INTELLANCE-2: ABT-414 Alone or ABT-414 Plus Temozolomide Versus Lomustine or Temozolomide for Recurrent Glioblastoma: A Randomized Phase 2 Study of the EORTC Brain Tumor Group
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 266
- 试验地点
- 102
- 主要终点
- Adult Study: Overall Survival (OS)
研究概览
简要总结
This study was conducted to evaluate the efficacy and safety of depatuxizumab mafodotin (ABT-414) alone or with temozolomide versus temozolomide or lomustine alone in adult participants with recurrent glioblastoma. The study also included a substudy to evaluate safety, tolerability and pharmacokinetics of ABT-414 in a pediatric population.
详细描述
The study objectives were to assess whether depatuxizumab mafodotin (ABT-414) alone or in combination with temozolomide (TMZ) improved overall survival (OS), progression-free survival (PFS), tumor response, quality of life, neurological deterioration-free survival (NDFS), and steroid use compared to standard treatment with lomustine single agent or TMZ re-challenge in adult subjects ≥ 18 years of age with centrally-confirmed recurrent epidermal growth factor receptor (EGFR)-amplified glioblastoma. The safety, pharmacokinetics, and efficacy of depatuxizumab mafodotin in children <18 years of age was evaluated in a pediatric substudy. The EMEA-001732-PIP02-15 pediatric investigation plan was withdrawn on 07 July 2019 due to the discontinuation of the depatuxizumab mafodotin research program.
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
- — 至 99 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult participants (greater than or equal to 18 years old):
- •Histologically confirmed de novo (primary) glioblastoma with unequivocal tumor progression or recurrence.
- •In case of testing at the time of first progression: either at least 3 months after the end of radiotherapy or have tumor progression that is clearly outside the radiation field or have tumor progression unequivocally proven by surgery/biopsy
- •Absence of any psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule; such conditions should be assessed with the patient before registration in the trial.
- •Availability of adequate biological material (formalin-fixed paraffin embedded [FFPE] tumor) for central testing of Epithelial Growth Factor Receptor (EGFR) amplification
- •Presence of EGFR amplification confirmed by central assessment; participants with undetermined EGFR status are excluded
- •World Health Organization (WHO) Performance status 0 - 2
- •No more than one line of chemotherapy (concurrent and adjuvant Temozolomide based chemotherapy including in combination with another investigational agent is considered one line of chemotherapy). Chemotherapy must have been completed at least 4 weeks prior to randomization.
- •Post surgery MRI within 48 hours following surgery, however an MRI scan has to be done within 2 weeks prior to randomization.
- •Surgery completed at least 2 weeks before randomization and patients should have fully recovered as assessed by investigators.
- •Renal function: calculated creatinine clearance ≥ 30 mL/min by the Cockcroft-Gault formula.
- •Liver function: bilirubin < 1.5× upper limit of the normal range (ULN), alkaline phosphatase and transaminases (ASAT) < 2.5× ULN
- •Pediatric sub-study participants (less than 18 years old):
- •Histologically proven high grade glioma (HGG: WHO grade III glioma [e.g anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma], grade IV glioma [e.g. glioblastoma, gliosarcoma] or diffuse intrinsic pontine glioma [DIPG]).
- •Must either have recurrent/progressive tumor or, if newly diagnosed, have completed any planned radiation therapy at least 4 weeks prior to first dose of ABT-
- •The tumor tissue must have been determined to have EGFR amplification, (by local or other testing service).
- •Availability of adequate biological material for retrospective confirmatory central testing of EGFR amplification
- •Participant has sufficiently recovered from previous therapy. The investigator believes that benefit of treating the pediatric subject with ABT-414 outweighs the expected risks and that this treatment is in the best interests of the pediatric subject.
- •Renal function: calculated creatinine clearance ≥ 30 mL/min by the Cockcroft-Gault formula for pediatric patients ≥12 years of age and estimated glomerular filtration rate ≥ 30 mL/min/1.73 m^2 by modified Schwartz equation for pediatric patients < 12 years of age.
- •Liver function: Total bilirubin ≤ 1.5× upper limit of the normal range (ULN), Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) <= 3× ULN. Participants with Gilbert's syndrome documented in medical history may be enrolled if total bilirubin is < 3 times ULN. Not allowed are participants with known chronic liver disease and/or cirrhosis.
