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

Summary

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.

Conditions

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

Interventions

DRUG

Gemcitabine

Given intravenously (IV).

DRUG

ribociclib

Given orally (PO).

DRUG

sonidegib

Given PO.

DRUG

trametinib

Given PO.

BIOLOGICAL

filgrastim

Given subcutaneously (SQ).

Sponsors & Collaborators

• Novartis Pharmaceuticals

  collaborator INDUSTRY

• St. Jude Children's Research Hospital

  lead OTHER

Principal Investigators

• Giles W. Robinson, MD · St. Jude Children's Research Hospital

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

1 Year

Max Age

39 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2018-03-05

Primary Completion

2022-09-30

Completion

2024-05-24

FDA Drug

Yes

Countries

• United States

Study Locations