Clinical trial NCT04255875: Dose Escalation Study of PF-07209326 in Healthy Participants and Participants With Sickle Cell Disease
Official title: A RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED EVALUATION OF SINGLE DOSES OF PF-07209326 IN HEALTHY PARTICIPANTS (SAFETY, TOLERABILITY, AND PHARMACOKINETICS [PK]) FOLLOWED BY AN OPEN LABEL, REPEAT DOSE EVALUATION IN SICKLE CELL DISEASE PARTICIPANTS (SAFETY, TOLERABILITY, PK AND EFFICACY)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Sickle Cell Anemia
Keywords: Safety
Tolerability
Single ascending dose
Multiple dose
Pharmacokinetics
Phase 1
First in human
First in patient
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2020-02-05
Enrollment: 52
Sex: ALL
Minimum age (years): 16
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: BASIC_SCIENCE

Brief summary: This Phase 1 first-in-human, first-in-patient, single ascending dose and multiple dose study will be a randomized, double-blind, placebo-controlled investigation of the safety, tolerability, and pharmacokinetics of PF-07209326 in healthy participants and participants with sickle cell disease.

Detailed description: Part 1 will evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics of single ascending doses of PF-07209326 delivered by subcutaneous injection or intravenous delivery in healthy volunteer participants. After establishing the safety and tolerability in healthy participants, Part 2 will evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics of subcutaneously delivered multiple dose of PF-07209326 in participants with sickle cell disease.

Eligibility criteria: Inclusion Criteria Health Participants:

1. Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight \>50 kg (110 lbs).

Exclusion Criteria Healthy Participants:

1. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, immunocompromised (or known disorder of the immune system), cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
2. History of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C; positive testing for HIV, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody (HCVAb). Hepatitis B vaccination is allowed.
3. History of active or latent tuberculosis (TB) regardless of treatment or positive QuantiFeron TB test.
4. Participants with any of the following acute or chronic infections or infection history:

   * Any infection requiring treatment within 2 weeks prior to the screening visit.
   * Any infection requiring hospitalization, parenteral antimicrobial therapy within 30 days of the first dose of investigational product.
   * Any infection judged to be an opportunistic infection, within the past 6 months of the first dose of the investigational product.
   * Known active or history of frequent bacterial, viral, fungal, mycobacterial or other infections as determined by the PI.
   * Participants with a fever within the last 7 days prior to dosing.
5. Participants with a history of allergic or anaphylactic reaction to therapeutic or diagnostic protein.
6. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study.

Inclusion Criteria for SCD Participants

1. Participants between the ages of 16 and 70 years old with a confirmed diagnosis of stable sickle cell disease (HbSS or HBS β0 thalassemia).
2. Medical history of ≥2 and ≤ 10 medical utilization VOCs in 12 months prior to screening.
3. ≥75% of daily ePRO diary completion, over a minimum of 14 days during the screening period.
4. Fully vaccinated for COVID-19 in accordance with the Center for Disease Control guidance prior to Screening or must be negative for SARS-CoV-2 by polymerase chain reaction (PCR) within 72 hours of the Day 1 visit.
5. Body Mass Index (BMI) ≤34.9 kg/m2 and weight ≥50 kg.

Exclusion Criteria for SCD Participants

1. Evidence of ongoing uncontrolled clinically significant co-morbidity (e.g. intercurrent events that result in signs symptoms that have an adverse impact on the respective individual's usual function) hematological (non-SCD), renal, endocrine, pulmonary, gastrointestinal, cardiovascular (including stroke within 2 years prior to screening), hepatic, psychiatric or neurological.
2. Evidence or history of cardiac disease includes myocardial infarction, clinically significant cardiac arrhythmia (eg, atrial fibrillation, paroxysmal atrial fibrillation, atrial flutter, supraventricular tachycardia, and ventricular tachycardia), left ventricular failure, unstable angina, and coronary artery bypass grafting.
3. History of cancer (other than cutaneous basal cell or carcinoma in-situ) in the previous 5 years.
4. Active infection with Hepatitis B or C or HIV. Individuals seropositive for infection with Hepatitis C must be negative for viral RNA by PCR on at least 2 determinations.
5. History of active or latent tuberculosis (TB) regardless of treatment or positive QuantiFeron TB test.
6. Major surgery \<3 months prior to baseline or planned significant medical procedures during the study.
7. Participants with any of the following acute or chronic infections or infection history:

   * Any infection requiring systemic treatment within 2 weeks prior to the screening visit.
   * Any infection requiring hospitalization, parenteral antimicrobial therapy within 30 days of the first dose of investigational product.
   * Any infection judged to be an opportunistic infection, within the past 6 months of the first dose of the investigational product.
   * Known active or history of frequent viral, fungal or other infections as determined by the Investigator.
   * Participants with a fever within the last 7 days prior to dosing.
8. Evidence or history of clinically significant orthostatic blood pressure changes.
9. Other acute or chronic medical or psychiatric condition that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study.
10. Participants with a history of allergic or anaphylactic reaction to therapeutic or diagnostic protein.
11. Administration of voxelotor within 4 weeks prior to screening or planned use during the study.
12. Administration of crizanlizumab within 12 weeks prior to screening or planned use during the study.
13. Planned transfusion during the study.

