Ignite Creation Date:
2024-05-06 @ 7:52 PM
Last Modification Date:
2024-10-26 @ 3:15 PM
Study NCT ID:
NCT06161519
Status:
RECRUITING
Last Update Posted:
2024-06-05
First Post:
2023-12-01
Brief Title:
PLX038 in Primary Central Nervous System Tumors Containing MYC or MYCN Amplifications
Sponsor:
National Cancer Institute NCI
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Phase III Trial of PLX038 in Primary Central Nervous System Tumors Containing MYC or MYCN Amplifications
Status:
RECRUITING
Status Verified Date:
2024-09-26
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:
Background
About 90000 new cases of brain and spinal cord tumors are diagnosed annually in the United States Most of these tumors are benign however about 30 are malignant and 35 of people with malignant tumors in the brain and spinal cord will die within 5 years Many of these people have changes in certain genes MYC or MYCN that drive the development of their cancers
Objective
To test a study drug PLX038 in people with tumors of the brain or spinal cord
Eligibility
People aged 18 years or older with a tumor of the brain or spinal cord Some participants must also have tumors with changes in the MYC or MYCN genes
Design
Participants will be screened They will have a physical exam and blood tests They will have imaging scans and a test of their heart function They may need to have a biopsy A sample of tissue will be removed from their tumor
PLX038 is given through a tube attached to a needle inserted into a vein in the arm All participants will receive PLX038 on the first day of each 21-day treatment cycle They will take a second drug 3 days later to help reduce the risk of infection for this drug participants will be shown how to inject themselves under the skin at home
Blood tests imaging scans and other tests will be repeated during study visits Hair samples will also be collected during these visits Some participants may have an additional biopsy
Study treatment will continue up to 7 months
Follow-up visits will continue every few months for up to 5 years
About 90000 new cases of brain and spinal cord tumors are diagnosed annually in the United States Most of these tumors are benign however about 30 are malignant and 35 of people with malignant tumors in the brain and spinal cord will die within 5 years Many of these people have changes in certain genes MYC or MYCN that drive the development of their cancers
Objective
To test a study drug PLX038 in people with tumors of the brain or spinal cord
Eligibility
People aged 18 years or older with a tumor of the brain or spinal cord Some participants must also have tumors with changes in the MYC or MYCN genes
Design
Participants will be screened They will have a physical exam and blood tests They will have imaging scans and a test of their heart function They may need to have a biopsy A sample of tissue will be removed from their tumor
PLX038 is given through a tube attached to a needle inserted into a vein in the arm All participants will receive PLX038 on the first day of each 21-day treatment cycle They will take a second drug 3 days later to help reduce the risk of infection for this drug participants will be shown how to inject themselves under the skin at home
Blood tests imaging scans and other tests will be repeated during study visits Hair samples will also be collected during these visits Some participants may have an additional biopsy
Study treatment will continue up to 7 months
Follow-up visits will continue every few months for up to 5 years
Detailed Description:
Background
The MYC genes encode a family of transcription factors MYC-C MYC-N and MYC-L that regulate the expression of a wide range of genes involved in cell division in development and adulthood
Supraphysiologic levels of MYC are oncogenic and drive aggressive behavior across a range of human malignancies Amplifications of MYC and MYCN are seen in multiple types of primary central nervous system CNS tumors including gliomas medulloblastomas and ependymomas
These CNS tumors are rare and there are limited prospective data to inform treatment choices and few efficacious options At present they are typically treated with maximal safe surgical resection followed by external beam radiation therapy with the variable inclusion of cytotoxic chemotherapy regimens as first-line treatment andor at recurrence These standard options carry the risk of substantial side effects and have limited to no antitumor activity for many of these tumors leading to short patient survival measured in several months to a few years and significant morbidity from therapy
