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

Anaplastic Astrocytoma, Anaplastic Ependymoma, Anaplastic Ganglioglioma, Anaplastic Meningioma, Anaplastic Oligodendroglioma, Atypical Teratoid/Rhabdoid Tumor, Brain Cancer, Brain Tumor, Central Nervous System Neoplasms, Choroid Plexus Carcinoma, CNS Embryonal Tumor With Rhabdoid Features, CNS Tumor, Embryonal Tumor, NOS, Embryonal Tumor of CNS, Embryonal Tumor With Multilayered Rosettes (ETMR), Ependymoma, Ependymoma, NOS, WHO Grade II, Ependymoma, NOS, WHO Grade III, Ependymoma, Recurrent, Ependymoma, RELA Fusion Positive, 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, Medulloblastoma, Non-WNT Non-SHH, NOS, Medulloblastoma, PTCH1 Mutation, Medulloblastoma, SHH-activated and TP53 Mutant, Medulloblastoma, SHH-activated and TP53 Wildtype, Medulloblastoma; Unspecified Site, Medulloblastoma, WNT-activated, 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

ATRT, Brain Tumors in Adolescents, Brain Tumors in Children, Brain Tumors in Young Adults, CDK4 amplification, CDK 4/6, CDK 4/6 inhibitor, CDK 4/6 pathway, CDK 4/6/cyclin/RB/E2F pathway, CDK6 amplification, CyclinD1, DAWN, D-type Cyclins, Hedgehog pathway inhibitor, HGG, MAPK pathway, MEK, MEK inhibitor, MEK1, MEK2, Mekinist, Molecular, Molecular therapy, MYC amplification, PTCH1, Rare brain tumor, Recurrent ATRT, Recurrent brain tumor, Recurrent ependymoma, Recurrent high grade glioma, Recurrent malignant glioma, Recurrent medulloblastoma, Refractory brain tumor, Small molecule inhibitor, SMO antagonist, Smoothened protein, Sonic hedgehog, Combination therapy

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.

Patients will be stratified by the molecular and histologic characteristics of their tumor to one of three treatment strata. STRATUM A: * Combination Treatment: ribociclib and gemcitabine. * Patient Population: 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). STRATUM B: * Combination Treatment: ribociclib and trametinib. * Patient Population: Participants with a diagnosis of one of the following refractory or recurrent CNS diseases: medulloblastoma \[sonic hedgehog (SHH)\], medulloblastoma (WNT), 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) or select central nervous system (CNS) embryonal tumors (including: embryonal tumors with multilayered rosettes, C19MC-altered; embryonal tumors with multilayered rosettes, not otherwise specified (NOS); medulloepithelioma; CNS neuroblastoma; CNS ganglioneuroblastoma; CNS embryonal tumor, NOS; atypical teratoid/rhabdoid tumor; CNS embryonal tumor with rhabdoid features). STRATUM C: * Combination Treatment: ribociclib and sonidegib. * Patient Populations: Participants with refractory or recurrent medulloblastoma (SHH) \>6 months off smoothened inhibitor, presence of 9q loss or PTCH1 mutant, skeletally mature. The rolling 6 design will be used separately in each stratum to estimate the MTD or RP2D and determine the dose-limiting toxicity (DLT) of the combination of escalating doses. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in the absence of disease progression or unacceptable toxicity. Stratum A participants may continue therapy past 24 months in absence of disease progression or unacceptable toxicity. Patients will receive doublet therapy in cycles of 28 days. The dose-limiting toxicity (DLT)-evaluation period will consist of the first cycle (i.e. first 4 weeks of therapy). Research participants will be evaluated at least once a week during the DLT-evaluation period and at regular intervals thereafter. Standard (e.g., physical exam, blood tests, and disease evaluations) tests will be obtained at regular intervals. Research-associated evaluations (e.g., pharmacokinetic studies, etc.) will also be obtained during therapy. Treatment may be continued for up to 2 years in the absence of disease progression or unacceptable toxicity. Stratum A participants may continue past 2 years in the absence of disease progression or unacceptable toxicity.

United States