Recurrent High Grade Gliomas, Glioblastoma (GBM), Astrocytoma, Oligodendroglioma, Diffuse Hemispheric Glioma
Conditions
Keywords
Gene therapy, Interferon beta, Intratumoral therapy, Convection-enhanced delivery, ALERT-1, SRN-101, Adeno-associated virus
Brief summary
ALERT-1 is a Phase 1/2 study evaluating the safety and preliminary anti-tumor activity of SRN-101, an investigational gene therapy, in adults with recurrent high-grade glioma. High-grade glioma is a type of brain cancer. This study is for adults whose cancer has returned for the first time and for whom surgical removal of the tumor is not planned. SRN-101 uses an adeno-associated virus (AAV) to deliver a gene for human interferon beta, a protein within the tumor. The safety and effectiveness of SRN-101 in this setting have not been established. Each participant will receive one infusion of SRN-101 directly into the brain tumor during an MRI-guided procedure. The study will first evaluate different dose levels and then evaluate a selected dose in additional participants. Participants will have MRI scans, blood tests and other health assessments, and follow-up visits to assess safety and changes in their cancer.
Detailed description
ALERT-1 is a multicenter, open-label, Phase 1/2 study of SRN-101 in adults with recurrent high-grade glioma. SRN-101 is an investigational adeno-associated virus (AAV)-based gene therapy encoding an optimized human interferon beta (hIFNβ), intended to produce local hIFNβ expression within the tumor. Each participant receives a single intratumoral infusion of SRN-101 using magnetic resonance imaging (MRI)-guided convection-enhanced delivery (CED). Part 1 evaluates the safety and tolerability of different dose levels and identifies the Recommended Phase 2 Dose (RP2D). Part 2 further evaluates SRN-101 in an expansion cohort treated at the RP2D selected in Part 1.
Interventions
GENETICSRN-101
SRN-101 is an investigational AAV-based gene therapy encoding human interferon beta (hIFNβ). SRN-101 is administered as a single intratumoral infusion using MRI-guided CED.
Sponsors
Siren Biotechnology
California Institute for Regenerative Medicine (CIRM)
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The study has two sequential parts. Part 1 includes a safety run-in and dose-escalation cohorts, with protocol-specified review of available safety data. Part 2 is an expansion cohort treated at the RP2D selected in Part 1.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* First recurrence of high-grade glioma for which surgical resection is not planned * Eligible tumor type, including Grade 3 or Grade 4 astrocytoma, Grade 3 oligodendroglioma, glioblastoma, or diffuse hemispheric glioma, with histologic confirmation of malignancy * Received prior standard treatment for high-grade glioma, including surgery followed by radiation alone or radiation with temozolomide * A single tumor located above the tentorium that is accessible for treatment with SRN-101 and is 1 to 4 centimeters in diameter * Karnofsky performance status of at least 70% * Life expectancy of at least 3 months * Recovered from the acute effects of prior anti-cancer treatment and meets required waiting periods following prior chemotherapy, radiation therapy, and major surgery * Adequate bone marrow, kidney, liver, and blood-clotting function * Willing to participate in the long-term safety follow-up study
Exclusion criteria
* Disseminated or multifocal disease * Pregnant or breastfeeding * History of or current liver disease, including active hepatitis B or hepatitis C, or human immunodeficiency virus * Receiving another tumor immunotherapy * Recent initiation or increase in systemic immunosuppressive therapy, including corticosteroids, except as permitted by the protocol * Recent neurologic dysfunction or abnormality that, in the Investigator's judgment, would prevent participation * Unable to comply with the study's safety monitoring requirements * Other medical conditions that, in the Investigator's judgment, could negatively affect the participant's ability to benefit from or tolerate the study * Unable to undergo magnetic resonance imaging (MRI)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of the safety and tolerability of SRN-101 in adult participants with recurrent high-grade glioma. | From administration of SRN-101 through 12 months after treatment | Safety and tolerability will be assessed by the frequency and severity of study-related adverse events and serious adverse events (SAEs) through study period following administration of SRN-101. Adverse events will be graded according to the NCI CTCAE and summarized by relationship to SRN-101. |
| Determination of the RP2D of SRN-101 | Through determination of the RP2D following completion of dose escalation, approximately 18 months | The RP2D of SRN-101 will be determined based on the safety and tolerability of the dose levels evaluated during Part 1, including the occurrence of dose-limiting toxicities (DLTs). Dose-escalation decisions will be made by the Sponsor following review of available safety data and recommendations from the Data Safety Monitoring Board (DSMB). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor response by Response Assessment in Neuro-Oncology (RANO) 2.0 | From baseline through disease progression or up to 12 months after SRN-101 administration | Tumor response will be assessed using RANO 2.0 criteria based on serial brain MRI and clinical status. |
| Progression-free survival | Up to 12 months | Time from SRN-101 administration to disease progression or death, whichever occurs first. |
| Clinical benefit rate | Through 6 months after SRN-101 administration | Description: Proportion of participants with complete response, partial response, or stable disease lasting 6 months. |
| Overall survival | Up to 12 months | Time from SRN-101 administration to death from any cause. |
Outcome results
None listed