Glioblastoma, Malignant Glioma, Recurrent Glioblastoma, Recurrent Malignant Glioma
Conditions
Brief summary
This phase I trial tests the safety, side effects, best dose and how well FPS-ZM1 works for controlling post operative cerebral edema in patients with glioblastoma. FPS-ZM1 works by blocking the pathway that controls inflammation. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Giving FPS-ZM1 with or without dexamethasone may be safe and/or effective in controlling post operative cerebral edema in patients with glioblastoma.
Detailed description
PRIMARY OBJECTIVE: I. Determine the maximum feasible dose (MFD) of RAGE antagonist FPS-ZM1 (FPS-ZM1) administered peri-operatively to participants with newly diagnosed or recurrent glioblastoma. SECONDARY OBJECTIVES: I. Assess the ability of FPS-ZM1 to control participants' symptoms of post-operative cerebral edema when administered as monotherapy. II. Describe the systemic pharmacokinetics and central nervous system (CNS) penetration of FPS-ZM1 based on concentrations of FPS-ZM1 in peripheral blood, cerebrospinal fluid (CSF), brain tumor tissue and resection cavity fluid (when obtainable). III. Characterize cytokine concentrations over time in brain interstitial fluid, peripheral blood and resection cavity fluid (when obtainable) by dose level. IV. Assess for evidence of RAGE inhibition in tumor tissue, CSF, brain interstitial fluid, resection cavity fluid (when obtainable) and peripheral blood by dose level. V. Qualitatively and quantitatively assess changes in volume of cerebral edema on pre-operative brain magnetic resonance imaging (MRIs) and brain MRIs performed on post-operative Days 2 and 14 across dose levels. OUTLINE: This is a dose-escalation study of FPS-ZM1 in combination with fixed-dose dexamethasone. Patients are assigned to 1 of 2 arms. ARM I (DOSE LEVELS 1-3): Starting 2 days prior to surgery, patients receive FPS-ZM1 orally (PO) daily (QD) until post operative day 11, and dexamethasone intravenously (IV) or PO QD taper until post operative day 14, in the absence of disease progression or unacceptable toxicity. On day of surgery patients undergo standard of care resection and, if possible, undergo placement of a temporary peritumoral microdialysis catheter and intracavity drain for collection of dialysate and intracavity fluid. Patients undergo urine sample collection during screening, lumbar puncture with CSF collection and computed tomography (CT) scan on study and brain MRI, and blood sample collection throughout the study. ARM II (DOSE LEVEL 4): Starting 2 days prior to surgery, patients receive FPS-ZM1 PO QD and, if needed for physiologic replacement, a smaller dose of dexamethasone IV or PO QD until post operative day 11, in the absence of disease progression or unacceptable toxicity. On day of surgery patients undergo standard of care resection and, if possible, undergo placement of a temporary peritumoral microdialysis catheter and intracavity drain for collection of dialysate and intracavity fluid. Patients undergo urine sample collection during screening, lumbar puncture with CSF collection and CT scan on study and brain MRI, and blood sample collection throughout the study. After completion of study treatment, patients are followed up at day 30.
