Clinical trial NCT04607668: Trilaciclib, a CDK 4/6 Inhibitor, in Patients Receiving FOLFOXIRI/Bevacizumab for Metastatic Colorectal Cancer (mCRC):
Official title: PRESERVE 1: A Phase 3 Randomized, Double-blind Trial of Trilaciclib Versus Placebo in Patients Receiving FOLFOXIRI/Bevacizumab for Metastatic Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Colorectal Cancer Metastatic
Myelosuppression-Adult
Chemotherapeutic Toxicity
Keywords: Colorectal Cancer
mCRC
colon
chemotherapy-induced myelosuppression
chemotherapy-induced neutropenia
chemotherapy-induced anemia
CDK 4/6 inhibitor
trilaciclib
FOLFOXIRI
bevacizumab
myelosuppression
cyclin-dependent kinase 4/6 inhibitor
myelopreservation
rectum
Preserve
PRESERVE 1
Lead sponsor: G1 Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2020-10-29
Enrollment: 326
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 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.

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.

Primary outcomes:
measure: Duration of Severe Neutropenia (DSN)
timeFrame: Cycles 1 to 4 (14-day cycles up to 56 days)
measure: Occurrence of Severe Neutropenia (SN) During Induction
timeFrame: Induction Period, cycles 1-12 (14-day cycles up to 168 days)
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to 52 months
measure: Additional Myelopreservation Measures
timeFrame: Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
measure: Red Blood Cell Lineage
timeFrame: Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
measure: Platelet Lineage
timeFrame: Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
measure: Multiple Lineage
timeFrame: Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
measure: Standard of Care Dosing
timeFrame: Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
measure: Healthcare Utilization
timeFrame: Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
measure: Best Overall Response (BOR)
timeFrame: Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
measure: Objective Response Rate (ORR)
timeFrame: 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
measure: Duration of Objective Response (DOR)
timeFrame: 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
measure: Progression Free Survival (PFS)
timeFrame: 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
measure: Quality of Life/ Effects on Chemotherapy-Induced Fatigue
timeFrame: Through Induction Period- on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
measure: Number of Participants With Reported Adverse Events to Measure Safety and Tolerability
timeFrame: 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
Other outcomes:
Locations:
city: Tucson
country: United States
facility: AZ Oncology Associates - HOPE
state: Arizona
city: Beverly Hills
country: United States
facility: Beverly Hills Cancer Center
state: California
city: Los Angeles
country: United States
facility: Keck Medical Center of USC Pasadena
state: California
city: Whittier
country: United States
facility: The Oncology Institute of Hope & Innovation\ Innovative Clinical Research Institute
state: California
city: Washington
country: United States
facility: Georgetown University - Lombardi Comprehensive Cancer Center
state: District of Columbia
city: Fort Myers
country: United States
facility: Florida Cancer Specialists (South Region)
state: Florida
city: Fort Myers
country: United States
facility: Florida Cancer Specialists NORTH
state: Florida
city: Orange City
country: United States
facility: Mid-Florida Hematology & Oncology Centers, P.A.
