Trilaciclib, a CDK 4/6 Inhibitor, in Patients Receiving FOLFOXIRI/Bevacizumab for Metastatic Colorectal Cancer (mCRC):

NCT ID: NCT04607668

Last Updated: 2024-11-26

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 326 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-01-06
• Study Completion Date: 2023-03-31

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.

Conditions

Colorectal Cancer Metastatic; Myelosuppression-Adult; Chemotherapeutic Toxicity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

trilaciclib + FOLFOXIRI/bevacizumab

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.

Group Type: EXPERIMENTAL

Trilaciclib

Intervention Type: DRUG

Trilaciclib diluted in dextrose 5% in water or normal saline (sodium chloride solution 0.9%) administered by IV infusion over approximately 30 (±10) minutes no more than 4 hours prior to each Day 1 chemotherapy administration. Second dose of trilaciclib was administered on Day 2.

placebo + FOLFOXIRI/bevacizumab

The subjects in the placebo arm will follow the same schedule as the trilaciclib arm, but will receive placebo instead of trilaciclib.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Dextrose 5% in water or normal saline (sodium chloride solution 0.9%) administered by IV infusion over 30 (±10) minutes no more than 4 hours prior to each Day 1 chemotherapy administration. Second dose of placebo was administered on Day 2.

Interventions

Trilaciclib

Trilaciclib diluted in dextrose 5% in water or normal saline (sodium chloride solution 0.9%) administered by IV infusion over approximately 30 (±10) minutes no more than 4 hours prior to each Day 1 chemotherapy administration. Second dose of trilaciclib was administered on Day 2.

Intervention Type: DRUG

Placebo

Dextrose 5% in water or normal saline (sodium chloride solution 0.9%) administered by IV infusion over 30 (±10) minutes no more than 4 hours prior to each Day 1 chemotherapy administration. Second dose of placebo was administered on Day 2.

Intervention Type: DRUG

Other Intervention Names

G1T28; CDK 4/6 inhibitor

Eligibility Criteria

Inclusion Criteria

1. 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.

2. 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.

3. Unresectable and measurable or metastatic colorectal cancer per RECIST v1.1

4. ECOG performance status of 0 to 1

5. 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).

6. Hemoglobin ≥ 9.0 g/dL in the absence of RBC transfusion or ESA administration within 14 days prior to first dose of trilaciclib/placebo

7. Absolute neutrophil count (ANC) ≥ 1.5 × 10^9 /L

8. Platelet count ≥ 100 × 10^9 /L

9. Estimated glomerular filtration rate (eGFR) ≥ 30 mL/minute/1.73m^2

10. Total bilirubin ≤ 1.5 × upper limit of normal (ULN)

11. 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

12. Resolution of nonhematologic toxicities from prior therapy or surgical procedures to ≤ Grade 1 or baseline (except alopecia)

13. 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

14. 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.

15. 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.

Exclusion Criteria

1. 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.

2. 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.

3. 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.

4. 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).

5. QTcF interval > 450 msec (males) or > 470 msec (females) at screening. For patients with ventricular pacemakers, QTcF > 500 msec.

6. Personal or family history of long QT syndrome

7. Symptomatic peripheral neuropathy

8. History of interstitial lung disease (ILD)

9. Uncontrolled hypertension (blood pressure ≥ 150/90mm Hg)

10. 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])

11. Serious, non-healing wound, ulcer, or bone fracture

12. 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.

13. Known serious active infection (e.g., human immunodeficiency virus [HIV], hepatitis B or C, tuberculosis, etc.)

14. Known Gilbert's Syndrome or homozygous for the UGT1A1*28 allele. UGT1A1 genotyping is not required for this study.

15. Chronic inflammatory bowel disease and/or active intestinal obstruction. Patients should not be treated until the intestinal obstruction has resolved.

16. Previous history of significant/severe hemorrhage, within 1 month before randomization. History of previous abdominal fistula or gastrointestinal perforation within 6 months before randomization

17. Known history of bleeding diathesis or coagulopathy

18. 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.

19. 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.

20. Patients with ongoing or anticipated treatment with sorivudine or its chemically related analogues, such as brivudine.

21. Chronic, daily treatment with high-dose aspirin (> 325 mg/day)

22. Prior allogeneic or autologous hematopoietic stem cell or bone marrow transplantation

23. Receipt of any live attenuated vaccines within 4 weeks prior to first dose of study treatment

24. Known hypersensitivity to any of the drugs used in this study

25. Pregnant or lactating women

26. Legal incapacity or limited legal capacity

27. 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

28. Any contraindications to the administration of FOLFOXIRI and bevacizumab at the discretion of the investigator.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

G1 Therapeutics, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Contact

Role: STUDY_DIRECTOR

G1 Therapeutics, Inc.

Locations

AZ Oncology Associates - HOPE

Tucson, Arizona, United States

Beverly Hills Cancer Center

Beverly Hills, California, United States

Keck Medical Center of USC Pasadena

Los Angeles, California, United States

The Oncology Institute of Hope & Innovation\ Innovative Clinical Research Institute

Whittier, California, United States

Georgetown University - Lombardi Comprehensive Cancer Center

Washington D.C., District of Columbia, United States

Florida Cancer Specialists (South Region)

Fort Myers, Florida, United States

Florida Cancer Specialists NORTH

Fort Myers, Florida, United States

Mid-Florida Hematology & Oncology Centers, P.A.

Orange City, Florida, United States

Florida Cancer Specialists

St. Petersburg, Florida, United States

Florida Cancer Specialists - Panhandle

Tallahassee, Florida, United States

Northside Hospital - Georgia Cancer Specialists

Atlanta, Georgia, United States

Illinois Cancer Specialists

Arlington Heights, Illinois, United States

Boston Medical Center

Boston, Massachusetts, United States

University of Massachusetts Memorial Medical Center

Worcester, 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

Gettysburg Cancer Center

Gettysburg, Pennsylvania, United States

Tennessee Oncology

Nashville, Tennessee, United States

UT Southwestern Medical Center

Dallas, Texas, United States

Millennium Oncology

Kingswood, Texas, United States

Inova Schar Cancer Institute

Fairfax, Virginia, United States

Onc and Hem Assoc of SW VA

Roanoke, Virginia, United States

Henan Cancer Hospital

Zijingshan, Henan, China

Wuhan Union Hospital

Wuhan, Hubei, China

Jilin Provincial Tumor Hospital

Changchun, Jilin, China

The First Affiliated Hospital of Zhejiang University

Hangzhou, Zhejiang, China

Zhejiang Cancer Hospital

Hangzhou, Zhejiang, China

The Affiliated Tumor Hospital of Harbin Medical University

Heilongjiang, , China

Jinan Central hospital

Shandong, , China

Zhongshan Hospital Fudan University

Shanghai, , China

Xuzhou Central hospital

Xuzhou, , China

First Affiliated Hospital of Zhengzhou University

Zhengzhou, , China

Orszagos Onkologiai Intezet

Budapest, , Hungary

Bekes Megyei Kozponti Korhaz Pandy Kalman Tagkorhaza

Gyula, , Hungary

Bacs-Kiskun Megyei Oktatokorhaz

Kecskemét, , Hungary

SzSzB Megyei Korhazak es Egyetemi Oktatokorhaz

Nyíregyháza, , Hungary

ASL Regionale Piemonte - Ospedale Santo Spirito Casale Monferrato (Ospedale di Casale Monferrato)

Casale Monferrato, Alessandria, Italy

Azienda Ospedaliera Universitaria Policlinico Tor Vergata

Rome, Roma, Italy

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Rome, Roma, Italy

Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico

Cremona, , Italy

Azienda Ospedaliera Universitaria Careggi

Florence, , Italy

Szpitale Pomorskie spółka z ograniczoną odpowiedzialnością

Gdynia, , Poland

Szpital Specjalistyczny im. L.Rydygiera w Krakowie

Krakow, , Poland

Mrukmed Lekarz Beata Madej Mruk i Partner Spółka Partnerska Oddział nr 1 w Rzeszowie

