SJDAWN: St. Jude Children's Research Hospital Phase 1 Study Evaluating Molecularly-Driven Doublet Therapies for Children and Young Adults With Recurrent Brain Tumors
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|ClinicalTrials.gov Identifier: NCT03434262|
Recruitment Status : Recruiting
First Posted : February 15, 2018
Last Update Posted : April 10, 2018
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.
- 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.
- To estimate the rate and duration of objective response and progression free survival (PFS) by stratum.
|Condition or disease||Intervention/treatment||Phase|
|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||Drug: Gemcitabine Drug: ribociclib Drug: sonidegib Drug: trametinib Biological: filgrastim Biological: pegfilgrastim||Phase 1|
Patients will be stratified by the molecular and histologic characteristics of their tumor to one of three treatment strata.
- 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).
- 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).
- 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.
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.
|Study Type :||Interventional|
|Estimated Enrollment :||108 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||This is a phase 1 limited dose escalation to define RP2D of the doublets with an early expansion cohort to evaluate preliminary efficacy.|
|Masking:||None (Open Label)|
|Official Title:||Molecularly-Driven Doublet Therapy for All Children With Refractory or Recurrent CNS Malignant Neoplasms and Young Adults With Refractory or Recurrent SHH Medulloblastoma|
|Actual Study Start Date :||March 5, 2018|
|Estimated Primary Completion Date :||February 2025|
|Estimated Study Completion Date :||March 2025|
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 or pegfilgrastim.
Given intravenously (IV).
Other Name: Gemzar®
Given orally (PO).
Given subcutaneously (SQ). Alternatively, pegfilgrastim may be given.
Other Name: G-CSF
Given subcutaneously (SQ). Alternatively, filgrastim may be given.
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.
Given orally (PO).
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.
Given orally (PO).
- Estimate the Maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of each doublet by stratum [ Time Frame: 1 month after start of therapy ]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).
- Pharmacokinetics of combination treatment: Stratum A [ Time Frame: Course 1: Days -1, 0, 1 and 15 and 16; Course 2: Day 1 ]Plasma concentration will be provided.
- Pharmacokinetics of combination treatment: Stratum B [ Time Frame: Course 1: Days 1, 2, 3, 14 and 15 ]Plasma concentration will be provided.
- Pharmacokinetics of combination treatment: Stratum C [ Time Frame: Course 1: Days -1, 0, 1, 2, 21, 22 and 28; Course 2: Day 1 ]Plasma concentration will be provided.
- Response rate by stratum [ Time Frame: Up to 1 year after completion of therapy (up to 3 years after start of therapy) ]The response rate, defined as the rate of complete response (CR) or partial response (PR), and long-term stable disease (SD) will be calculated as the percentage of confirmed responders among all response assessable patients. These rates as well as their exact confidence intervals will be provided and will be summarized by each response category (i.e., CR, PR, and SD). Descriptive summaries of response per dose level may also be provided. Subjects without an assessment will be considered non-responders.
- Duration of objective response by stratum [ Time Frame: Up to 1 year after completion of therapy (up to 3 years after start of therapy) ]Duration of response defined as the time from the initial documented response (CR or PR) to the first confirmed progressive disease (PD). We will use progression free survival (PFS) for describing duration of SD. Subjects without a documented progression will be censored at the time of their last tumor assessment. Duration of Response will be assessed using the Kaplan-Meier method to calculate the median time as well as the proportion remaining progression free at given time points. The corresponding 95% confidence intervals will be presented.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03434262
|Contact: Tabatha E. Doyle, RNfirstname.lastname@example.org|
|United States, Tennessee|
|St. Jude Children's Research Hospital||Recruiting|
|Memphis, Tennessee, United States, 38105|
|Contact: Tabatha E. Doyle, RN 901-595-2544 email@example.com|
|Principal Investigator: Giles W. Robinson, MD|
|Principal Investigator:||Giles W. Robinson, MD||St. Jude Children's Research Hospital|