SurVaxM Vaccine Therapy and Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma

Study Overview
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Brief Summary
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This phase II trial studies the side effects and how well vaccine therapy works when given together with temozolomide in treating patients with newly diagnosed glioblastoma. Vaccines made from the survivin peptide or antigen may help the body build an effective immune response to kill tumor cells that express survivin. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether temozolomide is more effective with or without vaccine therapy in treating glioblastoma.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate 6-month progression-free survival (PFS6) in patients with survivin positive newly diagnosed glioblastoma multiforme (GBM) treated with at least 4 doses of SVN53-67/M57-keyhole limpet hemocyanin (KLH) peptide vaccine (SurVaxM) and standard of care temozolomide. SECONDARY OBJECTIVES: I. To determine the safety and tolerability of SurVaxM in patients receiving standard care adjuvant temozolomide. II. To evaluate overall survival (OS) in patients with survivin positive newly diagnosed GBM treated with SurVaxM and adjuvant temozolomide. III. To describe the immune response in patients treated with SurVaxM and predictors of response. IV. To evaluate objective tumor response rate (applicable only for patients with evaluable disease at study entry, as defined per Response Assessment in Neuro-Oncology [RANO] criteria) and predictors of response. OUTLINE: Patients receive the first priming dose of SVN53-67/M57-KLH peptide vaccine in emulsion with montanide ISA 51 subcutaneously (SC) and sargramostim SC within 7-28 days after completion of chemoradiation. Treatment repeats every 2 weeks for a total of 4 doses in the vaccine priming phase and then every 12 weeks during the adjuvant phase in the absence of disease progression or unacceptable toxicity. Patients also receive standard adjuvant temozolomide orally (PO) or intravenously (IV) on days 1-5. Treatment repeats every 28 days for 6 courses or more (at the discretion of the investigator) in the absence of disease progression or unacceptable toxicity. Patients may then receive maintenance SVN53-67/M57-KLH peptide vaccine in emulsion with montanide ISA 51 SC and sargramostim SC every 12 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 12 weeks.

Official Title
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A Phase II Study of the Safety and Efficacy of SVN53-67/M57-KLH (SurVaxM) in Survivin-Positive Newly Diagnosed Glioblastoma

Conditions
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Glioblastoma, Gliosarcoma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Montanide ISA 51 VG
* Biological: Sargramostim
* Biological: SVN53-67/M57-KLH Peptide Vaccine
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a Karnofsky performance status >= 70 (i.e. the patient must be able to care for himself/herself with occasional help from others) Documented survivin-positive tumor status Pathologically confirmed diagnosis of glioblastoma multiforme (GBM); or World Health Organization (WHO) grade IV [gliosarcoma] Absolute neutrophil count (ANC) >= 1.5 x 10^9/L Platelets >= 100 x 10^9/L Hemoglobin (Hgb) > 9.0 g/dL Serum total bilirubin: =< 1.5 x upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 4.0 x ULN Patients on full-dose anticoagulants (e.g., warfarin or low molecular weight [LMW] heparin) must meet the following criteria: No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices) Creatinine =< 1.8 mg/dl Human leukocyte antigen (HLA)-A*02, HLA-A*03, HLA-A*11 or HLA-A*24 positive patients No evidence of progressive disease from the postoperative period to the post-chemoradiation period, based on changes in the neurologic exam, steroid use, or evident radiographic progression, according to RANO criteria; Patients with increased or new gadolinium enhancement may continue on protocol if in the investigator's judgment that enhancement is likely due to pseuodoprogresion. The use of correlative imaging studies (including PWI) or diffusion weighted imaging (DWI) and repeat imaging after an interval of 2-4 weeks is strongly encouraged to help distinguish between pseudoprogression and true progression. Magnetic resonance imaging (MRI) (ideally completed within 96 hours after surgery) documenting gross total resection consisting of no gadolinium enhancement; or subtotal resection consisting of linear enhancement with (or without) nodular gadolinium enhancement measuring no greater than 1 cm x 1 cm x 1 cm total volume or 100 mm^2 in cross sectional area Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry, and have a negative pregnancy test prior to starting study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately Dexamethasone dose less than or equal to 4 mg daily at time of study enrollment Patients must have completed initial radiation therapy (RT) and temozolomide (TMZ) for the treatment of their glioblastoma (i.e., completed 6-week course of RT and, completed >= 75% of 6-week course of induction TMZ chemotherapy) Participant must understand the investigational nature of this study and sign an independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure Exclusion Criteria: The patient must not have received any immunotherapy for their brain tumor Patients with serious concurrent infection or medical illness, which in the treating physician's opinion would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety Patients who are pregnant or breast-feeding Patients receiving concurrent therapy for their tumor (i.e. chemotherapeutics or investigational agents) other than temozolomide Patients with a concurrent or prior malignancy are ineligible unless they are patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the skin; patients who have been free of disease (any prior malignancy) for at least 3 years are eligible for this study Patients who have had repeat craniotomy for tumor therapy after receiving RT and TMZ treatment Patients who received other chemotherapeutics or investigational agents in addition to their radiation therapy and concomitant temozolomide treatment Patients who have received Gliadel wafers or alternating electrical field therapy (ETTF) are not eligible for this study Known history of an autoimmune disorder Known human immunodeficiency virus (HIV) positivity or acquired immunodeficiency syndrome (AIDS) related illness or other serious medical illness Patients who have contraindication to MRI Unwilling or unable to follow protocol requirements Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug Received an investigational agent within 30 days prior to registration

