Prevention of chemotherapy-induced myelosuppression in patients receiving FOLFOXIRI/bevacizumab for mCRC MedDRA version: 21.0 Level: PT Classification code 10052358 Term: Colorectal cancer metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: LLT Classification code 10052362 Term: Metastatic colorectal cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) Med
Conditions
Sponsors
G1 Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion 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. 3. Unresectable and measurable or evaluable 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 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) = 30mL/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 =65 years) yes F.1.3.1 Number of subjects for this age range 89
Exclusion criteria
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 intestina obstruction. Patients should not be treated until the intestinal obstruction has resolved. 16. Previous history of significant/severe hemorrhage within 1 monthbefore randomization. History of previous abdominal fistula or gastrointestinal perforation withing 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 naticipated treatment with potent cytochrome inhibitors CYP450 3A4 (such as ketoconazole) or inducers (such as rifamcicin, carbamazepne, 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 br
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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).;Secondary Objective: - 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.;Primary end point(s): - Duration of severe (Grade 4) neutropenia in Cycles 1-4 - Occurrence of severe neutropenia during Induction;Timepoint(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) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary 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;Timepoint(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 redu | — |
Countries
China, France, Hungary, Italy, Poland, Slovakia, Spain, Ukraine, United Kingdom, United States
Contacts
Public ContactClinical Information Point
G1 Therapeutics, Inc.
Outcome results
None listed