A Phase 1b/2 Study to Assess the Safety, Tolerability and Efficacy of BGB-290 in Combination With Radiation Therapy (RT) and/or Temozolomide (TMZ) in Subjects With First-line or Recurrent/Refractory Glioblastoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 116
- 试验地点
- 22
- 主要终点
- Phase 2 Arm C: Objective Response Rate (ORR) as Assessed Using RANO Criteria
研究概览
简要总结
The primary objective of this study is to evaluate the safety, efficacy and clinical activity of Pamiparib in combination with radiation therapy (RT) and/or temozolomide (TMZ) in participants with newly diagnosed or recurrent/refractory glioblastoma.
详细描述
An open-label, multiple-dose, dose-escalation study to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of Pamiparib in combination with radiation therapy (RT) and/or TMZ.
In dose escalation/Phase 1b, Pamiparib will be combined with RT (Arm A) or RT and TMZ (Arm B) in participants with newly diagnosed unmethylated glioblastoma (GBM) and in Arm C of the study Pamiparib will be combined with TMZ in participants with methylated or unmethylated recurrent/refractory GBM.
The dose expansion/Phase 2 phase will enroll up to 4 cohorts: participants with newly diagnosed unmethylated GBM in Arms A and B, and 2 cohorts of participants with recurrent/refractory GBM grouped by O-6-methylguanine-DNA methyltransferase (MGMT) status - unmethylated or methylated - in Arm C.
Participants in Arms A and B are treated until completion of RT and participants in Arm C may continue treatment in the absence of safety concerns and disease progression.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
No Masking
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
- •All participants
- •Age ≥ 18 years old.
- •Confirmed diagnosis of glioblastoma (WHO Grade IV).
- •Agreement to provide archival tumor tissue for exploratory biomarker analysis
- •Ability to undergo serial MRIs.
- •Eastern Cooperative Oncology Group (ECOG) status ≤
- •Adequate hematologic and end-organ function
- •Females of childbearing potential and non-sterile males must agree to use highly effective methods of birth control throughout the course of study and at least up to 6 months after last dosing.
- •Ability to swallow whole capsules.
- •Participants in Arms A and B (not Arm C) must meet inclusion criteria # 9 - 11:
- •No previous treatment for GBM except surgery.
- •Able to start radiation therapy ≤ 49 days after surgery but ≥ 14 days after a biopsy or ≥28 days after an open biopsy or craniotomy with adequate wound healing.
- •Documented unmethylated MGMT promoter status.
- •Participants in Arm C Escalation (Phase 1b) must meet inclusion criteria # 12 - 15:
- •Documentation of MGMT promoter status
- •No prior systemic chemotherapy other than TMZ for GBM.
- •Histologically confirmed secondary glioblastoma
- •Disease that is evaluable or measurable as defined by Response Assessment in Neuro-Oncology (RANO) criteria
- •Participants in Arm C Expansion (Phase 2), must meet criteria # 16 - 18:
- •Histologically confirmed de novo (primary) glioblastoma with unequivocal first progressive disease (PD) after RT with concurrent/adjuvant TMZ chemotherapy
- •Disease that is measurable as defined by RANO criteria
- •Documentation of MGMT promoter status
排除标准
- •All participants
- •Prior chemotherapy, biologic therapy, immunotherapy or investigational agents ≤21 days prior to start of study treatment.
- •Toxicity of ≥ Grade 2 from prior therapy.
- •Major surgery or significant other injury ≤ 4 weeks prior to start of study treatment.
- •History of other active malignancies within 2 years with exception of (i) adequately treated in situ cancer of the cervix, (ii) non-melanoma skin cancer, or (iii) localized adequately treated cancer with curative intent or malignancy diagnosed > 2 years ago with no evidence of disease and no treatment ≤ 2 years prior to study treatment.
- •Active infection requiring systemic treatment.
- •Known human immunodeficiency virus (HIV) or active viral hepatitis.
- •Active, clinically significant cardiac disease or any Class 3 or 4 cardiac disease, ventricular arrhythmia or Cerebrovascular Accident (CVA) ≤ 6 months prior to start of treatment.
