A Phase 2a Trial of Immune Modulation in Combination With Ultrasound-mediated Blood Brain Barrier Opening in Patients With Newly Diagnosed Glioblastoma
Sponsor: Northwestern University (other)
Phase: 2
Start date: Jan. 31, 2024
Planned enrollment: 25
Show Summary from Sponsor
Show for: Balstilimab (AGEN2034, BAL)
Balstilimab (AGEN2034; BAL) is an investigational, fully human IgG4 monoclonal antibody targeting PD‑1. It has been evaluated as monotherapy and in combination with the CTLA‑4 antibody zalifrelimab in previously treated recurrent/metastatic cervical cancer, with published phase 2 data. A U.S. BLA for second‑line cervical cancer was submitted in April 2021, accepted for Priority Review in June 2021, and voluntarily withdrawn in October 2021 after full approval of pembrolizumab in the same setting; development has continued in combinations. (pubmed.ncbi.nlm.nih.gov)
Cervical cancer (previously treated, recurrent/metastatic)
Balstilimab monotherapy (open‑label, single‑arm, phase 2; n=140 efficacy‑evaluable): Confirmed ORR 15.0% (95% CI, 10.0–21.8), including 3.6% complete responses; median duration of response (DoR) 15.4 months. ORR 20.0% in PD‑L1–positive tumors and 7.9% in PD‑L1–negative tumors. DCR 49.3%. Dosing: 3 mg/kg IV every 2 weeks (up to 24 months). (pubmed.ncbi.nlm.nih.gov)
Balstilimab + zalifrelimab (open‑label, single‑arm, phase 2; n=125 efficacy‑evaluable): Confirmed ORR 25.6% (95% CI, 18.8–33.9), with 10 complete and 22 partial responses; median DoR not reached at median follow‑up 21 months (response durability 64.2% at 12 months). ORR 32.8% in PD‑L1–positive and 9.1% in PD‑L1–negative tumors. DCR 52%. Dosing: balstilimab 3 mg/kg Q2W + zalifrelimab 1 mg/kg Q6W (up to 24 months). (pubmed.ncbi.nlm.nih.gov)
Other tumor types (early signals)
Note: Additional early‑phase combination studies with botensilimab (next‑generation CTLA‑4) have reported responses in ovarian and other solid tumors, but these are primarily from conference presentations and company communications and remain exploratory. (cancernetwork.com)
Balstilimab monotherapy (phase 2 cervical cancer): Most common grade ≥3 treatment‑related AEs were immune‑mediated enterocolitis (3.1%) and diarrhea (1.9%). Overall safety was consistent with PD‑1 inhibitors. (pubmed.ncbi.nlm.nih.gov)
Balstilimab + zalifrelimab (phase 2 cervical cancer): Grade ≥3 treatment‑related AEs occurred in 20.0%; common immune‑mediated AEs included hypothyroidism (14.2%) and hyperthyroidism (7.1%). Serious TRAEs occurred in 10.3%; three treatment‑related deaths (pneumonitis, immune‑mediated nephritis, diabetes mellitus) were reported. (ascopubs.org)
Doxorubicin + zalifrelimab + balstilimab in soft tissue sarcoma: Grade 3/4 TRAEs in 45%; immune‑mediated AEs requiring immunosuppression in 9%. (pubmed.ncbi.nlm.nih.gov)
Notes: Balstilimab is not FDA‑approved as of October 7, 2025. Efficacy and safety summaries above reflect non‑randomized trials; comparative effectiveness versus approved PD‑1 inhibitors has not been established. (investor.agenusbio.com)
Last updated: Oct 2025
Show for: Botensilimab (AGEN1181, BOT)
Botensilimab (AGEN1181; BOT) is an Fc‑engineered, next‑generation anti–CTLA‑4 monoclonal antibody being developed primarily in combination with the anti–PD‑1 antibody balstilimab (BAL). Early clinical activity has been reported across “cold” or immunotherapy‑refractory tumors, especially microsatellite‑stable (MSS) metastatic colorectal cancer (mCRC) without active liver metastases and in relapsed/refractory metastatic sarcomas. Fast Track designation has been granted by the FDA for BOT/BAL in non‑MSI‑H mCRC without active liver involvement. (pmc.ncbi.nlm.nih.gov)
Microsatellite‑stable metastatic colorectal cancer (MSS mCRC)
Relapsed/refractory metastatic sarcomas
Neoadjuvant, resectable colorectal cancer
Combination with chemotherapy
Notes: Reported efficacy in MSS mCRC is largely confined to patients without active liver metastases in early‑phase studies; definitive benefit will require results from randomized phase 3 testing. (pmc.ncbi.nlm.nih.gov)
Last updated: Oct 2025
Goal: Assess safety, feasibility, and preliminary efficacy of combining immune checkpoint modulation with ultrasound-mediated, temporary blood–brain barrier opening to enhance intratumoral drug delivery in newly diagnosed glioblastoma.
