Key Points
- The SONOBIRD trial is comparing the use of Carthera’s SonoCloud-9 device plus chemotherapy to standard-of-care chemotherapy.
- It is enrolling participants with a first recurrence of GBM at nearly 30 sites across Europe and the US

Almost a year ago in February 2024, Carthera launched its large comparative SonoCloud® Blood-Brain Barrier Opening for Recurrent Disease (SONOBIRD*) clinical trial (NCT 05902169) in Europe and the United States.
Carthera’s SonoCloud-9 is an implantable, therapeutic ultrasound device that was designed to open the blood-brain barrier (BBB) for improving brain exposure to circulating drugs. The SONOBIRD trial is comparing the use of Carthera’s SonoCloud-9 device plus chemotherapy to standard-of-care therapies in patients with recurrent glioblastoma (GBM).
When a GBM returns, median overall survival is less than one year. One thing that makes this disease challenging to treat is the BBB, which is a protective layer of tightly joined cells that lines the blood vessels in the brain and prevents harmful substances, such as toxins and infectious agents, from diffusing into the surrounding brain tissue. However, it can also inhibit drugs from entering the brain in high enough concentrations. The goal of this Phase III clinical trial is to prolong survival by increasing chemotherapy passage across the BBB to better control tumor growth.
With 28 sites now enrolling and new sites being added, the company is on track to enroll 560 participants within the next two years. We recently spoke with Adam Sonabend, MD, a neurosurgeon at Northwestern University in Chicago, who is a principal investigator in the study, along with Carole Desseaux, PhD, Carthera’s chief clinical officer, and Michael Canney, PhD, the company’s chief scientific officer, to learn more about the SONOBIRD trial.
HEAR FROM A PARTICIPANT IN THE TRIAL: READ LYNN’S STORY
What is the SONOBIRD clinical trial about, and what is its goal?
Dr. Sonabend: It is a randomized, phase III, comparative clinical trial that has the goal of demonstrating a survival advantage for patients with recurrent GBM when BBB opening is combined with the delivery of carboplatin chemotherapy, as compared with standard of care. The chemotherapy BBB opening procedure is repeated every three weeks during the clinical trial, up to seven cycles. That equates to up to six months of treatment.
Dr. Desseaux: The trial has two arms. One group is treated with SonoCloud plus carboplatin. The comparative arm receives standard of care using lomustine or temozolomide chemotherapy according to physician choice. We will compare survival as a primary objective and progression-free survival as secondary objective.
Trial enrollment began early in 2024. How many sites are now enrolling, and where are they?
Dr. Desseaux: We are planning for at least 40 sites to be involved in the trial. So far, nearly 30 of them have been activated. In Europe, the sites are located in Belgium, France, Germany, Italy, the Netherlands, Spain, and Switzerland (Denmark and Sweden will be added soon). In the United States, we have enrollment sites arranged in California, Colorado, Florida, Illinois, Indiana, Maryland, Minnesota, New York, North Carolina, Pennsylvania, Texas, and Utah.
Is this the largest clinical trial that Carthera has ever conducted?
Dr. Canney: Yes, and it is the largest clinical trial that has ever been done with ultrasound-mediated BBB disruption for brain drug delivery.
Is the clinical trial only for patients with recurrent GBM?
Dr. Sonabend: Yes. This trial is designed for patients who have a first recurrence of a GBM. Patients who have already been diagnosed with GBM, and who have already been treated with the standard of care (which usually involves surgical resection followed by chemotherapy and radiation), are eligible for screening. If there is a reemergence of disease, it is at this point that a patient can enroll in the clinical trial – before undergoing a second surgery. This is very important, because a patient who is interested but undergoes another line of therapy instead cannot be included per the protocol. So, it is important to think about this clinical trial early on, as soon as there is a suspicious MRI.
Also, and this is very important: GBM is defined molecularly. Participants with an IDH1 mutation on their tumors are excluded from this trial. In the past, having this mutation could still be considered GBM, but this is no longer the case.
The only other requirement is that the patient needs to be amenable to undergo a craniotomy for removal of the recurring tumor.
Besides trying other treatments and having the IDH1 mutation, what are the other exclusion criteria?
