Ultrasound Techniques for Detecting Immunotherapy Response in Solid Tumors

Overseen By Christian R Hoerner

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Stanford University

Must be taking: ICI therapy

Disqualifiers: Hypersensitivity to sulfur hexafluoride, others

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

Compensation: Varies

Number of Visits: 3

Duration: 6 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if ultrasound techniques can predict how well solid tumors respond to immunotherapy, a treatment that helps the immune system fight cancer. Researchers seek to identify whether changes in blood flow to the tumor, observed through various ultrasound methods like contrast-enhanced ultrasound (CEUS) and Doppler ultrasound, can indicate early signs of treatment effectiveness. The study seeks participants with solid tumors larger than 1 cm who are about to begin immunotherapy. Participants must have a tumor that can be imaged with ultrasound. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research that could enhance cancer treatment strategies.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It is best to discuss this with the trial coordinators or your doctor.

What prior data suggests that these ultrasound techniques are safe for detecting immunotherapy response in solid tumors?

A previous study found that contrast-enhanced ultrasound (CEUS) is safe and well-tolerated, even in children with cancer, suggesting it is likely safe for adults too. Research shows that CEUS provides a non-invasive method to diagnose and monitor tumors.

Studies have shown that Doppler ultrasound effectively checks blood flow in tissues and usually does not cause harm, making it a reliable choice for observing changes in tumors.

Specific information about the safety of Long Ensemble Angular-coherence Doppler (LEAD) ultrasound is limited. However, it resembles other Doppler methods, which are generally safe.

Researchers are studying these ultrasound techniques to assess their ability to predict responses to cancer treatment. They have shown promise without major safety concerns. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about these ultrasound techniques because they offer a non-invasive way to monitor how well immunotherapy is working in solid tumors. Unlike current methods like CT or MRI scans, which can be costly and time-consuming, these ultrasound techniques—Contrast-enhanced ultrasound (CEUS), Doppler ultrasound, and Long Ensemble Angular-coherence Doppler (LEAD) ultrasound—can provide real-time feedback quickly and safely. This means doctors can potentially adjust treatments sooner, leading to better patient outcomes. Overall, these ultrasound methods could revolutionize how we track the effectiveness of cancer treatments, making it easier to personalize care for each patient.

What evidence suggests that these ultrasound techniques are effective for detecting immunotherapy response in solid tumors?

Research has shown that contrast-enhanced ultrasound (CEUS) is a promising method for assessing how well solid tumors respond to treatment. In previous studies, CEUS demonstrated a decrease in blood flow to the tumor after treatment, indicating a positive response to therapy. This trial will monitor participants using ultrasound techniques, including CEUS and Doppler ultrasound, while they receive standard immune checkpoint inhibitors. Doppler ultrasound observes changes in the tumor's blood vessels, which may reveal how the immune system interacts with the tumor. These techniques offer a non-invasive way to monitor the effectiveness of cancer treatments, potentially leading to better care and outcomes for patients. ^{2 6 7 8 9}

Who Is on the Research Team?

Aya Kamaya, MD

Principal Investigator

Stanford University

Alice C. Fan, MD

Principal Investigator

Stanford University

Jeremy Dahl, Ph.D

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for adults with a confirmed cancer diagnosis who are about to start treatment with immunotherapy drugs like ipilimumab plus nivolumab. They must have at least one solid tumor lesion larger than 1 cm that can be seen on an ultrasound. People allergic to sulfur hexafluoride lipid microsphere or PEG, or those with other serious health issues, cannot participate.

Inclusion Criteria

My cancer diagnosis has been confirmed by lab tests.

Subjects may participate in the study more than once at the discretion of the Protocol Director, for example, if they receive different lines of treatment that all qualify for the study.

I am scheduled for immune checkpoint inhibitor therapy.

Exclusion Criteria

Any comorbid condition that, in the opinion of the treating provider or the Protocol Directors, compromises the participant's ability to participate in the study

I am allergic to sulfur hexafluoride lipid microsphere or PEG.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive standard of care immune checkpoint inhibitor and are followed with ultrasound studies at treatment baseline, 3 weeks, and 6 weeks

6 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments of tumor burden and progression-free survival

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Contrast-enhanced ultrasound (CEUS)
• Doppler ultrasound
• Long Ensemble Angular-coherence Doppler [LEAD] ultrasound

Trial Overview

The study aims to see if early changes in blood flow within tumors, as shown by different types of ultrasound (Doppler, LEAD, and contrast-enhanced), can predict how well the treatment works after three weeks. It also looks at which ultrasound method and timing might best forecast treatment response and survival without disease progression over 12 months.

How Is the Trial Designed?

Group I: Ultrasound Experimental Treatment 3 Interventions

Patients receiving standard of care immune checkpoint inhibitor are followed with the ultrasound studies at treatment baseline, 3 weeks and 6 weeks.

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a pilot study involving 14 women with confirmed breast cancer, contrast-enhanced ultrasound (CEUS) effectively distinguished between malignant tumors and normal tissue by analyzing blood flow dynamics.

CEUS showed a significantly higher peak intensity in tumor tissue compared to normal tissue, indicating its potential as a reliable imaging technique for evaluating response to neoadjuvant treatment in breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contrast-enhanced ultrasound of breast tumors: an initial experience. Kristiansen, MU., Martiniussen, MA., Larsen, ASF.[2022]

In a study of 66 patients with unresectable hepatocellular carcinoma (HCC) undergoing combined immune checkpoint inhibitor and anti-angiogenesis therapies, certain contrast-enhanced ultrasound (CEUS) parameters were found to significantly differ between responders and non-responders, indicating their potential as predictive tools for treatment efficacy.

The rising time (RT) ratio was identified as the only independent factor associated with treatment response, with a median RT ratio of 36.9 for responders compared to 58.9 for non-responders, suggesting that lower RT ratios correlate with better progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative Parameters of Contrast-Enhanced Ultrasound Predicting the Response to Combined Immune Checkpoint Inhibitor and Anti-angiogenesis Therapies for Unresectable Hepatocellular Carcinoma. Zhang, Y., Zheng, R., Liu, M., et al.[2023]

In a study of breast cancer patients receiving neoadjuvant chemotherapy, high-frequency ultrasound effectively assessed tumor response, showing a consistent decrease in tumor volume after each treatment cycle.

Patients treated with Paclitaxel demonstrated a better response in terms of complete and partial tumor responses compared to those receiving the CAF regimen, indicating that Paclitaxel may be more effective for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of response of neoadjuvant chemotherapy in carcinoma breast patients by high-frequency ultrasound. Dighe, S., Shinde, R., Shinde, S., et al.[2022]

In a study of nine patients with immune checkpoint inhibitor (ICI)-induced inflammatory arthritis, musculoskeletal ultrasound revealed synovitis in 12 out of 18 assessed joints, indicating significant joint inflammation associated with cancer immunotherapy.

Tendon involvement was also common, with tenosynovitis and tendinitis observed in 13 of the 18 joints, while bony erosions were less frequent, suggesting a complex range of inflammatory changes in patients undergoing ICI treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sonographic Findings in Inflammatory Arthritis Secondary to Immune Checkpoint Inhibition: A Case Series. Albayda, J., Dein, E., Shah, AA., et al.[2022]

In a study of 53 cancer patients treated with anti-PD1 antibodies, medical imaging successfully detected 74% of immune-related adverse events (irAEs), highlighting its effectiveness in monitoring treatment side effects.

Different imaging techniques showed varying detection rates, with positron emission tomography (PET) and magnetic resonance imaging (MRI) both identifying 83% of irAEs, suggesting that these methods are particularly useful for assessing complications from anti-PD1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Detection of immune-related adverse events by medical imaging in patients treated with anti-programmed cell death 1. Mekki, A., Dercle, L., Lichtenstein, P., et al.[2019]

In a study of 24 patients with unresectable hepatocellular carcinoma (HCC) treated with tyrosine kinase inhibitors and anti-PD-1 therapy, contrast-enhanced ultrasound (CEUS) was found to be as effective as contrast-enhanced MRI/CT in evaluating treatment response, showing a high degree of agreement in assessing tumor necrosis.

