Identification of Treatment Concentrations of Defactinib or VS-6766 for the Treatment of Patients With Glioblastoma

Phase 1

Recruiting

• Conditions: Glioblastoma; Recurrent Glioblastoma

• Registration Number: NCT05798507
• Lead Sponsor: Emory University

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2023-3-3
• Last Update Posted: 2 September 2024

Recruitment & Eligibility

• Status: Recruiting
• Sex: All
• Target Recruitment: 12

Inclusion Criteria

Inclusion Criteria:<br><br> - New or recurrent glioblastoma diagnosed by neuroimaging techniques for which<br> surgical resection is indicated<br><br> - Age older than 21 years<br><br> - An Eastern Cooperative Group (ECOG) performance status =< 1<br><br> - Hemoglobin (Hb) >= 9.0 g/dL. If a red blood cell transfusion has been administered<br> the Hb must remain stable and >= 9.0 g/dL for at least 1 week prior to first dose of<br> study therapy.<br><br> - Platelets >= 100,000/mm^3<br><br> - Absolute neutrophil count (ANC) >= 1500/mm^3<br><br> - Total bilirubin =< 1.5 × upper limit of normal (ULN) per the institution; patients<br> with Gilbert syndrome may enroll if total bilirubin < 3.0 mg/dL (51 umole/L)<br><br> - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 × ULN (or<br> < 5x ULN in patients with liver metastases)<br><br> - Creatinine clearance rate of >= 50 mL/min as calculated by the Cockcroft-Gault<br> formula or serum creatinine of =< 1.5 x ULN<br><br> - Albumin >= 3.0 g/dL (451 umole/L)<br><br> - Creatine phosphokinase (CPK) =< 2.5 x ULN<br><br> - Left ventricular ejection fraction >= 50% by echocardiography (ECHO) or<br> multiple-gated acquisition (MUGA) scan<br><br> - Baseline QTc interval < 460 ms for women and =< 450 ms for men (average of<br> triplicate readings) (Common Terminology Criteria for Adverse Events [CTCAE] Grade<br> 1) using Fredericia's QT correction formula. NOTE: This criterion does not apply to<br> subjects with a right or left bundle branch block<br><br> - Adequate recovery from toxicities related to prior treatments to at least Grade 1 by<br> CTCAE v 5.0. Exceptions include alopecia and peripheral neuropathy grade =< 2<br><br> - Male and female patients with reproductive potential agree to use highly effective<br> method of contraceptive (per Clinical Trial Facilitation Group [CFTG]<br> recommendations) during the trial and for 3 months following the last dose of<br> VS-6766 for male patients, and 1 month following the last dose of VS-6766 for female<br> patients.<br><br>Exclusion Criteria:<br><br> - Clinically significant gastrointestinal abnormalities, requirement for systemic<br> anticoagulation or potent CYP 2C8 inhibitors, and history of clinically significant<br> cardiac or pulmonary disorders<br><br> - Minors will be excluded from the investigation. Glioblastoma is the major form of<br> brain cancer in people over 50 years old. Pediatric cases of glioblastoma are<br> relatively rare. Besides this, there are crucial molecular differences between adult<br> and pediatric gliomas. Our preliminary data for proposed investigation were obtained<br> on GBM specimens and cultures developed from GBM tissues donated by adult subjects.<br> Results of investigation of adult glioma tissue cannot simply be extrapolated to<br> children. Therefore, our primary research focus is the investigation of GBM in<br> adults. If appropriate, a separate, age-specific study in children will be performed<br><br> - Pregnant women will be excluded from the study as altered hormonal and immunological<br> status can affect the study results<br><br> - Prisoners will be excluded from the study<br><br> - Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy<br><br> - History of prior malignancy, with the exception of curatively treated malignancies<br> or malignancies with very low potential for recurrence or progression<br><br> - Major surgery within 4 weeks (excluding placement of vascular access), minor surgery<br> within 2 weeks, or palliative radiotherapy within 1 week of the first dose of<br> VS-6766<br><br> - Exposure to medications (with or without prescription), supplements, herbal<br> remedies, or foods with potential for drug-drug interactions with VS-6766 within 14<br> days prior to the first dose of VS-6766 and during the course of therapy, including:<br><br> - VS-6766: strong CYP3A4, inhibitors or inducers, due to potential drug-drug<br> interactions with VS-6766 and/or defactinib<br><br> - Defactinib: strong CYP3A4, CYP2C9, and P-glycoprotein (P-gp) inhibitors or<br> inducers, due to potential drug-drug interactions with VS-6766 and/or<br> defactinib<br><br> - Known hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection that<br> is active and/or requires therapy<br><br> - Active skin disorder that has required systemic therapy within the past 1 year<br><br> - History of rhabdomyolysis<br><br> - Concurrent ocular disorders:<br><br> - Patients with history of glaucoma, history of retinal vein occlusion (RVO),<br> predisposing factors for RVO, including uncontrolled hypertension, uncontrolled<br> diabetes<br><br> - Patients with history of retinal pathology or evidence of visible retinal<br> pathology that is considered a risk factor for RVO, intraocular pressure > 21<br> mm Hg as measured by tonometry, or other significant ocular pathology, such as<br> anatomical abnormalities that increase the risk for RVO<br><br> - Patients with a history of corneal erosion (instability of corneal epithelium),<br> corneal degeneration, active or recurrent keratitis, and other forms of serious<br> ocular surface inflammatory conditions<br><br> - Concurrent congestive heart failure, prior history of class III/ IV cardiac disease<br> (New York Heart Association [NYHA]), myocardial infarction within the last 6 months,<br> unstable arrhythmias, unstable angina, or severe obstructive pulmonary disease<br><br> - Patients with the inability to swallow oral medications or impaired gastrointestinal<br> absorption due to gastrectomy or active inflammatory bowel disease<br><br> - Patients with a history of hypersensitivity to any of the inactive ingredients<br> (hydroxypropylmethylcellulose, mannitol, magnesium stearate) of the investigational<br> product

Exclusion Criteria

Not provided

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Concentration of defactinib that accumulates in the glioblastoma (GBM) and brain around tumor;Concentration of avutometinib (VS-6766) that accumulates in the GBM and brain around tumor;Incidence of adverse events associated with defactinib;Incidence of adverse events associated with VS-6766

Secondary Outcome Measures

Name	Time	Method
Pyk2 and FAK phosphorylation in tumor, brain around tumor, and serum;MEK and Erk in tumor, brain around tumor, and serum