Dr. Sonabend: Importantly, the tumors must be 5 cm or less in size. This limitation is based on the size of the implanted SonoCloud device. The device must cover the entire tumor area (i.e., in 80% to 90% of cases, tumor cells can be found 1- to 2-cm around where the tumor used to be). Smaller tumors are more likely to respond to treatment. Thinking about this trial early on is important for these reasons.
What considerations are important for referring physicians?
Dr. Sonabend: In some cases, oncologists should not wait to get another confirmatory scan if they are suspicious about a recurrence. That is clinically reasonable, but there is a risk if the tumor is borderline too large that waiting further might preclude the patient from getting into the study. There are so few treatment options for recurrence, but this trial presents an opportunity to try something new.
Does the location of the tumor matter?
Dr. Sonabend: Yes, because not all GBMs that recur are operable. Tumors that are deep or are located across different parts of the brain cannot be treated in this clinical trial.
During the consent process, what are the side effects and the adverse events that you tell potential participants they could expect to experience?
Dr. Sonabend: It is important to think about three types of symptoms. The first are those that are related to the disease. A patient might have a seizure or weakness that is completely unrelated to the experimental treatment. Secondly, the symptoms and adverse events related to the ultrasound therapy and device can include skull pain during the needle insertion and transient neurological deficits. Thirdly, it is important to consider the effects of systemic chemotherapy. Those adverse events are well known in oncology, and clinicians know how to manage those symptoms.
How are patients randomized? Do they make a personal decision?
Dr. Sonabend: The randomization takes place after enrollment but before surgery. All patients who enroll in this clinical trial (both treatment groups) undergo surgery. After they have consented and enrolled, they are randomized to receive either the standard of care (in which surgery will proceed as planned followed by the chemotherapy as per their oncologist’s preference) or experimental treatment (in which surgery is planned with implantation of the SonoCloud-9 device followed by carboplatin infusion with BBB opening).
Tell us about the procedure.
Dr. Sonabend: The procedure is done in the hospital, in the operating room immediately after the tumor is resected. There is not a separate surgery: The patient is already undergoing a craniotomy surgery to remove the recurrent tumors. Instead of putting the bone back and plating it after the craniotomy for removal of the tumor, the surgeon tailors the window in the bone to fit in the SonoCloud ultrasound device. The skin is replaced over the device. After surgery, the patient goes home, and there is no major difference in the postoperative period. The patient now has an ultrasound device underneath the skin that can make, when activated, the brain more permeable to the chemotherapy.
Is the device visible after it has been implanted?
Dr. Sonabend: You cannot see the implanted device. It sits underneath the skin, and, if the patient has hair, the hair covers the device. If the patient does not have hair, they might see a small bump in the skin (which is the port). It is not something that people can see, and it does not prevent patients from undergoing MRIs. It is really not disturbing to patients.
What concerns and questions do patients have before joining the clinical trial?
Dr. Sonabend: There is an element of novelty in having an ultrasound device implanted in the skull. People need to get used to the idea that they will have hardware implanted. Patients commonly tell me the experience is better and more seamless than expected.
What is the procedure for treatment days, when participants come in for their chemotherapy and the SonoCloud device gets activated?
Dr. Sonabend: First, the patient is given the carboplatin through an i.v. in an infusion suite, as is done regularly with chemotherapy treatments.
Toward the end of the carboplatin infusion, the SonoCloud device is connected to an energy source using a needle that goes through the skin. We can numb the area if needed. When this connection is made, the ultrasound is activated.
At the same time that the ultrasound is activated, an FDA-approved microbubble formulation called DEFINITY®, used here as an off-label indication, is injected through the i.v. These microbubbles are injected at the same time that the ultrasound is activated. The patient will hear some clicks. This part of the procedure – the ultrasound activation and microbubble infusion – takes about four minutes.
Participants stay for observation for a short time before going home. If it is the first cycle of treatment, the participant undergoes an MRI scan after the sonication to confirm the BBB opening.
Do the participants feel anything during the SonoCloud part of the procedure?
Dr. Sonabend: The participants commonly experience minor neurological symptoms during the sonication. The symptoms usually depend on which part of the brain is being targeted. The participant might have slight slurred speech or slight weakness. These effects usually resolve within a few minutes to an hour.
A patient with GBM might become too sick to come in for the infusions and sonications. What are the criteria for continuing on if symptoms progress?
Dr. Sonabend: The definition of progression is per the clinical judgement of the physician according to Response Assessment in Neuro-Oncology (RANO) criteria. For the trial endpoints perspective, we also rely on RANO criteria. The clinical trial protocol offers guidance, but it needs to be matched with patient care and reality. I have had several patients across the various clinical trials who tolerated all of the treatment cycles very well, but there are definitely cases in which progression occurred during treatment. A disease evaluation scan is scheduled every few treatment cycles. If the participant has a neurological decline and progression is confirmed with a scan, the physician might stop the treatment early. I want to clarify, though, that we have seen and reported cases of pseudoprogression after the treatment cycles where there was initial enhancement that then went away. Therefore, we strongly recommend to the treating physicians that if the patient is clinically doing well, and the scan looks a little worse, it might be worth continuing to give the patient the benefit of the doubt.
How does this trial build on previous SonoCloud clinical trials?
Dr. Canney: Our phase 1/2 trial demonstrated the safety of activating all of the SonoCloud emitters and achieving a large region of BBB disruption. It also allowed us to discover the optimal sequence of giving carboplatin chemotherapy right before the activating the device. So now we are timing it so that there is very little delay between the end of the chemotherapy infusion and the activation of the device.
Dr. Sonabend: Another thing we learned from our previous clinical trials is that this procedure truly delivers chemotherapy into the brain. We have confirmed that this technology achieves a 4- to 6-fold increase in absolute drug concentrations in the brain. We even found a 5.9-fold increase in the concentration of carboplatin across several patients, and there was one case in which we saw a 9-fold increase. We can also track carboplatin concentrations over time. What we are learning is that after a few hours, there is more carboplatin in the sonicated brain than in the blood. This means we are trapping drugs that are not BBB permeable in the brain. We open the BBB, allow the drug to pass into the brain, and after the BBB is restored, the drug starts to get trapped in the brain.
Does Carthera continue to follow participants from previous clinical trials?
Dr. Sonabend: Some of the patients enrolled into the previous trial have been long-term survivors. I have at least one patient who is still alive three years from the recurrence – so that is remarkable.
How does the Carthera device compare with other types of BBB opening devices?
Dr. Canney: SonoCloud’s main advantage is its fast treatment time. Patients do not have to lay down or stay in an MRI. They can be treated in four minutes in the infusion suite at the same time that they receive chemotherapy. The treatment does not add an extra burden for the patient (as far as getting repeated treatments).
How long will take to complete enrollment?
Dr. Sonabend: It will take a couple of years. We are raising awareness, and patients are reaching out early on. Physicians are becoming engaged and learning about this option.
How can potential participants learn more about this clinical trial?
Dr. Desseaux: We will keep updating the information on clinicaltrials.gov, which also includes the key criteria and the summary of the study. We also have a public website with the names and locations of all recruiting sites plus some additional information.
Is there anything else you would like to add?
Dr. Sonabend: I really appreciate the interest from the community and the collaboration with the Focused Ultrasound Foundation and the patients. There is a lot of interest in this clinical trial, and I hope that this technology can ultimately help patients.
*SONOBIRD is an acronym. ‘SONO’ stands for SonoCloud, the ‘B’ stands for BBB, the ‘I’ is for in, and the ‘RD’ is for recurrent disease. We say, “SONO-Cloud for BBB opening in GBM recurrent disease.”
Related Stories
Recurrent Glioblastoma Clinical Trial Results of SonoCloud-9 Plus Chemotherapy April 2024
Focused Ultrasound for Glioblastoma: Carthera Launches Large Comparative Trial February 2024
Carthera’s SonoCloud-9 Device Facilitates Delivery of Chemotherapy to Glioblastomas May 2023
Carthera’s SonoCloud-9 System Designated as a Breakthrough Device June 2022
CarThera Launches New Glioblastoma Trial in Chicago January 2021
Company Profile: CarThera April 2019