SJDAWN: St. Jude Children's Research Hospital Phase 1 Study Evaluating Molecularly-Driven Doublet Therapies for Children and Young Adults With Recurrent Brain Tumors

Conditions

• Anaplastic Astrocytoma
• Anaplastic Ependymoma
• Anaplastic Ganglioglioma
• Anaplastic Meningioma
• Anaplastic Oligodendroglioma
• Atypical Teratoid/Rhabdoid Tumor
• Brain Cancer
• Brain Tumor
• CNS Embryonal Tumor With Rhabdoid Features
• CNS Tumor
• Central Nervous System Neoplasms
• Choroid Plexus Carcinoma
• Embryonal Tumor With Multilayered Rosettes (ETMR)
• Embryonal Tumor of CNS
• Embryonal Tumor, NOS
• Ependymoma
• Ependymoma, NOS, WHO Grade II
• Ependymoma, NOS, WHO Grade III
• Ependymoma, RELA Fusion Positive
• Ependymoma, Recurrent
• Ganglioneuroblastoma of Central Nervous System
• Glioblastoma
• Glioblastoma, IDH-mutant
• Glioblastoma, IDH-wildtype
• Glioma
• Glioma, Diffuse Midline, H3K27M-mutant
• Glioma, High Grade
• Glioma, Malignant
• Glioma, Recurrent High Grade
• Glioma, Recurrent Malignant
• Medulloblastoma
• Medulloblastoma, Chromosome 9q Loss
• Medulloblastoma, G3/G4
• Medulloblastoma, Group 3
• Medulloblastoma, Group 4
• Medulloblastoma, Non-WNT Non-SHH, NOS
• Medulloblastoma, Non-WNT/Non-SHH
• Medulloblastoma, PTCH1 Mutation
• Medulloblastoma, SHH-activated and TP53 Mutant
• Medulloblastoma, SHH-activated and TP53 Wildtype
• Medulloblastoma, WNT-activated
• Medulloblastoma; Unspecified Site
• Medulloepithelioma
• Neoplasms
• Neoplasms, Neuroepithelial
• Neuroblastoma. CNS
• Neuroepithelial Tumor
• Neuroepithelial Tumor, High Grade
• Papillary Tumor of the Pineal Region (High-grade Only)
• Pediatric Brain Tumor
• Pineal Parenchymal Tumor of Intermediate Differentiation (High-grade Only)
• Pineoblastoma
• Pleomorphic Xanthoastrocytoma, Anaplastic
• Primitive Neuroectodermal Tumor
• Recurrent Medulloblastoma
• Refractory Brain Tumor

Eligibility Criteria

Sex

ALL

Age

1 Year - 39 Years

Healthy Volunteers

Not accepted

Interventions

• Gemcitabine — DRUG
  Given intravenously (IV).
• ribociclib — DRUG
  Given orally (PO).
• sonidegib — DRUG
  Given PO.
• trametinib — DRUG
  Given PO.
• filgrastim — BIOLOGICAL
  Given subcutaneously (SQ).

Study Details

Approximately 90% of children with malignant brain tumors that have recurred or relapsed after receiving conventional therapy will die of disease. Despite this terrible and frustrating outcome, continued treatment of this population remains fundamental to improving cure rates. Studying this relapsed population will help unearth clues to why conventional therapy fails and how cancers continue to resist modern advances. Moreover, improvements in the treatment of this relapsed population will lead to improvements in upfront therapy and reduce the chance of relapse for all. Novel therapy and, more importantly, novel approaches are sorely needed. This trial proposes a new approach that evaluates rational combination therapies of novel agents based on tumor type and molecular characteristics of these diseases. The investigators hypothesize that the use of two predictably active drugs (a doublet) will increase the chance of clinical efficacy. The purpose of this trial is to perform a limited dose escalation study of multiple doublets to evaluate the safety and tolerability of these combinations followed by a small expansion cohort to detect preliminary efficacy. In addition, a more extensive and robust molecular analysis of all the participant samples will be performed as part of the trial such that we can refine the molecular classification and better inform on potential response to therapy. In this manner the tolerability of combinations can be evaluated on a small but relevant population and the chance of detecting antitumor activity is potentially increased. Furthermore, the goal of the complementary molecular characterization will be to eventually match the therapy with better predictive biomarkers. PRIMARY OBJECTIVES: * To determine the safety and tolerability and estimate the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of combination treatment by stratum. * To characterize the pharmacokinetics of combination treatment by stratum. SECONDARY OBJECTIVE: * To estimate the rate and duration of objective response and progression free survival (PFS) by stratum.

Key Dates

Start date

Mar 5, 2018

Status verified

May 2024

Primary completion

Sep 30, 2022

Completion

May 24, 2024

Study Design

Enrollment

68 participants (actual)

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Arms

• Experimental: A: ribociclib + gemcitabine
  Stratum A participants with a diagnosis of refractory or recurrent medulloblastoma (Group 3/4) or refractory or recurrent ependymoma. (including: ependymoma, not otherwise specified (NOS), WHO Grade III; ependymoma, RELA fusion positive; anaplastic ependymoma; ependymoma, NOS, WHO grade II). They receive combination treatment with ribociclib and gemcitabine. They may also receive growth therapy support with filgrastim. Stratum A has completed all the necessary accrual
• Experimental: B: ribociclib + trametinib
  Stratum B participants with a diagnosis of one of the following refractory or recurrent CNS diseases: medulloblastoma, \[sonic hedgehog (SHH)- or WNT-activated\];; high grade glioma (including: high grade glioma, (NOS), WHO Grade III or IV; anaplastic astrocytoma, IDH mutant; glioblastoma, IDH-wildtype; glioblastoma, IDH-mutant; diffuse midline glioma, H3K27-mutant; anaplastic oligodendroglioma, IDH mutant and 1p/19q-codeleted; anaplastic pleomorphic xanthoastrocytoma); select CNS embryonal tumors (including: embryonal tumors with multilayered rosettes, C19MC-altered; embryonal tumors with multilayered rosettes, NOS; medulloepithelioma; CNS neuroblastoma; CNS ganglioneuroblastoma; CNS embryonal tumor, NOS; atypical teratoid/rhabdoid tumor; CNS embryonal tumor with rhabdoid features). They receive combination treatment with ribociclib and trametinib. Stratum B has completed all the necessary accrual
• Experimental: C: ribociclib + sonidegib
  Stratum C participants with refractory or recurrent medulloblastoma (SHH-activated) \>6 months off smoothened inhibitor, presence of 9q loss or PTCH1 mutant, skeletally mature. They received combination treatment with ribociclib and sonidegib. Stratum C is being closed due to low accrual

Primary Outcome Measure

Estimate the Maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of each doublet by stratum [ Time Frame: 1 month after start of therapy ]

Locations (1)

Find similar trials in Memphis, TN

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