Ultrasound-Assisted Chemotherapy for Glioblastoma

(SONOBIRD Trial)

Recruiting at36 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: CarThera

Must not be taking: Corticosteroids, Anticoagulants, Antiepileptics, others

Disqualifiers: Multifocal tumor, Posterior fossa tumor, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial tests a new method to treat recurrent brain cancer using an ultrasound device called SonoCloud-9. The device helps open the brain's protective barrier so that more of the chemotherapy drug carboplatin can reach the tumor. The goal is to see if this combination makes the treatment more effective. Carboplatin has been used in various studies for treating high-grade gliomas and glioblastomas, often showing modest efficacy due to low tissue concentration when delivered intravenously.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that patients on certain enzyme-inducing antiepileptic drugs must switch to another regimen. Additionally, those on anti-platelet or anticoagulation therapy may need to temporarily interrupt their medication after discussion with the sponsor.

What data supports the effectiveness of the treatment SonoCloud-9 with Carboplatin for glioblastoma?

Research shows that using ultrasound to temporarily open the blood-brain barrier can help more Carboplatin reach brain tumors, which slows tumor growth and improves survival in animal models. This method has been shown to be safe and well-tolerated in early human trials, suggesting it could make chemotherapy more effective for glioblastoma patients. ^{1 2 3 4 5}

Is ultrasound-assisted chemotherapy with carboplatin safe for humans?

Research shows that using ultrasound to help deliver carboplatin to the brain can be done safely in animal models, with no significant damage observed in healthy rats. A Phase I trial in humans is exploring the safe dose of carboplatin delivered directly into the brain, which suggests careful monitoring is needed to ensure safety. ^{1 2 6 7 8}

What makes ultrasound-assisted chemotherapy with carboplatin unique for treating glioblastoma?

This treatment is unique because it uses ultrasound to temporarily open the blood-brain barrier (a protective layer that prevents many drugs from entering the brain), allowing higher concentrations of carboplatin to reach the brain and potentially improve its effectiveness against glioblastoma. ^{1 4 8 9 10}

Research Team

Eligibility Criteria

Adults over 18 with confirmed glioblastoma who've had prior surgery, radiotherapy, and chemotherapy can join. They must have a tumor that's grown after treatment but is less than 5 cm wide. Participants need good organ function, no severe allergies to trial drugs or device components, and not be on certain medications like anti-platelet drugs.

Inclusion Criteria

Adequate hematologic, hepatic, and renal laboratory values within 14 days of inclusion

I agree to use condoms and not donate sperm during treatment.

Patient of childbearing potential must have a negative pregnancy test within 14 days of inclusion and must agree to use a medically-acceptable method of birth control

Exclusion Criteria

I am at risk of getting an infection at my surgery site.

I do not have uncontrolled seizures or signs of high pressure inside my skull.

I do not have any serious health or mental conditions that could affect my treatment.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either SonoCloud-9 with Carboplatin or standard chemotherapy (TMZ or CCNU). SonoCloud-9 with Carboplatin is administered every 3 weeks for up to 7 cycles, while TMZ is given every 4 weeks for up to 6 cycles, and CCNU every 6 weeks for up to 4 cycles.

Up to 24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, with survival status collected during the treatment period and every 3 months thereafter.

Up to 24 months

Long-term follow-up

Participants continue to be monitored for overall survival and progression-free survival every 3 months as part of standard care follow-up.

Long-term

Treatment Details

Interventions

• Carboplatin (Chemotherapy)
• SonoCloud-9 (SC9) (Device)

Trial Overview The trial tests if using SonoCloud-9 (SC9), an ultrasound device designed to temporarily open the blood-brain barrier (BBB), increases the effectiveness of Carboplatin in treating recurrent glioblastoma compared to standard chemotherapies Lomustine or Temozolomide alone.

Participant Groups

Group I: Experimental Arm: SonoCloud-9 Ultrasound + Carboplatin Experimental Treatment 2 Interventions

The SonoCloud-9 (SC9) device will be implanted in the skull bone window upon completion of tumor resection and routine craniotomy. Carboplatin (CBDCA) will be administered intravenously prior to sonication. The CBDCA/SC9 treatment will be repeated every 3 weeks (depending on patient's tolerability) until disease progression or as clinically indicated. Administration of up to 7 cycles is planned.

Group II: Control Arm: SoC single agent chemotherapy TMZ or CCNU Active Control 2 Interventions

Standard of Care (SoC) treatment with either temozolomide (TMZ) or lomustine (CCNU). Standard TMZ chemotherapy as a single oral dose every 4 weeks for up to 6 cycles. Standard CCNU chemotherapy as a single oral dose every 6 weeks for up to 4 cycles.

Carboplatin is already approved in Canada for the following indications:

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

CarThera

Lead Sponsor

Trials

6

Recruited

710+

Findings from Research

Using ultrasound to open the blood-brain barrier significantly increased the concentration of carboplatin in brain tissue by 5.2 times in the targeted area, suggesting a more effective delivery method for treating glioblastoma.

This method of enhancing drug delivery is currently being evaluated in a phase 1 clinical trial, indicating its potential as a promising approach for improving treatment outcomes in patients with aggressive brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced brain distribution of carboplatin in a primate model after blood-brain barrier disruption using an implantable ultrasound device. Goldwirt, L., Canney, M., Horodyckid, C., et al.[2016]

Using focused ultrasound (FUS) to disrupt the blood-brain barrier (BBB) in rats allowed for significantly enhanced delivery of carboplatin to brain tumors, increasing drug concentrations in tumor tissue by up to 7.3 times without causing neurotoxicity.

Rats treated with FUS and carboplatin showed a 96% increase in tumor volume doubling time and a 48% increase in median survival compared to those receiving carboplatin alone, indicating a promising approach for improving treatment outcomes in brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acoustic feedback enables safe and reliable carboplatin delivery across the blood-brain barrier with a clinical focused ultrasound system and improves survival in a rat glioma model. McDannold, N., Zhang, Y., Supko, JG., et al.[2020]

The study demonstrates the successful use of a novel implantable convection-enhanced delivery (CED) system for carboplatin in a patient with recurrent glioblastoma, showing precise catheter placement and well-tolerated drug infusions.

Follow-up MRI results indicated a significant reduction in tumor volume from 42.6 ml to 24.6 ml after treatment, suggesting that CED of carboplatin may improve clinical outcomes for glioblastoma patients by effectively bypassing the blood-brain barrier.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel implantable catheter system with transcutaneous port for intermittent convection-enhanced delivery of carboplatin for recurrent glioblastoma. Barua, NU., Hopkins, K., Woolley, M., et al.[2022]

Combining carboplatin chemotherapy with ultrasound-induced blood-brain barrier opening (US-BBB) significantly improved survival and delayed tumor growth in mouse models of glioblastoma, with a 4.2-fold increase in drug penetration into the brain.

The treatment showed no significant neurological or systemic toxicity, suggesting that US-BBB could be a safe and effective method to enhance the delivery of chemotherapy for glioblastoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temporary blood-brain barrier disruption by low intensity pulsed ultrasound increases carboplatin delivery and efficacy in preclinical models of glioblastoma. Dréan, A., Lemaire, N., Bouchoux, G., et al.[2020]

The interim results from a phase 1/2a clinical trial involving patients with recurrent glioblastoma show that using pulsed ultrasound to disrupt the blood-brain barrier (BBB) is safe and well tolerated, with no detectable adverse effects observed during MRI or clinical examinations.

This method, which combines pulsed ultrasound with systemic microbubble injection, effectively increases drug delivery to the brain and has the potential to enhance the efficacy of chemotherapy treatments like carboplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Carpentier, A., Canney, M., Vignot, A., et al.[2017]

A phase I dose-escalation study is being conducted to evaluate the safety and maximum tolerated dose of carboplatin delivered directly into the brain using convection-enhanced delivery (CED) in patients with recurrent glioblastoma multiforme (GBM), involving 18 patients divided into 6 cohorts.

