Combination Therapy for Brain Cancer

Recruiting in Palo Alto (17 mi)

Overseen byGiles W. Robinson, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Waitlist Available

Sponsor: St. Jude Children's Research Hospital

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

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.

Research Team

Giles W. Robinson, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for children and young adults aged 1 to less than 25 years with recurrent brain tumors, except those with specific low-grade gliomas or retinal vein occlusion. Participants must have completed previous cancer treatments at least 4 weeks prior, be able to swallow medication (or use a g-tube), not be pregnant or breastfeeding, and agree to use effective contraception. They should also have stable health without serious medical issues that could affect the study.

Inclusion Criteria

My brain tumor is growing or returning despite treatment.

My tumor is a specific type of brain cancer that has not responded to treatment.

I am between 1 and 24 years old.

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Exclusion Criteria

I have not taken smoothened inhibitors in the last 6 months.

I have a history of serious heart disease that is not under control.

You have a history of prolonged QTc interval (more than 450 milliseconds).

See 13 more

Treatment Details

Interventions

Filgrastim (N/A)
Gemcitabine (Anti-metabolite)
Ribociclib (CDK4/6 Inhibitor)
Sonidegib (Hedgehog Pathway Inhibitor)
Trametinib (MEK Inhibitor)

Trial OverviewThe SJDAWN trial tests combinations of drugs like Gemcitabine, Trametinib, Filgrastim, Sonidegib, and Ribociclib on various types of recurrent brain tumors in children and young adults. It aims to find safe dosages and see how well these drug pairs work together based on tumor type and molecular characteristics.

Participant Groups

3Treatment groups

Experimental Treatment

Group I: C: ribociclib + sonidegibExperimental Treatment2 Interventions

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

Group II: B: ribociclib + trametinibExperimental Treatment2 Interventions

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

Group III: A: ribociclib + gemcitabineExperimental Treatment3 Interventions

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

Gemcitabine is already approved in Canada, Japan for the following indications: