Phase I/Randomized Phase II Trial of Either Dasatinib or Placebo Combined With Standard Chemo-Radiotherapy for Newly Diagnosed Glioblastoma Multiforme (GBM)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 217
- 试验地点
- 206
- 主要终点
- Overall Survival
研究概览
简要总结
Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It may also make tumor cells more sensitive to radiation therapy. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. This randomized phase I/II trial is studying the best dose of dasatinib and to see how well it works compared with a placebo when given together with radiation therapy and temozolomide in treating patients with newly diagnosed glioblastoma multiforme.
详细描述
This trial includes a phase I dose-escalation study and a double-blind randomized phase II trial for patients with newly diagnosed glioblastoma multiforme (GBM). Phase I will be a cohort of 3 dose-escalation trial of dasatinib in combination with radiation and concomitant temozolomide. Patients receive concomitant chemotherapy and radiation therapy for cycle one. Patients receive adjuvant chemotherapy 28-42 days post cycle one treatment. Patients receive only dasatinib post cycle 8 treatment until progressive disease, unacceptable adverse events or refusal.
Phase II will be a randomized trial with two treatment arms. Patients will be randomized at the time of registration at a ratio of 1:2 respectively to either standard therapy arm (continuous daily placebo prior, during and after standard radiotherapy/temozolomide followed by temozolomide. For more information please see the Arms section. The primary objectives are listed below.
Primary Objectives:
- To establish a maximum tolerated dose of dasatinib combined with radiation and temozolomide in this patient population (Phase I)
- To determine the efficacy of dasatinib in combination with radiotherapy and concomitant and adjuvant temozolomide in patients with newly diagnosed glioblastoma, and compare it with the standard of care approach in the treatment of these patients consisting of radiotherapy and temozolomide, followed by adjuvant temozolomide (Phase II)
Patients are followed for 5 years post treatment. The study permanently closed to accrual on January 31, 2014.
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
- Double (Participant, Investigator)
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
- •Central Pathology Review - Central pathology review submission. This review is mandatory prior to registration to confirm eligibility.
- •Registration Inclusion Criteria:
- •Age ≥ 18 years
- •Histological Confirmation of Glioblastoma - Histologically confirmed newly diagnosed glioblastoma (GBM) (grade 4 astrocytoma) as determined by pre-registration central pathology review. Note: GBM with oligodendroglial features are not permitted in this study if they are 1p19q codeleted. Sites submitting GBM with oligodendroglial features will be asked to provide results of 1p/19q codeletion status.
- •Measurable or Evaluable Disease - Measurable or evaluable disease by gadolinium MRI or contrast CT scan. Note: Patients who have had a gross total resection are eligible on the basis of evaluable disease.
- •ECOG Performance Status 0, 1 or
- •Required Laboratory Values:
- •The following laboratory values obtained ≤ 14 days prior to registration.
- •Absolute neutrophil count (ANC) ≥ 1500/mm3
- •Platelet count ≥ 100,000/mm3
- •Hemoglobin > 9.0 g/dL
- •Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
- •SGOT (AST) ≤ 2.5 x ULN
- •Creatinine ≤ 1.5 x ULN
- •Required INR Value: The following INR value obtained ≤ 28 days prior to registration
- •INR ≤ 1.5
- •Urine or Serum Pregnancy Test - Negative urine or serum pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only.
- •Written Informed Consent - Patient must provide written informed consent.
- •Return to Enrolling Institution - Patient must be willing to return to Alliance enrolling institution for follow-up.
- •Tissue Samples - Patient must be willing to provide tissue samples for research purposes.
- •Patient must be willing to provide tissue samples for research purposes.
- •Required Antibiotic Prophylaxis - Patient must be willing to comply with antibiotic prophylaxis with trimethoprim/sulfamethoxazole, pentamidine or dapsone.
- •Grapefruit and Grapefruit Juice - Patient must be willing to abstain from eating grapefruit or drinking grapefruit juice for the duration of the study treatment.
- •Ability to Swallow - Patient must have the ability to take oral medication (dasatinib must be swallowed whole).
