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A SAD/MAD to Assess the Safety, PK/PD of FT-4202 in Healthy Volunteers and Sickle Cell Disease Patients

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ClinicalTrials.gov Identifier: NCT03815695
Recruitment Status : Completed
First Posted : January 24, 2019
Last Update Posted : July 15, 2022
Sponsor:
Collaborator:
Medpace, Inc.
Information provided by (Responsible Party):
Forma Therapeutics, Inc.

Study Description
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Brief Summary:
FT-4202 is an oral small-molecule agonist of pyruvate kinase red blood cell isozyme (PKR) being developed for the treatment of hemolytic anemias. This initial study will characterize the safety, tolerability and the pharmacokinetics/pharmacodynamics (PK/PD) of a single ascending dose and multiple ascending doses of FT-4202 in the context of Phase 1 studies in healthy volunteers and sickle cell disease patients. The effects of food on the absorption of FT-4202 will also be evaluated in healthy volunteers.

Condition or disease Intervention/treatment Phase
Healthy Volunteers Sickle Cell Disease Drug: FT-4202/Placebo Drug: FT-4202 Phase 1

Detailed Description:
This is a first-in-human (FIH), Phase 1 study of FT-4202 that will characterize the safety, PK and PD of FT-4202 after a single dose and after repeated dosing first in healthy adult volunteers and then in adolescents or adults with sickle cell disease (SCD). Initially, a dose range of FT-4202 in single ascending dose (SAD) escalation cohorts will be explored in healthy subjects. Enrollment of healthy subjects into 2-week multiple ascending dose (MAD) escalation cohorts will be initiated once the safety and PK from at least two SAD cohorts is available to inform the doses for the 2-week MAD portion of the study. The MAD cohorts will then run in parallel to the single dose cohorts. A single dose cohort of healthy subjects is planned to understand food effects (FE) on the PK of FT-4202. After the SAD and FE studies in healthy subjects are completed, the safety, PK, and PD of a single dose of FT-4202 that was found to be safe in healthy subjects will then be evaluated in SCD subjects. Multiple dose studies in SCD subjects will then be initiated upon completion of MAD studies in healthy volunteers.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Single ascending dose escalation and multiple ascending dose escalation study followed by an evaluation of food effects on absorption
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: randomized double blind
Primary Purpose: Treatment
Official Title: A Randomized, Placebo-controlled, Double Blind, Single Ascending and Multiple Ascending Dose Study to Assess the Safety, Pharmacokinetics and Pharmacodynamics of FT-4202 in Healthy Volunteers and Sickle Cell Disease Patients
Actual Study Start Date : December 11, 2018
Actual Primary Completion Date : December 17, 2021
Actual Study Completion Date : December 17, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Single ascending dose cohorts in healthy subjects
Healthy volunteer subject cohorts randomized 6:2 receiving a single dose of FT-4202 or placebo. The first cohort will receive 200 mg of FT-4202 or placebo. Dose escalation will occur if FT-4202 or placebo is tolerated. The maximum dose of FT-4202 or placebo will be 1500 mg.
 Drug: FT-4202/Placebo
Healthy volunteer subjects will receive FT-4202/placebo and monitored for side effects while undergoing pharmacokinetics and pharmacodynamic studies
Experimental: Multiple ascending dose cohorts in healthy subjects
Healthy volunteer subject cohorts randomized 9:3 to receive FT-4202 or placebo for 14 days continuous dosing. The first cohort will receive 100 mg of FT-4202 or placebo daily X 14 days. The maximum dose of FT-4202/placebo will be 600 mg FT-4202/placebo daily for 14 days.
 Drug: FT-4202/Placebo
Healthy volunteer subjects will receive FT-4202/placebo and monitored for side effects while undergoing pharmacokinetics and pharmacodynamic studies
Experimental: Food Effect Cohort in healthy subjects
Health Volunteer subject cohort of 10 subjects who will receive a single dose of FT-4202 with food and without food. Dose will be administered per the protocol defined dose.
 Drug: FT-4202
Healthy volunteer subjects will receive FT-4202 with or without food and undergo pharmacokinetic studies
Experimental: Single ascending dose cohorts in SCD subjects
Sickle cell disease subject cohort randomized 6:2 receiving a single dose of FT-4202 or placebo. The dose of FT-4202/placebo administered will be a dose that was found to be safe in healthy subjects.
 Drug: FT-4202/Placebo
SCD subjects will receive FT-4202/placebo and monitored for side effects while undergoing pharmacokinetics and pharmacodynamic studies
Experimental: Multiple ascending dose cohorts in SCD subjects
Sickle cell disease subject cohorts randomized 9:3 to receive FT-4202 or placebo for 14 days continuous dosing. The dose of FT-4202/placebo administered will be a dose less than the maximum tolerable dose evaluated in MAD healthy volunteers.
 Drug: FT-4202/Placebo
SCD subjects will receive FT-4202/placebo and monitored for side effects while undergoing pharmacokinetics and pharmacodynamic studies
Experimental: 12-week dosing cohort in SCD subjects
Sickle cell disease subjects cohort to receive up to 84 consecutive daily doses of open-label FT-4202. The dose of FT-4202 administered will not exceed the highest dose evaluated in the MAD SCD subject cohorts
 Drug: FT-4202
SCD subjects will receive FT-4202 and monitored for side effects while undergoing pharmacokinetics and pharmacodynamic studies


Outcome Measures
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Primary Outcome Measures :
  1. Incidence, frequency, and severity of adverse events (AEs) per CTCAE v5.0 of a single ascending dose and multiple ascending doses of FT-4202 in adult healthy volunteers and SCD patients. [ Time Frame: Up to 3 weeks of monitoring ]
  2. Maximum observed plasma concentration (Cmax) [ Time Frame: Up to 3 weeks of testing ]
  3. Time to maximum observed plasma concentration (Tmax) [ Time Frame: Up to 3 weeks of testing ]
  4. Area under the plasma concentration-time curve from time zero until the 24-hour time point (AUC0-24) [ Time Frame: Up to 3 weeks of testing ]
  5. Area under the plasma concentration-time curve from time zero until the last quantifiable time point (AUC0-last) [ Time Frame: Up to 3 weeks of testing ]
  6. Area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) [ Time Frame: Up to 3 weeks of testing ]
  7. Terminal elimination half-life (t1/2) [ Time Frame: Up to 3 weeks of testing ]
  8. Apparent clearance (CL/F) [ Time Frame: Up to 3 weeks of testing ]
  9. Apparent volume of distribution (Vd/F) [ Time Frame: Up to 3 weeks of testing ]
  10. Terminal disposition rate constant (Lz) [ Time Frame: Up to 3 weeks of testing ]
  11. Renal clearance (ClR) [ Time Frame: Up to 3 weeks of testing ]

Secondary Outcome Measures :
  1. Change from baseline in the levels of 2,3-diphosphoglycerate (DPG) and adenosine triphosphate (ATP) in the red blood cells (RBCs) of healthy volunteers and SCD patients after single and multiple doses of FT-4202. [ Time Frame: Up to 3 weeks of testing ]
  2. Model-based estimate of change from baseline QT interval corrected using Fridericia's correction formula (QTcF) and 90% confidence interval at the estimated Cmax after a single dose of FT-4202 in healthy volunteers [ Time Frame: up to 7 days ]
  3. Change from baseline heart rate after a single dose of FT-4202 in healthy volunteers [ Time Frame: up to 7 days ]
  4. Change from baseline PR after a single dose of FT-4202 in healthy volunteers [ Time Frame: up to 7 days ]
  5. Change from baseline QRS after a single dose of FT-4202 in healthy volunteers [ Time Frame: up to 7 days ]
  6. Change from baseline T-wave morphology after a single dose of FT-4202 in healthy volunteers [ Time Frame: up to 7 days ]

Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

SCD Key Inclusion Criteria:

  • Must be between 12 and 65 years of age
  • Previously diagnosed sickle cell disease (hemoglobin electrophoresis or genotype)
  • Must have a minimum body weight of 40 kg (88 lbs) at the Screening Visit
  • Must have the ability to understand and sign written informed consent (and assent where applicable), which must be obtained prior to any study-related procedures being completed
  • All male and female patients of child bearing potential must agree to use medically accepted contraceptive regimen during study participation and for 90 days after last study drug administration
  • Must be willing to abide by all study requirements and restrictions

SCD Key Exclusion Criteria:

  • Had more than 6 episodes of vaso-occlusive crisis (VOC) within the past 12 months that required a hospital, emergency room, or clinic visit
  • Had a least one episode of acute chest syndrome in the last 6 months

  • Received any of the following approved therapies for use in SCD:

    • Hydroxurea (HU): excluded if started HU < 90 days prior to Day 1 of study treatment
    • Adakveo®: excluded if received an infusion within 14 days prior to Day 1 of study treatment
    • Oxbryta®: excluded if received a dose within 7 days prior to start of Day 1 of study treatment
  • Received a red blood cell transfusion within 30 days of starting the study drug
  • Hemoglobin < 7.0 g/dL or > 10.5 g/dL
  • Unable to take and absorb oral medications

HEALTHY VOLUNTEER Inclusion Criteria: [NOTE: no longer recruiting subjects for this portion of the study]

  • Subjects must be between 18 and 60 years of age
  • Subjects must have the ability to understand and sign written informed consent, which must be obtained prior to any study-related procedures being completed
  • Subjects must be in general good health, based upon the results of medical history, a physical examination, vital signs, laboratory profile, and a 12-lead ECG
  • All males and females of child bearing potential must agree to use medically accepted contraceptive regimen during study participation and up to 90 days after
  • Subjects must be willing to abide by all study requirements and restrictions

HEALTHY VOLUNTEER Exclusion Criteria: [NOTE: no longer recruiting subjects for this portion of the study]

  • Evidence of clinically significant medical condition or other condition that might significantly interfere with the absorption, distribution, metabolism, or excretion of study drug, or place the subject at an unacceptable risk as a participant in this study
  • History of clinically significant cardiac diseases including condition disturbances
  • Abnormal hematologic, renal and liver function studies
  • History of drug or alcohol abuse
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03815695


Locations
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Sponsors and Collaborators
Forma Therapeutics, Inc.
Medpace, Inc.
Investigators
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Study Director: Patrick Kelly, MD Forma Therapeutics, Inc.
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Forma Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03815695    
Other Study ID Numbers: 4202-HVS-101
First Posted: January 24, 2019    Key Record Dates
Last Update Posted: July 15, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
 Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn