Trilaciclib, a CDK 4/6 Inhibitor, in Patients Receiving FOLFOXIRI/Bevacizumab for Metastatic Colorectal Cancer (mCRC):
- Conditions
- Colorectal Cancer MetastaticMyelosuppression-AdultChemotherapeutic Toxicity
- Interventions
- Drug: Placebo
- Registration Number
- NCT04607668
- Lead Sponsor
- G1 Therapeutics, Inc.
- Brief Summary
This was a randomized, double-blind, placebo-controlled, global, multicenter, Phase 3 trial evaluating the impact of trilaciclib on myelopreservation and anti-tumor efficacy when administered prior to FOLFOXIRI/bevacizumab in patients with pMMR/MSS mCRC who have not received systemic therapy for metastatic disease.
- Detailed Description
Patients were randomly assigned (1:1) to receive placebo or trilaciclib on Days 1 and 2 administered intravenously (IV) prior to FOLFOXIRI/bevacizumab in 14-day cycles for up to 12 cycles (Induction).
Following completion of Induction, patients continued in Maintenance, where they received trilaciclib or placebo per randomization allocation at study entry. Trilaciclib/placebo will be administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule used during Induction. The patient continued to receive treatment on study until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever occurs first. Treatment cycles occurred consecutively without interruption, except when necessary to manage toxicities or for administrative reasons.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 326
- Age ≥ 18 years of age at the time of signing the informed consent. Patients > 70 years of age must have a G8 Health State Screening Tool (geriatric screening tool) score > 14.
- Proficient mismatch repair/microsatellite stable (pMMR/MSS), histologically or cytologically-confirmed adenocarcinoma of the colon or rectum. Patients with any BRAF or KRAS mutation status (wild type or mutant) are eligible. If historical pMMR/MSS and/or BRAF V600E mutational status are not known, a tumor specimen (archival or fresh biopsy) must be sent for testing and results must be available at the time of randomization in interactive web response system (IWRS). If testing cannot be completed using a standard clinical assay performed institutionally/locally, the tumor specimen may be sent to the Sponsor's designated central laboratory for analysis; only historical KRAS mutational status will be collected (ie, no testing required prior to study entry). Note: Any sample sent for MSS/BRAF analysis will be in addition to that required per Inclusion Criterion 5.
- Unresectable and measurable or metastatic colorectal cancer per RECIST v1.1
- ECOG performance status of 0 to 1
- A formalin-fixed paraffin-embedded (FFPE) tumor specimen (from archival or fresh biopsy) with an associated pathology report documenting pMMR/MSS mCRC must be confirmed to be available to send to the Sponsor for planned retrospective biomarker analyses (tissue requirements are provided in the associated laboratory manual).
- Hemoglobin ≥ 9.0 g/dL in the absence of RBC transfusion or ESA administration within 14 days prior to first dose of trilaciclib/placebo
- Absolute neutrophil count (ANC) ≥ 1.5 × 10^9 /L
- Platelet count ≥ 100 × 10^9 /L
- Estimated glomerular filtration rate (eGFR) ≥ 30 mL/minute/1.73m^2
- Total bilirubin ≤ 1.5 × upper limit of normal (ULN)
- AST, ALT, and alkaline phosphatase ≤ 3 × ULN for patients without liver or bone metastases; AST, ALT and alkaline phosphatase ≤ 5 × ULN in the presence of liver metastases; AST and ALT ≤ 3 x ULN and alkaline phosphatase ≤ 5 × ULN in the presence of bone metastases
- Resolution of nonhematologic toxicities from prior therapy or surgical procedures to ≤ Grade 1 or baseline (except alopecia)
- Urine dipstick protein < 2+. If ≥ 2+ at Screening, then a 24-hour urine collection must be done to demonstrate ≤ 1 g of protein/24 hours
- Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Please see Section 17.4 for detailed instructions on methods of contraception requirements.
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
- Prior systemic therapy for mCRC. Patients who received adjuvant/neoadjuvant therapy (ie, treatment with curative intent) for colorectal cancer are eligible if it has been ≥ 6 months between the last dose of systemic chemotherapy and the date of informed consent.
- Any radiotherapy, chemotherapy, immunotherapy, biologic, investigational, or hormonal therapy for cancer treatment (except for adjuvant hormonal therapy for breast cancer or prostate cancer defined as M0 disease or PSA persistence/recurrence without metastatic disease) within 3 weeks prior to the first dose of trilaciclib/placebo.
- Receipt of any low-dose systemic chemotherapeutic agent (e.g., low-dose methotrexate for rheumatoid arthritis) administered for a nononcologic purpose within 3 weeks prior to the first dose of trilaciclib/placebo.
- Presence of central nervous system (CNS) metastases/leptomeningeal disease requiring immediate treatment with radiation therapy or steroids (i.e., patient must be off steroids administered for brain metastases for at least 14 days prior to the first dose of trilaciclib/placebo).
- QTcF interval > 450 msec (males) or > 470 msec (females) at screening. For patients with ventricular pacemakers, QTcF > 500 msec.
- Personal or family history of long QT syndrome
- Symptomatic peripheral neuropathy
- History of interstitial lung disease (ILD)
- Uncontrolled hypertension (blood pressure ≥ 150/90mm Hg)
- Clinically significant (i.e., active) cardiovascular disease at the time of signing the informed consent; for example cerebrovascular accidents (≤ 6 months before the first dose of trilaciclib/placebo), myocardial infarction (≤ 6 months before the first dose of trilaciclib/placebo), unstable angina, serious cardiac arrhythmia requiring medication, or uncontrolled symptomatic congestive heart failure [Class II or higher as defined by the New York Heart Association [NYHA] functional classification system])
- Serious, non-healing wound, ulcer, or bone fracture
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study.
- Known serious active infection (e.g., human immunodeficiency virus [HIV], hepatitis B or C, tuberculosis, etc.)
- Known Gilbert's Syndrome or homozygous for the UGT1A1*28 allele. UGT1A1 genotyping is not required for this study.
- Chronic inflammatory bowel disease and/or active intestinal obstruction. Patients should not be treated until the intestinal obstruction has resolved.
- Previous history of significant/severe hemorrhage, within 1 month before randomization. History of previous abdominal fistula or gastrointestinal perforation within 6 months before randomization
- Known history of bleeding diathesis or coagulopathy
- INR > 1.5 within 14 days prior to starting study treatment. EXEMPTION: patients on full anticoagulation must have an in-range INR (usually between 2 to 3) if INR is used for monitoring. Any anticoagulation therapy must be at stable dosing prior to enrollment.
- Ongoing or anticipated treatment with potent cytochrome inhibitors CYP450 3A4 (such as ketoconazole) or inducers (such as rifampicin, carbamazepine, phenobarbital, phenytoin or St. John's wort). Irinotecan should not be delivered concurrently.
- Patients with ongoing or anticipated treatment with sorivudine or its chemically related analogues, such as brivudine.
- Chronic, daily treatment with high-dose aspirin (> 325 mg/day)
- Prior allogeneic or autologous hematopoietic stem cell or bone marrow transplantation
- Receipt of any live attenuated vaccines within 4 weeks prior to first dose of study treatment
- Known hypersensitivity to any of the drugs used in this study
- Pregnant or lactating women
- Legal incapacity or limited legal capacity
- Other uncontrolled serious chronic disease or psychiatric condition that in the Investigator's opinion could affect patient safety, compliance, or follow-up in the protocol
- Any contraindications to the administration of FOLFOXIRI and bevacizumab at the discretion of the investigator.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description trilaciclib + FOLFOXIRI/bevacizumab Trilaciclib During Induction the following study drugs are administered on Day 1: Irinotecan - IV, Oxaliplatin - IV, Leucovorin- IV, Fluorouracil - continuous infusion (CI) over 46 to 48 hours beginning on Day 1, Bevacizumab - IV Following completion of Induction, patients will continue in Maintenance, where they will continue to receive trilaciclib per randomization allocation at study entry. Trilaciclib will be administered prior to infusional- 5FU/leucovorin/bevacizumab at the same dose and schedule used during Induction. placebo + FOLFOXIRI/bevacizumab Placebo The subjects in the placebo arm will follow the same schedule as the trilaciclib arm, but will receive placebo instead of trilaciclib.
