Clinical trial NCT02514447: Trilaciclib (G1T28) in Patients With Previously Treated Extensive Stage SCLC Receiving Topotecan Chemotherapy
Official title: Phase 1b/2a Safety and Pharmacokinetic Study of G1T28 in Patients With Previously Treated Extensive Stage Small Cell Lung Cancer (SCLC) Receiving Topotecan Chemotherapy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Small Cell Lung Cancer
Keywords: SCLC
CDK4/6 Inhibitor
Lead sponsor: G1 Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2015-08-03
Enrollment: 123
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), a Cyclin Dependent Kinase (CDK) 4/6 inhibitor, in preserving the bone marrow and the immune system, in order to decrease chemotherapy-induced myelosuppression and improve anti-tumor efficacy when administered prior to topotecan in patients previously treated for extensive-stage SCLC.

The study consisted of 2 parts: a limited open-label, dose-finding portion (Part 1), and a randomized double-blind portion (Part 2). Both parts included 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.

Detailed description: Overall, up to 130 patients were planned to be enrolled in the study. In Part 1, approximately 40 patients were planned to be enrolled, assuming 9 to 10 cohorts. Part 1 was open-label, and no randomization or blinding was required. In Part 2A, approximately 45 patients were to be enrolled and randomly assigned (2:1) to trilaciclib (240 mg/m2) and topotecan (0.75 mg/m2) or placebo and topotecan (1.5 mg/m2). In Part 2B, approximately 45 patients were to be enrolled and randomly assigned (2:1) to trilaciclib (240 mg/mg2) and topotecan (1.5 mg/m2) or placebo and topotecan (1.5 mg/m2).

Patients who received placebo in Part 2A and Part 2B were to be combined into a single placebo group for the analysis to compare with trilaciclib+topotecan 1.5 mg/m2 with placebo + topotecan 1.5 mg/m2 (proximately 30 per treatment group).

The sample size calculation was to demonstrate the superiority of trilaciclib + topotecan 1.5 mg/m2 over placebo + topotecan 1.5 mg/m2 with respect to at least 1 of the primary endpoints. The overall type I error rate was 1-sided 0.10. Using the most conservative Bonferroni procedure for the 2 primary endpoints, a 1-sided individual type I error rate 0.10/2=0.05 was assigned to each outcome variable (DSN in Cycle 1 and occurrence of SN) in the sample size calculation. Assuming a common standard deviation of 2.5, a difference in the duration of SN in Cycle 1 of at least 2 days between the treatment groups, a sample size of 28 per arm was required to have 90% power to detect the assumed treatment effect. For occurrence of SN, assuming the event rate was 45% for placebo group, to detect an absolute reduction of 37% by trilaciclib group with 90% power would require a sample size of at least 29 per arm. Thus, 30 per arm was needed to ensure 90% power to detect assumed treatment effect for DSN in Cycle 1 and occurrence of SN. All calculations were carried out using the POWER procedure in SAS®, Version 9.4 procedure in SAS®, Version 9.4 or higher.

The results from endpoints that were commonly collected at Part 1 and part 2 are presented together in this report.

The posted results represent the final results of Study G1T28-03, a Phase 1b/2a safety and pharmacokinetic (PK) study of trilaciclib (G1T28) in patients with previously treated extensive-stage small cell lung cancer (SCLC) receiving topotecan chemotherapy in the second/third-line (2/3L) setting. The final myelopreservation efficacy results for both parts and exposure for Part 1 are from database lock 1 (data cut-off \[DCO\] for Primary Completion Date \[PCD\] 28 September 2018). The final anti-tumor efficacy (BOR, DOR, PFS) for both parts, final overall survival for Part 1 and exposure data from Part 2 are from a second database lock 2 (DCO 31 May 2019) and the final overall survival for Part 2 and safety (adverse events) are through the end of the study on October 4, 2021 which resulted in the final database lock (DCO 01 Nov 2021).

The maximum time frames provided reflect the time from when the first patient could be evaluated for an endpoint (ie. date of first dose of first patient) to the time when the data from both parts presented for that endpoint was considered final.

Eligibility criteria: Key Inclusion Criteria:

* Male or female subjects aged ≥18 years
* Confirmed diagnosis of SCLC by histology or cytology, preferably including the presence of neuroendocrine features by immunohistochemistry
* Progression during or after prior first- or second-line chemotherapy and eligible to receive topotecan therapy
* At least 1 target lesion that is measurable by RECIST, Version 1.1
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2
* Adequate organ function

Key Exclusion Criteria:

* Presence of 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
* Receipt of any systemic chemotherapy regimen within 4 weeks prior to enrollment or a noncytotoxic investigational medication within 2 weeks prior to enrollment
* History of topotecan treatment for SCLC

Primary outcomes:
measure: Duration of Severe (Grade 4) Neutropenia in Cycle 1
timeFrame: Evaluated for Cycle 1 (i.e., from date of first dose of study drug (Part 1)/randomization (Part 2) to the end of Cycle 1, each cycle = 21 days)
measure: Occurrence of Severe (Grade 4) Neutropenia
timeFrame: During the treatment period. From date of first dose (Part 1)/randomization (Part 2), 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator (assessed up to 1090 days).
measure: Assess the Dose Limiting Toxicities (DLTs) of G1T28/Trilaciclib Administered With Topotecan in Part 1
timeFrame: Evaluated for Cycle 1 (i.e., from date of first dose of study drug (Part 1) to the end of Cycle 1, each cycle = 21 days)
Secondary outcomes:
measure: Pharmacokinetic Profile for Trilaciclib (G1T28) When Administered With Topotecan
timeFrame: Part 1 of the study during Cycle 1 Day 4 : predose, 0.5, 1, 1.5, 2, 2.5, 3, 4.5, 6.5, 8.5 (optional), and 24.5 hours post dose. Part 2 of the study during Cycle 1 Day 4 : predose, 0.5, 1, between 3 to 4 hours and between 5.5 to 6.5 hours post dose.
measure: Progression Free Survival (PFS)
timeFrame: From date of first dose of study drug (Part 1)/randomization (Part 2), until date of documented disease progression or death due to any cause (evaluated up to a maximum of 1335 days).
measure: Overall Survival (OS)
timeFrame: From date of first dose of study drug (Part 1)/randomization (Part 2) until the date of death due to any cause (evaluated up to a maximum of 2220 days).
measure: Assess the Hematologic Profile of G1T28/Trilaciclib Administered With Topotecan
timeFrame: During the treatment period. From date of first dose (Part 1)/randomization (Part 2), 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator (assessed up to 1090 days).
measure: Tumor Response Based on RECIST, Version 1.1
timeFrame: From date of first dose of study drug (Part 1)/randomization (Part 2) until the occurrence of progressive disease, withdrawal of consent, or initiation of subsequent anti-cancer therapy, (assessed up to a maximum of 1335 days).
measure: Occurrence of RBC Transfusions
timeFrame: During the treatment period. From date of first dose (Part 1)/randomization (Part 2), 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator (assessed up to 1056 days).
measure: Need for Treatment With Hematopoietic Growth Factors
timeFrame: During the treatment period. From date of first dose (Part 1)/randomization (Part 2), 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator (assessed up to 1090 days).
measure: Chemotherapy Cycles and Modifications Overall
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 1335 days).
measure: Pharmacokinetic Profile for Topotecan When Administered With Trilaciclib (G1T28)
timeFrame: Part 1 of the study during Cycle 1 Day 4 : predose, 0.5, 1, 1.5, 2, 2.5, 3, 4.5, 6.5, 8.5 (optional), and 24.5 hours post dose. Part 2 of the study during Cycle 1 Day 4 : predose, 0.5, 1, between 3 to 4 hours and between 5.5 to 6.5 hours post dose.
measure: Duration of Response (DOR)
timeFrame: From date of first dose of study drug (Part 1)/randomization (Part 2) until the occurrence of progressive disease, withdrawal of consent, or initiation of subsequent anti-cancer therapy, (assessed up to a maximum of 1335 days).
measure: Occurrence of Intravenous (IV) Antibiotic Use
timeFrame: During the treatment period. From date of first dose (Part 1)/randomization (Part 2), 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator (assessed up to 1090 days).
measure: Occurrence of Platelet Transfusions
timeFrame: During the treatment period. From date of first dose (Part 1)/randomization (Part 2), 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator (assessed up to 1090 days).
measure: Occurrence of Febrile Neutropenia Adverse Events
timeFrame: During the treatment period. From date of first dose (Part 1)/randomization (Part 2), 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator (assessed up to 1090 days).
measure: Occurrence of Infection Serious Adverse Events (SAEs)
timeFrame: During the treatment period. From date of first dose (Part 1)/randomization (Part 2), 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator (assessed up to 1090 days).
measure: Occurrence of Pulmonary Infection Serious Adverse Events (SAEs)
timeFrame: During the treatment period. From date of first dose (Part 1)/randomization (Part 2), 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator (assessed up to 1090 days).
measure: Dose Reductions in Chemotherapy (Topotecan)
timeFrame: During the treatment period. From date of first dose (Part 1)/randomization (Part 2), 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator (assessed up to 1090 days).
measure: Occurrence of Grade 3 and 4 Hematologic Toxicities
timeFrame: During the treatment period. From date of first dose (Part 1)/randomization (Part 2), 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator (assessed up to 1090 days).
measure: Occurrence of Grade 4 and Grade 3/4 Decreased Platelet Count Laboratory Values (Thrombocytopenia)
timeFrame: During the treatment period. From date of first dose (Part 1)/randomization (Part 2), 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator (assessed up to 1090 days).
