

Sex: ALLMin age: 2 YearsMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Male or female patients ages 2 to \<18 years 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.

Locations (35)

University Of Alabama

Birmingham, Alabama, United States

Childrens National Hospital

Washington D.C., District of Columbia, United States

University of Florida

Gainesville, Florida, United States

Joe DiMaggio Childrens Hospital

Hollywood, Florida, United States

Childrens Healthcare of Atlanta

Atlanta, Georgia, United States

Outcomes

Primary Outcomes

Pharmacokinetics (PK): AUCd15 of Crizanlizumab After First Dose - Part A

The area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1) following the first dose. AUCd15 was calculated based on serum concentrations of crizanlizumab.

Time frame: Day 1 to Day 15

Pharmacokinetics (PK) - AUCtau for Serum Crizanlizumab After Multiple Doses - Part A - Steady State

The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1).

Time frame: Week 15 - Steady state

Pharmacokinetics (PK) - Cmax for Crizanlizumab After First Dose and Multiple Doses - Part A - Steady State

The maximum (peak) observed, serum, drug concentration after single or multiple dose administration (mass x volume-1)

Time frame: Week 1 (after first dose) and Week 15 (steady state)

Pharmacodynamics (PD) - P-selectin Inhibition Parameters for Crizanlizumab After First Dose - Part A - AUCd15

The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1) following the first dose. AUCd15 was calculated based on P-selectin inhibition curves.

Time frame: Day 1 to Day 15

Pharmacodynamics (PD) - P-selectin Inhibition Parameters for Crizanlizumab - Part A - AUCtau After Multiple Dose - Steady State

The AUC of %inhibition calculated to the end of a dosing interval (tau) after multiple dose. AUCtau was calculated based on P-selectin inhibition curves.

Time frame: Week 15 - Steady state

Frequency of Any Adverse Events (AEs) as a Measure of Safety and Tolerability

An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject

Time frame: Adverse events are reported from the first dose of study treatment until end of study treatment Week 103 plus 105 days post-treatment follow-up, up to a maximum timeframe of approximately 2 years and 3.25 months.

Secondary Outcomes

Annualized Rate Vaso Occlusive Crisis (VOC) Events Leading to Healthcare Visit in Clinic / Emergency Room (ER) / Hospital

VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. The baseline annualized rate of VOC was defined as the number of VOCs leading to healthcare visit occurring within the last 12 months prior to screening until first dose. This annualized rate of VOC was calculated by multiplying the number of VOCs by 365 and dividing by the number of days in the observation period. (Parts A and B)

Time frame: Baseline, Year 1 and Year 2

Annualized Rate Vaso Occlusive Crisis (VOC) Events Treated at Home (Based on Documentation by Health Care Provider Following Phone Contact With the Patient)

Time frame: Up to Year 2

Annualized Rate Vaso Occlusive Crisis (VOC) Events Leading to Healthcare Visit - Uncomplicated Pain Crisis

VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. This annualized rate of VOC was calculated by multiplying the number of VOCs by 365 and dividing by the number of days in the observation period. (Parts A and B) Uncomplicated pain crisis is defined as an acute episode of pain with no known cause for pain other than a vaso-occlusive event; and requiring treatment with a parenteral or oral opioids or other parenteral analgesic; but is NOT classified as an acute chest syndrome, hepatic sequestration, splenic sequestration or priapism. The end of an uncomplicated pain crisis will be considered the resolution of acute pain, such that residual pain (or absence of any pain) is considered to be chronic, and the current pain medication regimen is considered to be for this chronic pain.

Time frame: Up to Year 2

Annualized Rate Vaso Occlusive Crisis (VOC) Events Leading to Healthcare Visit - Acute Chest Syndrome

VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. This annualized rate of VOC was calculated by multiplying the number of VOCs by 365 and dividing by the number of days in the observation period. (Parts A and B) Acute Chest Syndrome (ACS) is defined on the basis of the finding of a new pulmonary infiltrate involving at least one complete lung segment that was consistent with alveolar consolidation, but excluding atelectasis (as indicated by chest X-ray). At least one of the following additional signs or symptoms needs to be present as well: chest pain, a temperature of more than 38.5°C, tachypnea, wheezing or cough. ACS will be considered resolved when the patient is no longer hospitalized (unless for reason other than the ACS episode) and none of the additional signs or symptoms above are present (unless for reason other than the ACS).

Data from ClinicalTrials.gov

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Childrens Hosp Boston Dept of Hematology

Boston, Massachusetts, United States

Childrens Hospital at Montefiore

The Bronx, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

East Carolina University

Greenville, North Carolina, United States

Childrens Hospital Of Philadelphia

Philadelphia, Pennsylvania, United States

...and 25 more locations

Time frame: Up to Year 2

Annualized Rate Vaso Occlusive Crisis (VOC) Events Treated at Home (Based on Documentation by Health Care Provider Following Phone Contact With the Patient) - Hepatic Sequestration

VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. This annualized rate of VOC was calculated by multiplying the number of VOCs by 365 and dividing by the number of days in the observation period. (Parts A and B) Hepatic sequestration is defined on the basis of findings of right upper quadrant pain, an enlarged liver, and an acute decrease in hemoglobin concentration (e.g. a decrease in hemoglobin of \~ 2 g/dL). Acute hepatic sequestration will be considered resolved when right upper quadrant pain has returned to baseline (pre-event) levels and hemoglobin has been stable for 24 hrs. There were no patients with VOC events of hepatic sequestration treated at home. Therefore, there were no observations which met the report criteria.

Time frame: Up to Year 2

Annualized Rate Vaso Occlusive Crisis (VOC) Events Leading to Healthcare Visit - Splenic Sequestration

VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. This annualized rate of VOC was calculated by multiplying the number of VOCs by 365 and dividing by the number of days in the observation period. (Parts A and B) Splenic sequestration if defined on the basis of findings of left upper quadrant pain, an enlarged spleen, and an acute decrease in hemoglobin concentration (e.g., a decrease in hemoglobin of \~ 2 g/dL). Acute splenic sequestration will be considered resolved when left upper quadrant pain has returned to baseline (pre-event) levels and hemoglobin has been stable for 24 hrs.

Time frame: Up to Year 2

Annualized Rate Vaso Occlusive Crisis (VOC) Events Leading to Healthcare Visit - Priapism

Time frame: Up to Year 2

Annualized Rate of Hospitalizations and Emergency Room (ER) Visits (VOC-related)

VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. This rate was calculated by multiplying the number of hospitalizations and ER visits (VOC-related) by 365 and dividing by the number of days in the observation period. Units would be something like: hospitalizations and ER visits per year. (Parts A and B)

Time frame: Up to Year 2

Annualized Rate of Hospitalizations and Emergency Room (ER) Visits (Total)

VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. The baseline annualized rate of VOC was defined as the number of VOCs leading to healthcare visit occurring within the last 12 months prior to screening until first dose. This rate was calculated by multiplying the number of hospitalizations and ER visits (VOC-related) by 365 and dividing by the number of days in the observation period. Units would be something like: hospitalizations and ER visits per year. (Parts A and B)

Time frame: Up to Year 2

Annualized Days of Emergency Room (ER) / Hospitalization (Both Overall and VOC-related)

VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. The baseline annualized rate of VOC was defined as the number of VOCs leading to healthcare visit occurring within the last 12 months prior to screening until first dose. This rate was calculated by multiplying the number of days of ER/hospitalizations (both overall and VOC-related) by 365 and dividing by the number of days in the observation period. (Parts A and B)

Time frame: Years 1 and 2

Annualized Rate of Dactylitis Events

Dactylitis, also known as 'hand-foot syndrome', is a complication of acute vaso-occlusive disease characterized by pain and edema of the digits as well as the dorsum of the hands or feet, or both simultaneously, often accompanied by increased local temperature and erythema. There were no patients with dactylitis events. Therefore, there were no observations which met the report criteria.

