A Phase I and Surgical Study of Ribociclib and Everolimus (RAD001) in Children With Recurrent or Refractory Malignant Brain Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 22
- 试验地点
- 12
- 主要终点
- Maximum Tolerated Dose of Ribociclib and Everolimus
研究概览
简要总结
This phase I trial studies the side effects and best dose of ribociclib and everolimus and to see how well they work in treating patients with malignant brain tumors that have come back or do not respond to treatment. Ribociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as everolimus, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ribociclib and everolimus may work better at treating malignant brain tumors.
详细描述
PRIMARY OBJECTIVES:
I. To estimate the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) of ribociclib and everolimus in children with refractory or recurrent central nervous system (CNS) tumors. (Phase I) II. To describe the toxicity profile and define the dose-limiting toxicities (DLTs) of ribociclib and everolimus in children with refractory or recurrent CNS tumors. (Phase I) III. To characterize the pharmacokinetics of ribociclib and everolimus in children with refractory or recurrent CNS tumors, and the potential for drug-drug interactions between the two compounds in this population. (Phase I) IV. To characterize ribociclib concentrations in tumor, and plasma in children with refractory or recurrent CNS malignancies undergoing neurosurgical procedures. (Surgical Study)
SECONDARY OBJECTIVES:
I. To describe the response rate of relapsed and refractory malignant brain tumors to ribociclib and everolimus in the context of a phase I study. (Phase I) II. To explore the effect of ribociclib treatment on Ki-67 by immunohistochemistry (IHC) by comparing archival and post-treatment tumor tissue. (Surgical Study)
TERTIARY OBJECTIVES:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •ELIGIBILITY FOR SCREENING
- •Patients with a histologically confirmed diagnosis of high-grade glioma (HGG), medulloblastoma, CNS embryonal tumor (not otherwise specified [NOS]), ependymoma, or atypical teratoid rhabdoid tumor (ATRT) that is recurrent, progressive or refractory
- •Patients with recurrent diffuse intrinsic pontine glioma (DIPG) with typical radiographic appearance who have undergone biopsy are eligible provided there is histologic confirmation of malignant glioma World Health Organization (WHO) II-IV; Rb1 screening for these patients is required only if adequate tissue is available
- •Patients with recurrent brainstem tumors with an atypical presentation who have undergone biopsy are eligible provided there is histologic confirmation of malignant glioma WHO II-IV; these patients must undergo Rb1 screening; these patients must have radiographic evidence of progression
- •Patients with secondary malignant gliomas will be eligible for this study but should conform to all other eligibility requirements; patients with low-grade gliomas are excluded
- •Formalin fixed paraffin embedded tumor tissue (preferably from the most recent recurrence) must be available to assess Rb1 protein status prior to enrollment on phase I or surgical study; if the subject has results from prior Rb1 IHC testing in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory the requirement for screening to assess Rb1 protein status is waived
- •Patients with recurrent diffuse intrinsic brain stem glioma (DIPG) that has an atypical presentation must also submit the tumor tissue for Rb1 protein status confirmation or provide previous testing results from a CLIA certified laboratory; patients who have been biopsied for atypical DIPG but do not have sufficient tissue for Rb1 screening are not eligible
- •Body surface area (BSA)
- •Patients enrolled on dose level -1 must have BSA >= 0.55m^2
- •Patients enrolled on dose level -0.5 must have BSA >= 0.75m^2
- •Patients enrolled on dose level 0 must have BSA >= 0.55m^2
- •Patients enrolled on dose level 1 must have BSA >= 0.75m^2
- •Patients enrolled on dose level 2 and 3 must have BSA >= 0.45m^2
- •Patients who are candidates for enrollment for the phase I or surgical studies must sign a screening consent and provide pre-trial tumor material for Rb1 testing unless testing is not needed due to diagnosis or the availability of prior Rb1 IHC results; the screening consent is to be obtained according to institutional guidelines
- •Patients screened for this trial should be expected to meet the criteria for treatment
- •PRIOR TO STUDY ENROLLMENT
- •PHASE I (STRATUM 1): Patient has intact Rb1 protein confirmed either from previous results or screened tissue; all testing must be performed in a CLIA certified laboratory; DIPG patients with radiographically typical appearance will be waived from this requirement
- •PHASE I (STRATUM 1): Patients with a histologically confirmed diagnosis of a primary CNS tumor that is recurrent, progressive, or refractory; all tumors must have histologic verification of HGG, medulloblastoma, CNS embryonal tumor (NOS), ependymoma, or ATRT; patients with low-grade gliomas are excluded
- •PHASE I (STRATUM 1): Patients with progressive DIPG, as defined by progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity wean, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR an increase in the bi-dimensional measurement, taking as a reference the smallest disease measurement recorded since last treatment, OR the appearance of a new tumor lesion since diagnosis
- •Please note:
- •Patients with a radiographically typical DIPG, defined as a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons, are eligible without histologic confirmation
- •Patients with pontine lesions that do not meet these radiographic criteria will be eligible if there is histologic confirmation of malignant glioma WHO II-IV. These patients must have radiographic evidence of progression
- •SURGICAL STUDY (STRATUM 2): Patients must have recurrent or refractory disease with a histological diagnosis at either the time of diagnosis or at the time of recurrence of one of the following:
- •Medulloblastoma,
- •CNS embryonal tumor (NOS),
- •Ependymoma, or
- •SURGICAL STUDY (STRATUM 2): Patients for whom surgical intervention is clinically indicated (gross total resection or sub-total resection) at recurrence and are amenable to receiving ribociclib for 7 ? 10 days prior to resection
- •Note: patients with DIPG are excluded from the surgical study
- •Patients enrolled on dose level -1 must have BSA >= 0.55m2
- •Patients enrolled on dose level -0.5 must have BSA >= 0.75m2
- •Patients enrolled on dose level 0 must have BSA >= 0.55m2
- •Patients enrolled on dose level 1 must have BSA >= 0.75m2
- •Patients enrolled on dose level 2 and 3 must have BSA >= 0.45m2
- •Patients must have received prior therapy other than surgery and must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment
- •Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if nitrosourea
- •Biologic or investigational agent (anti-neoplastic): patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent >= 7 days prior to study enrollment
- •For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
- •Monoclonal antibody treatment and agents with known prolonged half-lives: At least three half-lives must have elapsed prior to enrollment.
- •Patients must have had their last fraction of:
- •Craniospinal irradiation (> 24 GRAY [Gy]) or total body irradiation > 12 weeks prior to enrollment
- •Focal irradiation > 2 weeks prior to enrollment
- •>= 3 months since autologous bone marrow/stem cell transplant prior to enrollment
- •Neurologic status
- •Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment
- •Patients with seizure disorders may be enrolled if seizures are well controlled on an anti-epileptic drug that is not a strong inducer or inhibitor of CYP3A4/5 are eligible
- •Performance status
- •Phase I: Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within one week of enrollment must be >= 50
- •Surgical study: Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within one week of enrollment must be >= 60
- •Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
- •Absolute neutrophil count >= 1.0 x 10^9 cells/ L
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排除标准
- •Patients who are otherwise deemed clinically unsuitable for surgical resection (applicable for surgical study only)
- •Patients who are breast feeding
- •Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that would compromise the patient?s ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results
- •Patients who are receiving any other anticancer or investigational or/and anti-neoplastic therapies, including chemotherapy, immunotherapy, target therapy, biological response modifiers
- •Previous treatment with CDK4/6 inhibitors (such as PD-0332991, abemaciclib) and/or mTOR inhibitors (such as sirolimus, temsirolimus or everolimus)
- •Patients who are currently receiving treatment with agents that are known to cause corrected QT (QTc) prolongation or induce Torsades de Pointes
- •Known need for major surgery within 14 days of the first dose of ribociclib and everolimus; please note: gastrostomy, insertion of a gastrostomy (G) tube, ventriculo-peritoneal shunt, endoscopic ventriculostomy and central venous access are NOT considered major surgery
- •Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to enrollment:
- •Known strong and moderate inducers or inhibitors of CYP3A4/5, including enzyme inducing anti-convulsant drugs (EIACDs), grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges
- •Substrates of CYP3A4/5 with a narrow therapeutic index
- •Herbal preparations/medications (except for vitamins) including, but not limited to: St. John?s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng; patients should stop using all herbal medications and dietary supplements at least 7 days prior to enrollment
- •Clinically significant active cardiac disease, uncontrolled heart disease and/or a history of cardiac dysfunction including any of the following:
- •History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 12 months prior to screening
- •History of documented congestive heart failure (New York Heart Association functional classification III-IV)
- •Documented cardiomyopathy
- •Patient has a left ventricular ejection fraction (LVEF) < 50% as determined by echocardiogram (ECHO)
- •History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months of screening
- •Long QT syndrome or known family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
- •Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
- •Concomitant use of medication(s) with a known risk to prolong the QT interval and/or days prior to starting study drug) or replaced by safe alternative medication
- •12-lead electrocardiogram (ECG), any of the following cardiac parameters:
- •QTc > 480 msec
- •Hypertension defined as:
- •Patients 1-17 years of age with blood pressure that is greater than or equal to the 95th percentile for age, height and gender at the time of enrollment; Patients who are ≥ 18 years of age with blood pressure > 140/90 mm of Hg at the time of enrollment.
- •Patient is currently receiving warfarin or other coumadin-derived anticoagulant for treatment, prophylaxis or otherwise.
- •Patient has a known hypersensitivity to ribociclib or any of its excipients
- •Patients with inability to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions.
研究组 & 干预措施
Treatment (ribociclib, everolimus)
Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses. Patients who are undergoing surgery also receive ribociclib PO QD on days 7-10 before surgery. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease after 13 courses may continue receiving ribociclib and everolimus every 28 days for up to 13 additional courses in the absence of disease progression or unacceptable toxicity.
干预措施: Everolimus (Drug)
Treatment (ribociclib, everolimus)
Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses. Patients who are undergoing surgery also receive ribociclib PO QD on days 7-10 before surgery. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease after 13 courses may continue receiving ribociclib and everolimus every 28 days for up to 13 additional courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (ribociclib, everolimus)
Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses. Patients who are undergoing surgery also receive ribociclib PO QD on days 7-10 before surgery. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease after 13 courses may continue receiving ribociclib and everolimus every 28 days for up to 13 additional courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Treatment (ribociclib, everolimus)
Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses. Patients who are undergoing surgery also receive ribociclib PO QD on days 7-10 before surgery. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease after 13 courses may continue receiving ribociclib and everolimus every 28 days for up to 13 additional courses in the absence of disease progression or unacceptable toxicity.
干预措施: Ribociclib (Drug)
结局指标
主要结局
Maximum Tolerated Dose of Ribociclib and Everolimus
时间窗: 4 weeks
Defined as the highest dose level at which six patients have been treated with at most one patient experiencing a dose limiting toxicity (DLT) and the next higher dose level has been determined to be too toxic. Will be estimated using a Rolling-6 phase I design. Only patients who are evaluable for DLT will be consider for estimating of Maximum Tolerated Dose. Patient who were enrolled under Surgical cohort but received sufficient study defined treatment would also be evaluable for DLT.
Average Tumor and Plasma Concentrations of Ribociclib for the Surgical Study
时间窗: Surgical study: Prior to starting ribociclib (day -7 or -10), prior to ribociclib dose on days -5 & -2, day 0, and at the time of surgery
Average tumor Ribociclib concentrations will be compared to plasma concentrations. The mean tumor-to-plasma ratio of Ribociclib at the time of surgery will be described.
次要结局
- Objective Responses (Complete Response + Partial Response)(Up to 2 years)
- Percent Change in ki67 Between Archival and Post-treatment Tissue(Up to 2 years)