Brain and Central Nervous System Tumors
Conditions
Keywords
adult glioblastoma, recurrent adult brain tumor
Brief summary
Vaccines made from a person's tumor cells, such as gp96 heat shock protein-peptide complex, may help the body build an effective immune response to kill tumor cells. This phase I/II trial is studying the side effects and best dose of gp96 heat shock protein-peptide complex vaccine to see how well it works in treating patients with recurrent or progressive high-grade glioma over time.
Detailed description
PRIMARY OBJECTIVES: * Phase 1: \[closed to accrual as of 7/25/2007\]: Determine the safety and best tolerated dose and frequency of gp96 heat shock protein-peptide complex vaccine in patients with recurrent or progressive high-grade glioma. * Phase 2: Determine the clinical response to treatment, time to disease recurrence and progression, and overall survival of patients treated with this vaccine. SECONDARY OBJECTIVES: * Determine the immune response in patients treated with this vaccine. * Determine survival outcomes in patients treated with this vaccine. OUTLINE: This is a dose-escalation, phase I study (closed to accrual as of 7/25/2007) followed by a phase II study. PHASE I \[closed to accrual as of 7/25/2007\]: Patients underwent surgical resection. Viable tumor tissue is used to generate the gp96 heat shock protein-peptide complex (HSPPC-96) vaccine. Patients with primary disease receive standard adjuvant therapy after surgery. Patients whose disease progresses during or after standard adjuvant therapy receive the HSPPC-96 vaccine. Patients with recurrent disease receive the HSPPC-96 vaccine between 2-8 weeks after surgery. The HSPPC-96 vaccine is administered intradermally every 1-3 weeks for at least 4 doses and then every 2-3 weeks thereafter in the absence of disease progression, unacceptable toxicity, or vaccine depletion. Cohorts of 6 patients received the HSPPC-96 vaccine at escalating dose frequencies until the maximum tolerated dose (MTD) was determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experienced a dose-limiting toxicity. PHASE II: Patients received the HSPPC-96 vaccine as in phase I at the appropriate dose frequency determined in phase I (closed to accrual as of 7/25/2007). The HSPPC-96 vaccine is administered intradermally every 1-3 weeks for at least 4 doses and then every 2 weeks thereafter in the absence of disease progression, unacceptable toxicity, or vaccine depletion. After completion of study treatment, patients are followed periodically until death, lost to follow-up, or end of study. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.
Interventions
BIOLOGICALHSPPC-96
25 mcg
PROCEDUREStandard Surgical Resection
Patients will undergo standard surgical resection of intracranial tumor
Sponsors
National Cancer Institute (NCI)
Agenus Inc.
American Brain Tumor Association
University of California, San Francisco
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed malignant recurrent glioma\*, including any of the following: * Glioblastoma * Glioblastoma multiforme * Recurrent disease or progressive primary disease * Surgically accessible tumor for which surgical resection is indicated and has not been previously irradiated * Prior radiotherapy required * No prior oncophage therapy or immunotherapy for glioma PATIENT CHARACTERISTICS: * Karnofsky performance status 80-100% * Life expectancy ≥ 8 weeks * Absolute granulocyte count ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Alkaline phosphatase and serum glutamic-pyruvic transaminase (SGPT) \<=2.5 times normal * Bilirubin \< 1.5 mg/dL * Blood Urea Nitrogen (BUN) \< 1.5 times normal OR creatinine \< 1.5 times normal * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective barrier contraception during and for at least 4 weeks after completion of study treatment * No uncontrolled active infection * No bleeding diathesis * No psychiatric or medical situation that would preclude study compliance * No unstable or severe concurrent medical condition * No other cancer or concurrent malignancy within the past 5 years except adequately treated nonmetastatic in situ carcinoma of the uterine cervix, nonmetastatic nonmelanoma skin cancer, or in complete remission and off all therapy for that disease * No systemic autoimmune disease (e.g., Hashimoto's thyroiditis) and/or any history of primary or secondary immunodeficiency PRIOR CONCURRENT THERAPY: * See Disease Characteristics * At least 2 weeks since prior vincristine * At least 6 weeks since prior nitrosoureas * At least 4 weeks since prior temozolomide or other cytotoxic chemotherapy * At least 4 weeks since prior investigational agents * At least 1 week since prior noncytotoxic agents * At least 3 weeks since prior procarbazine * No radiotherapy within the past 4 weeks
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) (Phase 1) | Up to 4 weeks | MTD determination will be based on the occurrence of dose-limiting toxicities. The MTD will be 1 dose below the dose that defined the dose-limiting toxicities |
| Frequency of gp96 Heat Shock Protein-peptide Complex Vaccine (Phase 1) | Up to 6 months | The frequency of dosing of the first 4 injections to be recommended for Phase 2 will be determined by reviewing the reported number of dose-limiting toxicities for weekly or bi-weekly injections. |
| Number of Participants With Dose Limiting Toxicities (Phase 1) | Up to 4 weeks | Systemic toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Dose-limiting toxicity is defined as any of the following that are attributable to vaccine therapy: Any grade 3, 4 or 5 toxicity, Any grade \>=2 clinical autoimmunity with the potential to threaten critical organs (including lungs, heart, kidney, bowel, bone marrow, liver or central nervous system (CNS), or eyes), and any removal of a patient from therapy due to toxicity |
| Median Progression-free Survival at 6 Months (Phase 2) | 6 months | — |
| Percentage of Participants With Progression-free Survival at 12 Months (Phase 2) | Up to 12 months | Defined as the percentage of participants with confirmed response and who have not progressed from date of surgical resection until death or censored at 12 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With an Immunological Response (Phase 1) | Up to 12 months | An immunological response is defined as an absolute lymphocyte count (ALC) less than the lower limit of normal (1.0 × 109cells/L), according to the standard laboratory reference range |
| Percentage of Participants Surviving at 12 Months (Phase 2) | Up to 12 months | Defined as the percentage of participants still alive from date of surgical resection until death or censored at 12 months |
| Number of Patients With an Immunological Response (Phase 2) | Up to 2 years | An immunological response is defined as an absolute lymphocyte count (ALC) less than the lower limit of normal (1.0 × 109cells/L), according to the standard laboratory reference range |
| Number of Participants With Grade 3 or Higher, Vaccine Treatment-Related Adverse Events by Toxicity (Phase 2) | Up to 2 years | Vaccine treatment-related Adverse Events with a grade \>=3 according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4 will be reported. |
| Median Overall Survival (Phase 2) | Up to 2 years | Overall survival is defined as the length of time from date of surgical resection until death or censored at end of study period |
| Percentage of Participants Surviving at 6 Months (Phase 2) | Up to 6 months | Defined as the percentage of participants still alive from date of surgical resection until death or censored at 6 months |
Countries
United States
Participant flow
Recruitment details
Phase 1 Recruitment took place between August 11, 2005 and July 25, 2007 for participants scheduled for gross total resection of recurrent Glioblastoma multiforme (GBM) Phase 2 Recruitment took place between October 3, 2007 and October 24, 2011 for participants scheduled for gross total resection of recurrent Glioblastoma multiforme (GBM)
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Vaccine Patients received 25 micrograms of HSPPC-96 bi-weekly or weekly for the first 4 vaccinations followed by biweekly injections. | 28 |
| Phase 2: Vaccine Treatment consisted of 25 mcg of HSPPC-96 weekly for at least 4 weeks, followed by biweekly injections (pending vaccine availability) for up to 52 weeks from the date of surgical resection. | 68 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Surgical Resection | disease progression prior to initial vaccination | 2 | 9 |
| Surgical Resection | Insufficient tumor obtained to generate vaccine | 9 | 13 |
| Surgical Resection | Less than a 90% extent of resection | 0 | 1 |
| Surgical Resection | Postoperative Karnofsky Performance Score <70% | 0 | 4 |
| Surgical Resection | processing error during surgical resection | 1 | 0 |
| Surgical Resection | Withdrawal by Subject | 4 | 0 |
| Vaccination Treatment Period | Received < 4 required vaccinations | 0 | 3 |
Baseline characteristics
| Characteristic | Phase 1: Vaccine | Phase 2: Vaccine | Total |
|---|---|---|---|
| Age, Customized 20-29 years old | 0 Participants | 3 Participants | 3 Participants |
| Age, Customized 30-39 years old | 3 Participants | 2 Participants | 5 Participants |
| Age, Customized 40-49 years old | 5 Participants | 14 Participants | 19 Participants |
| Age, Customized 50-59 years old | 12 Participants | 23 Participants | 35 Participants |
| Age, Customized 60-69 years old | 6 Participants | 20 Participants | 26 Participants |
| Age, Customized 70-79 years old | 2 Participants | 6 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 68 Participants | 96 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Median Number of Vaccine Doses Administered | 6 vaccine injections | 6 vaccine injections | 6 vaccine injections |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 65 Participants | 92 Participants |
| Region of Enrollment United States | 28 participants | 68 participants | 96 participants |
| Sex: Female, Male Female | 13 Participants | 19 Participants | 32 Participants |
| Sex: Female, Male Male | 15 Participants | 49 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 39 / 41 |
| other Total, other adverse events | 12 / 12 | 41 / 41 |
| serious Total, serious adverse events | 0 / 12 | 8 / 41 |
Outcome results
Primary
Frequency of gp96 Heat Shock Protein-peptide Complex Vaccine (Phase 1)
The frequency of dosing of the first 4 injections to be recommended for Phase 2 will be determined by reviewing the reported number of dose-limiting toxicities for weekly or bi-weekly injections.
Time frame: Up to 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Vaccine | Frequency of gp96 Heat Shock Protein-peptide Complex Vaccine (Phase 1) | 2 weeks between doses |
Primary
Maximum Tolerated Dose (MTD) (Phase 1)
MTD determination will be based on the occurrence of dose-limiting toxicities. The MTD will be 1 dose below the dose that defined the dose-limiting toxicities
Time frame: Up to 4 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Vaccine | Maximum Tolerated Dose (MTD) (Phase 1) | 25 micrograms |
Primary
Median Progression-free Survival at 6 Months (Phase 2)
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Vaccine | Median Progression-free Survival at 6 Months (Phase 2) | 19.1 weeks |
Primary
Number of Participants With Dose Limiting Toxicities (Phase 1)
Systemic toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Dose-limiting toxicity is defined as any of the following that are attributable to vaccine therapy: Any grade 3, 4 or 5 toxicity, Any grade \>=2 clinical autoimmunity with the potential to threaten critical organs (including lungs, heart, kidney, bowel, bone marrow, liver or central nervous system (CNS), or eyes), and any removal of a patient from therapy due to toxicity
Time frame: Up to 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: Vaccine | Number of Participants With Dose Limiting Toxicities (Phase 1) | 0 Participants |
Primary
Percentage of Participants With Progression-free Survival at 12 Months (Phase 2)
Defined as the percentage of participants with confirmed response and who have not progressed from date of surgical resection until death or censored at 12 months
Time frame: Up to 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Vaccine | Percentage of Participants With Progression-free Survival at 12 Months (Phase 2) | 29.3 percentage of participants |
Secondary
Median Overall Survival (Phase 2)
Overall survival is defined as the length of time from date of surgical resection until death or censored at end of study period
Time frame: Up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Vaccine | Median Overall Survival (Phase 2) | 42.6 weeks |
Secondary
Number of Participants With Grade 3 or Higher, Vaccine Treatment-Related Adverse Events by Toxicity (Phase 2)
Vaccine treatment-related Adverse Events with a grade \>=3 according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4 will be reported.
Time frame: Up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Vaccine | Number of Participants With Grade 3 or Higher, Vaccine Treatment-Related Adverse Events by Toxicity (Phase 2) | 1 participants |
Secondary
Number of Patients With an Immunological Response (Phase 1)
An immunological response is defined as an absolute lymphocyte count (ALC) less than the lower limit of normal (1.0 × 109cells/L), according to the standard laboratory reference range
Time frame: Up to 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Vaccine | Number of Patients With an Immunological Response (Phase 1) | 11 participants |
Secondary
Number of Patients With an Immunological Response (Phase 2)
An immunological response is defined as an absolute lymphocyte count (ALC) less than the lower limit of normal (1.0 × 109cells/L), according to the standard laboratory reference range
Time frame: Up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: Vaccine | Number of Patients With an Immunological Response (Phase 2) | 27 Participants |
Secondary
Percentage of Participants Surviving at 12 Months (Phase 2)
Defined as the percentage of participants still alive from date of surgical resection until death or censored at 12 months
Time frame: Up to 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Vaccine | Percentage of Participants Surviving at 12 Months (Phase 2) | 29.3 percentage of participants |
Secondary
Percentage of Participants Surviving at 6 Months (Phase 2)
Defined as the percentage of participants still alive from date of surgical resection until death or censored at 6 months
Time frame: Up to 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Vaccine | Percentage of Participants Surviving at 6 Months (Phase 2) | 90.2 percentage of participants |