Regorafenib for the Treatment of Bevacizumab Refractory Recurrent Glioblastoma

Inclusion Criteria

• The participant (or legally representative if applicable) provides written informed consent for the trial
• Patients with histologically confirmed glioblastoma or other grade IV malignant glioma (i.e. gliosarcoma, small cell glioblastoma, etc.), recurrent after prior external-beam fractionated radiotherapy and temozolomide chemotherapy
• Patients with documented radiographic progression following bevacizumab therapy for treatment of glioblastoma
• Patients with up to 3 prior recurrences are allowed (patients could have received bevacizumab or bevacizumab containing regimen either in first or second recurrence)
• Karnofsky performance status >= 70%
• Absolute neutrophil count (ANC) >= 1.5 x 10^9 /L
• Platelets >= 100 x 10^9 /L
• Hemoglobin (Hgb) > 9 g/dL
• Serum total bilirubin: =< 1.5 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN
• Serum creatinine =< 1.5 x ULN
• International Normalized Ratio (INR) =< 1.5
• Minimum interval since completion of radiation treatment is 12 weeks
• Minimum interval since last drug therapy: * 3 weeks since last non-cytotoxic therapy * 3 weeks must have elapsed since the completion of a non-nitrosourea containing chemotherapy regimen * 6 weeks since the completion of a nitrosourea containing chemotherapy regimen
• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study drug. Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test. The definition of adequate contraception will be based on the judgment of the investigator
• Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the informed consent form (ICF) until at least 2 months after the last dose of study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate
• Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix and breast, adequately treated stage I or II cancer from which the patient is in complete remission. Patients with other prior malignancies must be disease-free for >= three years
• Patients must be maintained on a stable or decreasing corticosteroid regimen from the time of their baseline scan until the start of treatment and/or for at least 5 days before starting treatment. The maximum dosing of corticosteroid therapy is 4 mg/day
• Life expectancy of at least 12 weeks (3 months)
• Subject must be able to swallow and retain oral medication

Exclusion Criteria

• Patients who have had previous treatment with regorafenib
• Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury =< 4 weeks prior to starting study drug, or patients who have had minor procedures, percutaneous biopsies or placement of vascular access device =< 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury
• Patients with impaired cardiac function or clinically significant cardiac diseases, including any of the following: * Congestive heart failure – New York Heart Association (NYHA) > class II * History or presence of serious uncontrolled ventricular arrhythmias. Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin * Clinically significant resting bradycardia (defined as bradycardia that required intervention) * Active coronary artery disease defined as any of the following within 6 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG) * Cerebrovascular accident (CVA), transient ischemic attack (TIA), pulmonary embolism (PE) in the last 6 months * Uncontrolled hypertension (defined by a systolic blood pressure [SBP] >= 160 mm Hg or diastolic blood pressure [DBP] >= 100 mm Hg despite anti-hypertensive medications)
• Patients with cirrhosis, or active viral or nonviral hepatitis
• Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)
• Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
• Pregnant or breast-feeding women
• Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human, chimeric, or humanized antibodies
• Patients with active bleeding or pathologic conditions that carry a high risk of bleeding, (i.e. hereditary hemorrhagic telangiectasia)
• Patients who are currently receiving anticoagulation treatment (warfarin is not allowed, low weight heparin is allowed). Evidence or history of bleeding diathesis or coagulopathy
• Patients unwilling or unable to comply with the protocol
• Any hemorrhage or bleeding event >= National Cancer Institute (NCI) CTCAE version (v)5.0 grade 3 within 4 weeks prior to start of study medication
• Patients with phaeochromocytoma
• Ongoing infection > grade 2 NCI-CTCAE v5.0
• Presence of a non-healing wound, non-healing ulcer, or bone fracture
• Persistent proteinuria >= grade 3 NCI-CTCAE v5.0 (> 3.5 g/24 hours [hrs], measured by urine protein: creatinine ratio on a random urine sample)
• Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
• Pleural effusion or ascites that causes respiratory compromise (>= NCI-CTCAE version 5.0 grade 2 dyspnea)
• History of organ allograft (including corneal transplant)
• Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulations given during the course of this trial
• Any malabsorption condition
• Women who are pregnant or breast-feeding
• Any condition which, in the investigator’s opinion, makes the subject unsuitable for trial participation
• Substance abuse, medical, psychological or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results
• Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other than study treatment (regorafenib, other agents being investigated in combination with regorafenib)
• Prior use of regorafenib
• Concurrent use of another investigational drug or device therapy (i.e., outside of study treatment) during, or within 4 weeks of trial entry (signing of the informed consent form)
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication
• Therapeutic anticoagulation with vitamin-K antagonists (e.g., warfarin)
• Use of any herbal remedy (e.g. St. John’s wort [Hypericum perforatum])