Malignant Glioma
Conditions
Keywords
HLA-A2 positive, Malignant Gliomas, Vaccine
Brief summary
This is a single-institution Phase I/II study designed to evaluate the safety and induction of an immune response, and preliminary clinical response of vaccinations with Type-1 alpha-DCs (alpha-DC1) loaded with glioma-associated antigen (GAA) epitopes and administration of poly-ICLC in patients with recurrent malignant gliomas. Approximately 30 subjects will be enrolled in this study at UPMC/UPCI Hillman Cancer Center. The study participants in this trial will be HLA-A2 positive male or female adults over 18 years of age. The primary objective is to establish the safety of this approach. The endpoints will be to determine the maximum tolerated dose (MTD) of alpha-DC1 vaccines in combination with a fixed dose of poly-ICLC, using standard criteria and close clinical followups. The secondary objectives are 1) to assess the immunological response against GAAs in patients with recurrent malignant gliomas immunized with DCs loaded with GAA-derived peptides using enzyme-linked immuno-spot (ELISPOT), delayed-type hypersensitivity (DTH) and tetramer assays; and 2) to assess the preliminary anti-tumor clinical activity of the vaccines as measured by radiological response (MRI), overall survival, and 4- and 6-month progression-free survival (PFS).
Detailed description
This is a single-institution Phase I/II study designed to evaluate the safety, the induction of an immune response, and the preliminary clinical response of vaccinations with Type-1 αDCs (αDC1) loaded with glioma-associated antigen (GAA) epitopes and administration of poly-ICLC in patients with recurrent malignant gliomas. The hypothesis is that this form of vaccines in combination with poly-ICLC treatment will prove to be safe, and will induce potent anti-glioma immune responses. The primary objective is to establish the safety of the approach. The secondary objectives are to 1) assess the immunological response against GAAs in patients with recurrent malignant gliomas immunized with DCs loaded with GAA-derived peptides using enzyme-linked immuno-spot (ELISPOT), delayed-type hypersensitivity (DTH) and tetramer assays and 2) assess the preliminary anti-tumor clinical activity of the vaccines as measured by radiological response (MRI), overall survival, and four- and six-month progression-free survival (PFS).
Interventions
BIOLOGICALDendritic vaccine pulsed with multiple peptides
Subjects will receive four (4) injections of the vaccine into the lymph nodes. Injection is guided by ultrasonography. Subjects will receive the first cycle of vaccine in the right groin. Two weeks after the first vaccine, subjects receive the same vaccine at the left groin, followed by the 3rd and the 4th vaccines in the left and right armpits, respectively, with two-week intervals. Each injection contains 0.2cc (less than 1/20th of a teaspoon) of a saline solution containing the vaccine cell mixture.
BIOLOGICALThe first booster vaccine phase:
This phase will begin at week 13. These subjects will be treated with additional vaccinations every 4 weeks to a maximum of 5 vaccine injections and, if poly-ICLC is available from the supplier starting on the day of the first additional vaccine and twice/week for 8 injections following each additional vaccine. If poly-ICLC supply is not available from the supplier, DC vaccines only will be given in the booster phases.
BIOLOGICALThe second booster vaccine phase:
At week 33, following the completion of 5 additional vaccines, if participants demonstrate stable disease or positive clinical response, if poly-ICLC supply is still available, participants will be offered additional DC-vaccines and poly-ICLC treatment. The second phase booster vaccines can be continued as long as the patient shows continued positive response or stable disease (both radiological and clinically) with no major adverse events, and as long as funding is available for the study. DC vaccines in this phase will be administered every 6 months+/- 2 weeks. 2). Poly-ICLC at 10µg/kg and up to 1640 µg/injection will be administered intramuscularly (i.m.) on the day of each booster DC vaccine. Poly-ICLC will be administered weekly thereafter for twice (at one week and two weeks after each vaccine) (e.g. if the previous DC vaccine was administered on a Thursday, subsequent poly-ICLC will be administered on the next two Thursdays
Sponsors
Oncovir, Inc.
