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

• ClinicalTrials.gov Identifier: NCT03455829
• Recruitment Status: Completed
• First Posted: March 7, 2018
• Results First Posted: May 1, 2023
• Last Update Posted: May 6, 2023
• Sponsor: G1 Therapeutics, Inc.
• Information provided by (Responsible Party): G1 Therapeutics, Inc.

Tracking Information

• First Submitted Date: February 28, 2018
• First Posted Date: March 7, 2018
• Results First Submitted Date: December 13, 2022
• Results First Posted Date: May 1, 2023
• Last Update Posted Date: May 6, 2023
• Actual Study Start Date: March 29, 2018
• Actual Primary Completion Date: December 14, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 13, 2022)

Dose Limiting Toxicity [ Time Frame: Cycle 1 Day -16 to Cycle 1 Day 28 ]

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).

Original Primary Outcome Measures (submitted: February 28, 2018)

• Dose Limiting Toxicity [ Time Frame: Cycle 1 Day -14 to Cycle 1 Day 28 ]
• Recommended Phase 2 dose [ Time Frame: 9 months ]
• Number of Treatment Related Adverse Event, including Abnormal Laboratory Events [ Time Frame: 36 months ]
  All AEs, including clinical laboratory, vitals signs, physical examinations and ECGs will be analyzed in all patients receiving study drug from the signing of the informed consent until 30 days after the last dose of study medication
• Progression free survival (PFS) using blinded independent central review (BICR) [ Time Frame: 36 months ]

Current Secondary Outcome Measures (submitted: April 7, 2023)

• Progression Free Survival (PFS) [ Time Frame: 36 months ]
  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 [ Time Frame: 21 months ]
  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) [ Time Frame: Part 1, Cycle 1 Day -16 to Day -2. ]
  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 [ Time Frame: Part 1, Cycle 1 Day -16 to Day -2. ]
  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) [ Time Frame: Part 1, Cycle 1 Day -16 to Day -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 [ Time Frame: Part 1, Cycle 1 Day -16 to Day -2. ]
  Volume of distribution in the terminal elimination phase, calculated as: Vz/F = (CL/F)/λz

Original Secondary Outcome Measures (submitted: February 28, 2018)

• Tumor response based on RECIST, Version 1.1 [ Time Frame: 21 months ]
• Pharmacokinetics of G1T38 and metabolite G1T30: Maximum Plasma Concentration (Cmax) [ Time Frame: Part 1, Cycle 1 Day -14 to Day -2. Part 2, Cycle 1 Day 15 to Cycle 2 Day 1. ]
• Pharmacokinetics of G1T38 and metabolite G1T30: Area under Curve - plasma concentration (AUC) [ Time Frame: Part 1, Cycle 1 Day -14 to Day -2. Part 2, Cycle 1 Day 15 to Cycle 2 Day 1. ]
• Pharmacokinetics of G1T38 and metabolite G1T30: Plasma: terminal half life (T1/2) [ Time Frame: Part 1, Cycle 1 Day -14 to Day -2. Part 2, Cycle 1 Day 15 to Cycle 2 Day 1. ]
• Pharmacokinetics of G1T38 and metabolite G1T30: Plasma - Volume of distribution [ Time Frame: Part 1, Cycle 1 Day -14 to Day -2. Part 2, Cycle 1 Day 15 to Cycle 2 Day 1. ]
• PFS using investigator assessment [ Time Frame: 36 months ]
• 1-year PFS using investigator assessment and BICR [ Time Frame: 33 months ]
• Overall survival (OS) [ Time Frame: 60 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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)

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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Carcinoma, Non-Small-Cell Lung
• Lung Cancer
• Non-small Cell Lung Cancer

Intervention

• Drug: G1T38
  CDK 4/6 inhibitor
  Other Name: Lerociclib
• Drug: Osimertinib
  EGFR TKI; 80 mg
  Other Name: Tagrisso

Study Arms

• 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).
  Interventions:

  • Drug: G1T38
  • Drug: Osimertinib
• 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).
  Interventions:

  • Drug: G1T38
  • Drug: Osimertinib
• 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).
  Interventions:

  • Drug: G1T38
  • Drug: Osimertinib
• 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).
  Interventions:

  • Drug: G1T38
  • Drug: Osimertinib
• 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).
  Interventions:

  • Drug: G1T38
  • Drug: Osimertinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 22, 2020): 30
• Original Estimated Enrollment (submitted: February 28, 2018): 144
• Actual Study Completion Date: February 14, 2022
• Actual Primary Completion Date: December 14, 2021 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03455829
• Other Study ID Numbers: G1T38-03; 2017-004315-39 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: G1 Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: G1 Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Contact; G1 Therapeutics, Inc.

• PRS Account: G1 Therapeutics, Inc.
• Verification Date: May 2023