DSMB futility analysis

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.

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:

1. to evaluate the safety and tolerability of HSPPC-96 with bevacizumab
2. 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.

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