Savolitinib in Treating Patients With Recurrent or Refractory Primary CNS Tumors

NCT03598244 | Active Not Recruiting Phase 1 Results FDA Drug

• 3 other identifiers: NCI-2018-01499PBTC-049UM1CA081457
• Study Type: interventional
• Target: 41
• Locations: 2 countries
• Sites: 12

Brief Summary

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.

Conditions

Recurrent Diffuse Intrinsic Pontine Glioma; Recurrent Malignant Glioma; Recurrent Medulloblastoma; Recurrent Primary Central Nervous System Neoplasm; Refractory Diffuse Intrinsic Pontine Glioma; Refractory Malignant Glioma; Refractory Medulloblastoma; Refractory Primary Central Nervous System Neoplasm

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  Up to 30 days post treatment initiation

Secondary Outcomes (17)

• Number of Patients With Sustained Objective Responses (Complete Response + Partial Response)

  Up to 2 years

• Pharmacokinetic Parameters: AUC0-infinity

  up to 10 days from treatment initiation

• Pharmacokinetic Parameters of Interest: Cmax

  up to 10 days from treatment initiation

• Pharmacokinetic Parameters: Clearance/F

  up to 10 days from treatment initiation

• Population Parameters: Fixed-Effect Parameter Estimates: Tlag_pop

  up to 10 days from treatment initiation

Study Arms (1)

Treatment (savolitinib)

EXPERIMENTAL

Patients receive savolitinib PO 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 MRI scans throughout study.

Procedure: Biospecimen Collection; Procedure: Magnetic Resonance Imaging; Drug: Savolitinib; Procedure: X-Ray Imaging

Interventions

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

Treatment (savolitinib)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI scan

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (savolitinib)

Savolitinib DRUG

Given PO

Also known as: AZD 6094, AZD-6094, AZD6094, HMPL 504, HMPL-504, HMPL504, Orpathys, Volitinib

Treatment (savolitinib)

X-Ray Imaging PROCEDURE

Undergo X-ray imaging

Also known as: Conventional X-Ray, Diagnostic Radiology, Medical Imaging, X-Ray, Plain film radiographs, Radiographic Imaging, Radiographic imaging procedure (procedure), Radiography, RG, Static X-Ray, X-Ray

Treatment (savolitinib)

Eligibility Criteria

• Age: 6 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients with a histologically confirmed diagnosis of a primary CNS tumor (medulloblastoma, high-grade glioma, or diffuse intrinsic pontine glioma \[DIPG\]) that is recurrent, refractory, or progressive. All tumors must have histologic verification at either the time of diagnosis or recurrence except patients with diffuse intrinsic brain stem tumors. These patients must have radiographic or clinical evidence of progression. Patients with a recurrent, progressive, or refractory primary CNS tumor with evidence of genetic activation of the MET pathway, regardless of histology, are also eligible to the Phase I component of this study
• Note: Refractory disease is defined as the presence of persistent abnormality on conventional MRI imaging that is further distinguished by histology (biopsy or sample of lesion) or advanced imaging, OR as determined by the treating physician and discussed with the primary investigator prior to enrollment
• Efficacy Expansion Cohort: Patients must have a recurrent, progressive, or refractory primary CNS tumor with evidence of genetic activation of the MET pathway, regardless of histology. Specimens can be from diagnosis or recurrence and there is no time limit from when the specimen was obtained prior to enrollment onto the efficacy expansion cohort. Results from a Clinical Laboratory Improvement Act (CLIA)-certified laboratory will be accepted for this eligibility criterion. Sites must provide a redacted copy of the local CLIA-certified sequencing laboratory report to the study chair via email prior to enrollment. MET pathway activation is defined as:
• MET mutations, OR
• MET or HGF amplification, OR
• MET fusion
• Recurrent or refractory primary malignant CNS tumor patients must have adequate pre-trial frozen or formalin-fixed paraffin-embedded (FFPE) tumor material available for the required correlative studies. If target amounts of tissue or number of slides are not available, the site must obtain study chair/co-chair approval for adequacy of submitted tumor samples and prioritization of studies to be performed, prior to patient enrollment
• Patients with DIPG who have pre-trial tumor tissue available are requested to submit tissue; however, this is not required for eligibility
• Patients must have evaluable disease to be eligible. Evaluable disease is defined as the presence of at least one lesion that can be measured accurately in at least 2 (two) dimensions
• Patients must be \> 5 years and =\< 21 years of age at the time of study enrollment
• Body surface area (BSA)
• Patients enrolled on 75 mg/m\^2/day (dose level 0) must have a BSA \>= 1.00 m\^2
• Patients enrolled on 150 mg/m\^2/day (dose level 1) must have a BSA \>= 0.55 m\^2
• Patients enrolled on 240 mg/m\^2/day (dose level 2) must have a BSA \>= 0.67 m\^2
• Patients enrolled on 350 mg/m\^2/day (dose level 3) must have a BSA \>= 0.73 m\^2

You may not qualify if:

• Pregnant women or nursing mothers are excluded from this study. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Pregnant women are excluded from this study because there are unknown but potential risks to an unborn baby from savolitinib. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with savolitinib, breastfeeding should be discontinued if the mother is treated with savolitinib
• Patients with a known serious active infection including, but not limited to human immunodeficiency virus, and tuberculosis
• Patients with a known active or resolved viral hepatitis infection
• Patients with any clinically significant unrelated systemic illness or significant cardiac, pulmonary, hepatic, or other organ dysfunction), that in the opinion of the investigator 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 with uncontrolled hypertension (i.e., a blood pressure \[BP\] \> 95th percentile for age, height, and sex, patients with values above these levels must have their blood pressure controlled with medication prior to starting study drug)
• The normal blood pressure by height, age, and sex can be assessed by using the NIH Guidelines on the PBTC Member's website (Protocols- Generic Forms and Templates- Normal Blood Pressure by Height and Age)
• Patients with any of the following cardiac diseases
• Congestive heart failure (New York Heart Association \>= grade 2)
• Clinically significant cardiac arrhythmia
• Mean resting corrected QT interval (QTc Bazett) \> 450 msec on screening obtained from 3 electrocardiograms (EKGs) or
• Factors that may increase the risk of QTc prolongation such as chronic hypokalemia not correctable with supplements, congenital or familial long QT syndrome, or
• Family history of unexplained sudden death under 40 years of age in first-degree relatives or
• Any concomitant medication known to prolong the QT interval and cause Torsade de Pointes. These drugs must have been discontinued prior to the start of administration of study treatment in accordance with guidance
• Any clinically important abnormalities in rhythm, conduction, or morphology of resting EKG, e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval \> 250 msec
• Patients with history of liver cirrhosis of any origin and clinical stage; or history of other serious liver disease or chronic disease with relevant liver involvement, with or without normal liver function tests (LFTs), including but not limited to:

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (12)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Lucile Packard Children's Hospital Stanford University

Palo Alto, California, 94304, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Lurie Children's Hospital-Chicago

Chicago, Illinois, 60611, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224, United States

Location

Saint Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

MeSH Terms

Conditions

Diffuse Intrinsic Pontine Glioma; Glioma; Medulloblastoma; Central Nervous System Neoplasms

Interventions

Specimen Handling; Magnetic Resonance Spectroscopy; 1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine; X-Rays; Phantoms, Imaging

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Brain Stem Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuroectodermal Tumors, Primitive

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical; Electromagnetic Radiation; Electromagnetic Phenomena; Magnetic Phenomena; Physical Phenomena; Radiation; Radiation, Ionizing; Equipment and Supplies

Limitations and Caveats

PBTC-049 closed to accrual on 03/21/2025 one patient short of the planned accrual when it was determined that the efficacy aim would not be met. All patients are off treatment and off study.

Results Point of Contact

• Title: Dr. Arzu Onar-Thomas
• Organization: St.Jude Children's Research Hospital

arzu.onar@stjude.org

9012182532

Study Officials

• Ralph Salloum

  Pediatric Brain Tumor Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 24, 2018
• First Posted: July 26, 2018
• Study Start: November 27, 2018
• Primary Completion: April 22, 2026
• Study Completion (Estimated): May 27, 2027
• Last Updated: July 30, 2026
• Results First Posted: June 23, 2026

Record last verified: 2026-05

Locations

US (11); CA (1)