A Phase IB/II Open-label Study of the Safety and Preliminary Efficacy of CTX-009 Administered Either as a Monotherapy or in Combination With CTX-471 in Patients With Recurrent Glioblastoma
概览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 54
- 试验地点
- 1
- 主要终点
- Phase IB Arm 1: Toxicity as measured by number of participants with adverse events
概览
简要总结
This is a phase IB/II, open-label study evaluating CTX-009 as monotherapy and in combination with CTX-471. The study evaluates the safety and efficacy of the monotherapy and the combination in patients with recurrent glioblastoma. The study tests the hypothesis that treatment with CTX-009 alone or in combination with CTX-471 will lead to enhanced tumor control and prolongation of overall survival of patients with recurrent glioblastoma.
CTX-009 expands on existing anti-angiogenic therapies by ablating key compensatory and resistance mechanisms to bevacizumab, CTX-471 restores local immune reactivity through activation of costimulatory immune mediators. Combination of these two agents may further impair tumor proliferation through synergistic effects on the tumor microenvironment
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
- None
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 radiographically confirmed recurrent CNS WHO grade 4 IDH wild-type glioma following standard of care treatment including radiation, chemotherapy, and/or tumor-treating fields. No more than 2 recurrences are allowed.
- •At least 18 years of age.
- •KPS performance status ≥ 60%
- •Adequate bone marrow and organ function as defined below:
- •Absolute neutrophil count ≥ 1.0 K/cumm
- •Platelets ≥ 75 K/cumm
- •Hemoglobin ≥ 8.0 g/dL
- •Total bilirubin ≤ 1.5 x IULN, unless suspected or documented history of Gilbert's Syndrome, in which case ≤ 2.5 x IULN
- •AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
- •Creatinine clearance \> 30 mL/min by Cockcroft-Gault
排除标准
- •Have progressed on prior anti-VEGF-A therapy (i.e., bevacizumab) or developed clinically significant adverse reaction to any anti-VEGF therapy (i.e., bevacizumab, regorafenib) which led to discontinuation of treatment. Prior treatment with low dose anti-VEGF therapy for management of symptomatic vasogenic edema or radiation necrosis is permitted as long as progression was not noted while receiving treatment with the anti-VEGF agent, and is not needed for continued control of symptoms. A 4-week washout from last dose of low-dose anti-VEGF therapy is required.
- •Prior systemic anti-cancer therapy including: investigational agents or immunotherapy within 4 weeks (can consider 2 week interval for agents with known 5 half-lives \<14 days following discussion with study PI); chemotherapy within 4 weeks (6 weeks for BCNU or CCNU); or targeted therapy within 2 weeks prior to treatment.
- •Note: participants must have recovered from all clinically significant AEs due to previous therapies to ≤ grade 1 or baseline. This does not include AEs deemed not clinically significant by treating physician (i.e., alopecia). Participants with endocrine-related AEs ≤ grade 2 requiring treatment or hormone replacement are eligible if controlled (i.e., clinically asymptomatic) on stable dose of replacement therapy.
- •Use of aspirin, NSAIDs, or other antiplatelet agents within 7 days of study drug(s) initiation. Regular use (i.e., daily) of these agents should be avoided while on study treatment.
- •Use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes within 7 days of study drug(s) initiation. Prophylactic dosing of DOAC, such as apixaban or edoxaban, or LMWH for patency of venous access devices is allowed (preference is given to DOAC over LMWH).
- •History of intraparenchymal or subdural hemorrhage. History of hemorrhage-related or gastroenterological disease including active hemorrhage, hemorrhagic diathesis, coagulopathy, or tumor in great arteries. History of clinically significant gastroenterological disease, such as peptic ulcer, GI bleeding, GI or non-GI fistula, perforation, abdominal abscess, percutaneous drains, clinical symptoms and signs of GI obstruction, need for parenteral hydration or nutrition, or inflammatory bowel disease (IBD).
- •History of unprovoked high-risk thromboembolic events.
- •A history of the following cardiovascular diseases in the past 5 years (a case-by-case evaluation can be considered in consultation with the study PI):
- •Congestive heart failure that corresponds to Class II or a higher class under NYHA classification or \< 50% of LVEF
- •Uncontrolled hypertension (140/90 mmHg despite best care including anti-hypertensive medications). White coat hypertension is not exclusionary.
