This phase I trial studies the side effects and best dose of savolitinib in treating patients with primary central nervous system (CNS) tumors that have come back (recurrent) or does not respond to treatment (refractory). Savolitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) and recommend a phase II dose of savolitinib administered orally daily in children with refractory, progressive or recurrent primary CNS tumors. II. To define and describe the toxicities of savolitinib in children with refractory, progressive, or recurrent primary CNS tumors. III. To characterize the pharmacokinetics of savolitinib in children with refractory, progressive, or recurrent primary CNS tumors. SECONDARY OBJECTIVES: I. To preliminarily define the antitumor activity of savolitinib within the confines of a phase I study. II. To perform a genomic analysis within the confines of a phase I study to investigate correlation between response to treatment (as measured by objective response or progression free survival \[PFS\]) and the presence of specific genomic alterations (e.g., MET or HGF amplification, MET mutations, or MET fusion) and/or specific subgroups of disease. OUTLINE: This is a dose-escalation study of savolitinib followed by a dose-expansion study. Patients receive savolitinib orally (PO) once daily (QD). Treatment repeats every 28 days for up to 39 courses in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection X-ray imaging, and magnetic resonance imaging (MRI) scans throughout study. After completion of study treatment, patients are followed up at 30 days, then periodically for up to 2 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
41
Undergo blood sample collection
Undergo MRI scan
Given PO
Undergo X-ray imaging
Children's Hospital Los Angeles
Los Angeles, California, United States
Lucile Packard Children's Hospital Stanford University
Palo Alto, California, United States
Children's Hospital Colorado
Aurora, Colorado, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Lurie Children's Hospital-Chicago
Chicago, Illinois, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Nationwide Children's Hospital
Columbus, Ohio, United States
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States
Saint Jude Children's Research Hospital
Memphis, Tennessee, United States
...and 2 more locations
The Maximum Tolerated Dose (MTD) and Recommended Phase II Dose
The maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of savolitinib were determined using a Rolling-6 Phase I dose-escalation design. Dose escalation was conducted in cohorts of two to six participants, starting at Dose Level 1. The MTD was defined based on the occurrence of dose-limiting toxicities during the dose-finding period (Course 1: 28 days) according to protocol-specified criteria. No intra-patient dose escalation was permitted. Participants were considered evaluable for dose-limiting toxicity assessment if they received the required dose of study drug and completed the dose-limiting toxicity observation period or experienced a dose-limiting toxicity during that period.
Time frame: Up to 30 days post treatment initiation
Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)
Dose-limiting toxicity (DLT) was defined as any adverse event at least possibly related to savolitinib occurring during the dose-finding period that met protocol-specified hematologic or non-hematologic criteria, including severe toxicity, treatment delay, dose reduction, or permanent discontinuation.
Time frame: Up to 30 days post treatment initiation
Number of Patients With Sustained Objective Responses (Complete Response + Partial Response)
The number of objective responses (complete or partial) sustained for at least 8 weeks is counted and reported by dose level. Complete disappearance on MR of all evaluable tumor and mass effect, on a stable or decreasing dose of corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or improving neurologic examination. Complete response will be confirmed if it is maintained for at least 8 weeks. If CSF was positive, it must be negative. Greater than or equal to 50% reduction in tumor size by bi-dimensional measurement, as compared with the baseline measurements, on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurologic examination. Partial response will be confirmed if it is maintained for at least 8 weeks.
Time frame: Up to 2 years
Pharmacokinetic Parameters: AUC0-infinity
This analysis includes savolitinib concentrations from 37 individuals with 2 pharmacokinetic studies (days 1 and 8). The individual posthoc parameter values were used to estimate the area under the concentration curve (AUC0-infinity).
Time frame: up to 10 days from treatment initiation
Pharmacokinetic Parameters of Interest: Cmax
Pharmacokinetic (PK) studies were conducted in 37 participants, with two PK assessment occasions corresponding to Day 1 and Day 8 for each patient. A one-compartment PK model with first-order absorption was used to describe the concentration-time data. Individual post hoc parameter estimates were then used to derive the maximum concentration (Cmax).
Time frame: up to 10 days from treatment initiation
Pharmacokinetic Parameters: Clearance/F
This analysis includes savolitinib concentrations from 37 individuals with 2 pharmacokinetic studies (days 1 and 8). A one-compartment PK model with first-order absorption was used to describe the data.
Time frame: up to 10 days from treatment initiation
Population Parameters: Fixed-Effect Parameter Estimates: Tlag_pop
Population PK parameters were estimated using nonlinear mixed-effects modeling. And nonlinear mixed-effects modeling was performed with Monolix (version 2024R1) using the Stochastic Approximation Expectation-Maximization (SAEM) method. Reported values are fixed-effect population estimates for lag time (absorption lag time (Tlag (hrs)).
