THERESA Study: Final Reporting of Phase I Study of Safety and Efficacy of Hepatic Histotripsy

Objective: Histotripsy is a therapeutic ultrasound ablation modality that is the first to allow creation of non-invasive, non-thermal, and non-ionizing ablations. Combining this therapeutic ultrasound with robotic micropositioning allows ablation of a prescribed volume of tissue, which has yielded promising results in multiple pre-clinical studies and applications. This study reports the final outcomes of a Phase I trial of hepatic histotripsy.

Methods: The Theresa study was a phase I, open-label, non-randomized trial with a primary endpoint of technical success, defined as creation of an ablation zone greater than 75% of the planned volume as assessed by MRI 1 day post-procedure. Secondary endpoints include: safety (CTCAE v4.0), local tumor control, liver function, involution of ablation zone, and analgesic requirements. All procedures were performed under general anesthesia. Procedures were performed with a prototype therapy system (HistoSonics, Inc., Ann Arbor, MI). Trial follow-up procedures included MRI, laboratory studies, and a clinic visit within 1 week prior to the procedure and 1 day, 1 week, 4 weeks, and 8 weeks following the procedure. MRI studies were evaluated by an independent central reader for tumor or ablation zone size at each time point. Although not a listed objective of the study, non-target disease response was evaluated for each treated patient at follow-up.

Results: Eleven tumors were targeted in 8 patients (mean age 59, range 46 to 87 years) in the protocol. All patients had multifocal liver malignancy with primary disease of colorectal metastases (CRM) in 5 patients (7 tumors), gallbladder carcinoma in 1 patient (2 tumors), and hepatocellular carcinoma (HCC) and breast cancer in 1 patient (1 tumor) each. Average targeted tumor largest diameter was 1.3 cm (range 0.5 to 2.1). All procedures achieved technical success with the ablation zone being greater than 75% of the planned volume. The lateral, anteroposterior, and craniocaudal treatment dimensions each averaged larger than prescribed by 0.3 (SD 0.6), 0.3 (0.4), and 0.6 (0.6) cm respectively. Five patients (6 tumors) completed 8 weeks of follow-up. Two patients (4 tumors) withdrew following 4 weeks and a single patient (1 tumor) withdrew following 1 week of follow-up. Each patient withdrawing from the study did so to pursue alternative therapies. One ablation (1/11, 9.1%) was mis-targeted due to poor ultrasound visualization of a 5 mm tumor. The remainder of the ablations encompassed the tumor with no local tumor progression noted during trial follow-up. Volume contraction of the ablation zone averaged 36.0% at 1 week, 53.6% at 1 month, and 71.8% at 2 months respectively. No procedure-related significant adverse events (CTCAE grade 3 or higher) occurred. Two procedure-related minor adverse events occurred, Grade 2 fever in the patient with 3 treated tumors and Grade 1 nausea and fatigue the day following the ablation in a second patient. Two patients (2/8, 25%) had continuous decline in tumor markers following the procedure, one each with multifocal HCC and CRM. In each patient a single tumor was treated and non-target tumors were either stable at 8 weeks (patient with HCC) or were decreased in diameter (patient with CRM).

Conclusions: This first-in-human trial demonstrates that hepatic histotripsy is effective at creating a planned ablation volume and that the treatment was well-tolerated with no identified serious adverse events. Tumors are locally controlled in the short term and 2 of 8 patients had non-target tumor response. Progression to expanded trials is warranted.