Clinical trial NCT02978716: Trilaciclib (G1T28), a CDK 4/6 Inhibitor, in Combination With Gemcitabine and Carboplatin in Metastatic Triple Negative Breast Cancer (mTNBC)
Official title: Phase 2 Study of the Safety, Efficacy, and Pharmacokinetics of G1T28 in Patients With Metastatic Triple Negative Breast Cancer Receiving Gemcitabine and Carboplatin Chemotherapy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Triple-Negative Breast Neoplasms
Breast Neoplasm
Breast Cancer
Triple-Negative Breast Cancer
Keywords: Breast Cancer
CDK 4/6 Inhibitor
Triple Negative Breast Cancer
Metastatic
Lead sponsor: G1 Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2016-12-01
Enrollment: 102
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: Duration of Severe (Grade 4) Neutropenia (DSN) During Cycle 1
timeFrame: From randomization to the end of Cycle 1 (Each cycle= 21 days)
measure: Number of Participants With Severe (Grade 4) Neutropenia (SN)
timeFrame: 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
Secondary outcomes:
measure: Number of Participants With Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
timeFrame: From date of randomization until the occurrence of progressive disease or a censoring event, assessed up to a maximum of 875 days
measure: Duration of Objective Response (DOR) as Per RECIST v1.1 as Determined by Investigator
timeFrame: From date of randomization until the occurrence of progressive disease or a censoring event, assessed up to a maximum of 875 days
measure: Overall Survival (OS)
timeFrame: From date of randomization to date of death due to any cause, assessed up to a maximum of 1120 days
measure: Progression Free Survival (PFS) as Per RECIST v1.1 as Determined by Investigator
timeFrame: 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
measure: Relative Dose Intensity of Gemcitabine and Carboplatin
timeFrame: 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
measure: Duration of Exposure
timeFrame: 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
measure: Number of Cycles Participants Received Treatment in Each Treatment Arm
timeFrame: 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
measure: Cumulative Dose of Gemcitabine
timeFrame: 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
measure: Cumulative Dose of Carboplatin
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of Trilaciclib
timeFrame: 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)
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to t Hours (AUC0-t) of Trilaciclib
timeFrame: 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)
measure: Terminal Elimination Half-Life (t1/2) of Trilaciclib
timeFrame: 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)
measure: Maximum Observed Plasma Concentration (Cmax) of Gemcitabine
timeFrame: 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)
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to t Hours (AUC0-t) of Gemcitabine
timeFrame: 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)
measure: Terminal Elimination Half-Life (t1/2) of Free Carboplatin
timeFrame: 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)
measure: Clearance (CL) of of Free Carboplatin
timeFrame: 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)
measure: Volume of Distribution at Steady State (Vss) of Free Carboplatin
timeFrame: 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)
measure: Number of Participants With Grade 3 and 4 Hematologic Toxicities
timeFrame: 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
measure: Number of Participants With Grade 3 or 4 Thrombocytopenia
timeFrame: 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
measure: Major Adverse Hematologic Event (MAHE) Rate
timeFrame: 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
measure: Number of Participants With Febrile Neutropenia (FN)
timeFrame: 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
measure: Number of Participants With Infection SAEs
timeFrame: 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
measure: Number of Participants With Red Blood Cell (RBC) Transfusions On/After Week 5 (Day 35)
timeFrame: 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
measure: Number of Participants With Platelet Transfusions
timeFrame: 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
measure: Number of Participants With Granulocyte Colony-stimulating Factor (G-CSF) Administration
timeFrame: 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
measure: Number of Participants With Erythropoiesis Stimulating Agent (ESA) Administration
timeFrame: 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
measure: Number of Participants With Intravenous Antibiotics Use
timeFrame: 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
measure: All-cause Dose Reductions, Event Rate (Per Cycle)
timeFrame: 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
measure: Dose Modifications: Number of Participants With Cycle Delays
timeFrame: 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
measure: Dose Modifications - Number of Participants With Skipped Doses
timeFrame: 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
measure: Dose Modifications: Number of Participants With Any Dose Interruptions
timeFrame: 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
measure: Dose Modifications - Number of Participants With Dose Reductions
timeFrame: 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
Other outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: 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 1116 days
Locations:
city: Tucson
country: United States
facility: Arizona Oncology Associates, PC - HOPE
state: Arizona
city: Burbank
country: United States
facility: Disney Family Cancer Center
state: California
city: San Diego
country: United States
facility: Sharp Clinical Oncology
state: California
city: Whittier
country: United States
facility: Innovative Clinical Research Institute
state: California
city: Colorado Springs
country: United States
facility: Memorial UC Health
state: Colorado
city: Lakewood
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Plantation
country: United States
facility: Florida Cancer Research Institute, LLC.
