• HEPAR I was a first-in-man, phase I dose finding study, focused on safety, feasibility and finding the Maximum Tolerated Radiation Dose (MTRD).
• 15 patients with liver metastases from various primary origins were treated in cohorts of 3 with escalating aimed whole-liver absorbed doses.
• The results showed that ¹⁶⁶holmium SIRT is considered safe and feasible.
• Toxicity after treatment was mainly confined to the expected post-embolization syndrome, and the MTRD was identified to be 60 Gy. This study paved the way for the second study (HEPAR II) on ¹⁶⁶holmium SIRT.

Study completed. View publication by Smits et al. in Lancet Oncology on Pubmed (External link)

Clinicaltrials.gov Identifier NCT01031784 (External link)

• HEPAR II was a single-center phase II efficacy trial, and enrolled 38 patients with unresectable, chemo refractory liver metastases of various origin.
• The main primary malignancies were colorectal carcinoma (61%), breast cancer (11%), cholangiocarcinoma (11%), neuroendocrine tumors (5%) and uveal melanoma (5%). In this study, an aimed whole liver absorbed dose of 60 Gy was administered, the determined MTRD in HEPAR I.
• The results showed that ¹⁶⁶holmium SIRT was efficacious; 73% of the patients the target lesions showed disease control after 3 months.
• The adverse events profile was similar to that reported in comparable studies, with transient abdominal pain (18%) and nausea (8%) the most frequent grade 3 adverse events.
• Additionally, it was shown that ¹⁶⁶holmium microspheres could be quantified with high accuracy and precision using SPECT.

Study completed. View publication by Prince et al. in Journal of Nuclear Medicine on Pubmed (External link)

Clinicaltrials.gov Identifier NCT01612325 (External link)

• Patients with gastroenteropancreatic neuroendocrine tumours (GEP-NET) who have intrahepatic metastases have a poorer prognosis. Liver metastases are the most common type of metastases in patients with GEP-NET.
• HEPAR Plus is an efficacy study of ¹⁶⁶holmium-SIRT in patients with hepatic metastases from GEP-NET who underwent ¹⁷⁷lutetium-dotatate treatment (PRRT) (N=30)
• The pivotal study for PRRT registration in NET (NETTER-1) reported overall response rates of 18%. HEPAR Plus hypothesized that an additional adjuvant liver local boost with ¹⁶⁶holmium-SIRT for selected patients, even in the absence of imaging evidence of progression, could increase overall response rates, and possibly benefit overall patient outcomes such as progression free survival and overall survival.

Results

• Efficacy in terms of response at 3 months of adjuvant ¹⁶⁶holmium-SIRT after ¹⁷⁷lutetium-dotatate was evaluated in 30 patients
• Per protocol analysis demonstrated objective response in the treated volume in 13 patients (43%)
• The adverse event profile was similar to previous studies, with grade 3-4 CTCAE adverse events including abdominal pain (10%), increased gamma glutamyl transpeptidase (54%), lymphocytopenia (23%).
• One patient developed radioembolization-induced liver disease. In hindsight, the relative hypovascularity of disease and concomitant liver toxic medication should have been reason to exclude the patient from receiving ¹⁶⁶holmium-SIRT.
• Quality of life and symptom scales were not significantly affected with the exception of role functioning, but showed a temporary decrease at 3 weeks, in line with postembolization syndrome.

Conclusion

• The combination of PRRT and ¹⁶⁶holmium-SIRT is safe, and demonstrated substantial tumor reduction with acceptable side effects in patients with hypervascular liver metastases of GEP-NET.

Clinicaltrials.gov Identifier NCT02067988 (External link)

Study completed. View publication by Braat et al. in the Lancet Oncology

• Observational, Multicenter Study to Further Confirm The Efficacy and Safety of QuiremSpheres^® (¹⁶⁶Holmium Microspheres) SIRT in Unresectable Liver Cancer Patients
• The main purpose of this study is to further assess treatment efficacy and safety after using QuiremSpheres^® for the treatment of patients with unresectable primary liver cancer or unresectable liver metastases suitable for SIRT and allocated to this treatment by a multidisciplinary tumor board

• Tumor response in the liver, assessed at 3 months as per routine assessment
• Safety, expressed by the frequency and severity of adverse events

• In this multi-center, dose-finding study, patients with early stage hepatocellular carcinoma according to the Barcelona Clinic Liver Cancer (BCLC) staging system will be included to receive percutaneous radiofrequency ablation in combination with RFA with adjuvant segmental ¹⁶⁶holmium SIRT
• Objective is to find the treatment area dose that will result in delivery of a radiation absorbed dose of ≥ 120Gy to the target area in at least 90% of patients.

Principal Investigator: Mark. C. Burgmans, MD, PhD, Leiden UMC

Clinicaltrials.gov Identifier NCT03437382 (External link)

• This is a study of ¹⁶⁶holmium-SIRT in Hepatocellular Carcinoma Patients (N=30)
• Patients with hepatocellular carcinoma often die from intrahepatic disease since current treatment options are generally limited.
• Local treatment using ¹⁶⁶holmium SIRT could offer an effective treatment and a more personal approach than ⁹⁰yttrium SIRT as ¹⁶⁶holmium has more imaging options.

Objectives:

• To establish the safety and toxicity profile of holmium radioembolization in patients with hepatocellular carcinoma.
• To evaluate efficacy of holmium radioembolization in hepatocellular carcinoma without curative treatment options in a non-comparative phase II study.

Principal Investigator: Marnix G. Lam, MD, PhD, UMC Utrecht

Clinicaltrials.gov Identifier NCT03379844 (External link)