A clinical study to assess how safe and effective it is for subjects with hepatocellular carcinoma (HCC) to receive radiation therapy with TheraSphere followed by immunotherapy (durvalumab and tremelimumab treatment)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Biocompatibles UK Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

11 Oct 2023 → ongoing

Decision date (initial)

2023-12-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Boston Scientific International SA

External identifiers

EU CT number

2023-508945-41-00

EudraCT number

2021-001907-33

ClinicalTrials.gov

NCT05063565

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess the efficacy of treatment with TheraSphere followed by durvalumab and tremelimumab in HCC patients

Secondary objectives 4

1. To explore whether treatment with TheraSphere followed by systemic treatment with durvalumab and tremelimumab can enhance other efficacy endpoints
2. To assess the safety and toxicity of TheraSphere followed by durvalumab and tremelimuma
3. To determine tumor and normal tissue absorbed radioembolization dose and its relationship with response, outcomes, and liver volume changes after treatmen
4. To describe the difference in quality of life before and after treatment using the FACT-Hep and EQ-5D questionnaires

Conditions and MedDRA coding

Hepatocellular Carcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 22

1. Participants must be aged ≥18 years at the time of screening.
2. Dosimetry criteria for tumor(s) and normal tissue can be determined. Please refer to Supplement B for further details
3. Patients with previous liver resection or ablation ≥6 months from end of previous treatment to TheraSphere administration
4. Previous transarterial chemoembolization (TACE) is permitted if: a. Previous TACE performed ≥8 months before TheraSphere administration and b. Result of previous TACE was CR and c. Current tumor is not a recurrence of previously treated lesion
5. Patients with no portal vein thrombosis (PVT) Vp0, OR patients with Vp1, or Vp2 are eligible Refer to Protocol Appendix F for details regarding PVT classification.
6. Patients with HBV or HCV infection must have documented HBV deoxyribonucleic acid (DNA) or HCV ribonucleic acid (RNA)status and appropriate treatment must be provided as follows a. HBV DNA ≥10 IU/mL (or above the limit of detection per local laboratory): Patient must receive antiviral therapy per institutional practice. Patients must show evidence of HBV stabilization or signs of viral response (e.g., reduction HBV DNA levels) prior to enrollment. Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment. b. HBV DNA <10 IU/mL (or under the limit of detection per local laboratory): Patients do not require antiviral therapy. These patients will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥10 IU/mL or above the limit of detection per local laboratory). Patients with detectable HBV DNA during the study must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment. c. Detectable HCV RNA: Patients with active HCV infection must be managed per local institutional practice for the study duration.
7. Patients with Human Immunodeficiency Virus (HIV) infection are eligible, provided the HIV infection is well controlled with no current or previous AIDS-related complications and CD4+ T-cell (CD4+) counts ≥ 350 cells/μL
8. Negative urine/serum pregnancy test in females of childbearing potential
9. Adequate contraception for the patient and his/her sexual partner.
10. Adequate renal and marrow function as defined below: a. Hemoglobin (Hgb) ≥9.0 g/dL b. Absolute neutrophil count (ANC) ≥1.0 x 109/L c. Platelet count ≥50 x 109/L d. Measured or calculated creatinine clearance ≥40 mL/min as determined by Cockcroft-Gault (using actual body weight)
11. Absolute lymphocyte count ≥0.5 X 109/L
12. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the US, European Union [EU] data privacy regulations in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
13. Adequate liver function, as defined by a. Child-Pugh A b. Albumin-bilirubin (ALBI) score ≤ -2 with upper limit for(i.e., ALBI score ≤ -grade 1 and subset of ALBI grade 2.). Patients with confirmed Gilbert’s syndrome may not have an evaluable bilirubin value; therefore, ALBI score should not be considered for such patients. Patients with Gilbert’s syndrome will be eligible with any bilirubin value, as long as Albumin level is ≥ 34 g/L. . c. AST and ALT <3 x ULN
14. Body weight >30 kg and BMI ≥18 kg/m2.
15. Life expectancy ≥6 months
16. HCC, diagnosed by radiographic imaging or histology
17. Patient not a candidate for liver resection, thermal ablation, or transplantation at the time of study entry.
18. ECOG 0 or 1
19. At least one HCC lesion measurable by mRECIST criteria (e.g. ≥10 mm of enhancement).
20. Tumor volume ≤35% of whole liver volume (determined by imaging).
21. Future remnant liver volume (FRLV) ≥30% of whole liver volume. FRLV is the volume of liver not planned to be treated with TheraSphere and free of HCC.
22. Patients that have had previous ascites/encephalopathy episodes should be free of symptoms and of supportive treatment (lactulose or equivalent, diuretics) at study entry.

Exclusion criteria 30

1. Any contraindication to angiography or selective visceral catheterization.
2. Cone Beam CT (CBCT) or Technetium-99m macroaggregated Albumin (99mTc-MAA) hepatic arterial perfusion scintigraphy shows any deposition to the gastrointestinal tract that may not be corrected by angiographic techniques.
3. 99mTc-MAA hepatic arterial perfusion scintigraphy shows poor tumor and/or portal vein thrombosis (PVT) targeting that would lead to a dose that does not meet the liver dosing criteria. Please refer to Supplement B for further details
4. Shunting of blood to the lungs that could result in delivery of >30 Gy to the lungs in a single treatment, or >50 Gy cumulative dose to the lungs in case of multiple TheraSphere treatments, as seen on 99mTc-MAA hepatic arterial perfusion scintigraphy.
5. Vp3, Vp4, hepatic vein invasion, or inferior vena cava (IVC) invasion
6. Extrahepatic metastases (patients with extrahepatic spread [EHS]): a. EHS is any extrahepatic lesion that, according to clinical symptoms, histology, or radiological imaging data, is highly suspicious of being metastases. b. For patients with bone pain/neurological symptoms (deficit, seizure or else) at baseline and suspected of metastases at screening, a bone scan/brain MRI is recommended prior to study entry. c. Extrahepatic nontarget non-measurable lesions (<1 cm per RECIST 1.1) are acceptable if considered not suspicious by the investigator.
7. Any previous systemic HCC treatment
8. Prior exposure to immune mediated therapy for other disease, such as other anti-PD-1, anti-PDL-1, anti-PDL-2, anti-CTLA-4, antibodies, etc
9. Previous liver radiation (external beam radiation therapy (EBRT) or peptide receptor radionuclide therapy (PRRT) or selective internal radiation therapy (SIRT).
10. Concurrent treatment for HCC or treatment in the last 4 weeks in another clinical study, unless it is an observational study (non-interventional) or during a non-interventional follow-up stage of an interventional study, or prior to inclusion in this study.
11. HCC with infiltrative disease that is not evaluable by mRECIST.
12. Pulmonary insufficiency (defined by an arterial oxygen pressure (PaO2) of <60 mmHg, or oxygen saturation (SaO2) of <90% or clinically evident chronic obstructive pulmonary disease (COPD).
13. Medical history of radiation pneumonitis or recent pneumonitis, regardless of causality
14. History of any organ allograft, including bone marrow allo and autograft.
15. History of active primary/acquired immunodeficiency, that makes patients unsuitable for additional immunotherapy in this study (per investigator and as detailed in exclusion criterion #17).
16. Active or prior documented autoimmune or inflammatory disorders (including but not limited to auto immune hepatitis, inflammatory bowel disease [e.g. ulcerative colitis or Crohn’s disease], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis]). The following are exceptions to this criterion a. Patients with vitiligo or alopecia b. Patients with hypothyroidism (e.g. following Hashimoto’s syndrome) stable on hormone replacement therapy c. Any chronic skin condition that does not require systemic therapy. d. Patients without active disease in the last 5 years may be included but only after consultation with the Sponsor Study physician. e. Patients with celiac disease controlled by diet alone
17. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: a. Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra-articular injection) b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent. c. Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication).