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (SurVaxM, temozolomide)<br>Patients receive the first priming dose of SVN53-67/M57-KLH peptide vaccine in emulsion with montanide ISA 51 SC and sargramostim SC within 7-28 days after completion of chemoradiation. Treatment repeats every 2 weeks for a total of 4 doses in the vaccine priming phase and then every 12 weeks during the adjuvant phase in the absence of disease progression or unacceptable toxicity. Patients also receive standard adjuvant temozolomide PO or IV on days 1-5. Treatment repeats every 28 days for 6 courses or more (at the discretion of the investigator) in the absence of disease progression or unacceptable toxicity. Patients may then receive maintenance SVN53-67/M57-KLH peptide vaccine in emulsion with montanide ISA 51 SC and sargramostim SC every 12 weeks in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Montanide ISA 51 VG<br>* Given SC<br>Biological: Sargramostim<br>* Given SC<br>* Other names: Sargramostatin;Biological: SVN53-67/M57-KLH Peptide Vaccine<br>* Given SC<br>Drug: Temozolomide<br>* Given PO or IV<br>* Other names: Temomedac;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | The 6-month progression-free survival (PFS6) estimated using the Kaplan-Meier methods. PFS6 is defined as the percentage of patients without tumor progression or death from any cause 6 months after the date of diagnosis by biopsy. Corresponding confidence intervals will be computed. | Date of diagnosis to the date of first observed disease progression or death due to any cause, assessed at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune Responses to SurVaxM and Predictors of Response | A series of exploratory analyses will initially take place including individual subject-level profile plots and overall mean plots used to examining the mean structure. Formal statistical examination of longitudinal patterns will be done through the use of a mixed model. Restricted maximum likelihood estimation will be utilized in the model fitting procedures. Once the model is fit, specific linear contrasts based on the estimated model parameters will be constructed and used to test hypotheses concerning between time point comparisons. | Up to 30 days after completion of study treatment | 
| Incidence of Grade 3 or 4 Toxicities, According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4 | Toxicities will be summarized using simple frequencies by grade. CTEP Version 4 of the NCI Common Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. Results are presented for the number of participants with drug-related Grade 3 or 4 toxicity/adverse event (AE). Grades range from 0 (none) to 5 (death), with Grade 3 and 4 being defined as follows: Grade 0 = No AE; Grade 1 = Mild AE; Grade 2 = Moderate AE; Grade 3 = Severe AE; Grade 4 = Life-threatening or disabling AE; Grade 5 = Death related to AE. | Up to 30 days after completion of study treatment | 
| Overall Survival | The median overall survival estimated using the Kaplan-Meier methods. Estimates of quantities such as median survival will be obtained. Corresponding confidence intervals will be computed. | Date of diagnosis until (1) date of death or (2) the last date patient known alive (if death is not observed), assessed up to 2 years |