SJ901: Phase 1/2 Evaluation of Single Agent Mirdametinib (PD-0325901), a Brain-Penetrant MEK1/2 Inhibitor, for the Treatment of Children, Adolescents, and Young Adults With Low-Grade Glioma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 132
- 试验地点
- 1
- 主要终点
- Phase 1: Estimate the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of mirdametinib dosed twice daily on a continuous schedule in pediatric patients with progressive or recurrent low-grade glioma.
研究概览
简要总结
This is an open-label, multi-center, Phase 1/2 study of the brain-penetrant MEK inhibitor, mirdametinib (PD-0325901), in patients with pediatric low-grade glioma (pLGG).
详细描述
The objectives of this study are:
Phase 1
Primary Objectives:
- To determine the safety and tolerability and estimate the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of mirdametinib dosed twice daily on a continuous schedule in pediatric patients with progressive or recurrent low-grade glioma.
- To characterize the plasma pharmacokinetics (PK) of mirdametinib.
Phase 2
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 24 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Screening Phase
- •Participants with histologically confirmed or suspected low-grade glioma, including neuronal and mixed neuronal-glial tumors
- •Participant must have adequate tumor tissue from primary and/or relapsed tumor for central pathology review
- •For Phase 1: Projected to be ≥ 2 years and < 25 years at the time of study enrollment
- •Participant's body surface area (BSA) at time of study enrollment must fall within the range outlined in the protocol for the specific dose level under evaluation:
- •Phase 1: Dose Finding/Dose-escalation
- •For Phase 1 participant's BSA must fall within the range specified in the protocol for the specific dose level under evaluation.
- •Phase 2: All Cohorts:
- •For Phase 2 of the study the upper BSA restrictions will be removed.
- •Participant and/or guardian can understand and is willing to sign a written informed consent document according to institutional guidelines
排除标准
- •Screening Phase
- •Participants with known current retinal pathology that is consistent with or a precursor for central serous retinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration
- •Participants with a known malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of mirdametinib (e.g., gastric bypass, lap band, or other gastric procedures)
- •Participant with a known history of liver disease or known hepatic or biliary abnormalities (except for Gilbert's syndrome or asymptomatic gallstones)
- •Participants with a clinically significant history of chronic interstitial lung disease (such as bronchopulmonary dysplasia, chronic bronchiolitis, obliterative bronchiolitis, chronic aspiration pneumonia, surfactant protein disorder, or other serious chronic pulmonary condition). Participants with a history of asthma, reactive airways disease, or viral pneumonitis are not to be excluded if disease has resolved or is well-controlled.
- •Inclusion Criteria: Phase 1 and Phase 2, All Cohorts
- •Participant must be ≥ 2 years and < 25 years of age at the time of enrollment
- •Participant's BSA at time of study enrollment must fall within the range outlined below for the specific dose level under evaluation:
- •Phase 1: Dose-finding/Dose-escalation
- •For Phase 1 participant's BSA must fall within the range specified in the protocol for the specific dose level under evaluation.
- •Phase 2: All Cohorts
- •For Phase 2 of the study the upper BSA restrictions will be removed.
- •Participant must have confirmation of one of the following diagnosis per St. Jude Children's Research Hospital central pathology review of primary and/or relapsed tumor:
- •Eligible tumors include:
- •Low-grade glioma/astrocytic tumor/glioneuronal tumor/neuroepithelial tumor, not otherwise specified (NOS) or not elsewhere classified (NEC)
- •Pilocytic astrocytoma
- •Pilomyxoid astrocytoma
- •Pleomorphic xanthroastrocytoma
- •Ganglioglioma
- •Gangliocytoma
- •Diffuse glioma, diffuse astrocytoma, oligodendroglioma, or oligoastrocytoma
- •Papillary glioneuronal tumor
- •Rosette-forming glioneuronal tumor
- •Diffuse leptomeningeal glioneuronal tumor
- •Central neurocytoma, extraventricular neurocytoma
- •Angiocentric glioma
- •Dysembryoplastic neuroepithelial tumor (DNET), septal DNET, myxoid glioneuronal tumor
- •Tectal glioma
- •Desmoplastic infantile astrocytoma / ganglioglioma
- •Polymorphous low-grade neuroepithelial tumor of the young
- •Multinodular and vacuolating neuronal tumor
- •In addition, tumor on central review must show evidence supporting MAPK pathway activation as defined by IHC, FISH and/or DNA/RNA sequencing (i.e. BRAF fused or rearranged, FGFR1/2/3 aberration, NF1, NF2, PTPN11, SOS1, RAF1 mutations, MYB or MYBL1 fused or rearranged, etc.) or occur in a participant with known NF1, NF2, SOS1, RAF1, or PTPN11 germline mutation. (Note: tests that show evidence supporting MAPK pathway activation that have been already performed do not need to be repeated as long as deemed acceptable by central review).
