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PBTC-049: A Phase I study of Savolitinib in Recurrent, Progressive or Refractory Medulloblastoma, High-Grade Glioma, Diffuse Intrinsic Pontine Glioma, and CNS tumors harboring MET aberrations

Study category: Cancer

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Description

This is a dose escalation study of savolitinib administered orally once a day to patients with recurrent, progressive or refractory central nervous system tumors. There are three stages in this study: a dose escalation cohort, PK expansion cohort, and an efficacy expansion cohort. The dose escalation cohort is designed to determine the maximum tolerated dose (MTD)/recommended Phase II dose (RP2D), to evaluate the pharmacokinetics, safety and preliminary anti-tumor activity of savolitinib. Once the MTD/RP2D is determined, the enrollment for an efficacy expansion cohort will open for patients whose tumors harbor genetic MET activation as determined by CLIA tests performed at participating sites, and confirmed by FDA approved tests.

Details
Age

Child to Adult

Eligibility

ELIGIBILITY CRITERIA FOR ENROLLMENT 2.1.1 Diagnosis Patients with a histologically confirmed diagnosis of a primary CNS tumor (medulloblastoma, high-grade glioma, or 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. 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. The submitted specimen can be from diagnosis or recurrence and there is no time limit from when the specimen was obtained to enrollment onto the efficacy expansion cohort. The assessment will be performed in a CLIA certified laboratory. MET pathway activation status must be confirmed using FDA approved testing prior to enrollment. MET pathway activation is defined as: - MET kinase domain mutations, allelic frequency ≥ 5% OR - 61607; MET or HGF amplification, - 6 copies OR Chromosome 7 gain OR MET fusion If a MET aberration is identified using local testing at a PBTC institution, final confirmation for eligibility to the efficacy cohort will be confirmed using MSKCC’s FDA approved IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) panel. Alternatively, if a MET aberration is identified at a PBTC site using another FDA approved panel (Foundation Medicine or Oncomine), the result will be considered sufficient for eligibility following study PI review. Refer to Appendix for more information on MET activation testing for the efficacy expansion cohort. 2.1.2 Available Pre-trial Tumor Tissue Recurrent or refractory primary malignant CNS tumor patients must have adequate pre-trial frozen or FFPE tumor material available for the required correlative studies (section 9.1.4 and 9.1.5). If target amounts of tissue or number of slides are not available, the site must obtain study Chair/coChair 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. 2.1.3 Disease Status 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. 2.1.4 Age Patients must be > 5 years and less than/equal to 21 years of age at the time of study enrollment. 2.1.5 BSA Patients enrolled on 75 mg/m2 /day (dose level 0) must have a BSA ≥ 1.00 m2 . Patients enrolled on 150 mg/m2 /day (dose level 1) must have a BSA ≥ 0.55 m2 . Patients enrolled on 240 mg/m2 /day (dose level 2) who weigh < 50kg must have a BSA ≥ 0.63 m2 but ≤ 2.00 m2 . Patients enrolled on 240 mg/m2 /day (dose level 2) who weigh ≥ 50kg must have a BSA ≥ 0.63 m2

Type of Study

Treatment

Location

Childrens Hospital Colorado

Principal Investigator
Kathleen Dorris,  MD

Kathleen Dorris, MD

Study ID

Protocol Number: 18-2432

More information available at ClinicalTrials.gov: NCT03598244

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