- Primary Outcome Measures
Name Time Method Duration of Severe Neutropenia (DSN) Cycles 1 to 4 (14-day cycles up to 56 days) The DSN was defined as the number of days for the first severe neutropenia (SN) event in Cycles 1, 2, 3, or 4 for participants who had at least one SN event in the first 4 cycles of Induction. It was calculated as the days from the date of the first absolute neutrophil count (ANC) value of \< 0.5 × 10\^9/L to the date of the first ANC value ≥ 0.5 × 10\^9/L where no additional ANC values \< 0.5 × 10\^9/L were observed for the remainder of that cycle.
Occurrence of Severe Neutropenia (SN) During Induction Induction Period, cycles 1-12 (14-day cycles up to 168 days) Severe neutropenia was defined as the absolute neutrophil count (ANC) laboratory value that met the Common Terminology Criteria for Adverse vents (CTCAE) criteria for ≥ Grade 4 toxicity (ie, ANC \< 0.5 × 10\^9/L in SI Unit)
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) Up to 52 months Overall survival is defined as the time from the date of the first dose of study treatment to the date of death from any cause.
Additional Myelopreservation Measures Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab To assess the effects of trilaciclib on additional measures of the neutrophil lineage compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC as measured by the number of SN events, granulocyte-colony stimulating factor (G-CSF) administration and febrile neutropenia (FN) adverse events (AE)
Red Blood Cell Lineage Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab To assess the effects of trilaciclib on the red blood cell (RBC) lineage compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC by measure of Grade 3 or 4 decreased hemoglobin laboratory values, RBC transfusions on or after Week 5, and erythropoiesis-stimulating agents (ESA) administration
Platelet Lineage Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab To assess the effects of trilaciclib on the platelet lineage compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCR by measure of Grade 3 or 4 decreased platelet count laboratory values and Platelet transfusions.
Multiple Lineage Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab To assess the effects of trilaciclib on multiple lineages compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC by measure of Grade 3 or 4 hematologic lab values.
Standard of Care Dosing Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab To assess the effects of trilaciclib on standard of care dosing compared with placebo in patients receiving FOLFOXIRI/ bevacizumab for pMMR/MSS mCRC by measure of all-cause dose reductions or cycle delays and relative dose intensity for FOLFOXIRI/bevacizumab
Healthcare Utilization Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab To assess the effects of trilaciclib on healthcare utilization compared with placebo in patients receiving FOLFOXIRI/ bevacizumab for pMMR/MSS mCRC by measure of hospitalizations and antibiotic use.
Best Overall Response (BOR) Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab Best overall response (BOR) will be determined using all visit responses prior to or on the date of (i) radiographic disease progression; (ii) withdrawal of consent to obtain scans; (iii) death; (iv) lost to follow-up; or (v) initiation of subsequent anti-cancer therapy other than the study drugs, whichever is earlier will be based on RECIST v1.1.
Objective Response Rate (ORR) Assessed from the day of the first dose of the study drug, through 30 days after the last dose of the study drug, up to 115 weeks ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR) defined as a disappearance of all target lesions with pathological lymph nodes having a reduction in short axis to \<10 mm or Partial Response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions, using the baseline sum diameters as a reference based on RECIST v1.1.
Duration of Objective Response (DOR) Assessed from the day of the first dose of the study drug, through 30 days after the last dose of the study drug, up to 115 weeks DOR is the time between first objective response of CR or PR and the first date that progressive disease is objectively documented or death, whichever comes first.
Progression Free Survival (PFS) Assessed from the day of the first dose of the study drug, through 30 days after the last dose of the study drug, up to 115 weeks PFS is defined as the time from the date of randomization until the date of documented radiologic disease progression per RECIST v1.1 or death due to any cause, whichever comes first.
Quality of Life/ Effects on Chemotherapy-Induced Fatigue Through Induction Period- on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab To assess the effects of trilaciclib on chemotherapy-induced fatigue compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC, as measured by Time To First Confirmed Deterioration of Fatigue (TTCD-fatigue) during Induction, as measured by the FACIT-F (Functional Assessment of Chronic Illness Therapy-Fatigue).
Number of Participants With Reported Adverse Events to Measure Safety and Tolerability Safety was assessed from the day of the first dose of the study drug, through 30 days after the last dose of the study drug, up to 115 weeks To assess the safety and tolerability of trilaciclib compared with placebo in patients receiving FOLFOXIRI/ bevacizumab for pMMR/MSS mCRC by measure of occurrence and severity of AEs by National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, changes in laboratory parameters, vital signs and electrocardiogram (ECG) parameters, grade 3 or 4 abnormalities in chemistry laboratory parameters, and study treatment discontinuation due to AEs.
Trial Locations
- Locations (82)
AZ Oncology Associates - HOPE
🇺🇸Tucson, Arizona, United States
Keck Medical Center of USC Pasadena
🇺🇸Los Angeles, California, United States
Florida Cancer Specialists - Panhandle
🇺🇸Tallahassee, Florida, United States
Northside Hospital - Georgia Cancer Specialists
🇺🇸Atlanta, Georgia, United States
Beverly Hills Cancer Center
🇺🇸Beverly Hills, California, United States
University of Massachusetts Memorial Medical Center
🇺🇸Worcester, Massachusetts, United States
UT Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Bekes Megyei Kozponti Korhaz Pandy Kalman Tagkorhaza
🇭🇺Gyula, Hungary
Hospital Universitario Miguel Servet
🇪🇸Zaragoza, Spain
Treatment-Diagnostic Center of Private Enterprise of PPC Atsynus
🇺🇦Kropyvnytskyi, Ukraine
ASL Regionale Piemonte - Ospedale Santo Spirito Casale Monferrato (Ospedale di Casale Monferrato)
🇮🇹Casale Monferrato, Alessandria, Italy
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Florida Cancer Specialists (South Region)
🇺🇸Fort Myers, Florida, United States
The Oncology Institute of Hope & Innovation\ Innovative Clinical Research Institute
🇺🇸Whittier, California, United States
Florida Cancer Specialists NORTH
🇺🇸Fort Myers, Florida, United States
Illinois Cancer Specialists
🇺🇸Arlington Heights, Illinois, United States
Mid-Florida Hematology & Oncology Centers, P.A.
🇺🇸Orange City, Florida, United States
Florida Cancer Specialists
🇺🇸Saint Petersburg, Florida, United States
Gettysburg Cancer Center
🇺🇸Gettysburg, Pennsylvania, United States
The First Affiliated Hospital of Zhejiang University
🇨🇳Hangzhou, Zhejiang, China
Millennium Oncology
🇺🇸Kingswood, Texas, United States
Inova Schar Cancer Institute
🇺🇸Fairfax, Virginia, United States
Jilin Provincial Tumor Hospital
🇨🇳Changchun, Jilin, China
Henan Cancer Hospital
🇨🇳Zijingshan, Henan, China
Onc and Hem Assoc of SW VA
🇺🇸Roanoke, Virginia, United States
Wuhan Union Hospital
🇨🇳Wuhan, Hubei, China
Jinan Central hospital
🇨🇳Shandong, China
The Affiliated Tumor Hospital of Harbin Medical University
🇨🇳Heilongjiang, China
Orszagos Onkologiai Intezet
🇭🇺Budapest, Hungary
Xuzhou Central hospital
🇨🇳Xuzhou, China
Zhejiang Cancer Hospital
🇨🇳Hangzhou, Zhejiang, China
