Neoadjuvant Chemoradiation for Resectable Glioblastoma

Study Overview
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Brief Summary
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Preoperative therapy has not been well studied in resectable glioblastoma. This study attempts to prospectively assess the feasibility and efficacy of preoperative chemo radiation in improving local control, as this is the predominant mode of failure in these patients leading to poor outcomes. This Phase II study design would be used to proceed with the study treatment after meeting pre-specified events in the initial phase, with goal being to determine whether the new treatment paradigm is sufficiently promising to warrant a major controlled clinical evaluation against the standard therapy.

Detailed Description
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Neo adjuvant, preoperative chemo radiation has consistently shown improvements in local disease control or organ preservation in many cancers including head and neck, esophageal, rectal, bladder cancers and sarcomas, leading to improvements in overall survival and limb or organ preservation. This interventional study will be done in two phases using the Simon two-stage Phase II study design. The median progression-free survival of these patients with current standard of care therapy is in the range of 6-8 months (6.9 months in the standard of care). With the proposed trial of surgical resection of the tumor after chemotherapy and radiation the median progression free survival is anticipated to be approximately 11-12 months from subset analysis of available literature and based on prior data on other disease sites. In other words, the 7-month local progression rates is anticipated to decrease from 50% to 25%, or progression free survival improve from 50-75%

Official Title
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Phase II Study of Neoadjuvant Chemoradiation for Resectable Glioblastoma (NeoGlio)

Conditions
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Surgery, Glioblastoma, High Grade Glioma

Intervention / Treatment
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* Radiation: Neoadjuvant chemoradiation
* Drug: Drug Therapy with Temozolomide (benzolamide) (Standard of Care)
* Procedure: Surgery post Radiation and Temozolomide (benzolamide)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed GBM with histopathological confirmation. Surgically suitable for subtotal or gross total resection as determined by central review. Karnofsky Performance Status (KPS)>70 No contraindication for chemoradiation. Complete blood count (CBC)/differential obtained within 28 days prior to registration, with adequate bone marrow function defined as follows: Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3; Platelets ≥ 100,000 cells/mm3; Hemoglobin ≥ 8.0 g/dl (Note: the use of transfusion or other intervention to achieve Hgb ≥8.0 g/dl is acceptable) Adequate hepatic function within 28 days prior to registration, as defined below: Alanine Aminotransferase (ALT) and Aspartate transaminase (AST) ≤ 3 x ULN Bilirubin ≤ 1.5 upper limit of normal (ULN) Negative serum pregnancy test obtained for females of child-bearing potential within 28 days prior to step 2 registration. Ability to get multiplanar contrast enhanced Magnetic Resonance Imaging (MRI) Exclusion Criteria: Recurrent, unresectable or multifocal malignant gliomas. Any site of distant disease (for example, drop metastases from the GBM tumor site) Prior radiation or chemotherapy or radiosensitizers for cancers of the brain and head and neck region; note that prior chemotherapy for a different cancer is allowable (except temozolomide). 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. Patents treated on any other therapeutic clinical protocols within 30 days prior to registration. Inability to undergo MRI (e.g., due to safety reasons, such as presence of a pacemaker, or severe claustrophobia). Severe, active co-morbidity, defined as follows: Transmural myocardial infarction within the last 6 months prior to registration History of recent myocardial infarction 1month prior New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 3 months prior to registration. Serious or non-healing wound, ulcer or bone fracture or history of abdominal fistula, intra-abdominal abscess requiring major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to registration, with the exception of the craniotomy for surgical resection Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol. Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration 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 because the treatments involved in this protocol may be significantly immunosuppressive with potentially fatal outcomes in patients already immunosuppressed. Any other severe immuno-compromised condition. 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. End-stage renal disease (i.e. on dialysis or dialysis has been recommended). Any other major medical illnesses or psychiatric treatments that in the investigator's opinion will prevent administration or completion of protocol therapy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 89 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: After standard treatment of Glioblastoma multiforme (GBM) with resection and adjuvant therapy, local failure the dominant pattern of failure. Neo adjuvant therapy consistently provides the potential for improved local control and removal of residual stem cell niches. The hypothesis is that earlier institution of neo adjuvant chemo radiation therapy in GBM would improve local control and potentially overall survival. Involved field radiation is often employed to treat unresectable or sub totally resected GBM. Radiating native GBM is not uncommon as many tumors are not safely resectable due to its location in eloquent brain. Planned neoadjuvant chemo radiation prior to immediate surgical resection in glioblastoma is a novel approach in resectable tumors.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Neoadjuvant chemoradiation and surgical resection<br>The experimental part of the study would be this selection of resectable patients and sequencing neoadjuvant chemoradiation prior to surgery. | Radiation: Neoadjuvant chemoradiation<br>* Intensity modulation radiation therapy (IMRT) with a simultaneous integrated boost with Fixed-gantry IMRT, helical tomotherapy, or Vesicular Modulated Arc Therapy (VMAT) can be used. All photon treatments shall be delivered with megavoltage machines of a minimum energy of 6 Megavolt (MV) photons. Selection of the appropriate photon energy(ies) should be based on optimizing the radiation dose distribution within the target volume and minimizing dose to non-target normal tissue.<br>* Other names: Standard adjuvant therapy;Drug: Drug Therapy with Temozolomide (benzolamide) (Standard of Care)<br>* During Concomitant Radiation Therapy on the same day as the first fraction of radiotherapy. Temozolomide will be administered continuously from day 1 of radiotherapy to the last day of radiation at a daily oral dose of 75 mg/m2 for a maximum of 49 days. The drug will be administered orally daily during radiotherapy, as best tolerated by the patient. During weekends without radiotherapy (Saturday and Sunday), the drug will be taken in the morning. The dose will be determined using actual body surface area (BSA) as calculated in square meters at the beginning of the concomitant treatment. The BSA will be calculated from the height obtained at the pretreatment visit. Capsules of temozolomide are available in 5, 20, 100, 140, 180, and 250 mg. The daily dose will be rounded to the nearest 5 mg.<br>* Other names: Neoadjuvant therapy;Procedure: Surgery post Radiation and Temozolomide (benzolamide)<br>* Surgical resection of GBM will be done after radiation and Temozolomide treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| No study related undue toxicity or progression in >6 of 11 patients. | No study related undue toxicity (as defined below) or progression within the limits of stage one patients. Toxicity is defined as: progression precluding surgery, unanticipated neurological decompensation, non-completion of neoadjuvant therapy (other than protocol defined dose adjustments or discontinuation), treatment related delay of >6 weeks to surgery, and/or major unforeseen surgical complication requiring repeat surgical intervention including other than non-life-threatening infection like meningitis/encephalitis or septicemia. | 7 months for each patient from registration. | 
| Progression Free Survival | Progression Free Survival defined as MRI defined progression (increasing FLAIR, enhancement, diffusion and or perfusion) 3 months after completion of therapy (to allow for excluding pseudo progression) OR clinical progression with new or worsening neurological symptoms related to the tumor (by MRI or clinical correlation with location) and not due to non-tumor or study related symptoms. | 7 months after completion of therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma