Treatment of Cancer With Immune Checkpoint Inhibition Therapy Boosted by High Intensity Focused Ultrasound Histotripsy

Official title

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

Overview

This phase 1 clinical trial aims to evaluate the safety, tolerability and feasibility of combination treatment of High Intensity Focused Ultrasound Histotripsy (HIFU-HT) and immune checkpoint inhibitors (ICI) in adult patients with metastatic or unresectable cancer that have progressive disease after regular treatment. Patients will undergo one single session of HIFU-HT during treatment with ipilimumab and nivolumab. Safety, tolerability and feasibility endpoints will be studied as well as radiologic, immunologic and clinical response.

Interventions

• Device HIFU-HT
  High-Intensify Focused Ultrasound Histotripsy
• Drug ICI
  Ipilimumab and nivolumab

Primary outcome measures

• Number and severity of adverse events until 100 days after the last study treatment [Time frame: Adverse events will be assessed up to 100 days after the last study treatment]
• Tolerability: Discontinuation rate [Time frame: At every visit untill 2 years after first study treatment]
• Tolerability: Patient reported tolerability by HIFU-HT-tolerability questionnaire [Time frame: Day 8 + 15]
• Tolerability: Patient reported tolerability by EQ-5D [Time frame: Baseline, days 1, 8, 15, 22, 43, 64, 91; thereafter every 4 to 8 weeks until 2 years after start of therapy]
• Tolerability: Patient reported tolerability by USD-I [Time frame: Baseline, days 1, 8, 15, 22, 43, 64, 91; thereafter every 4 weeks until 2 years after start of therapy]
• Feasibility: Number of technically effective HIFU-HT procedures [Time frame: Day 8]
• Feasibility: Percentage of screening failures [Time frame: Baseline]
• Feasibility: Time burden [Time frame: Through study completion, up to two years after start of study treatment]

Secondary outcome measures (5)

• Radiological response: MRI [Time frame: Directly after HIFU-HT and 12 weeks after start of treatment]
• Radiological response: CT [Time frame: 12 weeks after start of treatment; every 12 weeks while on treatment up to two years after start therapy]
• Immunologic response [Time frame: Baseline and days 1, 8, 9, 15, 22, 64]
• Overall survival [Time frame: Every 12 weeks until 2 years]
• Progression free survival [Time frame: Every 12 weeks until 2 years]

Eligibility criteria

Inclusion criteria

• Histologically confirmed metastatic or unresectable cancer that progressed under standard of care treatment options.
• Age ≥ 18 years.
• Has signed and dated written informed consent before performing any study procedure, including screening.
• Anticipated life expectancy ≥ 12 weeks by investigator judgement.
• 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.
• Sonication will be performed on tumors that have not previously directly been treated with radiation therapy or surgery unless they showed significant mass regrowth.
• 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.
• Performance status of 0 or 1 on the WHO Performance Scale.
• 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
• 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.
• Patients must be willing to undergo tumor biopsy.
• Sufficient proficiency in the Dutch language to provide informed consent or comply with study procedures

Exclusion criteria

• 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.
• 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.
• Prior chemotherapy, targeted small molecule therapy or monoclonal antibodies within 4 weeks prior to the first dose of the study treatment.
• 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.
• 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.
• 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.
• History of other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years.
• Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids; exceeding prednisolone 10 mg or equivalent.
• 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.
• Active infection requiring systemic therapy.
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Known history of active Tuberculosis.
• Receipt of a live vaccine within 4 weeks prior to the first dose of the study treatment.
• Hypersensitivity to any of the study drugs or their excipients.
• 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.
• Pregnancy or lactation.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Netherlands · 1 center

• University Medical Center Utrecht — Utrecht

Identifiers

NCT: NCT06524570 · NL85300.041.23

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