Ultrasound-assisted Chemotherapy for Glioblastoma

(SC9/ABX Trial)

Overseen By Roger Stupp, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Northwestern University

Must not be taking: Enzyme-inducing antiepileptics

Disqualifiers: Uncontrolled epilepsy, Peripheral neuropathy, Active malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 7

57 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Paclitaxel is among the most active agents against glioblastoma in preclinical models. However, its clinical use has been hampered by the blood-brain barrier (BBB). In this trial we will implant a novel device with 9 ultrasound emitters allowing to temporarily and reversibly open the BBB immediately prior to chemotherapy infusion with albumin-bound paclitaxel. In the phase 1 component, increasing doses of chemotherapy will be delivered as long deemed safe based on the prior patient not experiencing severe toxicity. Once the the recommended dosing has been established, carboplatin will be added to the regimen and additional patients will be treated in order to better evaluate the antitumor efficacy of this novel treatment. The device will be implanted at the time of surgical resection of the recurrent tumor. During that procedure and when feasible, a first test dose of the chemotherapy will be administered in the operating room after sonication (procedure of activating ultrasound and opening the BBB) and tissue concentrations in different parts of the resected tumor will be measured. In select patients, the sonication procedure may occur immediately after the test dose of chemotherapy is administered. The objectives of this trial are to establish a safe and effective dose of albumin-bound paclitaxel, to demonstrate that the opening of the BBB increases chemotherapy concentration in the tumor, and to estimate how effective this treatment is in reducing the tumor burden and prolonging life.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on enzyme-inducing antiepileptics or need to continue antiplatelet therapy, you may not be eligible to participate.

Is the combination of paclitaxel and carboplatin generally safe for humans?

The combination of paclitaxel and carboplatin has been studied in various cancers, showing that it is generally well tolerated. Common side effects include low blood cell counts, hair loss, mild muscle pain, and fatigue, with some rare cases of severe allergic reactions. ^{1 2 3 4 5}

What makes ultrasound-assisted chemotherapy for glioblastoma unique?

This treatment uses ultrasound to temporarily open the blood-brain barrier, allowing higher concentrations of chemotherapy drugs like carboplatin and paclitaxel to reach the brain, which is not possible with standard intravenous delivery. ^{6 7 8 9 10}

What data supports the effectiveness of the treatment for glioblastoma?

Research shows that using ultrasound to open the blood-brain barrier can increase the concentration of carboplatin in brain tissue, potentially improving its effectiveness against glioblastoma. Additionally, carboplatin has shown some effectiveness in glioblastoma when used before radiation therapy, with a median survival of 19.2 months. ^{6 11 12 13 14}

Who Is on the Research Team?

Roger Stupp, MD

Principal Investigator

Northwestern University

Adam M Sonabend, MD

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

Adults over 18 with a specific type of brain cancer called IDH1 wild-type glioblastoma, who are fit for surgery and have had up to two prior treatments. They must not be pregnant, agree to use contraception, and have stable vital organ functions. Excluded are those with uncontrolled epilepsy, certain allergies or medical conditions that conflict with the trial's procedures.

Inclusion Criteria

It has been over 12 weeks since I finished my radiation therapy.

For patients with a childbearing potential

Be willing and able to comply with the protocol for the duration of the study

Exclusion Criteria

Have an uncontrolled intercurrent illness

Have clinical evidence of peripheral neuropathy on examination

I cannot take Abraxane or carboplatin due to health reasons.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgical Resection and Device Implantation

Eligible patients undergo craniotomy for tumor resection and implantation of the sonication device. A test dose of chemotherapy may be administered.

1 day

1 visit (in-person)

Phase 1 Treatment

Sonication and administration of albumin-bound paclitaxel every 3 weeks to establish a safe dose. Blood samples collected for circulating tumor DNA.

Until disease progression

Every 3 weeks (in-person)

Phase 2 Treatment

Addition of carboplatin to the regimen with sonication and albumin-bound paclitaxel administration every 3 weeks.

Until disease progression

Every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Paclitaxel
• Sonication for opening of blood-brain barrier

Trial Overview The trial tests if using ultrasound to open the blood-brain barrier before giving chemotherapy (albumin-bound paclitaxel followed by carboplatin) can safely improve treatment outcomes in recurrent glioblastoma patients. The study will determine safe dosages and measure how well this method delivers chemo into the tumor.

How Is the Trial Designed?

Group I: SC9/ABX (phase 1); SC9/ABX/Carboplatin (phase 2) Experimental Treatment 3 Interventions

Infusion of albumin-bound paclitaxel immediately followed by sonication using the SC9 device and microbubbles in order to open the blood-brain barrier in phase 1. In phase 2, patients will receive carboplatin immediately prior to sonication using the SC9 device and microbubbles in order to open the blood-brain barrier, then will receive albumin-bound paclitaxel upon completion of sonication.

Carboplatin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

CarThera

Industry Sponsor

Trials

6

Recruited

710+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Lantheus Medical Imaging

Industry Sponsor

Trials

57

Recruited

4,333,000+

Published Research Related to This Trial

In a study of 84 glioblastoma patients, various chemotherapy combinations including cisplatin and carboplatin showed tolerability and efficacy, with no statistically significant differences in treatment effectiveness among the groups.

Patients treated with carboplatin had a significantly longer survival time compared to those treated with BCNU, with over half of the carboplatin-treated patients alive at 18 months, indicating a beneficial effect of platinum-based chemotherapy on glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin combined with carmustine and etoposide in the treatment of glioblastoma. Boiardi, A., Silvani, A., Milanesi, I., et al.[2019]

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]

In a study involving 883 chemotherapy-naive patients with advanced-stage non-small cell lung cancer, both weekly and every-3-week schedules of paclitaxel and carboplatin showed similar efficacy in terms of response rates and survival times.

While both treatment schedules were well tolerated, the weekly schedule had a lower incidence of severe sensory neuropathy (4.4% vs. 9.1%), whereas the every-3-week schedule had a lower incidence of severe diarrhea (1.1% vs. 4.2%), highlighting the importance of considering side effects when choosing a treatment plan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. Schuette, W., Blankenburg, T., Guschall, W., et al.[2019]

In a study of 48 patients with recurrent glioblastoma, the combination of bevacizumab (BEV) and carboplatin (CBDCA) resulted in a significantly higher objective response rate of 66% compared to 24% for CBDCA alone.

Patients receiving the BEV and CBDCA combination also experienced improved progression-free survival (PFS) of 6.7 months versus 3.1 months for CBDCA alone, although overall survival (OS) showed a trend towards improvement without reaching statistical significance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The added value of bevacizumab concomitantly administered with carboplatin versus carboplatin alone in patients with recurrent glioblastomas. Kaloshi, G., Diamandi, P., Cakani, B., et al.[2017]

In a study of 25 patients with glioblastoma multiforme, neoadjuvant carboplatin chemotherapy showed promising results, with 6 partial responses and 1 complete response among those with assessable tumors, indicating its potential efficacy before radiation therapy.

The treatment was found to be feasible with modest side effects, and the median survival of 19.2 months suggests that carboplatin could be a valuable option in the management of newly diagnosed glioblastoma multiforme, warranting further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin chemotherapy before irradiation in newly diagnosed glioblastoma multiforme. Gruber, ML., Glass, J., Choudhri, H., et al.[2019]

A phase I trial showed that carboplatin and paclitaxel can be safely combined at full doses for treating advanced ovarian cancer, indicating acceptable toxicity levels for patients.

The combination therapy is moving forward to larger randomized trials to compare its effectiveness against cisplatin plus paclitaxel, with specific dosing strategies planned for optimal treatment cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and paclitaxel in ovarian cancer. Ozols, RF.[2015]

In two ongoing dose-finding studies involving 33 patients with advanced non-small cell lung cancer (NSCLC) and 11 with advanced ovarian cancer, the combination of paclitaxel and carboplatin is being tested to determine optimal dosing, with paclitaxel administered as a 3-hour infusion.

The most common side effect observed was neutropenia, but it did not lead to any infections, indicating a manageable safety profile; other side effects included hair loss and mild nausea, with no significant differences in toxicity based on the order of drug administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary results of two dose-finding studies of paclitaxel (Taxol) and carboplatin in non-small cell lung and ovarian cancers: a European Cancer Centre effort. Giaccone, G., Huizing, M., ten Bokkel Huinink, W., et al.[2015]

The combination of paclitaxel and carboplatin demonstrated a 53.3% objective response rate in 15 patients with stage III B and IV non-small cell lung cancer (NSCLC), indicating moderate efficacy in treating advanced disease.

While the regimen was associated with significant myelosuppression, including grade 3-4 granulocytopenia in 18% of treatment courses, most toxicities were manageable and well tolerated, suggesting a favorable safety profile for this chemotherapy combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer (NSCLC): a preliminary study. Ratanatharathorn, V., Jirajarus, M., Sirachainan, E., et al.[2015]

In a phase II trial involving 31 patients with nonoperable stage III and IV non-small cell lung cancer (NSCLC), the combination of paclitaxel and carboplatin showed promising efficacy, with 33% of evaluable patients achieving a partial response and 48% having stable disease.

The treatment was generally well tolerated, with manageable side effects; however, 10.7% of patients experienced grade 2/3 neutropenia, and there was one reported death due to a severe allergic reaction, indicating the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel and carboplatin in nonoperable non-small cell lung cancer. Kosmidis, P., Mylonakis, N., Fountzilas, G., et al.[2015]

In a multicenter phase II study involving 50 patients with advanced ovarian cancer who had previously undergone platinum-based chemotherapy, the combination of paclitaxel and carboplatin showed an overall response rate of 43%, indicating its efficacy in this patient population.

The treatment was generally safe, with myelosuppression being the most common severe side effect, but only one case of neutropenic fever was reported, suggesting that this regimen can be administered safely to outpatients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of the combination paclitaxel/carboplatin in patients with previously treated advanced ovarian carcinoma: a multicenter French Groupe des Investigateurs Nationaux pour l'Etude des Cancers Ovariens phase II study. Pujade-Lauraine, E., Guastalla, JP., Weber, B., et al.[2015]

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]

The study demonstrated that low-intensity pulsed ultrasound combined with intravenous microbubbles (LIPU-MB) can safely and effectively open the blood-brain barrier, allowing for increased delivery of albumin-bound paclitaxel and carboplatin to the brain in patients with recurrent glioblastoma.

In a trial involving 17 patients, LIPU-MB resulted in a significant increase in drug concentrations in the brain (3.7 times for paclitaxel and 5.9 times for carboplatin), with manageable side effects and no treatment-related deaths, supporting its potential for further clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial. Sonabend, AM., Gould, A., Amidei, C., et al.[2023]

The biomimetic nanosonosensitizer systems (MDNPs) effectively target glioblastoma (GBM) by using human GBM cell membranes to enhance drug delivery and can cross the blood-brain barrier with the help of ultrasound, improving treatment accessibility.

MDNPs not only induce cancer cell death through the generation of reactive oxygen species (ROS) but also reduce drug resistance, leading to significantly improved survival rates in mice treated with low-dose doxorubicin and ultrasound, demonstrating both efficacy and safety in repeated treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomimetic Nanosonosensitizers Combined with Noninvasive Ultrasound Actuation to Reverse Drug Resistance and Sonodynamic-Enhanced Chemotherapy against Orthotopic Glioblastoma. Chen, H., Zhang, S., Fang, Q., et al.[2023]

Citations

1. Italy pubmed.ncbi.nlm.nih.gov

Carboplatin combined with carmustine and etoposide in the treatment of glioblastoma. [2019]

2. 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]

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

Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. [2019]

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

The added value of bevacizumab concomitantly administered with carboplatin versus carboplatin alone in patients with recurrent glioblastomas. [2017]

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

Carboplatin chemotherapy before irradiation in newly diagnosed glioblastoma multiforme. [2019]

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

Carboplatin and paclitaxel in ovarian cancer. [2015]

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

Preliminary results of two dose-finding studies of paclitaxel (Taxol) and carboplatin in non-small cell lung and ovarian cancers: a European Cancer Centre effort. [2015]

8. Thailand pubmed.ncbi.nlm.nih.gov

Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer (NSCLC): a preliminary study. [2015]

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

Paclitaxel and carboplatin in nonoperable non-small cell lung cancer. [2015]

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

Efficacy and safety of the combination paclitaxel/carboplatin in patients with previously treated advanced ovarian carcinoma: a multicenter French Groupe des Investigateurs Nationaux pour l'Etude des Cancers Ovariens phase II study. [2015]

11. 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]

12. 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]

13. England pubmed.ncbi.nlm.nih.gov

Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial. [2023]

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

Biomimetic Nanosonosensitizers Combined with Noninvasive Ultrasound Actuation to Reverse Drug Resistance and Sonodynamic-Enhanced Chemotherapy against Orthotopic Glioblastoma. [2023]