A Study of the Safety and Antitumoral Efficacy of Nivolumab After SIRT for the Treatment of Patients With HCC

NCT03380130 | Completed Phase 2 DMC

• 1 other identifier: NASIR-HCC/CA209-992
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 9

Brief Summary

The purpose of this study is to evaluate the effect of the anti-programmed death 1 (PD-1) agent nivolumab following selective internal radiation therapy (SIRT) for patients with unresectable hepatocellular carcinoma (HCC). SIRT using yttrium90-loaded microspheres is increasingly used to treat patients with HCC, particularly those that are not good candidates for transarterial chemoembolization or TACE. SIRT induces disease control (objective tumor remission or stabilization) in most patients while progression usually results from the growth of new lesions. SIR-Spheres are resin-made microspheres used for SIRT. On the other hand, nivolumab is under clinical development for the treatment of more advanced HCC. Available data in patients that mostly had progression to other therapies and vascular involvement or metastatic disease show significant systemic antitumor activity that results in durable objective remissions and disease stabilizations. Therefore, in patients with HCC that has not spread beyond the liver, the systemic action of nivolumab may improve the anti-tumor effect of SIRT. Furthermore, by inducing immunogenic tumor cell death, SIRT may have a synergistic effect with nivolumab.

Conditions

Hepatocellular Carcinoma

Keywords

Hepatocellular Carcinoma; Liver cancer; Hepatoma

Outcome Measures

Primary Outcomes (1)

• Rate and type of adverse events, liver decompensation, and transient and permanent drug discontinuations due to toxicity.

  The incidence of observed adverse events (AE) will be evaluated according to NCI CTCAE version 4.03. Particular attention will be given to adverse events that may follow enhanced T cell activation (hepatitis, dermatitis, colitis, pneumonitis, endocrinopathy or other immune-mediated AEs) and radiation damage to non-target organs (REILD, radiation pneumonitis and GI ulcers).

  Two years

Secondary Outcomes (7)

• Response rate

  Two years

• Disease control rate

  Two years

• Duration of response

  From date of complete or partial response to the date of progression, assessed up to 36 months.

• Time to progression

  From date of SIRT to the date of progression, assessed up to 36 months.

• Progression-free survival

  From date of SIRT to the date of progression or death, whichever came first, assessed up to 36 months.

Study Arms (1)

SIRT and Nivolumab

EXPERIMENTAL

SIRT (selective internal radiation therapy) will be performed in a single session using SIR-Spheres resin microspheres. After 3 weeks, nivolumab 240 mg every 2 weeks will be initiated

Drug: Nivolumab; Device: SIR-Spheres

Interventions

Nivolumab DRUG

An anti-programmed death 1 monoclonal antibody

Also known as: Opdivo

SIRT and Nivolumab

SIR-Spheres DEVICE

Resin microspheres labeled with the radioactive isotope yttrium 90 that serves as a source of beta radiation

Also known as: radioembolization, transarterial radioembolization (TARE)

SIRT and Nivolumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of HCC based on histology or non-invasive criteria if cirrhotics. Patients with fibrolamellar carcinoma are not excluded.
• Cirrhosis absent, non-viral or due to hepatitis C or B virus infection. Subjects with chronic hepatitis B virus infection must be on effective antiviral therapy
• Preserved liver function (without cirrhosis or with compensated cirrhosis in Child Pugh Class A).
• ECOG performance status 0 or 1
• Willing to have a liver biopsy pre-treatment
• Considered candidates for locoregional therapy using SIR-Spheres based on
• the absence of extrahepatic disease (patients with regional lymph nodes \< 2 cm in short axis are accepted)
• unsuitability for liver resection or transplantation, or percutaneous ablation
• considered not good candidates for TACE because they have; Single tumors larger than 5 cm. Multiple tumors that cannot be targeted superselectively. Unilobar tumors with segmental or lobar portal vein thrombosis.
• At least one measurable lesion by RECIST 1.1 criteria.
• Adequate organ and marrow function as evidenced by:
• White blood cell count ≥ 2000/μL.
• Neutrophils ≥ 1000/μL.
• Platelets ≥ 60 x 103/μL.
• Hemoglobin ≥ 9.0 g/dL.

You may not qualify if:

• Any history of hepatic encephalopathy
• Any prior (within 6 months) or current clinical ascites.
• Any history of clinically meaningful variceal bleeding within the last three months.
• Active coinfection with both hepatitis B and C or hepatitis D infection in subjects with hepatitis B
• Occlusive main trunk portal vein thrombosis or absence of intrahepatic portal blood flow if patient carries a portocaval shunt.
• Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured.
• Any autoimmune disease that may require immunosuppressive therapy.
• Any severe organ disease
• Prior therapy with any drug specifically targeting T-cell costimulation or checkpoint pathways.
• Prior organ allograft or allogeneic bone marrow transplantation
• Active bacterial or fungal infections within 7 days of study entry.
• Any condition requiring systemic treatment with corticosteroids or other immunosuppressive medications within 14 days of study drug administration.

