Phase 2a Immune Modulation With Ultrasound for Newly Diagnosed Glioblastoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Newly Diagnosed Glioblastoma, Glioblastoma, Isocitric Dehydrogenase (IDH)-Wildtype, Gliosarcoma, Glioblastoma Multiforme

Intervention / Treatment
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* Drug: Balstilimab
* Drug: Botensilimab
* Drug: Liposomal Doxorubicin
* Device: Sonocloud-9 (SC-9)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blood-brain barrier opening with concomitant BAL, BOT, DOX<br>Patients will undergo implantation of Sonocloud-9 after completion of radiotherapy. Within 21 days after implant, ultrasound-based BBB opening with concomitant administration of DOX (30 mg) + BAL (450 mg) every 3 weeks, and BOT (dose 1mg/kg) every 6 weeks will be initiated. | Drug: Balstilimab<br>* Balstilimab 450 mg IV over 30 minutes every 3 weeks<br>* Other names: BAL;Drug: Botensilimab<br>* Botensilimab1mg/kg mg IV over 30 minutes every 6 weeks<br>* Other names: BOT;Drug: Liposomal Doxorubicin<br>* Liposomal Doxorubicin 30 mg IV over 30 minutes every 3 weeks<br>* Other names: DOX;Device: Sonocloud-9 (SC-9)<br>* Device activation of 9 ultrasound emitters during IV injection of microbubbles every 3 weeks<br>* Other names: SC-9;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Unacceptable toxicity rate | Unacceptable toxicity rate in cycle 1 of < 33% | 42 days | 
| Landmark survival analyses | Overall survival and progression-free survival at 12 and 18 months, as well as median progression-free and overall survival. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Predictive value of phospho-extracellular signal-related kinase (p-ERK) expression | Predictive value of baseline tissue p-ERK expression for response/benefit of immunotherapy | 18 months | 
| Response rate | Measurement of tumor shrinkage using Response Assessment in Neuro-oncology criteria in those with residual or tumor | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Ultrasound, Blood-brain barrier, Sonocloud, Balstilimab (BAL), Botensilimab (BOT), Doxorubicin (DOX)