Phase 2 Study of the Safety, Efficacy, and Pharmacokinetics of G1T28 in Patients With Metastatic Triple Negative Breast Cancer Receiving Gemcitabine and Carboplatin Chemotherapy
Overview
- Phase
- Phase 2
- Intervention
- Gemcitabine
- Conditions
- Triple-Negative Breast Neoplasms
- Sponsor
- G1 Therapeutics, Inc.
- Enrollment
- 102
- Locations
- 51
- Primary Endpoint
- Duration of Severe (Grade 4) Neutropenia (DSN) During Cycle 1
- Status
- Terminated
- Last Updated
- 4 years ago
Overview
Brief Summary
This was a study to investigate the potential clinical benefit of trilaciclib (G1T28) in preserving the bone marrow and the immune system, and enhancing chemotherapy antitumor efficacy when administered prior to carboplatin and gemcitabine (GC therapy) for participants with metastatic triple negative breast cancer.
The study was an open-label and 102 participants were randomly assigned (1:1:1 fashion) to 1 of the 3 following treatment groups:
- Group 1: GC therapy (Days 1 and 8 of 21-day cycles) only (n=34)
- Group 2: GC therapy (Days 1 and 8) plus trilaciclib (G1T28) on Days 1 and 8 of 21-day cycles (n=33)
- Group 3: GC therapy (Days 2 and 9) plus trilaciclib (G1T28) on Days 1, 2, 8, and 9 of 21-day cycles (n=35)
The study included 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-up Phase. The Treatment Phase begins on the day of first dose with study treatment and completes at the Post-Treatment Visit.
Detailed Description
The posted results represent the final results of Study G1T28-04, a Phase 2 study of the safety, efficacy and pharmacokinetics of trilaciclib (G1T28) in patients with locally recurrent/metastatic triple negative breast cancer receiving gemcitabine and carboplatin chemotherapy. The final myelopreservation efficacy results are reported from database lock 1 (\[DBL1\], data cut-off \[DCO\] date of 30 July 2018). Final anti-tumor efficacy (ORR, PFS), and final summary exposure and safety data are reported from database lock 2 (\[DBL2\], DCO 28 June 2019) which occurred to support filing of the trilaciclib New Drug Application (NDA). Final overall survival (OS) data are reported from the final database lock which occurred on 17 July 2020 (with a last patient last visit date of 28 February 2020).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Confirmed diagnosis of hormone receptor (HR)-negative, human epidermal growth factor receptor 2 (HER2)-negative (locally recurrent or metastatic TNBC) breast cancer
- •Available TNBC diagnostic tumor tissue (archived tissue allowed)
- •Evaluable disease
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
- •Adequate organ function
- •Predicted life expectancy of 3 or more months
Exclusion Criteria
- •More than 2 prior chemotherapy regimens for locally recurrent or metastatic TNBC. If \> 12 months have elapsed between the date of last adjuvant/neoadjuvant chemotherapy administration and first documented local or distant disease recurrence the therapy will not be considered a line of therapy in the locally recurrent or metastatic TNBC setting.
- •CNS metastases or leptomeningeal disease requiring immediate treatment with radiation therapy or steroids.
- •Investigational drug within 30 days of first trilaciclib (G1T28) dose
- •Concurrent radiotherapy, radiotherapy within 14 days of first trilaciclib (G1T28) dose
- •Cytotoxic chemotherapy within 3 weeks of first trilaciclib (G1T28) dose
- •Prior hematopoietic stem cell or bone marrow transplantation
Arms & Interventions
Group 1: Gemcitabine/Carboplatin (Days 1 and 8)
Participants received Intravenous (IV) infusion of standard GC chemotherapy (gemcitabine 1000 milligrams per meter square \[mg/m\^2\] and carboplatin area under the curve \[AUC\] 2) on Days 1 and 8 of 21-day cycle. The carboplatin dose was calculated using the Calvert formula, with a target AUC 2 (maximum 300 mg).
Intervention: Gemcitabine
Group 1: Gemcitabine/Carboplatin (Days 1 and 8)
Participants received Intravenous (IV) infusion of standard GC chemotherapy (gemcitabine 1000 milligrams per meter square \[mg/m\^2\] and carboplatin area under the curve \[AUC\] 2) on Days 1 and 8 of 21-day cycle. The carboplatin dose was calculated using the Calvert formula, with a target AUC 2 (maximum 300 mg).
Intervention: Carboplatin
Group 2: Trilaciclib + Gemcitabine/ Carboplatin (Days 1 and 8)
Participants received IV infusion of trilaciclib 240 mg/m\^2 plus GC chemotherapy (gemcitabine 1000 mg/m\^2 and carboplatin AUC 2) IV infusion on Days 1 and 8 of 21-day cycle. Trilaciclib was administered prior to chemotherapy.
Intervention: Trilaciclib
Group 2: Trilaciclib + Gemcitabine/ Carboplatin (Days 1 and 8)
Participants received IV infusion of trilaciclib 240 mg/m\^2 plus GC chemotherapy (gemcitabine 1000 mg/m\^2 and carboplatin AUC 2) IV infusion on Days 1 and 8 of 21-day cycle. Trilaciclib was administered prior to chemotherapy.
Intervention: Gemcitabine
Group 2: Trilaciclib + Gemcitabine/ Carboplatin (Days 1 and 8)
Participants received IV infusion of trilaciclib 240 mg/m\^2 plus GC chemotherapy (gemcitabine 1000 mg/m\^2 and carboplatin AUC 2) IV infusion on Days 1 and 8 of 21-day cycle. Trilaciclib was administered prior to chemotherapy.
