Ignite Creation Date:
2025-12-24 @ 5:08 PM
Ignite Modification Date:
2025-12-28 @ 9:31 PM
Study NCT ID:
NCT03605550
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2025-02-24
First Post:
2018-07-20
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
A Phase 1b Study of PTC596 in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma and High Grade Glioma
Sponsor:
Nationwide Children's Hospital
Organization:
Study Overview
Official Title:
A Phase 1b Study of PTC596 in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma and High Grade Glioma
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2025-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The goal of this study is to evaluate the safety of the study drug PTC596 (Unesbulin) taken in combination with radiotherapy (RT) when given to pediatric patients newly diagnosed with High-Grade Glioma (HGG) including diffuse intrinsic pontine glioma (DIPG).
The main aims of the study are to:
* Find the safe dose of the study drug PTC596that can be given without causing serious side effects.
* Find out the amount of drug that enters blood (in all patients) and tumor (in patients who receive drug prior to a planned surgery for removal of their brain tumor)
During the first cycle (6-7weeks), patients will receive drug orally twice a week in combination with daily RT. During subsequent cycles (4 weeks each), they will receive only the study drug orally twice a week.
Funding Source - FDA OOPD
The main aims of the study are to:
* Find the safe dose of the study drug PTC596that can be given without causing serious side effects.
* Find out the amount of drug that enters blood (in all patients) and tumor (in patients who receive drug prior to a planned surgery for removal of their brain tumor)
During the first cycle (6-7weeks), patients will receive drug orally twice a week in combination with daily RT. During subsequent cycles (4 weeks each), they will receive only the study drug orally twice a week.
Funding Source - FDA OOPD
Detailed Description:
This study consists of 3 parts:
1. The Phase I (Parts A and C), dose-finding component of the trial, to estimate the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of PTC596 in combination with RT followed by maintenance therapy with PTC596, in children with newly-diagnosed DIPG and HGG.
Once the RP2D has been determined,
2. An early efficacy expansion cohort of up to 17 patients at the RP2D (Part C expansion, and Part D)
3. A surgical cohort (part B) of 12 patients with newly diagnosed DIPG who are amenable to undergo biopsy or HGG for whom a second surgical resection is warranted
For patients on cohorts A, C and D, PTC596 will be given orally twice weekly for 6-7 weeks along with daily RT for the first cycle. In subsequent cycles (4 weeks each), all patients will continue with maintenance therapy which will begin immediately after completion of RT for up to 26 cycles (2 years).
For the surgical cohort, patients will be treated with 2 doses of PTC596, on days 1 and 4 prior to biopsy or re-resection; the second dose of PTC596 should ideally be administered 3-6 hrs before surgery. The surgical cycle will end when patients begin RT which should take place at least two weeks after the date of surgery and may restart PTC596 (twice weekly) after starting RT. Following completion of RT, patients will immediately start maintenance therapy with twice weekly PTC596 for up to 26 cycles.
Primary Objectives Parts A, C
* To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of PTC596 given concurrently with radiation in newly-diagnosed patients with DIPG or HGG (Parts A and C)
* To determine the toxicities of PTC596 given concurrently with RT and during maintenance therapy (Parts A, C).
* To characterize the pharmacokinetics of PTC596 given as a capsule and as a tablet in children with newly diagnosed DIPG or HGG when given concurrently with RT and during maintenance (Parts A, C).
Primary Objectives Surgical Cohort -Part B
* To test the ability of PTC596 to inhibit BMI-1 activity in tumor and PBMCs
* To characterize the pharmacokinetics of PTC596 in plasma, cerebrospinal fluid (CSF), and tumor tissue
Secondary Objectives
* To evaluate the overall survival (OS) for newly-diagnosed patients with DIPG treated with PTC596 and compare to historical controls.
* To estimate the progression-free survival (PFS) distribution for newly-diagnosed patients with HGG ttreated with PTC596 and compare to historical controls
* To determine the effects of BMI-1 modulation in DIPG and HGG on BMI-1 levels, H2A monoubiquitination, cell proliferation, cell death, gene regulation, through gene expression profiling and epigenetic studies such as RNA sequencing and ChIP-Seq within the confines of a Phase I study.
