Boosting checkpoint immunotherapy with focused ultrasound histotripsy for metastatic or unresectable cancer

Treatment of Cancer With Immune Checkpoint Inhibition Therapy Boosted by High Intensity Focused Ultrasound Histotripsy; the iFOCUS Study

This trial will test whether a single session of focused ultrasound histotripsy combined with ipilimumab and nivolumab helps adults with metastatic or unresectable cancer that has progressed after standard treatments.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 24 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: UMC Utrecht (Academic / other)
• Drugs / interventions: chemotherapy, radiation, prednisone, ipilimumab, nivolumab
• Locations: 1 site (Utrecht, Utrecht)
• Trial ID: NCT06524570 on ClinicalTrials.gov

What this trial studies

This is a Phase 1, single-center trial combining one session of High Intensity Focused Ultrasound Histotripsy (HIFU-HT) with the immune checkpoint inhibitors ipilimumab and nivolumab in adults with metastatic or unresectable cancer that progressed on standard therapy. The primary focus is on safety, tolerability and feasibility of the combined approach, with secondary measures including radiologic, immunologic and clinical responses. Eligible patients must have at least one tumor lesion accessible to HIFU (near the skin but with a safe margin from vulnerable structures) and an anticipated life expectancy of at least 12 weeks. The intervention is delivered at the University Medical Center Utrecht and patients are followed for adverse events and response signals.

Who should consider this trial

Good fit: Adults (≥18 years) with histologically confirmed metastatic or unresectable cancer that progressed after standard treatment, an anticipated life expectancy ≥12 weeks, and at least one tumor lesion accessible to HIFU (within ~30 mm of the skin and with ≥10 mm safe margin to vulnerable structures) are ideal candidates.

Not a fit: Patients whose tumors are not reachable by HIFU (for example most deep liver metastases), who have very limited life expectancy, or who cannot tolerate ipilimumab/nivolumab are unlikely to benefit.

Why it matters

Potential benefit: If successful, the combination could amplify the immune response against tumors and improve tumor control beyond checkpoint inhibitors alone.

How similar studies have performed: Preclinical studies and small early clinical reports suggest HIFU can boost immune responses and may synergize with checkpoint inhibitors, but robust clinical proof in larger trials is still limited.

Eligibility criteria

Inclusion Criteria:

1. Histologically confirmed metastatic or unresectable cancer that progressed under standard of care treatment options.
2. Age ≥ 18 years.
3. Has signed and dated written informed consent before performing any study procedure, including screening.
4. Anticipated life expectancy ≥ 12 weeks by investigator judgement.
5. At least one tumor lesion (primary tumor or metastasis) which is amenable to application of high intensity focused ultrasound histotripsy (determined by a radiologist with HIFU-expertise).

   * The lesion must have a distance of ≤30 mm to the skin.
   * At least part of the lesion must have a distance of ≥10 mm to the skin and other vulnerable structures (e.g. large blood vessels). This part should be sufficient to be able to select at least one HT focus in an area of solid tumor.

   Most liver metastases cannot be treated currently (due to their depth, overlying ribs and movement during breathing), some superficial large left-sided and caudally located right-sided liver metastases excepted

   • If the target lesion contains cystic or necrotic regions: the solid component should be ≥10 mm in diameter, sufficient to be able to select at least one HIFU-HT focus in an area of solid tumor with ≥10 mm distance to the skin.
6. Sonication will be performed on tumors that have not previously directly been treated with radiation therapy or surgery unless they showed significant mass regrowth.
7. Measurable disease (at least one lesion besides the HIFU-HT treated lesion) on CT according to RECIST V 1.1 criteria (or on PET-CT according to PERCIST criteria) as assessed by investigator and local radiology review.
8. Performance status of 0 or 1 on the WHO Performance Scale.
9. Screening laboratory values must meet the following criteria:

   * WBC ≥ 2.0x109/L,
   * Neutrophils ≥1.5x109/L
   * Platelets ≥100 x109/L
   * Hemoglobin ≥5.5 mmol/L
   * Serum creatinine ≤1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥60 mL/minute (≤Grade 1)
   * Aspartate aminotransferase (AST) ≤2.5 x ULN; alanine aminotransferase (ALT) ≤2.5 x ULN; AST/ALT \<5 x ULN if liver involvement
   * Serum bilirubin ≤1.5 x ULN or direct bilirubin ≤ULN for subjects with total bilirubin levels \>1.5xULN, except in subjects with Gilbert's Syndrome
10. Patients must agree to use an adequate method of contraception for the course of the study through 180 days after the last dose of study medication.
11. Patients must be willing to undergo tumor biopsy.
12. Sufficient proficiency in the Dutch language to provide informed consent or comply with study procedures

Exclusion Criteria:

1. Presence of known central nervous system, meningeal, or epidural metastatic disease. However, subjects with known brain metastases are allowed if the brain metastases are stable for ≥4 weeks before the first dose of study treatment. Stable is defined as neurological symptoms not present or resolved to baseline, no radiologic evidence of progression, and steroid requirement of prednisone ≤10 mg/day or equivalent.
2. Patients currently participating and receiving study therapy or patients who participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of the study treatment.
3. Prior chemotherapy, targeted small molecule therapy or monoclonal antibodies within 4 weeks prior to the first dose of the study treatment.
4. Prior radiotherapy within 8 weeks prior to the first dose of the study treatment. The patient will be excluded from the study if the only targetable lesion has directly been treated with radiation therapy in the past with an exception for lesions that showed massive regrowth.
5. Prior surgery or ablative therapy within 4 weeks prior to the first dose of the study treatment. The patient will be excluded from the study if the only targetable lesion has directly been treated with ablative therapy in the past.
6. Ongoing adverse events \> Grade 1 due to a previously administered therapy. Subjects with ≤ Grade 2 neuropathy, vitiligo, thyroid disorders, hypocortisolism or alopecia of any grade are an exception to this criterion and may qualify for the study.
7. History of other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years.
8. Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids; exceeding prednisolone 10 mg or equivalent.
9. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, high-dose corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
10. Active infection requiring systemic therapy.
11. History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
12. Known history of active Tuberculosis.
13. Receipt of a live vaccine within 4 weeks prior to the first dose of the study treatment.
14. Hypersensitivity to any of the study drugs or their excipients.
15. Contra-indications to MR imaging (e.g. certain pacemakers or severe claustrophobia). Contra-indications to gadolinium-based contrast agents are not an exclusion criterion, as a different brand of gadolinium can be used or if necessary the MRI can be performed without contrast.
16. Pregnancy or lactation.
17. Any other medical or social condition that, in the opinion of the Principal Investigator, might put the subject at risk of harm during the study or might adversely affect the interpretation of the study data.

Where this trial is running

Utrecht, Utrecht

• University Medical Center Utrecht — Utrecht, Utrecht, Netherlands (Recruiting)

Study contacts

• Study coordinator: Karijn P.M. Suijkerbuijk, Prof.

Conditions Cancer; Metastatic Cancer; Metastasized; Unresectable; Progressive after regular treatment