An Open-label Phase 1/2a Study of Oral BAL101553 in Adult Patients With Advanced Solid Tumors and in Adult Patients With Recurrent or Progressive Glioblastoma or High-grade Glioma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 72
- 试验地点
- 13
- 主要终点
- Phase 2a: Best Objective Response
研究概览
简要总结
First in human, open-label, dose escalation (Phase I) and expansion study (Phase 2a) of oral lisavanbulin (BAL101553) in adult patients with advanced solid tumors and adult patients with recurrent or progressive glioblastoma (GBM) or high-grade glioma (HGG).
详细描述
This was the first study of the oral formulation (hard capsules) of lisavanbulin. Lisavanbulin was administered once daily during each day of a 28-day treatment cycle to adults with advanced or recurrent solid tumors or recurrent or progressive GBM / HGG who had failed standard therapy, or for whom no effective standard therapy was available.
In Phase 1, the highest dose of lisavanbulin was determined that could safely be given to adults with advanced or recurrent solid tumors, recurrent or progressive GBM / HGG.
In Phase 2a, the tolerability and potential anticancer activity of oral lisavanbulin was assessed in patients with recurrent GBM whose tumor tissue tests positive for end-binding protein 1 (EB1). The study also measured pharmacokinetics.
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
- 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
- •Age ≥ 18 years
- •Patients who had in the Phase 1 portion either of the following:
- •a histologically- or cytologically confirmed advanced or recurrent solid tumor, who failed standard therapy, or for whom no effective standard therapy was available to them
- •histologically-confirmed GBM or HGG, with progressive or recurrent disease after prior radiotherapy, with or without chemotherapy. This also included patients with histologically-confirmed low-grade glioma who presented with unequivocal evidence by imaging of transformation to GBM / HGG
- •Phase 2a dose expansion portion:
- •Recurrent, histologically confirmed, glioblastoma with tumor tissue positive for EB1; eligible patients with de novo glioblastoma after prior radical chemo-radiotherapy or secondary glioblastoma after prior chemotherapy or radiotherapy.
- •Phase 1: Patients had to have measurable disease; according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria v1.1 for patients with advanced or recurrent solid tumors, and per radiological assessment in neuro-oncology (RANO) criteria for patients with recurrent or progressive GBM /HGG. Phase 2a: Patients had to be evaluable per RANO criteria.
- •Life expectancy ≥ 12 weeks
- •Acceptable organ and marrow function at baseline (protocol defined laboratory parameters)
- •Patients with advanced solid tumors had to have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 and patients with recurrent or progressive glioblastoma had to have an ECOG performance status ≤ 2
排除标准
- •Patients with advanced or recurrent solid tumors who had received chemotherapy, radiotherapy, immunotherapy, or investigational agents within 4 weeks (2 weeks for single fraction of palliative radiotherapy, 6 weeks for nitrosoureas or mitomycin C) prior to starting study drug or who had not recovered from side effects of prior therapies
- •Patients with recurrent or progressive GBM / HGG who had: received radiotherapy within 6 weeks (Phase 1) or 12 weeks (Phase 2a), unless there was a new area of enhancement consistent with recurrent tumor outside the radiation field; received administration of prior anti-tumor chemotherapy within 4 weeks, or within 6 weeks for nitrosoureas; undergone surgical resection within 4 weeks (Phase 2a: 2 weeks) or a stereotactic biopsy/core biopsy within 1 week prior to starting study drug;
- •Patients who have had prior exposure to lisavanbulin
- •Inability to swallow oral medication
- •Increase in steroid dose in GBM or HGG patients within 5 days prior to first study-drug administration or requirement for > 6 mg/day dexamethasone or equivalent for symptom control.
- •Patients with gastrointestinal disease or those who have had a procedure that was expected to interfere with the oral absorption or tolerance of lisavanbulin
- •Symptomatic brain metastases or leptomeningeal disease, which was indicative of active disease, in patients with advanced or recurrent solid tumors.
- •Peripheral neuropathy ≥ CTCAE grade
- •Uncontrolled intercurrent illness that would have unduly increased the risk of toxicity or limit compliance with study requirements
- •Systolic blood pressure (SBP) ≥ 160 mmHg or diastolic blood pressure (DBP) ≥ 100 mmHg at the screening visit.
- •Blood pressure (BP) combination treatment with more than two antihypertensive medications.
- •Women who were pregnant or breast-feeding. Men or women of reproductive potential who were not willing to apply effective birth control
研究组 & 干预措施
Phase 1 dose escalation portion
Phase 1 dose escalation portion - an accelerated 3+3 titration design in patients with:
- advanced or recurrent solid tumors
- recurrent or progressive GBM / HGG
干预措施: Lisavanbulin Phase 1 dose escalation portion (Drug)
Phase 2a dose expansion portion
Phase 2a expansion portion (Simon's two-stage design) - Patients with recurrent and EB1-positive GBM
干预措施: Lisavanbulin Phase 2a expansion portion (Drug)
结局指标
主要结局
Phase 2a: Best Objective Response
时间窗: Until the study discontinuation, on average 161 days (maximum of 381 days)
The best objective response was calculated as the proportion of patients responding (i.e., with a best observed objective response of complete or partial response) based on "radiological assessment in neuro-oncology (RANO)" criteria
Phase 2a: Objective Response Rate (ORR)
时间窗: Until the study discontinuation, on average 161 days (maximum of 381 days)
The ORR was calculated as the percentage of patients (rate) with complete and partial responses and its 95% Confidence Interval (CI) based on RANO criteria
Phase 1: Maximum Tolerated Dose (MTD) of Daily Oral Lisavanbulin
时间窗: During first 28 day cycle
First 28-day treatment cycle dose limiting toxicities (DLT) graded according to Common Terminology Criteria for Adverse Events (CTCAE) in the MTD-determining population in Phase 1 based on the number of participants with adverse effects as measure of tolerability at various dose levels
次要结局
- Cmax of Avanbulin (BAL27862)(Plasma PK profiles were obtained on Cycle 1, Day 1 and on Cycle 2, Day 1 (pre-dose and from 0 up to 24 h post-dose) for all patients in the Phase 1 study who received lisavanbulin. For Phase 2 a study, PK parameters were obtained only on Cycle 1, Day 1)
- Phase 1: Best Objective Response(Until the end of treatment, on average 151 days (maximum of 1653 days), every other 28 day cycle)
- Phase 2a: PFS at 6 Months(6 months)
- Number of Patients With CTCAE Grade 3-4 TEAEs(TEAEs were defined as all events occurring after lisavanbulin treatment began and up to 28 days after last study drug administration which corresponded to a maximum of 1653 days (4,5 years))
- Tmax of Avanbulin (BAL27862)(Plasma PK profiles were obtained on Cycle 1, Day 1 and on Cycle 2, Day 1 (pre-dose and from 0 up to 24 h post-dose) for all patients in the Phase 1 study who received lisavanbulin. For Phase 2 a study, PK parameters were obtained only on Cycle 1, Day 1)
- AUC of Avanbulin (BAL27862)(Plasma PK profiles were obtained on Cycle 1, Day 1 and on Cycle 2, Day 1 (pre-dose and from 0 up to 24 h post-dose) for all patients in the Phase 1 study who received lisavanbulin. For Phase 2 a study, PK parameters were obtained only on Cycle 1, Day 1)
- Phase 2a: PFS(1 year)
- Phase 1: Objective Response Rate (ORR)(Until the study discontinuation, on average 151 days (maximum 1653 days), every other 28 day cycle)
- Phase 2a: Overall Survival (OS) at 12 Months(1 year)