* Correlate pre-treatment and post-treatment concentrations of potential biomarkers in biological specimens (e.g., blood and tissue) with response/toxicity, PFS, OS within the confines of a phase I study.
* To examine H3F3A, HIST1H3B (H3.3 and H3.1 genes), ATRX, and DAXX mutations and examine the effects of these alterations using targeted gene, exome, RNA sequencing and methylation arrays of targeted genomic regions in DIPG and HGG.
* To assess the health-related quality-of-life of patients by parent report, and when possible, patient report at key points in therapy using the patient reported outcomes measurement information system (PROMIS) survey.
* To explore tumor volumetric measurements on MRI and correlate with 2-dimensional measurements and compare response criteria.
* To correlate early measures of tumor response (volumetric and 2-dimensional measurements with overall survival.
1. The Phase I (Parts A and C), dose-finding component of the trial, to estimate the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of PTC596 in combination with RT followed by maintenance therapy with PTC596, in children with newly-diagnosed DIPG and HGG.
Once the RP2D has been determined,
2. An early efficacy expansion cohort of up to 17 patients at the RP2D (Part C expansion, and Part D)
3. A surgical cohort (part B) of 12 patients with newly diagnosed DIPG who are amenable to undergo biopsy or HGG for whom a second surgical resection is warranted
For patients on cohorts A, C and D, PTC596 will be given orally twice weekly for 6-7 weeks along with daily RT for the first cycle. In subsequent cycles (4 weeks each), all patients will continue with maintenance therapy which will begin immediately after completion of RT for up to 26 cycles (2 years).
For the surgical cohort, patients will be treated with 2 doses of PTC596, on days 1 and 4 prior to biopsy or re-resection; the second dose of PTC596 should ideally be administered 3-6 hrs before surgery. The surgical cycle will end when patients begin RT which should take place at least two weeks after the date of surgery and may restart PTC596 (twice weekly) after starting RT. Following completion of RT, patients will immediately start maintenance therapy with twice weekly PTC596 for up to 26 cycles.
Primary Objectives Parts A, C
* To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of PTC596 given concurrently with radiation in newly-diagnosed patients with DIPG or HGG (Parts A and C)
* To determine the toxicities of PTC596 given concurrently with RT and during maintenance therapy (Parts A, C).
* To characterize the pharmacokinetics of PTC596 given as a capsule and as a tablet in children with newly diagnosed DIPG or HGG when given concurrently with RT and during maintenance (Parts A, C).
Primary Objectives Surgical Cohort -Part B
* To test the ability of PTC596 to inhibit BMI-1 activity in tumor and PBMCs
* To characterize the pharmacokinetics of PTC596 in plasma, cerebrospinal fluid (CSF), and tumor tissue
Secondary Objectives
* To evaluate the overall survival (OS) for newly-diagnosed patients with DIPG treated with PTC596 and compare to historical controls.
* To estimate the progression-free survival (PFS) distribution for newly-diagnosed patients with HGG ttreated with PTC596 and compare to historical controls
* To determine the effects of BMI-1 modulation in DIPG and HGG on BMI-1 levels, H2A monoubiquitination, cell proliferation, cell death, gene regulation, through gene expression profiling and epigenetic studies such as RNA sequencing and ChIP-Seq within the confines of a Phase I study.
* Correlate pre-treatment and post-treatment concentrations of potential biomarkers in biological specimens (e.g., blood and tissue) with response/toxicity, PFS, OS within the confines of a phase I study.
* To examine H3F3A, HIST1H3B (H3.3 and H3.1 genes), ATRX, and DAXX mutations and examine the effects of these alterations using targeted gene, exome, RNA sequencing and methylation arrays of targeted genomic regions in DIPG and HGG.
* To assess the health-related quality-of-life of patients by parent report, and when possible, patient report at key points in therapy using the patient reported outcomes measurement information system (PROMIS) survey.
* To explore tumor volumetric measurements on MRI and correlate with 2-dimensional measurements and compare response criteria.
* To correlate early measures of tumor response (volumetric and 2-dimensional measurements with overall survival.
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
Secondary ID Infos
| Secondary ID | Type | Domain | Link | View |
|---|---|---|---|---|
| 5R01FD006352-03 | FDA | None | https://reporter.nih.gov/quic… | View |