Clinical trial NCT02499770: Trilaciclib (G1T28), a CDK 4/6 Inhibitor, in Combination With Etoposide and Carboplatin in Extensive Stage Small Cell Lung Cancer (SCLC)
Official title: Phase 1b/2a Safety and Pharmacokinetic Study of G1T28 in Patients With Extensive Stage Small Cell Lung Cancer (SCLC) Receiving Etoposide and Carboplatin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Small Cell Lung Cancer
Keywords: Small Cell Lung Cancer
CDK 4/6 Inhibitor
Lead sponsor: G1 Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2015-07-16
Enrollment: 122
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 is 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 etoposide in first line treatment for patients with newly diagnosed extensive-stage SCLC.

The study consists of 2 parts: a limited open-label, dose-finding portion (Part 1), and a randomized double-blind portion (Part 2). Both parts include 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. Approximately, 90 patients will be enrolled in the study; 20 patients in the Part 1 and 70 patients in the Part 2 portion.


Eligibility criteria: 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
* At least 1 target lesion that is unirradiated and measurable by RECIST, Version 1.1
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2
* Adequate organ function

Exclusion Criteria:

* Prior chemotherapy for extensive-stage SCLC
* Presence of symptomatic brain metastases requiring immediate treatment with radiation therapy or steroids.
* Uncontrolled ischemic heart disease or uncontrolled symptomatic congestive heart failure
* Known history of stroke or cerebrovascular accident within 6 months prior to enrollment
* Other uncontrolled serious chronic disease or conditions that in the investigator's opinion could affect compliance or follow-up in the protocol
* Concurrent radiotherapy to any site or radiotherapy within 2 weeks prior to enrollment or previous radiotherapy to the target lesion sites (the sites that are to be followed for determination of a response)
* Receipt of any investigational medication within 4 weeks prior to enrollment

