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

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.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* 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.
  * Creatinine Clearance \> 40 mL/min.
  * AST and ALT ≤ 5 X ULN
  * Bilirubin ≤ 2 mg/dL
  * INR ≤ 1.8.
  * Albumin ≥ 3.0 g/dL
* Willing and able to comply with immune-monitoring sample collection and required study follow-up.

Exclusion Criteria:

* 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.

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