Interventions
PROCEDUREBiospecimen Collection
Undergo blood, dialysate, intracavity fluid, and urine sample collection
PROCEDUREComputed Tomography
Undergo CT scan
DRUGDexamethasone
Given IV or PO
PROCEDUREInvasive Procedure
Undergo placement of a temporary peritumoral microdialysis catheter
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
DRUGRAGE Antagonist FPS-ZM1
Given PO
PROCEDUREResection
Undergo resection surgery
Sponsors
City of Hope Medical Center
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Patients assigned to dose levels 1-3 are assigned to arm I, patients assigned to dose level 4 are assigned to arm II.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented informed consent given by the participant. Non-English speaking adults are eligible for participation if they have the capacity to understand and consent to the study procedures * Age: ≥ 18 years * Karnofsky Performance Status (KPS) ≥ 70% * Histologically confirmed glioblastoma or radiographic findings consistent with a high grade glioma * Newly diagnosed or recurrent tumor * The patient is planning to undergo a standard-of-care craniotomy for gross total resection of enhancing tumor * The patient's pre-operative brain MRI shows the presence of mild to moderate cerebral edema, defined as a midline shift of less than 10 mm * Dose Levels 1-3 participants: If taking more than a total of 6 mg a day of dexamethasone at the time of signing the consent form, it is anticipated by the neurosurgeon that the participant will be able to decrease their dose of dexamethasone to 6 mg daily by 4 days before the surgery (pre-operative Day -4) * Dose Level 4 participants: If taking more than 1 mg a day of dexamethasone at the time of signing the consent form, it is anticipated by the neurosurgeon that the participant will be able to taper their dose of dexamethasone to 1 mg daily or less by pre-operative Day -4 * The patient is not planning to be in another clinical trial during the study period * The patient has recovered from any acute toxic effects (except alopecia) to ≤ grade 1 of prior anti-cancer therapy * No limit to prior number of therapies. The following time periods must have elapsed prior to the start of study treatment: 6 weeks from nitrosourea-containing chemotherapy, 4 weeks from non-nitrosourea-containing cytotoxic chemotherapy (except 23 days from last daily dose of temozolomide taken in a 5 of 28 day regimen, 5 half-lives from last dose of a targeted agent, and 4 weeks from the last dose of bevacizumab). There is no time period requirement for prior radiation therapy * Absolute neutrophil count (ANC) ≥ 1,000/mm\^3 * Platelets ≥ 100,000/mm\^3 * Hemoglobin ≥ 9g/dL * Total bilirubin ≤ 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease) * Aspartate aminotransferase (AST) ≤ 1.5 x ULN * Alanine aminotransferase (ALT) ≤ 1.5 x ULN * Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min * International Normalized Ratio (INR) OR Prothrombin (PT) ≤ 1.5 x ULN * Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN * Corrected QT interval (QTc) ≤ 450 ms * Must have a Fridericia's corrected QT interval (QTcF) ≤ 450 msec calculated with Fridericia formula * Left ventricular ejection fraction (LVEF) ≥ 50% * People of childbearing potential who have uteri: negative urine or serum pregnancy test * Contraception: * Agreement by participants of childbearing potential or participants who are partners of people with childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of protocol therapy. Contraception guidance (as per the information included in the informed consent document): * Acceptable medically effective forms of birth control are: * Surgical sterilization (tubal ligation or hysterectomy, or vasectomy, as applicable), * Double-barrier methods (i.e. condoms, diaphragm, cervical cap, or sponge used with spermicidal gel or foam), * Intrauterine device (IUD) (i.e. Progestin, Copper), * Hormonal Contraceptives (Birth control patches, implants, pills, rings, or injections)
Exclusion criteria
* The patient is taking a medication that is a strong or moderate inducer or inhibitor of major CYP450 isoenzymes and drug transporters, and the patient is not able to stop that medication at least 14 days prior to start of study treatment * The patient has a risk factor for torsades de pointes, such as structural heart disease (history of myocardial infarction, congestive heart failure, left ventricular hypertrophy), electrolyte abnormalities (hypokalemia, hypomagnesemia), bradycardia or heart blocks, or a family history of Long QT syndrome * The patient is taking a medication that prolongs the QT/QTc interval and is not able to stop that medication at least 14 days prior to start of study treatment * The patient is unwilling to stop taking herbal medications prior to the start of study treatment * The patient is taking a hepatic enzyme-inducing anti-seizure medication within 14 days prior to start of study treatment * Patient is planning to participate in clinical trial or start a new therapy for their brain tumor during the study period: Day -2 to Day 14 * Patient has not recovered from toxicities of prior therapy (must be grade 1 or less) except alopecia * Adults who lack the capacity to provide informed consent, including individuals who would require consent from a Legally Authorized Representative (LAR) * Clinically significant uncontrolled illness * Active infection requiring antibiotics * Participants with human immunodeficiency virus (HIV) are excluded due to concerns about inadvertent augmentation of infectious and/or inflammatory activity * Undergoing treatment for another cancer * Issues with tolerating oral medication (e.g. inability to swallow, malabsorption issues, ongoing nausea or vomiting) * Chronic or active viral infection of the CNS * Participant is pregnant or breastfeeding * Coagulopathy or bleeding disorder * Inability to undergo a brain MRI * Inability to tolerate dexamethasone * Any other condition that would, in the investigator's judgment, contraindicate participation in the clinical study due to safety concerns with clinical study procedures * Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| RAGE Antagonist FPS-ZM1 (FPS-ZM1) related adverse events | Up to 30 days post surgery | Assessed per Common Terminology Criteria for Adverse Events (CTCAE) version 6.0. |
| Dose limiting toxicity rate | Up to 30 days post surgery | Assessed per CTCAE version 6.0. |
Secondary
| Measure | Time frame |
|---|---|
| Doses of dexamethasone taken post-operatively by study participants on dose Level 4 | Up to 30 days post surgery |
| FPS-ZM1 concentrations in enhancing tumor tissue | Up to 30 days post surgery |
| FPS-ZM1 concentrations in non-enhancing tumor tissue | Up to 30 days post surgery |
| FPS-ZM1 concentrations in cerebrospinal fluid (CSF) | Up to 30 days post surgery |
| FPS-ZM1 concentrations in resection cavity fluid | Up to 30 days post surgery |
| Cytokine concentrations in brain interstitium | Up to 30 days post surgery |
| Cytokine concentrations in peripheral blood | Up to 30 days post surgery |
| Cytokine concentrations in resection cavity fluid | Up to 30 days post surgery |
| Concentrations of RAGE ligands in brain extracellular fluid | Up to 30 days post surgery |
| Concentrations of RAGE ligands in CSF | Up to 30 days post surgery |
| Concentrations of RAGE ligands in resection cavity fluid | Up to 30 days post surgery |
| Concentrations of RAGE ligands in peripheral blood | Up to 30 days post surgery |
| Expression of activating markers on tumor infiltrating lymphocytes | Up to 30 days post surgery |
| Expression of activating markers on myeloid cells | Up to 30 days post surgery |
| Expression of activating markers on lymphocytes in resection cavity fluid | Up to 30 days post surgery |
| Expression of activating markers on myeloid cells in resection cavity fluid | Up to 30 days post surgery |
| Expression of activating markers on lymphocytes in peripheral blood | Up to 30 days |
| Expression of activating markers on myeloid cells in peripheral blood | Up to 30 days post surgery |
| T1 enhancing tumor volume from segmented T1-weighted magnetic resonance imaging (MRI) | Up to 30 days post surgery |
| Mean intratumoral perfusion from dynamic contrast enhanced (DCE)-MRI | Up to 30 days post surgery |
| Interstitial fluid flow from DCE-MRI | Up to 30 days post surgery |
| T2-FLAIR enhancing edema from segmented T2-FLAIR MRI | Up to 30 days post surgery |
| Mean intratumoral blood volume from relative cerebral blood volume as calculated from DSC-MRI | Up to 30 days post surgery |
| Mean intratumoral tissue density as measured by the apparent diffusion coefficient derived from diffusion-weighted MRI | Up to 30 days post surgery |
| Mean intratumoral lactate and glutatione concentration as measured by multiplexed MR spectroscopy | Up to 30 days post surgery |
| FPS-ZM1 plasma pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) | Up to 30 days post surgery |
| FPS-ZM1 plasma pharmacokinetics: Area Under the Plasma Concentration-Time Curve (AUC) | Up to 30 days post surgery |
| FPS-ZM1 plasma pharmacokinetics: Terminal Elimination Half-Life (t½) | Up to 30 days post surgery |
| FPS-ZM1 plasma pharmacokinetics: Clearance (CL) | Up to 30 days post surgery |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJana L Portnow
City of Hope Medical Center
Outcome results
None listed