Molecularly-Driven Doublet Therapy for All Children With Refractory or Recurrent CNS Malignant Neoplasms and Young Adults With Refractory or Recurrent SHH Medulloblastoma

Who is this study for? Children with refractory or recurrent CNS malignant neoplasms and young adults with refractory or recurrent SHH medulloblastoma
What treatments are being studied? Molecularly-Driven Doublet Therapy
Status: Recruiting
Location: See location...
Intervention Type: Drug, Biological
Study Type: Interventional
Study Phase: Phase 1

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.

Participation Requirements
Sex: All
Minimum Age: 1
Maximum Age: 39
Healthy Volunteers: No

• Evaluable disease, as defined as meeting any of the following:

• Patients who have measurable disease

• Patients with radiologically discernible but non-measurable lesions (i.e. leptomeningeal disease)

• Patients with CSF positive disease

• Participants must have received their last dose of anticancer therapy (including experimental) at least 4 weeks prior to study enrollment.

• Note: Participants must have relapsed with recurrent, progressive or refractory disease on or after any prior anticancer therapy.

• Participants must have had their last fraction of radiation at least 4 weeks prior to study enrollment. Participants who received radiation therapy for palliation must have had their last fraction of radiation at least 2 weeks prior to study enrollment.

• Note: Participants must have relapsed with recurrent, progressive or refractory disease after any prior radiation therapy that is not considered palliative. Palliative radiation therapy is defined as local small port RT to alleviate and/or palliate symptoms. (CSI, whole brain RT, large field/port RT, or large field/port multilevel spinal RT will not be considered palliative at any dose.)

• Participants who are receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to study enrollment with no plans for escalation.

• Participants who are receiving known strong inducers and/or strong inhibitors of CYP3A4/5, drugs that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5, and medications that carry a known risk for QT prolongation must discontinue these drugs at least 7 days prior to study enrollment.

• Participants must discontinue herbal preparations, herbal medication, and dietary supplements, with the exception of multivitamins, at least 7 days prior to study enrollment.

• Participants must be able to swallow medication. It is acceptable to administer medication via a g-tube if participant has a g-tube. It is not acceptable to place a g-tube for the purpose of delivering study medication.

• Participants must have a Lansky (≤ 16 years) or Karnofsky (> 16 years) score of at least 50 and, in the opinion of the investigator, a minimum life expectancy of at least 6 weeks at the time of study enrollment.

• Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

• Participant must have adequate bone marrow and organ function defined as:

• ANC ≥ 1000/mm3 without growth factor support within 7 days of the test

• Platelet count ≥ 50,000/mm^3 without support of a platelet transfusion within 7 days of the test

• Hemoglobin ≥ 8.0 g/dL without support of a blood transfusion within 7 days of the test

• Creatinine clearance ≥ 70 mL/min/1.73 m^2 or serum creatinine ≤ the maximum serum creatinine based on age/gender (threshold creatinine values derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control and Prevention or creatinine clearance ≥70 mL/min/1.73 m^2).

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN. For the purposes of eligibility the ULN of ALT and AST is 45 U/L.

• Total bilirubin ≤ ULN or if > ULN then direct bilirubin ≤ 1.5xULN.

• Participants and/or guardian have the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines.

United States
St. Jude Children's Research Hospital
Contact Information
Tabatha E. Doyle, RN
Time Frame
Start Date: March 5, 2018
Estimated Completion Date: March 2025
Target number of participants: 108
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.
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.
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.
Collaborators: Novartis Pharmaceuticals
Leads: St. Jude Children's Research Hospital

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