A Multi-centre, Open-label, Single-arm, Dose-finding Phase I/II Study to Evaluate Safety, Tolerability, Dosing Schedule, and Preliminary Efficacy of Carrier-added 4-L-[131I]Iodo-phenylalanine (131I-IPA), Administered as Single or Repetitive Injections in Patients With Recurrent Glioblastoma Multiforme (GBM), Concomitantly to 2nd Line External Radiation Therapy (XRT) - IPAX- 1
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 10
- 试验地点
- 10
- 主要终点
- Safety parameter blood pressure
研究概览
简要总结
A multi-centre, open-label, single-arm, dose-finding phase I/II study to evaluate safety, tolerability, dosing schedule, and preliminary efficacy of carrier-added 4-L-[131I]iodo-phenylalanine (131I-IPA), administered as single or repetitive injections in patients with recurrent glioblastoma multiforme (GBM), concomitantly to 2nd line external radiation therapy (XRT) - IPAX-1
详细描述
The IPAX-1 study is an open-label, single-arm, randomised, parallel-group, multi-centre dose-finding study to evaluate ascending radioactive dose levels of 131I-IPA, intravenously administered using different dose schedules (fractionations), concomitantly to 2nd line XRT (36 Gy, administered in 18 fractions of 2 Gy). Gross tumour volume will be determined using contrast-enhanced MRI and amino acid-based PET imaging (18F-FET or 11C-methionine).
Patients will be included if they meet all of the following criteria:
- Previously confirmed histological diagnosis of GBM, with current clinical or imaging evidence for first recurrence according to modified RANO criteria (2017). History of GBM standard therapy (debulking surgery, followed by radio-chemotherapy (50-60 Gy in 2 Gy fractions, temozolomide)
- Interval since end of 1st line XRT ≥6 months
- Amino acid-based molecular imaging (preferably 18F-FET- PETor 11C-methionine, as institutionally established) indicating pathologically increased amino acid uptake inside or in the vicinity of the tumour, clearly discernible from background activity.
- Current indication for repeat radiation therapy as discussed at the multidisciplinary neuro-oncological tumour board meeting, planned as standard fractionated dose schedule (18*2 Gy)
- Gross tumour volume (GTV) of up to 4.8 cm diameter, clinical target volume (CTV) 0.5 cm margin and planning target volume (PTV) less than or equal to 0.5 cm margin
- Male or female ≥18 years of age.
- Karnofsky performance status (KPS) ≥70. Life expectancy of at least 16 weeks.
- Haematological, liver and renal function test results as follows:
- WBC: >3*109/L
- Haemoglobin >80 g/L
- PLT >100*109/L
- ALT, ALP, AST: ≤5 times upper international limit of normal (UILN)
- Bilirubin ≤3 times UILN
- Serum creatinine: within normal limits or <120 μmol/L for patients aged 60 years or older
- Urine protein dipstick: no protein
- Female patients surgically sterile or postmenopausal for at least 2 years. Participants of generative potential agreeing to use effective contraception during the period of therapy and 6 months after the end of study.
- Written informed consent
A patient will be excluded from participation in the trial if one or more of the following criteria are met:
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Previously confirmed histological diagnosis of GBM, with current clinical or imaging evidence for first recurrence according to modified RANO criteria (2017). History of GBM standard therapy (debulking surgery, followed by radio-chemotherapy (50-60 Gy in 2 Gy fractions, temozolomide)
- •Interval since end of 1st line XRT ≥6 months
- •Amino acid-based molecular imaging (preferably 18F-FET-PETor 11C-methionine, as institutionally established) indicating pathologically increased amino acid uptake inside or in the vicinity of the tumour, clearly discernible from background activity.
- •Current indication for repeat radiation therapy as discussed at the multidisciplinary neuro-oncological tumour board meeting, planned as standard fractionated dose schedule (18*2 Gy)
- •Male or female ≥18 years of age.
- •Karnofsky performance status ≥
- •Life expectancy of at least 16 weeks.
- •Haematological, liver and renal function test results as follows:
- •WBC: >3*109/L
- •Haemoglobin >80 g/L
- •PLT >100*109/L
- •ALT, ALP, AST: ≤5 times upper international limit of normal (UILN)
- •Bilirubin ≤3 times UILN
- •Serum creatinine: within normal limits or <120 μmol/L for patients aged 60 years or older
- •Urine protein dipstick: no protein
- •Female patients surgically sterile or postmenopausal for at least 2 years. Participants of generative potential agreeing to use effective contraception during the period of therapy and 6 months after the end of study.
- •Written informed consent
排除标准
- •Primary XRT dose < 60 Gy
- •Doses to organs at risk defined by Yasar and Tugrul (2005) exceeded or reached by prior radiation therapy; e.g. cumulative total dose on the optical chiasm >54 Gy for 2 Gy/fraction, alphas/beta=2
- •Multifocal distant recurrence, defined as tumour lesion outside the primary XRT field, as evidenced by amino acid-based PET imaging
- •Prior treatment with brachytherapy
- •Prior treatment with bevacizumab
- •Baseline steroid requirement , exceeding physiologic replacement doses ( <1.5 mg dexamethasone or equivalent per day)
- •History or evidence of delayed-type hypersensitivity (DTH)-dependent chronic infection (e.g. tuberculosis, systemic fungal or parasitic infection), potentially exacerbating under systemic corticoid therapy
- •Localisation of tumour related to brain stem or axis, unless sufficient reserve capacity (e.g. remnant resection cavity, marked atrophy) to accommodate possible post-procedural tissue reactions, or pre-therapeutic consent for emergency trepanation
- •Haemostaseologic conditions, precluding catheterisation or invasive procedures
- •Clinically significant illness or clinically relevant trauma within 2 weeks before the administration of the investigational product
- •Known impairment of liver or kidney function or known liver or kidney disease, such as hepatitis, cirrhosis, renal failure
- •Known human immunodeficiency virus (HIV) positive serology or chronically active hepatitis B or C
- •Ongoing toxicity > grade 2 NCI-CTC (version 4.03) from previous standard or investigational therapies
- •Administration of another investigational medicinal product within 90 days prior to screening
- •Expected non-compliance with longer-term admission at isolated nuclear medicine ward
- •In pre-menopausal women: Pregnant as evidenced by a positive pregnancy test, or breast-feeding
- •Patients with known phenylketonuria
结局指标
主要结局
Safety parameter blood pressure
时间窗: From first administration of 131I-IPA until 12 months after first administration
Frequency of occurrence and severity of abnormal findings as measured by mmHg
Safety parameter heart rate
时间窗: From first administration of 131I-IPA until 12 months after first administration
Frequency of occurrence and severity of abnormal findings as measured by beats per minute
Safety and tolerability parameter Adverse Events
时间窗: From first administration of 131I-IPA until 12 months after first administration
Treatment-related adverse events according to NCI-CTCAE v 4.03 criteria will be captured and evaluated for each patient
Safety parameter Liver function test
时间窗: From first administration of 131I-IPA until 12 months after first administration
This outcome will be measured on all patients with treatment-related adverse events based on criteria as determined by the NCI CTCAE v 5.0 criteria. Results will be assessed by number of participants with abnormal laboratory values.
Safety parameter Renal function test
时间窗: From first administration of 131I-IPA until 12 months after first administration
This outcome will be measured on all patients with treatment-related adverse events based on criteria as determined by the NCI CTCAE v 5.0 criteria. Results will be assessed by number of participants with abnormal laboratory values.
Safety parameter Full Blood Count
时间窗: From first administration of 131I-IPA until 12 months after first administration
This outcome will be measured on all patients with treatment-related adverse events based on criteria as determined by the NCI CTCAE v 5.0 criteria. Results will be assessed by number of participants with abnormal laboratory values.
次要结局
- Dosimetry(Up to 30 days after completion of study therapy)
- To evaluate the efficacy of a fractionated administration of 131I-IPA(Up to 6 months after completion of study therapy)
- To evaluate the maximum tolerated dose (MTD) of 131I -IPA administered concomitantly to 2nd line XRT in recurrent GBM 2(Evaluation of patient up to 30 days after completion of study therapy)
- To explore the antineoplastic effect of 131I-IPA + XRT combination therapy(Commencing just prior to first administration of 131I-IPA until 12 months from time of first therapeutic administration)
- To explore the occurrence and frequency of pseudo-progression (PP) in response to 131I-IPA + XRT combination therapy(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months)
- To explore the cognitive function of participants(Test will be adminsterd at baseline, 45 days post dose of 131I-IPA, Month 3 and Month 6)