Primary outcomes:
measure: Frequency, severity and causal relationship of treatment emergent adverse events (TEAEs) and withdrawals due to TEAEs
timeFrame: Day 1 up to Day 85 (SAD) or Day 113 (MD)
measure: Percentage of subjects with laboratory abnormalities
timeFrame: Day 1 up to Day 85 (SAD) or Day 113 (MD)
measure: Number of subjects with change from baseline in vital signs
timeFrame: Day 1 up to Day 85 (SAD) or Day 85 (MD)
measure: Number of subjects with change from baseline in electrocardiogram (ECG) parameters
timeFrame: Day 1 up to Day 85 (SAD) or Day 85 (MD)
measure: Percentage of subjects with injection site reactions
timeFrame: Day 1 up to Day 11 post (SAD) Day 1 up to Day 85 (MD)
measure: Percentage of subjects with infusion site reactions
timeFrame: Day 1 up to Day 11 post each dose (SD)
Secondary outcomes:
measure: SAD: Single Dose PK /Cmax
timeFrame: Day 1 up to Day 85
measure: SAD: Single Dose PK / DN Cmax
timeFrame: Day 1 up to Day 85
measure: SAD: Single Dose PK / Tmax
timeFrame: Day 1 up to Day 85
measure: SAD: Single Dose PK / AUClast
timeFrame: Day 1 up to Day 85
measure: SAD: Single Dose PK / DN AUClast
timeFrame: Day 1 up to Day 85
measure: SAD: Single Dose PK / AUCinf
timeFrame: Day 1 up to Day 85
measure: SAD: Single Dose PK / DN AUCinf
timeFrame: Day 1 up to Day 85
measure: SAD: Single Dose PK / t½
timeFrame: Day 1 up to Day 85
measure: SAD: Single Dose PK / CL (IV only)
timeFrame: Day 1 up to Day 85
measure: SAD: Single Dose PK / CL/F (SC only)
timeFrame: Day 1 up to Day 85
measure: SAD: Single Dose PK / Vss (IV only)
timeFrame: Day 1 up to Day 85
measure: SAD: Single Dose PK / Vz/F (SC only)
timeFrame: Day 1 up to Day 85
measure: SAD: Single Dose PK / F (SC only)
timeFrame: Day 1 up to Day 85
measure: MD: AUCtau
timeFrame: Day 1 up to Day 22
measure: SAD:ADA and/or NAb
timeFrame: Day 1 up to Day 85
measure: MD:ADA and/or NAb
timeFrame: Day 1 up to Day 113
measure: Patient-reported VOC event rate and VOC day rate
timeFrame: Day 1 to 85
Other outcomes:
Locations:
city: New Haven
country: United States
facility: New Haven Clinical Research Unit
state: Connecticut
city: Washington
country: United States
facility: Howard University College of Medicine
state: District of Columbia
city: Fort Myers
country: United States
facility: Golisano Children's Hospital of Southwest Florida
state: Florida
city: Fort Myers
country: United States
facility: Lee Health - Golisano Children's Hospital of Southwest Florida
state: Florida
city: Hollywood
country: United States
facility: Foundation for Sickle Cell Disease Research
state: Florida
city: Hollywood
country: United States
facility: Foundation for Sickle Cell Disease Research
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Egleston Hospital-Aflac Cancer and Blood Disorders Center
state: Georgia
city: Chicago
country: United States
facility: University of Illinois at Chicago Clinical Research Center
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: Saint Paul
country: United States
facility: Prism Research LLC dba Nucleus Network
state: Minnesota
city: New York
country: United States
facility: Columbia University Medical Center - Herbert Irving Pavilion
state: New York
city: New York
country: United States
facility: CUIMC Research Pharmacy
state: New York
city: New York
country: United States
facility: CUMC Research Pharmacy
state: New York
city: Houston
country: United States
facility: UT Physicians Comprehensive Sickle Cell Center Houston
state: Texas
city: Houston
country: United States
facility: Memorial Hermann clinical research unit
state: Texas
city: Houston
country: United States
facility: UT Physicians Comprehensive Sickle Cell Center Houston
state: Texas
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: