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

Study Overview
=================
Brief Summary
-----------------
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.

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

Conditions
-----------------
Healthy Volunteers

Intervention / Treatment
-----------------
* Drug: G1T28-1 (CDK 4/6 Inhibitor)
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>6mg/m2 of G1T28-1 or placebo will be administered in 50mL of 5% dextrose by IV infusion | Drug: G1T28-1 (CDK 4/6 Inhibitor)<br> <br> Drug: Placebo<br> <br> |
| Experimental: Cohort 2<br>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: G1T28-1 (CDK 4/6 Inhibitor)<br> <br> Drug: Placebo<br> <br> |
| Experimental: Cohort 3<br>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: G1T28-1 (CDK 4/6 Inhibitor)<br> <br> Drug: Placebo<br> <br> |
| Experimental: Cohort 4<br>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: G1T28-1 (CDK 4/6 Inhibitor)<br> <br> Drug: Placebo<br> <br> |
| Experimental: Cohort 5<br>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: G1T28-1 (CDK 4/6 Inhibitor)<br> <br> Drug: Placebo<br> <br> |
| Experimental: Cohort 6<br>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: G1T28-1 (CDK 4/6 Inhibitor)<br> <br> Drug: Placebo<br> <br> |
| Experimental: Cohort 7 - Bone Marrow Cohort<br>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)<br> <br> |

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 |