Zhongshan Hospital Fudan University
🇨🇳Shanghai, China
First Affiliated Hospital of Zhengzhou University
🇨🇳Zhengzhou, China
Bacs-Kiskun Megyei Oktatokorhaz
🇭🇺Kecskemet, Hungary
SzSzB Megyei Korhazak es Egyetemi Oktatokorhaz
🇭🇺Nyiregyhaza, Hungary
Azienda Ospedaliera Universitaria Policlinico Tor Vergata
🇮🇹Rome, Roma, Italy
Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
🇮🇹Cremona, Italy
Azienda Ospedaliera Universitaria Careggi
🇮🇹Firenze, Italy
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
🇮🇹Rome, Roma, Italy
ICO l'Hospitalet - Hospital Duran i Reynals
🇪🇸Barcelona, Spain
Szpitale Pomorskie spółka z ograniczoną odpowiedzialnością
🇵🇱Gdynia, Poland
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Szpital Specjalistyczny im. L.Rydygiera w Krakowie
🇵🇱Krakow, Poland
Centrum Medyczne Pratia Poznan
🇵🇱Skórzewo, Poland
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Hospital Universitario Virgen del Rocio
🇪🇸Sevilla, Spain
Hospital Universitario Lucus Augsti
🇪🇸Lugo, Spain
Hospital Universitari Arnau de Vilanova
🇪🇸Lleida, Spain
Hospital General Universitario Gregorio Marañon
🇪🇸Madrid, Spain
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Hospital Universitario HM Madrid Sanchinarro
🇪🇸Madrid, Spain
CI Cherkasy Regional Oncological Dispensary of CRC
🇺🇦Cherkasy, Ukraine
Dnipropetrovsk City Multispecialty Clinical Hospital #4
🇺🇦Dnipro, Ukraine
Hospital Universitario Puerta de Hierro Majadahonda
🇪🇸Madrid, Spain
Hospital Universitario Virgen Macarena
🇪🇸Sevilla, Spain
Hospital Clinico Universitario de Valencia
🇪🇸Valencia, Spain
MI Regional Clinical Oncologycal Dispensary
🇺🇦Dnipro, Ukraine
Limited Liability Company "Medical Center named by Academician Yuriy Prokopovich Spizhenko"
🇺🇦Kapitanivka, Ukraine
Communal Non-profit Enterprise Regional Center of Oncology, Kharkiv NMU
🇺🇦Kharkiv, Ukraine
CNE Prof. O.O. Shalimov Kharkiv City Clinical Hospital #2 of KCC
🇺🇦Kharkiv, Ukraine
CI Kryvyi Rih Oncological Dispensary of DRC
🇺🇦Kryvyi Rih, Ukraine
Communal Institution Odesa Regional Clinical Hospital; Department of Surgery
🇺🇦Odesa, Ukraine
Medical Center Asklepion LLC
🇺🇦Kyiv, Ukraine
Communal Enterprise Volyn Regional Medical Center of Oncology of Volyn Regional Council
🇺🇦Lutsk, Ukraine
Medical Center of Limited Liability Company Medical Center Concilium Medical
🇺🇦Kyiv, Ukraine
University Hospital of Sumy State University
🇺🇦Sumy, Ukraine
The Christie
🇬🇧Manchester, Greater Manchester, United Kingdom
Barts Hospital
🇬🇧London, Greater London, United Kingdom
CNE CCCH of Uzh CC Oncological Center, Ther Dept, SHEI UNU
🇺🇦Uzhgorod, Ukraine
Royal Free Hospital
🇬🇧London, Greater London, United Kingdom
Velindre Cancer Centre
🇬🇧Cardiff, South Glamorgan, United Kingdom
Georgetown University - Lombardi Comprehensive Cancer Center
🇺🇸Washington, District of Columbia, United States
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
Mrukmed Lekarz Beata Madej Mruk i Partner Spółka Partnerska Oddział nr 1 w Rzeszowie
🇵🇱Rzeszów, Poland
Centrum Zdrowia MDM
🇵🇱Warszawa, Poland
Medical center "Oncolife" LLC
🇺🇦Zaporizhzhia, Ukraine
Boston Medical Center
🇺🇸Boston, Massachusetts, United States
Mayo Clinic - Rochester
🇺🇸Rochester, Minnesota, United States
Comp. Cancer Centers of Nevada
🇺🇸Las Vegas, Nevada, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
Tennessee Oncology
🇺🇸Nashville, Tennessee, United States