Efficacy and Safety of AP 12009 in Adult Patients With Recurrent or Refractory Anaplastic Astrocytoma or Secondary Glioblastoma as Compared to Standard Chemotherapy Treatment: A Randomized, Actively Controlled, Open Label Clinical Phase III Study.
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 27
- 试验地点
- 67
- 主要终点
- Survival Rate at 24 Months in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)
研究概览
简要总结
In this multinational Phase III study the efficacy and safety of 10 µM AP 12009 is compared to standard chemotherapy (temozolomide or BCNU or CCNU) in adult patients with confirmed recurrent or refractory anaplastic astrocytoma (WHO grade III) or secondary glioblastoma (WHO grade IV).
详细描述
The purpose of this study is to compare the safety and efficacy of the 10 µM concentration of AP 12009 and standard chemotherapy (temozolomide, BCNU, CCNU) in adult patients with recurrent or refractory anaplastic astrocytoma (AA, WHO grade III) or secondary glioblastoma (GBM, WHO grade IV). AP 12009 (trabedersen) is a phosphorothioate antisense oligodeoxynucleotide specific for the mRNA of human Transforming Growth Factor beta 2 (TGF-beta-2), which is applied intratumorally. The growth factor TGF-beta plays a key role in malignant progression of various tumors by inducing proliferation, invasion, metastasis, angiogenesis, and escape from immunosurveillance. In patients with high-grade glioma, the TGF-beta-2 overexpression is associated with disease stage, clinical prognosis, and the immunodeficient state of the patients. Main objective of the study is to determine survival (rate) and tumor response.
Important note: Due to early trial termination, resulting in limited data availability, all analyses remain descriptive by nature, only. No conclusive endpoint analysis can be performed.
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The patient has provided written informed consent prior to any study-related procedure.
- •The patient is at least 18 years of age and equal to or below 70 years.
- •The patient has a present diagnosis of AA or secondary GBM.
- •The patient has a measurable lesion (> 1 ccm in volume, central MRI review).
- •The lesion (or sum of lesions) does not exceed 50 ccm in volume (central MRI review).
- •The tumor is localized supratentorially (central MRI review).
- •All patients have recurrent or refractory disease, i.e. disease has progressed after prior surgery and radiotherapy at any time of the disease course or stage. Secondary GBM patients have progressed after a previous diagnosis of A and/or AA.
- •The patient has not received more than one chemotherapy regimen. Radiation with concomitant chemotherapy, followed by adjuvant chemotherapy, is considered as one chemotherapy regimen.
- •The patient is eligible for chemotherapy.
- •The patient is on a maximum dose of 4 mg/day dexamethasone or equivalent doses for other corticosteroids, which has been stable or decreasing for at least 3 weeks prior to Screening.
- •The patient is male or a non-pregnant, non-lactating female.
- •Females of childbearing potential must have a negative beta-HCG pregnancy test at Screening.
- •Females of childbearing potential and males must practice strict birth control.
- •The patient must have recovered from acute toxicity caused by any previous therapy.
- •The patient has a life expectancy of at least 3 months.
- •The patient has a Karnofsky Performance Status of at least 70%.
- •The patient shows adequate organ functions as assessed by the following screening laboratory values:
- •Adequate renal function determined by serum creatinine and urea < 2 times the upper limit of normal
- •Adequate liver function with ALT, AST and AP < 3 times the upper limit of normal, and bilirubin < 2.5 mg/dL
- •INR < 1.5 and aPTT < 1.5 x ULN
- •Hemoglobin > 9 g/dL
- •Platelet count > 100 x 10E9/L
- •WBC > 3 x 10E9/L
- •ANC > 1.5 x 10E9/L (or WBC > 3.0 x 10E9/L)
排除标准
- •Patient unable or not willing to comply with the protocol regulations.
- •The investigator deems it necessary to surgically (re-)resect the present tumor (NOTE: the patient might still be eligible for randomization at a later timepoint).
- •Tumor surgery, tumor debulking, or other neurosurgery within 3 months prior to randomization. If a ≤48-hour routine post-surgery MRI (in accordance with study specifications) qualifies the patient for study participation, the patient can be randomized 30 ± 7 days post-surgery.
- •Radiotherapy or stereotactic (gamma knife) radiosurgery within 3 months prior to randomization.
- •Prior interstitial brachytherapy of the brain with permanent implants. Prior interstitial brachytherapy of the brain with removable implants within 3 months prior to randomization.
- •Chemotherapy, hormone therapy, or any other therapy with established or suggested anti-tumor effects within 4 weeks (nitrosoureas: 6 weeks) prior to randomization.
- •Prior anti-TGF-beta 2 targeted therapy.
- •Screening MRI shows a mass effect caused by the tumor defined as significant compression of the ventricular system and/or a midline shift (≥ 3 mm, central MRI review). Compression of the ventricular system and/or a midline shift ≥ 3 mm only due to the presence of (a) cyst(s) or scarring processes does not exclude an individual from the study.
- •Participation in another clinical study with another investigational medicinal product within 30 days prior to randomization.
- •History of a second independent malignant disorder within 5 years, except for carcinoma in situ of the cervix and basal cell carcinoma.
- •Presence of poorly controlled seizures.
- •Clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure, unstable angina, or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to randomization.
- •Known HIV, HBV or HCV infection.
- •Acute viral, bacterial, or fungal infection.
- •Acute medical problems that may be considered to become an unacceptable risk, or any conditions, which might be contraindications for starting study treatment.
- •Presence of high risk for pulmonary toxicities, defined as:
- •Lung function: vital capacity ≤ 70%
- •Status following sequential or concomitant thoracic irradiation
- •Increased risk for a pulmonary toxicity induced by BCNU (Carmustine) or CCNU (Lomustine). Risk factors include smoking, presence of a respiratory condition, pre-existing radiographic pulmonary abnormalities, exposure to agents that cause lung damage.
- •History of allergies to reagents used in this study, history of celiac disease.
- •Drug abuse or extensive use of alcohol.
- •Clinically relevant psychiatric disorders / legal incapacity or a limited legal capacity.
- •Concomitant treatment with yellow fever vaccine.
研究组 & 干预措施
trabedersen 10 µM
10 µM trabedersen (AP 12009), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks
干预措施: trabedersen (Drug)
trabedersen 10 µM
10 µM trabedersen (AP 12009), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks
干预措施: Drug delivery system for administration of AP 12009 (Device)
trabedersen 10 µM
10 µM trabedersen (AP 12009), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks
干预措施: Placement of Drug Delivery System (Procedure)
Chemotherapy
temozolomide: capsules, up to 200 mg/sqm/day, 5 days per cycle, up to 26 cycles; carmustine: i.v. administration, up to 200 mg/sqm/day, 1 day per cycle, up to 8 cycles; lomustine: capsules, 110 mg/sqm/day, 1 day per cycle, up to 8 cycles. Only 1 of these 3 drugs/interventions is administered per patient in the comparator arm.
干预措施: temozolomide (Drug)
Chemotherapy
temozolomide: capsules, up to 200 mg/sqm/day, 5 days per cycle, up to 26 cycles; carmustine: i.v. administration, up to 200 mg/sqm/day, 1 day per cycle, up to 8 cycles; lomustine: capsules, 110 mg/sqm/day, 1 day per cycle, up to 8 cycles. Only 1 of these 3 drugs/interventions is administered per patient in the comparator arm.
干预措施: carmustine (Drug)
Chemotherapy
temozolomide: capsules, up to 200 mg/sqm/day, 5 days per cycle, up to 26 cycles; carmustine: i.v. administration, up to 200 mg/sqm/day, 1 day per cycle, up to 8 cycles; lomustine: capsules, 110 mg/sqm/day, 1 day per cycle, up to 8 cycles. Only 1 of these 3 drugs/interventions is administered per patient in the comparator arm.
干预措施: lomustine (Drug)
结局指标
主要结局
Survival Rate at 24 Months in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)
时间窗: 24 months
Survival rate was defined as the proportion of participants known to be alive at 24 months from randomization. If a participant's status was unknown and there was no follow-up information available, they were categorized as 'Died' for the purposes of the analysis.
Survival at 24 Months in the Intent-to-treat Population - Number of Participants
时间窗: 24 months
Survival status was assessed at 24 months from randomization. Participants with unknown or missing status were considered treatment failures, i.e., assumed to be dead. The category "Lost to / insufficient follow-up" includes participants who were alive at last data collection point but did not yet have enough follow-up time to reach the 24 month time point.
次要结局
- Median Overall Survival (Days) From Randomization in the Intent-to-treat Population (Descriptive Analysis, Only)(Up to 24 months)
- Survival Rate at 12, 18, and 21 Months in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)(12, 18, and 21 months)
- Survival at 12, 18, and 21 Months in the Intent-to-treat Population - Number of Participants(12, 18, and 21 months)
- Overall Response Rate (CR+PR) by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)(Up to 24 months)
- Response Category by Independent Review in the Intent-to-treat Population - Number of Participants(Up to 24 months)
- Median Time to Progression (Days) by Independent Review for the Intent-to-treat Population (Descriptive Analysis, Only)(Up to 24 months)
- Median Duration of Response (Days) by Independent Review (Descriptive Analysis, Only)(Up to 24 months)
- Tumor Control Rate (CR+PR+SD) by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)(Up to 24 months)
- Disease Progression at 10, 12, 14, 16, 18, 21, and 24 Months by Independent Review in the Intent-to-treat Population - Number of Participants(10, 12, 14, 16, 18, 21, and 24 months)
- Disease Progression Rate at 10, 12, 14, 16, 18, 21, and 24 Months by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)(10, 12, 14, 16, 18, 21 and 24 months)