Intervention: Carboplatin
Group 3: Trilaciclib (Days 1, 2, 8 and 9) + Gemcitabine/Carboplatin (Days 2 and 9)
Participants received IV infusion of trilaciclib 240 mg/m\^2 on Days 1, 2, 8, and 9 plus GC chemotherapy (gemcitabine 1000 mg/m\^2 and carboplatin AUC 2) IV infusion on Day 2 and 9 of 21-day Cycle. Trilaciclib was administered prior to chemotherapy.
Intervention: Trilaciclib
Group 3: Trilaciclib (Days 1, 2, 8 and 9) + Gemcitabine/Carboplatin (Days 2 and 9)
Participants received IV infusion of trilaciclib 240 mg/m\^2 on Days 1, 2, 8, and 9 plus GC chemotherapy (gemcitabine 1000 mg/m\^2 and carboplatin AUC 2) IV infusion on Day 2 and 9 of 21-day Cycle. Trilaciclib was administered prior to chemotherapy.
Intervention: Gemcitabine
Group 3: Trilaciclib (Days 1, 2, 8 and 9) + Gemcitabine/Carboplatin (Days 2 and 9)
Participants received IV infusion of trilaciclib 240 mg/m\^2 on Days 1, 2, 8, and 9 plus GC chemotherapy (gemcitabine 1000 mg/m\^2 and carboplatin AUC 2) IV infusion on Day 2 and 9 of 21-day Cycle. Trilaciclib was administered prior to chemotherapy.
Intervention: Carboplatin
Outcomes
Primary Outcomes
Duration of Severe (Grade 4) Neutropenia (DSN) During Cycle 1
Time Frame: From randomization to the end of Cycle 1 (Each cycle= 21 days)
DSN was defined as the number of days from the date of the first absolute neutrophil count (ANC) value of less than (\<) 0.5 × 10\^9 cells/liter (L) observed between Day 1 Cycle 1 and the end of Cycle 1 to the date of the first ANC value greater than or equal to (\>=) 0.5 × 10\^9/L that met the following: (1) occurred after the ANC value of \< 0.5 × 10\^9 cells/L and (2) no other ANC values \< 0.5 × 10\^9 cells/L occurred between this day and the end of Cycle 1. Severe neutropenia (SN) was set to zero for participants who did not experience severe (Grade 4) neutropenia in Cycle 1, including those who were randomized but never treated.
Number of Participants With Severe (Grade 4) Neutropenia (SN)
Time Frame: During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days
Number of participants with Grade 4 SN was a binary variable. If a participants had at least 1 ANC value \< 0.5 ×10\^9/L during the treatment period, the participants was assigned as "yes" to the occurrence of SN. Otherwise, it was "no".
Secondary Outcomes
- Number of Participants With Grade 3 and 4 Hematologic Toxicities(During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days)
- Number of Participants With Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)(From date of randomization until the occurrence of progressive disease or a censoring event, assessed up to a maximum of 875 days)
- Duration of Objective Response (DOR) as Per RECIST v1.1 as Determined by Investigator(From date of randomization until the occurrence of progressive disease or a censoring event, assessed up to a maximum of 875 days)
- Duration of Exposure(During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days)
- Progression Free Survival (PFS) as Per RECIST v1.1 as Determined by Investigator(From date of randomization until the occurrence of disease progression, death due to any cause or a censoring event, assessed up to a maximum of 875 days)
- Relative Dose Intensity of Gemcitabine and Carboplatin(During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days)
- Number of Cycles Participants Received Treatment in Each Treatment Arm(During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days)
- Maximum Observed Plasma Concentration (Cmax) of Trilaciclib(Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days))
- Cumulative Dose of Carboplatin(During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days)
- Terminal Elimination Half-Life (t1/2) of Free Carboplatin(Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days))
- Clearance (CL) of of Free Carboplatin(Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days))
- Major Adverse Hematologic Event (MAHE) Rate(During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days)
- Terminal Elimination Half-Life (t1/2) of Trilaciclib(Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days))
- Maximum Observed Plasma Concentration (Cmax) of Gemcitabine(Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days))
- Number of Participants With Febrile Neutropenia (FN)(During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days)
- Number of Participants With Infection SAEs(During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days)
- Number of Participants With Red Blood Cell (RBC) Transfusions On/After Week 5 (Day 35)(From Day 35 through the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 508 days)
- Area Under the Plasma Concentration-Time Curve From Time 0 to t Hours (AUC0-t) of Gemcitabine(Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days))
- Volume of Distribution at Steady State (Vss) of Free Carboplatin(Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days))
- Number of Participants With Grade 3 or 4 Thrombocytopenia(During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days)
- Overall Survival (OS)(From date of randomization to date of death due to any cause, assessed up to a maximum of 1120 days)
- Cumulative Dose of Gemcitabine(During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days)
- Area Under the Plasma Concentration-Time Curve From Time 0 to t Hours (AUC0-t) of Trilaciclib(Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days))
- Number of Participants With Erythropoiesis Stimulating Agent (ESA) Administration(During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days)
- Number of Participants With Platelet Transfusions(During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days)
- Number of Participants With Intravenous Antibiotics Use(During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days)
- Dose Modifications - Number of Participants With Skipped Doses(During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days)
- Dose Modifications - Number of Participants With Dose Reductions(During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days)
- Number of Participants With Granulocyte Colony-stimulating Factor (G-CSF) Administration(During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days)
- All-cause Dose Reductions, Event Rate (Per Cycle)(During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days)
- Dose Modifications: Number of Participants With Cycle Delays(During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days)
- Dose Modifications: Number of Participants With Any Dose Interruptions(During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days)