measure: Occurrence of Erythropoietin-stimulating Agent (ESA) Administrations
timeFrame: During the treatment period. From date of first dose (Part 1)/randomization (Part 2), 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator (assessed up to 1090 days).
measure: Chemotherapy 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 1335 days).
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: Corona
country: United States
facility: Compassionate Cancer Care Medical Group, Inc.
state: California
city: Sacramento
country: United States
facility: Sutter Medical Group
state: California
city: Whittier
country: United States
facility: The Oncology Institute of Hope and Innovation
state: California
city: Colorado Springs
country: United States
facility: Memorial Hospital - University of Colorado Health
state: Colorado
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Fort Collins
country: United States
facility: University of Colorado Health, Oncology Clinical Research Northern Region
state: Colorado
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: Athens
country: United States
facility: University Cancer and Blood Center, LLC
state: Georgia
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital - Georgia Cancer Specialists
state: Georgia
city: Kansas City
country: United States
facility: Saint Luke's Cancer Institute
state: Missouri
city: Lebanon
country: United States
facility: Norris Cotton Cancer Center
state: New Hampshire
city: East Setauket
country: United States
facility: North Shore Hematology Oncology Associates PC
state: New York
city: Wilson
country: United States
facility: Regional Medical Oncology Center
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma University - Peggy and Charles Stephenson Cancer Center
state: Oklahoma
city: Sayre
country: United States
facility: Guthrie Medical Group, PC
state: Pennsylvania
city: Anderson
country: United States
facility: AnMed Health
state: South Carolina
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: Hanna Cancer Associates - University of Tennessee
state: Tennessee
city: Nashville
country: United States
facility: Meharry Medical College
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Dallas
country: United States
facility: Texas Oncology- Baylor Charles A. Sammons Cancer Center
state: Texas
city: Houston
country: United States
facility: M.D. Anderson
state: Texas
city: Houston
country: United States
facility: Millennium Oncology
state: Texas
city: Lubbock
country: United States
facility: Southwest Cancer Center
state: Texas
city: Tyler
country: United States
facility: Texas Oncology
state: Texas
city: Tyler
country: United States
facility: The University of Texas Health Science Center at Tyler
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Vancouver
country: United States
facility: Northwest Cancer Specialists, P.C.
state: Washington
city: Brasschaat
country: Belgium
facility: AZ Klina
city: Banja Luka
country: Bosnia and Herzegovina
facility: University Clinical Centre Banja Luka
city: Sarajevo
country: Bosnia and Herzegovina
facility: University Clinical Centre Sarajevo
city: Osijek
country: Croatia
facility: Clinical Hospital Centre Osijek
city: Zagreb
country: Croatia
facility: University Clinical Hospital Centre " Sestre Milosrdnice"
city: Zagreb
country: Croatia
facility: University Hospital Centre Zagreb, Clinic For Pulmonary Diseases Jordanovac
city: Skopje
country: North Macedonia
facility: University Clinic of Radiotherapy and Oncology Skopje
city: Belgrade
country: Serbia
facility: Clinic for Pulmology, Clinical Centre of Serbia
city: Belgrade
country: Serbia
facility: Clinical Hospital Centre Bezanijska Kosa
city: Belgrade
country: Serbia
facility: Oncology and Radiology Institute of Serbia
city: Nis
country: Serbia
facility: Clinical Center Nis, Clinic for Lung Diseases
city: Sremska Kamenica
country: Serbia
facility: Institute for Pulmonary Diseases of Vojvodina Clinic for Thoracic Oncology
city: Kosice
country: Slovakia
facility: VOU Department of Radiotherapy and Oncology
city: Poprad
country: Slovakia
facility: POKO POPRAD, s.r.o.
city: Golnik
country: Slovenia
facility: University Clinic of Respiratory and Allergic Diseases Golnik
Study officials:
affiliation: G1 Therapeutics, Inc.
name: Clinical Contact
role: STUDY_DIRECTOR
References:
citation: Hart LL, Ferrarotto R, Andric ZG, Beck JT, Subramanian J, Radosavljevic DZ, Zaric B, Hanna WT, Aljumaily R, Owonikoko TK, Verhoeven D, Xiao J, Morris SR, Antal JM, Hussein MA. Myelopreservation with Trilaciclib in Patients Receiving Topotecan for Small Cell Lung Cancer: Results from a Randomized, Double-Blind, Placebo-Controlled Phase II Study. Adv Ther. 2021 Jan;38(1):350-365. doi: 10.1007/s12325-020-01538-0. Epub 2020 Oct 29.
citation: Li C, Horton JK, Sale M, Curd L, Goti V, Tao W, Beelen A. Pharmacokinetic Drug-Drug Interaction Studies Between Trilaciclib and Midazolam, Metformin, Rifampin, Itraconazole, and Topotecan in Healthy Volunteers and Patients with Extensive-Stage Small-Cell Lung Cancer. Clin Drug Investig. 2022 Aug;42(8):679-692. doi: 10.1007/s40261-022-01179-x. Epub 2022 Jul 16.
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.