Vaccine Therapy With Bevacizumab Versus Bevacizumab Alone in Treating Patients With Recurrent Glioblastoma Multiforme That Can Be Removed by Surgery

Study Overview
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Brief Summary
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This randomized phase II trial studies how well giving vaccine therapy with or without bevacizumab works in treating patients with recurrent glioblastoma multiforme that can be removed by surgery. Vaccines consisting of heat shock protein-peptide complexes made from a person's own tumor tissue may help the body build an effective immune response to kill tumor cells that may remain after surgery. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them. It is not yet known whether giving vaccine therapy is more effective with or without bevacizumab in treating glioblastoma multiforme.

Detailed Description
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The purpose of this study is to compare the effects of a vaccine with bevacizumab versus bevacizumab alone on a patient's brain tumor. The vaccine is called heat shock protein peptide complex 96 (HSPPC-96). HSPPC-96 is experimental. Specifically, HSPPC-96 is a protein that may work to help the body have a response against remaining brain tumor cells. Bevacizumab has been approved by the Food and Drug administration for treating brain tumors that grow back. In this study, patients will either get HSPPC-96 vaccine at the same time as bevacizumab, HSPPC vaccine first and then bevacizumab if the tumor comes back, or bevacizumab alone. The use of HSPPC-96 and bevacizumab is investigational. The primary objective of the study is to determine whether there is an overall survival advantage of HSPPC-96 administered with bevacizumab, given concomitantly or at the point of progression, in comparison with bevacizumab alone in patients with surgically resectable recurrent glioblastoma multiforme. The secondary objectives are: to evaluate the safety and tolerability of HSPPC-96 with bevacizumab to evaluate the progression free survival of HSPPC-96 with bevacizumab, given concomitantly or at the point of progression. Patients must undergo surgery within 28 days from pre-registration. There must be confirmation of adequacy of tissue for vaccine manufacture, tumor tissue submitted to Agenus, confirmation of ≥ 90% resection by central radiology review and vaccine manufacture of at least six vials. Patients will be randomized to one of three treatment arms. Please see the Arms section for more details. Patients will be monitored approximately 5 years post-surgery.

Official Title
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A Phase II Randomized Trial Comparing the Efficacy of Heat Shock Protein-Peptide Complex-96 (HSPPC-96) (NSC #725085, ALLIANCE IND # 15380) Vaccine Given With Bevacizumab Versus Bevacizumab Alone in the Treatment of Surgically Resectable Recurrent Glioblastoma Multiforme (GBM)

Conditions
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Recurrent Glioblastoma, Recurrent Adult Brain Tumor, Gliosarcoma

Intervention / Treatment
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* Biological: HSPPC-96
* Drug: bevacizumab


