Back to resultsG1T38, a CDK 4/6 Inhibitor, in Combination With Osimertinib in EGFR-Mutant Non-Small Cell Lung Cancer
Primary Purpose
Carcinoma, Non-Small-Cell Lung, Lung Cancer, Non-small Cell Lung Cancer
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
G1T38
Osimertinib
Sponsored by
About this trial
This is an interventional treatment trial for Carcinoma, Non-Small-Cell Lung focused on measuring Lung Cancer, Non-small Cell Lung Cancer, CDK 4/6 Inhibitor, EGFR-Positive, EGFR Mutation- Positive, T790M, EGFR Mutant, lerociclib
Eligibility Criteria
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
Sites / Locations
- Beverly Hills Cancer Center
- UCLA Medical Center, Division of Hematology/Oncology/Clinical Research Unit
- St Joseph Heritage Healthcare
- Sylvester Comprehensive Cancer Center/University of Miami Miller School of Medicine Fox Building, Suite 200 G
- Mofitt Cancer Center
- Univ. of Michigan Hospitals
- Virginia Cancer Specialists
- Froedtert Hospital & the Medical College of Wisconsin
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
Part 1: Cohort 1 G1T38 + Osimertinib
Part 1: Cohort 2 G1T38 + Osimertinib
Part 1: Cohort 3 G1T38 + Osimertinib
Part 1: Cohort 4 G1T38 + Osimertinib
Part 1: Cohort 5 G1T38 + Osimertinib
Arm Description
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).
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).
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).
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).
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).
Outcomes
Primary Outcome Measures
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).
Secondary Outcome Measures
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).
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.
Pharmacokinetics of G1T38 and Metabolite G1T30: Maximum Plasma Concentration (Cmax)
The observed peak plasma concentration determined from the plasma concentration versus time data.
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.
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.
Pharmacokinetics of G1T38: Plasma - Volume of Distribution
Volume of distribution in the terminal elimination phase, calculated as:
Vz/F = (CL/F)/λz
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03455829
Brief Title
G1T38, a CDK 4/6 Inhibitor, in Combination With Osimertinib in EGFR-Mutant Non-Small Cell Lung Cancer
Official Title
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)
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
March 29, 2018 (Actual)
Primary Completion Date
December 14, 2021 (Actual)
Study Completion Date
February 14, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
G1 Therapeutics, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Carcinoma, Non-Small-Cell Lung, Lung Cancer, Non-small Cell Lung Cancer
Keywords
Lung Cancer, Non-small Cell Lung Cancer, CDK 4/6 Inhibitor, EGFR-Positive, EGFR Mutation- Positive, T790M, EGFR Mutant, lerociclib
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Part 1: Cohort 1 G1T38 + Osimertinib
Arm Type
Experimental
Arm Description
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).
Arm Title
Part 1: Cohort 2 G1T38 + Osimertinib
Arm Type
Experimental
Arm Description
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).
Arm Title
Part 1: Cohort 3 G1T38 + Osimertinib
Arm Type
Experimental
Arm Description
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).
Arm Title
Part 1: Cohort 4 G1T38 + Osimertinib
Arm Type
Experimental
Arm Description
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).
Arm Title
Part 1: Cohort 5 G1T38 + Osimertinib
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
G1T38
Other Intervention Name(s)
Lerociclib
Intervention Description
CDK 4/6 inhibitor
Intervention Type
Drug
Intervention Name(s)
Osimertinib
Other Intervention Name(s)
Tagrisso
Intervention Description
EGFR TKI; 80 mg
Primary Outcome Measure Information:
Title
Dose Limiting Toxicity
Description
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).
Time Frame
Cycle 1 Day -16 to Cycle 1 Day 28
Secondary Outcome Measure Information:
Title
Progression Free Survival (PFS)
Description
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).
Time Frame
36 months
Title
Best Overall Tumor Response
Description
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.
Time Frame
21 months
Title
Pharmacokinetics of G1T38 and Metabolite G1T30: Maximum Plasma Concentration (Cmax)
Description
The observed peak plasma concentration determined from the plasma concentration versus time data.
Time Frame
Part 1, Cycle 1 Day -16 to Day -2.
Title
Pharmacokinetics of G1T38 and Metabolite G1T30: Area Under Curve - Plasma Concentration (AUC) Infinity
Description
Area under the concentration-time curve from time zero extrapolated to infinity using the linear-up log-down trapezoidal rule.
Time Frame
Part 1, Cycle 1 Day -16 to Day -2.
Title
Pharmacokinetics of G1T38 and Metabolite G1T30: Plasma: Terminal Half Life (T1/2)
Description
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.
Time Frame
Part 1, Cycle 1 Day -16 to Day -2.
Title
Pharmacokinetics of G1T38: Plasma - Volume of Distribution
Description
Volume of distribution in the terminal elimination phase, calculated as:
Vz/F = (CL/F)/λz
Time Frame
Part 1, Cycle 1 Day -16 to Day -2.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Contact
Organizational Affiliation
G1 Therapeutics, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Beverly Hills Cancer Center
City
Beverly Hills
State/Province
California
ZIP/Postal Code
90211
Country
United States
Facility Name
UCLA Medical Center, Division of Hematology/Oncology/Clinical Research Unit
City
Santa Monica
State/Province
California
ZIP/Postal Code
90404
Country
United States
Facility Name
St Joseph Heritage Healthcare
City
Santa Rosa
State/Province
California
ZIP/Postal Code
95403
Country
United States
Facility Name
Sylvester Comprehensive Cancer Center/University of Miami Miller School of Medicine Fox Building, Suite 200 G
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Mofitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Univ. of Michigan Hospitals
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Virginia Cancer Specialists
City
Fairfax
State/Province
Virginia
ZIP/Postal Code
22301
Country
United States
Facility Name
Froedtert Hospital & the Medical College of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
12. IPD Sharing Statement
Learn more about this trial
G1T38, a CDK 4/6 Inhibitor, in Combination With Osimertinib in EGFR-Mutant Non-Small Cell Lung Cancer
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