Time frame: up to 10 days from treatment initiation
Population Parameters: Fixed-Effect Parameter Estimates: ka_pop
Population PK parameters were estimated using nonlinear mixed-effects modeling. And nonlinear mixed-effects modeling was performed with Monolix (version 2024R1) using the Stochastic Approximation Expectation-Maximization (SAEM) method. Reported values are fixed-effect population estimates absorption rate constant (absorption (ka (1/hr))).
Time frame: up to 10 days from treatment initiation
Population Parameters: Fixed-Effect Parameter Estimates: V_pop
Population PK parameters were estimated using nonlinear mixed-effects modeling. And nonlinear mixed-effects modeling was performed with Monolix (version 2024R1) using the Stochastic Approximation Expectation-Maximization (SAEM) method. Reported values are fixed-effect population estimates volume (V/F (L).
Time frame: up to 10 days from treatment initiation
Population Parameters: Fixed-Effect Parameter Estimates: Cl_pop
Population PK parameters were estimated using nonlinear mixed-effects modeling. And nonlinear mixed-effects modeling was performed with Monolix (version 2024R1) using the Stochastic Approximation Expectation-Maximization (SAEM) method. Reported values are fixed-effect population estimates for clearance (CL/F (L/hr) ).
Time frame: up to 10 days from treatment initiation
Population Parameters: Inter-individual Variability Estimates for Population PK Parameters: omega_Tlag
Reported values are standard deviations of random effects from the nonlinear mixed-effects population pharmacokinetic model. "Omega" represents the standard deviation of between-subject variability (inter-individual variability).
Time frame: up to 10 days from treatment initiation
Population Parameters: Inter-individual Variability Estimates for Population PK Parameters: omega_ka
Reported values are standard deviations of random effects from the nonlinear mixed-effects population pharmacokinetic model. "Omega" represents the standard deviation of between-subject variability (inter-individual variability).
Time frame: up to 10 days from treatment initiation
Population Parameters: Inter-individual Variability Estimates for Population PK Parameters: omega_V
Reported values are standard deviations of random effects from the nonlinear mixed-effects population pharmacokinetic model. "Omega" represents the standard deviation of between-subject variability (inter-individual variability).
Time frame: up to 10 days from treatment initiation
Population Parameters: Inter-individual Variability Estimates for Population PK Parameters: omega_Cl
Reported values are standard deviations of random effects from the nonlinear mixed-effects population pharmacokinetic model. "Omega" represents the standard deviation of between-subject variability (inter-individual variability).
Time frame: up to 10 days from treatment initiation
Population Parameters: Inter-individual Variability Estimates for Population PK Parameters: gamma_Tlag
Reported values are standard deviations of random effects from the nonlinear mixed-effects population pharmacokinetic model. "Gamma" represents the standard deviation of inter-occasion variability. Two occasions correspond to pharmacokinetic measurements obtained on Day 1 and Day 8 for each patient.
Time frame: up to 10 days from treatment initiation
Population Parameters: Inter-individual Variability Estimates for Population PK Parameters: gamma_ka
Reported values are standard deviations of random effects from the nonlinear mixed-effects population pharmacokinetic model. "Gamma" represents the standard deviation of inter-occasion variability. Two occasions correspond to pharmacokinetic measurements obtained on Day 1 and Day 8 for each patient.
Time frame: up to 10 days from treatment initiation
Population Parameters: Inter-individual Variability Estimates for Population PK Parameters: gamma_V
Reported values are standard deviations of random effects from the nonlinear mixed-effects population pharmacokinetic model. "Gamma" represents the standard deviation of inter-occasion variability. Two occasions correspond to pharmacokinetic measurements obtained on Day 1 and Day 8 for each patient.
Time frame: up to 10 days from treatment initiation
Population Parameters: Inter-individual Variability Estimates for Population PK Parameters: gamma_Cl
Reported values are standard deviations of random effects from the nonlinear mixed-effects population pharmacokinetic model. "Gamma" represents the standard deviation of inter-occasion variability. Two occasions correspond to pharmacokinetic measurements obtained on Day 1 and Day 8 for each patient.
Time frame: up to 10 days from treatment initiation
Molecular Analyses of Tumor
To perform a genomic analysis within the confines of a Phase I study to investigate correlation between response to treatment (as measured by objective response or PFS) and the presence of specific genomic alterations (e.g., MET or HGF amplification, MET mutations, or MET fusion) and/or specific subgroups of disease.
Time frame: Up to 2 years
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