Please select the eligibility criteria that correspond to the clinical trial below.
Title: Cilengitide for Subjects With Newly Diagnosed Glioblastoma and Methylated MGMT Gene Promoter - A Multicenter, Open-label, Controlled Phase III Study, Testing Cilengitide in Combination With Standard Treatment (Temozolomide With Concomitant Radiation Therapy, Followed by Temozolomide Maintenance Therapy) Versus Standard Treatment Alone (CENTRIC)
Brief Summary: CENTRIC is a Phase 3 clinical trial assessing efficacy and safety of the investigational integrin inhibitor, cilengitide, in combination with standard treatment versus standard treatment alone in newly diagnosed glioblastoma subjects with a methylated O6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) gene promoter in the tumor tissue.

The MGMT gene promoter is a section of deoxyribonucleic acid (DNA) that acts as a controlling element in the expression of MGMT. Methylation of the MGMT gene promoter has been found to be a predictive marker for benefit from temozolomide (TMZ) treatment.


Options:
A: Inclusion Criteria:

* Histologically proven diagnosis of glioblastoma or gliosarcoma (World Health Organization \[WHO\] grade IV) confirmed by central review prior to step 2 registration
* Tumor tissue that is determined by central pathology review prior to step 2 registration to be of sufficient size for analysis of O-6-methylguanine-DNA methyltransferase (MGMT) and determination of molecular profile

  * Patients must have at least 1 block of tumor tissue; submission of 2 blocks is strongly encouraged to maximize the chances of eligibility; at least 1 cubic centimeter of tissue composed primarily of tumor must be present
  * CUSA (Cavitron ultrasonic aspirator)-derived material is not allowed; fresh frozen tumor tissue acquisition is encouraged
  * Diagnosis must be made by surgical excision, either partial or complete; stereotactic biopsy is not allowed because it will not provide sufficient tissue for MGMT analysis
  * The tumor tissue should be sent as soon as possible to maximize the likelihood of eligibility; tumor tissue should be submitted by 4 weeks after the surgical procedure so that the study registration and treatment can commence by the mandatory 5 week post-surgery outer limit
  * Sites must submit tissue fir central review in order to obtain the MGMT analysis; patients from sites not following protocol-specified process for obtaining MGMT results will be made ineligible
* The tumor must have a supratentorial component
* History/physical examination within 14 days prior to step 2 registration
* The patient must have recovered from the effects of surgery, postoperative infection, and other complications before step 2 registration
* A diagnostic contrast-enhanced MRI of the brain must be performed preoperatively and postoperatively prior to the initiation of radiotherapy; the postoperative scan must be performed within 28 days prior to step 1 registration

  * An MRI or computed tomography (CT) scan (potentially in addition to the postoperative scan) must be obtained within 10 days prior to the start of radiation therapy and must not demonstrate significant postoperative hemorrhage defined as \> 1 cm diameter of blood; if \> 1 cm of acute blood is detected, the patient will be ineligible for this trial; the radiation planning MRI or CT scan may be used to determine presence of hemorrhage
  * Patients unable to undergo MR imaging because of non-compatible devices can be enrolled, provided pre- and postoperative contrast-enhanced CT scans are obtained and are of sufficient quality; preoperative and postoperative scans must be the same type; such patients cannot be enrolled into the advanced imaging component
* Documentation of steroid doses within 14 days prior to step 2 registration
* Karnofsky performance status \>= 70
* Absolute neutrophil count (ANC) \>= 1,800 cells/mm\^3
* Platelets \>= 100,000 cells/mm\^3
* Hemoglobin \>= 10.0 g/dL (Note: the use of transfusion or other intervention to achieve hemoglobin \[Hgb\] \>= 10.0 g/dl is acceptable)
* Blood urea nitrogen (BUN) =\< 30 mg/dL within 14 days prior to step 2 registration
* Creatinine =\< 1.7 mg/dl within 14 days prior to step 2 registration
* Urine protein screened by urine analysis for urine protein creatinine (UPC) ratio; for UPC ratio \> 0.5, 24-hour urine protein should be obtained and the level should be \< 1000 mg
* Bilirubin =\< 2.0 mg/dl within 14 days prior to step 2 registration
* Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =\< 3 x normal range within 14 days prior to step 2 registration
* Systolic blood pressure =\< 160 mg Hg or diastolic pressure =\< 90 mm Hg within 14 days prior to step 2 registration
* Electrocardiogram without evidence of acute cardiac ischemia within 14 days prior to step 2 registration
* Prothrombin time/international normalized ratio (PT INR) \< 1.4 for patients not on warfarin confirmed by testing within 14 days prior to step 2 registration
* Patients on full-dose anticoagulants (e.g., warfarin or low molecular weight \[LMW\] heparin) must meet both of the following criteria:

  * No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
  * In-range INR (between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of LMW heparin
* Patient must provide study specific informed consent prior to study entry
* Women of childbearing potential and male participants must practice adequate contraception
* For females of child-bearing potential, negative serum pregnancy test within 14 days prior to step 2 registration

Exclusion Criteria:

* Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease free for \>= 3 years; (for example, carcinoma in situ of the breast, oral cavity, and cervix are all permissible)
* Recurrent or multifocal malignant gliomas
* Metastases detected below the tentorium or beyond the cranial vault
* Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable, except prior temozolomide or bevacizumab; prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted
* Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields
* Severe, active co-morbidity, defined as follows:

  * Unstable angina and/or congestive heart failure within the last 6 months
  * Transmural myocardial infarction within the last 6 months
  * Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of \>= 2 mm using the analysis of an electrocardiogram (EKG) performed within 14 days of step 2 registration
  * New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to step 2 registration
  * History of stroke, cerebral vascular accident (CVA) or transient ischemic attack within 6 months
  * Serious and inadequately controlled cardiac arrhythmia
  * Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or clinically significant peripheral vascular disease
  * Evidence of bleeding diathesis or coagulopathy
  * Serious or non-healing wound, ulcer, or bone fracture or history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to step 2 registration, with the exception of the craniotomy for tumor resection
  * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
  * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration
  * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol
  * Acquired immune deficiency syndrome (AIDS) based upon current Center for Disease Control (CDC) definition; note, however, that HIV testing is not required for entry into this protocol; the need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive
  * Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity
  * Any other major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy
* Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
* Pregnant or lactating women
* Patients treated on any other therapeutic clinical protocols within 30 days prior to study entry or during participation in the study
* For American College of Radiology Imaging Network (ACRIN) 6686 Advanced Imaging: inability to undergo MRI (e.g., due to safety reasons, such as presence of a pacemaker)
B: Inclusion Criteria:

* Adult patients, \>/=18 years of age
* Diagnosis of recurrent glioblastoma multiforme (Grade IV)
* Previous treatment with temozolomide and radiotherapy
* First recurrence after standard adjuvant treatment (surgery, followed by radiotherapy and chemotherapy)
* Adequate hematological, biochemical and organ functions

Exclusion Criteria:

* Previous treatment with Avastin or other anti-angiogenic drugs
* Residual relevant toxicity resulting from previous therapy
* Radiotherapy within the 3 months prior to the diagnosis of disease progression
* Chemotherapy in the previous 4 weeks
* Other active or inactive malignancies (except for carcinoma in situ of the cervix, of the prostate or basal cell carcinoma)
* Clinically significant cardiovascular diseases
C: Inclusion Criteria:

1. Tumor tissue specimens from the glioblastoma surgery or open biopsy (formalin-fixed, paraffin-embedded block; stereotactic biopsy not allowed) must be available for MGMT status analysis and central pathology review
2. Newly diagnosed histologically proven supratentorial glioblastoma (World Health Organization \[WHO\] Grade IV)
3. Proven methylated MGMT gene promoter methylation status
4. Available post-operative gadolinium-enhanced magnetic resonance imaging (Gd-MRI) performed within less than (\<) 48 hours after surgery (in case it was not possible to obtain a Gd-MRI within \<48 hours post surgery, a Gd-MRI is to be performed prior to randomization)
5. Stable or decreasing dose of steroids for greater than or equal to (\>=) 5 days prior to randomization
6. Eastern Cooperative Oncology Group performance score (ECOG PS) of 0-1
7. Meets 1 of the following recursive partitioning analysis (RPA) classifications: Class III (Age \< 50 years and ECOG PS 0). Class IV (meeting one of the following criteria: a) Age \< 50 years and ECOG PS 1 or b) Age \>= 50 years, underwent prior partial or total tumor resection, mini mental state examination \[MMSE\] \>= 27). Class V (meeting one of the following criteria: a) Age \>= 50 years and underwent prior partial or total tumor resection, MMSE \< 27 or b) Age \>= 50 years and underwent prior tumor biopsy only)
8. Other protocol defined inclusion criteria could apply

