Clinical trial NCT03041311: Carboplatin, Etoposide, and Atezolizumab With or Without Trilaciclib (G1T28), a CDK4/6 Inhibitor, in Extensive-Stage SCLC
Official title: Phase 2 Study of Carboplatin, Etoposide, and Atezolizumab With or Without Trilaciclib in Patients With Untreated Extensive-Stage Small Cell Lung Cancer (SCLC)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Small Cell Lung Cancer
Keywords: Small Cell Lung Cancer
CDK4/6 Inhibitor
Immune Checkpoint Inhibitor
Lead sponsor: G1 Therapeutics, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Roche-Genentech
First posted: 2017-02-02
Enrollment: 107
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 antitumor efficacy when administered with carboplatin, etoposide, and atezolizumab (E/P/A) therapy in first line treatment for patients with newly diagnosed extensive-stage SCLC.

The study was a randomized, double-blinded, placebo-controlled design. Approximately, 100 patients were randomized to trilaciclib + E/P/A or placebo + E/P/A in the study.

Detailed description: The posted results represent the final results from Study G1T28-05, a Phase 2 study of carboplatin, etoposide, and atezolizumab with or without trilaciclib (G1T28) in patients with untreated extensive-stage small cell lung cancer (SCLC).

The final myelopreservation efficacy results are from database lock 1 (data cut-off \[DCO\] 17 Aug 2018). The final anti-tumor efficacy data (BOR, DOR, PFS) are from a second database lock 2 (DCO 28 June 2019) that occurred to support the trilaciclib New Drug Application (NDA). Final overall survival and safety data are reported from the final study database lock (DCO 11 Dec 2020, last patient last visit date of 29 October 2020).

Please note the last patient last visit date description above which is recorded as the study completion date. Following the last patient last visit, the final database lock occurred a few weeks later which accounts for the discrepancy between the study completion date and the reported assessment time frames.

Eligibility criteria: Key Inclusion Criteria:

* Male or female subjects aged ≥18 years
* Unequivocally confirmed diagnosis of SCLC by histology or cytology, preferably including the presence of neuroendocrine features by immunohistochemistry
* Extensive-stage SCLC
* At least 1 target lesion that is measurable by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
* Adequate organ function
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2
* Predicted life expectancy of ≥3 months
* Able to understand and sign an informed consent

Exclusion Criteria:

* Limited-stage SCLC
* Prior chemotherapy for limited or extensive-stage SCLC
* Prior treatment with immunotherapies including but not limited to cluster of differentiation 137 agonists or immune checkpoint blockade therapies (such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1(PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapeutic antibodies).
* Presence of symptomatic brain metastases requiring immediate treatment with radiation therapy or steroids.
* Malignancies other than SCLC within 3 years prior to randomization, with the exception of those with negligible risk of metastasis or death treated with expected curative outcome
* History of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
* Active, known, suspected autoimmune disease requiring systemic treatment in the past 2 years
* Uncontrolled ischemic heart disease or uncontrolled symptomatic congestive heart failure
* Known history of stroke or cerebrovascular accident within 6 months prior to enrollment
* Serious active infection at the time of enrollment
* Psychiatric illness/social situations that would limit study compliance
* Other uncontrolled serious chronic disease or conditions that in the investigator's opinion could affect compliance or follow-up in the protocol
* Known human immunodeficiency virus, known active hepatitis B, or hepatitis C
* Radiotherapy to any site or radiotherapy within 2 weeks prior to enrollment
* Receipt of any investigational medication within 4 weeks prior to enrollment
* Administration of attenuated vaccine within 4 weeks before enrollment or anticipation that such a live attenuated vaccine will be required during the study
* Influenza vaccination should be given during influenza season only (approx. Oct to March). Patients must not receive live, attenuated influenza vaccine (eg, FluMist) within 4 weeks prior to enrollment at any time during the study, and at least 5 months after the last dose of atezolizumab.
* Patients with a condition requiring systemic treatment with either corticosteroids ( \> 10 mg daily prednisone equivalents) or other immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 14 days of study drug administration. Inhaled or topical steroids ad adrenal replacement dosed \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
* Hypersensitivity to any of the components of the formulation of etoposide or etoposide phosphate
* Hypersensitivity to carboplatin or other platinum-containing compounds or to mannitol
* History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
* Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
* Legal incapacity or limited legal capacity
* Pregnant or lactating women

Primary outcomes:
measure: Duration of Severe (Grade 4) Neutropenia in Cycle 1
timeFrame: Evaluated for Cycle 1 of the Induction Period (i.e., from randomization to the end of Cycle 1, each cycle = 21 days).
measure: Number of Participants With at Least 1 Occurrence of Severe (Grade 4) Neutropenia
timeFrame: Induction Period. From date of randomization, 21 day treatment cycles up to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.
Secondary outcomes:
measure: All-Cause Dose Reductions
timeFrame: Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.
measure: Number of Participants With at Least 1 Occurrence of RBC Transfusion on/After Week 5 (Proportion of Patients)
timeFrame: Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 374 days.
measure: Occurrence of Granulocyte Colony-Stimulating Factor (G-CSF) Administration (Proportion of Patients)
timeFrame: Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.
measure: Overall Survival (OS)
timeFrame: From date of randomization to date of death due to any cause, assessed up to a maximum of 38.1 months.
measure: Major Adverse Hematologic Events (MAHE) (Composite Endpoint)
timeFrame: Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.
measure: Best Overall Response
timeFrame: From date of randomization, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 724 days.
measure: Duration of Objective Response (Complete Response or Partial Response)
timeFrame: From date of randomization, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 724 days.
measure: Progression-Free Survival
timeFrame: From date of randomization, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 724 days.
measure: Number of Participants With at Least 1 Occurrence of Febrile Neutropenia
timeFrame: Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.
measure: Number of Participants With at Least 1 Occurrence of Grade 3 or 4 Hematologic Laboratory Abnormalities
timeFrame: Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.
measure: Number of Participants With at Least 1 Occurrence of Erythropoiesis Stimulating Agent (ESA) Administration
timeFrame: Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.
measure: Number of Participants With at Least 1 Occurrence of Platelet Transfusion
timeFrame: Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.
measure: Number of Participants With at Least 1 Occurrence of Infection Serious Adverse Events (SAEs)
timeFrame: Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.
measure: Number of Participants With at Least 1 Occurrence of Pulmonary Infection Serious Adverse Events (SAEs)
timeFrame: Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.
measure: Number of Participants With at Least 1 Occurrence of IV Antibiotic Uses
timeFrame: Induction Period. From date of randomization, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.
measure: Duration of Study Drug Exposure (Induction Period and Maintenance Period)
timeFrame: From date of first dose, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 1162 days.
measure: Number of Cycles Completed (Induction Period and Maintenance Period)
timeFrame: From date of first dose, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 49 cycles.
measure: Relative Dose Intensity of Trilaciclib/Placebo, Carboplatin, Etoposide, Atezolizumab (Induction Period) and Atezolizumab (Maintenance Period)
timeFrame: From date of first dose, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 724 days.
measure: Number of Participants With Any Cycle Delays and the Number of Cycles Delayed (Induction Period)
timeFrame: Induction Period. From date of first dose, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.
measure: Number of Participants With Any Cycle Delays and the Number of Cycles Delayed (Maintenance Period)
timeFrame: Maintenance Period. From date of first maintenance dose, 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 1160 days.
measure: Number of Participants With Any Missed Doses [for Each Study Drug: Trilaciclib/Placebo, Carboplatin and Etoposide] (Induction Period)
timeFrame: Induction Period. From date of first dose, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.
measure: Number of Participants With Any Missed Doses of Atezolizumab (Overall Treatment Period)
timeFrame: From date of first dose, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 1162 days.
measure: Number of Participants With Any Dose Interruptions [for Each Study Drug: Trilaciclib/Placebo, Carboplatin and Etoposide] (Induction Period)
timeFrame: Induction Period. From date of first dose, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.
measure: Number of Participants With Any Interrupted Doses of Atezolizumab (Overall Treatment Period)
timeFrame: From date of first dose, up to four 21-day cycles of Induction therapy, followed by 21 day cycles of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the patient or investigator, assessed up to 1162 days.
measure: Number of Participants With Any Dose Reductions of Carboplatin and Etoposide (Induction Period)
timeFrame: Induction Period. From date of first dose, 21 day treatment cycles to a maximum of 4 cycles or until (if earlier) disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 409 days.
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: Beverly Hills Cancer Center
state: California
city: Fullerton
country: United States
facility: St. Jude Heritage Healthcare
state: California
city: Loma Linda
country: United States
facility: Loma Linda University
state: California
city: Santa Monica
country: United States
facility: UCLA Medical Center - Santa Monica Hematology And Oncology
state: California
city: Santa Rosa
country: United States
facility: Redwood Regional Medical Group (RRMG) - Fountain Grove
state: California
city: Whittier
country: United States
facility: Singing River Health System
state: California
city: Atlanta
country: United States
facility: Piedmont Cancer Institute
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital - Georgia Cancer Specialists
state: Georgia
city: Joliet
country: United States
facility: Joliet Oncology-Hematology Associates
state: Illinois
city: Lafayette
country: United States
facility: Horizon Oncology Center
state: Indiana
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Bridgeton
country: United States
facility: St. Louis Cancer Care, LLP, North County
state: Missouri
city: Saint Louis
country: United States
facility: The Alvin J. Siteman Cancer Center - Center for Advanced Med
state: Missouri
city: Morristown
country: United States
facility: Summit Medical Group, P.A.
state: New Jersey
city: Mount Kisco
country: United States
facility: Northern Westchester Hospital
state: New York
city: Minot
country: United States
facility: Trinity Health - Trinity CancerCare Center
state: North Dakota
city: Oklahoma City
country: United States
facility: Oklahoma University - Peggy and Charles Stephenson Cancer Center
state: Oklahoma
city: Spartanburg
country: United States
facility: Gibbs Cancer Center
state: South Carolina
city: Harlingen
country: United States
facility: Valley Cancer Associates
state: Texas
city: Houston
country: United States
facility: Millennium Oncology
state: Texas
city: Arlington
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Blacksburg
country: United States
facility: Blue Ridge Cancer Care
state: Virginia
city: Fort Belvoir
country: United States
facility: Fort Belvoir Community Hospital
state: Virginia
city: Burgas
country: Bulgaria
facility: Complex Oncology Center - Burgas
city: Sofia
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment "Serdika", Sofia
city: Sofia
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment "Serdika"
city: Tallinn
country: Estonia
facility: East Tallinn Central Hospital Ltd., Clinic of Internal Medicine, Center for Oncology
city: Caen
country: France
facility: CHU Caen De La Côte De Nacre
