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Regorafenib for the Treatment of Bevacizumab Refractory Recurrent Glioblastoma

Trial Status: Active

This phase II trial studies how well regorafenib works in treating patients with glioblastoma that has come back (recurrent) and that does not respond to treatment (refractory) with bevacizumab. Regorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

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])

Ohio

Cleveland
Case Comprehensive Cancer Center
Status: ACTIVE
Contact: Manmeet Singh Ahluwalia
Phone: 216-445-6145

PRIMARY OBJECTIVE:

I. Determine median overall survival (OS) in patients with recurrent or progressive glioblastoma (GBM) who have progressed on bevacizumab.

SECONDARY OBJECTIVES:

I. Assess safety and tolerability of regorafenib by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

II. Determine objective response rate (ORR) by modified Response Assessment in Neuro-Oncology (RANO) criteria.

III. Determine progression free survival at 6 months (PFS-6).

IV. Determine the median time to progression.

OUTLINE:

Patients receive regorafenib orally (PO) once daily (QD) on days 1-21. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Case Comprehensive Cancer Center

Principal Investigator
Manmeet Singh Ahluwalia

  • Primary ID CASE7318
  • Secondary IDs NCI-2019-05910
  • Clinicaltrials.gov ID NCT04051606