MYC-driven increase in transcription induces the formation of topoisome complexes MYC-CN Topoisomerase 1 TOP1 Topoisomerase 2 TOP2 DNA that are essential to managing the torsional strain that would otherwise oppose transcription and replication
PLX038 is a PEGylated macromolecule that contains 4 molecules of SN-38 the active metabolite of irinotecan that is currently being investigated in non-CNS solid tumor trials SN38 binds to and inhibits Topoisomerase I and the unique formulation of PLX038 lead to a longer half-life which is thought to increase tumor accumulation and decrease toxicity
Objectives
Phase I To confirm the recommended Phase II dose RP2D of PLX038 in participants with progressive or recurrent primary CNS tumors
Phase II To assess the efficacy of PLX038 in primary CNS tumors containing MYC or MYCN amplifications as measured by
Progression-free survival PFS for Cohort Phase IIA adjuvant treatment and
Disease control rate DCR defined as confirmed complete response CR partial response PR or durable stable disease SD NOTE Durable SD is SD lasting for at least 6 months for Cohorts Phase IIB and Phase IIC treatment for recurrence
Eligibility
Subjects with histologically confirmed primary CNS tumors corresponding to any progressive or recurrent tumor type Phase I or one of the following tumor types Phase II
Cohort Phase IIA Newly diagnosed MYCN amplified ependymoma post resection and radiotherapy
Cohort Phase IIB Recurrent or progressive MYCN amplified ependymoma or medulloblastoma with MYC or MYCN amplifications
Cohort Phase IIC All other recurrent or progressive primary CNS tumors containing MYC or MYCN amplifications
Age 18 years
Karnofsky Performance Status 70
Ability to self-report symptoms and physical function as determined by assessment of the clinical team
Tumor tissue available for central review and confirmation of diagnosis
Design
This is an open-label phase III clinical trial
During Phase I RP2D and maximum tolerated dose MTD of PLX038 will be estimated
In the Phase II component participants will be treated with the TOP1 inhibitor PLX038 at the RP2D intravenously every 3 weeks - 3 days 1 cycle The Phase II study will be comprised of 3 independent disease cohorts that can enroll simultaneously and will be evaluated independently for efficacy
Treatment will continue until progression or unacceptable toxicity or a maximum of 10 cycles whichever occurs first
Safety and toxicity assessments will occur prior to each treatment cycle every 3 weeks
Efficacy by magnetic resonance MR imaging andor other imaging techniques if extra CNS tumor is present and patient-reported outcomes measures PROs participant reported toxicity using predetermined patient-reported outcomes Common Terminology Criteria for Adverse Events PRO-CTCAE symptoms Patient Global Impression of Severity PGI-S Patient Global Impression-Change PGI-C Overall Side Effect Bother self-reported symptom severity and interference with daily activities using MD Anderson Symptom Inventory for brain tumor MDASI-BT andor MD Anderson Symptom Inventory for spine tumors MDASI-SP questionnaires self-reported physical functioning using Patient-Reported Outcomes Measurement Information System PROMIS Physical Functioning form 10b PRO-CTCAE PGI-S PGI-C Overall Side Effect Bother and PROMIS Physical Function 10b will be obtained at baseline and weekly for the first two cycles of treatment then these and all other PRO assessments will be obtained at the time of disease imaging evaluation every 2 cycles 6 weeks The only exceptions are the PGI-C and Overall Side Effect Bother which will not be obtained at baseline and Day 1 of Cycle 1 PRO measures will be completed prior to participants being informed of imaging results
PLX038 drug distribution will be investigated in peripheral blood and tumor tissue post-treatment administration Molecular biomarkers of treatment response or resistance will be investigated in an exploratory manner pre and post-treatment after cycle 2 and after tumor progression in tumor tissue hair follicles and peripheral blood
The MYC genes encode a family of transcription factors MYC-C MYC-N and MYC-L that regulate the expression of a wide range of genes involved in cell division in development and adulthood
Supraphysiologic levels of MYC are oncogenic and drive aggressive behavior across a range of human malignancies Amplifications of MYC and MYCN are seen in multiple types of primary central nervous system CNS tumors including gliomas medulloblastomas and ependymomas