- •Quality of Life (QOL) Questionnaires - Phase II patients only: Patients must be willing and able to complete QOL questionnaires independently or with the help of a caregiver.
- •Other Anti-Tumor Drug Therapies - Patient must be willing to forego other cytotoxic and non-cytotoxic drug therapy against the tumor while being treated with dasatinib and temozolomide.
- •Registration
排除标准
- •Pregnancy, Nursing and Required Contraception - Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
- •Pregnant women
- •Nursing women
- •Men or women of childbearing potential who are unwilling to employ adequate contraception throughout study treatment and for at least 12 weeks after study drug is stopped.
- •Prior Radiotherapy or Chemotherapy for Any CNS Neoplasm - Received any prior radiotherapy or chemotherapy for any CNS neoplasm (hormones, vitamins and growth factors are not considered chemotherapy for the purposes of this study.
- •Prior Surgery for Any CNS Neoplasm - Prior surgeries for any CNS neoplasms, other than surgery related to the current GBM diagnosis. Note: If Gliadel wafers are placed at time of primary resection, this would be considered prior therapy and patient would be ineligible.
- •Concurrent Illness or Disease - Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens. Including but not limited to:
- •History of bleeding diathesis
- •Current use of chronic systemic anticoagulation therapy that cannot be discontinued (antiplatelet agents, Aspirin)
- •Current chronic use of NSAIDs which cannot be discontinued
- •Pleural or Pericardial Effusions - Pleural or pericardial effusion of any grade.
- •Immunocompromised Status - Immunocompromised patients (other than that related to the use of corticosteroids) and patients known to be HIV positive and currently receiving antiretroviral therapy. Note: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
- •Uncontrolled Intercurrent Illness - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Other Investigational Agents - Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
- •Other Active Malignancies - Other active malignancy ≤ 5 years prior to registration.
- •Exceptions: Non-melanotic skin cancer or carcinoma-in-situ of the cervix. Note: If there is a history of prior malignancy, they must not be receiving other specific treatment other than hormonal therapy for their cancer.
- •History of Cardiac or Metabolic Conditions:
- •Myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
- •Diagnosed congenital long QT syndrome
- •Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)
- •Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec)
- •Patients with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration.
- •Clinically Significant Cardiovascular Disease - Patients may not have any clinically significant cardiovascular disease including the following:
- •Myocardial infarction or ventricular tachyarrhythmia within 6 months.
- •Ejection fraction less than institutional normal
- •Major conduction abnormality (unless a cardiac pacemaker is present)
- •Note: Patients with any cardiopulmonary symptoms of unknown cause (e.g., shortness of breath, chest pain, etc.) should be evaluated by a baseline echocardiogram with or without stress test as needed in addition to ECG to rule out QTc prolongation. The patient may be referred to a cardiologist at the discretion of the principal investigator.
- •Patients with underlying cardiopulmonary dysfunction should be excluded from the study.
- •Congestive Heart Failure - New York Heart Association classification ≥ Class II Congestive Heart Failure.
- •Prohibited or Restricted Concomitant Treatments - Currently taking one of the following medications:
- •Enzyme inducing anti-convulsants (EIACs) Note: To be eligible, patient must be switched to non-EIAC medications ≥7 days prior to registration. See protocol for a list of EIAC and non-EIAC medications.
- •Potent inhibitors of CYP3A4 which cannot be discontinued. See protocol for a list of medications known to inhibit CYP3A
- •Medications known to prolong QT interval which cannot be discontinued or switched. See Appendix II for a list of medications which are known to prolong the QT interval.
- •Medications that may possibly prolong QT interval and produce a QTc that is ≥ 60 msec or a QTcF that is ≥ 450 msec. See Appendix II for a list of medications that may possibly prolong QTc.
- •St. John's Wort
- •H2 blockers or proton pump inhibitors (PPIs), such as famotidine (Pepcid) and omeprazole (Prilosec) respectively, which cannot be discontinued or switched to locally acting agents, such as Maalox, Mylanta and TUMS.
