Safety, Pharmacokinetic and Pharmacodynamic Study of the CDK 4/6 Inhibitor G1T28-1

First-In-Human Phase 1 Safety, Pharmacokinetic and Pharmacodynamic Study of G1T28-1 in Healthy Male and Female Subjects

This first-in-human (FIH) study will provide the first safety, PK, and PD data of G1T28-1 in humans and will allow further development of G1T28 1 in patients with cancer to reduce chemotherapy-induced myelosuppression.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Placebo; Drug: G1T28-1 (CDK 4/6 Inhibitor)

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands
    • PRA Early Development Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy male and female volunteers, 18-60 years of age; no clinically significant findings reported following detailed physical examination, medical history, vital signs, clinical laboratory tests, and ECGs as deemed by the PI
• Body mass index (BMI) in the range of 18 to 32 kg/m2 (inclusive) and weighing at least 50 kg
• Non-smokers / non-users of nicotine containing products for at least the previous 3 months
• Agreement to use birth control during the study and 3 months post last visit
• Able to comply with all protocol requirements and procedures

Exclusion Criteria:

• Clinically significant abnormalities found during physical examination, medical history review, ECGs (including QTcf interval > 450 msec), vital signs and laboratory tests (including positive test for HIV, hepatitis B and/or C)
• History of any serious allergic reaction to any medication
• Participated in a previous clinical trial with an investigational product in the last 60 days
• Any blood or plasma donation or other loss of blood at a volume exceeding 500 mL within 3 months before dosing
• History of drug or alcohol abuse in the last 2 years and positive test for drug abuse
• Use of any systemic medication within the past 2 weeks, including use of herbal products
• Pregnant or lactating women
• Any other issue which, in the opinion of the PI, will make the subject ineligible for study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Double

