Phase 2a Immune Modulation With Ultrasound for Newly Diagnosed Glioblastoma

NCT ID: NCT05864534

Last Updated: 2025-10-03

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-01-31
• Study Completion Date: 2026-08-31

Brief Summary

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

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.

Conditions

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Blood-brain barrier opening with concomitant BAL, BOT, DOX

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.

Group Type: EXPERIMENTAL

Balstilimab

Intervention Type: DRUG

Balstilimab 450 mg IV over 30 minutes every 3 weeks

Botensilimab

Intervention Type: DRUG

Botensilimab1mg/kg mg IV over 30 minutes every 6 weeks

Liposomal Doxorubicin

Intervention Type: DRUG

Liposomal Doxorubicin 30 mg IV over 30 minutes every 3 weeks

Sonocloud-9 (SC-9)

Intervention Type: DEVICE

Device activation of 9 ultrasound emitters during IV injection of microbubbles every 3 weeks

Interventions

Balstilimab

Balstilimab 450 mg IV over 30 minutes every 3 weeks

Intervention Type: DRUG

Botensilimab

Botensilimab1mg/kg mg IV over 30 minutes every 6 weeks

Intervention Type: DRUG

Liposomal Doxorubicin

Liposomal Doxorubicin 30 mg IV over 30 minutes every 3 weeks

Intervention Type: DRUG

Sonocloud-9 (SC-9)

Device activation of 9 ultrasound emitters during IV injection of microbubbles every 3 weeks

Intervention Type: DEVICE

Other Intervention Names

BAL; BOT; DOX; SC-9

Eligibility 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

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Agenus Inc.

INDUSTRY

Sponsor Role: collaborator

CarThera

INDUSTRY

Sponsor Role: collaborator

Northwestern University

OTHER

Sponsor Role: lead

Responsible Party

Adam M Sonabend

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Adam Sonabend, MD

Role: PRINCIPAL_INVESTIGATOR

Northwestern University

Roger Stupp, MD

Role: STUDY_DIRECTOR

Northwestern University

Locations

Northwestern University

Chicago, Illinois, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Neurological Surgery

Role: CONTACT

braintumortrials@nm.org

(312) 695-8143

Facility Contacts

Neurological Surgery

Role: primary

braintumortrials@nm.org

(312) 695-8143

References

Das R, Verma R, Sznol M, Boddupalli CS, Gettinger SN, Kluger H, Callahan M, Wolchok JD, Halaban R, Dhodapkar MV, Dhodapkar KM. Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. J Immunol. 2015 Feb 1;194(3):950-9. doi: 10.4049/jimmunol.1401686. Epub 2014 Dec 24.

Reference Type: BACKGROUND

PMID: 25539810 (View on PubMed)

O'Malley DM, Oaknin A, Monk BJ, Selle F, Rojas C, Gladieff L, Berton D, Leary A, Moore KN, Estevez-Diz MDP, Hardy-Bessard AC, Alexandre J, Opperman CP, de Azevedo CRAS, Randall LM, Feliu WO, Ancukiewicz M, Ray-Coquard I. Phase II study of the safety and efficacy of the anti-PD-1 antibody balstilimab in patients with recurrent and/or metastatic cervical cancer. Gynecol Oncol. 2021 Nov;163(2):274-280. doi: 10.1016/j.ygyno.2021.08.018. Epub 2021 Aug 25.

Reference Type: BACKGROUND

PMID: 34452745 (View on PubMed)

Treat LH, McDannold N, Zhang Y, Vykhodtseva N, Hynynen K. Improved anti-tumor effect of liposomal doxorubicin after targeted blood-brain barrier disruption by MRI-guided focused ultrasound in rat glioma. Ultrasound Med Biol. 2012 Oct;38(10):1716-25. doi: 10.1016/j.ultrasmedbio.2012.04.015. Epub 2012 Jul 19.

Reference Type: BACKGROUND

PMID: 22818878 (View on PubMed)

Beccaria K, Sabbagh A, de Groot J, Canney M, Carpentier A, Heimberger AB. Blood-brain barrier opening with low intensity pulsed ultrasound for immune modulation and immune therapeutic delivery to CNS tumors. J Neurooncol. 2021 Jan;151(1):65-73. doi: 10.1007/s11060-020-03425-8. Epub 2020 Feb 28.

Reference Type: BACKGROUND

PMID: 32112296 (View on PubMed)

Duerinck J, Schwarze JK, Awada G, Tijtgat J, Vaeyens F, Bertels C, Geens W, Klein S, Seynaeve L, Cras L, D'Haene N, Michotte A, Caljon B, Salmon I, Bruneau M, Kockx M, Van Dooren S, Vanbinst AM, Everaert H, Forsyth R, Neyns B. Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial. J Immunother Cancer. 2021 Jun;9(6):e002296. doi: 10.1136/jitc-2020-002296.

Reference Type: BACKGROUND

PMID: 34168003 (View on PubMed)

Shimozaki K, Sukawa Y, Sato Y, Horie S, Chida A, Tsugaru K, Togasaki K, Kawasaki K, Hirata K, Hayashi H, Hamamoto Y, Kanai T. Analysis of risk factors for immune-related adverse events in various solid tumors using real-world data. Future Oncol. 2021 Jul;17(20):2593-2603. doi: 10.2217/fon-2020-0861. Epub 2021 Apr 21.

Reference Type: BACKGROUND

PMID: 33878916 (View on PubMed)

Kim KS, Habashy K, Gould A, Zhao J, Najem H, Amidei C, Saganty R, Arrieta VA, Dmello C, Chen L, Zhang DY, Castro B, Billingham L, Levey D, Huber O, Marques M, Savitsky DA, Morin BM, Muzzio M, Canney M, Horbinski C, Zhang P, Miska J, Padney S, Zhang B, Rabadan R, Phillips JJ, Butowski N, Heimberger AB, Hu J, Stupp R, Chand D, Lee-Chang C, Sonabend AM. Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated blood-brain barrier opening: A novel combinatorial immunotherapy regimen for gliomas. Neuro Oncol. 2024 Nov 4;26(11):2044-2060. doi: 10.1093/neuonc/noae135.

Reference Type: DERIVED

PMID: 39028616 (View on PubMed)

Other Identifiers

NU23C03

Identifier Type: -

Identifier Source: org_study_id