Patients: Adults (≥18) with newly diagnosed, IDH1/2–wild-type, MGMT promoter–unmethylated glioblastoma who have completed standard radiotherapy (with or without temozolomide), ECOG/WHO PS ≤2, and lesions/resection cavities amenable to coverage by the Sonocloud-9 sonication field. Key exclusions include posterior fossa disease, multifocal disease not coverable within a 50‑mm field, prior immunotherapy, uncontrolled illness or epilepsy, autoimmune disease contraindicating checkpoint inhibitors, recent other investigational agents, active non-CNS malignancy within 12 months, and pregnancy or breastfeeding.
Design: Phase 2a, single-arm, open-label study with a 6-patient safety run-in through the end of cycle 2. Approximately 25 patients will receive protocol therapy; allocation is not randomized. Treatment cycles are every 21 days for up to 9 cycles, with potential continuation if clinically beneficial.
Treatments: All patients receive implantation of the Sonocloud-9 device 1–5 weeks after completing radiotherapy. Starting 1–3 weeks post-implant, ultrasound sonication to transiently open the blood–brain barrier is performed every 3 weeks with concomitant intravenous liposomal doxorubicin 30 mg q3w and balstilimab 450 mg q3w; botensilimab 1 mg/kg is added q6w. Balstilimab is a fully human IgG4 anti–PD-1 antibody that blocks PD-1 interaction with PD-L1/PD-L2 to enhance T-cell activation and effector function. In a phase II study in recurrent/metastatic cervical cancer it produced an objective response rate of about 15% with durable responses, and in combination with CTLA-4 blockade higher response rates have been observed, indicating synergistic activity. Botensilimab is an Fc‑engineered anti–CTLA‑4 antibody designed to enhance T-cell priming and Treg depletion while reducing complement-mediated toxicity; in early-phase studies, especially in combination with balstilimab, it has shown activity across multiple solid tumors including immunotherapy‑refractory MSS colorectal cancer, with manageable immune‑related adverse events. Liposomal doxorubicin is a standard anthracycline formulation used to provide cytotoxic chemotherapy with altered pharmacokinetics and reduced peak free doxorubicin exposure. The Sonocloud-9 ultrasound emitter array enables repeated, reversible BBB opening to increase intraparenchymal delivery of co-administered agents.
Outcomes: Primary outcomes: unacceptable toxicity rate in cycle 1 (<33% within 42 days) and landmark efficacy (12- and 18-month progression-free and overall survival, plus median PFS and OS). Secondary and exploratory outcomes: response by RANO in patients with measurable disease; predictive value of baseline tissue p‑ERK expression for benefit; MRI-defined patterns of recurrence relative to the sonication field; circulating biomarkers including nucleic acids, exosomes, peripheral blood cell profiles, and ctDNA dynamics correlated with PFS.
Burden on patient: High. Patients undergo a neurosurgical implant of the Sonocloud-9 device shortly after radiotherapy, followed by frequent in-clinic visits every 3 weeks for sonication procedures synchronized with IV balstilimab and liposomal doxorubicin, and botensilimab every 6 weeks. Each treatment visit is likely prolonged due to device activation, infusion administration, and monitoring. Serial contrast-enhanced MRIs are required to quantify BBB opening and assess disease, along with repeated blood draws before and after each sonication for ctDNA and immune profiling. The initial safety run-in entails intensified monitoring through at least two cycles. Travel and time commitments are considerable, and patients are exposed to the risks of immune-related adverse events, anthracycline toxicities, and device-related or procedure-related complications.
Last updated: Oct 2025
Show Criteria
Inclusion Criteria:
* Have newly diagnosed pathologically proven glioblastoma, isocitric dehydrogenase-1/2 wild-type
* Tumor with methyl guanine methyl transferase (MGMT) gene promoter unmethylated
* Available paraffin embedded tumor tissue for the study
* Have completed standard radiotherapy with or without temozolomide
* 18 years of age or older
* Able to undergo contrast-enhanced MRI
* Have an Eastern Cooperative Oncology Group/World Health Organization performance status ≤ 2
* Size and location of the residual tumor and/or resection cavity must allow to be able to be covered by the sonication field
* Have not received any prior treatment with immunotherapeutic agents treatments for glioblastoma or other indications
* Have the ability to understand and willingness to sign a written informed consent prior to registration on study.
* Be willing and able to comply with the protocol.
* Have adequate organ and bone marrow function
* Agree to use adequate contraception if appropriate
Exclusion Criteria: Patients will be ineligible if they have:
* Multifocal tumor (unless all localized in a 50-mm diameter area accessible to ultrasound field) or tumor located in the posterior fossa.
* Uncontrolled epilepsy.
* Received other investigational agents within 2 weeks of registration
* Received prior therapy with or have history of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in this study.
* Contraindication to checkpoint inhibitor therapy (e.g., history of autoimmune disease)
* Uncontrolled illness
* History of active malignancy other than the brain tumor within 12 months prior to registration.
* Are pregnant or breastfeeding.
Chicago, Illinois, 60611, United States
[email protected] / (312) 695-8143
Status: Recruiting
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