- •Active clinically significant gastrointestinal disease.
- •Active bleeding disorder ≤ 6 months prior to start of treatment.
- •Need for therapeutic anti-coagulation with heparin, warfarin or other anticoagulants.
- •Use of any medications or food known to be strong or moderate cytochrome P450, family 3, subfamily A (CYP3A) inhibitors or strong inducers.
- •Pregnant or nursing females.
- •Significant intercurrent illness that may result in participant's death prior to death from glioblastoma.
- •Arms B and C Only:
- •Known hypersensitivity to any component of TMZ or decarbazine (DTIC).
- •Have hereditary problems of galactose intolerance
- •NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Arm C (Dose Expansion-Cohorts C1 and C2)
Participants with recurrent/refractory methylated or unmethylated GBM will receive Pamiparib and TMZ.
干预措施: TMZ (Drug)
Arm A (Dose Escalation)
Participants with newly diagnosed unmethylated GBM will receive Pamiparib and radiation therapy.
干预措施: Radiation (Radiation)
Arm A (Dose Escalation)
Participants with newly diagnosed unmethylated GBM will receive Pamiparib and radiation therapy.
干预措施: Pamiparib (Drug)
Arm B (Dose Escalation)
Participants with newly diagnosed unmethylated GBM will receive Pamiparib, radiation therapy (RT) and temozolomide (TMZ).
干预措施: Pamiparib (Drug)
Arm B (Dose Escalation)
Participants with newly diagnosed unmethylated GBM will receive Pamiparib, radiation therapy (RT) and temozolomide (TMZ).
干预措施: TMZ (Drug)
Arm B (Dose Escalation)
Participants with newly diagnosed unmethylated GBM will receive Pamiparib, radiation therapy (RT) and temozolomide (TMZ).
干预措施: Radiation (Radiation)
Arm A (Dose Expansion)
Participants with newly diagnosed unmethylated GBM will receive Pamiparib and radiation therapy.
干预措施: Pamiparib (Drug)
Arm A (Dose Expansion)
Participants with newly diagnosed unmethylated GBM will receive Pamiparib and radiation therapy.
干预措施: Radiation (Radiation)
Arm C (Dose Escalation)
Participants with recurrent/refractory methylated or unmethylated GBM will receive Pamiparib and TMZ.
干预措施: Pamiparib (Drug)
Arm C (Dose Escalation)
Participants with recurrent/refractory methylated or unmethylated GBM will receive Pamiparib and TMZ.
干预措施: TMZ (Drug)
Arm C (Dose Expansion-Cohorts C1 and C2)
Participants with recurrent/refractory methylated or unmethylated GBM will receive Pamiparib and TMZ.
干预措施: Pamiparib (Drug)
结局指标
主要结局
Phase 2 Arm C: Objective Response Rate (ORR) as Assessed Using RANO Criteria
时间窗: From the date of first dose up to first documentation of disease progression while participant is alive (up to 3 years and 7.5 months)
ORR (objective response rate) is defined as percentage of participants with best overall response of CR or PR per RANO criteria (confirmed by a subsequent tumor assessment at least four weeks apart).
Phase 1b Arm C: Number of Cycles of Treatment Received by Participants
时间窗: From the date of first dose up to EOS visit ( up to 3 years and 7.5 months)
Data shows the number of participants who received treatment for the given number of cycles.
Phase 2 Arm A: Modified Disease Control Rate (DCR) as Assessed by Response Assessment in Neuro-Oncology (RANO) Criteria
时间窗: From the date of first dose up to first documentation of disease progression while participant is alive ( up to 3 years and 7.5 months)
Modified DCR is defined as the percentage of participants with complete response (CR), partial response (PR) or stable disease (SD) per RANO criteria as the response assessment at the end-of-treatment (EOT) visit.
