A Study of the Safety, Tolerability and Pharmacokinetics of Orally-administered GC4702 in Healthy Volunteers
Condition: Healthy Volunteer
Study type: Interventional
Phase: Phase 1

Summary: 
      A Phase 1 study will test the safety, tolerability and pharmacokinetics of a single dose of
      GC4702 when given as an oral tablet. This study will compare capsules containing a dry powder
      or gel suspension of GC4702 when given orally to a similar drug called GC4419 which will be
      given as an intravenous infusion. This study will also assess the effect of food on the
      GC4702 effects.
    

Detailed description: 
      The study will be conducted in two parts: Part 1, the main study, will be a double-blind,
      randomized, placebo-controlled, single-ascending dose assessment of GC4702. Part 2, which
      will be conducted only after Part 1 and contingent upon results from Part 1, will include a
      food-effect cohort using a randomized design of fed/fasted conditions.

      Consenting subjects will undergo screening procedures within 28 days of the start of dosing.
      Pharmacokinetics (PK) (parent drug and major metabolites) will be assessed in plasma and
      urine from all subjects.

      Part 1: GC4702 or matched placebo will be administered once by mouth for a single dose.
      Subjects in Cohort 3 will receive a dose of (dry powder formulation) oral GC4702 48 hours
      after a single dose of IV GC4419 administered over 60 minutes, and a dose of (lipid
      suspension formulation) GC4702 one week later. Subjects in Cohorts 4 will receive a single
      dose of (lipid suspension formulation) oral GC4702 48 hours after a single dose of IV GC4419
      administered over 60 minutes. The first 8 Subjects in Cohort 4 are dosed as required by
      GTO-001 Protocol Amendment 1. Upon approval of GTO-001 Protocol Amendment 2, the first 8
      previously dosed Subjects (fasted with water only) are considered dosing arm 4a for the
      analysis, and this and subsequent cohorts become eligible for expansion to study to other
      dosing conditions. Cohort 4 and up will receive a single dose of IV GC4419 on Day 1
      administered over 60 minutes, followed by a single dose of (lipid suspension formulation)
      oral GC4702 48 hours after IV dosing, under varying and distinct GC4702 dosing conditions per
      dose level. At discretion of Medical Monitor and upon agreement by the Principal Investigator
      based on available data, up to 4 arms may be evaluated, where GC4702 doses are fixed within
      the cohort, but oral intake conditions are modified as described below:

        1. with 240 mL (8 fluid ounces) of tap water only

        2. with 240 mL (8 fluid ounces) of tap water following a high calorie/high fat meal.
           Subjects assigned to the fed condition will receive a standard meal per U.S. FDA
           guidelines consisting of high calorie/high fat meal prior to dosing consisting of total
           calories of 800-1000 of which 150, 250 and 500-600 calories are from protein,
           carbohydrate and fat, respectively. For the fed condition, GC4702 will be administered
           following an overnight fast of at least 10 hours. Subjects will start the standard meal
           30 minutes prior to administration of GC4702, and will be instructed to eat the meal in
           30 minutes or less; however, the GC4702 will be administered 30 minutes after the start
           of the meal, with 240 mL (8 fluid ounces) of water. No food will be allowed for at least
           4 hours post-dose. Water will be allowed as desired except for one hour before and after
           GC4702 administration. Subjects will receive standardized meals scheduled at the same
           time in each period of the study.

        3. with 240 mL (8 fluid ounces) of orange juice only

        4. with 240 mL (8 fluid ounces) of tap water, immediately followed by a single unit adult
           dose of the over-the-counter antacid Rennie® only Subjects will be assigned to available
           arms (i.e., not all arms may be tested at every cohort), and dosing arms may be
           evaluated concurrently, or in sequence, both considerations determined by the Medical
           Monitor and Principal Investigator as warranted by available data and resources.

      Two forms of the oral GC4702 drug product will be tested; both formulations will be
      enteric-coated Capsugel Vcap Plus hard gel capsule containing (1) a dry powder formulation or
      (2) lipid suspension formulation.

      It is anticipated that a total of 6-7 dose cohorts will be tested, including the first two
      dose cohorts receiving only a single oral dose of escalating doses of the encapsulated dry
      powder GC4702 formulation, the third cohort receiving a single oral dose of each of oral
      GC4702 formulation sequentially after a single IV dose of GC4419, and 3-4 subsequent cohorts
      receiving a single oral dose of escalating doses of the oral encapsulated lipid suspension
      GC4702 formulation after a single IV dose of GC4419. Depending on safety and PK results,
      additional cohorts may be added with either drug product preparation. See below for an
      overview of study design.

      The first two cohorts of subjects will receive only the encapsulated dry powder formulation,
      to assess acute safety and oral absorption of GC4702. Six subjects will be enrolled in each
      of the first two cohorts, randomized 4:2 to active GC4702 or matched placebo. After each of
      these two cohorts, safety data will be reviewed by the internal Galera Therapeutics, Inc.
      (Galera) study team before proceeding to the next cohort.

