AV-GBM-1 vs Control as Adjunctive Therapy After RT/TMZ for Newly Diagnosed GBM
Study Details
Study Description
Brief Summary
This is a multi-center, double-blind, 2:1 randomized phase III trial to determine whether the addition of AV-GBM-1, a therapeutic, patient-specific dendritic cell vaccine, to standard therapy increases OS of patients with a recent diagnosis of primary GBM.
The intent is to enroll approximately 726 patients for tumor collection to enroll 690 who are eligible for treatment at the time of randomization and who have granted consent for participation. Because of the lack of toxicity, there are no restrictions related to performance status or blood tests at the time of treatment. The key endpoint is OS from date of first injection after RT/TMZ; secondary endpoints are PFS from date of first injection, and OS and PFS from date of randomization prior to RT/TMZ. Date of PFS will be determined by the principal investigator at each site.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
This is a multi-center, double-blind, 2:1 randomized phase III trial to determine whether the addition of AV-GBM-1 to standard therapy increases OS of patients with a recent diagnosis of primary GBM.
Patients will sign two treatment-related consents, one for obtaining fresh tumor tissue at the time of craniotomy for the purpose of establishing a short-term tumor cell line and for awareness of subsequent leukapheresis procedure, and the other for randomization and participation in the randomized trial. As required for related medical procedures, patients will sign medical consents for craniotomy/tumor resection, and for leukapheresis to obtain monocytes for the MC control arm, or to manufacture DC.
Key eligibility criteria are (1) recovered from debulking surgery from which a short-term cell culture has been established, (2) undergone leukapheresis prior to planned concurrent RT/TMZ, from which a sufficient number of MC have been derived, (3) screened, stratified and randomized prior to starting RT/TMZ. Patients will be stratified by KPS and by whether MGMT promotor-methylated and/or IDH-mutated, then randomized 2:1 (AV-GBM-1 vs MC control).
The final products will be manufactured while the patient is being treated with RT/TMZ. After recovery from RT/TMZ, one of the study agents, either the DC-ATA AV-GBM-1 or autologous MC control, will be administered weekly for three weeks just prior to starting adjuvant TMZ, and then every four weeks concurrently with, adjuvant TMZ or second-line therapy per managing physician. Both products are admixed with adjuvant 500 mcg of GM-CSF by a local pharmacist, just prior to each injection. The pharmacist, the patient, their health care givers and local research team will be masked as to whether the patient is receiving AV-GBM-1 or MC control, which are similar in appearance. Only the AIVITA manufacturing team will be aware of randomization so that the appropriate product can be manufactured per SOPs.
The first 3 weekly SC injections of study agent will be administered prior to beginning adjuvant or salvage chemotherapy. Subsequently study agents will be injected about every 28 days as long as treatment product is available until one month before completion of follow up, which at the most will be 2.5 years from the start of injections of the study agent. Depending on the number of study agent doses available, additional leukaphereses and manufacturing of more study agent may be required if treatment is to continue up to 2.5 years. In previous trials, 8 total injections were given over 6 months.
In previous trials each patient-specific batch of DC-ATA was divided into 10 aliquots, 8 of which were intended for injection. The range of cells was from 1 to over 30 million per aliquot. However, the clinical trials have consistently suggested that 1 to 2 million cells is a sufficient dose. Therefore, for this trial each patient-specific batch of DC-ATA will be divided into aliquots containing 2 million cells (prior to cryopreservation), and after the initial series of three weekly injections, subsequent injections will be administered up to two years from the first injection. If the product is used up, a cryopreserved cell line can be re-expanded and an additional leukapheresis procedure performed in order to make more AV-GBM-1, if the patient and their physician wish to continue treatment. For patients in the control arm, this would involve collecting additional monocytes by leukapheresis. If an additional patient-specific DC-ATA or monocyte batch is required, the patient will undergo a repeat leukapheresis. For those who were randomized to AV-GBM-1, a GBM cell culture would be re-established from a cryopreserved sample of the original cell line. If for some reason the cell line cannot be reestablished, then patients randomized to the AV-GBM-1 arm would receive injections of their monocytes with GM-CSF to preserve the double-blind conditions.
Patients who are determined to have experienced PD while on study may continue AV-GBM-1 treatment in conjunction with any other standard systemic therapy as prescribed by their managing oncologist.
The intent is to enroll approximately 726 patients for tumor collection to have 690 patients who are eligible for treatment at the time of randomization and who have granted consent for participation. Because of the lack of toxicity, there are no restrictions related to performance status or blood tests at the time of treatment. The key endpoint is OS from date of first injection after RT/TMZ; secondary endpoints are PFS from date of first injection, and OS and PFS from date of randomization prior to RT/TMZ. Date of PFS will be determined by the principal investigator at each site.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: AV-GBM-1 Autologous dendritic cells loaded with autologous tumor antigens cryopreserved in CryoStor 5, and admixed 500 mcg GM-CSF diluted in saline |
Biological: AV-GBM-1
Therapeutic autologous dendritic cell vaccine
|
| Placebo Comparator: Autologous monocyte control (MC) Autologous monocytes cryopreserved in CryoStor 5, and admixed 500 mcg GM-CSF diluted in saline |
Biological: Autologous monocytes
Autologous monocyte control
|
Outcome Measures
Primary Outcome Measures
- Overall survival from date of first AV-GBM-1 injection [2.5 years]
Overall survival
Secondary Outcome Measures
- PFS from date of first AV-GBM-1 injection [2.5 years]
Progression-free survival
- PFS from date of randomization [2.5 years]
Progression-free survival
- OS from date of randomization [2.5 years]
Overall survival
- Determine and compare TEAE for both study arms [2.5 years]
Safety measurement
Eligibility Criteria
Criteria
Inclusion Criteria:
-
For tumor collection: Age >18, Presumptive diagnosis of primary GBM with plans for surgical resection, Written informed consent to provide tumor and blood and intent to proceed with leukapheresis
-
For randomization: Confirmation of GBM histology, AIVITA Biomedical confirmation of established cancer cell line and sufficient monocytes derived from PBMC during leukapheresis collection, KPS > or = 70, Planning to initiate RT/TMZ, MGMT promotor methylation classified as positive or negative, IDH mutation classified as mutated or wild-type, Written informed consent for randomization and treatment per protocol
Exclusion Criteria:
-
For tumor collection: Prior history of astrocytoma or other glial tumor, Known autoimmune disease or immunodeficiency, Known previous or current diagnosis of active HBV, HCV or HIV, Diagnosis of any other invasive cancer or disease process considered to be life-threatening within the next 5 years, Known allergy to GM-CSF
-
For randomization: Active infection or other active medical condition that could be life-threatening, Diagnosis of underlying cardiac disease that requires active medical treatment, Pregnant, Enrolled in anotehr investigational trial to receive an investigational treatment, KPS < 70, Did not meet inclusion/exclusion criteria for tumor collection
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Aivita Biomedical, Inc.
Investigators
- Study Chair: Robert O Dillman, MD, Aivita Biomedical, Inc.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CL-GBM-P02-US