18. History of gastrointestinal bleeding (GI) within 42 days prior to study inclusion, active GI bleeding and any bleeding diathesis or coagulopathy that is not correctable by usual therapy or hemostatic agents (e.g. closure device). Patients with gastrointestinal bleeding related to portal hypertension that cannot be controlled with a non-selective betablocker. Patients with known varices that have not bled or which have been clinically addressed can enter the study. No endoscopic exploration is required before study inclusion.
19. Presence of biliary stent or sphincterotomy within one year prior to study inclusion
20. History of malignancy, other than HCC, within three years, except the condition is one of the following: a. Adequately treated carcinoma in situ of the cervix, early squamous cell carcinoma or basal cell carcinoma of the skin, localized prostate cancer, breast ductal carcinoma in situ, or low-grade endometrial carcinoma with no myometrial invasion b. Localized prostate cancer under active surveillance. c. Other cancer when there is a negligible risk of recurrence or progression or death (5-year OS rate > 90%).
21. Major surgical procedure (as defined by the Investigator) within 42 days prior to study inclusion
22. A history of severe allergy or intolerance to contrast agents, narcotics, sedatives, or atropine that cannot be managed medically
23. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients that cannot be managed medically
24. Active infection, including: a. Tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), b. HBV and HCV co-infection, c. HBV and Hep D co-infection, d. Human immunodeficiency virus (HIV 1/2 antibodies) plus HCV or HBV coinfection.
25. Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab and/or tremelimumab. Note: patients, if enrolled, should not receive live vaccine whilst receiving durvalumab and/or tremelimumab and up to 30 days after the last dose of durvalumab and/or tremelimumab
26. Female patients who are pregnant or breastfeeding and who do not want to stop breastfeeding. Male or female patients of reproductive potential who are not willing to employ any effective birth control method from screening and for at least 90 days after TheraSphere administration, 90 days after the last dose of durvalumab, and 6 months after the last dose of tremelimumab.
27. Unstable chronic disease or evidence of any disease or condition that would place the patient at undue risk and preclude safe use of TheraSphere, durvalumab and tremelimumab treatment as deemed by the site principal investigator. Patients who have stable respiratory disease adequately treated with medication are not excluded, for example COPD.
28. Patients who are not able to follow the TheraSphere, durvalumab or tremelimumab treatment requirements.
29. Patients that have had previous ascites/encephalopathy episode should be free of symptoms and of supportive treatment (lactulose or equivalent, diuretics) at study entry.
30. For France Patients Only Persons deprived of their liberty by a judicial or administrative decision, persons subject to psychiatric care under articles L. 3212-1 and L. 3213-1 who are not covered by the provisions of Article L. 1121-8 and persons admitted to a health or social establishment for purposes other than research, including: a. Pregnant, parturient, breast-feeding women (see also inclusion criterion 16 and exclusion criterion 27) b. Minors (see also inclusion criterion 1) c. Persons receiving psychiatric treatment (see also exclusion criteria 28) d. Persons admitted to a health or social establishment for purposes other than research e. Person of full age under curatorship f. Adult subject to a mandate for future protection, a family authorization, or a guardianship measure g. Person not affiliated or not beneficiary of a social security scheme

