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    Summary
    EudraCT Number:2019-003826-25
    Sponsor's Protocol Code Number:G1T28-207
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-11-20
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2019-003826-25
    A.3Full title of the trial
    PRESERVE 1: A Phase 3 Randomized, Double-blind Trial of Trilaciclib versus Placebo in Patients Receiving FOLFOXIRI/Bevacizumab for Metastatic Colorectal Cancer
    PRESERVE 1: III. fázisú, randomizált, kettős vak vizsgálat a trilaciclib összehasonlítására placebóval FOLFOXIRI/bevacizumab kezelésben részesülő, áttétes vastag- és végbélrákban szenvedő betegek esetében
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Trilaciclib versus placebo in patients receiving FOLFOXIRI/bevacizumab for metastatic colorectal cancer
    A.3.2Name or abbreviated title of the trial where available
    PRESERVE 1
    A.4.1Sponsor's protocol code numberG1T28-207
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorG1 Therapeutics, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportG1 Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationG1 Therapeutics, Inc.
    B.5.2Functional name of contact pointClinical Information Point
    B.5.3 Address:
    B.5.3.1Street AddressPO Box 110341
    B.5.3.2Town/ cityResearch Triangle Park
    B.5.3.3Post codeNC 27709
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 919 213 9835
    B.5.5Fax number+1 919 741 5830
    B.5.6E-mailclinicalinfo@g1therapeutics.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTrilaciclib hydrochloride
    D.3.2Product code G1T28
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTrilaciclib
    D.3.9.1CAS number 1977495-97-8
    D.3.9.2Current sponsor codeG1T28
    D.3.9.3Other descriptive nameG1T28 di-HCl, G1T28, G1T28-1, CGB3RG-28-1, TRILA-IV, TRILA Di-HCl
    D.3.9.4EV Substance CodeSUB189859
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Prevention of chemotherapy-induced myelosuppression in patients receiving FOLFOXIRI/bevacizumab for mCRC
    E.1.1.1Medical condition in easily understood language
    Chemotherapy-induced myelosuppression
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10052358
    E.1.2Term Colorectal cancer metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10052362
    E.1.2Term Metastatic colorectal cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level LLT
    E.1.2Classification code 10028585
    E.1.2Term Myelosuppression adult
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the effects of trilaciclib on the neutrophil lineage compared with placebo in patients receiving FOLFOXIRI/bevacizumab for proficient mismatch repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer (mCRC).
    E.2.2Secondary objectives of the trial
    - To assess the effects of trilaciclib on chemotherapy-induced fatigue compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC.
    - To assess the effect of trilaciclib on progression free survival (PFS) and overall survival (OS) compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC.

    Efficacy objectives
    To assess the effect of trilacilib on:
    - Additional measures of the neutrophil lineage
    - RBC lineage
    - Platelet lineage
    - Multiple lineages
    - Standard of care dosing
    - Healthcare utilization
    - To evaluate the anti-tumor activity of trilaciclib

    Safety objectives
    - To assess the safety and tolerability of trilaciclib compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC.
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    3. Unresectable and measurable or evaluable metastatic colorectal
    cancer disease 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
    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 × 109/L
    8. Platelet count ≥ 100 × 109/L
    9. Estimated glomerular filtration rate (eGFR) ≥ 30 mL/minute/1.73m2
    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.
    15. Capable of giving signed informed consent which includes compliance with the requirements
    E.4Principal 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 (confirmed on repeat). 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 arrythmia 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.
    E.5 End points
    E.5.1Primary end point(s)
    - Duration of severe (Grade 4) neutropenia in Cycle 1
    - Occurrence of severe neutropenia during Induction
    E.5.1.1Timepoint(s) of evaluation of this end point
    Cycle 1: Day 1, 2, 4, 6, 8, 10, 12
    Cycles 2-12: Day 1, 8 (during cycles 2-4 only), 15 (during last cycle if no maintenance)
    E.5.2Secondary end point(s)
    - TTCD-fatigue during Induction, as measured by the FACIT-F
    - progression free survival (PFS) (per RECIST 1.1) as assessed by Investigator
    - Overall Survival (OS)

    Efficacy:
    - Severe Neutropenia (SN) (number of events only)
    - G-CSF administration
    - FN AEs
    - Grade 3 or 4 decreased hemoglobin laboratory values
    - Red blood cells (RBC) transfusions on or after Week 5
    - ESA administration
    - Grade 3 or 4 decreased platelet count laboratory values
    - Platelet transfusions
    - Grade 3 or 4 hematologic lab values
    - All-cause dose reductions or cycle delays
    - Relative dose intensity for FOLFOXIRI/bevacizumab
    - Hospitalizations
    • All cause
    • Febrile neutropenia/ neutropenia
    • Anemia/RBC transfusions
    • Thrombocytopenia/bleeding
    • Infections
    - Antibiotic use
    • IV
    • Oral
    • Oral and IV
    - Best overall response (BOR) and objective response (CR or PR) per RECIST v1.1
    - Duration of objective response (DOR)

    Safety:
    - Occurrence and severity of AEs by NCI-CTCAE v5 including diarrhoea, stomatitis, and hematologic AEs (neutropenia, anemia, thrombocytopenia)
    - Changes in laboratory parameters (hematology, chemistry, urinalysis), vital signs and ECG parameters
    - Grade 3 or 4 abnormalities in chemistry laboratory parameters
    - Trilaciclib AESIs
    - Trilaciclib infusion interruptions
    - Chemotherapy infusion interruptions
    - Study treatment discontinuation due to AEs
    E.5.2.1Timepoint(s) of evaluation of this end point
    - FACIT-F: Induction Cycles 1-4 (day 1, 8) Induction Cycles 5-12 (day 1), D15 of last induction if not proceeding into Maintainance, Day 1 of each Maintencne cycle, Post Treatment Visit (PTV)
    - PFS/BOR/DOR: Induct cycles 2-12 every 8 weeks, Maint every 12 weeks, PTV, Survival follow-up
    - SN/Grade 3 or 4 decreased hemoglobin, hematologic or platelet count lab values: Induction Cycle 1 (Day 1, 2, 4, 6, 8, 10, 12), Induction Cycles 2-12 (Day 1, 8 during Cycles 2-4, 15 during last cycle of Induction if not proceeding to Maint), Day 1 of every Maint cycle, PTV
    - Dose reductions or cycle delays/relative dose intensity for FOLFOXIRI/bevacizumab/G-CSF/ESA administration/Platelet or RBC transfusions: During Induction or Maintenance
    - Hospitalizations/Antibiotic use/OS/FN AEs/safety:entire study
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarkers
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Information not present in EudraCT
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Information not present in EudraCT
    E.8.5.1Number of sites anticipated in the EEA50
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    China
    Hungary
    Italy
    Poland
    Slovakia
    Spain
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS or last survival follow-up contact
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 207
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 89
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 175
    F.4.2.2In the whole clinical trial 296
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Normal/Standard of care treatment
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-01-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-15
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2023-02-14
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