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Tallahassee
country: United States
facility: Florida Cancer Specialists - Panhandle
state: Florida
city: Atlanta
country: United States
facility: Northside Hospital - Georgia Cancer Specialists
state: Georgia
city: Arlington Heights
country: United States
facility: Illinois Cancer Specialists
state: Illinois
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Memorial Medical Center
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Las Vegas
country: United States
facility: Comp. Cancer Centers of Nevada
state: Nevada
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Gettysburg
country: United States
facility: Gettysburg Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Kingswood
country: United States
facility: Millennium Oncology
state: Texas
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute
state: Virginia
city: Roanoke
country: United States
facility: Onc and Hem Assoc of SW VA
state: Virginia
city: Zijingshan
country: China
facility: Henan Cancer Hospital
state: Henan
city: Wuhan
country: China
facility: Wuhan Union Hospital
state: Hubei
city: Changchun
country: China
facility: Jilin Provincial Tumor Hospital
state: Jilin
city: Hangzhou
country: China
facility: The First Affiliated Hospital of Zhejiang University
state: Zhejiang
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Zhejiang
city: Heilongjiang
country: China
facility: The Affiliated Tumor Hospital of Harbin Medical University
city: Shandong
country: China
facility: Jinan Central hospital
city: Shanghai
country: China
facility: Zhongshan Hospital Fudan University
city: Xuzhou
country: China
facility: Xuzhou Central hospital
city: Zhengzhou
country: China
facility: First Affiliated Hospital of Zhengzhou University
city: Budapest
country: Hungary
facility: Orszagos Onkologiai Intezet
city: Gyula
country: Hungary
facility: Bekes Megyei Kozponti Korhaz Pandy Kalman Tagkorhaza
city: Kecskemet
country: Hungary
facility: Bacs-Kiskun Megyei Oktatokorhaz
city: Nyiregyhaza
country: Hungary
facility: SzSzB Megyei Korhazak es Egyetemi Oktatokorhaz
city: Casale Monferrato
country: Italy
facility: ASL Regionale Piemonte - Ospedale Santo Spirito Casale Monferrato (Ospedale di Casale Monferrato)
state: Alessandria
city: Rome
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Tor Vergata
state: Roma
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
state: Roma
city: Cremona
country: Italy
facility: Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Gdynia
country: Poland
facility: Szpitale Pomorskie spółka z ograniczoną odpowiedzialnością
city: Krakow
country: Poland
facility: Szpital Specjalistyczny im. L.Rydygiera w Krakowie
city: Rzeszów
country: Poland
facility: Mrukmed Lekarz Beata Madej Mruk i Partner Spółka Partnerska Oddział nr 1 w Rzeszowie
city: Skórzewo
country: Poland
facility: Centrum Medyczne Pratia Poznan
city: Warszawa
country: Poland
facility: Centrum Zdrowia MDM
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: ICO l'Hospitalet - Hospital Duran i Reynals
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova
city: Lugo
country: Spain
facility: Hospital Universitario Lucus Augsti
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Universitario HM Madrid Sanchinarro
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Cherkasy
country: Ukraine
facility: CI Cherkasy Regional Oncological Dispensary of CRC
city: Dnipro
country: Ukraine
facility: MI Regional Clinical Oncologycal Dispensary
city: Dnipro
country: Ukraine
facility: Dnipropetrovsk City Multispecialty Clinical Hospital #4
city: Kapitanivka
country: Ukraine
facility: Limited Liability Company "Medical Center named by Academician Yuriy Prokopovich Spizhenko"
city: Kharkiv
country: Ukraine
facility: CNE Prof. O.O. Shalimov Kharkiv City Clinical Hospital #2 of KCC
city: Kharkiv
country: Ukraine
facility: Communal Non-profit Enterprise Regional Center of Oncology, Kharkiv NMU
city: Kropyvnytskyi
country: Ukraine
facility: Treatment-Diagnostic Center of Private Enterprise of PPC Atsynus
city: Kryvyi Rih
country: Ukraine
facility: CI Kryvyi Rih Oncological Dispensary of DRC
city: Kyiv
country: Ukraine
facility: Medical Center Asklepion LLC
city: Kyiv
country: Ukraine
facility: Medical Center of Limited Liability Company Medical Center Concilium Medical
city: Lutsk
country: Ukraine
facility: Communal Enterprise Volyn Regional Medical Center of Oncology of Volyn Regional Council
city: Odesa
country: Ukraine
facility: Communal Institution Odesa Regional Clinical Hospital; Department of Surgery
city: Sumy
country: Ukraine
facility: University Hospital of Sumy State University
city: Uzhgorod
country: Ukraine
facility: CNE CCCH of Uzh CC Oncological Center, Ther Dept, SHEI UNU
city: Zaporizhzhia
country: Ukraine
facility: Medical center "Oncolife" LLC
city: London
country: United Kingdom
facility: Barts Hospital
state: Greater London
city: London
country: United Kingdom
facility: Royal Free Hospital
state: Greater London
city: Manchester
country: United Kingdom
facility: The Christie
state: Greater Manchester
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
state: South Glamorgan
Study officials:
affiliation: G1 Therapeutics, Inc.
name: Clinical Contact
role: STUDY_DIRECTOR
References: