A Phase I/II Randomized, Double-blind, Placebo-controlled Trial (1-BETTER) Examining XB2001 (Anti-IL-1⍺ True Human Antibody) in Combination With ONIVYDE + 5-FU/LV (+Folinic Acid) in Advanced Pancreatic Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 76
- 试验地点
- 30
- 主要终点
- To Establish the Maximum Tolerated Dose (MTD) of XB2001 as Measured by Dose-Limiting Toxicity (DLT), in Combination With ONIVYDE + LV + 5-FU Chemotherapy Regimen in Patients With Advanced Pancreatic Cancer.
研究概览
简要总结
This trial will include 2 portions (phase 1 and phase 2).
The first portion will be a Phase I, open label, dose escalation study to establish the maximum tolerated dose (MTD) of XB2001 as measured by Dose-Limiting Toxicity (DLT), in combination with ONIVYDE + LV + 5-FU chemotherapy regimen in patients with advanced pancreatic cancer and to determine the recommended dose for the subsequent Phase 2 study.
The phase 2 portion will be implemented with the maximum established tolerated dose (MTD) of XB2001. The target enrollment in the phase 2 portion is 60 patients which will be randomized on a 1:1 basis to XB2001 plus ONIVYDE + LV + 5-FU (Arm 1) or placebo plus ONIVYDE + LV + 5-FU (Arm 2).
详细描述
Study Title: A Phase I/II randomized, double-blind, placebo-controlled trial (1-BETTER) examining XB2001 (anti-IL-1⍺ True Human antibody) in combination with ONIVYDE + 5-FU/LV (+folinic acid) in advanced pancreatic cancer
Sponsor: XBiotech USA, Inc.
Sample Size: Approximately 69 patients will be enrolled in the USA (at least 9 patients in the open label phase 1 portion and 60 patients in the randomized phase 2 portion)
Approximate Duration:
This trial will include 2 phases. The first portion will be a Phase I, open label, dose escalation study evaluating the safety, tolerability and establishing the Maximum Tolerated Dose (MTD) of XB2001 in at least nine patients with metastatic pancreatic adenocarcinoma who are receiving ONIVYDE + Leucovorin l + d racemic + 5-Fluorouracil chemotherapy treatment. The duration for each patient in the Phase I portion will be 14 days (1 treatment cycle) in which they will be given one intravenous dose of XB2001 prior to receiving ONIVYDE + Leucovorin l + d racemic + 5-Fluorouracil chemotherapy treatment and assessed for Dose Limited Toxicities (DLT). The Phase II portion will be implemented following the completion of the Phase I portion and declaration of the MTD. The duration of subject participation in the randomized, double-blind, placebo-controlled Phase II portion of the trial is approximately 28 weeks: including a screening period of up to 30 days, and 24-week treatment period. All study subjects can continue treatment with XB2001 in an open label extension, for as long as they are judged to be benefitting clinically and have had no unacceptable toxicities.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-blinded study
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
- •Histologically or cytologically confirmed pancreatic adenocarcinoma of exocrine pancreas that is metastatic, unresectable, or recurrent
- •At least one measurable lesion according to Response Evaluation Criteria in Solid Tumor V1.1
- •Documented disease progression after one prior gemcitabine-based therapy OR one FOLFIRINOX and gemcitabine combination therapy
- •Eastern Cooperative Oncology Group (ECOG) performance of 0 or 1 or Karnofsky performance status (KPS) ≥ 70
- •Adequate hepatic, renal and bone marrow function
排除标准
- •Clinically significant decrease in performance status (medical records) within 2 weeks of intended first dose administration
- •Clinically significant GI disorders
- •Severe arterial thromboembolic events less than 6 months before inclusion
- •Prior Whole Brain Radiation Therapy (WBRT)
- •Evidence of brain metastases
- •NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure (defined as ≥ 160/100 mm Hg)
- •Use of strong CYP3A4 inducers or inhibitors and/or UGT1A1 inhibitors within 14 days prior to Visit 1/Baseline visit.
研究组 & 干预措施
Phase I: Dose Escalation Phase
In Phase I (Dose escalation phase), 3 sequential dose levels were administered by participants; 250 mg (dose cohort 1), 500 mg (dose cohort 2), and 1000 mg (dose cohort 3), and traditional 3:3 design was used. Dose-escalation will continue if none of three subjects experience a dose-limiting toxicity (DLT).
After enrollment participants received two treatment cycles (a total of 28 days) in which they were given one intravenous (IV) dose of XB2001 prior to receiving ONIVYDE 70 mg/m2 IV over 90 minutes, followed by leucovorin 400 mg/m2 IV over 30 minutes, followed by 5-Fluorouracil 2400 mg/m2 intravenously over 46 hours at each cycle.
干预措施: Phase I: XB2001 250 mg (Biological)
Phase I: Dose Escalation Phase
In Phase I (Dose escalation phase), 3 sequential dose levels were administered by participants; 250 mg (dose cohort 1), 500 mg (dose cohort 2), and 1000 mg (dose cohort 3), and traditional 3:3 design was used. Dose-escalation will continue if none of three subjects experience a dose-limiting toxicity (DLT).
After enrollment participants received two treatment cycles (a total of 28 days) in which they were given one intravenous (IV) dose of XB2001 prior to receiving ONIVYDE 70 mg/m2 IV over 90 minutes, followed by leucovorin 400 mg/m2 IV over 30 minutes, followed by 5-Fluorouracil 2400 mg/m2 intravenously over 46 hours at each cycle.
干预措施: Phase I: XB2001 500 mg (Biological)
Phase I: Dose Escalation Phase
In Phase I (Dose escalation phase), 3 sequential dose levels were administered by participants; 250 mg (dose cohort 1), 500 mg (dose cohort 2), and 1000 mg (dose cohort 3), and traditional 3:3 design was used. Dose-escalation will continue if none of three subjects experience a dose-limiting toxicity (DLT).
After enrollment participants received two treatment cycles (a total of 28 days) in which they were given one intravenous (IV) dose of XB2001 prior to receiving ONIVYDE 70 mg/m2 IV over 90 minutes, followed by leucovorin 400 mg/m2 IV over 30 minutes, followed by 5-Fluorouracil 2400 mg/m2 intravenously over 46 hours at each cycle.
干预措施: Phase I: XB2001 1000 mg (Biological)
Phase II: Dose Expansion Phase
In Phase II (dose expansion phase), participants were randomized in 1:1 fashion and received:
- XB2001 1000 mg combination with ONIVYDE, Leucovorin, and 5-Fluorouracil
- Placebo 1000 mg in combination with ONIVYDE, Leucovorin, and 5-Fluorouracil
干预措施: Phase II: XB2001 1000 mg (Biological)
Phase II: Dose Expansion Phase
In Phase II (dose expansion phase), participants were randomized in 1:1 fashion and received:
- XB2001 1000 mg combination with ONIVYDE, Leucovorin, and 5-Fluorouracil
- Placebo 1000 mg in combination with ONIVYDE, Leucovorin, and 5-Fluorouracil
干预措施: Phase II: Placebo (Biological)
结局指标
主要结局
To Establish the Maximum Tolerated Dose (MTD) of XB2001 as Measured by Dose-Limiting Toxicity (DLT), in Combination With ONIVYDE + LV + 5-FU Chemotherapy Regimen in Patients With Advanced Pancreatic Cancer.
时间窗: 28 days (consisting of the first two 14-day treatment cycles or the formal DLT observation window).
The primary objective of the Phase I portion is to identify the MTD of XB2001 when administered in combination with ONIVYDE + LV + 5-FU. The MTD is defined as the highest dose level at which no more than one out of six subjects experience a DLT. If two or more subjects in a cohort of six experience a DLT, the MTD is considered exceeded, and the previous lower dose level will be identified as the MTD. If no DLTs are observed at the highest dose level studied, that dose will be used for Phase II. A DLT is defined as any Grade 3-4 adverse event (per NCI CTCAE v5.0) occurring within the first 28 days that is deemed possibly related to the combination regimen, unless the toxicity is clearly attributable to a single non-XB2001 component. Specific DLT criteria include: 1. Inability to deliver all scheduled doses during the 28-day window due to unexpected drug-related toxicity. 2. Inability to deliver the intended dose of XB2001 due to drug-related toxicity.
Safety and Tolerability of XB2001 in Combination With ONIVYDE + LV + 5-FU
时间窗: From post-infusion visit 1(week 0) through visit 13 (week 24), which is two weeks after the last infusion.
This endpoint evaluates the cumulative safety profile and patient tolerance of XB2001 when administered at the Maximum Tolerated Dose (MTD) or the maximum dose studied in Phase I, in combination with the ONIVYDE + LV + 5-FU regimen. Safety is characterized by the total number of participants in each cohort who experienced one or more adverse events. For the purpose of this count, each participant is counted only once, regardless of the total number of individual adverse events experienced.
次要结局
- Progression Free Survival (PFS)(From baseline until the date of first documented disease progression or date of death (from any cause), whichever come first.)
- Overall Survival (OS)(From baseline until death from any cause)
- Objective Response Rate (ORR)(Analyses performed at Visit 5 (Week 8), Visit 9 (Week 16), and Visit 13 (Week 24). This outcome measure was reported for Visit 13.)
- Time to Treatment Failure(TTF)(From baseline until treatment failure assessed up to Visit 13 (Week 24))
- Number of Serious Adverse Events (SAEs)(From post-infusion visit 1(week 0) through visit 13 (week 24), which is two weeks after the last infusion.)
- Incidence of Grade 3-4 Diarrhea(From post-infusion visit 1(week 0) through visit 13 (week 24), which is two weeks after the last infusion.)
- Duration of Hospitalization(From post-infusion visit 1(week 0) through visit 13 (week 24), which is two weeks after the last infusion.)
- Plasma Concentration of Natrunix(Reported results Natrunix: Phase I: V1 post-dose collected at 30 min post-infusion at visit 1(Week 0), which represents Cmax of Cycle 1. Phase II: V6 pre-dose, at Visit 6 (Week 10), represents the trough of steady state concentration.)
- Number of Treatment Cycles(From randomization to end of study or study discontinuation for any reasons, up to 24 weeks)