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists - North (FCS North)
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists - East (FCS East)
state: Florida
city: Boise
country: United States
facility: Saint Alphonsus Regional Medical Center
state: Idaho
city: Arlington Heights
country: United States
facility: Illinois Cancer Specialists
state: Illinois
city: Indianapolis
country: United States
facility: Community Health Network
state: Indiana
city: Baltimore
country: United States
facility: University of Maryland Greenebaum Comprehensive Cancer Center
state: Maryland
city: Towson
country: United States
facility: The University of Maryland St. Joseph Medical Center
state: Maryland
city: Kansas City
country: United States
facility: Saint Luke's Cancer Institute
state: Missouri
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Charlotte
country: United States
facility: Levine Cancer Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Forsyth Memorial Hospital, Novant Health Oncology Specialists
state: North Carolina
city: Chattanooga
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Austin
country: United States
facility: Texas Oncology-Dallas Presbyterian Hospital
state: Texas
city: Austin
country: United States
facility: Texas Oncology, P.A.
state: Texas
city: Bedford
country: United States
facility: Texas Oncology, P.A.
state: Texas
city: Dallas
country: United States
facility: Texas Oncology - Baylor Charles A. Sammons Cancer Center
state: Texas
city: El Paso
country: United States
facility: Texas Oncology-El Paso Cancer Treatment Center Grandview
state: Texas
city: Fort Worth
country: United States
facility: The Center for Cancer and Blood Disorders
state: Texas
city: San Antonio
country: United States
facility: Texas Oncology-San Antonio Northeast
state: Texas
city: Tyler
country: United States
facility: Tyler Hematology-Oncology, PA
state: Texas
city: Tyler
country: United States
facility: Texas Oncology, P.A.
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Virginia Beach
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Tacoma
country: United States
facility: Northwest Medical Specialties, PLLC
state: Washington
city: Edegem
country: Belgium
facility: Antwerp University Hospital (UZA)
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment
city: Sofia
country: Bulgaria
facility: MHAT for Womens Health - Nadezhda OOD
city: Sofia
country: Bulgaria
facility: Special Hospital For Active Treatment In Oncology
city: Varna
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment
city: Osijek
country: Croatia
facility: University Hospital Centre Osijek
city: Varazdin
country: Croatia
facility: General Hospital Varaždin
city: Zagreb
country: Croatia
facility: University Hospital Centre "Sestre milosrdnice"
city: Zagreb
country: Croatia
facility: University Hospital Centre Zagreb
city: Bitola
country: North Macedonia
facility: Clinical Hospital Dr. Trifun Panovski
city: Skopje
country: North Macedonia
facility: University Clinic of Radiotherapy and Oncology
city: Belgrade
country: Serbia
facility: Special Hospital for Internal Diseases , Oncomed
city: Belgrade
country: Serbia
facility: Clinical Hospital Centre Bezanijska Kosa, Oncology Clinic
city: Kragujevac
country: Serbia
facility: Center for Oncology and Radiotherapy, Clinical Centre
city: Nis
country: Serbia
facility: Clinical Centre Nis, Clinic of Oncology
city: Sremska Kamenica
country: Serbia
facility: Oncology Institute of Vojvodina, Clinic for Internal Oncology
city: Banská Bystrica
country: Slovakia
facility: Mammacentrum, Sv.Agáty
city: Košice
country: Slovakia
facility: Cancer Institute VOU, Rastislavova
city: Maribor
country: Slovenia
facility: University Medical Centre Maribor
Study officials:
affiliation: G1 Therapeutics, Inc.
name: Clinical Contact
role: STUDY_DIRECTOR
References:
citation: Tan AR, Wright GS, Thummala AR, Danso MA, Popovic L, Pluard TJ, Han HS, Vojnovic Z, Vasev N, Ma L, Richards DA, Wilks ST, Milenkovic D, Yang Z, Antal JM, Morris SR, O'Shaughnessy J. Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. 2019 Nov;20(11):1587-1601. doi: 10.1016/S1470-2045(19)30616-3. Epub 2019 Sep 28.
citation: Tan AR, Wright GS, Thummala AR, Danso MA, Popovic L, Pluard TJ, Han HS, Vojnovic Z, Vasev N, Ma L, Richards DA, Wilks ST, Milenkovic D, Xiao J, Sorrentino J, Horton J, O'Shaughnessy J. Trilaciclib Prior to Chemotherapy in Patients with Metastatic Triple-Negative Breast Cancer: Final Efficacy and Subgroup Analysis from a Randomized Phase II Study. Clin Cancer Res. 2022 Feb 15;28(4):629-636. doi: 10.1158/1078-0432.CCR-21-2272.