Carboplatin is chosen for this method because glioblastoma cells are sensitive to it at non-toxic levels for normal brain tissue, potentially improving treatment efficacy while minimizing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of carboplatin administered by convection-enhanced delivery to patients with recurrent/progressive glioblastoma multiforme. White, E., Bienemann, A., Taylor, H., et al.[2021]

In a study of 56 patients with newly diagnosed glioblastoma, treatment with radiotherapy and concurrent carboplatin plus teniposide followed by carmustine resulted in a median survival time of 12.5 months and a time to progression of 7.5 months.

The treatment was generally well-tolerated, with acceptable levels of toxicity, although 7.1% of patients experienced radiation necrosis, indicating that while the regimen is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and teniposide concurrent with radiotherapy in patients with glioblastoma multiforme: a phase II study. Brandes, AA., Rigon, A., Zampieri, P., et al.[2020]

A Phase I clinical trial involving 10 patients with recurrent high-grade gliomas demonstrated that intracerebral convection-enhanced delivery (CED) of carboplatin is feasible and safe at doses up to 4μg over 72 hours, with only one possible adverse event reported.

The median progression-free survival (PFS) and overall survival (OS) after treatment were 2.1 months and 9.6 months, respectively, indicating that while the treatment is safe, further studies are needed to assess its efficacy in improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of intracerebral convection-enhanced delivery of carboplatin for treatment of recurrent high-grade gliomas. Wang, JL., Barth, RF., Cavaliere, R., et al.[2021]

Low-intensity pulsed ultrasound (LIPU) significantly enhances the delivery of paclitaxel across the blood-brain barrier, increasing drug concentration in the brain by 3- to 5-fold, which improves treatment efficacy for glioma.

Among the two formulations tested, albumin-bound paclitaxel (ABX) not only extended survival in glioma models but also showed better tolerability compared to paclitaxel dissolved in cremophor (CrEL-PTX), making ABX the preferred option for future clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrasound-mediated Delivery of Paclitaxel for Glioma: A Comparative Study of Distribution, Toxicity, and Efficacy of Albumin-bound Versus Cremophor Formulations. Zhang, DY., Dmello, C., Chen, L., et al.[2021]

In a clinical trial involving 21 patients with recurrent glioblastoma, the use of the SonoCloud-1 device to transiently disrupt the blood-brain barrier (BBB) before chemotherapy with carboplatin was well tolerated, with only manageable and transient side effects observed.

Patients who experienced clear BBB disruption had significantly better outcomes, with a median progression-free survival of 4.11 months and overall survival of 12.94 months, compared to those with poor disruption, highlighting the potential of LIPU to enhance drug delivery in brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Feasibility of Repeated and Transient Blood-Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma. Idbaih, A., Canney, M., Belin, L., et al.[2019]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Enhanced brain distribution of carboplatin in a primate model after blood-brain barrier disruption using an implantable ultrasound device. [2016]

2. Australia pubmed.ncbi.nlm.nih.gov

Acoustic feedback enables safe and reliable carboplatin delivery across the blood-brain barrier with a clinical focused ultrasound system and improves survival in a rat glioma model. [2020]

3. England pubmed.ncbi.nlm.nih.gov

A novel implantable catheter system with transcutaneous port for intermittent convection-enhanced delivery of carboplatin for recurrent glioblastoma. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Temporary blood-brain barrier disruption by low intensity pulsed ultrasound increases carboplatin delivery and efficacy in preclinical models of glioblastoma. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Clinical trial of blood-brain barrier disruption by pulsed ultrasound. [2017]

6. United States pubmed.ncbi.nlm.nih.gov

A phase I trial of carboplatin administered by convection-enhanced delivery to patients with recurrent/progressive glioblastoma multiforme. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Carboplatin and teniposide concurrent with radiotherapy in patients with glioblastoma multiforme: a phase II study. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Phase I trial of intracerebral convection-enhanced delivery of carboplatin for treatment of recurrent high-grade gliomas. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Ultrasound-mediated Delivery of Paclitaxel for Glioma: A Comparative Study of Distribution, Toxicity, and Efficacy of Albumin-bound Versus Cremophor Formulations. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Safety and Feasibility of Repeated and Transient Blood-Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma. [2019]