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary Effectiveness Endpoint Objective response rate (ORR: complete response and partial response) evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST) by investigator assessment Primary Safety Endpoint Number of adverse events (AEs) and serious adverse events (SAEs)

Secondary endpoints 37

1. Number of immune mediated AEs and SAEs.
2. Number of patients whose durvalumab and/or tremelimumab treatment was temporarily halted, postponed, or permanently discontinued due to an AE.
3. Change from baseline in liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [GGT], alkaline phosphatase [ALP], bilirubin, albumin).
4. Change from baseline in Child-Pugh score
5. Change from baseline in Albumin Bilirubin (ALBI) score.
6. Change from baseline in Eastern Cooperative Oncology Group (ECOG) score
7. ORR according to localized mRECIST# and RECIST 1.1. #Localized mRECIST is defined as mRECIST assessment within the TheraSphere treatment area. The TheraSphere treatment area is the liver volume infused with TheraSphere.
8. Disease Control Rate (DCR) according to mRECIST, localized mRECIST#, and RECIST 1.1
9. Duration of disease control (DoDC) according to mRECIST, localized mRECIST#, and RECIST 1.1
10. Time to best response (Complete Response [CR] or Partial Response [PR]) according to mRECIST, localized mRECIST#, and RECIST 1.1.
11. Complete Response Rate (CRR) according to mRECIST, localized mRECIST#, and RECIST 1.1.
12. Duration of Complete Response (DoCR) according to mRECIST, localized mRECIST#, and RECIST 1.1.
13. Hepatic Time to Progression (hTTP) according to mRECIST, and RECIST 1.1
14. Time to Progression (TTP) according to mRECIST, localized mRECIST#, and RECIST 1.1.
15. Progression Free Survival (PFS) according to mRECIST, localized mRECIST#, and RECIST 1.1; this will include an evaluation of the PFS rate at 6, 12, 18, and 24 months
16. Hepatic Progression Free Survival (hPFS) by mRECIST and RECIST 1.1.
17. Overall survival (OS)
18. Disease specific survival (DSS)
19. Proportion of patients receiving subsequent treatment for HCC after study treatment, and type of HCC treatment received.
20. Proportion of patients to undergo surgery (transplantation or resection).
21. Time to subsequent anti-cancer treatment for HCC (local or systemic therapy).
22. Reason for starting subsequent anti-cancer treatment for HCC
23. Alpha-fetoprotein (AFP) response.
24. Change from baseline in Quality of Life (QoL) by Functional Assessment of Cancer Therapy – Hepatobiliary (FACT-Hep).
25. Change from baseline in QoL by EuroQol-5D (EQ-5D).
26. Pre- treatment volumes will be determined using baseline CT/MRI angiography or cone beam computed tomography (CBCT) or single photon emission computerized tomography/computed tomography (SPECT/CT) following Technetium-99m macroaggregated albumin (99mTc-MAA) and Symplicit90Y software
27. Association between tumoral absorbed doses, determined by 99mTc-MAA SPECT/CT, with efficacy endpoints
28. Association between perfused liver absorbed doses, determined by 99mTc-MAA SPECT/CT, with efficacy endpoints
29. Association between normal tissue absorbed doses, determined by 99mTc-MAA SPECT/CT, with safety endpoints.
30. Association between tumoral absorbed doses, determined by Y-90 PET/CT or PET/MRI or Y-90 SPECT/CT, with efficacy endpoints
31. Association between perfused liver absorbed doses, determined by Y-90 PET/CT or PET/MRI or Y-90 SPECT/CT, with efficacy endpoints.
32. Association between normal tissue absorbed doses, determined by 99mTc-MAA SPECT/CT and by Y-90 PET/CT or PET/MRI or Y-90 SPECT/CT
33. Determination of dose volume histogram (DVH) for tumoral VOIs and normal liver tissue VOIs, using 99mTc-MAA SPECT/CT and Y-90 PET or SPECT/CT.
34. Whole liver and remnant liver volumes at baseline and follow-up volume imaging assessments measured using Simplicit90Y software
35. Association between normal tissue absorbed doses, determined by Y-90 PET/CT or PET/MRI or Y-90 SPECT/CT, with safety endpoints.
36. Association between tumoral absorbed doses, determined by 99mTc-MAA SPECT/CT and Y-90 PET/CT or PET/MRI or Y-90 SPECT/CT.
37. Association between perfused liver absorbed doses, determined by 99mTc-MAA SPECT/CT and Y-90 PET/CT or PET/MRI or Y-90 SPECT/CT.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Biocompatibles UK Limited

Sponsor organisation

Biocompatibles UK Limited

Address

Chapman House, Farnham Business Park, Weydon Lane Farnham Business Park Weydon Lane

City

Farnham

Postcode

GU9 8QL

Country

United Kingdom

Scientific contact point

Organisation

Biocompatibles UK Limited

Contact name

BSC Clinical Trials

Public contact point

Organisation

Biocompatibles UK Limited

Contact name

BSC Clinical Trials

Third parties 6

Locations

3 EU/EEA countries · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Temporary halts 1 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 56 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications