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The Holmium Platform

Featured products: QuiremScout™ Microspheres, QuiremSpheres™ Microspheres

10/30/2020 - Global

Primary unresectable liver cancer: 


HEPAR PRIMARY1: 

​Objective

To establish the safety and toxicity profile of 166Ho-radioembolization in patients with HCC.

Methods

  • 31 patients with liver-dominant HCC, no curative treatment options, CP ≤B7, ECOG 0-1, no prior radioembolization, no portal vein thrombosis (PVT).
  • Single treatment with 166Ho-SIRT; same-day QuiremScout and QuiremSpheres procedure in 28/31 patients; no personalized treatment planning (aiming at 60Gy average absorbed dose to the perfused liver); MRI evaluation at 24h, SPECT-CT at 3-5 days
  • 20 unilobar, 9 bilobar, 2 whole liver treatments, 7 patients had dose adjustment (median reduction -45%)
  • Primary endpoint: rate of unacceptable toxicity (CTCAE methodology) defined as REILD (grade 3 hyperbilirubinemia in combination with ascites and low albumin in the absence of disease progression) or any serious adverse event or serious device defect, possibly, probably or causally related to treatment
  • Secondary endpoints: overall toxicity, response rates, survival, AFP and QoL

Results

Primary endpoint:

  • 19 SAEs,  4 events in 3 patients (<10%): 3 possibly related to treatment, 1 definitely related to treatment.
  • Laboratory events: vast majority of patients have grade 1-2 increase in liver enzymes, but dynamic trajectory of changes over 6 months follow up did not show a clear peak or slope.

Secondary endpoints:

  • ORR: 19% CR + 35% PR = 54% at 3 months by mRECIST evaluation of target lesions (26 pts evaluable)
  • DCR: 19% + 35% + 42% SD = 96% at 3 months
  • mOS was 14.9 months

Conclusion

This interventional non-randomized study showed an acceptable low rate of holmium-166 radioembolization-related serious toxicity (3 out of 31 patients; <10%) in patients with hepatocellular carcinoma.

Key Takeaways

  • 166Ho-SIRT can be considered a safe and effective treatment for HCC patients with BCLC B-C disease
  • Acceptable safety profile
  • Future studies should focus on establishing dose-effect thresholds

Link to the full publication: 


HORA EST2 HCC:

Publication 

Dr. Mark C. Burgmans, UMC Leiden, Belgium 

Sites enrolling: Leiden UMC, Netherlands; Amsterdam Medical Centre

Patients: 20, early stage HCC 

This is a dose-finding study, where patients receive Radiofrequency thermal ablation and adjuvant segmental Holmium-166 SIRT (QuiremSpheres®).

Purpose: Combining radiofrequency ablation with adjuvant Ho-166 SIRT in HCC patients (1-3 HCC lesions) 

Primary objective: 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. Holmium-6 SIRT, when

Secondary Objectives:

  • Toxicity

  • Local tumor recurrence at 6 months

  • Time to progression

  • Progression-free survival

  • Quality of Life

Enrolment Status: Ongoing 

Expected Completion: 2021


Metastatic unresectable liver cancer

The safety and efficacy of 166Holmium-SIRT in the treatment of liver metastases has been evaluated in HEPAR I (phase I) and HEPAR II (phase II) studies and retrospectively analysed to establish dose-response thresholds. 


HEPAR I3: 

Publication

Phase I -Dose Escalation Study, recruited 15 patients with different liver metastases from various primary tumors (Ocular melanoma, colorectal cancer, cholangiocarcinoma, breast cancer) 



Purpose: Primary endpoint: Determination of Maximum Tolerated Radiation Dose (MTRD) 

Results: 

  • MTRD was found to be 60 Gy

  • Disease control rate (PR+SD) in target lesions at 12 weeks was reported in 64% patients 



Conclusion: Holmium-166 SIRT is safe and technically effective for the treatment of patients with unresectable and chemo-refractory liver metastases with an aimed total liver dose of 60Gy.


HEPAR II4: 

Publication

Purpose:

  • Safety & efficacy evaluation of Holmium-166 SIRT

  • Phase II study in 37 patients with metastases from different primaries 

  • 23 of these patients had metastatic CRC


 

Primary Endpoint: Tumor Response at 3 months (RECIST 1.1) 

Results: 

  • Time to liver specific progression was 3 months

  • Median overall survival was 14.5 months 

  • Median overall survival for mCRC patients was 13.4 months 

Conclusion: 

  • Radioembolization with QuiremSpheres® is technically effective, with an acceptable toxicity profile in the salvage treatment of patients with liver metastases


Neuroendocrine metastases (mNET): 

HEPAR PLUS5

Publication

Purpose: to evaluated the safety and technical efficacy of 166Holmium-SIRT as adjunct treatment after systemic 177Lu-dotatate in 30 patients with mNET. Prospective, single arm study. 

Design: 

  • Patients received 4 cycles of PRRT (peptide receptor radionuclide therapy)

  • Followed by QuiremSpheres® administration to achieve local radiation boost 

Patients: 40% of the patients were NET G1 and 60% were NET G2. 80% of these had extra-hepatic disease and 57% received treatment the whole liver in one session. 

Results: 



  • The toxicity profile is comparable to literature, mainly grade 1-2 abdominal pain, fatigue and nausea.

  • The overall toxicity was low: CTCAE v 4.03 grade 3 - 4 with one fatal REILD, while the QoL recovered at 3 months.

Conclusion: Additional embolization with Holmium-166 is effective and safe in the treatment of bulky liver disease after PRRT


Holmium-166 scout dose (QuiremScout® Microspheres):

The safety and performance of the use of 166Holmium as Scout Dose in comparison to 99mTc-MAA has been evaluated in different studies,6,7,8 concluding that:

  • 250 MBq is safe to use prior to SIRT as an alternative to 99mTc-MAA with superior predictive value in estimating the lung shunt in patients with primary and secondary liver tumors7

  • QuiremScout® showed to be safe in all the patients with extrahepatic depositions7Publication

  • QuiremScout® could lead to more reliable pre-treatment imaging and subsequently to improved individualized treatment planning due to the identical morphology of the microspheres7

  • QuiremScout® is more accurate than the commonly used surrogate 99mTc-MAA in predicting lung shunting8 and intrahepatic distribution.7

  • Qualitative and quantitative analysis of the intrahepatic distribution demonstrated significant better agreement between 166Ho Scout and 166Ho treatment versus 99mTc-MAA.8

  • 99mTc-MAA could lead to unnecessary patient exclusion from SIRT and/ or under-dosing of tumor due to overestimation of lung shunt and other off-target tissue embolization. 8Publication


References: 

  1. https://www.clinicaltrials.gov/ct2/show/NCT03379844?term=HEPAR+Primary&draw=2&rank=1 
  2. https://www.clinicaltrials.gov/ct2/show/NCT03437382?term=HORA+EST&draw=2&rank=1 
  3. Smits MLJ et al., Lancet Oncol, 2012; 13: 1025–34 
  4. Prince JF et al., J Nucl Med., 2018; 59:582-588 
  5. Braat A. et al Lancet Oncol 2020; 26 
  6. Elschot, M. et al. Eur. J. Nucl. Med. Mol. Imaging 2014 
  7. Braat AJAT et al. Eur Radiol 2017; 28:920-928 
  8. Smits et al. European Journal of Nuclear Medicine and Molecular Imaging - 2019