Clinical trial NCT03264989: Pharmacokinetics and Pharmacodynamics Study of SEG101 (Crizanlizumab) in Sickle Cell Disease (SCD) Patients With Vaso- Occlusive Crisis (VOC)
Official title: A Phase 2, Multicenter, Open-Label Study to Assess PK/PD of SEG101 (Crizanlizumab), With or Without Hydroxyurea/Hydroxycarbamide, in Sickle Cell Patients With Vaso-Occlusive Crisis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Sickle Cell Disease (SCD)
Keywords: Sickle cell disease
SCD
sickle cell anemia
vaso-occlusive crisis
P-selectin
SEG101
crizanlizumab
monoclonal antibody
Anemia, Sickle Cell
HbS Disease
Hemoglobin SC Disease
Sickle Cell Disorders
Sickling Disorder Due to Hemoglobin S
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2017-08-29
Enrollment: 57
Sex: ALL
Minimum age (years): 16
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of the CSEG101A2202 study was to characterize the Pharmacokinetic (PK) and Pharmacodynamic (PD) of SEG101/crizanlizumab and to evaluate the safety and efficacy of SEG101/crizanlizumab in sickle cell disease (SCD) patients.

Detailed description: Study CSEG101A2202 was designed as a Phase II, multicenter, open-label study. The first 45 patients (to identify 27 evaluable patients) were enrolled to the treatment group crizanlizumab 5.0 mg/kg to complete full Pharmacokinetic/Pharmacodynamic (PK/PD) sampling at week 1 and week 15. In all patients, trough PK/PD samples were collected prior to each dose. In addition, throughout the study (and when possible), all patients had blood drawn for serum to assess PK and PD drawn at times of onset and resolution of each VOC event, fever, or infection. Once the up to 45 patients were enrolled, 12 additional patients were enrolled to the exploratory treatment group and began at 7.5 mg/kg of crizanlizumab.

The study was initiated on 19-Dec-2017. This study provides five years follow up data that fully characterizes the safety, tolerability and treatment effect of the 5.0 mg/kg and 7.5 mg/kg doses of crizanlizumab along with the initially planned PK and PD data.

At the time of study closure, crizanlizumab 5.0 mg/kg was an FDA approved treatment in the United States (US) for patients with sickle-cell disease. Therefore, the patients treated with crizanlizumab 5.0 mg/kg dose were encouraged to transition to commercial supply of crizanlizumab. The patients treated with the not currently approved dose of crizanlizumab 7.5 mg/kg were allowed to join a multi-center, multi-national, rollover clinical trial (Study SEG101A2401B), for continued access to treatment with crizanlizumab.

Eligibility criteria: Inclusion Criteria:

* Male and non-pregnant female patients 16-70 years of age (inclusive)
* Confirmed diagnosis of sickle cell disease by hemoglobin electrophoresis or high-performance liquid chromatography (HPLC) \[performed locally\]. All sickle cell disease genotypes are eligible.
* Experienced at least 1 VOC within the preceding 12 months prior to Screening, as determined by medical history.
* If receiving HU/HC or erythropoietin stimulating agent, must have been receiving the drug for at least 6 months prior to Screening
* Hemoglobin ≥4.0 g/dL. Absolute neutrophil count ≥1.0 x 109/L and platelet count ≥75 x 109/L
* Adequate renal and hepatic function as defined:
* GFR ≥45 mL/min/1.73 m2 calculated by CKD-EPI
* ALT ≤3 x ULN
* Direct (conjugated) bilirubin ≤2 x ULN
* ECOG performance status ≤2
* Written informed consent (or assent/ parental consent for minor subjects) prior to any screening procedures

Exclusion Criteria:

* History of stem cell transplant.
* Acute VOC ending 7 days prior to first dosing
* Ongoing hospitalization prior to Screening
* Received blood products within 30 days to first dosing
* Participating in a chronic transfusion program (pre-planned series of transfusions for prophylactic purposes)
* History of severe hypersensitivity reactions to other monoclonal antibodies
* Received a monoclonal antibody or immunoglobulin -based agent within 1 year of Screening, or has documented immunogenicity to a prior biologic.
* Received active treatment on another investigational trial within 30 days (or 5 half-lives of that agent, whichever is greater) prior to Screening
* Significant active infection or immune deficiency (including chronic use of immunosuppressive drugs)
* Resting QTcF ≥470 msec at pretreatment (baseline) or other cardiac or cardiac repolarization abnormality

Primary outcomes:
measure: Pharmacokinetic (PK): AUCd15 and AUCtau of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients
timeFrame: 1st dose: Day 1: (pre-dose, 0.5, 1, 2, 4, 6 & 24 hours post dose, Days 4, 8 & 15; 5th dose: Day 1 (pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post dose), Days 4, 8, 15, 22 & 29
measure: PK: Cmax of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients
timeFrame: After the starting dose (Week 1) and after multiple doses (steady state, Week 15)
measure: Pre-dose Concentrations Prior to Each Study Drug Dose
timeFrame: Pre-dose at Day 1 on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51
measure: Percentage of P-selectin Inhibition After the Starting Dose (PD-AUCd15), After Multiple Doses (PD-AUCd29) of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients
timeFrame: 1st dose: Day 1: (pre-dose, 0.5, 1, 2, 4, 6 & 24 hours post dose, Days 4, 8, 15; 5th dose: Day 1(pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post dose), Days 4, 8, 15, 22 & 29
measure: Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients
timeFrame: Pre-dose on Day 1 for Weeks 3, 7, 11, 15, 19, 23, 27, 31,35, 39, 43, 47, 51 (at 0 hr or pre-dose)
Secondary outcomes:
measure: Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to Healthcare Visit in Clinic/Emergency Room (ER)/Hospital
timeFrame: Baseline (Week 1) through approx. 45 months (median exposure to treatment)
measure: Annualized Rate of VOC Events Treated at Home (Based on Documentation by Health Care Provider Following Phone Contact With Patient)
timeFrame: Baseline (Week 1) through approx. 45 months (median exposure to treatment)
measure: Annualized Rate of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits
timeFrame: Baseine (Week 1) through approx. 45 months (median exposure to treatment)
measure: Annualized Days of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits
timeFrame: Baseline (Week 1) through approx. 45 months (median exposure to treatment)
measure: Annualized Rate of Each Subcategory of All VOC Events (Acute Chest Syndrome (ACS), Priapism, Uncomplicated Sickle Cell-vaso-occlusive Cisis (Uncomplicated SC-VOCs))
timeFrame: Baseline (Week 1) through approx. 45 months (median exposure to treatment)
measure: Annualized Rate of VOC Events (Including Both Healthcare Visit and Home Treatment)
timeFrame: Baseline (Week 1) through approx. 45 months (median exposure to treatment)
measure: Number of Participants With Immunogenicity (IG) by Any Positive Status
timeFrame: Baseline (Week 1), post-baseline (approx. 45 months (median exposure))
Other outcomes:
Locations:
city: Orange
country: United States
facility: Novartis Investigative Site
state: Florida
city: Tampa
country: United States
facility: Novartis Investigative Site
state: Florida
city: Atlanta
country: United States
facility: Childrens Healthcare of Atlanta .
state: Georgia
city: Augusta
country: United States
facility: Augusta University Georgia Patient Treatment
state: Georgia
city: Baltimore
country: United States
facility: University of Maryland Medical Ctr
state: Maryland
city: Bronx
country: United States
facility: Childrens Hospital at Montefiore
state: New York
city: Durham
country: United States
facility: Duke University Medical Center Patient Treatment
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University East Carolina University
state: North Carolina
city: Philadelphia
country: United States
facility: Childrens Hospital Of Philadelphia Patient Treatment
state: Pennsylvania
city: Charleston
country: United States
facility: Medical Uni of South Carolina Medical Univ of SC
state: South Carolina
city: Columbia
country: United States
facility: M Francisco Gonzalez MD PA .
state: South Carolina
city: Rock Hill
country: United States
facility: Carolina Blood and Cancer Care of South Carolina
state: South Carolina
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Kanter J, Brown RC, Norris C, Nair SM, Kutlar A, Manwani D, Shah N, Tanaka C, Bodla S, Sanchez-Olle G, Albers U, Liles D. Pharmacokinetics, pharmacodynamics, safety, and efficacy of crizanlizumab in patients with sickle cell disease. Blood Adv. 2023 Mar 28;7(6):943-952. doi: 10.1182/bloodadvances.2022008209.