A Phase 2 Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of the PI3K/mTOR Inhibitor Paxalisib (GDC-0084) Administered to Patients With Glioblastoma Characterized by Unmethylated O6-methylguanine-methyltransferase Promoter Status Following Surgical Resection and Standard Concomitant Chemoradiation Therapy With Temozolomide
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 30
- 试验地点
- 6
- 主要终点
- Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
This protocol has a 2-part design:
This phase 2 study is an open-label, multicenter, dose-escalation and expansion study to assess the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK) and clinical activity of paxalisib in patients with newly-diagnosed glioblastoma (GBM) with unmethylated MGMT promoter status as adjuvant therapy following surgical resection and initial chemoradiation with temozolomide (TMZ).
详细描述
Stage 1 Dose-Escalation and Maximum Tolerated Dose The dose-escalation portion of the study (Stage 1) will use a standard "3 + 3" design to determine the MTD for QD dosing.
Approximately 6 - 12 patients with newly diagnosed GBM will be enrolled in Stage 1.
The MTD for QD dosing will be determined. The initial dose level for QD dosing will be 60 mg (Dose Level 0). This dose is based on the phase 1 findings outlined in the rationale in the protocol, adding 1 dose level to test for a potential MTD increase.
Dose-escalation will occur in Stage 1:
- The initial dose (Dose Level 0) for QD MTD determination in Step 1 will be 60 mg. Dose levels will increase in 15 mg steps;
- The dose-escalation portion of the study (Stage 1) will use a standard "3 + 3" design to assess the safety, tolerability, and PK of paxalisib administered orally in 28-day cycles;
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Patients must meet all the following inclusion criteria to be eligible for enrollment into the study:
- •Age ≥ 18 years;
- •Life expectancy > 12 weeks;
- •Present with histologically confirmed intracranial (supratentorial) unmethylated MGMT promotor status GBM (WHO Grade lV astrocytoma) with a MGMT status that has been confirmed by validated PCR or validated alternate genomic analysis;
- •Have undergone maximal surgical resection of their tumor and within 6 weeks of surgery received initial treatment with XRT/TMZ which consisted of XRT by external beam to a partial brain field in daily fractions of 2.0 Gray (Gy), to a planned total dose to the tumor of 60.0 Gy, in conjunction with TMZ oral QD 75 mg/m2 in accordance with the Stupp regimen;
- •Must have measurable disease, according to RANO criteria for inclusion in the expansion cohort. Patients with non-measurable disease can be included in the dose-escalation cohorts;
- •Cranial magnetic resonance imaging (MRI) must have been performed within 7 days prior to or on the day of the Randomization/Week 1 Visit;
- •Stable or decreasing corticosteroid dose within 7 days prior to the first dose;
- •Adequate bone marrow/hematological function within 7 days prior to Day 1;
- •Adequate liver and renal function within 14 days prior to Day 1;
- •International normalized ratio (INR) or prothrombin time (PT) (secs) and activated partial thromboplastin time (aPTT) within 7 days prior to randomization:
- •Patients must be willing to forego other drug therapy against the tumor while enrolled in the study.
排除标准
- •Previous radiotherapy to the brain or cytotoxic drug therapy (including Gliadel® wafers) in addition to the required postoperative radiation plus TMZ, non-cytotoxic drug therapy, or experimental drug therapy directed against the brain tumor prior to this regimen, will be excluded. Patients may have received or be receiving corticosteroids, analgesics, and other drugs to treat symptoms or prevent complications but the dose must be stable at treatment start. NOTE: 5 aminolevulinic acid-mediated photodynamic therapy administered prior to surgery to aid in optimal surgical resection is not considered a chemotherapy agent;
- •Any prior or anticipated concomitant treatment involving a medical device (such as Optune®) applying tumor treating fields (TTF);
- •QT interval time of ≥ 470 msec;
- •Undetermined/indeterminate MGMT status;
- •Diabetic patients; prediabetic patients treated with metformin;
- •Use of any CYP3A4 inducing or inhibiting agents;
- •Significant medical illnesses;
- •Women who are pregnant or who are lactating;
- •Diagnosed with infratentorial GBM, a tumor outside of brain or gliomatosis cerebri;
- •Evidence of recent hemorrhage on postoperative MRI of the brain;
- •Any previous malignancy; except for adequately controlled limited basal cell carcinoma of the skin, squamous carcinoma of the skin or carcinoma in situ of the cervix, or one which has been absent for ≥3 years;
研究组 & 干预措施
Dose Escalation and Expansion Cohorts
This is an open-label study.
Patients in Stage 1 will be enrolled and sequentially assigned to a dose cohort.
The initial cohort will receive an oral dose of 60 mg paxalisib QD (4 x 15 mg capsules). Patients of future dose cohorts will receive paxalisib at increasing levels with 15 mg steps until a dose-limiting toxicity occurs (DLT) occurs. The dose level where <1/3 of the patients exhibit a DLT will be determined the Maximum Tolerated Dose (MTD).
In stage 1, dose escalation will occur for QD dosing.
In stage 2, the expansion phase, patients will receive doses of oral paxalisib at the MTD in stage 1, until disease progression or an unacceptable toxicity, whichever occurs first.
Patients will be randomized in a 1:1 ratio to fed or fasted schedules.
干预措施: Paxalisib (GDC-0084) (Drug)
结局指标
主要结局
Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
时间窗: Cycle 1, Days 1-28
A DLT was defined as a Grade 3 or 4 toxicity occurring within the DLT assessment window and assessed to be probably or possibly related to paxalisib. DLTs were graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. CTCAE Grade 3 is a severe adverse event (AE) and Grade 4 is a life-threatening or disabling AE. DLTs were collected to determine the maximum tolerated dose (MTD), which was defined as the dose level below the dose at which less than 33% of participants experienced a DLT.
次要结局
- Incidence of Treatment-emergent Adverse Events (TEAEs)(24 months)
- Incidence of Serious Adverse Events (SAEs)(24 months)
- Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events(24 months)
- Number of Participants Who Experienced a Change in Electrocardiogram (ECG) Parameter QTc(24 months)
- Number of Participants Who Experienced a Change Left Ventricular Ejection Fraction(24 months)
- Progression-free Survival Interval Using Using mRANO Criteria/Investigator Review.(24 months)
- Overall Survival Using RANO Criteria.(24 months)