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; 6mg/m2 of G1T28-1 or placebo will be administered in 50mL of 5% dextrose by IV infusion	Drug: Placebo; Drug: G1T28-1 (CDK 4/6 Inhibitor)
Experimental: Cohort 2; Dose of G1T28-1 or placebo will be determined based on the safety and PK data from Cohort 1; G1T28-1 or placebo will be administered in 50mL of 5% dextrose by IV infusion.	Drug: Placebo; Drug: G1T28-1 (CDK 4/6 Inhibitor)
Experimental: Cohort 3; Dose of G1T28-1 or placebo will be determined based on the safety and PK data from Cohort 2; G1T28-1 or placebo will be administered in 50mL of 5% dextrose by IV infusion.	Drug: Placebo; Drug: G1T28-1 (CDK 4/6 Inhibitor)
Experimental: Cohort 4; Dose of G1T28-1 or placebo will be determined based on the safety and PK data from Cohort 3; G1T28-1 or placebo will be administered in 50mL of 5% dextrose by IV infusion.	Drug: Placebo; Drug: G1T28-1 (CDK 4/6 Inhibitor)
Experimental: Cohort 5; Dose of G1T28-1 or placebo will be determined based on the safety and PK data from Cohort 4; G1T28-1 or placebo will be administered in 50mL of 5% dextrose by IV infusion. Subjects from this cohort may be selected to participate in the Whole Blood Ex-Vivo Stimulation group.	Drug: Placebo; Drug: G1T28-1 (CDK 4/6 Inhibitor)
Experimental: Cohort 6; Dose of G1T28-1 or placebo will be determined based on the safety and PK data from Cohort 5; G1T28-1 or placebo will be administered in 50mL of 5% dextrose by IV infusion. Subjects from this cohort may be selected to participate in the Whole Blood Ex-Vivo Stimulation group.	Drug: Placebo; Drug: G1T28-1 (CDK 4/6 Inhibitor)
Experimental: Cohort 7 - Bone Marrow Cohort; All subjects in this cohort will receive active drug, G1T28-1. Dose of G1T28-1 will be determined based on the safety and PK data from previous cohorts. G1T28-1 will be administered in 50mL of 5% dextrose by IV infusion. Subjects in this cohort will be selected for the Ex-Vivo Stimulation group and will have a one time bone marrow aspirate at one of the following time points: pre dose, 12 or 24 hours post dose.	Drug: G1T28-1 (CDK 4/6 Inhibitor)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	All Adverse events, including-clinical laboratory data, vital signs and ECGs will be analyzed in all subjects receiving study drug through 14 days post dose of study drug.	Up to day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of G1T28-1 in Plasma: Peak Plasma Concentration (Cmax)	The observed peak plasma concentration determined from the plasma concentration vs. time data	Day 1, Day 2, Day 3 and Day 4
Pharmacokinetics of G1T28-1 in Plasma: Time to reach the observed peak plasma concentration (tmax)	The time to reach the observed peak plasma concentration from the plasma concentration vs. time data	Day 1, Day 2, Day 3 and Day 4
Pharmacokinetics of G1T28-1 in Plasma: Area under the plasma concentration -time curve from 0-12 hrs (AUC 0-12)	Area under the plasma concentration-time curve from 0 to 12 hours post dosing, calculated by linear/log trapezoidal method	Day 1
Pharmacokinetics of G1T28-1 in Plasma: Area under the plasma concentration- time curve from 0 to last (AUC 0-last)	Area under the plasma concentration-time curve from time 0 to time of last measurable concentration calculated by linear/log trapezoidal method	Day 1, Day 2, Day 3, Day 4
Pharmacokinetics of G1T28-1 in Plasma: Area under the plasma concentration-time curve from time zero to infinity	Area under the concentration time curve from time zero extrapolated to infinity	Day 1, Day 2, Day 3, Day 4
Pharmacokinetics of G1T28-1 in Plasma: terminal half life (T1/2)	Terminal half-life, defined as 0.693 divided by λzλ	Day 1
Pharmacokinetics of G1T28-1 in Plasma: Terminal phase rate constant	Determined by linear regression of at least 3 points on the terminal phase of the log-linear plasma concentration-time curve.	Day 1
Pharmacokinetics of G1T28-1 in Plasma: Clearance	Clearance after intravenous administration	Day 1
Pharmacokinetics of G1T28-1 in Plasma: Volume of distribution	Volume of distribution in the terminal elimination phase	Day 1
Pharmacodynamics-Whole Blood Ex Vivo Stimulation	Analysis of peripheral blood cell proliferation	Day 1
Pharmacodynamic - Bone Marrow Analysis	Analysis of hematopoietic stem and progenitor cell (HSPC)	Day 1

Collaborators and Investigators

• Sponsor: G1 Therapeutics, Inc.
• Investigators: Principal Investigator: Renger Tiessen, MD, PRA Clinic Netherlands

Publications and helpful links

General Publications

• Li C, Hart L, Owonikoko TK, Aljumaily R, Rocha Lima CM, Conkling PR, Webb RT, Jotte RM, Schuster S, Edenfield WJ, Smith DA, Sale M, Roberts PJ, Malik RK, Sorrentino JA. Trilaciclib dose selection: an integrated pharmacokinetic and pharmacodynamic analysis of preclinical data and Phase Ib/IIa studies in patients with extensive-stage small cell lung cancer. Cancer Chemother Pharmacol. 2021 May;87(5):689-700. doi: 10.1007/s00280-021-04239-9. Epub 2021 Feb 17.

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): February 1, 2015
• Study Completion (Actual): December 18, 2015

Study Registration Dates

• First Submitted: September 9, 2014
• First Submitted That Met QC Criteria: September 16, 2014
• First Posted (Estimate): September 17, 2014

Study Record Updates

• Last Update Posted (Actual): December 17, 2018
• Last Update Submitted That Met QC Criteria: December 14, 2018
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Other Study ID Numbers: G1T28-1-01