Frank Lieberman
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
* Patients must have a histologically confirmed * recurrent glioblastoma (GBM) * anaplastic astrocytoma (AA) * anaplastic oligodendroglioma (AO) * anaplastic mixed oligoastrocytoma (AMO) * other anaplastic glioma * Patients must have received prior external beam radiotherapy and/or chemotherapy unless patients refused the options. * Patients may have had treatment for no more than 2 prior relapses. Relapse is defined as progression following initial therapy (i.e. radiation +/- chemo if that was used as initial therapy). * Patients must be HLA-A2 positive. * All patients must sign an informed consent document indicating that they are aware of the investigational nature of this study. * Patients must sign an authorization for the release of their protected health information. * Patients must be \> 18 years old, and with a life expectancy \> 8 weeks. -Patients must have a Karnofsky performance status of \> 60. * Patients must have recovered from the toxic effects of prior therapy: 4 weeks from any investigational agent, 4 weeks from prior cytotoxic therapy and/or at least two weeks from vincristine, 4 weeks from nitrosoureas, 3 weeks from procarbazine administration, and 1 week for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count). Any questions related to the definition of non-cytotoxic agents should be directed to the principal investigator. * Patients must not have any disease that will obscure toxicity or dangerously alter drug metabolism. * Patients must not have any serious concurrent medical illness. * Documented negative serum beta-HCG for female patients of child-bearing age. * Patients must be free of systemic infection. Subjects with active infections (whether or not they require antibiotic therapy) may be eligible after complete resolution of the infection. Subjects on antibiotic therapy must be off antibiotics for at least 7 days before beginning treatment. * Patients must have adequate organ function as measured by: 1. Hematopoietic: * granulocytes at least 2500/mm3 * lymphocytes at least 1000/mm3 * platelets at least 100,000/mm3 * hemoglobin at least 10.0 g/dL 2. Cardiac: Asymptomatic or, if symptomatic, then left ventricular ejection fraction at rest must be at least 50% or within the normal range of the institution. A cardiology clearance will be required for LV ejection fraction 50%. 3. Hepatic: AST, ALT, GGT, LDH, Alk phos within 2.5 x upper normal limit and total bilirubin no greater than 2.0 mg/dL. 4. Renal: Serum creatinine up to 1.5 x upper normal limit. 5. Pretreatment baseline evaluations for laboratory parameters must be obtained within 10 to 18 days of subject registration.
Exclusion criteria
* Pregnant or breast-feeding. * Presence of metastatic disease. * Active bacterial, viral or fungal infections. Subjects with active infections (whether or not they require antibiotic therapy) may be eligible after complete resolution of the infection. Subjects on antibiotic therapy must be off antibiotics for at least 7 days before beginning treatment. * Chemotherapy, biologic therapy or radiation therapy less than one month prior to study entry. * History or presence of autoimmune disease. * Use of immunosuppressives within 4 weeks prior to study entry or anticipated use of immunosuppressive agents. Minimum doses of corticosteroid (dexamethasone up to 4 mg/day) is permitted. * Subjects with uncontrolled pain. -Subjects who have sensitivity to drugs to provide local anesthesia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Treatment-related Dose Limiting Toxicities (DLT) | up to 8 weeks | Number of participants who experienced treatment-related Dose Limiting Toxicities (DLT) at any dose level. |
| Median Time To Progression | At baseline, 9, 17, 25, and 33 weeks, and every 3 months; up to 23 months | Median number of months until disease progression. Tumor size was assessed using magnetic resonance imaging (MRI) scans with contrast enhancement to detect change from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 12-month- Progression Free Survival (PFS) | Up to 12 months | Number of patients with progression-free status lasting at least 12 months |
| Overall Survival (OS) | Up to 102 months | Time interval from start of treatment until date of death. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AlphaDC1 - Dose Level 1(1 X 10 7) + Poly-ICLC Patients with recurrent malignant glioma treated with novel vaccination with -type 1 polarized dendritic cells ( DC1) loaded with synthetic peptides for glioma-associated antigen (GAA) epitopes and administration of polyinosinic-polycytidylic acid \[poly(I:C)\] stabilized by lysine and arboxymethylcellulose (poly-ICLC) | 11 |
| AlphaDC1 - Dose Level 2 (3 x 10 7) + Poly-ICLC Patients with recurrent malignant glioma treated with novel vaccination with -type 1 polarized dendritic cells ( DC1) loaded with synthetic peptides for glioma-associated antigen (GAA) epitopes and administration of polyinosinic-polycytidylic acid \[poly(I:C)\] stabilized by lysine and arboxymethylcellulose (poly-ICLC) | 11 |
| Total | 22 |
Baseline characteristics
| Characteristic | AlphaDC1 - Dose Level 1(1 X 10 7) + Poly-ICLC | AlphaDC1 - Dose Level 2 (3 x 10 7) + Poly-ICLC | Total |
|---|---|---|---|
| Age, Continuous | 52 years | 46 years | 48 years |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 22 / 22 |
| serious Total, serious adverse events | 3 / 22 |
Outcome results
Primary
Median Time To Progression
Median number of months until disease progression. Tumor size was assessed using magnetic resonance imaging (MRI) scans with contrast enhancement to detect change from baseline.