研究组 & 干预措施
Phase IB Arm 1: CTX-009 monotherapy
CTX-009 will be given intravenously at the assigned dose level on an outpatient basis every 2 weeks of a 28-day cycle.
干预措施: CTX-009 (Drug)
Phase IB Arm 2: CTX-009 and CTX-471 combination therapy
CTX-009 will be given intravenously at the dose determined to be the recommended phase II dose (RP2D) in Arm 1 every 2 weeks, and CTX-471 will be given intravenously at a dose of 0.3 mg/kg every 2 weeks (day 1 and day 15). On days when both drugs are given, CTX-009 will be given first, followed by a 30-minute observation period, followed by CTX-471. Cycles will be 28 days.
干预措施: CTX-009 (Drug)
Phase IB Arm 2: CTX-009 and CTX-471 combination therapy
CTX-009 will be given intravenously at the dose determined to be the recommended phase II dose (RP2D) in Arm 1 every 2 weeks, and CTX-471 will be given intravenously at a dose of 0.3 mg/kg every 2 weeks (day 1 and day 15). On days when both drugs are given, CTX-009 will be given first, followed by a 30-minute observation period, followed by CTX-471. Cycles will be 28 days.
干预措施: CTX-471 (Drug)
Phase II Expansion Arm 1: CTX-009 monotherapy
CTX-009 will be given intravenously at the recommended phase 2 dose (RP2D) determined from Phase IB on an outpatient basis every 2 weeks of a 28-day cycle.
干预措施: CTX-009 (Drug)
Phase II Expansion Arm 2: CTX-009 and CTX-471 combination therapy
CTX-009 will be given intravenously at the dose determined to be the recommended phase II dose (RP2D) every 2 weeks (day 1 and day 15). CTX-471 will be given intravenously at a dose of 0.3 mg/kg every 2 weeks (day 1 and day 15). On days when both drugs are given, CTX-009 will be given first, followed by a 30-minute observation period, followed by CTX-471. Cycles will be 28 days.
干预措施: CTX-009 (Drug)
Phase II Expansion Arm 2: CTX-009 and CTX-471 combination therapy
CTX-009 will be given intravenously at the dose determined to be the recommended phase II dose (RP2D) every 2 weeks (day 1 and day 15). CTX-471 will be given intravenously at a dose of 0.3 mg/kg every 2 weeks (day 1 and day 15). On days when both drugs are given, CTX-009 will be given first, followed by a 30-minute observation period, followed by CTX-471. Cycles will be 28 days.
干预措施: CTX-471 (Drug)
结局指标
主要结局
Phase IB Arm 1: Toxicity as measured by number of participants with adverse events
时间窗: Start of treatment through 60 days after treatment (estimated to be 14 months)
Adverse events will be graded according to CTCAE v5.0
Phase IB Arm 1: Recommended Phase 2 Dose (RP2D)
时间窗: Start of treatment through completion of cycle 1 (each cycle is 28 days)
RP2D will be determined from the phase IB portion of Arm 1 by assessing tolerability. Tolerability is defined as ≤1 among patients experiencing excessive dose limiting toxicities (DLTs). The dose level in phase IB determined to be tolerable is the RP2D.
Phase IB Arm 2: Toxicity as measured by number of participants with adverse events
时间窗: Start of treatment through 60 days after treatment (estimated to be 14 months)
Adverse events will be graded according to CTCAE v5.0
Phase II Arm 1: Overall survival rate at 12 months (OS12)
时间窗: 12 months
Overall survival is defined from time of treatment start to time of death due to any cause or latest follow-up, whichever is earlier, with an inference focus on 12-month overall survival.
Phase II Arm 2: Overall survival rate at 12 months (OS12)
时间窗: 12 months
Overall survival is defined from time of treatment start to time of death due to any cause or latest follow-up, whichever is earlier, with an inference focus on 12-month overall survival.
次要结局
- Overall response rate (ORR)(Start of treatment to end of treatment (estimated total time to be 12 months))
- Duration of response (DoR)(Start of treatment to disease progression/recurrence (estimated total time to be 36 months))
- Median progression-free survival (mPFS)(Start of treatment to disease progression (estimated to be 36 months))
- Median overall survival (mOS)(Start of treatment through completion of follow up or death (estimated to be 36 months))
- Progression free survival at 9 months (PFS9)(9 months)