Participation Criteria
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Eligibility Criteria
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Pre-registration (Pre-Surgery) Eligibility Criteria Histologic documentation: Prior histologic diagnosis of GBM at first occurrence Stage: First or second recurrence of GBM or gliosarcoma considered to be surgically resectable Prior Treatment: No radiotherapy within 90 days prior to pre-registration No prior treatment with any anti-angiogenic agent targeting the VEGF pathway including but not limited to bevacizumab, cediranib, vandetanib, sunitinib, pazopanib, aflibercept, or sorafenib No prior treatment with HSPPC-96 or other investigational immunotherapy Must have received prior treatment with radiotherapy and temozolomide for histologically confirmed GBM at initial diagnosis No tumor directed therapy for most recent progression No prior Gliadel® wafers No clinically significant cardiovascular disease: Patients with a history of hypertension must be well controlled (<150/90) on a regimen of antihypertensive therapy. History of arterial thrombotic events within the past 6 months, including transient ischemic attack (TIA), cerebrovascular accident (CVA), peripheral arterial thrombus, unstable angina or angina requiring surgical or medial intervention in the past 6 months, or myocardial infarction (MI). Patients with clinically significant peripheral artery disease (i.e., claudication on less than one block), significant vascular disease (i.e., aortic aneurysm, history of aortic dissection) are not eligible. Patients who have had a deep vein thrombosis or pulmonary embolus within the past 6 months are eligible if they are on stable therapeutic anticoagulation No current New York Heart Association classification II, III or IV congestive heart failure No significant bleeding within the past 6 months; no bleeding diathesis or coagulopathy No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within past 12 months No evidence of any systemic autoimmune disease (e.g. Hashimoto's thyroiditis) and/or any history of primary or secondary immunodeficiency, and no immunosuppressant therapy (with the exception of dexamethasone as noted below) for any reason Age ≥ 18 years of age Karnofsky functional status rating ≥70 No more than 16 mg dexamethasone (or equivalent) per day Non-pregnant and non-nursing Registration (Post-Surgery) Eligibility Criteria Pre-registration eligibility criteria continue to be met Histologic documentation: confirmed histological diagnosis of recurrent GBM or gliosarcoma ≥ 90% surgical resection of recurrent GBM confirmed by central radiology review by MRI with or without gadolinium per institutional guidelines. A CT scan is allowable in place of MRI only in situations where an MRI is contraindicated (e.g., patient has a heart pacemaker, metallic devices in the eye, brain or spine, severe claustrophobia). ≥ 7 grams of resected tumor available for vaccine manufacture as determined by institutional pathologist Availability of ≥ 6 clinical vials of HSPPC-96 Required Initial Laboratory Values: Granulocytes ≥1,500/µL Platelet count ≥100,000/µL Total Bilirubin ≤ 2.0 x ULN UPC ratio <1 or Urine protein ≤ 1+ Calculated creatinine clearance ≥ 45 ml/min SGOT/SGPT(AST/ALT) ≤ 2.5 x ULN No serious, non-healing wounds or ulcers At least 7 days since any minor surgery such as port placement No major surgical procedures, open biopsy or significant traumatic injury ≤ 28 days prior to registration or anticipation of need for elective or planned major surgical procedure during the study. Core biopsy or other minor surgical procedures ≤7 days prior to registration. No active or recent hemoptysis (≥½ teaspoon of bright red blood per episode) ≤ 30 days prior to registration No new bleeding on D28 (+/-3) MRI (or CT if MRI is contraindicated) No clinical deterioration at the time of registration/randomization If a second surgery is needed for completion of resection, this should be within 30 days from the first surgery

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1, HSPPC-96 + concomitant bevacizumab<br>HSPPC-96 0.4mL intradermal on days 1 and 8 of cycles 1 and 2, then on day 1 of each cycle, up to a maximum of 12 doses (10 cycles), plus bevacizumab 10 mg/kg intravenous (IV) on day 1 of each cycle, until progression. HSPPC-96 should be administered at least 60 minutes prior to starting bevacizumab infusion. (1 cycle=14 days) Note: If HSPPC-96 treatment has ended but there is no evidence of disease progression, the patient should continue to receive bevacizumab at the specified dose until progression. | Biological: HSPPC-96<br>* intradermal infusion<br>Drug: bevacizumab<br>* intravenous<br>|
| Experimental: Arm 2, HSPPC-96 with bevacizumab at progression<br>HSPPC-96 0.4mL intradermal on days 1 and 8 of cycles 1 and 2, then on day 1 of each cycle, up to a maximum of 12 doses (10 cycles). At progression: bevacizumab 10mg/kg intravenous (IV) on day 1 of each cycle, until further progression. (1 cycle = 14 days) NOTE: It is possible that HSPPC-96 vaccination may end prior to evidence of progression. In this instance it is important to wait until there is confirmed evidence of progression before initiating treatment with bevacizumab. Upon confirmation of progression the patient should initiate bevacizumab within 7-42 days from the last dose of vaccine. | Biological: HSPPC-96<br>* intradermal infusion<br>Drug: bevacizumab<br>* intravenous<br>|
| Active Comparator: Arm 3, Bevacizumab<br>Bevacizumab 10mg/kg intravenous (IV) on day 1 of each cycle, until progression. (1 cycle = 14 days) | Drug: bevacizumab<br>* intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | The primary endpoint is overall survival (OS), which is defined as the date from study> registration to the date of death, due to any cause. | Up to 5 years post-surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Time to progression free survival: which is defined as the date from study registration to the date of first observation of disease progression or death due to any cause (whichever comes first). Progressive disease is defined as one or more of the following:New contrast-enhancing lesion outside of radiation field on decreasing, stable, or increasing doses of corticosteroids, increase by > 50% enhancement from the first post-surgical scan, or a subsequent scan with smaller tumor size, and the scan 8 weeks or later on stable or increasing doses of corticosteroids, clinical deterioration not attributable to concurrent medication or comorbid conditions is sufficient to declare progression on current treatment, for patients receiving bevacizumab therapy, significant increase in T2/FLAIR non-enhancing lesion. | Up to 5 years post-surgery | 
| Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (v5) | The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either unrelated or unlikely to be related to study treatment in the event of an actual relationship developing. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below. | Up to 3 years |