Phase 1b Escalation Phase: Number of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by CTCAE
时间窗: Arm A:Day 1 Pamiparib dose until 4 weeks after the last RT; Arm B: Day 1 of Pamiparib and Temozolomide until 4 weeks after the last RT; Arm C: 1st cycle of 28 days
A DLT is defined as one of the following toxicities occurring during the DLT assessment window: Grade ≥3 non-hematologic, non-hepatic major organ adverse event (AE) Grade 4 neutropenia lasting \>7 days Grade ≥3 febrile neutropenia Grade 3 thrombocytopenia with clinically significant bleeding Grade 4 thrombocytopenia lasting \> 3 days and requiring transfusion, or any decreased platelet count \<15,000/mm3/ \<15.0 x 109/L Grade ≥4 anemia Grade ≥3 total bilirubin or hepatic transaminases (ALT or AST)
Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE
时间窗: From initiation of study treatment (for TEAE) or from the date informed consent has been signed (for SAE), until 30 days after last study treatment or initiation of new anticancer therapy, whichever occurs first (up to 3 years and 7.5 months)
A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date on or after first dose of study treatment or was worsening in severity from baseline (pretreatment) up to 30 days following permanent study treatment discontinuation or initiation of new anti-cancer therapy, whichever occurs first. An SAE is any untoward medical occurrence that, at any dose meets at least one of the following criteria: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is considered a significant medical AE based on medical judgment.
Phase 1b Escalation Phase Arm C: Number of Participants With Clinically Relevant Changes in Vital Signs and Clinical Laboratory Measurements
时间窗: From the date of first dose up to end of study (EOS) visit (up to 3 years and 7.5 months)
Phase 1b Arm C: Average Dose Intensity of Pamiparib And TMZ Received Per Participant
时间窗: From the date of first dose until EOS visit (up to 3 years and 7.5 months)
The average dose intensity per participant = total dose (mg) per participant / duration of treatment (days).
次要结局
- Phase 1b and Phase 2 Arms A, B and C: Overall Survival (OS)(From the date of first dose up to the date of death (up to 3 years and 7.5 months))
- Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants(From date of first dose up to EOS Visit (up to 3 years and 7.5 months))
- Phase 1b and Phase 2 Arms A, B and C: Duration of Response (DOR) as Assessed Using RANO Criteria(From first documentation of CR or PR to first documentation of disease progression or death (up to 3 years and 7.5 months))
- Phase 1b and Phase 2 Arms A, B and C: Progression Free Survival (PFS) as Assessed Using RANO Criteria(From the date of first dose up to first documentation of disease progression or death (up to 3 years and 7.5 months))
- Phase 2 Arms A and C Expansion Phase: Average Dose Intensity of Pamiparib and TMZ Received Per Participant(From date of first dose up to EOS Visit (up to 3 years and 7.5 months))
- Phase 1B and Phase 2: Pharmacokinetics: Ctrough of Pamiparib(Pre-dose, 2 hours post dose on Days 1 and 15 of radiation Therapy)
- Phase 1b Arm A and Arm B Escalation Phase: Modified Disease Control Rate as Assessed by RANO Criteria(From the date of first dose up to first documentation of disease progression while participant is alive (approximately 3 years and 7.5 months))
- Phase 1b and Phase 2 Arms A and B: ORR as Assessed Using RANO Criteria(From the date of first dose up to first documentation of disease progression while participant is alive ( up to 3 years and 7.5 months))
- Phase 2 Arms A and C Expansion Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)(From initiation of study treatment (for TEAE) or from the date informed consent has been signed (for SAE), until 30 days after last study treatment or initiation of new anticancer therapy, whichever occurs first (up to 3 years and 7.5 months))
- Phase 1b Escalation Phase Arm C: Disease Control Rate as Assessed by RANO Criteria(From the date of first dose up to first documentation of disease progression while participant is alive (up to 3 years and 7.5 months))
- Phase 1b and Phase 2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria(From the date of first dose up to first documentation of disease progression while participant is alive (up to 3 years and 7.5 months))
- Phase 2 Expansion Phase Arm A and C: Number of Participants With Clinically Relevant Changes in Vital Signs and Clinical Laboratory Measurements(From the date of first dose up to EOS visit (up to 3 years and 7.5 months))