PNOC021: A Phase I Trial Evaluating the Combination of Trametinib and Everolimus in Pediatric and Young Adult Patients With Recurrent Low-Grade Gliomas and High Grade Gliomas
概览
- 阶段
- 1 期
- 干预措施
- Trametinib
- 疾病 / 适应症
- Recurrent World Health Organization (WHO) Grade II Glioma
- 发起方
- University of California, San Francisco
- 入组人数
- 50
- 试验地点
- 32
- 主要终点
- Incidence of adverse events for both continuous and intermittent dosing schedules
- 状态
- 暂停
- 最后更新
- 19天前
概览
简要总结
This phase I trial studies the side effects and best dose of trametinib and everolimus in treating pediatric and young adult patients with gliomas that have come back (recurrent). Trametinib acts by targeting a protein in cells called MEK and disrupting tumor growth. Everolimus is a drug that may block another pathway in tumor cells that can help tumors grow. Giving trametinib and everolimus may work better to treat low and high grade gliomas compared to trametinib or everolimus alone.
详细描述
PRIMARY OBJECTIVES: I. To estimate the recommended phase 2 dose (RP2D) of trametinib given orally in combination with everolimus in pediatric and young adult patients with gliomas. II. To describe the toxicity profile and define the dose limiting toxicities (DLTs) of the combination of trametinib and everolimus in pediatric and young adult patients with recurrent low-grade gliomas (LGG) or high grade glioma (HGG). III. To characterize the pharmacokinetic profile of trametinib and everolimus when given in combination. EXPLORATORY OBJECTIVES: I. To describe the objective response rate and the 2-year progression-free survival (PFS) of LGGs to this therapy in the context of a phase I study. II. To assess quality of life (QOL) and cognitive measures in pediatric and young adult patients with LGG or HGG. III. To identify potential predictive biomarkers to targeted therapy in pediatric and young adult patients with LGGs. IV. To assess endocrine outcomes in pediatric and young adult patients with LGGs. V. To explore magnetic resonance (MR) quantitative measures of relative cerebral blood volume, permeability and apparent diffusion coefficient within the region of hyperintensity on T2-weighted images as markers of disease response and/or progression in comparison to institutional evaluation of disease response and/or progression and quantitative measures of tumor response as determined by central review (based upon both area and volumetric measures). OUTLINE: This is a dose-escalation study. Patients receive a combination of trametinib orally (PO) and everolimus in either of two dosing scheduled (continuous and intermittent). Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, then every 6 months for 5 years from the start of therapy.
研究者
Sabine Mueller, MD, PhD
Principal Investigator
University of California, San Francisco
入排标准
入选标准
- •Participants must have histologically confirmed diagnosis of an LGG (WHO grade I-II) that is recurrent or progressive after prior treatment (biologic, chemotherapy or radiation therapy) or must have a histologically confirmed diagnosis of a high grade glioma (HGG) (WHO grade III-VI)
- •Participants with LGG who have had surgery alone are not eligible.
- •Participants with neurofibromatosis type 1 (NF-1) are eligible but must have available tissue per study requirements neurofibromatosis (NF) status will be collected
- •Participants with spinal cord primaries or disseminated disease are eligible
- •For enrollment, snap frozen tissue (150 mg) or 10 unstained 10 um formalin-fixed, paraffin-embedded (FFPE) slides for comprehensive genomic testing or results of prior testing is required
- •If clinical comprehensive testing has already been performed, the requirement for submission of tissue may be waived after discussion and review of results with study chairs
- •Participants must have evaluable disease
- •Prior therapy: Participants must have received prior therapy other than surgery and must have fully recovered from the acute toxic effects of all prior chemotherapy, biologics, immunotherapy, or radiotherapy prior to entering this study
- •Myelosuppressive chemotherapy: Participants must have received their last dose of known myelosuppressive anticancer chemotherapy at least three weeks prior to study registration or at least six weeks if they had received nitrosourea. Biologic agents: Participant must have recovered from any acute toxicity potentially related to the agent and received their last dose of the biologic agent \>= 7 days prior to study registration. For biologic agents that have a prolonged half-life, at least three half-lives must have elapsed prior to registration
- •Participants may have received prior treatment with a mitogen-activated extracellular signal-regulated kinase (MEK) or Mechanistic target of rapamycin (mTOR) inhibitor but must not have developed severe (grade III or IV) clinically significant toxicity. (Participants who developed grade III or IV toxicity which was not presumed by the treating physician to be medically significant should be discussed with the study chair or co-chair)
排除标准
- •Participants who are receiving any other investigational agent for treatment of their tumor
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to everolimus or trametinib
- •Participants without available tissue from prior surgery. (If clinical comprehensive testing has already been performed, the requirement for submission of tissue may be waived after discussion and review of results with study chairs)
- •Participant is receiving any of the following medications within 7 days prior to enrollment (If participants require (re)initiation of these agents after enrollment and prior to start of therapy they will not be eligible to initiate study therapy):
- •Known strong inducers or inhibitors of CYP3A4/5, including enzyme inducing anti-convulsant drugs (EIACDs), grapefruit, grapefruit hybrids, pomelos, starfruit, 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. Participants should stop using all herbal medications at least 7 days prior to enrollment
- •As part of the enrollment/informed consent procedures, the participant and/or legal parent or guardian will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product
- •Women of childbearing potential who are pregnant or breast-feeding
- •Female participants of childbearing potential must have a negative serum or urine pregnancy test within 72 hours of enrollment AND within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
研究组 & 干预措施
Treatment (trametinib, everolimus)
Patients receive dosing per their assigned dose level. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Trametinib
Treatment (trametinib, everolimus)
Patients receive dosing per their assigned dose level. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Everolimus
结局指标
主要结局
Incidence of adverse events for both continuous and intermittent dosing schedules
时间窗: Up to 30 days after the last day of treatment
Toxicities will be graded based on Common Terminology Criteria for Adverse Events (CTCAE) V5 .0 and followed for 30 days after last treatment or until resolution or returned to baseline values.
Dose limiting toxicities (DLTs) of the combination for both continuous and intermittent dosing schedules
时间窗: Up to 28 days
Any treatment related adverse event during the first cycle of therapy that leads to a dose reduction or results in delay of treatment \> 7 days or which results in the permanent cessation of therapy will be considered dose limiting.
Maximum tolerated dose (MTD) of trametinib in combination with everolimus for both continuous and intermittent dosing schedules
时间窗: Up to 28 days
We will employ the Bayesian optimal interval (BOIN) design to find the MTD for both continuous and intermittent dosing schedules. The BOIN design is implemented in a simple way similar to the traditional 3+3 design, but is more flexible and possesses superior operating characteristics that are comparable to those of the more complex model-based designs, such as the continual reassessment method (CRM).
Maximum Concentration (Cmax) of trametinib and everolimus
时间窗: Up to 5 years
Plasma trametinib and everolimus concentration-time data will be analyzed using a classic non-compartmental approach and/or population-based compartmental methods using non-linear mixed effects modeling. Individual pharmacokinetic parameters of interest after single and repeated doses (i.e., maximum plasma concentration Cmax from 0 to 24h will be calculated from the pharmacokinetic model. Trametinib and everolimus pharmacokinetics after single dose will be compared to trametinib and everolimus pharmacokinetics after repeated doses.
Recommended phase 2 dose (RP2D)
时间窗: Up to 28 days
The RP2D rate is selected based on isotonic regression as specified in Liu and Yuan (2015). This computation is implemented by the shiny app "BOIN" available at http://www.trialdesign.org. Specifically, select as the RP2D the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate.
Area Under the Curve (AUC) of trametinib and everolimus
时间窗: Up to 5 years
Plasma trametinib and everolimus concentration-time data will be analyzed using a classic non-compartmental approach and/or population-based compartmental methods using non-linear mixed effects modeling. Individual pharmacokinetic parameters of interest after single and repeated doses (i.e., area under the curve from 0 to 24h will be calculated from the pharmacokinetic model. Trametinib and everolimus pharmacokinetics after single dose will be compared to trametinib and everolimus pharmacokinetics after repeated doses.