Time frame: On Treatment, up to Year 2

Absolute Change From Baseline in Hemoglobin

Hemoglobin is a protein that carries oxygen through the body. It attaches to red blood cells, delivers oxygen throughout the body, and transports carbon dioxide back to the lungs. In sickle cell disease, red blood cells are crescent or sickle-shaped due to a genetic mutation, and those sickled red blood cells can clog blood flow, causing debilitating pain and even organ damage.

Time frame: Baseline, Week 27, Year 2

Immunogenicity: Measurement of Anti-drug Antibodies (ADA) to Crizanlizumab

Anti-drug antibodies (ADA) are antibodies elicited from therapeutics and they are used to measure immunogenicity.

Time frame: up to Year 2

Notable On-treatment Findings From the Electrocardiogram (ECG) Assessments

QTcF = QT interval corrected by Fridericia's formula QTcB = Corrected QT interval Bazett's Formula QT = QT interval PR = PR interval QRS = QRS interval RR = RR interval HR = heart rate

Time frame: Baseline, up to Year 2

Growth and Sexual Maturation Assessments (Tanner Stage) - Abnormalities - for Female Participants at Risk of Delayed Puberty at Start Date of Study Treatment

As assessed per Tanner criteria. The number of Participants Analyzed row refer to participants who have not started puberty and have not had delayed puberty prior to start date of study treatment. Delayed puberty in females is defined as failure to attain Tanner Stage 2 (for both breast development and pubic hair) by age 13, or absence of menarche by age 15 or within 5 years of attainment of Tanner Stage 2.

Time frame: Week 51

Growth and Sexual Maturation Assessments (Tanner Stage) - Abnormalities - for Male Participants at Risk of Delayed Puberty at Start Date of Study Treatment

As assessed per Tanner criteria. The number of Participants Analyzed row refer to participants who have not started puberty and have not had delayed puberty prior to start date of study treatment. Delayed puberty in males is defined as failure to attain Tanner Stage 2 (for both genitalia and pubic hair) by age 14.

Time frame: Week 51

PK Pre-dose Concentrations of Crizanlizumab Prior to Each Study Drug Dose - Part A

Time frame: Week 3, Week 7, Week 11, Week 15, Week 19, Week 23, Week 27, Week 31, Week 35, Week 39, Week 43, Week 47 and Week 51 (Day 1, 0 hr (pre-dose))

PK Pre-dose Concentrations of Crizanlizumab Prior to Each Study Drug Dose - Parts A and B

Time frame: Week 3, Week 7, Week 11, Week 15, Week 19, Week 23, Week 27, Week 31, Week 35, Week 39, Week 43, Week 47 and Week 51 (0 hr (pre-dose))

Percent P-selectin Inhibition of Crizanlizumab Prior to Dosing - Part A

A PD marker of crizanlizumab is the ex vivo P-selectin inhibition measured by a surface plasmon resonance assay using human serum samples. Crizanlizumab in serum samples binds to spiked Psel-Ig (P-selectin coupled to Ig) and inhibits its binding to a PSGL1 peptide.

Time frame: Weeks 3, 7, 11,15, 19, 23, 27, 31, 35, 39, 43,47,51 (Day 1, 0 hr (pre-dose))

Percent P-selectin Inhibition of Crizanlizumab Prior to Dosing - Part A and B

Time frame: Weeks 3, 7, 11,15, 19, 23, 27, 31, 35, 39, 43,47,51 (Day 1, 0 hr (pre-dose))

Adverse Events by Preferred Term Related to Study Treatment

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

Overview

Conditions

Interventions

Eligibility

Locations (35)

Outcomes

Primary Outcomes

Secondary Outcomes