Overview
- Background
About 90,000 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 PCX038 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.
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 and/or 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-C/N, 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 I/II 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 and/or 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), and/or 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
- 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.
Eligibility
- INCLUSION CRITERIA:
- Participants must have histologically confirmed by NCI Laboratory of Pathology (LP)
primary central nervous system (CNS) tumor with one of the below diagnoses:
- Cohort Phase I: Any recurrent or progressive primary CNS tumor, regardless of molecular features.
- Cohort Phase IIA: Newly diagnosed MYCN amplified ependymoma after surgery and radiation.
- Cohort Phase IIB:
- Recurrent or progressive MYCN amplified ependymoma, OR
- Recurrent or progressive medulloblastoma with MYC or MYCN amplifications
- Cohort Phase IIC: Any other recurrent or progressive primary CNS tumor with MYC
or MYCN amplifications.
- Participants must have histologically confirmed by NCI Laboratory of Pathology (LP)
primary central nervous system (CNS) tumor with one of the below diagnoses:
NOTE 1: Recurrence or progression may involve CNS, extra CNS, or both.
NOTE 2: The presence of MYCN or MYC amplification will be determined by NSR device (via
next generation sequencing panel TSO500) and the threshold of MYCN or MYC amplification for
eligibility purposes is a fold change (FC) of >= 2.5X (5 copies) with a minimum tumor
content of 20%.
- Participants must have archival tumor tissue (either a block or 20 formalin-fixed
paraffin-embedded (FFPE) unstained slides) available for NCI LP review and
confirmation of diagnosis:
- Cohorts Phase I, Phase IIB, and Phase IIC: tumor tissue obtained at any point
before trial treatment initiation, but preferably from most recent surgical
resection before study treatment initiation.
- Cohort Phase IIA: tumor tissue obtained at original diagnosis.
- Participants in Cohort Phase IIA must have completed surgery followed by radiation at
least 4 weeks and no more than 10 weeks from the last dose of radiation prior to study
treatment initiation.
- Participants in Cohorts Phase I, Phase IIB, and Phase IIC must have completed prior
cytotoxic chemotherapy or radiation at least 4 weeks prior to study treatment
initiation (at least 6 weeks if the last regimen included lomustine (CCNU) or
carmustine (BCNU); at least 3 weeks if the last regimen included bevacizumab; at least
5 half-lives if the last regimen included any investigational agent(s). Participants
previously treated with PHOTON radiation to at least 2 segments of the spine must have
completed radiation at least 12 months before study treatment initiation.
- Age >= 18 years.
- Karnofsky >= 70% (Cares for self, unable to carry on normal activity or to do active
work.) NOTE: Participants with severe paraparesis/paraplegia who need minimal
assistance for self-care due to their motor deficit but are otherwise functionally
independent will be eligible.
- Participants must have adequate organ and marrow function as defined below:
- leukocytes >4=3,000/microliter
- absolute neutrophil count >1,500/microliter
- platelets >100,000/microliter
- hemoglobin >= 9 g/ dL (may be transfused within 2 weeks prior to treatment to
achieve this level)
- total bilirubin within normal institutional limits
- aspartate aminotransferase (AST) / alanine aminotransferase (ALT) <2.5 X
institutional upper limit of normal (ULN)
- creatinine within normal institutional limits OR estimated glomerular filtrate
rate (eGFR) using chronic kidney disease epidemiology collaboration) (CKD-EPI)
equation:within normal institutional limits OR >= 60 mL/min/1.73 m^2 for
participants with creatinine levels above institutional normal
- Women of child-bearing potential (WOCBP) and men must agree to use effective
contraception (barrier, hormonal contraception, intrauterine device (IUD), surgical
sterilization for women, barrier, surgical sterilization for men) at the study entry,
for the duration of study treatment and up to 6 months (women) and 3 months (men)
after the last dose of study treatment.
- Breastfeeding participants must be willing to discontinue breastfeeding from study
treatment initiation through 6 months after the last dose of the study drug.
- Ability to self-report symptoms and physical function as determined by assessment of
the clinical team performed at screening.
- Participants must be able to understand and willing to sign a written informed consent
document.
EXCLUSION CRITERIA:
- History of allergic reactions to compounds of similar chemical composition to PLX038.
- Major surgery within 2 weeks prior to study treatment initiation. NOTE: The surgery is
considered major if a mesenchymal barrier is opened (pleural cavity, peritoneum,
meninges).
- Participants who require treatment with strong inhibitors or inducers of CYP3A or with
UGT1A1 inhibitors during the planned period of investigational treatment with PLX038.
Lists including medications and substances known or with the potential to interact
with CYP3A or UGT1A1 are provided in
https://www.fda.gov/drugs/drug-interactionslabeling/drug-development-and-drug-interact
ions-table-substrates-inhibitors-andinducers.
- History of treatment with pegylated topoisomerase inhibitors.
- History of treatment with PHOTON craniospinal irradiation (CSI).
- Participants with history of homozygous for the UGT1A1*28 variant allele with severely
reduced UGT1A1 activity.
- Participants positive for Human immunodeficiency virus (HIV), Hepatitis C virus (HCV),
and Hepatitis B virus (HBV).
- Pregnancy (confirmed with beta human chorionic gonadotropin (beta-HCG) serum or urine
pregnancy test performed in females of childbearing potential at screening).
- Participants unable to have MRIs.
- Prior or concurrent malignancy unless its natural history or treatment does not have
the potential to interfere with the safety or efficacy assessment of the
investigational regimen
(https://deainfo.nci.nih.gov/advisory/ctac/1117/4-JournalClinicalOncology.pdf,
https://ctep.cancer.gov/protocolDevelopment/docs/CTEP_Broadened_Eligibility_Criteria_G
uidance.pdf)
- Uncontrolled intercurrent illness evaluated by history, weight, and physical exam that
would limit compliance with study requirements.