Exclusion Criteria:

1. Prior chemotherapy within the last 5 years
2. Prior RTX of the head
3. Receiving concurrent investigational agents or has received an investigational agent within the past 30 days prior to the first dose of cilengitide
4. Prior systemic antiangiogenic therapy
5. Placement of Gliadel® wafer at surgery
6. Inability to undergo Gd-MRI.
7. Planned surgery for other diseases
8. History of recent peptic ulcer disease (endoscopically proven gastric ulcer, duodenal ulcer, or esophageal ulcer) within 6 months of enrollment
9. History of malignancy. Subjects with curatively treated cervical carcinoma in situ or basal cell carcinoma of the skin, or subjects who have been free of other malignancies for \>= 5 years are eligible for this study
10. History of coagulation disorder associated with bleeding or recurrent thrombotic events
11. Clinically manifest myocardial insufficiency (New York Heart Association \[NYHA\] III, IV) or history of myocardial infarction during the past 6 months; uncontrolled arterial hypertension
12. Other protocol defined exclusion criteria could apply
D: Histologically confirmed de novo glioblastoma (primary) with unequivocal first progression after RT concurrent/adjuvant chemotherapy at least 3 months off the concomitant part of the chemoradiotherapy

* Availability of biological material (tumor) for central review processes and translational research projects (tumor and blood)
* No more than one line of chemotherapy (concurrent and adjuvant temozolomide based chemotherapy including in combination with another investigational agent is considered one line of chemotherapy). Chemotherapy must have been completed at least 4 weeks prior to randomization if prior temozolomide
* No current or recent (within 4 weeks before randomization) treatment with another investigational drug
* No prior treatment with bevacizumab or other VEGF inhibitors or VEGF-Receptor signaling inhibitors
* No prior treatment with nitrosoureas
* Patient may have been operated for recurrence. If operated:
* residual and measurable disease after surgery is not required but surgery must have confirmed the recurrence
* a post-surgery MRI should be available within 48 hours following surgery
* Surgery completed at least 2 weeks before randomization and patients should have fully recovered
* Craniotomy or intracranial biopsy site must be adequately healed free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of randomization.
* Study treatment should be initiated \> 28 days following the last surgical procedure (including biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity)
* For non operated patients recurrent disease must be 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 MRI scan done within two weeks prior to randomization
* Stable or decreasing dosage of steroids for 7 days prior to the baseline MRI scan.
* Patients who require anti-convulsant therapy must be taking non-enzyme inducing antiepileptic drugs (non-EIAED). Patients previously on EIAED must be switched to non-EIAED at least 2 weeks prior to randomization
* No non tumor related surgery or other invasive procedures (major surgical procedure, open biopsy or significant traumatic injury) within 4 weeks prior to randomization, or anticipation of the need for major surgery during the course of the study treatment.
* No core biopsy or other minor surgical procedure within 7 days prior to randomization. Placement of a central vascular access device (CVAD) if performed at least 2 days prior to study treatment administration is allowed
* No radiotherapy within the three months prior to the diagnosis of progression
* No radiotherapy with a dose over 65 Gy, stereotactic radiosurgery or brachytherapy unless the recurrence is histologically proven No previous other malignancies, except for any previous malignancy which was treated with curative intent more than 5 years prior to randomization, and except for adequately controlled limited basal cell carcinoma of the skin, squamous carcinoma of the skin or carcinoma in situ of the cervix
* Absence of any cardiovascular disorder, including but not limited to:
* No history of myocardial infarction, unstable angina within 6 months prior to randomization
* No "New York Heart Association" (NYHA) Grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication.
* No significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to randomization
* No prior history of hypertensive crisis or hypertensive encephalopathy
* No inadequately controlled hypertension (defined as systolic blood pressure \>150 mmHg and/or diastolic blood pressure \>100 m Hg)
