A Safety Study of RTA 744 in Patients With Recurrent High-Grade Gliomas

Study Overview
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Brief Summary
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This study assesses the tolerability, safety, efficacy and pharmacokinetics of RTA 744 in recurrent high-grade gliomas.

Detailed Description
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Malignant gliomas, glioblastoma multiforme and anaplastic astrocytoma, are rapidly growing primary brain tumors associated with a high degree of morbidity and mortality. Despite aggressive treatment, the median survival rate for GBM is approximately 12 months, with two-year survival rates no more than 8 to 12%, while median survival for patients with AA ranges from 2 to 3 years from time of first diagnosis. RTA 744 is a close chemical analogue of the well characterized anti-cancer agent doxorubicin. Unlike doxorubicin, RTA 744 has shown ability to cross the blood brain barrier and to achieve high concentration in CNS tumor tissue in animal models. It will be administered by i.v. infusions either daily for 3 consecutive days repeated every three weeks, or once weekly for 4 consecutive weeks repeated every 5 weeks. Once the maximum tolerated dose is determined , a new group of patients will be enrolled into the study to evaluate the tolerability and MTD when administered on an expanded schedule (once a week). This study was previously posted by Reata Pharmaceuticals. In September 2023, sponsorship of the trial was transferred to Biogen.

Official Title
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A Phase I Dose-finding and Pharmacokinetic Study of Intravenous RTA 744 Injection in Patients With Recurrent or Refractory Anaplastic Astrocytoma (AA), Anaplastic Oligodendroglioma (AO), Anaplastic Mixed Oligo-astrocytoma (AOA), Glioblastoma Multiforme (GBM) or Gliosarcoma (GS), With or Without Concurrent Treatment With Enzyme-inducing Anticonvulsant Therapy

Conditions
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Glioma

Intervention / Treatment
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* Drug: RTA 744
* Drug: RTA 744 injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Prior histologically confirmed anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligo-astrocytoma, glioblastoma multiforme, or gliosarcoma, for whom no other effective therapy is available. A prior histologic diagnosis of a lower grade of glioma is allowed if there is current histologic proof of progression to a diagnosis of AA, AO, AOA, GBM or GS Unequivocal evidence of recurrence or progression by neuroimaging procedure. Surgical resection at least 2 weeks prior to enrollment and must have completely recovered from the side effects. A stable dose of steroids for at least 7 days prior to obtaining the Gd-MRI of the brain. Previously implanted Gliadel® wafer may be eligible. Karnofsky Performance Status (KPS) of ≥ 60. Laboratory parameters: Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L, Hemoglobin (Hgb) ≥ 9 g/dl, Platelets ≥ 100 x 109/L, AST and ALT ≤ 3.0 x Upper Limit of Normal (ULN), Serum bilirubin ≤ 1.5 x ULN, Serum creatinine ≤ 1.5 x ULN and 24 hour creatinine clearance ≥ 50 ml/min Life expectancy of greater than 12 weeks. Written informed consent obtained. Exclusion Criteria: Pregnancy or breast feeding, or adults of reproductive potential not employing an effective method of birth control Total urinary protein in 24 hours urine collection > 500 mg Any concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study. Impaired cardiac function, other significant prior cardiac disease or arrhythmia of any A history of CHF or arrhythmias. Therapeutic doses of warfarin sodium (Coumadin®). Prior or concurrent therapy, or not recovered from the toxic effects of such therapy: investigational drugs, chemotherapy, metronomic daily dosing of chemotherapy agents, biologic, immunotherapy or cytostatic agents within 4 weeks prior to study entry; radiation therapy within 2 weeks prior to study entry, any medication known to cause QT interval prolongation Any surgery other than resection of a brain tumor within 2 weeks prior to enrollment. A contraindication to MRI imaging.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A (RTA 744)<br>Receive study drug for three consecutive days, Cycle repeated every 21 days. | Drug: RTA 744<br>* Aqueous solution added to 10%D/W and infused over 2 hours on three consecutive days. 5 mg vials contain 1 mg/ml.<br>|
| Experimental: Group C (RTA 744 Injection)<br>Receive study drug once a week for four consecutive weeks. Repeat cycle every 5 weeks. | Drug: RTA 744 injection<br>* Aqueous solution in 1mg/ml. Doses are escalated. Drug is infused intravenously over 2 hours one day a week for four consecutive weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of RTA 744 Injection in the patient population studied and to determine the qualitative and quantitative toxic effects of RTA 744 Injection. |  | at end of first cycle for each patient cohort | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the multiple-dose pharmacokinetics of RTA 744 and to document any potential antitumor activity of RTA 744 in those patients with measurable disease. |  | end of study |