A Phase 2a Trial of Immune Modulation in Combination With Ultrasound-mediated Blood Brain Barrier Opening in Patients With Newly Diagnosed Glioblastoma

Brain tumor treatment is hampered by the blood-brain barrier (BBB). This barrier prevents drugs carried in the bloodstream from getting into the brain. If the BBB can be opened, making it temporarily more permeable, drugs may able to better reach the brain tumor. In this trial we will implant a novel device with 9 ultrasound emitters, allowing temporary and reversible opening of the BBB to maximize brain penetration of drugs that modulate the immune system. The device will be implanted after radiation is completed. Immune modulating drugs will be given every 3 weeks in conjunction with activation of the device to open the BBB. The objectives of this trial are to establish whether it is safe and feasible to administer immune modulating drugs in this manner, and identify whether the treatment is effective in treating glioblastoma.

More details:

Eligible patients will undergo implant of the Soncloud-9 device within 1-5 weeks of completion of radiotherapy. About 1-3 weeks after surgery, patients will undergo sonication and intravenous administration of balstilimab, botensilimab and liposomal doxorubicin. Brain MRI will be done to quantify extent of blood brain barrier opening. The dose for balstilimab is 450 mg every 3 weeks. The dose for botensilimab is 1mg/kg every 6 weeks. The dose for liposomal doxorubicin is 30 mg every 3 weeks. Sonication and administration of study agents will continue every 3 weeks (21 days= 1 cycle) for a total of 9 cycles (approx. 6 months). Additional cycles may be considered if deemed beneficial and in the patient's best interest. Blood samples for circulating tumor DNA will also be collected before and after each sonication. The first 6 patients will comprise a safety run-in cohort with intensified safety monitoring through the end of the second cycle.

Balstilimab (AGEN2034, BAL) is a fully human monoclonal IgG4 antibody that binds with high affinity to programmed death 1 (PD-1), preventing its interaction with PD-L1 and PD-L2 ligands. The drug is designed to enhance T cell activation and effector function [1]. It is being developed by Agenus Inc. as both a monotherapy and in combination with other immunotherapy agents, particularly botensilimab (an anti-CTLA-4 antibody).

Clinical Trial Results

As a monotherapy, balstilimab showed activity in a phase II trial for recurrent/metastatic cervical cancer, with an objective response rate (ORR) of 15% and median duration of response of 15.4 months. In PD-L1 positive patients with squamous cell carcinoma, the ORR was 21%. The drug also showed some activity in PD-L1 negative patients [2]. When combined with zalifrelimab (anti-CTLA-4), the ORR increased to 25.6% in cervical cancer patients, with a disease control rate of 52% [3].

Safety Profile

The safety profile appears manageable based on clinical trials. In combination therapy with zalifrelimab for cervical cancer, the most common treatment-related adverse events were hypothyroidism (16.8%), diarrhea (14.2%), fatigue (11.6%), and nausea (9.0%) [3]. Development history includes a withdrawn BLA for cervical cancer in 2021, but the drug continues to be studied in various combinations and indications, particularly with botensilimab in colorectal cancer and other solid tumors [4].

Sources:

[1] Phase II Trial Results in Journal of Clinical Oncology [2] Clinical Trial Results in Gynecologic Oncology [3] Phase II Combination Trial Results in Journal of Clinical Oncology [4] Recent Development Update from BioSpace

Last updated: Dec 2024

Botensilimab is an investigational Fc-enhanced anti-CTLA-4 monoclonal antibody being developed by Agenus Inc. for cancer immunotherapy. It is designed to boost both innate and adaptive anti-tumor immune responses through multiple mechanisms: enhanced T cell priming and activation, depletion of regulatory T cells (Tregs) in the tumor microenvironment, activation of myeloid cells, and induction of long-term memory responses [1]. The drug's novel Fc-enhanced design allows it to bind more effectively to both high and low-affinity FcγRIIIA variants, potentially extending its benefits to a broader patient population compared to first-generation CTLA-4 inhibitors. Additionally, botensilimab is engineered to reduce complement-mediated toxicity through reduced C1q binding [2].

Clinical Efficacy

The drug has shown promising results in clinical trials, particularly in combination with the PD-1 inhibitor balstilimab. In a phase 1 trial of patients with microsatellite stable (MSS) metastatic colorectal cancer without liver metastases, the combination achieved a 23% objective response rate with a median overall survival of 21.2 months [3]. More recently, in the neoadjuvant NEST-1 trial for resectable colorectal cancer, the combination showed impressive pathologic response rates, with tumor shrinkage of ≥50% observed in 67.5% of MSS CRC patients [4]. The drug has demonstrated clinical responses across nine different types of metastatic, late-line cancers, including traditionally immunotherapy-resistant tumors.

Safety

The safety profile of botensilimab appears manageable based on clinical trial data. In the phase 1 trial combining botensilimab with balstilimab, the most common treatment-related adverse events were diarrhea/colitis, fatigue, and decreased appetite. Grade 3-4 adverse events occurred in approximately 39% of patients, with diarrhea/colitis being the most frequent serious adverse event. Notably, unlike some other CTLA-4 inhibitors, no cases of hypophysitis were reported in the monotherapy arm, which may be attributed to the drug's reduced complement activation [2]. As of 2024, approximately 1100 patients have been treated with botensilimab in phase 1 and phase 2 clinical trials.

Sources:

[1] Cancer Discovery Article on Botensilimab Mechanism and Clinical Results [2] OncoDaily Detailed Review of Botensilimab [3] Phase 1 Trial Results in OncoLive [4] NEST-1 Trial Results Press Release

Last updated: Dec 2024

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.