These CNS tumors are rare and there are limited prospective data to inform treatment choices and few efficacious options At present they are typically treated with maximal safe surgical resection followed by external beam radiation therapy with the variable inclusion of cytotoxic chemotherapy regimens as first-line treatment andor at recurrence These standard options carry the risk of substantial side effects and have limited to no antitumor activity for many of these tumors leading to short patient survival measured in several months to a few years and significant morbidity from therapy
MYC-driven increase in transcription induces the formation of topoisome complexes MYC-CN Topoisomerase 1 TOP1 Topoisomerase 2 TOP2 DNA that are essential to managing the torsional strain that would otherwise oppose transcription and replication
PLX038 is a PEGylated macromolecule that contains 4 molecules of SN-38 the active metabolite of irinotecan that is currently being investigated in non-CNS solid tumor trials SN38 binds to and inhibits Topoisomerase I and the unique formulation of PLX038 lead to a longer half-life which is thought to increase tumor accumulation and decrease toxicity
Objectives
Phase I To confirm the recommended Phase II dose RP2D of PLX038 in participants with progressive or recurrent primary CNS tumors
Phase II To assess the efficacy of PLX038 in primary CNS tumors containing MYC or MYCN amplifications as measured by
Progression-free survival PFS for Cohort Phase IIA adjuvant treatment and
Disease control rate DCR defined as confirmed complete response CR partial response PR or durable stable disease SD NOTE Durable SD is SD lasting for at least 6 months for Cohorts Phase IIB and Phase IIC treatment for recurrence
Eligibility
Subjects with histologically confirmed primary CNS tumors corresponding to any progressive or recurrent tumor type Phase I or one of the following tumor types Phase II
Cohort Phase IIA Newly diagnosed MYCN amplified ependymoma post resection and radiotherapy
Cohort Phase IIB Recurrent or progressive MYCN amplified ependymoma or medulloblastoma with MYC or MYCN amplifications
Cohort Phase IIC All other recurrent or progressive primary CNS tumors containing MYC or MYCN amplifications
Age 18 years
Karnofsky Performance Status 70
Ability to self-report symptoms and physical function as determined by assessment of the clinical team
Tumor tissue available for central review and confirmation of diagnosis
Design
This is an open-label phase III clinical trial
During Phase I RP2D and maximum tolerated dose MTD of PLX038 will be estimated
In the Phase II component participants will be treated with the TOP1 inhibitor PLX038 at the RP2D intravenously every 3 weeks - 3 days 1 cycle The Phase II study will be comprised of 3 independent disease cohorts that can enroll simultaneously and will be evaluated independently for efficacy
Treatment will continue until progression or unacceptable toxicity or a maximum of 10 cycles whichever occurs first
Safety and toxicity assessments will occur prior to each treatment cycle every 3 weeks
Efficacy by magnetic resonance MR imaging andor other imaging techniques if extra CNS tumor is present and patient-reported outcomes measures PROs participant reported toxicity using predetermined patient-reported outcomes Common Terminology Criteria for Adverse Events PRO-CTCAE symptoms Patient Global Impression of Severity PGI-S Patient Global Impression-Change PGI-C Overall Side Effect Bother self-reported symptom severity and interference with daily activities using MD Anderson Symptom Inventory for brain tumor MDASI-BT andor MD Anderson Symptom Inventory for spine tumors MDASI-SP questionnaires self-reported physical functioning using Patient-Reported Outcomes Measurement Information System PROMIS Physical Functioning form 10b PRO-CTCAE PGI-S PGI-C Overall Side Effect Bother and PROMIS Physical Function 10b will be obtained at baseline and weekly for the first two cycles of treatment then these and all other PRO assessments will be obtained at the time of disease imaging evaluation every 2 cycles 6 weeks The only exceptions are the PGI-C and Overall Side Effect Bother which will not be obtained at baseline and Day 1 of Cycle 1 PRO measures will be completed prior to participants being informed of imaging results
PLX038 drug distribution will be investigated in peripheral blood and tumor tissue post-treatment administration Molecular biomarkers of treatment response or resistance will be investigated in an exploratory manner pre and post-treatment after cycle 2 and after tumor progression in tumor tissue hair follicles and peripheral blood
Study Oversight
Has Oversight DMC:
None
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?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 001534-C | None | None | None |