PRESERVE 1: A Phase 3 Randomized, Double-blind Trial of Trilaciclib Versus Placebo in Patients Receiving FOLFOXIRI/Bevacizumab for Metastatic Colorectal Cancer
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 326
- 试验地点
- 82
- 主要终点
- Duration of Severe Neutropenia (DSN)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
Double-Blinded Trial
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 >
- •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
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Trilaciclib (Drug)
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.
干预措施: Placebo (Drug)
结局指标
主要结局
Duration of Severe Neutropenia (DSN)
时间窗: 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
时间窗: 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)
次要结局
- Overall Survival (OS)(Up to 52 months)
- Additional Myelopreservation Measures(Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab)
- Red Blood Cell Lineage(Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab)
- Platelet Lineage(Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab)
- Multiple Lineage(Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab)
- Standard of Care Dosing(Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab)
- Healthcare Utilization(Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab)
- Best Overall Response (BOR)(Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab)
- 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)
- 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)
- 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)
- Quality of Life/ Effects on Chemotherapy-Induced Fatigue(Through Induction Period- on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab)
- 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)