Time frame: At baseline, 9, 17, 25, and 33 weeks, and every 3 months; up to 23 months
Population: Patients with recurrent malignant glioma treated with novel vaccination with type 1 polarized dendritic cells ( DC1) loaded with synthetic peptides for (GAA) epitopes and administration of polyinosinic-polycytidylic acid \[poly(I:C)\] stabilized by lysine and arboxymethylcellulose (poly-ICLC) who received at least one vaccine up to 4 vaccines
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AlphaDC1 - Dose Level 1(1 X 10^7) + Poly-ICLC | Median Time To Progression | WHO3 AG (anaplastic glioma) | 5 months |
| AlphaDC1 - Dose Level 1(1 X 10^7) + Poly-ICLC | Median Time To Progression | WHO4 GBM (glioblastoma multiforme) | 4 months |
| AlphaDC1 - Dose Level 2 (3 x 10^7) + Poly-ICLC | Median Time To Progression | WHO3 AG (anaplastic glioma) | 15 months |
| AlphaDC1 - Dose Level 2 (3 x 10^7) + Poly-ICLC | Median Time To Progression | WHO4 GBM (glioblastoma multiforme) | 4 months |
Primary
Number of Participants Who Experienced Treatment-related Dose Limiting Toxicities (DLT)
Number of participants who experienced treatment-related Dose Limiting Toxicities (DLT) at any dose level.
Time frame: up to 8 weeks
Population: Participants at any dose level, through the first booster phase.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AlphaDC1 - Dose Level 1(1 X 10^7) + Poly-ICLC | Number of Participants Who Experienced Treatment-related Dose Limiting Toxicities (DLT) | 0 Participants |
| AlphaDC1 - Dose Level 2 (3 x 10^7) + Poly-ICLC | Number of Participants Who Experienced Treatment-related Dose Limiting Toxicities (DLT) | 0 Participants |
Secondary
12-month- Progression Free Survival (PFS)
Number of patients with progression-free status lasting at least 12 months
Time frame: Up to 12 months
Population: Patients with recurrent malignant glioma treated with novel vaccination with type 1 polarized dendritic cells ( DC1) loaded with synthetic peptides for (GAA) epitopes and administration of polyinosinic-polycytidylic acid \[poly(I:C)\] stabilized by lysine and arboxymethylcellulose (poly-ICLC) who received at least one vaccine up to 4 vaccines
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AlphaDC1 - Dose Level 1(1 X 10^7) + Poly-ICLC | 12-month- Progression Free Survival (PFS) | AA (anaplastic astrocytoma) | 2 participants |
| AlphaDC1 - Dose Level 1(1 X 10^7) + Poly-ICLC | 12-month- Progression Free Survival (PFS) | AO (anaplastic oligodendroglioma) | 1 participants |
| AlphaDC1 - Dose Level 1(1 X 10^7) + Poly-ICLC | 12-month- Progression Free Survival (PFS) | AOA (anaplastic oligoastrocytoma) | 0 participants |
| AlphaDC1 - Dose Level 1(1 X 10^7) + Poly-ICLC | 12-month- Progression Free Survival (PFS) | GBM (glioblastoma multiforme) | 2 participants |
| AlphaDC1 - Dose Level 2 (3 x 10^7) + Poly-ICLC | 12-month- Progression Free Survival (PFS) | GBM (glioblastoma multiforme) | 2 participants |
| AlphaDC1 - Dose Level 2 (3 x 10^7) + Poly-ICLC | 12-month- Progression Free Survival (PFS) | AA (anaplastic astrocytoma) | 1 participants |
| AlphaDC1 - Dose Level 2 (3 x 10^7) + Poly-ICLC | 12-month- Progression Free Survival (PFS) | AOA (anaplastic oligoastrocytoma) | 1 participants |
| AlphaDC1 - Dose Level 2 (3 x 10^7) + Poly-ICLC | 12-month- Progression Free Survival (PFS) | AO (anaplastic oligodendroglioma) | 1 participants |
Secondary
Overall Survival (OS)
Time interval from start of treatment until date of death.
Time frame: Up to 102 months
Population: Patients with recurrent malignant glioma treated with novel vaccination with type 1 polarized dendritic cells ( DC1) loaded with synthetic peptides for (GAA) epitopes and administration of polyinosinic-polycytidylic acid \[poly(I:C)\] stabilized by lysine and arboxymethylcellulose (poly-ICLC) who received at least one vaccine up to 4 vaccines
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AlphaDC1 - Dose Level 1(1 X 10^7) + Poly-ICLC | Overall Survival (OS) | 32.88 months |
| AlphaDC1 - Dose Level 2 (3 x 10^7) + Poly-ICLC | Overall Survival (OS) | 13.28 months |