Phase Ib/II Multicenter Study of Buparlisib Plus Carboplatin or Lomustine in Patients With Recurrent Glioblastoma Multiforme
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 35
- 试验地点
- 6
- 主要终点
- Progression Free Survival (PFS) [phase II lomustine combinations]
研究概览
简要总结
This is a multi-center, phase Ib/ II study (two parts) with patients that had recurrent glioblastoma multiforme. The first part (phase Ib) was to investigate the maximum tolerated dose/Recommended phase ll dose (MTD/RP2D) of once daily buparlisib in combination with every-three-week carboplatin or buparlisib once daily in combination with every-six-week lomustine (CCNU) using a Bayesian model. Once MTD/ RP2D is established in either of the 2 arms, the corresponding phase II portion of the study was to start. Phase II was to assess the treatment effect of buparlisib in combination with carboplatin in terms of Progression Free Survival (PFS) and was to compare the treatment effect of buparlisib with lomustine versus lomustine plus placebo in terms of PFS.
A preliminary assessment for both combinations (buparlisib plus carboplatin or lomustine) demonstrated that there was not enough antitumor activity compared to historical data with single agent carboplatin or lomustine. Based on the overall safety profile, and preliminary anti-tumor activity observed in this study, Novartis decided that no additional patients would be enrolled into this study. As a consequence, the Phase II part of the study was not conducted.
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
- •Patient is an adult ≥ 18 years old at the time of informed consent.
- •Patient has histologically confirmed diagnosis of GBM with documented recurrence after first line treatment including radiotherapy and TMZ (SoC), not suitable for curative surgery or re-irradiation.
- •Patient has at least one measurable and/or non-measurable lesion as per RANO criteria
- •Patient has recovered (to Grade ≤1) from all clinically significant toxicities related to prior antineoplastic therapies.
- •Patient has Karnofsky performance status (KPS) ≥70%.
- •Patient has adequate organ and bone marrow functions:
- •Absolute Neutrophils Count (ANC) ≥ 1.5 x 109/L
- •Platelets ≥ 100 x 109/L (in case of transfusion stable for ≥14 days prior to treatment start)
- •Hemoglobin ≥ 9.0 g/dL (in case of transfusion stable for ≥14 days prior to treatment start)
- •INR ≤ 1,5
- •Serum Creatinine ≤ 1.5 x ULN, or Creatinine Clearance > 45mL/min
- •Potassium and calcium (corrected for albumin), sodium and magnesium within institutional normal limits
- •Serum Bilirubin ≤ ULN, AST and ALT ≤ ULN
- •HbA1c ≤ 8%
- •Fasting plasma glucose (FPG) ≤ 120 mg/dL or ≤ 6.7 mmol/L
- •Patient has tumor tissues available (archival or fresh).
排除标准
- •Patient has received previous treatment with PI3K inhibitors, lomustine or carboplatin.
- •Patient has received previous antineoplastic treatment for recurrent GBM (e.g. VEGF inhibitors, cytotoxic agents).
- •Patient has received more than one line of cytotoxic chemotherapy
- •Patient has concurrent use of anti-neoplastic agents including investigational therapy
- •Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.
- •Patient is currently receiving treatment with drugs known to be moderate or strong inhibitors or inducers of isoenzyme CYP3A. The patient must have discontinued strong inducers for at least one week and must have discontinued strong inhibitors before the treatment is initiated. Switching to a different medication prior to randomization is allowed.
- •Patient is currently receiving an enzyme-inducing anti-epileptic drug (EIAED). The patient must have discontinued EIAED therapy for at least two weeks prior to starting study drug.
- •Other protocol-defined Inclusion/exclusion criteria may apply.
研究组 & 干预措施
lumustine + placebo (Phase II)
干预措施: lomustine (Drug)
lomustine+ buparlisib (Phase II)
干预措施: lomustine (Drug)
Lomustine+ buparlisib (Phase Ib)
干预措施: buparlisib (Drug)
Lomustine+ buparlisib (Phase Ib)
干预措施: lomustine (Drug)
carboplatin+ buparlisib (Phase Ib)
干预措施: buparlisib (Drug)
carboplatin+ buparlisib (Phase Ib)
干预措施: carboplatin (Drug)
lomustine+ buparlisib (Phase II)
干预措施: buparlisib (Drug)
lumustine + placebo (Phase II)
干预措施: placebo (Drug)
carboplatin+ buparlisib (Phase II)
干预措施: buparlisib (Drug)
carboplatin+ buparlisib (Phase II)
干预措施: carboplatin (Drug)
结局指标
主要结局
Progression Free Survival (PFS) [phase II lomustine combinations]
时间窗: Randomization until date of the event (expected average 3 months).
Progression Free Survival (PFS) is defined as the time from date of randomization to the date of the event, which is the first radiologically documented disease progression \[per local investigator assessment according to Response Assessment in Neuro-Oncology (RANO) criteria\] or death due to any cause.
12 week Progression Free Survival (PFS) rate (Phase II- Carboplatin combination)
时间窗: 12 weeks
12-week Progression Free Survival (PFS) is defined as the percentage of patients who are progression free 12 weeks after the date of the start of the treatment ("success"). Patients who progressed, died or discontinued within the 12 weeks of observation are counted as "failure".
Number of Total Dose-limiting Toxicity (DLT) during Dose Escalation part to determine Maximum Tolerated Dose (MTD) [Phase Ib]
时间窗: Cycle 1 (21 days carboplatin combination or 42 days lomustine combination )
Maximum Tolerated Dose (MTD) is defined as the highest BKM120 dosage that does not cause medically unacceptable Dose Limiting Toxicities (DLTs) in more than 35% of the treated patients during the first cycle of treatment. DLT is defined as treatment-related toxicity occurring during the phase Ib cycle 1 and meeting specific protocol-predefined criteria. The information will be integrated in a Bayesian logistic regression model with overdose control to estimate the MTD.
次要结局
- Overall response rate (ORR) [Phae II, carboplatin combination](Baseline, every 6 weeks from treatment start until disease progression or until start of another antineoplastic treatment or death which ever occurs first up to 1 year)
- Progression Free Survival (PFS) [Phase Ib- both combinations](Time from treatment start to the date of the event (expected average 3 months))
- 24 week Progression Free Survival (PFS) rate (Phase II- lomustine combinations)(24 weeks)
- Overall Response Rate (ORR) as per Response Assessment in Neuro-Oncology (RANO) [Phase Ib , both combinations](Baseline, every 6 weeks from treatment start until disease progression or until start of another antineoplastic treatment or death which ever occurs first up to 1 year)
- Overall survival (OS) [Phase II lomustine combinations](12 months)
- Frequency and severity of Adverse Events (AEs) [Phase Ib, Phase II, all treatment arms](Until 30 days after treatment discontinuation)
- Progression Free Survival (PFS) [Phase II, carboplatin combination](Time from treatment start to the date of the event (Expected average: 3 months))
- 24 week Progression Free Survival (PFS) rate (Phase II carboplatin combination)(24 weeks)
- Overall Response Rate (ORR) (Phase II Lomustine combinations)(Baseline, every 6 weeks from treatment start until disease progression or until start of another antineoplastic treatment or death which ever occurs first up to 1 year)
- 12 week Progression Free Survival (PFS) rate (Phase II- lomustine combinations)(12 weeks)
- Overall Survival (OS) (Phase II Carboplatin combination)(12 months)