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1
timeFrame: Days 1-21 of Cycle 1
measure: Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1
timeFrame: TEAEs were any AE that started on or after the first dose of study drug and up to the last dose +30 days (a minimum of 51 days up to a maximum of 374 days)
measure: Duration of Severe (Grade 4) Neutropenia in Part 2
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of Trilaciclib in Cycle 1, Part 1
timeFrame: Days 1 and 3 of Cycle 1 for a 21-day cycle
measure: Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Trilaciclib in Cycle 1, Part 1
timeFrame: Days 1 and 3 of Cycle 1 for a 21-day cycle
measure: Time of Maximum Observed Concentration (Tmax) of Trilaciclib in Cycle 1, Part 1
timeFrame: Days 1 and 3 of Cycle 1 for a 21-day cycle
measure: Cmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1
timeFrame: Days 1 and 3 of Cycle 1 for a 21-day cycle (carboplatin was only dosed on Day 1 so there are no Day 3 Cmax values)
measure: AUC0-inf of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1
timeFrame: Days 1 and 3 of Cycle 1 for a 21-day cycle (carboplatin was only dosed on Day 1 so there are no Day 3 AUC0-inf values)
measure: Tmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1
timeFrame: Days 1 and 3 of Cycle 1 for a 21-day cycle (carboplatin was only dosed on Day 1 so there are no Day 3 Tmax values)
measure: Duration of Severe (Grade 4) Neutropenia in Part 1
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Occurrence of Severe (Grade 4) Neutropenia in Part 1
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Occurrence of Febrile Neutropenia in Part 1
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Duration of Grade 3/4 Neutropenia in Part 1
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Occurrence of Grade 3/4 Neutropenia in Part 1
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Nadir of Absolute Neutrophil Count in Cycle 1, Part 1
timeFrame: From baseline to the end of Cycle 1
measure: Occurrence of Granulocyte-Colony Stimulating Factor (G-CSF) Administration in Part 1
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Occurrence of Red Blood Cell (RBC) Transfusion in Part 1
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Change From Baseline of Hemoglobin at the End of Cycle 6, Part 1
timeFrame: Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6
measure: Occurrence of Erythropoietin Stimulating Agent (ESA) Administration in Part 1
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Occurrence of Platelet Transfusion in Part 1
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Change From Baseline of Platelet Count at the End of Cycle 6, Part 1
timeFrame: Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6
measure: Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 1
timeFrame: Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6
measure: Occurrence of Dose Reduction in Part 1
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Occurrence of Infectious SAEs in Part 1
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Occurrence of Pulmonary Infection SAE in Part 1
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Occurrence of IV Antibiotic Administration in Part 1
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Time to First Major Adverse Hematologic Event (MAHE) in Part 1
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Best Overall Tumor Response Based on Assessments in Part 1
timeFrame: Baseline, end of every two 21-day cycles, up until disease progression to a maximum of the time at least 70% overall survival (OS) events observed (a maximum of 4 years)
measure: Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1
timeFrame: Baseline, end of every two 21-day cycles, up until disease progression to a maximum of the time at least 70% OS events observed (a maximum of 4 years)
measure: Progression Free Survival (PFS) Based on Assessments in Part 1
timeFrame: Baseline, end of every two 21-day cycles, up until disease progression to a maximum of the time at least 70% OS events observed (a maximum of 4 years)
measure: OS in Part 1
timeFrame: Baseline up until death or a maximum of the time at least 70% OS events observed (a maximum of 4 years)
measure: Occurrence of Severe (Grade 4) Neutropenia in Part 2
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Occurrence of Febrile Neutropenia in Part 2
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Duration of Grade 3/4 Neutropenia in Part 2
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Occurrence of Grade 3/4 Neutropenia in Part 2
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Nadir of Absolute Neutrophil Count in Cycle 1, Part 2
timeFrame: From baseline to the end of Cycle 1
measure: Occurrence of G-CSF Administration in Part 2
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Occurrence of RBC Transfusion in Part 2
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Change From Baseline of Hemoglobin at the End of Cycle 6, Part 2
timeFrame: Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6
measure: Occurrence of ESA Administration in Part 2
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Occurrence of Platelet Transfusion in Part 2
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Change From Baseline of Platelet Count at the End of Cycle 6, Part 2
timeFrame: Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6
measure: Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 2
timeFrame: Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6
measure: Occurrence of Dose Reduction in Part 2
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Occurrence of Infectious SAEs in Part 2
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Occurrence of Pulmonary Infection SAE in Part 2
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Occurrence of IV Antibiotic Administration in Part 2
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Time to First MAHE in Part 2
