Brain and Central Nervous System Tumors
Conditions
Keywords
Newly Diagnosed Glioblastoma Multiforme, vaccine
Brief summary
This phase II trial studies the side effects and how well HSPPC-96 (vitespen) and temozolomide work in treating patients with newly diagnosed glioblastoma multiforme. Vaccines made from a person's tumor cells and heat shock protein peptide may help the body to build an effective immune response to kill tumor cells. 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. Giving HSPPC-96 (vitespen) together with temozolomide may kill more tumor cells.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the safety profile of HSPPC-96 (vitespen) administered concurrently with temozolomide in patients with newly diagnosed glioblastoma multiforme (GBM). II. To evaluate survival in patients treated with an autologous tumor-derived heat shock protein peptide-complex (HSPPC-96) with concurrent temozolomide. SECONDARY OBJECTIVES: I. To evaluate progression-free survival (PFS) from date of surgical resection. II. To evaluate the immunologic response to vaccine treatment in a subset of evaluable patients. OUTLINE: Approximately 2-5 weeks after standard radiation therapy and temozolomide completion, patients receive vitespen intradermally (ID) on days 1, 8, 15, and 22. Beginning 2 weeks after the 4th dose of vitespen, patients receive a 5th dose of vitespen ID and maintenance temozolomide orally (PO) on days 1-5 (of 28 day courses). On day 21 of course 1, patients receive the 6th dose of vitespen ID and continue vaccinations monthly. Courses repeat every 28 days in the absence of vaccine depletion, disease progression, or unacceptable toxicity. After completion of study treatment, patients are followed up every 12 weeks.
Interventions
BIOLOGICALHSPPC-96
Autologous tumor-derived heat shock protein peptide-complex (HSPPC-96) administered at 25 μg per dose injected intradermally once weekly for 4 consecutive weeks and monthly following standard treatment with radiation and temozolomide.
DRUGTemozolomide
Maintenance temozolomide treatment is given 2 weeks after administration of the fourth vaccine at an initial dose of 150 mg per square meter (mg/m2) for 5 consecutive days in a 28-day cycle. The dose was increased to 200 mg/m2 for 5 days in subsequent cycles.
PROCEDUREStandard Surgical Resection
Patients will undergo standard surgical resection of intracranial tumor
Sponsors
Agenus Inc.
University of California, San Francisco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Pre-surgery tissue acquisition Inclusion criteria 1. Age \> or equal to 18 years old 2. Life expectancy of greater than 12 weeks. 3. Able to read and understand the informed consent document; must sign the informed consent 4. Must have suspected diagnosis of Glioblastoma Multiforme with a surgical intent to resect at least 90% of enhancing disease 5. Must be eligible for post-surgical treatment with radiotherapy and temozolomide Post-radiation therapy/pre-vaccine eligibility Inclusion criteria 1. Agree to use contraception or abstain from sexual activity from the time of consent through 1 month after the end of study drug administration 2. Negative serum pregnancy test for female patients of childbearing potential 3. Patients with histologically proven, non-progressive glioblastoma multiforme (GBM) 4. Patient must have received standard of care radiation and temozolomide therapy 5. Must have undergone a at least a 90% resection (determined by the principal investigator (PI)) measured by postoperative magnetic resonance imaging (MRI) scan, T1-weighted contrast scan, or CT scan if clinically indicated, performed within 72 hours after surgery 6. All radiotherapy must be discontinued at least 2 weeks and no more than 5 weeks prior to the first planned vaccine administration 7. Availability of at least 4 doses of vaccine (at least 4 vials for clinical administration produced from the tumor provided) 8. Karnofsky functional status rating \> or equal to 70 9. Adequate bone marrow function including the absence of lymphopenia (ANC \> 1,500/ mm3; absolute lymphocyte count (ALC) \> 500/mm3 ; platelet count \>100,000/mm3), adequate liver function (serum glutamic oxaloacetic transaminase/ aspartate aminotransferase (AST), alanine amino transferase (ALT), and alkaline phosphatase \<2.5 times institutional upper limit of normals \[IULNs\] and bilirubin (total) \<1.5 mg\*IULN), and adequate renal function (BUN and creatinine \<1.5 times IULNs
Exclusion criteria
