G1T38, a CDK 4/6 Inhibitor, in Combination With Osimertinib in EGFR-Mutant Non-Small Cell Lung Cancer

Phase 1b/2 Safety, Pharmacokinetic, and Efficacy Study of G1T38 in Combination With Osimertinib in Patients With EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)

This was a study to investigate the potential clinical benefit of G1T38 as an oral therapy in combination with osimertinib in patients with EGFR mutation-positive metastatic non-small cell lung cancer.

The study was an open-label design, planned to consist of 2 parts: a safety, pharmacokinetic, and dose-finding portion (Part 1), and a randomized portion (Part 2). Both parts were to include 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-up Phase. The Treatment Phase began on the day of first dose with study treatment and completes at the Post-Treatment Visit. Approximately, 144 patients were planned to be enrolled in the study.

Study Overview

• Status: Completed
• Conditions: Carcinoma, Non-Small-Cell Lung; Lung Cancer; Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: G1T38; Drug: Osimertinib

Detailed Description

Part 2, the Phase 2 part of the study, was not conducted due to changes in corporate strategy. There were no safety signals identified in Phase 1/Part 1 that would have precluded the conduct of Part 2. As a result, 30 out of the planned 144 patients were enrolled.

All tumor assessments were conducted by the Investigators or site radiologist. In order to reduce the burden to the patients, data of overall survival (OS) were no longer required (since 29 January 2020). No OS analysis was conducted for Part 1 due to limited data in Part 1.

PK data for Cohorts 4 (150 BID) and 5 (200 BID) were not analyzed as they were deemed unnecessary, as the PK data from Cohorts 1-3 were sufficient to achieve the secondary study objective of assessing the effect of osimertinib on PK parameters of G1T38.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Beverly Hills Cancer Center
    • Santa Monica, California, United States, 90404
      • UCLA Medical Center, Division of Hematology/Oncology/Clinical Research Unit
    • Santa Rosa, California, United States, 95403
      • St Joseph Heritage Healthcare
  • Florida
    • Miami, Florida, United States, 33136
      • Sylvester Comprehensive Cancer Center/University of Miami Miller School of Medicine Fox Building, Suite 200 G
    • Tampa, Florida, United States, 33612
      • Mofitt Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Univ. of Michigan Hospitals
  • Virginia
    • Fairfax, Virginia, United States, 22301
      • Virginia Cancer Specialists
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Hospital & the Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Confirmed EGFR mutation for non-small cell lung cancer associated with EGFR TKI sensitivity
• For Part 2, EGFR T790M mutation-positive tumor status
• Left ventricular ejection fraction (LVEF) ≥ institution's lower limit of the reference range
• For Part 1, evaluable or measurable disease as defined by RECIST, Version 1.1
• For Part 2, measurable disease as defined by RECIST, Version 1.1
• ECOG performance status 0 to 1
• Adequate organ function

Exclusion Criteria:

• Prior treatment with EGFR TKI within 9 days of first study dose
• For Part 1, prior treatment with more than 2 prior lines of chemotherapy for advanced NSCLC
• For Part 2, prior treatment with osimertinib or other T790M active EGFR TKI
• For Part 2, prior chemotherapy for advanced NSCLC
• Active uncontrolled/symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease
• Investigational drug within 3 months or 5 half-lives, whichever is longer, of first study dose
• Concurrent radiotherapy, radiotherapy within 28 days of first study dose, previous radiotherapy to the target lesion sites, or prior radiotherapy to > 25% of bone marrow
• Prior hematopoietic stem cell or bone marrow transplantation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Cohort 1 G1T38 + Osimertinib; Patients will receive a single oral dose of G1T38 on Cycle 1 Day -16 and on Cycle 1 Day -2. Patients will receive oral osimertinib 80 mg beginning Cycle 1 Days -14. Patients will begin G1T38 once-daily dosing on Cycle 1 Day 1 (in combination with osimertinib 80 mg).	Drug: G1T38; CDK 4/6 inhibitor; Other Names: Lerociclib; Drug: Osimertinib; EGFR TKI; 80 mg; Other Names: Tagrisso
Experimental: Part 1: Cohort 2 G1T38 + Osimertinib; Patients will receive a single oral dose of G1T38 on Cycle 1 Day -16 and on Cycle 1 Day -2. Patients will receive oral osimertinib 80 mg beginning Cycle 1 Days -14. Patients will begin G1T38 once-daily dosing on Cycle 1 Day 1 (in combination with osimertinib 80 mg).	Drug: G1T38; CDK 4/6 inhibitor; Other Names: Lerociclib; Drug: Osimertinib; EGFR TKI; 80 mg; Other Names: Tagrisso
Experimental: Part 1: Cohort 3 G1T38 + Osimertinib; Patients will receive a single oral dose of G1T38 on Cycle 1 Day -16 and on Cycle 1 Day -2. Patients will receive oral osimertinib 80 mg beginning Cycle 1 Days -14. Patients will begin G1T38 once-daily dosing on Cycle 1 Day 1 (in combination with osimertinib 80 mg).	Drug: G1T38; CDK 4/6 inhibitor; Other Names: Lerociclib; Drug: Osimertinib; EGFR TKI; 80 mg; Other Names: Tagrisso
Experimental: Part 1: Cohort 4 G1T38 + Osimertinib; Patients will receive a single oral dose of G1T38 on Cycle 1 Day -16 and on Cycle 1 Day -2. Patients will receive oral osimertinib 80 mg beginning Cycle 1 Days -14. Patients will begin G1T38 once-daily dosing on Cycle 1 Day 1 (in combination with osimertinib 80 mg).	Drug: G1T38; CDK 4/6 inhibitor; Other Names: Lerociclib; Drug: Osimertinib; EGFR TKI; 80 mg; Other Names: Tagrisso
Experimental: Part 1: Cohort 5 G1T38 + Osimertinib; Patients will receive a single oral dose of G1T38 on Cycle 1 Day -16 and on Cycle 1 Day -2. Patients will receive oral osimertinib 80 mg beginning Cycle 1 Days -14. Patients will begin G1T38 once-daily dosing on Cycle 1 Day 1 (in combination with osimertinib 80 mg).	Drug: G1T38; CDK 4/6 inhibitor; Other Names: Lerociclib; Drug: Osimertinib; EGFR TKI; 80 mg; Other Names: Tagrisso

