Please select the eligibility criteria that correspond to the clinical trial below.
Title: Multi-Center, Randomized, Double-Blind Phase II Study Comparing Cediranib (AZD2171) Plus Gefitinib (Iressa, ZD1839) With Cediranib Plus Placebo in Subjects With Recurrent/Progressive Glioblastoma (DORIC Trial)
Brief Summary: RATIONALE: Cediranib Maleate and gefitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It is not yet known whether cediranib maleate given together with gefitinib is more effective than cediranib maleate given alone in treating patients with recurrent or progressive glioblastoma.

PURPOSE: This randomized phase II trial is studying the side effects of giving cediranib maleate together with gefitinib and to see how well it works compared with giving cediranib maleate together with a placebo in treating patients with recurrent or progressive glioblastoma.


Options:
A: Inclusion Criteria:

1. Patients with histologically proven recurrent malignant primary glioma will be eligible. Glioma type will be restricted to: GBM, gliosarcoma (GS), anaplastic gliomas \[anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic infiltrating glioma (AIG), mixed anaplastic glioma (MAG), anaplastic ependymoma\]
2. Patients must show unequivocal evidence for tumor recurrence or progression by MRI scan within 15 days prior to Day 0/Baseline procedure after failing prior surgical resection, biopsy, chemotherapy or radiation
3. For patients entered in Group A (see Treatment Plan) tumors must be accessible for stereotactic injection. Tumors must be between 1.0 - 5.0 cm in diameter
4. For patients entered in Group B (see Treatment Plan) tumors must be surgically resectable, and surgical resection must be indicated at the time of baseline evaluation. Tumors must be \>1.0 cm in diameter.
5. Patients will consent to have a biopsy taken at the time of the stereotactic injection to confirm the presence of malignant glioma (based on frozen section) before injection of DNX-2401
6. For each patient there must be a consensus between the physician investigators in this study that injection will not deliver DNX-2401 into the ventricular system. Patients must have a stable steroid regimen for at least 1 week prior to DNX-2401 administration
7. Patients may or may not have had prior chemotherapy
8. Patients must be willing and able to give informed consent
9. Age \> /= 18 years
10. Patients must have a Karnofsky performance status greater than or equal to 70
11. Patients must have recovered from the toxic effects of prior therapy (i.e., CTC grade 1 or less). For example, they must be at least two weeks after vincristine, 6 weeks after nitrosoureas, and 3 weeks after procarbazine or temozolomide administration
12. Patients must have adequate bone marrow function (absolute granulocyte count \> 1,500 and platelet count of \> 100,000), adequate liver function (SGPT and alkaline phosphatase \< 2 times institutional normals and bilirubin \<1.5 mg%), and adequate renal function (BUN or creatinine \<1.5 times institutional normal) prior to starting therapy
13. This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. Males and females will be recruited with no preference to gender
14. No exclusion to this study will be based on race. Minorities will actively be recruited to participate. The malignant glioma patient population treated at MDACC over the past year is as follows: American Indian or Alaskan Native - 0, Asian or Pacific Islander - \<2%, Black, not of Hispanic Origin - 3%, Hispanic - 6%, White, not of Hispanic Origin - 88%, Other or Unknown - 2%, Total - 100%

Exclusion Criteria:

1. Any radiotherapy within 4 weeks prior to date of DNX-2401 administration.
2. Active uncontrolled infection or severe intercurrent medical conditions. All patients must be afebrile at baseline (i.e., \< 38.0 Celsius \[C\])
3. Evidence of bleeding diathesis or use of anticoagulant medication or any medication that may increase the risk of bleeding that cannot be stopped prior to surgery. If the medication can be discontinued , based on the clinical judgment of the surgeon, prior to DNX-2401 injection then patient may be eligible.
4. History or current diagnosis of any medical or psychological condition that in the Investigator's opinion, might interfere with the subject's ability to participate or inability to obtain informed consent because of psychiatric or complicating medical problems
5. Female who is pregnant and/or nursing. Because of the potential risk of a recombinant virus containing a gene involved in cellular growth regulation and differentiation which could potentially affect a developing fetus or growing infant, females who are pregnant, at risk of pregnancy, or breast feeding a baby during the study period are excluded
6. Tumor position that, in the Investigator's opinion, would pose the risk of penetration of the cerebral ventricular system during injection with study drug. If, during the DNX-2401injection procedure, penetration of the ventricular system is suspected or confirmed, DNX-2401 administration will be aborted
7. Immunocompromised subjects, subjects with autoimmune conditions, active hepatitis (B or C) or HIV seropositivity
8. Patients with Li-Fraumeni Syndrome or with a known germ line deficit in the retinoblastoma gene or its related pathways
9. Multiple intracranial malignant glioma lesions at the time of recurrence. Multiple enhancing areas within a single tumor will not be considered multiple glioma lesions
10. Tumor involvement which would require ventricular, brainstem or posterior fossa injection or access through a ventricle in order to deliver the virus
11. Tumor involving the subependyma or suspected cerebrospinal fluid (CSF) dissemination
12. Documented extracranial metastasis
13. Biologic/immunotherapy (e.g., IL-2, IL-12, interferon) within 4 weeks of DNX-2401 administration
14. Concurrent chemotherapy, radiation or biological therapy
15. Any contraindication for undergoing MRI such as: individuals with pacemakers, epicardial pacer wires, infusion pumps, surgical and/or aneurysm clips, shrapnel, metal prosthesis, implants with potential magnetic properties, metallic bodies in the eyes, etc.
16. White blood cell (WBC) \< 2.5 x 103/mm3, absolute neutrophil count (ANC) \< 1.5 x 103/mm3, platelet \< 100,000/mm3, hemoglobin (Hgb) \< 10.0 gm/dL, prothrombin time/international normalized ratio (PT/INR) or partial thromboplastin time (PTT) \> 1.8 x control
17. Grade 4 hematological toxicity
18. Serum creatinine \> 1.5 mg/dL
19. Liver transaminases (aspartate aminotransferase \[AST\] and/or alanine aminotransferase \[ALT\]) or total bilirubin \> 2x the upper limits of normal
20. Vaccinations of any kind within 30 days prior to Delta-24-RGD-4C administration
21. Current diagnosis of other cancer except curative cervical cancer in situ, basal or squamous cell carcinoma of the skin. Patients with a history of another cancer, but who are cancer free for a minimum of three years remain eligible
22. History of encephalitis, multiple sclerosis, other CNS infection or primary CNS disease that would interfere with subject evaluation
23. Patients with history of prior gene transfer therapy or prior therapy with cytolytic virus of any type, especially DNX-2401
24. Males or females who refuse to use a double-barrier form of birth control during the study and for up to 6 months after injection with DNX-2401
B: 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.
C: DISEASE CHARACTERISTICS:

* Histologically or cytologically confirmed glioblastoma
* Measurable disease by MRI
* Completed standard first-line treatment for glioblastoma including surgery (unless not received due to anatomical location), radiotherapy and temozolomide (last dose given at least 28 days prior to enrollment)

  * No other prior treatment for glioblastoma except Gliadel or steroids
* Recurrent or progressive disease after standard first-line treatment

  * No disease progression within 3 months of completion of radiotherapy
* No intra- or peri-tumoral hemorrhage

PATIENT CHARACTERISTICS:

* Karnofsky performance status 70-100%
* Mini-mental status score ≥ 15
* Life expectancy ≥ 12 weeks
* Serum bilirubin, ALT/AST, creatinine, and urine protein normal
* Adequate bone marrow reserve
* Not pregnant or nursing
* Normal ECG
* No history of familial long QT syndrome
* No absorption or swallowing difficulties
* No uncontrolled hypertension or cardiac ventricular arrhythmias
* No current or history of uncontrolled hypertension or requiring maximal doses of calcium channel blockers
* No severe or uncontrolled disease
* No history of lung disease
* No recent hemorrhage or hemoptysis
* No known hypersensitivity to cediranib maleate, gefitinib, or any excipients
* No history of other malignancies except adequately treated basal cell or squamous cell carcinoma or carcinoma in situ within the past 5 years, unless disease-free for 2 years with tissue diagnosis
* No known HIV positivity
* No known hepatitis B or C infection
* No unhealed surgical incision
* Not involved in planning or conducting this study

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* Recovered from prior anticancer therapy, including radiotherapy
* At least 3 months since prior cranial radiation
* At least 30 days since prior investigational drugs
* At least 28 days since prior craniotomy
* At least 2 weeks since prior enzyme-inducing antiepileptic drugs
* At least 2 weeks since prior and no concurrent dexamethasone (\> 8 mg/day) or equivalent
* At least 14 days since prior major surgery or brain biopsy
* No concurrent steroids OR on stable dose 5 days prior to baseline MRI
* No other concurrent anticancer therapy, except for steroids (dexamethasone only)
* No previous enrollment on the current study
* No prior inhibitors of angiogenesis, EGFR, or downstream targets
* No prior radiosurgery or brachytherapy
D: Inclusion Criteria:

* unifocal, supratentorial recurrent glioma
* contrast enhancement on T1-weighted MRI and/or Amino-Acid-PET-positive high-grade tumor areas
* indication re-irradiation
* age ≥ 18 years of age
* Karnofsky Performance Score ≥60
* For women with childbearing potential, (and men) adequate contraception.
* Ability of subject to understand character and individual consequences of the clinical trial
* Written informed consent (must be available before enrolment in the trial)

Exclusion Criteria:

* Multifocal Glioma or Gliomatosis cerebri
* refusal of the patients to take part in the study
* previous re-irradiation or prior radiosurgery or prio treatment with interstitial radioactive seeds
* time interval of \< 6 months after primary radiotherapy
* Patients who have not yet recovered from acute toxicities of prior therapies
* Known carcinoma \< 5 years ago (excluding Carcinoma in situ of the cervix, basal cell carcinoma, squamous cell carcinoma of the skin) requiring immediate treatment interfering with study therapy
* Pregnant or lactating women
* Participation in another clinical study or observation period of competing trials, respectively.

Answer: C