排除标准
- •Adult population (greater than or equal to 18 years old):
- •Prior treatment with nitrosoureas
- •Prior treatment with bevacizumab
- •Previous exposure to Epithelial Growth Factor Receptor (EGFR) targeted agents, including EGFRvIII targeting agents
- •Prior discontinuation of temozolomide chemotherapy for toxicity reasons
- •Prior Radiation Therapy (RT) with a dose over 65 Gy to the brain, stereotactic radiosurgery or brachytherapy unless the recurrence is histologically proven
- •Previous other malignancies, except for any previous malignancy which was treated with curative intent more than 5 years prior to randomization, and except for adequately controlled limited basal cell carcinoma of the skin, squamous carcinoma of the skin or carcinoma in situ of the cervix
- •Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to randomization.
- •No history of wheat allergies and Coeliac disease.
- •No EIAED, patients who require anti-convulsant therapy must be taking non-enzyme inducing antiepileptic drugs (non-EIAED). Patients previously on EIAED must be fully switched to non-EIAED at least 2 weeks prior to randomization.
- •Pediatric sub-study (less than 18 years old):
- •(For recurrent disease) No prior RT with a dose over 65 Gy to the brain, stereotactic radiosurgery or brachytherapy unless the recurrence is histologically proven
- •No current or recent (within 4 weeks or 5 half-lives [whichever is shorter] before enrollment) treatment with another investigational drug
- •Female participants of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to randomization.
研究组 & 干预措施
ABT-414/temozolomide
Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks in combination with temozolomide (TMZ) to adult participants
干预措施: Depatuxizumab mafodotin (Drug)
ABT-414/temozolomide
Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks in combination with temozolomide (TMZ) to adult participants
干预措施: Temozolomide (Drug)
ABT-414_adult
Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to adult participants
干预措施: Depatuxizumab mafodotin (Drug)
Control_lomustine
Adult participants relapsing during temozolomide (TMZ) treatment or within the first 16 weeks after the first day of the last TMZ cycle received lomustine on Day 1 of every 42-day treatment period until one of the treatment withdrawal criteria was met, up to a maximum of 1 year.
干预措施: Lomustine (Drug)
Control_ temozolomide
Adult participants relapsing 16 weeks or more after the first day of the last temozolomide (TMZ) cycle received TMZ on Day 1 to Day 5 for the first 28-day cycle, with dose escalation in subsequent cycles in case of adequate tolerance and treatment continuing until one of the treatment withdrawal criteria was met.
干预措施: Temozolomide (Drug)
ABT-414_ pediatric
Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to pediatric participants. Temozolomide (TMZ) was only allowed for pediatric participants if its use was in accordance with local clinical practice, and was not considered an investigational product for the study (unless this was a local requirement).
干预措施: Depatuxizumab mafodotin (Drug)
结局指标
主要结局
Adult Study: Overall Survival (OS)
时间窗: From the date of randomization up to the date of participant's death; participants who completed treatment were to be assessed every 12 weeks, up to 28 months.
Overall Survival (OS) was defined as time from randomization to death due to any cause, regardless of whether the event occurred on or off study drug (depatuxizumab mafodotin/temozolomide/lomustine).
Adult Study: Progression-Free Survival (PFS)
时间窗: Measured every 8 weeks from date of randomization until the date of first objective progression or subject's death, whichever occurred first, up to 2 years
Progression-free survival was assessed per response assessment in neuro-oncology criteria (RANO) criteria and assessed by an independent review committee and was defined as the length of time during and after the treatment of a disease, that the participant lived with the disease but did not get worse.
Pediatric Study: Percentage of Participants With Adverse Events From the First Visit Until 49 Days After the Last Dose of Study Drug
时间窗: From participant's first visit until 49 days after the participant's last dose of study drug, up to 63 weeks
The severity of each adverse event was rated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 4.0)
Pediatric Study: Maximum Observed Serum Concentration (Cmax) of ABT-414
时间窗: Samples collected Cycle 1 Days 1, 2,3,5,8,15; Cycle 2 Day 1; Cycle 3 Day 1; Cycle 5 Day 1; Day 1 of every two cycles starting with Cycle 5; and 35 days after the last dose
Cmax is the peak concentration that a drug achieves in a specified compartment after the drug has been administrated and before administration of a second dose.
Pediatric Study: Maximum Observed Plasma Concentration (Cmax) of Cys-mcMMAF
时间窗: Samples collected Cycle 1 Days 1, 2, 3, 5, 8
Cmax is the peak concentration that a drug or drug metabolite achieves in a specified compartment after the drug has been administrated and before administration of a second dose. Cys-mcMMAF is a toxic metabolite of depatuxizumab mafodotin.
Pediatric Study: Half-life (t1/2) Observed for ABT-414
时间窗: Samples collected Cycle 1 Days 1, 2,3,5,8,15; Cycle 2 Day 1; Cycle 3 Day 1; Cycle 5 Day 1; Day 1 of every two cycles starting with Cycle 5; and 35 days after the last dose
Half-life is the calculated time it takes for half of the drug to leave the body.
Pediatric Study: Half-life (t1/2) Observed for Cys-mcMMAF
时间窗: Samples collected Cycle 1 Days 1, 2, 3, 5, 8
Half-life is the calculated time it takes for half of the drug or drug metabolite to leave the body. CysmcMMAF is a toxic metabolite of depatuxizumab mafodotin.
Pediatric Study: Area Under the Concentration-time Curve (AUC) Observed for ABT-414
时间窗: Samples collected Cycle 1 Days 1, 2,3,5,8,15; Cycle 2 Day 1; Cycle 3 Day 1; Cycle 5 Day 1; Day 1 of every two cycles starting with Cycle 5; and 35 days after the last dose
AUC is a measure of how long and how much drug is present in the body after dosing. The AUC of depatuxizumab mafodotin (ABT-414) in the pediatric population was measured following treatment to confirm that this was comparable to adults, and that the dosing levels are appropriate for a pediatric population.
Pediatric Study: Area Under the Concentration-time-curve (AUC) Observed for Unconjugated Cys-mcMMAF
时间窗: Samples collected Cycle 1 Days 1, 2, 3, 5, 8
AUC is a measure of how long and how much drug or drug metabolite is present in the body after dosing. The AUC of Cys-mcMMAF, a toxic metabolite of depatuxizumab mafodotin, in the pediatric population was measured following treatment to confirm that this was comparable to adults, and that the dosing levels are appropriate for a pediatric population.
次要结局
- Adult Study: Objective Response Rate (ORR)(Every 8 weeks at each assessment of disease, up to 28 months)
- Adult Study: Overall Survival in the Subgroup With Epidermal Growth Factor Receptor (EGFRvIII) Mutation(From the date of randomization up to the date of participant's death; participants who completed treatment were to be assessed every 12 weeks, up to 28 months)
- Pediatric Study: Objective Response Rate (ORR)(Evaluated every 8 weeks (+/- 7 days) at each assessment of disease according to response assessment in neuro-oncology criteria (RANO), until progression or withdrawal up to approximately 52 weeks)
- Pediatric Study: Best Tumor Response Rate(Evaluated every 8 weeks (+/- 7 days) at each assessment of disease according to response assessment in neuro-oncology criteria (RANO), until progression or withdrawal up to approximately 52 weeks)
- Pediatric Study: Duration of Response(Evaluated every 8 weeks (+/- 7 days) at each assessment of disease according to response assessment in neuro-oncology criteria (RANO), until progression or withdrawal up to approximately 52 weeks)
- Pediatric Study: Overall Survival(From the date of enrollment to the date of death; participants who completed treatment were to be assessed every 12 weeks, up to 28 months)
- Pediatric Study: Time to Progression(Evaluated every 8 weeks (+/- 7 days) from the date of enrollment until the date of first objective progression or participant's death, whichever occurs first, up to approximately 52 weeks)
- Pediatric Study: Progression-Free Survival(Evaluated every 8 weeks (+/- 7 days) from the date of enrollment until the date of first objective progression or participant's death, whichever occurs first, up to approximately 52 weeks)
- Pediatric Study: Percentage of Participants With Changes in Neurological Status and Functioning(Baseline, Day 1 and 15 of each cycle, every 6 months for 5 years thereafter, and then annually)