Sponsors & Collaborators

• Clinica Universidad de Navarra, Universidad de Navarra: lead
• Sirtex Medical: collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (9)

Hospital Universitario de Cruces

Barakaldo, Spain

Location

Hospital Clinic

Barcelona, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, Spain

Location

Hospital Universitario Gregorio Marañon

Madrid, Spain

Location

Hospital Universitario Ramon y Cajal

Madrid, Spain

Location

Hospital Universitario Central de Asturias

Oviedo, Spain

Location

Clinica Universidad de Navarra

Pamplona, 31008, Spain

Location

Hospital Universitario Donostia

San Sebastián, Spain

Location

Hospital Universitario Lozano Blesa

Zaragoza, Spain

Location

Related Publications (9)

• Sangro B, Salem R. Transarterial chemoembolization and radioembolization. Semin Liver Dis. 2014 Nov;34(4):435-43. doi: 10.1055/s-0034-1394142. Epub 2014 Nov 4.

  PMID: 25369305 BACKGROUND

• Bolondi L, Burroughs A, Dufour JF, Galle PR, Mazzaferro V, Piscaglia F, Raoul JL, Sangro B. Heterogeneity of patients with intermediate (BCLC B) Hepatocellular Carcinoma: proposal for a subclassification to facilitate treatment decisions. Semin Liver Dis. 2012 Nov;32(4):348-59. doi: 10.1055/s-0032-1329906. Epub 2013 Feb 8.

  PMID: 23397536 BACKGROUND

• Sangro B, Carpanese L, Cianni R, Golfieri R, Gasparini D, Ezziddin S, Paprottka PM, Fiore F, Van Buskirk M, Bilbao JI, Ettorre GM, Salvatori R, Giampalma E, Geatti O, Wilhelm K, Hoffmann RT, Izzo F, Inarrairaegui M, Maini CL, Urigo C, Cappelli A, Vit A, Ahmadzadehfar H, Jakobs TF, Lastoria S; European Network on Radioembolization with Yttrium-90 Resin Microspheres (ENRY). Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology. 2011 Sep 2;54(3):868-78. doi: 10.1002/hep.24451. Epub 2011 Jun 30.

  PMID: 21618574 BACKGROUND

• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.

  PMID: 19097774 BACKGROUND

• Gil-Alzugaray B, Chopitea A, Inarrairaegui M, Bilbao JI, Rodriguez-Fraile M, Rodriguez J, Benito A, Dominguez I, D'Avola D, Herrero JI, Quiroga J, Prieto J, Sangro B. Prognostic factors and prevention of radioembolization-induced liver disease. Hepatology. 2013 Mar;57(3):1078-87. doi: 10.1002/hep.26191. Epub 2013 Feb 15.

  PMID: 23225191 BACKGROUND

• El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH Rd, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 Jun 24;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2. Epub 2017 Apr 20.

  PMID: 28434648 BACKGROUND

• De la Torre-Alaez M, Matilla A, Varela M, Inarrairaegui M, Reig M, Lledo JL, Arenas JI, Lorente S, Testillano M, Marquez L, Iserte G, Argemi J, Gomez-Martin C, Rodriguez-Fraile M, Bilbao JI, Pollock RF, Pohlmann J, Agirrezabal I, Sangro B. Health-related quality of life in patients with unresectable hepatocellular carcinoma treated with SIRT and nivolumab: a sub-analysis of the NASIR-HCC trial. J Patient Rep Outcomes. 2025 Apr 8;9(1):39. doi: 10.1186/s41687-025-00873-6.

  PMID: 40198533 DERIVED

• de la Torre-Alaez M, Matilla A, Varela M, Inarrairaegui M, Reig M, Lledo JL, Arenas JI, Lorente S, Testillano M, Marquez L, Da Fonseca L, Argemi J, Gomez-Martin C, Rodriguez-Fraile M, Bilbao JI, Sangro B. Nivolumab after selective internal radiation therapy for the treatment of hepatocellular carcinoma: a phase 2, single-arm study. J Immunother Cancer. 2022 Nov;10(11):e005457. doi: 10.1136/jitc-2022-005457.

  PMID: 36450386 DERIVED

• Ezponda A, Rodriguez-Fraile M, Morales M, Vivas I, De La Torre M, Sangro B, Bilbao JI. Hepatic Flow Redistribution is Feasible in Patients with Hepatic Malignancies Undergoing Same-Day Work-Up Angiography and Yttrium-90 Microsphere Radioembolization. Cardiovasc Intervent Radiol. 2020 Jul;43(7):987-995. doi: 10.1007/s00270-019-02371-x. Epub 2019 Dec 17.

  PMID: 31848672 DERIVED

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Liver Neoplasms

Interventions

Nivolumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Bruno Sangro, MD

  Liver Unit, Clínica Universidad de Navarra

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 20, 2017
• First Posted: December 20, 2017
• Study Start: September 11, 2017
• Primary Completion: March 1, 2020
• Study Completion: November 4, 2020
• Last Updated: November 4, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

ES (9)