timeFrame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
measure: Best Overall Tumor Response Based on Assessments in Part 2
timeFrame: Baseline, end of every two 21-day cycles, up until disease progression to a maximum of the time at least 70% OS events observed (a maximum of 4 years)
measure: Best Overall Tumor Response Based on BICR Assessments in Part 2
timeFrame: Baseline, end of every two 21-day cycles, up until disease progression to a maximum of the time at least 70% OS events observed (a maximum of 4 years)
measure: PFS Based on Assessments in Part 2
timeFrame: Baseline, end of every two 21-day cycles, up until disease progression to a maximum of the time at least 70% OS events observed (a maximum of 4 years)
measure: OS in Part 2
timeFrame: Baseline up until death or a maximum of the time at least 70% OS events observed (a maximum of 4 years)
Other outcomes:
Locations:
city: Hot Springs
country: United States
facility: Genesis Cancer Center
state: Arkansas
city: Rogers
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Whittier
country: United States
facility: The Oncology Institute of Hope and Innovation
state: California
city: Colorado Springs
country: United States
facility: Memorial Hospital - Univ. of Colorado Health
state: Colorado
city: Fort Collins
country: United States
facility: University of Colorado Health, Oncology Clinical Research Northern Region
state: Colorado
city: Boca Raton
country: United States
facility: Boca Raton Regional Hospital - Lynn Cancer Institute
state: Florida
city: Fort Myers
country: United States
facility: Florida Cancer Specialists - South
state: Florida
city: Tavares
country: United States
facility: Florida Cancer Specialists - North
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists - East
state: Florida
city: Athens
country: United States
facility: University Cancer and Blood Center, LLC
state: Georgia
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Bethesda
country: United States
facility: Center For Cancer and Blood Disorders
state: Maryland
city: Lebanon
country: United States
facility: Norris Cotton Cancer Center
state: New Hampshire
city: Albuquerque
country: United States
facility: University of New Mexico Comprehensive Cancer Center
state: New Mexico
city: Buffalo
country: United States
facility: Roswell Park
state: New York
city: Chapel Hill
country: United States
facility: UNC - Lineberger Comprehensive Cancer Center
state: North Carolina
city: Oklahoma City
country: United States
facility: Oklahoma University - Peggy and Charles Stephenson Cancer Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Sayre
country: United States
facility: Guthrie Medical Group, PC
state: Pennsylvania
city: Greenville
country: United States
facility: Greenville Health System
state: South Carolina
city: Spartanburg
country: United States
facility: Gibbs Cancer Center
state: South Carolina
city: Knoxville
country: United States
facility: Tennessee Cancer Specialists
state: Tennessee
city: Knoxville
country: United States
facility: Hanna Cancer Associates - University of Tennessee
state: Tennessee
city: Tyler
country: United States
facility: Texas Oncology
state: Texas
city: Vancouver
country: United States
facility: Northwest Cancer Specialists, P.C.
state: Washington
city: Rennes
country: France
facility: CHU de Rennes Hopital Pontchaillou
city: Tbilisi
country: Georgia
facility: ARENSIA Exploratory Medicine LLC
city: Farkasgyepu
country: Hungary
facility: Veszprem Megyei Tudogyogyintezet
state: Veszprem
city: Budapest
country: Hungary
facility: Orszagos Koranyi Tbc es Pulmonologiai Intezet, XI. Tudobelosztaly
city: Szolnok
country: Hungary
facility: Hetenyi Geza Korhaz
city: Chisinau
country: Moldova, Republic of
facility: ARENSIA Exploratory Medicine Phase I Unit, The Institute of Oncology
city: Olsztyn
country: Poland
facility: Samodzielny Publiczny ZespAA GruAicy i ChorAb PA¿uc
city: Torun
country: Poland
facility: Wojewodzki Szpital Zespolony im. L. Rydygiera
city: Warszawa
country: Poland
facility: Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie
city: Malaga
country: Spain
facility: Hospital Regional Universitario HRU Carlos Haya Malaga
state: Andalucia
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Castillón
country: Spain
facility: Consorcio Hospitalario Provincial
city: Madrid
country: Spain
facility: Hgu Gregorio Maranon
city: Madrid
country: Spain
facility: Fundacion Jimenez Diaz
Study officials:
affiliation: G1 Therapeutics, Inc.
name: Clinical Contact
role: STUDY_DIRECTOR
References:
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.
citation: Li C, Hart L, Owonikoko TK, Aljumaily R, Rocha Lima CM, Conkling PR, Webb RT, Jotte RM, Schuster S, Edenfield WJ, Smith DA, Sale M, Roberts PJ, Malik RK, Sorrentino JA. Trilaciclib dose selection: an integrated pharmacokinetic and pharmacodynamic analysis of preclinical data and Phase Ib/IIa studies in patients with extensive-stage small cell lung cancer. Cancer Chemother Pharmacol. 2021 May;87(5):689-700. doi: 10.1007/s00280-021-04239-9. Epub 2021 Feb 17.
citation: Lai AY, Sorrentino JA, Dragnev KH, Weiss JM, Owonikoko TK, Rytlewski JA, Hood J, Yang Z, Malik RK, Strum JC, Roberts PJ. CDK4/6 inhibition enhances antitumor efficacy of chemotherapy and immune checkpoint inhibitor combinations in preclinical models and enhances T-cell activation in patients with SCLC receiving chemotherapy. J Immunother Cancer. 2020 Oct;8(2):e000847. doi: 10.1136/jitc-2020-000847.
citation: Weiss JM, Csoszi T, Maglakelidze M, Hoyer RJ, Beck JT, Domine Gomez M, Lowczak A, Aljumaily R, Rocha Lima CM, Boccia RV, Hanna W, Nikolinakos P, Chiu VK, Owonikoko TK, Schuster SR, Hussein MA, Richards DA, Sawrycki P, Bulat I, Hamm JT, Hart LL, Adler S, Antal JM, Lai AY, Sorrentino JA, Yang Z, Malik RK, Morris SR, Roberts PJ, Dragnev KH; G1T28-02 Study Group. Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial. Ann Oncol. 2019 Oct 1;30(10):1613-1621. doi: 10.1093/annonc/mdz278.