- •Allergy to Antibiotic Prophylaxis Medications - Severe allergy to sulfa medications and dapsone and pentamidine.
研究组 & 干预措施
Group 1 (Phase II) dasatinib + radiation + temozolomide
Patients receive concomitant chemotherapy and radiation for cycle one for a total of 42 days, then patients receive adjuvant chemotherapy 28-42 days post cycle one treatment. Patients receive only dasatinib post cycle 8 until progressive disease, unacceptable adverse events or refusal.
干预措施: dasatinib (Drug)
Group 1 (Phase II) dasatinib + radiation + temozolomide
Patients receive concomitant chemotherapy and radiation for cycle one for a total of 42 days, then patients receive adjuvant chemotherapy 28-42 days post cycle one treatment. Patients receive only dasatinib post cycle 8 until progressive disease, unacceptable adverse events or refusal.
干预措施: temozolomide (Drug)
Group 1 (Phase II) dasatinib + radiation + temozolomide
Patients receive concomitant chemotherapy and radiation for cycle one for a total of 42 days, then patients receive adjuvant chemotherapy 28-42 days post cycle one treatment. Patients receive only dasatinib post cycle 8 until progressive disease, unacceptable adverse events or refusal.
干预措施: radiation therapy (Radiation)
Group 2 (Phase II) placebo + radiation + temozolomide
Patients receive concomitant chemotherapy and radiation for cycle one for a total of 42 days, then patients receive adjuvant chemotherapy 28-42 days post cycle one treatment. Patients receive only placebo post cycle 8 until progressive disease, unacceptable adverse events or refusal.
干预措施: temozolomide (Drug)
Group 2 (Phase II) placebo + radiation + temozolomide
Patients receive concomitant chemotherapy and radiation for cycle one for a total of 42 days, then patients receive adjuvant chemotherapy 28-42 days post cycle one treatment. Patients receive only placebo post cycle 8 until progressive disease, unacceptable adverse events or refusal.
干预措施: placebo (Other)
Group 2 (Phase II) placebo + radiation + temozolomide
Patients receive concomitant chemotherapy and radiation for cycle one for a total of 42 days, then patients receive adjuvant chemotherapy 28-42 days post cycle one treatment. Patients receive only placebo post cycle 8 until progressive disease, unacceptable adverse events or refusal.
干预措施: radiation therapy (Radiation)
结局指标
主要结局
Overall Survival
时间窗: Up to 5 years post treatment
Overall survival (OS) is the primary endpoint and is defined as the time from study registration to time of death due to any cause. All patients who meet the eligibility criteria, have signed a consent form, and have received at least one dose of the regimens will be considered evaluable. Patients who are lost to follow-up will be censored at the date of their last follow-up. Patients still alive at the time of analysis will be censored. Only Phase II was evaluated for survival
The Number of Dose Limiting Toxicities(DLT) in Order to Determine Maximum Tolerable Dose(MTD) of Dasatinib Combined With Radiation and Temozolomide in This Patient Population.
时间窗: Every cycle from first dose to end of rest period prior cycle 3
Doselimiting toxicity will be defined as: Adverse event at least possibly related to the study medication. All by CTCAE v3.0 criteria: Greater than or equal to grade 3: diarrhea or skin rash or desquamation or (other) clinically relevant non-hematological adverse event or non-hematologic adverse event at least possibly due to drug therapy. Or greater than or equal to grade 4: neutropenia or leukopenia or thrombocytopenia or radiation dermatitis or hematologic adverse event OR failure to administer greater than 75% of dasatinib TMZ or interruption of RT for more than 5 days due to adverse events.OR severe acute central nervous system deterioration attributable to TMZ, RT and or dasatinib which cannot be controlled with corticosteroid administration. The MTD for this study will be defined as the highest safely tolerated dose level where at most 1 out of 6 patients experience DLT with the next higher dose having at least 2 patients out of a maximum of 6 patients experience DLT.
次要结局
- Progression-free Survival(Up to 5 years post treatment)
- Objective Response(Up to 5 years post treatment)