Pre-surgery tissue acquisition 1. Current diagnosis of Human Immunodeficiency Virus (HIV testing is not required per protocol) 2. Any prior diagnosis of any other cancer or other concurrent malignancy, with the exception of adequately treated nonmetastatic in situ carcinoma of the uterine cervix or nonmetastatic nonmelanoma skin cancer unless in complete remission and off all therapy for that disease for a minimum of 5 years 3. Any systemic autoimmune disease (e.g., Hashimoto's thyroiditis) and/or any history of primary or secondary immunodeficiency 4. Any prior therapy for glioma 5. Planned use or current use of other investigational therapy for the treatment of glioma Post-radiation therapy/pre-vaccine Exclusion 1. Inability to comply with study-related procedures 2. Prior diagnosis of any other cancer or other concurrent malignancy, with the exception of adequately treated nonmetastatic in situ carcinoma of the uterine cervix or nonmetastatic nonmelanoma skin cancer unless in complete remission and off all therapy for that disease for a minimum of 5 years 3. Current or active use of chemotherapy (except temozolomide) or immune therapy 4. Contrast MRI findings (or CT scan if MRI is clinically contraindicated) consistent with progression per protocol defined modified Response assessment in neuro-oncology criteria (RANO) criteria. Progression prior to vaccination as determined by the Principal Investigator 5. Patients with active uncontrolled infection 6. Evidence of bleeding diathesis 7. Unstable or severe intercurrent medical conditions 8. Female patients who are pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Related Adverse Events of Any Grade | Up to 3 years | — |
| Median Overall Survival | Up to 3 years | Overall survival is defined as the time from surgical resection to death of any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression Free Survival (PFS) | Up to 3 years | PFS is defined as the duration of progression-free survival from the time from resection until either documented disease progression or death |
| Median PD-L1 Positivity in Circulating Myeloid Cells | Up to 53 Weeks | Circulating myeloid cells (CD45+/CD11b+) obtained from patients at the time of surgery were analyzed for PD-L1 expression to determine the percent of myeloid cells positive for PD-L1 (cut off for positivity determined relative to Fluorescence Minus One (FMO) and isotype control). |
Countries
United States
Participant flow
Recruitment details
Recruitment took place between June 29, 2009 and April 2012 for participants scheduled for gross total resection of recurrent Glioblastoma multiforme (GBM) across 8 sites
Participants by arm
| Arm | Count |
|---|---|
| Protein Peptide-Complex (HSPPC-96) Patients will receive 4 weekly injections of HSPPC-96 followed by a 5th vaccine injection on the same day of the start of maintenance temozolomide administered 2 weeks (+ 4 days) following vaccine administration #4 on the same day of the start of maintenance temozolomide (Day 36). Monthly vaccine injections will then begin on day 21 (+/- 7 days) of the first 28 day temozolomide cycle (Day 56 of the study), 3 weeks following vaccine administration #5 and will continue every 28 days until depletion of vaccine or progression.
HSPPC-96: Autologous tumor-derived heat shock protein peptide-complex (HSPPC-96) administered at 25 μg per dose injected intradermally once weekly for 4 consecutive weeks and monthly following standard treatment with radiation and temozolomide. | 70 |
| Total | 70 |
Baseline characteristics
| Characteristic | Protein Peptide-Complex (HSPPC-96) |
|---|---|
| Age, Customized 30-39 years old | 2 Participants |
| Age, Customized 40-49 years old | 13 Participants |
| Age, Customized 50-59 years old | 19 Participants |
| Age, Customized 60-69 years old | 25 Participants |
| Age, Customized 70-79 years old | 11 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Median Number of Vaccination Doses Administered | 9 vaccine injections |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 65 Participants |
| Region of Enrollment United States | 70 participants |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 21 / 46 |
| other Total, other adverse events | 44 / 46 |
| serious Total, serious adverse events | 10 / 46 |
Outcome results
Primary
Median Overall Survival
Overall survival is defined as the time from surgical resection to death of any cause.
Time frame: Up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Protein Peptide-Complex (HSPPC-96) | Median Overall Survival | 23.8 months |
Primary
Number of Participants With Treatment-Related Adverse Events of Any Grade
Time frame: Up to 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Protein Peptide-Complex (HSPPC-96) | Number of Participants With Treatment-Related Adverse Events of Any Grade | 34 Participants |
Secondary
Median PD-L1 Positivity in Circulating Myeloid Cells
Circulating myeloid cells (CD45+/CD11b+) obtained from patients at the time of surgery were analyzed for PD-L1 expression to determine the percent of myeloid cells positive for PD-L1 (cut off for positivity determined relative to Fluorescence Minus One (FMO) and isotype control).
Time frame: Up to 53 Weeks
Population: Peripheral blood was available for analysis from 32 vaccine-treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Protein Peptide-Complex (HSPPC-96) | Median PD-L1 Positivity in Circulating Myeloid Cells | 54.5 percentage of PD-L1 positivity |
Secondary
Median Progression Free Survival (PFS)
PFS is defined as the duration of progression-free survival from the time from resection until either documented disease progression or death
Time frame: Up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Protein Peptide-Complex (HSPPC-96) | Median Progression Free Survival (PFS) | 18 months |