- •Participant must have measurable or evaluable disease (as defined in the protocol)
- •Note: Participants with metastatic disease or multiple independent primary LGGs are allowed on study.
- •Participants who are receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to enrollment with no plans for escalation.
- •Participant must have a Lansky (<16 years) or Karnofsky (≥16 years) performance score of ≥ 50 and, in the opinion of the investigator, a minimum life expectancy of at least 6 weeks.
- •Note: Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
- •Participant must have adequate bone marrow and organ function as defined as:
- •ANC ≥ 1.0 x 10^9/L without growth factor support within 7 days
- •Platelet count ≥ 75x 10^9/L without support of a platelet transfusion within 7 days
- •Hemoglobin ≥8.0 g/dL without support of a blood transfusion within 7 days
- •Potassium, total calcium (corrected for serum albumin), magnesium, sodium and phosphorus must be ≤ grade 1 or corrected to ≤ grade 1 with supplements before first dose of study medication
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN. For the purposes of this study the ULN of ALT and AST is 45 U/L.
- •Total bilirubin ≤ ULN; or if > ULN then direct bilirubin ≤ 1.5 x ULN
- •Adequate renal function defined as:
- •Serum creatinine ≤ the maximum serum creatinine based on age/gender: Age: 2 to < 6 years: maximum serum creatinine (mg/dL) 0.8 (male, female), Age: 6 to <10 years: maximum serum creatinine (mg/dL) 1 (male, female), Age: 10 to <13 years: maximum serum creatinine (mg/dL) 1.2 (male, female), Age: 13 to <16 years: maximum serum creatinine (mg/dL) 1.5 (male); 1.4 (female), Age: ≥ 16 years: maximum serum creatinine (mg/dL) 1.7 (male); 1.4 (female)
- •Adequate cardiac function defined as:
- •LVEF > 50% by ECHO
- •QTc interval ≤ 450 msec for male participants, ≤ 470 msec for female participants after electrolytes have been corrected.
- •Hypertension:
- 另有 88 项未显示
研究组 & 干预措施
Phase 2, Cohort 1: Newly diagnosed and/or previously untreated (except surgery)
Participants will receive the RP2D of mirdametinib. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.
干预措施: Mirdametinib (Drug)
Phase 2, Cohort 3b:
Participants with recurrent and/or progressive low-grade glioma who previously received ≥ 6 courses MEK inhibitor (including mirdametinib) and did not progress while on active MEKi therapy. Participants will receive the RP2D of mirdametinib. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.
干预措施: Mirdametinib (Drug)
Phase 2, Cohort 2: Recurrent and/or Progressive without prior exposure to MEK inhibitors
Participants will receive the RP2D of mirdametinib. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.
干预措施: Mirdametinib (Drug)
Phase I: Recurrent and/or progressive low-grade glioma without prior exposure to MEK inhibitors
Participants will receive mirdametinib at one of the dose levels twice daily days 1-28. For the first cycle of treatment, participants will take mirdametinib tablets dissolved in water. After the first cycle of treatment, participants may receive the medicine the same way (dissolved in water) or may receive capsules. Treatment repeats every 28 days for up to 26 cycles of treatment (24 months) in the absence of disease progression or unacceptable toxicity.
干预措施: Mirdametinib (Drug)
Phase 2, Cohort 3a:
Participants with recurrent and/or progressive low-grade glioma who previously received ≥ 6 courses MEK inhibitor (including mirdametinib) and did not progress while on active MEKi therapy. Participants will receive the RP2D of mirdametinib. Participants with previous exposure to mirdametinib may receive a starting dose lower than the RP2D, depending on the dose they tolerated during their previous exposure. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.
干预措施: Mirdametinib (Drug)
结局指标
主要结局
Phase 1: Estimate the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of mirdametinib dosed twice daily on a continuous schedule in pediatric patients with progressive or recurrent low-grade glioma.
