Peptide-based Glioma Vaccine IMA950 in Patients With Glioblastoma

Study Overview
=================
Brief Summary
-----------------
BACKGROUND: Active immunotherapy of cancer is based on the premise that the vaccine raises a cytotoxic immune response to tumor-associated antigens, thereby destroying malignant cells without harming normal cells. IMA950 is a therapeutic multi-peptide vaccine containing 11 tumor-associated peptides (TUMAPs) found in a majority of glioblastomas, and is designed to activate TUMAP-specific T cells. The use of 11 TUMAPs increases the likelihood of a multi-clonal, highly specific T-cell response against tumor cells leading to decreased likelihood of immune evasion of the tumor by down-regulation of target antigens. PURPOSE: The primary objective of this study is to determine the safety and tolerability of IMA950 when given with cyclophosphamide, granulocyte macrophage-colony stimulating factor (GM-CSF) and imiquimod in patients with glioblastoma and to determine if IMA950 shows sufficient immunogenicity in these patients. ELIGIBILITY: Patients with histologically proven GBMs who have completed radiotherapy, and have stable disease following at least 4 cycles of adjuvant temozolomide.

Official Title
-----------------
A Phase 1 Trial of Peptide-Based Glioma Vaccine IMA950 in Patients With Glioblastoma (GBM)

Conditions
-----------------
Glioblastoma

Intervention / Treatment
-----------------
* Drug: Cyclophosphamide
* Biological: IMA950 plus GM-CSF
* Biological: IMA950
* Drug: Imiquimod


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically proven glioblastoma Stable disease following ≥ 4 cycles of adjuvant temozolomide No progression or recurrence of disease PATIENT CHARACTERISTICS: HLA-A*02 positive ≥ 18 years old Life expectancy > 8 weeks Karnofsky performance status ≥ 60 WBC >3,500/µL ALC >350/mm3 ANC >1,500/mm3 Platelet count >100,000/mm3 Hemoglobin >10gm/dL AST, ALT and alkaline phosphatase <2.5 times upper limit of normal (ULN) Bilirubin <1.5 times ULN Creatinine <1.5 mg/dL and/or creatinine clearance >60cc/min Serum potassium, magnesium and calcium within normals levels (supplementation is allowed) Not pregnant or nursing Negative pregnancy test Practice birth control during and for 2 months after treatment with IMA950 (both genders) Women of childbearing age must agree to use adequate contraceptive methods No significant active hepatic, renal, infectious or psychiatric disease No HIV, active hepatitis infection, or any other active severe infectious disease No history of autoimmune disease or immunosuppression No clinically significant cardiovascular event within 3 months before study entry or an increased risk for ventricular arrhythmia No malignancy other than glioblastoma that required treatment during the last 12 months PRIOR and/or CONCURRENT THERAPY: See Disease Characteristics Completed radiotherapy and at least 4 cycles of adjuvant temozolomide Not be receiving steroids OR be on stable dose of steroids for ≥ 5 days prior to registration No other prior immunotherapy for glioblastoma No major surgery within 4 weeks prior to treatment start At least 4 weeks from cytotoxic therapies (incl. temozolomide) At least 2 weeks from non-cytotoxic therapies (e.g. interferon, tamoxifen) At least 3 weeks from bevacizumab No current treatment with imiquimod; prior use of imiquimod is allowed

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Cyclophosphamide|One single low-dose i.v. infusion of cyclophosphamide (300mg/m2) prior to the first vaccination as pre-treatment|
|Biological: IMA950 plus GM-CSF|Six vaccinations with IMA950 plus GM-CSF as adjuvant on 8 pre-defined days from Day 1 to Day 78|
|Biological: IMA950|After Day 78, vaccinations with IMA950 (no GM-CSF) will be given on a monthly basis for up to one year from start of vaccination or until disease progression|
|Drug: Imiquimod|Imiquimod will be topically applied 10-20 minutes after each vaccination. After the third vaccination onward patients will apply additional imiquimod 24 hours after each vaccination at home on their own|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of IMA950 administered with granulocyte macrophage colony stimulating factor (GM-CSF) and topical imiquimod together following a single low-dose application of cyclophosphamide. | Number of AEs and percentage of patients with AEs (listed per grade and MedDRA preferred terms) will be reported. | Continuously for up to 1 year plus follow-up | 
| Immunogenicity of IMA950 | Vaccine-induced immune responses to peptides contained in IMA950 will be measured by multimer assay using peripheral blood. Percentage of immune responders (patients with at least one vaccine-induced immune response to IMA950 peptides) and percentage of multi-TUMAP responders (patients with vaccine-induced immune responses to ≥2 peptides in IMA950) will be reported. | 6 time points (blood drawings) during the first 3 months (pre- and post-vaccination) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune status parameters | Relative frequencies and absolute numbers per µl blood of regulatory T-cells and (if sufficient cells are available) other immune cell populations will be measured from peripheral blood. Focus is on analysis of pre-vaccination frequencies. | 6 time points (blood drawings) during the first 3 months on study (pre-vaccination and during vaccination period) | 
| Biomarker assessment and correlation to clinical and immunological response | Serum levels of proteins and other factors that are indicative of the immune status of the patients will be measured (e.g TGF-beta) and will be correlated with immune response rates and clinical outcome. | Analysis time points are before the first vaccination and 15 weeks thereafter | 
| Clinical anti-tumor activity (response rate, 6-month progression-free survival) | Clinical response rates, survival and progression-free survival (PFS) will be followed. PFS at 6 month will be reported. | Will be followed for 1 year (until end of study visit), overall survival will also be followed thereafter | 
| Influence of corticosteroids on immunogenicity of IMA950 | Corticosteroid levels are not limited in this trial. It will descriptively reported whether the known immunosuppressive effects of corticosteroids are reflected in different immune response rates for patients treated or not treated with corticosteroids. | 6 time points (blood drawings) during the first 3 months (pre- and post-vaccination) | 
| Health-related quality of life | FACT-Br(4.0) questionnaire will be used to assess HRQL. HRQL scores (total, Trial Outcome Index, subscales) will be reported at baseline. Changes from baseline will also be evaluated. | Monthly for 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Glioblastoma, stable disease