['glioblastoma multiforme']
['regorafenib', 'lomustine']

        Inclusion Criteria:

          -  Male or female ≥ 18 years of age

          -  Histologically confirmed de novo glioblastoma multiforme (grade IV)

          -  First recurrence after adjuvant treatment (surgery followed by radiotherapy and
             temozolomide chemotherapy with or without bevacizumab) in patients who have not
             received further therapeutic interventions

          -  For patients not undergoing a second surgery at the time of relapse, recurrent disease
             must include at least one bi-dimensionally measurable contrast-enhancing lesion with
             clearly defined margins by MRI scan, with minimal diameters of 10 mm, visible on 2 or
             more axial slices 5 mm apart, based on an MRI scan done within 2 weeks prior to
             randomization

          -  Documented progression of disease as defined by RANO criteria at least 12 weeks after
             completion of radiotherapy, unless the recurrence is outside the radiation field or
             has been histologically documented

          -  Have adequate bone marrow function, liver function, and renal function, as measured by
             the following laboratory assessments conducted within 7 days prior to the initiation
             of study treatment:

               -  Hemoglobin >9.0 g/dl

               -  Absolute neutrophil count (ANC) >1500/mm3 without transfusions or granulocyte
                  colony stimulating factor and other hematopoietic growth factors

               -  Platelet count ≥100,000/μl

               -  White blood cell count (WBC) >3.0 x 109/L

               -  Total bilirubin <1.5 times the upper limit of normal

               -  ALT and AST <3 x upper limit of normal (<5 x upper limit of normal for patients
                  with liver involvement of their cancer and/or have bone metastasis)

               -  Serum creatinine <1.5 x upper limit of normal

               -  Alkaline phosphatase <2.5 x ULN (<5 x upper limit of normal for patients with
                  liver involvement of their cancer and/or have bone metastasis)

               -  PT-INR/PTT <1.5 x upper limit of normal (Patients who are being therapeutically
                  anticoagulated with an agent such as coumadin or heparin will be allowed to
                  participate provided that no prior evidence of underlying abnormality in these
                  parameters exists per medical history)

               -  Lipase ≤ 1.5 x the ULN

          -  Glomerular filtration rate ≥ 30 mL/min/1.73 m2 according to the Modified Diet in Renal
             Disease abbreviated formula

          -  Analyses of MGMT methylation status on tumoral tissue at first surgery (at own
             institution)

          -  Understand, be willing to give consent, and sign the written informed consent form
             (ICF) prior to undergoing any study-specific procedure

          -  If female and of childbearing potential, have a negative result on a pregnancy test
             performed a maximum of 7 days before initiation of study treatment

          -  If female and of childbearing potential, or if male, agree to use adequate
             contraception (eg, intrauterine device, oral contraceptive, or double-barrier method)
             based on the judgment of the investigator or a designated associate from the date on
             which the ICF is signed until 8 weeks after the last dose of study drug

          -  World Health Organization (WHO) Performance status ≤ 1 (or Karnofsky performance
             status (KPS) ≥70)) within 14 days prior to the initiation of study treatment

          -  Stable or decreasing dosage of steroids for 7 days prior to the baseline MRI scan.

          -  Patients may have undergone surgery for the recurrence; the histological report must
             document a glioblastoma recurrence. If operated:

               -  at least 28 days and maximum 42 days interval from the surgery is required prior
                  to administration of study drugs and patients should have fully recovered

               -  Exclusion Criteria:

          -  Are taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg, clarithromycin, indinavir,
             itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir,
             saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg, carbamazepine,
             phenobarbital, phenytoin, rifampin, St. John's Wort)

          -  Radiotherapy within 12 weeks prior to the diagnosis of progression, if the lesion is
             in the radiation field,

          -  Have had systemic anticancer therapy including cytotoxic therapy, signal transduction
             inhibitors, immunotherapy, and/or hormonal therapy within 4 weeks prior to initiation
             of study treatment

          -  Positioning of carmustin wafers during first or second surgery

          -  Other active or inactive malignancy (except for carcinoma in situ of the cervix, of
             the prostate or basal cell carcinoma). Malignancy will be considered inactive if
             patients are in complete remission for at least 3 years prior to study entry

          -  Have had prior treatment with regorafenib or any other VEGFR-targeting kinase
             inhibitor

          -  Have had a major surgical procedure, open biopsy, or significant traumatic injury
             within 28 days prior to initiation of study treatment

          -  Are pregnant

          -  Are breastfeeding

          -  Are unable to swallow oral tablets (crushing of study treatment tablets is not
             allowed)

          -  Have congestive heart failure classified as New York Heart Association Class 2 or
             higher

          -  Have had unstable angina (angina symptoms at rest) or new-onset angina ≤ 3 months
             prior to screening.

          -  Have had a myocardial infarction < 6 months prior to initiation of study treatment

          -  Have cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta
             blockers or digoxin

          -  Have uncontrolled hypertension (systolic blood pressure [SBP] > 140 mmHg or diastolic
             blood pressure [DBP] > 90 mmHg) despite optimal medical management

          -  Have had arterial thrombotic or embolic events such as cerebrovascular accident
             (including transient ischemic attacks), or pulmonary embolism within 6 months prior to
             the initiation of study treatment

          -  Have an ongoing infection with severity of Grade 2 or above (NCI-CTCAE v 4.0)

          -  Have a known history of human immunodeficiency virus infection

          -  Have either active or chronic hepatitis B or C requiring treatment with antiviral
             therapy

          -  Have a history of organ allograft

          -  Have evidence or history of any bleeding diathesis (including mild hemophilia),
             irrespective of severity

          -  Have had a hemorrhage or a bleeding event ≥ Grade 3 (NCI-CTCAE v 4.0) within 4 weeks
             prior to the initiation of study treatment

          -  Have a non-healing wound, ulcer, or bone fracture

          -  Have renal failure requiring hemodialysis or peritoneal dialysis

          -  Have dehydration ≥ Grade 1 (NCI-CTCAE v 4.0)

          -  Have interstitial lung disease with ongoing signs and symptoms at the time informed
             consent is obtained

          -  Have persistent proteinuria > 3.5 g/24 hours measured by urine protein creatinine
             ratio from a random urine sample (Grade 3, NCI-CTCAE v 4.0)

          -  Have any other serious or unstable illness, or medical, psychological, or social
             condition, that could jeopardize the safety of the subject and/or his/her compliance
             with study procedures, or may interfere with the subject's participation in the study
             or evaluation of the study results

          -  Have a known hypersensitivity to any of the study drugs, study drug classes, or
             excipients in the formulation of the study drugs

          -  Have any malabsorption condition

          -  Recurrent disease located outside of the brain
      