      The third cohort of subjects will receive both oral formulations of GC4702, sequentially,
      after an initial single dose of IV GC4419, to permit intra-subject assessment of the
      bioavailability of both formulations of GC4702. Pending initial safety and PK results in this
      cohort, subsequent single dose escalation is anticipated in serial cohorts receiving only the
      encapsulated lipid suspension formulation of GC4702 by a single dose, after an initial single
      dose of IV GC4419.

      For cohort 3 and 4 (Amendment 1), 8 subjects per cohort will be enrolled, randomized 6:2 to
      active GC4702 or matched placebo.

      For expansion Cohort 4 (Amendment 2), 5 and up, 8 subjects per dosing arm will be enrolled,
      randomized 6:2 to active or matched placebo. Assignment of Subjects to open dosing arms is at
      the discretion of the investigational site, which considers Subject availability, the number
      of dosing arms tests (1 - 4 arms per cohort), and the sequence in which each arm is evaluated
      with the cohort. Subject crossover to other arms is prohibited at any time, once GC4702 has
      been administered.

      All subjects enrolled in these cohorts will first receive IV GC4419. After each of these
      cohorts, safety and PK data will be reviewed by the internal Galera study team before
      proceeding to the next cohort. Depending on the inter-subject variability in oral
      bioavailability, additional subjects may be added to one or more dosing cohorts.

      Sentinel cohorts will be enrolled for Cohorts 1 and 3 and will be observed for 24 hours after
      each dose of GC4702, with safety data reviewed by the treating investigator, before
      additional subjects receive the scheduled dose of GC4702 in the relevant cohort. Subjects in
      the single-ascending dose portion of the study will also undergo electrocardiogram (ECG)
      monitoring at selected PK time points, to include the estimated Tmax, (anticipated to be 2-4
      hours after a dose of GC4702), to assess the relationship between drug exposure to
      GC4419/GC4702 and effects on the QT interval.

      Part 2: After completion of the single-ascending dose portion of the study, a separate cohort
      of subjects will receive a single dose of GC4702 (at a dose no higher than previously found
      to have an acceptable safety profile), with one of the oral drug products, under fasted or
      fed conditions, followed, after a 7-day washout period, of a second single dose of oral
      GC4702, at the same dose as before, under the opposite condition (fed or fasting). In the
      food effect cohort, subjects will be randomly assigned 1:1 to the fed-fasted sequence (i.e.,
      either fed-first or fasted-first). For the fed condition, subjects will receive a standard
      meal. There will be no placebo dosing or IV GC4419 dosing in the food effect cohort
    

Intervention name(s): GC4702 dry powder; GC4702 lipid suspension; GC4419 IV; Placebo Dry Powder; Placebo lipid suspension; Fed Condition; Fasting Condition; GC4702 lipid suspension - Part 2
Intervention type(s): Drug; Drug; Other; Other; Other; Other; Other; Drug
Intervention description(s): 5 mg GC4702 mixed with approximately 270 mg of Prosolv 90 LM - SMCC (siliconized microcrystalline cellulose). Planned dose levels of GC4702 encapsulated dry powder formulation are 50, 100, and 150 mg; 112 mg GC4702 mixed with Miglyol 812 plus 0.5% by weight BHA plus 1% by weight of Aerosil 200. Planned dose levels of GC4702 encapsulated lipid suspension formulation are 112, 224, and 336, 448, and 560 mg; infused IV as a single dose of 27 mg (3 mL GC4419 at 9 mg/mL) in 247 mL normal (0.9%) saline, totaling 250 mL, over a 60minute period using a programmable pump.; Product matches appearance of the GC4702 dry powder formulation. The Placebo will be 500 mg Miglyol 812 oil containing up to 1% of colloidal silicon dioxide in size 1 capsule.; Product matches appearance of the GC4702 lipid suspension formulation. The Placebo will be 500 mg Miglyol 812 oil containing up to 1% of colloidal silicon dioxide in size 1 capsule.; with 240 mL (8 fluid ounces) of tap water following a high calorie/high fat meal. Subjects assigned to the fed condition will receive a standard meal per U.S. FDA guidelines7 consisting of high calorie/high fat meal prior to dosing consisting of total calories of 800-1000 of which 150, 250 and 500-600 calories are from protein, carbohydrate and fat, respectively.; For the fasting condition, GC4702 will be administered following an overnight fast of at least 10 hours, with 240 mL (8 fluid ounces) of water. No food will be allowed for at least 4 hours post-dose. Water will be allowed as desired except for one hour before and after drug administration.; Two single doses of GC4702 (dose level to be selected based on Part 1 results), separated by a 7-day washout period
Intervention MeSH terms: Avasopasem manganese
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Supportive Care
Keywords: Oral Formulation; Food Effect; Superoxide Dismutase; Single Ascending Dose; GC4702; Bioavailability; Pharmacokinetics; Active Comparator