* Absence of any thrombotic or hemorrhagic event, including but not limited to:
* No evidence of recent hemorrhage on MRI of the brain. However, patients with clinically asymptomatic presence of hemosiderin depositions, resolving hemorrhagic changes related to surgery, and presence of punctate hemorrhage in the tumor are permitted entry into the study
* No history or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
* No arterial or venous thrombosis ≤ 6 months prior to randomization
* No history of stroke or TIAs within 6 months prior to randomization
* No history of pulmonary haemorrhage/haemoptysis ≥ grade 2 according to the NCI-CTCAE version 4.0 criteria within 1 month prior to randomization
* Absence of current or recent (within 10 days of first dose of bevacizumab) use of aspirin (\> 325 mg/day) or other NSAID with anti-platelet activity or treatment with dipyramidole, ticlopidine, clopidogrel or cilostaz.
* International normalized ratio (INR) \> 1.5 ULN and activated partial thromboplastin time (aPTT) \> 1.5 × the ULN. Use of full-dose anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose of anticoagulants for at least two weeks before randomization. As per ASCO guidelines, LMWH should be the preferred approach.
* Absence of known hypersensitivity:
* to any part of the bevacizumab or lomustine formulations.
* to Chinese hamster ovary cell products or other recombinant human or humanized antibody.
* No underlying or previous conditions that could interfere with treatment, including but not limited to:
* No history of intracranial abscess within 6 months prior to randomization
* No clinically serious (as judged by the investigator) non-healing wounds, active skin ulcers or incompletely healed bone fracture.
* No history of active gastroduodenal ulcer(s).
* No history of abdominal fistula as well as non-GI fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to inclusion.
* No evidence of active infection requiring hospitalization or antibiotics, within 2 weeks prior to randomization.
* No other diseases, interfering with follow up.
* Normal hematological functions: neutrophils ≥ 1.5 x 109 cells/l, platelets ≥ 100 x 109 cells/l and Hb ≥ 6.2 mmol/l (9.9 g/dl).
* Normal liver function: bilirubin \< 1.5 x upper limit of the normal range (ULN), alkaline phosphatase and transaminases (ASAT) \< 2.5 x ULN.
* Normal renal function: calculated (Cockcroft-Gault) or measured creatinine clearance \> 30 mL/min; Urine dipstick for proteinuria \< 2+. Patients with ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo 24 hours urine collection and must demonstrate ≤ 1 g of protein/24 hr.
* Age ≥ 18 years
* WHO Performance status 0 - 2
* Absence of pregnancy. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and 6 months beyond stop of treatment in such a manner that the risk of pregnancy is minimized. In general, the decision for appropriate methods to prevent pregnancy should be determined by discussions between the investigator and the study subject. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Females should not be breast feeding.
* Post menopause is defined as: amenorrhea ≥ 12 consecutive months without another cause or for women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level \> 35 mIU/mL
* Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicide) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential.
* Women of child bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product.
* Female patients within one year of entering the menopause must agree to use an effective non-hormonal method of contraception during the treatment period and for at least 6 months after the last study treatment.
* Males must agree to use an effective method of contraception during the treatment period and for at least 6 months after the last study treatment.
* Absence of any psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule; such conditions should be assessed with the patient before randomization in the trial.
* Before patient randomization and study related procedures (that would not have been performed as part as standard care), written informed consent must be given according to ICH/GCP, and national/local regulations. Informed consent should also be given for biological material to be stored and used for future research on brain tumors.
* Patients with a buffer range from the normal values of +/- 5 % for hematology and +/- 10% for biochemistry are acceptable. A maximum of +/- 2 days for timelines may be acceptable (one day for post operative MRI).

Answer: C