CEUS demonstrated superior performance compared to unenhanced ultrasound in determining treatment outcomes, although there was poor agreement between traditional RECIST criteria and the modified RECIST used with CEUS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response Evaluation Using Contrast-Enhanced Ultrasound for Unresectable Advanced Hepatocellular Carcinoma Treated With Tyrosine Kinase Inhibitors Plus Anti-PD-1 Antibody Therapy. Zhao, CK., Guan, X., Pu, YY., et al.[2023]

In a study of 30 patients with locally advanced breast cancer, contrast-enhanced ultrasound (CEUS) showed that changes in quantitative parameters like peak enhancement (PE), time-to-peak (TTP), and mean transit time (MTT) can effectively predict responses to neoadjuvant chemotherapy (NACT).

Responders to NACT exhibited significant changes in CEUS parameters after each treatment cycle, with TTP showing a diagnostic accuracy of 87.2% after the third cycle, suggesting that CEUS could help tailor chemotherapy regimens and improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contrast enhanced ultrasound quantitative parameters for assessing neoadjuvant chemotherapy response in patients with locally advanced breast cancer. Sharma, A., Grover, SB., Mani, C., et al.[2022]

In a study of 3,521 cancer patients, those treated with the immune checkpoint inhibitor ipilimumab (Ipi) and cytokines experienced a significantly higher incidence of acute adverse reactions (ARs) to iodinated contrast media (ICM) during contrast-enhanced computed tomography (CECT) scans, with rates of 12% and 5%, respectively, compared to just 2% in patients receiving standard chemotherapy.

These findings suggest that cancer immunotherapy increases the risk of allergic-like immediate ARs to ICM, highlighting the need for radiologists to closely monitor patients who have undergone immunotherapy to mitigate the risk of severe reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased frequency of acute reactions to iodinated contrast media in cancer patients treated with anti-CTLA-4 immunomodulatory antibodies. Ridolfi, L., De Rosa, F., Petracci, E., et al.[2018]

In a study of 21 lymphoma patients, B-mode ultrasound (B-US) effectively predicted treatment response, showing a median lymphoma shrinkage of 34% in patients achieving complete remission (CR) by day 30.

Contrast-enhanced ultrasound (CEUS) did not provide additional predictive value for treatment response, as enhancement patterns were similar in both complete and progressive disease patients, indicating that B-US may be the more reliable method for early response assessment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Early Therapy Response of Non-Hodgkin's and Hodgkin's Lymphoma Using B-Mode Ultrasound and Dynamic Contrast-Enhanced Ultrasound. Trenker, C., Kümpel, J., Michel, C., et al.[2022]

The study demonstrated that while there was strong reproducibility within individual echocardiography core laboratories (ECLs), significant differences in measurements of left ventricular function, such as ejection fraction, were observed between the two laboratories, indicating a need for standardized measurement practices.

Improvements in reproducibility for mitral inflow velocities were achieved by using multiple-beat measurements, but efforts to standardize global longitudinal strain measurements were limited due to a lack of established reference standards, highlighting the importance of consistent measurement techniques in cardiac safety assessments for cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Echocardiography Core Laboratory Reproducibility of Cardiac Safety Assessments in Cardio-Oncology. Khouri, MG., Ky, B., Dunn, G., et al.[2020]

This case study reports the first instance of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) occurring in a patient with metastatic prostate cancer undergoing treatment with second-generation hormonal therapies and ipilimumab, highlighting a potential immune-related adverse event (irAE) associated with immune checkpoint inhibitors.

The patient's RS3PE symptoms resolved after withholding ipilimumab and initiating methotrexate, suggesting that while ICIs can lead to inflammatory conditions like RS3PE, effective management strategies exist that can alleviate symptoms without compromising cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RS3PE Following Treatment With Combination of Hormonal Therapies Plus Ipilimumab in a Patient With Metastatic Prostate Cancer. Kim, ST., Murphy, WA., Aparicio, A., et al.[2022]

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