Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase II Trial of Vaccination with Lysate-loaded, Mature Dendritic Cells Integrated Into Standard Radiochemotherapy in Newly Diagnosed Glioblastoma
Brief Summary: The primary objective of the study is to determine whether overall survival of newly diagnosed glioblastoma patients treated with lysate-loaded, mature dendritic cell vaccines as add-on to the standard of care consisting of resection, radiotherapy with concomitant temozolomide chemotherapy and subsequent adjuvant temozolomide chemotherapy is superior to the treatment with the standard of care alone.


Options:
A: Inclusion Criteria:

* Patients with histological diagnosis of glioblastoma that have not received any previous chemotherapy or radiotherapy treatment.
* Patients are able to give informed consent and willing to comply with the protocol requirements during the study period.
* Age between 18 and 70 years
* Negative pregnancy test In female fertile subjects
* Patient is, in the investigator's opinion, willing and able to comply with the protocol requirements.
* Complete/Total resection of tumour with surgery guided by fluorescence microscopy and 5-aminolevulinic acid, observed with post operative magnetic resonance imaging. The residual lesion must be null or ≤ 1 cm3 by contrast capturing.
* Enough tumor tissue available for the cellular vaccine elaboration

Exclusion Criteria:

* Patients with infections, severe diseases or hepatic, renal or medullary failures, that in the investigator's opinion, are not eligible to participate in the study.
* Participation in other clinical trial. If the patient has participated in other clinical trial within previous months, the patient has to complete the washout period required by de the investigator.
* Patients with diagnosis of other neoplasia, except basal cell or squamous cell skin, carcinoma in situ of the cervix properly treated or other tumour curatively treated and no evidence of relapse for at least 3 years. Those cases with coexisting tumours of long-term survival prediction will be considered individually.
* Pregnant or breast-feeding women.
* Patients who need immunosuppressive drugs.
* Positive serology for HIV , hepatitis B (HBsAg) or hepatitis C virus.
* Impossible to get enough material for at least 6 cellular vaccine production.
* Absolute contraindication for the patient to receive other steps of standard treatment of glioblastoma (surgery, radio and chemotherapy)
B: Inclusion criteria:

1. Histopathologically proven diagnosis of glioblastoma. Since gliosarcoma is a variant of glioblastoma, gliosarcoma is also an eligible diagnosis.
2. Patients must have at least 1 block of tissue available for analysis of MGMT status; fresh frozen tumor tissue acquisition is encouraged.
3. Diagnosis must be established by open biopsy or tumor resection. Patients who have only had a stereotactic biopsy are not eligible.
4. The tumor must have a supratentorial component.
5. Patients must have recovered from the effects of surgery, postoperative infection, and other complications before study registration.
6. A diagnostic contrast-enhanced magnetic resonance imaging (MRI) or computerized tomography (CT) scan (if MRI is not available) of the brain must be performed preoperatively and postoperatively. The postoperative scan must be done within 28 days of registration and prior to the initiation of radiotherapy. Preoperative and postoperative scans must be the same type. If CT scans were performed perioperatively, a CT and an MRI should be performed before randomization.

   6.1. Patients unable to undergo MRI imaging because of non-compatible devices can be enrolled, provided pre- and post-operative contrast-enhanced CT scans are obtained and are of sufficient quality.
7. Therapy must begin ≤ 5 weeks after the most recent brain tumor surgery.
8. History/physical examination within 14 days prior to study registration.
9. Neurologic examination within 14 days prior to study registration.
10. Documentation of steroid doses within 14 days prior to study registration and stable or decreasing steroid dose within 5 days prior to registration.
11. Karnofsky performance status of ≥ 60.
12. Age ≥ 18 years.
13. Complete blood count (CBC)/differential obtained within 14 days prior to study registration, with adequate bone marrow function as defined below: 13.1 Absolute neutrophil count (ANC) ≥ 1500 cells/mm3. 13.2 Platelets ≥ 100,000 cells/mm3. 13.3 Hemoglobin ≥ 10 g/dl. (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10 g/dl is acceptable.)
14. Adequate renal function, as defined below:

    14.1 Blood urea nitrogen (BUN) ≤ 25 mg/dl within 14 days prior to study registration 14.2 Creatinine ≤ 1.7 mg/dl within 14 days prior to study registration
15. Adequate hepatic function, as defined below:

    15.1 Bilirubin ≤ 2.0 mg/dl within 14 days prior to study registration 15.2 Alanine aminotransferase (ALT) ≤ 3 x normal range within 14 days prior to study registration 15.3 Aspartate aminotransferase (AST) ≤ 3 x normal range within 14 days prior to study registration
16. Patients must sign a study-specific informed consent prior to study registration.

    If the patient's mental status precludes his/her giving informed consent, written informed consent may be given by the responsible family member.
17. For females of child-bearing potential, negative serum pregnancy test within 72 hours prior to starting temozolomide.
18. Women of childbearing potential and male participants must practice adequate

Exclusion criteria:

1. 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).
2. Recurrent or multifocal malignant gliomas
3. Metastases detected below the tentorium or beyond the cranial vault.
4. Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable. Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted. See Section 1.
5. Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields.
6. Severe, active co-morbidity, defined as follows:

   * 6.1. Unstable angina and/or congestive heart failure requiring hospitalization.
   * 6.2. Transmural myocardial infarction within the last 6 months.
   * 6.3. Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration.
   * 6.4. Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration.
   * 6.5. 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.
   * 6.6. Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (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.
   * 6.7. Major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy.
   * 6.8. 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.
7. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
8. Pregnant or lactating women, due to possible adverse effects on the developing fetus or infant due to study drug;
9. Prior allergic reaction to temozolomide.
10. Patients treated on any other therapeutic clinical protocols within 30 days prior to study entry or during participation in the study.
11. No tissue provided for histopathologic central review and MGMT status.
12. Tissue provided by stereotactic biopsy method.
C: Inclusion Criteria:

Determined at pre-screening (prior to surgery; wk-3 - wk-1):

* Patients ≥ 18 years of age at surgery.
* Patients must be in a cognitive state to understand and sign the informed consent indicating that they are aware of the investigational nature and procedures of the study.
* First written informed consent for screening for eligibility, including tumor tissue collection, transfer and processing, central neuropathological evaluation of Tumor sample, central neuroradiological assessment of extent of resection, infectious disease (HIV, HBV, HCV, Treponema pallidum) testing, determination of MGMT promoter methylation status and pregnancy testing.

Determined at screening (at and post-surgery; d0 - wk3):

* Newly diagnosed, monofocal GBM, IDH wildtype (WHO grade IV), including the histological variants of gliosarcoma and giant cell glioblastoma, confirmed by central neuropathologist according to the WHO classification of central nervous System tumors 2016. Tumors may cross into, but not beyond the corpus callosum.
* Near-complete resection (≤ 5 ml residual contrast enhancing tumor volume) confirmed by central neuroradiologist on MRI scan within 72 h postoperative; awake surgery and second look surgery are possible, if medically indicated.
* Sterile tumor sample of ≥ 150 mg with tumor cell frequency ≥ 60% as determined by central neuropathologist available for vaccine production.
* Successful production of sterile, avital tumor lysate.
* Karnofsky performance status ≥ 70%.
* Adequate hepatic (serum glutamate pyruvate transferase/alanine transaminase (SGPT/ALT), serum glutamic oxaloacetate transaminase/aspartate transaminase (SGOT/AST) and alkaline phosphatase ≤ 3-times upper limit of normal (ULN); bilirubin ≤ 1.5-times ULN) and renal functions (creatinine ≤ 1.5-times ULN).
* Adequate bone marrow function (hemoglobin ≥ 10 g/dl, thrombocytes ≥ 100,000/μl, white blood cell count ≥ 3,000/μl; neutrophil count ≥ 1,500/μl).
* Prothrombin time (PT) and activated partial thromboplastin time (PTT) ≤ 1.6x ULN unless therapeutically warranted. International normalized ratio (INR) (in absence of anticoagulation treatment) ≤ 1.5.
* Systemic corticosteroids tapered down to ≤ 2 mg of dexamethasone or equivalent per day within 7 days postoperative (use of corticosteroids during the treatment period should be avoided, however it is possible if clinically indicated, but may require interruption of dendritic cell vaccination).
* Female patients with reproductive potential and male generative patients and their female partners must agree to be true abstinent or to use a highly effective form of contraception (pearl index \< 1%) during the trial.
* Patients must be in a cognitive state to understand and sign the informed consent indicating that they are aware of the investigational nature and procedures of the study.
* Written informed consent to participate in study.

Exclusion Criteria:

determined at pre-screening (prior to surgery; wk-3 - wk-1):

* Medical history of severe acute or chronic disease with poor prognosis, e.g. severe coronary heart disease, heart failure (New York Heart Association classes III/IV), severe poorly controlled diabetes, severe mental retardation or other serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator).
* Medical history of severe autoimmune disorder or immunodeficiency or patients with organ allograft.
* Medical history of bleeding diathesis or coagulopathy.
* Prior malignancy during the last three years except non-melanoma skin cancer, in situ cervical cancer, treated superficial bladder cancer or cured, early-stage prostate cancer in a patient with prostate-specific antigen (PSA) level less than ULN.
* Previous radiotherapy to head and neck.
* Known allergy or intolerability to TMZ, dacarbazine, the contrast agent or to components of the dendritic cell vaccine.
* Current treatment of glioblastoma in another clinical trial with therapeutic intervention or current use of any other investigational agent.
* Known pregnancy or breast feeding.
* No known severe infection requiring treatment.
* Accommodation in an institution due to legal orders (§40(4) AMG).
* Evidence of current drug or alcohol abuse. determined at screening (at and post-surgery; d0 - wk3):
* Infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) or Treponema pallidum or other severe infection requiring treatment.
* Accommodation in an institution due to legal orders (§40(4) AMG).
* Pregnant or breast feeding female patients. From pre-menopausal female patients with childbearing potential a negative pregnancy test must be obtained.
* Any psycho-social condition hampering compliance with the study protocol.
* MGMT promoter methylation status equivocal.
D: Inclusion Criteria-

Among other criteria, patients must meet the following conditions to be eligible for the study:

1. Adult patients, ≥ 18 years old
2. Newly diagnosed glioblastoma
3. Attempted surgical resection followed by conventional chemoradiation
4. Documented EGFRvIII positive tumor status by a Sponsor designated laboratory
5. No evidence of progressive disease from the post-operative period to the post-chemoradiation period
6. Candidate for, and agrees to receive, adjuvant (maintenance) temozolomide therapy
7. Systemic corticosteroid therapy at ≤2 mg of dexamethasone or equivalent per day for at least 3 days prior to randomization
8. WHO-ECOG Performance Status ≤ 2
9. Patients of childbearing/reproductive potential will be instructed to use birth control as defined by your doctor.

Exclusion Criteria-

Among other criteria, patients who meet the following conditions are NOT eligible for the study:

1. Stereotactic biopsy only (without further surgical resection)
2. Presence of diffuse leptomeningeal disease, gliomatosis cerebri, or infratentorial disease.
3. History, presence, or suspicion of metastatic disease
4. Patients who have received any additional treatment for glioblastoma, aside from surgical resection and chemoradiation with temozolomide
5. Active systemic infection requiring treatment
6. History of any malignancy (other than glioblastoma) during the last three years except non-melanoma skin cancer, in situ cervical cancer, treated superficial bladder cancer, cured, early-stage prostate cancer in a patient with PSA level less than ULN,or other carcinoma in situ that has been adequately treated and cured.
7. Planned major surgery
8. Evidence of current drug or alcohol abuse
9. Known allergy or hypersensitivity to keyhole limpet hemocyanin (KLH), GM-CSF (sargramostim; LEUKINE®), polysorbate 80 or yeast derived products, or a history of anaphylactic reactions to shellfish proteins
10. Severe acute or chronic medical or psychiatric condition or laboratory abnormality that could increase the risk associated with participating in a clinical trial
11. Women who are pregnant or lactating

Answer: C