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Limiting Toxicity	The percentage of patients experiencing DLTs in Part 1 of the study in each cohort, including: Grade 4 neutropenia; ≥ Grade 3 neutropenic infection/febrile neutropenia; Grade 4 thrombocytopenia; ≥ Grade 3 thrombocytopenia with bleeding; ≥ Grade 3 nonhematologic toxicity (additional criteria for nausea, vomiting, diarrhea, or fatigue: lasting > 5 days with maximal medical management); Liver function test abnormalities meeting Hy's Law criteria (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] ≥ 3 × upper limit of normal [ULN] and total bilirubin ≥ 2 × ULN).	Cycle 1 Day -16 to Cycle 1 Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	Median time (months) and 95% CI from date of first dose of study drug/randomization until date of documented disease progression or death due to any cause. Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 guidelines for tumor assessments were used to determine progression. Progressive Disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).	36 months
Best Overall Tumor Response	The percentage of patients who fall into each category of Best overall response (BOR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 guidelines. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. When no imaging/measurement is done, the patient is not evaluable (NE); and if only a subset of lesion measurements are made, usually the case is also considered NE.	21 months
Pharmacokinetics of G1T38 and Metabolite G1T30: Maximum Plasma Concentration (Cmax)	The observed peak plasma concentration determined from the plasma concentration versus time data.	Part 1, Cycle 1 Day -16 to Day -2.
Pharmacokinetics of G1T38 and Metabolite G1T30: Area Under Curve - Plasma Concentration (AUC) Infinity	Area under the concentration-time curve from time zero extrapolated to infinity using the linear-up log-down trapezoidal rule.	Part 1, Cycle 1 Day -16 to Day -2.
Pharmacokinetics of G1T38 and Metabolite G1T30: Plasma: Terminal Half Life (T1/2)	Terminal half-life, defined as 0.693 divided by the terminal phase rate constant by λz , determined by linear regression of at least 3 points on the terminal phase of the log-linear plasma concentration-time curve.	Part 1, Cycle 1 Day -16 to Day -2.
Pharmacokinetics of G1T38: Plasma - Volume of Distribution	Volume of distribution in the terminal elimination phase, calculated as: Vz/F = (CL/F)/λz	Part 1, Cycle 1 Day -16 to Day -2.

Collaborators and Investigators

• Sponsor: G1 Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2018
• Primary Completion (Actual): December 14, 2021
• Study Completion (Actual): February 14, 2022

Study Registration Dates

• First Submitted: February 28, 2018
• First Submitted That Met QC Criteria: February 28, 2018
• First Posted (Actual): March 7, 2018

Study Record Updates

• Last Update Posted (Estimate): May 5, 2023
• Last Update Submitted That Met QC Criteria: May 3, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Lung Cancer; Non-small Cell Lung Cancer; CDK 4/6 Inhibitor; T790M; EGFR-Positive; EGFR Mutation- Positive; EGFR Mutant; lerociclib
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Osimertinib
• Other Study ID Numbers: G1T38-03; 2017-004315-39 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No