Treatment of Patients With Recurrent High-Grade Glioma With APG-157 and Bevacizumab

The goal of this interventional study is to evaluate the efficacy of APG-157 in combination with Bevacizumab in subjects with recurrent high-grade glioma who have previously progressed on bevacizumab alone. The main questions the study aims to answer are:

• Progression-free and overall survival of patients receiving this combination;
• Quality of Life (QOL); and
• Tumor response on imaging

Additional aims include:

• characterization of pharmacokinetics (PK) of APG-157 in the presence of bevacizumab; and
• optionally serum changes in VEGF and HIF-1 alpha, if the study shows preliminary indication of efficacy

The participants will take APG-157 daily by dissolving two pastilles in their mouth at around breakfast, lunch and dinner time (total of 6 pastilles per day). The pastilles dissolve in the mouth.

The participants will continue to receive Bevacizumab and be present for scheduled visits and examinations as standard of care.

Inclusion criteria

• Patients must have pathologically proven diagnosis of high grade (aka grade III or IV) glioma that has progressed on bevacizumab (anaplastic astrocytoma, anaplastic oligodendroglioma, glioblastoma, gliosarcoma, H3K27M mutant glioma).
• Patients must have received prior radiation therapy and standard temozolomide. Patients who have received any number of therapies for previous progressions will be considered eligible.
• Patients must be three or more months from the end of chemoradiotherapy or have biopsy or imaging consistent with disease progression.
• Physiologic Status/Age: Patients must be 19 years of age or older (the age of consent in Nebraska.)
• Patients must have recovered from any toxicity of prior therapy to Grade 1 or less.
• ECOG Performance Status of 0-3.
• Patients must have an adequate bone marrow reserve (ANC count ≥1,500/mm3, hemoglobin > 8 g/dL, platelet count ≥100,000/mm3).
• Patients must have adequate renal and hepatic function with:

• creatinine < 1.5 x institutional upper limit of normal (ULN).
• total bilirubin < 1.5 x ULN (unless due to Gilbert's disease)
• aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <2.5 x ULN
• serum alkaline phosphatase less than 2.5 times the upper limits of normal)
• The patient must willingly provide written, informed consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts.
• Women of reproductive potential must be non-pregnant and non-nursing and must agree to employ an effective barrier method of birth control throughout the study and for up to 6 months following treatment.
• Women of child-bearing potential must have a negative pregnancy test within 7 days of initiating study. (Non-child bearing potential is defined as age 55 years or older and no menses for two years or any age with surgical removal of the uterus and/or both ovaries).

Exclusion criteria

• Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of oral APG-157, or put the study outcomes at undue risk
• Immunotherapy, chemotherapy, radiotherapy, or experimental therapy within one full cycle period before first dose of study drug (i.e., for lomustine 6 weeks, for temozolomide 4 weeks)
• Lactating or pregnant
• History of uncontrollable allergic reactions to bevacizumab
• Clinically Significant Cardiovascular Disease Defined as follows:

• Inadequately controlled hypertension (i.e., systolic blood pressure (SBP) > 160 mm Hg and/or diastolic blood pressure (DBP) > 90 mm Hg despite antihypertensive therapy)
• History of cerebrovascular accident (CVA) within 6 months
• Myocardial infarction or unstable angina within 6 months
• Evidence or history of bleeding diathesis (greater than normal risk of bleeding, i.e., Hereditary Hemorrhagic Telangiectasia type I or HHT-1) or coagulopathy in the absence of therapeutic anti-coagulation or any hemorrhage/bleeding event > Grade 3 within 4 weeks prior to registration. Note: Patients with full-dose anticoagulants are eligible provided the patient has been on a stable dose for at least 2 weeks
• Active wound, a serious or non-healing wound, an active ulcer or untreated bone fracture within the last two months.
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess ≤ 6 months prior to registration.
• Major surgical procedure, open biopsy, or significant traumatic injury ≤ 28 days prior to registration
• Any other clinically significant medical disease or condition laboratory abnormality or psychiatric illness that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent