Phase I/II Studies of BAY 43-9006 (Sorafenib) in Combination With OSI-774 (Erlotinib), R115777 (Tipifarnib) or CCI-779 (Temsirolimus) in Patients With Recurrent Glioblastoma Multiforme or Gliosarcoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 92
- 试验地点
- 7
- 主要终点
- Pharmacokinetic cMax Group 1 Sorafenib and Erlotinib (Phase I)
研究概览
简要总结
This phase I/II trial is studying the side effects and best dose of erlotinib, tipifarnib, and temsirolimus when given together with sorafenib and to see how well they work in treating patients with recurrent glioblastoma multiforme or gliosarcoma. Sorafenib, erlotinib, tipifarnib, and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sorafenib and tipifarnib may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving sorafenib together with erlotinib, tipifarnib, or temsirolimus may kill more tumor cells.
详细描述
PRIMARY OBJECTIVES:
Phase 1
- Determine the maximum tolerated dose (MTD) of tipifarnib, erlotinib hydrochloride, or temsirolimus in combination with a fixed dose of sorafenib in patients with recurrent glioblastoma multiforme or gliosarcoma who are not taking enzyme-inducing antiepileptic drugs.
SECONDARY OBJECTIVES:
Phase 1 and 2
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
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 confirmed intracranial glioblastoma multiforme or gliosarcoma
- •Evidence of tumor progression by MRI or CT scan within the past 14 days AND on a steroid dose that has been stable for ≥ 5 days
- •Patients who underwent prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis by either positron emission tomography or thallium scanning, magnetic resonance (MR) spectroscopy, or surgical documentation of disease
- •Recent resection of recurrent or progressive tumor allowed
- •Residual disease is not required
- •Treatment for any number of prior relapses, defined as disease progression after initial therapy (i.e., radiotherapy with or without chemotherapy if used as initial treatment), allowed (phase I)
- •No more than 3 prior therapies (initial therapy and therapy for 2 relapses) (phase II)
- •Each of the following is considered 1 relapse:
- •Disease progression after initial therapy (i.e., radiotherapy with or without chemotherapy if used as initial therapy)
- •Underwent a surgical resection for relapsed disease and received no anticancer therapy for up to 12 weeks after surgical resection AND then underwent a subsequent surgical resection
- •Received prior therapy for a low-grade glioma, followed by a surgical diagnosis of glioblastoma
- •Failed prior radiotherapy
- •15 unstained paraffin slides or 1 tissue block must be available from original surgery, definitive surgery, or surgery closest to the initiation of this study (phase II)
- •Karnofsky performance status 60-100%
- •White Blood Cell (WBC) ≥ 3,000/mm^3
- •Absolute neutrophil count ≥ 1,500/mm^3
- •Platelet count ≥ 100,000/mm^3
- •Hemoglobin ≥ 10 g/dL (transfusion allowed)
- •Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) ≤ 2.5 times upper limit of normal (ULN)
- •Total bilirubin normal
- •Creatinine < 1.5 mg/dL
- •Prothrombin time (PT)/ international normalized ratio (INR) ≤ 1.5 (INR < 3.0 for patients on anticoagulation therapy)
- •INR < 1.1 times upper limit of normal (ULN) (for patients on prophylactic anticoagulation therapy [low-dose warfarin])
- •Fasting cholesterol < 350 mg/dL (for patients receiving temsirolimus and sorafenib)
- •Fasting triglycerides < 400 mg/dL (for patients receiving temsirolimus and sorafenib)
- •Well-controlled hypertension (e.g., systolic blood pressure ≤ 140 mm Hg or diastolic pressure ≤ 90 mm Hg) allowed
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective barrier contraception during and for at least 2 weeks (women) or 3 months (men) after completion of study treatment
- •No peripheral neuropathy > grade 1 (for patients receiving sorafenib and tipifarnib)
- •No evidence of bleeding diathesis or coagulopathy
- •No history of any other cancer (except nonmelanoma skin cancer or carcinoma in situ of the cervix), unless in complete remission and off all therapy for that disease for ≥ 3 years
- •No significant traumatic injury within the past 21 days
- •No active infection or serious medical illness that would preclude study treatment
- •No condition that would impair ability to swallow pills (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation or active peptic ulcer disease)
- •No HIV disease
- •No allergies to imidazoles (e.g., clotrimazole, ketoconazole, miconazole or econazole) or a history of allergic reactions attributed to any compound of similar chemical or biological composition to tipifarnib (for patients receiving sorafenib and tipifarnib)
- •No other disease that would obscure toxicity or dangerously alter drug metabolism
- •Recovered from prior therapy
- •At least 7 days since prior noncytotoxic agents (e.g., interferon, tamoxifen, thalidomide, or isotretinoin) (radiosensitizer does not count)
- •At least 14 days since prior vincristine
- •At least 21 days since prior procarbazine or major surgery
- •At least 28 days since prior investigational agent or cytotoxic therapy
- •At least 42 days since prior nitrosoureas or radiotherapy
- •No prior sorafenib, AEE788, or vatalanib
- •No prior surgical procedures affecting absorption
- •No prior tipifarnib, lonafarnib, or other agents targeting farnesyl transferase (for patients receiving sorafenib and tipifarnib)
- •No prior temsirolimus or mechanistic target of rapamycin (mTOR-targeting agent) (phase II), rapamycin or everolimus, or Akt-pathway inhibitors (for patients receiving sorafenib and temsirolimus)
- •No prior erlotinib hydrochloride, multitargeted human epidermal receptor (AEE788), or other epidermal growth factor receptor targeting agents (phase II) (for patients receiving sorafenib and erlotinib hydrochloride)
- •No concurrent enzyme-inducing antiepileptic drugs (e.g., carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, or primidone)
- 另有 7 项未显示
排除标准
- 未提供
研究组 & 干预措施
Group 1
Patients receive oral sorafenib tosylate twice daily and oral erlotinib hydrochloride once daily on days 1-28.
干预措施: sorafenib tosylate (Drug)
Group 1
Patients receive oral sorafenib tosylate twice daily and oral erlotinib hydrochloride once daily on days 1-28.
干预措施: erlotinib hydrochloride (Drug)
Group 2
Patients receive sorafenib tosylate as in group 1. Patients also receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22.
干预措施: sorafenib tosylate (Drug)
Group 2
Patients receive sorafenib tosylate as in group 1. Patients also receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22.
干预措施: temsirolimus (Drug)
Group 3
Patients receive sorafenib tosylate as in group 1. Patients also receive oral tipifarnib twice daily on days 1-21.
干预措施: sorafenib tosylate (Drug)
Group 3
Patients receive sorafenib tosylate as in group 1. Patients also receive oral tipifarnib twice daily on days 1-21.
干预措施: tipifarnib (Drug)
结局指标
主要结局
Pharmacokinetic cMax Group 1 Sorafenib and Erlotinib (Phase I)
时间窗: 28days (D1, D15, D28) (0,1,2,4,6,8,12,24hr post administration)
8 samples collected over 24 hours on Day 1, day 15 and day 28 13 total patients treated 100mg Erlotinib and either 200mg or 400mg of Sorafenib
Pharmacokinetic AUC 0-12 Group 1 Sorafenib and Erlotinib (Phase I)
时间窗: 28Days (D1, D15, D28) (0,1,2,4,6,8,12,24hr post administration) AUC 0-12
8 samples collected over 24 hours on Day 1, day 15 and day 28 16 patients Note that although 16 patients were accrued/analyzed some samples were incomplete or inevaluable or missing hence number analyzed difference AUC - Area Under Curve
12 Month Survival Rate (Phase II)
时间窗: 12 months
number of patients alive at 12 months
Pharmacokinetic CpMax Concentration of Group 3 Sorafenib and Tipifarnib (Phase I) 100mg BID
时间窗: Cycle 1 = 28 day PKs D1, D15,D28 (0,1,2,4,6,8,12,24hr post drug administration)
Group 3: patients were studied for their day 1 Cmax, and day 15 Cmax Tipifanib and Day 15 and Day 28 sorafenib Group 3: Only PKs for Dose level 1 and -1 were collected.
Progression-free Survival at 6 Months (Phase II)
时间窗: 6 months
Patients with a scan at 6 months without progressive disease Progressive disease defined as Progressive neurological abnormalities not explained by other causes or greater than 25% increase in size of tumor or if new lesion.
Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg QD (Level -1)
时间窗: Cycle 1 (D1, D15, D28) (0,1,2,4,6,8,12,24hr post drug administration)
Group 3: PKs for Dose level -1 100mg QD Note that although 9 patients were accrued/analyzed some samples were incomplete or inevaluable or missing hence number analyzed difference
Pharmacokinetic Max Concentration (Cmax) of Group 2 Sorafenib and Temsirolimus (Phase I)
时间窗: cycle 1 ((Day1, Day15, Day28)
Group 2: 13 patients received temsirolimus 25mg IV and 7 patients treated with 200mg Sorafenib and 6 patients treated with 400mg Sorafenib
Trough Concentration Group 2 Sorafenib and Temsirolimus (Phase I)
时间窗: 15 days
Group 2: 12 patients were analyzed for Day 1 (1 patient not evaluable), 5 patients were analyzed for Day 15 (8 patients not evaluable)
Plasma Time Curve (AUC) of Group 2 Sorafenib and Temsirolimus (Phase I)
时间窗: Cycle 1 (D1, D15, D28) (0,1,2,4,6,8,12,24hr post drug administration)
Day 1 = 12 patients (1 sample not evaluable) Day 15 = 5 patients (8 samples not evaluable) AUC - Area Under Curve 8 samples collected over 24 hours - 28 day PKs
Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I)
时间窗: 28 days
CTCAE 3.0
Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2)
时间窗: 1 year
Maximum Tolerated Dose (MTD) of the Each Combination Agent Combined With a Fixed Dose of BAY 43-9006 Determined by Dose-limiting Toxicities (DLT) (Phase I)
时间窗: 28 days
DLT defined as: any grade 4 hematologic toxicity; grade 3 thrombocytopenia \> 7 days, any grade 3/4 non-hematologic toxicity (despite maximal medical therapy), any intolerable grade 2 non-hematological, ro grade 3 hematological toxicity requiring deduction during first 28 days of treatment, any toxicity resulting in delay of \>1week during first 28 days of treatment
Pharmacokinetic Cpmax Group 3 Sorafenib and Tipifarnib (Phase I) 100 mg QD (Level -1)
时间窗: Cycle 1 = 28 day PKs D1, D15,D28 (0,1,2,4,6,8,12,24hr post drug administration)
Group 3: Only PKs for Dose level 1 and -1 were collected.
Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg BID (Level 1)
时间窗: Cycle 1 = 28 day PKs D1, D15,D28 (0,1,2,4,6,8,12,24hr post drug administration)
Group 3: PKs for Dose level 1 Tipifarnib 100mg BID
Objective Response Rate in Patients With Measurable Disease (Phase II)
时间窗: Up to 5 years
Measurable: Bidimensionally measurable lesions w/ clearly defined margins by MRI Evaluable: Unidimensionally measurable lesions, masses w/margins not clearly defined. Complete Response (CR): Complete disappearance of all measurable/evaluable disease. No new lesions. No evidence of non-evaluable disease. Patients on minimal/no steroids. Partial Response (PR): \>/= to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. Responders must be on same/decreasing doses of dexamethasone. Stable/No Response: Does not qualify for CR, PR, or progression. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over BL if no decrease), OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
次要结局
未报告次要终点