A Study to Evaluate BMS-986470 in Healthy Volunteers and Participants With Sickle Cell Disease

Official title

A Phase 1/2a, First-in-human, Randomized, Double-blinded, Placebo-controlled, Dose-finding Study in Healthy Volunteers and Participants With Sickle Cell Disease to Evaluate the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics, pH and Food Effect, and Preliminary Efficacy of BMS-986470

Overview

The purpose of this study is to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics, pH and food effect, and preliminary efficacy of BMS-986470 in healthy volunteers and participants with sickle cell disease.

Interventions

• Drug BMS-986470
  Specified dose on specified days
• Drug Placebo
  Specified dose on specified days
• Drug Famotidine
  Specified dose on specified days
• Drug Pantoprazole
  Specified dose on specified days

Primary outcome measures

• Number of participants with adverse events (AEs) [Time frame: Up to 26 months]
• Number of participants with serious adverse events (SAEs) [Time frame: Up to 26 months]
• Number of participants with AEs meeting protocol-defined Dose Limiting Toxicity (DLT) criteria [Time frame: Up to 26 months]
• Number of participants with AEs leading to discontinuation [Time frame: Up to 26 months]
• Number of deaths [Time frame: Up to 26 months]
• Proportion of participants achieving HbF ≥ 10% [Time frame: Up to 28 days after last dose]
• Proportion of participants achieving HbF ≥ 20% [Time frame: Up to 28 days after last dose]
• Proportion of participants achieving HbF ≥ 30% [Time frame: Up to 28 days after last dose]

Secondary outcome measures (12)

• Maximum observed plasma concentration (Cmax) [Time frame: Up to Day 28]
• Area under the concentration-time curve (AUC) [Time frame: Up to Day 28]
• Time of maximum observed plasma concentration (Tmax) [Time frame: Up to Day 28]
• Dose proportionality of BMS-986470 for Cmax and AUC [Time frame: Up to Day 28]
• Change from baseline in total hemoglobin (Hb) [Time frame: Up to 26 months]
• Change from baseline in total Hb fractions: adult Hb (HbA) [Time frame: Up to Day 28]
• Change from baseline in total Hb fractions: fetal Hb (HbF) [Time frame: Up to 26 months]
• Change from baseline in total Hb fractions: sickle Hb (HbS) [Time frame: Up to 26 months]
• Change from baseline in markers of red blood cell (RBC) lysis: total Hb [Time frame: Up to 26 months]
• Change from baseline in markers of RBC lysis: aspartate aminotransferase (AST) [Time frame: Up to 26 months]
• Change from baseline in markers of RBC lysis: lactate dehydrogenase (LDH) [Time frame: Up to 26 months]
• Change from baseline in markers of RBC lysis: total bilirubin [Time frame: Up to 26 months]

Eligibility criteria

Inclusion criteria

Cohort A:

• Healthy male and female (who are not of childbearing potential) participants, as determined by the investigator based on medical history and other determinations. Females not of childbearing potential must have been amenorrhoeic for at least 12 months without an alternative medical cause and have follicle-stimulating hormone (FSH) levels of at least 40 IU/L or have undergone a hysterectomy, bilateral oophorectomy, or bilateral salpingectomy.
• Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive. BMI = weight (kg)/\[height (m)\]2 as measured at screening.
• No evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG, or clinical laboratory assessments beyond what is consistent with the target population.

Cohort B:

• Participants with a documented diagnosis of sickle cell disease (SCD) with genotype HbSS, HbSβ0-thal, or HbSβ+-thal.
• For Cohort B Part 1 only: Participants with ≥ 4 vaso-occlusive crises (VOCs) within the previous 12 months or ≥ 2 VOCs within the previous 6 months. For Cohort B Part 2 only: Participants with ≥ 2 VOCs and ≤ 15 VOCs within the previous 12 months.
• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Participants must have the following laboratory values:

i) Hemoglobin ≥ 5.5 and ≤ 12 g/dL (males) or ≥ 5.5 and ≤ 10.6 g/dL (females). ii) Absolute neutrophil count ≥ 1500/μL. iii) Platelet count ≥ 100 × 10\^3/μL. iv) Absolute reticulocyte count > 100 × 10\^3/μL or > 50 × 10\^3/μL if taking hydroxyurea.

Exclusion criteria

Cohort A:

• Any significant medical condition or any condition that confounds the ability to interpret data from the study.
• Participant has any condition, including the presence of laboratory abnormalities, that places the participant at unacceptable risk if the participant was to participate in the study.
• Any major surgery or planned surgery (except GI surgery) within 12 weeks of the first study intervention administration.

Cohort B:

• Participants with any condition, including significant acute or chronic medical illness, active or uncontrolled infection, or the presence of laboratory abnormalities, that places participants at unacceptable risk if participating in this study.
• For Cohort B Part 1 only: participants with more than 6 severe VOCs defined as VOCs requiring ≥ 24 hours of hospital admission within 12 months prior to the first dose of study intervention.
• For Cohort B Part 1 only: participants with any episode of acute chest syndrome within the last 6 months prior to the first dose of study intervention.
• Creatinine clearance (CrCl) < 60 mL/min/1.72m2 using Chronic Kidney Disease Epidemiology (CKD-EPI) equation.

Cohort A and B:

• Participant is receiving regularly scheduled RBC or platelet transfusions or has received a RBC transfusion within 28 days and a platelet transfusion within 14 days prior to starting treatment with BMS-986470.
• Other protocol-defined Inclusion/Exclusion criteria apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 19 centers

• University of Alabama at Birmingham — Birmingham
• University of California San Diego - La Jolla — La Jolla
• UCSF Benioff Children's Hospital Oakland — Oakland
• Yale-New Haven Hospital — New Haven
• Winship Cancer Institute of Emory University — Atlanta
• Local Institution - 0034 — Chicago
• Local Institution - 0001 — Lenexa
• Local Institution - 0064 — Baltimore
• … and 11 more centers

United Kingdom · 5 centers

• University Hospitals Sussex NHS Foundation Trust — East Sussex
• Local Institution - 0044 — London
• King's College Hospital — London
• Local Institution - 0005 — Leeds
• Local Institution - 0047 — London

France · 4 centers

• Local Institution - 0061 — Créteil
• Assistance Publique Hôpitaux de Marseille - Hôpital de la Timone — Marseille
• Hôpital Universitaire Necker Enfants Malades — Paris
• CHU Strasbourg-Hautepierre — Strasbourg

Italy · 3 centers

• Local Institution - 0011 — Milan
• Local Institution - 0037 — Padua
• Local Institution - 0009 — Verona

Canada · 2 centers

• Local Institution - 0050 — Vancouver
• Local Institution - 0051 — Toronto

Identifiers

NCT: NCT06481306 · CA230-1019 · 2023-510283-12 · U1111-1301-6753

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