Rzeszów, , Poland

Centrum Medyczne Pratia Poznan

Skórzewo, , Poland

Centrum Zdrowia MDM

Warsaw, , Poland

Hospital Universitari Vall d'Hebron

Barcelona, , Spain

Hospital Clinic de Barcelona

Barcelona, , Spain

ICO l'Hospitalet - Hospital Duran i Reynals

Barcelona, , Spain

Hospital Universitari Arnau de Vilanova

Lleida, , Spain

Hospital Universitario Lucus Augsti

Lugo, , Spain

Hospital General Universitario Gregorio Marañon

Madrid, , Spain

Hospital Universitario Ramon y Cajal

Madrid, , Spain

Hospital Universitario 12 de Octubre

Madrid, , Spain

Hospital Universitario La Paz

Madrid, , Spain

Hospital Universitario HM Madrid Sanchinarro

Madrid, , Spain

Hospital Universitario Puerta de Hierro Majadahonda

Madrid, , Spain

Hospital Universitario Virgen Macarena

Seville, , Spain

Hospital Universitario Virgen del Rocio

Seville, , Spain

Hospital Clinico Universitario de Valencia

Valencia, , Spain

Hospital Universitario Miguel Servet

Zaragoza, , Spain

CI Cherkasy Regional Oncological Dispensary of CRC

Cherkasy, , Ukraine

MI Regional Clinical Oncologycal Dispensary

Dnipro, , Ukraine

Dnipropetrovsk City Multispecialty Clinical Hospital #4

Dnipro, , Ukraine

Limited Liability Company "Medical Center named by Academician Yuriy Prokopovich Spizhenko"

Kapitanivka, , Ukraine

CNE Prof. O.O. Shalimov Kharkiv City Clinical Hospital #2 of KCC

Kharkiv, , Ukraine

Communal Non-profit Enterprise Regional Center of Oncology, Kharkiv NMU

Kharkiv, , Ukraine

Treatment-Diagnostic Center of Private Enterprise of PPC Atsynus

Kropyvnytskyi, , Ukraine

CI Kryvyi Rih Oncological Dispensary of DRC

Kryvyi Rih, , Ukraine

Medical Center Asklepion LLC

Kyiv, , Ukraine

Medical Center of Limited Liability Company Medical Center Concilium Medical

Kyiv, , Ukraine

Communal Enterprise Volyn Regional Medical Center of Oncology of Volyn Regional Council

Lutsk, , Ukraine

Communal Institution Odesa Regional Clinical Hospital; Department of Surgery

Odesa, , Ukraine

University Hospital of Sumy State University

Sumy, , Ukraine

CNE CCCH of Uzh CC Oncological Center, Ther Dept, SHEI UNU

Uzhhorod, , Ukraine

Medical center "Oncolife" LLC

Zaporizhzhia, , Ukraine

Barts Hospital

London, Greater London, United Kingdom

Royal Free Hospital

London, Greater London, United Kingdom

The Christie

Manchester, Greater Manchester, United Kingdom

Velindre Cancer Centre

Cardiff, South Glamorgan, United Kingdom

Countries

United States; China; Hungary; Italy; Poland; Spain; Ukraine; United Kingdom

References

Lenz HJ, Liu T, Chen EY, Horvath Z, Bondarenko I, Danielewicz I, Ghidini M, Garcia-Alfonso P, Jones R, Aapro M, Zhang Y, Wang J, Wang W, Adeleye J, Beelen A, Hubbard J. Trilaciclib prior to FOLFOXIRI/bevacizumab for patients with untreated metastatic colorectal cancer: phase 3 PRESERVE 1 trial. JNCI Cancer Spectr. 2025 Jan 3;9(1):pkae116. doi: 10.1093/jncics/pkae116.

Reference Type: DERIVED

PMID: 39579142 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

G1T28-207

Identifier Type: -

Identifier Source: org_study_id