Clinical Trials /

Study of Y90-Radioembolization With Nivolumab in Asians With Hepatocellular Carcinoma

NCT03033446

Description:

The purpose of this study is to evaluate the effect of liver-localised radioembolization and nivolumab on liver cancer.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Y90-Radioembolization With Nivolumab in Asians With Hepatocellular Carcinoma
  • Official Title: A Phase II Open-Label, Single Centre, Non-Randomised Trial Of Y90-Radioembolization In Combination With Nivolumab In Asian Patients With Advanced Hepatocellular Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: CA209-678
  • NCT ID: NCT03033446

Conditions

  • HepatoCellular Carcinoma

Interventions

DrugSynonymsArms
NivolumabOpdivoY90-Radioembolization and Nivolumab

Purpose

The purpose of this study is to evaluate the effect of liver-localised radioembolization and nivolumab on liver cancer.

Detailed Description

      The hypothesis is that liver-localized radioembolization will stimulate tumour and/or HBV
      specific T cell responses that are associated with favourable patient outcomes and that can
      be boosted using nivolumab anti-PD1 checkpoint blockade immunotherapy.

      Primary objective

      To evaluate the response rates of Y90 radioembolization in combination with nivolumab in HCC

      Secondary objectives

        1. To evaluate time to response, response duration, time to treatment progression and sites
           of progression when RE is combined with nivolumab

        2. To assess progression free survival and overall survival when RE is combined with
           nivolumab

        3. To assess the quality of life using the FACT-HEP score and EORTC QLQ-C30

        4. To assess the safety and tolerability of the combination of RE and nivolumab

      Exploratory objectives

        1. To evaluate the relationship between tumor biopsy PD-L1 expression and response to
           treatment with Y90 radioembolization in combination with nivolumab

        2. To assess relationship between blood lymphocyte (e.g., T cell) activation and phenotypic
           profiles with response to treatment with Y90 radioembolization in combination with
           nivolumab, using mass cytometry and fluorescence flow cytometry.

        3. To assess relationship between HCC tumour mutational burden and response to treatment
           with Y90 radioembolization in combination with nivolumab using whole-exome sequencing of
           tumour biopsy samples

        4. Where possible, to evaluate antigen-specific T cell responses to known HBV, HCC tumour
           (including candidate mutation-derived tumour neo-antigens) and other unrelated antigens
           (e.g. CMV, EBV, Influenza) in the blood and to assess kinetic changes in these responses
           associated with response to treatment with Y90 radioembolization in combination with
           nivolumab using mass cytometry and fluorescence flow cytometry.

      Administration of study drug The first dose of nivolumab will be administered 21 days (+/- 3
      days) after completion of RE. [The dose of Yttrium-90 will be determined as per institution
      norm by the Nuclear Medicine physician, based on factors such as the subject's Body Surface
      Area (BSA), the size of the tumour within the liver, and any dose modifications required for
      percent lung shunting between 10 - 20% on the Tc-99MMA scan].

      The dose given will be intravenous 240mg absolute over 30 minutes. Subsequent doses of
      nivolumab will be administered in the outpatient setting at NCCS. After the first dose,
      intravenous nivolumab 240mg will be given every 2 weeks.

      A US or CT guided liver biopsy will be conducted by an interventional radiologist on C1D8
      Subjects will be assessed for the following at EVERY visit: physical examination, ECOG
      status, vital signs, Child-Pugh score and ALBI score CT or MRI scans to assess response to
      treatment will be done before cycle 4, 8, 12 and then after every 12 weeks thereafter (±7
      days).

      FACT-HEP and EORTC QLQ C30 version 3.0 questionnaire at cycle 4 and 8.

      Follow-Up Visit will be done 2-3 months after last dose. Survival updates will be obtained by
      phone every 3-4 months after the follow-up visit and any new anti-cancer treatment given to
      the subject will be recorded.
    

Trial Arms

NameTypeDescriptionInterventions
Y90-Radioembolization and NivolumabExperimental
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          1. Patients with hepatocellular carcinoma (HCC) that is not suitable for resection or
             liver transplant, who are planned for Y90 radioembolization as per institutional
             practice.

          2. Patients must have measurable disease with target lesion in liver, defined as at least
             one lesion that can be accurately measured in at least one dimension (longest diameter
             to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT
             scan.

          3. Diagnosis of HCC confirmed by histology/cytology or clinically by AASLD criteria in
             cirrhotic subjects. Patients without cirrhosis require histological confirmation of
             diagnosis

          4. No prior Y90 radioembolization therapy. Prior local therapies, such as surgery,
             hepatic artery embolization/chemoembolization, radiofrequency ablation, percutaneous
             ethanol injection or cryoabalastion is allowed, if the index lesion(s) remains outside
             of the treatment field or has progressed since prior treatment. Local therapy must
             have been completed at least 4 weeks prior to the baseline scan

          5. Age ≥ 21 years.

          6. ECOG performance status ≤ 2

          7. Life expectancy of greater than 3 months

          8. Only patients with Child-Pugh score for liver cirrhosis of A (sum of scores for five
             parameters: 5-6) will be allowed into this trial

          9. Subjects with HBV infection must be on antiviral therapy per regional standard of care
             guidelines prior to initiation of study therapy. Both HBeAg positive and negative
             subjects will be included.

         10. Patients must have lesions in the liver that are amenable to CT-guided liver biopsy

         11. Patients must have normal organ and marrow function as defined below:

               -  Haemoglobin ≥ 8.5g/dL

               -  Absolute Neutrophil Count ≥ 1.5 x 10^9/L

               -  Platelets ≥ 50 x 10^9/L

               -  Total Bilirubin < 3 mg/dL

               -  AST(SGOT)/ALT (SGPT) ≤ 3 x ULN

               -  Creatinine ≤ 1.5 x ULN or measured/calculated Creatinine Clearance (CrCl) ≥ 60
                  ml/min

         12. Ability to understand and the willingness to sign a written informed consent document.

         13. Any surgery must be more than 28 days before start of study drug and any surgical
             wounds must be completely healed

         14. Female subjects of childbearing potential must have a negative serum or urine
             pregnancy test within 3 days prior to receiving the first dose of study medication,
             and must agree to adequate contraception use from time of signing the informed consent
             through to 120 days after the last dose of the study drug. Male subjects must agree to
             adequate contraception use from time of signing the informed consent through 120 days
             after the last dose of the study drug.

        Exclusion Criteria:

          1. Patients are excluded if they are receiving any other investigational agents or using
             an investigational device within 4 weeks of first dose of treatment. Patients are
             excluded if they are receiving other systemic therapy within 2 weeks of first dose of
             treatment.

          2. Patients with known brain metastases should be excluded from this clinical trial
             because of their poor prognosis and because they often develop progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other adverse events.

          3. Prior use of anti-PD1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or
             any drug specifically targeted T-cell costimulatory checkpoint pathways

          4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that
             would limit compliance with study requirements.

          5. Subjects with any active autoimmune disease or history of known or suspected
             autoimmune disease requiring systemic therapy within the past 2 years, except for
             subjects with vitiligo, resolved childhood asthma/atopy or euthyroid patients with a
             history of Grave's disease (subjects with suspected autoimmune thyroid disorders must
             be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid
             stimulating immunoglobulin prior to randomization). Replacement therapy (e.g. with
             thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
             pituitary insufficiency etc) is not considered a form of systemic treatment

          6. Pregnant women or breastfeeding mothers are excluded from this study because of the
             potential risks to the foetus or baby. Women of child-bearing potential and men must
             agree to use adequate contraception (hormonal or barrier method of birth control;
             abstinence) prior to study entry and for the duration of study participation. Should a
             woman become pregnant or suspect she is pregnant while participating in this study,
             she should inform her treating physician immediately.

          7. Diagnosis of immunodeficiency, including HIV/AIDS

          8. Prior organ allograft or allogeneic bone marrow transplantation

          9. History of severe hypersensitivity reactions to other monoclonal antibodies.

         10. Prisoners or subjects who are involuntarily incarcerated

         11. Subjects who are compulsorily detained for treatment of either a psychiatric or
             physical (eg, infectious disease) illness

         12. Inability to comply with restrictions and prohibited activities/treatments in this
             study

         13. Chronic treatment with systemic steroids or other immunosuppressive agent.

         14. Subjects with concomitant second malignancies (except adequately treated
             non-melanomatous skin cancers, in situ cervical cancers, localized prostate cancer or
             in situ breast cancer) are excluded unless a complete remission was achieved at least
             3 years prior to study entry and no additional therapy is required or anticipated to
             be required

         15. Prior radiation therapy to the liver or upper abdomen

         16. Inability to undergo Y-90 radioembolisation due to inability to cathterise the hepatic
             artery, portal vein thrombosis/occlusion limiting the ability to perform selective
             infusion, Tc-99M MAA scan showing unfavourable shunt fraction between the liver and
             pulmonary parenchyma, any other contraindications to RE as determined by the
             interventional radiologist (e.g. other anatomic variants precluding safe
             administration of Y90, severe peripheral vascular disease, uncorrectable coagulopathy
             etc)
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:21 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response Rate
Time Frame:Tumour assessment at 8 weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Time to Response
Time Frame:From date of first dose with Y90 Radioemolization (RE) until best overall response of Complete Response (CR) or Partial Response (PR) is achieved, up to 12 weeks after last dose of Nivolumab
Safety Issue:
Description:
Measure:Duration of Response
Time Frame:From date of first assessment of CR or PR until the first date that progressive disease or death is documented, up to 2 years
Safety Issue:
Description:
Measure:Time to Progression
Time Frame:From date of first dose with Y90 RE until the first date that progressive disease is documented, up to 12 weeks after last dose of Nivolumab
Safety Issue:
Description:
Measure:Progression Free Survival
Time Frame:From date of first dose with Y90 RE until tumour progression, or death from any cause, up to 12 weeks after last dose of Nivolumab
Safety Issue:
Description:
Measure:Overall Survival
Time Frame:From date of first dose with Y90 RE until death from any cause, up to 2 years
Safety Issue:
Description:
Measure:Quality of Life using the FACT-HEP score
Time Frame:From date of screening until 3 months after last dose of Nivolumab
Safety Issue:
Description:
Measure:Quality of Life using EORTC QLQ-C30
Time Frame:From date of screening until 3 months after last dose of Nivolumab
Safety Issue:
Description:
Measure:Adverse events from the combination of RE and nivolumab assessed by NCI CTCAE v4.0
Time Frame:While receiving study agent and up to 100 days after last dose of Nivolumab
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Centre, Singapore

Last Updated

May 1, 2019