city: Lille
country: France
facility: Centre Oscar Lambret
city: Daugavpils
country: Latvia
facility: Daugavpils Regional Hospital, Department of Oncology
city: Riga
country: Latvia
facility: Pauls Stradiņš Clinical University Hospital, Oncology Clinic
city: Palma
country: Spain
facility: Hospital Universitario Son Espases
state: Islas Baleares
city: A Coruña
country: Spain
facility: Hospital Teresa Herrera
state: La Coruña
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda
state: Madrid
city: San Carlos
country: Spain
facility: Hospital Clínico
state: Madrid
city: Barcelona
country: Spain
facility: H.U. Quirón Dexeus, Hospital Universitario
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona- Servicio de Oncología Médica
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: San Sebastián
country: Spain
facility: H. Donostia, Hospital Donostia- Servicio de Oncología
city: Sevilla
country: Spain
facility: Hospital Universitario Ntra. Sra. de Valme
city: Valencia
country: Spain
facility: Hospital Arnau de Vilanova
city: Chernivtsi
country: Ukraine
facility: Chernivtsi Regional Clinical Oncology Center
city: Dnipro
country: Ukraine
facility: Dnipropetrovsk City Multispecialty Clinical Hospital #4
city: Lviv
country: Ukraine
facility: Lviv State Regional Treatment and Diagnostics Oncology Center
Study officials:
affiliation: G1 Therapeutics, Inc.
name: Clinical Contact
role: STUDY_DIRECTOR
References:
citation: Daniel D, Kuchava V, Bondarenko I, Ivashchuk O, Reddy S, Jaal J, Kudaba I, Hart L, Matitashvili A, Pritchett Y, Morris SR, Sorrentino JA, Antal JM, Goldschmidt J. Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: A multicentre, randomised, double-blind, placebo-controlled Phase II trial. Int J Cancer. 2021 May 15;148(10):2557-2570. doi: 10.1002/ijc.33453. Epub 2021 Jan 12.
citation: Weiss J, Goldschmidt J, Andric Z, Dragnev KH, Gwaltney C, Skaltsa K, Pritchett Y, Antal JM, Morris SR, Daniel D. Effects of Trilaciclib on Chemotherapy-Induced Myelosuppression and Patient-Reported Outcomes in Patients with Extensive-Stage Small Cell Lung Cancer: Pooled Results from Three Phase II Randomized, Double-Blind, Placebo-Controlled Studies. Clin Lung Cancer. 2021 Sep;22(5):449-460. doi: 10.1016/j.cllc.2021.03.010. Epub 2021 Mar 26.
citation: Abraham I, Onyekwere U, Deniz B, Moran D, Chioda M, MacDonald K, Huang H. Trilaciclib and the economic value of multilineage myeloprotection from chemotherapy-induced myelosuppression among patients with extensive-stage small cell lung cancer treated with first-line chemotherapy. J Med Econ. 2021 Nov;24(sup1):71-83. doi: 10.1080/13696998.2021.2014163.
citation: Zeng R, Liu F, Fang C, Yang J, Luo L, Yue P, Gao B, Dong Y, Xiang Y. PIV and PILE Score at Baseline Predict Clinical Outcome of Anti-PD-1/PD-L1 Inhibitor Combined With Chemotherapy in Extensive-Stage Small Cell Lung Cancer Patients. Front Immunol. 2021 Oct 29;12:724443. doi: 10.3389/fimmu.2021.724443. eCollection 2021.
citation: Hussein M, Maglakelidze M, Richards DA, Sabatini M, Gersten TA, Lerro K, Sinielnikov I, Spira A, Pritchett Y, Antal JM, Malik R, Beck JT. Myeloprotective Effects of Trilaciclib Among Patients with Small Cell Lung Cancer at Increased Risk of Chemotherapy-Induced Myelosuppression: Pooled Results from Three Phase 2, Randomized, Double-Blind, Placebo-Controlled Studies. Cancer Manag Res. 2021 Aug 9;13:6207-6218. doi: 10.2147/CMAR.S313045. eCollection 2021.
citation: Ferrarotto R, Anderson I, Medgyasszay B, Garcia-Campelo MR, Edenfield W, Feinstein TM, Johnson JM, Kalmadi S, Lammers PE, Sanchez-Hernandez A, Pritchett Y, Morris SR, Malik RK, Csoszi T. Trilaciclib prior to chemotherapy reduces the usage of supportive care interventions for chemotherapy-induced myelosuppression in patients with small cell lung cancer: Pooled analysis of three randomized phase 2 trials. Cancer Med. 2021 Sep;10(17):5748-5756. doi: 10.1002/cam4.4089. Epub 2021 Aug 18.