时间窗: 1 month after start of mirdametinib treatment
The maximum tolerated dose (MTD) is empirically 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 determined to be too toxic. The MTD estimate will not be available if the lowest dose level studied is too toxic or the highest dose level studied is considered safe. In the latter case, the highest studied safe dose may be considered as the recommended phase 2 dose (RP2D). The MTD estimation will be limited to evaluable patients and toxicity assessments from course 1 (28 days). We will require that at least 12 DLT evaluable subjects are assessed before the MTD/RP2D is declared.
Phase 1: Determine the safety and tolerability of mirdametinib dosed twice daily on a continuous schedule in pediatric patients with progressive or recurrent low-grade glioma.
时间窗: Up to 25 months after start of mirdametinib treatment
Incidence of adverse event data at least possibly related to treatment will be summarized in cohort specific tables by grade and attribution throughout treatment.
Characterize the maximum plasma concentration and area under the concentration-time curve (AUC0-8h) of mirdametinib.
时间窗: Course 1: Days 1 and 15
Mirdametinib plasma concentration will be provided and area under the curve (AUC0-8h) estimated based on course 1, days 1 and 15 PK samples
Phase 2, Cohort 1: Objective response rate observed anytime during active treatment and sustained for at least 8 weeks
时间窗: Up to 24 months after start of mirdametinib treatment
The response rate, defined as the rate of minor response, partial response (PR), major response, or complete response (CR) will be calculated as the percentage of confirmed responders among all response assessable patients. These rates as well as their exact confidence intervals will be provided and will be summarized by each response category (i.e., PR, major response, and CR). Subjects without an assessment will be considered non-responders.
Phase 2, Cohort 2: Objective response rate observed anytime during active treatment and sustained for at least 8 weeks
时间窗: Up to 24 months after start of mirdametinib treatment
The response rate, defined as the rate of minor response, partial response (PR), major response, or complete response (CR) will be calculated as the percentage of confirmed responders among all response assessable patients. These rates as well as their exact confidence intervals will be provided and will be summarized by each response category (i.e., PR, major response, and CR). Subjects without an assessment will be considered non-responders.
Phase 2, Cohort 3a: Estimate 1-year disease stabilization rate
时间窗: Up to 12 months (slight departures from this timing allowed based on MRI screening) after start of mirdamentinib treatment
Rate of stable disease from start of treatment until the time of progression or time of last follow-up.
Phase 2, Cohort 3b: Estimate 6-month disease stabilization rate
时间窗: Up to 6 months (slight departures from this timing allowed based on MRI screening) after start of mirdametinib treatment
Rate of stable disease from start of treatment until the time of progression or time of last follow-up.
Describe the toxicity profile of mirdametinib by cohort.
时间窗: Up to 25 months after start of mirdametinib treatment
Incidence of adverse event data at least possibly related to treatment will be summarized in cohort specific tables by grade and attribution throughout treatment.
次要结局
- Rates of Minor Response, by cohort(Up to 5 years after the last enrolled patient starts treatment)
- Progression-free survival (PFS) by cohort(Up to 5 years after the last enrolled patient starts treatment)
- Rates of Partial Response (PR), by cohort(Up to 5 years after the last enrolled patient starts treatment)
- Rates of Major Response, by cohort(Up to 5 years after the last enrolled patient starts treatment)
- Rates of Complete Response (CR), by cohort(Up to 5 years after the last enrolled patient starts treatment)
- Rates of Stable Disease, by cohort(Up to 5 years after the last enrolled patient starts treatment)
- Rates of Progressive Disease (PD), by cohort(Up to 5 years after the last enrolled patient starts treatment)
- Longitudinal change in intellectual function, by cohort(Baseline (at enrollment), 9 months, 2 years, and 5 years after start of mirdametinib treatment)
- Longitudinal change in attention and executive functions, by cohort(Baseline (at enrollment), 6 months, 9 months, 2 years, 3 years, 4 years, and 5 years after start of mirdametinib treatment)
- Longitudinal change in memory, by cohort(9 months, 2 years, and 5 years after start of mirdametinib treatment)
- Longitudinal change in processing speed, by cohort(9 months, 2 years, and 5 years after start of mirdametinib treatment)
- Longitudinal change in academic achievement, by cohort(2 years and 5 years after start of mirdametinib treatment)
- Longitudinal change in psychosocial functioning, by cohort(Baseline (at enrollment), 6 months, 9 months, 2 years, 3 years, 4 years, and 5 years after start of mirdametinib treatment)
- Longitudinal change in adaptive behavior, by cohort(Baseline (at enrollment), 9 months, 2 years, and 5 years after start of mirdametinib treatment)