A Phase 1b/2a Study of ACT001 and Anti-PD-1 in Patients With Surgically Accessible Recurrent Glioblastoma Multiforme
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 48
- 试验地点
- 2
- 主要终点
- 1b-Incidence, type and severity of treatment-emergent AEs (TEAEs)
研究概览
简要总结
The current design provides a window to analyze the impact of the ACT001+Pembrolizumab combination on the tumor microenvironment and disease outcomes.
详细描述
Phase 1b: The identified RP2D of combined ACT001 with Pembrolizumab will be determined by standard 3+3 dose escalation methodology among three ACT001 dosages (200mg, 400mg and 800mg, BID) with standard Pembrolizumab dosage. Patients will be dosed approximately 2 weeks prior to surgical resection with a single dose of Pembrolizumab and ACT001. Tumor resection will be performed and a biopsy will be obtained from the resected tumor tissue to evaluate the impact of the study drugs on the TME. After recovery from surgery, patients will resume ACT001 and Pembrolizumab until tumor progression (assessed by iRANO) or an AE requiring discontinuation of study drug. The Safety Monitoring Committee (SMC) will review the data available from all evaluable patients at each dose level prior to recommending escalation to the next dose level.
Phase 2a: Using the same dosing schedule and ACT001 dosage as determined in Phase 1b. Patients will be randomized to receive either Pembrolizumab only treatment (Arm A, 10 patients) or ACT001 plus Pembrolizumab treatment (Arm B, 20 patients).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 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
- •Patient has provided written informed consent.
- •≥ 18 years old at time of screening visit.
- •Histologically confirmed GBM at the time of diagnosis.
- •First or second relapse by the time of consenting.
- •Tumor progression (magnetic resonance imaging [MRI], defined by RANO) post prior treatments.
- •Feasibility for re-surgery.
- •Karnofsky Performance Status ≥ 70% (requires occasional assistance, but able to care for most of their needs, equivalent to < ECOG 2).
- •Must be ≥ 4 weeks from administration of last dose of cancer therapy (including radiation therapy or chemotherapy). The patient must have recovered from all treatment-related toxicities to less than grade 2 per Common Terminology Criteria for Adverse Events (CTCAE) version 5.
- •Life expectancy of ≥ 3 months.
- •Adequate organ function (absolute neutrophil count ≥1.5 x 109 /L, lymphocytes ≥ 0.5 x 109 /L, platelets ≥ 75 x 109 /L, hemoglobin ≥ 10 g/dl; total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5.0 x ULN if liver metastasis); plasma creatinine ≤ 1.5 x ULN; QTc < 450 ms (male), < 470 ms (female).
- •Female patients are eligible if they are of:
- •Non-childbearing potential, defined as
- •Previous hysterectomy or bilateral oophorectomy
- •Previous bilateral tubal ligation
- •Post-menopausal (total cessation of menses for ≥ 1 year)
- •Childbearing potential with a negative serum pregnancy test at screening (within 7 days of the first investigational product administration) and uses a highly effective method contraception before study entry and throughout the study until 28 days after the last investigational product administration. Highly effective contraception (<1% failure rate per year), when used consistently and in accordance with both the product label and the instructions of the physician, are defined as follows:
- •Vasectomized partner who is sterile prior to the female patient's enrolment and is her sole sexual partner
- •An intrauterine device with a documented failure rate of less than 1% per year
- •Double barrier contraception defined as condom with a female diaphragm
- •Male patients, if sexually active, must agree to use a highly effective method of contraception (< 1% failure rate per year) with their female partners from screening until 28 days following the last study drug administration.
- •Absence of deteriorating neurological symptoms, new onset of seizures and the need for increasing doses of corticosteroids.
- •Absence of toxicity from prior therapy (excluding alopecia) that has not resolved to ≤ Grade 1 unless otherwise specified.
- •Absence of other clinically significant concomitant active medical disorder, based on the investigator's judgement
排除标准
- •The patient has uncontrolled infection.
- •The patient has serious diseases such as unstable angina pectoris, myocardial infarction in the past 6 months, heart failure (New York Heart Association class > II) or stroke within 6 months prior to the enrollment.
- •A gastrointestinal absorption disorder that would limit the bioavailability of oral drugs or if patient cannot take oral drugs.
- •Uncontrolled brain metastases or spinal cord compression. Patients who were treated with surgical resection or radiation therapy completing at least 4 weeks earlier are eligible if they are neurologically stable, not taking glucocorticoids and have a follow-up. MRI scan performed within the previous 4 weeks showing no tumor progression.
- •Pre-existing allergy to ACT001 or related compounds.
- •A patient has active autoimmune disease managed by systemic treatments in the past 2 years (i.e. the use of corticosteroids, immunosuppressive drugs or other disease modifying agents). Of note, a replacement therapy, e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, is not considered a form of systemic treatment.
- •A known history of, or any evidence of an active non-infectious pneumonitis.
- •Treatment with cancer therapies such as chemotherapy or radiation therapy either currently or within 4 weeks of ACT001 dosing. An exception is focal radiation for symptomatic bone metastases, which must not be within 2 weeks of ACT001 dosing.
- •History of treatment with immune CPB and Avastin (or other antiangiogenic or anti-vascular endothelial growth factor agents).
- •High dose of corticosteroids (> 4mg/day of dexamethasone or equivalent for at least 3 consecutive days) within two weeks of enrolment for GBM treatment.
- •A patient has received other systemic immunosuppressive treatments such as mTOR inhibitor everolimus four weeks prior to registration.
- •A patient has a diagnosis of ongoing immunodeficiency due to other diseases such as human immunodeficiency virus (HIV) infection.
- •Unresolved toxicity from prior antitumor therapy, defined as toxicities (excluding alopecia) that have not resolved to < Grade 2 as scored using the CTCAE current version. Exceptions may be allowed for stable toxicities after discussion with the investigator and sponsor.
- •Major surgery within 30 days of commencing first study therapy.
- •Pregnant or breast-feeding females.
- •A history of infection with HIV or hepatitis B or C viruses.
- •The patient has participated in other drug clinical studies < 4 weeks prior to obtaining the informed consent.
- •The patient is, in the opinion of the investigator, unsuitable for any other reason.
研究组 & 干预措施
1b dose exploration
1b dose exploration for 18 patients - The starting dose of ACT001 will be administered in combination with a single intravenous (IV) infusion of Pembrolizumab. After recovery from surgical resection, dosing will resume on a 3 weekly cycle and will consist of Pembrolizumab (standard dosing) and daily ACT001. Evaluation of a dose level of at least three (3) patients after completing one cycle of treatment post-surgery is required prior to commencing the next dose level.
干预措施: ACT001 (Drug)
2a- Randomized/Two-treatment Arm
30 Patients will be randomized to Arm A or Arm B at a ratio of 1 (Arm A) : 2 (Arm B). 10 patients will be randomized to the Pembrolizumab only arm (Arm A) and 20 patients will be randomized to the ACT001 plus Pembrolizumab arm (Arm B).
干预措施: ACT001 + Pembrolizumab (Drug)
结局指标
主要结局
1b-Incidence, type and severity of treatment-emergent AEs (TEAEs)
时间窗: Approximately 7 months. Each cycle is 21 days; from start of first dose with investigational product until completion of the last study related procedure (including follow-up for safety assessments- 30days after last dose)
1b-Mean changes in vital sign measurements- supine blood pressure
时间窗: Approximately 8months/ patient.Each cycle is 21 days. Start at screening, Pre-surgical Treatment Period, Cycle 1 and each subsequent Cycle and 30 days after last dose
Mean change from baseline in vital sign measurements reported in mmHg at each study timepoint
1b-Mean changes in electrocardiogram (ECG) parameters
时间窗: approximately 8months/patient. Each cycle is 21 days. Start at screening, Pre-surgical Treatment Period, Cycle 1 and each subsequent Cycle and 30 days after last dose
Mean change from baseline in electrocardiogram (ECG) parameters of heart rate, ventricular rate, PR interval, QRS duration, and QTcF.
2a-Progression free survival (PFS) at 6 months
时间窗: Six months after initiation of study therapy
1b-Mean changes in vital sign measurements- respiratory rate
时间窗: Approximately 8months/ patient. Each cycle is 21 days. Start at screening, Pre-surgical Treatment Period, Cycle 1 and each subsequent Cycle and 30 days after last dose
Mean change from baseline in vital sign measurements reported in bpm at each study timepoint
1b-Dose limiting toxicities (DLTs)
时间窗: From first dose of study therapy until the end of the first post-surgery cycle (Cycle 1, Day 21).
A DLT is defined as any of the following * Haematological toxicity * Grade 4 neutropenia * Grade ≥ 3 febrile neutropenia or neutropenic infection * Grade 4 thrombocytopenia * Grade 3 thrombocytopenia with clinically significant bleeding * Non-haematological toxicity * Grade ≥ 3 nausea, vomiting or diarrhoea despite optimal supportive therapy * Grade ≥ 3 hypertension despite appropriate intervention * Other grade ≥ 3 non-haematological toxicity, except grade 3 fatigue or transient events (such as allergic reactions or electrolyte disturbances) that are readily controlled with medical therapy and/or are of no clinical concern
1b-Mean changes in vital sign measurements- body temperature
时间窗: Approximately 8months/ patient. Each cycle is 21 days. Start at screening, Pre-surgical Treatment Period, Cycle 1 and each subsequent Cycle and 30 days after last dose
Mean change from baseline in vital sign measurements reported in degrees Celsius (0C) at each study timepoint.
1b-Mean changes in vital sign measurements-Heart Rate
时间窗: Approximately 8months/ patient. Each cycle is 21 days. Start at screening, Pre-surgical Treatment Period, Cycle 1 and each subsequent Cycle and 30 days after last dose
Mean change from baseline in vital sign measurements reported in beats/min (inclusive) at each study timepoint.
1b-Mean changes in Karnofsky Performance Scale score
时间窗: Approximately 8 months/patient. Each cycle is 21 days. Start at screening, Pre-surgical Treatment Period, Cycle 1 and each subsequent Cycle and 30 days after last dose
Mean change from baseline in Karnofsky Performance Scale score
次要结局
- 2a-Concentration of ACT001 in resected tumor biopsy tissue.(Tissue at Surgical Resection only.)
- 2a-Overall survival(Approximately 7months/patient- screening period is not included. Cycle 1 Day 1 until death, loss to follow-up, withdrawal of consent, date of disease progression or whichever occurs first)
- 2a-Incidence, type and severity of TEAEs(From start of dosing until 30 days after the last dose of ACT001)
- 1b-Incidence of DLTs according to the MTD/RP2D evaluation process.(From first dose of study therapy (per surgery) until the end of the first post-surgery cycle (Cycle 1, Day 21). Each cycle is 21 days.)
- 1b- Pharmacokinetics (PK) of ACT001 in Plasma concentrations in tumor.(PK analysis will be collected on Day 1 of the pre surgical treatment period.)