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

NCT03434262 | Completed Phase 1 FDA Drug

• 2 other identifiers: SJDAWNNCI-2018-00284
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 1

Brief 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

Keywords

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

Outcome Measures

Primary Outcomes (4)

• Estimate the Maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of each doublet by stratum

  The MTD is empirically defined as the highest dose level at which six patients have been treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level has been determined to be too toxic. The MTD estimate will not be available, if the lowest dose level studied is too toxic or the highest dose level studied is considered safe. In the latter case, the highest studied safe dose will be considered the recommended phase 2 dose (RP2D). The MTD estimation will be limited to evaluable patients and toxicity assessments from course 1 (28 days).

  1 month after start of therapy

• Pharmacokinetics of combination treatment: Stratum A

  Plasma concentration will be provided.

  Course 1: Days -1, 0, 1 and 15 and 16; Course 2: Day 1

• Pharmacokinetics of combination treatment: Stratum B

  Plasma concentration will be provided.

  Course 1: Days 1, 2, 3, 14 and 15

• Pharmacokinetics of combination treatment: Stratum C

  Plasma concentration will be provided.

  Course 1: Days -1, 0, 1, 2, 21, 22 and 28; Course 2: Day 1

Secondary Outcomes (2)

• Response rate by stratum

  Up to 1 year after completion of therapy (up to 3 years after start of therapy)

• Duration of objective response by stratum

  Up to 1 year after completion of therapy (up to 3 years after start of therapy)

Study Arms (3)

A: ribociclib + gemcitabine

EXPERIMENTAL

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

Drug: Gemcitabine; Drug: ribociclib; Biological: filgrastim

B: ribociclib + trametinib

EXPERIMENTAL

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

Drug: ribociclib; Drug: trametinib

C: ribociclib + sonidegib

EXPERIMENTAL

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

Drug: ribociclib; Drug: sonidegib

Interventions

Gemcitabine DRUG

Given intravenously (IV).

Also known as: Gemzar®

A: ribociclib + gemcitabine

ribociclib DRUG

Given orally (PO).

Also known as: LEE011, LEE-011, KISQALI®

A: ribociclib + gemcitabine; B: ribociclib + trametinib; C: ribociclib + sonidegib

sonidegib DRUG

Given PO.

Also known as: LDE225, LDE-225, ODOMZO®

C: ribociclib + sonidegib

trametinib DRUG

Given PO.

Also known as: TMT212, TMT-212, MEKINIST(TM)

B: ribociclib + trametinib

filgrastim BIOLOGICAL

Given subcutaneously (SQ).

Also known as: G-CSF

A: ribociclib + gemcitabine

Eligibility Criteria

• Age: 1 Year - 39 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may not qualify if:

• Participants with recurrent, progressive, or refractory brain tumors.
• Age ≥ 1 year and \< 25 years at the time of screening. Exception: Participants with recurrent, progressive, or refractory Medulloblastoma and are ≥ 1 and \< 40 years of age at the time of study screening are eligible for screening.
• Participants and/or guardian have the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines.
• Participants with a diagnosis of recurrent, progressive, or refractory low grade glioma (LGG).
• Previous exposure to a CDK4/6 inhibitor (palbociclib, abemaciclib, or ribociclib).
• Participants with a history of clinically significant, uncontrolled heart disease and/or repolarization abnormalities.
• Participants with any history of QTc prolongation (i.e. QTc interval of \> 450 msec).
• 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.)

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (1)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude
• St. Jude Brain Tumor Studies

MeSH Terms

Conditions

Astrocytoma; Ependymoma; Meningioma; Oligodendroglioma; Rhabdoid Tumor; Brain Neoplasms; Central Nervous System Neoplasms; Choroid Plexus Carcinoma; Glioblastoma; Glioma; Medulloblastoma; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neoplasms; Pinealoma; Pyloric Stenosis, Hypertrophic; Recurrence; Neoplasms, Germ Cell and Embryonal; Lymphoma, Follicular; Microphthalmia, Isolated, with Coloboma 5

Interventions

Gemcitabine; ribociclib; sonidegib; trametinib; Filgrastim; Granulocyte Colony-Stimulating Factor

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neoplasms, Vascular Tissue; Meningeal Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Nervous System Diseases; Neoplasms, Complex and Mixed; Brain Diseases; Central Nervous System Diseases; Pyloric Stenosis; Gastric Outlet Obstruction; Stomach Diseases; Gastrointestinal Diseases; Digestive System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Giles W. Robinson, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a phase 1 limited dose escalation to define RP2D of the doublets with an early expansion cohort to evaluate preliminary efficacy.

Study Record Dates

• First Submitted: February 9, 2018
• First Posted: February 15, 2018
• Study Start: March 5, 2018
• Primary Completion: September 30, 2022
• Study Completion: May 24, 2024
• Last Updated: May 31, 2024

Record last verified: 2024-05

Locations

US (1)