Please select the eligibility criteria that correspond to the clinical trial below.
Title: Regorafenib in Relapsed Glioblastoma REGOMA Study Randomized, Controlled Open-label Phase II Clinical Trial
Brief Summary: This study aims to evaluate the role of Regorafenib in prolonging the overall survival of glioblastoma multiforme patients who progressed after surgery and Stupp regimen with or without bevacizumab.


Options:
A: Inclusion Criteria:

* Local recurrence of GBM (WHO grade IV) and either not eligible for tumor resection or with macroscopic residual tumor after resection of recurrent GBM
* Recurrent tumor visible on AA-PET and MRI-T1-Gd with the diameter measuring 1 cm to 6 cm by either technique
* Target volume definition possible according to both study arms
* Previous radiation therapy of the primary with a maximal total dose 60 Gy
* At least 9 months since the end of pre-irradiation and randomisation
* At most 2 prior chemotherapy regimes
* Start of radiation therapy possible within 2 weeks from AA-PET
* Karnofsky Performance Score (KPS) ≥ 70%
* Age ≥ 18 years
* Written informed consent (IC) obtained

Exclusion Criteria:

* - No histological confirmation of Glioma at initial diagnosis)
* Recent (≤ 4 weeks before IC) histological result showing no tumor recurrence
* No recurrent tumor detectable on last AA-PET or MRI-T1-Gd
* Technical impossibility to use existing AA-PET for RT-planning
* No prior radiation treatment to the primary tumor
* less than 9 months between the end of first radiation treatment and randomisation
* more than 2 previous chemotherapy regimes or previous treatment with Avastin or other molecular targeted therapies
* less than 2 weeks between application of chemotherapy and randomisation
* additional chemotherapy or molecular targeted therapy or further surgery planned before diagnosis of further tumor progression after study intervention
* pregnancy, nursing or patient not willing to prevent pregnancy during treatment
B: DISEASE CHARACTERISTICS:

* Histopathologically confirmed glioblastoma multiforme

  * Grade IV disease by WHO classification
  * Newly diagnosed disease
* Initial diagnostic surgery or biopsy performed within the past 4 weeks
* Not a candidate for standard radiotherapy (60Gy/30 fractions over 6 weeks) in combination with temozolomide

PATIENT CHARACTERISTICS:

* ECOG performance status 0-2
* Absolute granulocyte count ≥ 1,500/mm³
* Platelet count ≥ 100,000/mm³
* Creatinine ≤ 1.5 times upper limit of normal (ULN)
* Bilirubin ≤ 1.5 times ULN
* ALT and AST \< 2.5 times ULN
* No known hypersensitivity to temozolomide or compounds with similar chemical composition to temozolomide
* No history of other malignancies except adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the cervix, or other curatively treated solid tumors with no evidence of disease for at least 5 years
* No serious active infection (e.g., wound infection requiring parenteral antibiotics) or other serious underlying medical conditions that would preclude study treatment
* No other condition (e.g., psychological or geographical) that would preclude study compliance

PRIOR CONCURRENT THERAPY:

* No prior chemotherapy
* No prior radiotherapy
* No prior or concurrent investigational therapy
* No concurrent surgical procedures for tumor debulking
* No concurrent stereotactic boost radiotherapy
* No other concurrent chemotherapy, immunotherapy, or biological therapy
* No concurrent epoetin alfa
* Concurrent corticosteroids allowed provided the patient has been on a stable or decreasing dose for at least 14 days
C: Inclusion Criteria:

1. Pathological evidence of GBM using WHO classification criteria.
2. \> 18 years of age.
3. Received maximal debulking surgery and radiotherapy concomitant with Temozolomide (45-70Gy):

   1. Patients may enroll in the study if received Gliadel wafers before entering the trial
   2. Any additional treatments received prior to enrollment will be considered an exclusion.
   3. Minimal dose for concomitant radiotherapy is 45 Gy
4. Karnofsky scale ≥ 70
5. Life expectancy at least 3 months
6. Participants of childbearing age must use effective contraception.
7. All patients must sign written informed consent.
8. Treatment start date at least 4 weeks out from surgery.
9. Treatment start date at least 4 weeks out but not more than 7 weeks from the later of last dose of concomitant Temozolomide or radiotherapy.

Exclusion Criteria:

1. Progressive disease (according to MacDonald Criteria). If pseudoprogression is suspected, additional imaging studies must be performed to rule out true progression.
2. Actively participating in another clinical treatment trial
3. Pregnant
4. Significant co-morbidities at baseline which would prevent maintenance Temozolomide treatment:

   1. Thrombocytopenia (platelet count \< 100 x 103/μL)
   2. Neutropenia (absolute neutrophil count \< 1.5 x 103/μL)
   3. CTC grade 4 non-hematological Toxicity (except for alopecia, nausea, vomiting)
   4. Significant liver function impairment - AST or ALT \> 3 times the upper limit of normal
   5. Total bilirubin \> upper limit of normal
   6. Significant renal impairment (serum creatinine \> 1.7 mg/dL)
5. Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other implanted electronic devices in the brain, or documented clinically significant arrhythmias.
6. Infra-tentorial tumor
7. Evidence of increased intracranial pressure (midline shift \> 5mm, clinically significant papilledema, vomiting and nausea or reduced level of consciousness)
8. History of hypersensitivity reaction to Temozolomide or a history of hypersensitivity to DTIC.
D: 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

Answer: D