A Pilot Study of Combined Immune Checkpoint Inhibition in Combination With Ablative Therapies in Subjects With Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinomas (BTC)
Condition: Biliary Tract Neoplasms; Liver Cancer; Hepatocellular Carcinoma; Cholangiocarcinoma; Bile Duct Cancer
MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Cholangiocarcinoma; Bile Duct Neoplasms; Biliary Tract Neoplasms
Intervention: Durvalumab; Tremelimumab; Trans-arterial Catheter Chemoembolization (TACE); Radiofrequency Ablation (RFA); Cryoablation
Intervention description: Flat dose of 1500 mg every 4 weeks.; Flat dose of 75 mg every 4 weeks for up to 4 doses.; TACE will be performed on Day 36 (+/-96hrs).; RFA will be performed on Day 36 (+/-96hrs).; Cryoablation will be performed on Day 36 (+/-96hrs).
Intervention MeSH terms: Durvalumab; Tremelimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 54.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: PDL1-Mediated Adaptive Resistance; Monoclonal Antibody; CTLA-4; Ablative Therapy; Combination of Tremelimumab and Durvalumab

Summary:

      BACKGROUND:

        -  Various tumor ablative procedures and techniques have been shown to result in
           immunogenic cell death and induction of a peripheral immune response. The term ablative
           therapies applies to trans-arterial catheter chemoembolization (TACE), radiofrequency
           ablation (RFA) and cryoablation (CA).

        -  The underlying hypothesis of this study is that the effect of immune checkpoint
           inhibition can be enhanced by TACE, CA and RFA in patients with advanced hepatocellular
           carcinoma (HCC) and biliary tract carcinomas (BTC). We have already demonstrated proof
           of principle as well as safety and feasibility of this approach with anti-cytotoxic
           T-lymphocyte-associated antigen 4 (CTLA-4) therapy.

        -  Based on the concept of programmed death-ligand 1 (PDL1)-mediated adaptive resistance
           and the emerging role of programmed cell death protein 1 (PD1) therapy in HCC, we would
           like to evaluate the combination of tremelimumab and durvalumab (with ablative
           therapies) in HCC and BTC.

      Objectives:

      - To preliminarily evaluate the 6-month progression free survival (PFS) of combining
      tremelimumab and durvalumab in patients with advanced HCC (either alone or with cryoablation,
      TACE or RFA) and in patients with advanced biliary tract carcinoma (BTC) (either alone or
      with cryoablation or RFA).

      ELIGIBILITY:

        -  Histologically or cytologically confirmed diagnosis of HCC or biliary tract carcinoma OR
           histopathological confirmation of carcinoma in the setting of clinical and radiological
           characteristics which, together with the pathology, are highly suggestive of a diagnosis
           of HCC (or biliary tract carcinoma).

        -  Childs-Pugh A/B7 cirrhosis only is allowed. If patient does not have cirrhosis, this
           limitation does not apply.

        -  Patients must have disease that is not amenable to potentially curative resection,
           radiofrequency ablation, or liver transplantation.

      DESIGN:

      We will evaluate the combination of tremelimumab and durvalumab (with ablative therapies) in
      cohorts A (HCC; N=40) and B (BTC; N=30). The first N=10 patients in both cohorts will receive
      tremelimumab and durvalumab only (i.e. No interventional radiologic procedures).

        -  A: Advanced HCC, BCLC# Stage B/C

             -  N= 1st 10 pts: No ablative procedure Cryoablation/RFA/TACE##

             -  Tremelimumab 75mg flat dose every (q)28 days for 4 doses; Durvalumab 1500mg flat
                dose q28 days until end of study (EOS)###

             -  40 total: 10 trem+ dur alone; 10 trem+ dur + TACE; 10 trem + dur + RFA; 10 trem +
                dur + cryo

        -  B: Intra/extra-hepatic cholangiocarcinoma

             -  N= 1st 10 patients (pts): No ablative procedure; RFA/ cryoablation

             -  Tremelimumab 75mg flat dose q28 days for 4 doses; Durvalumab 1500mg flat dose q28
                days until EOS###

             -  30 total: 10 trem+ dur alone; 10 trem + dur + RFA; 10 trem

                  -  BCLC = Barcelona clinic liver cancer staging system

                       -  For BCLC stage B patients TACE may be repeated as per standard of care

                            -  EOS = End of study treatment or meeting any of the off-treatment or
                               off study criteria.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Patients must have histopathological confirmation of hepatocellular carcinoma
                  (HCC) or biliary tract carcinoma (BTC) by the Laboratory of Pathology of the
                  National Cancer Institute (NCI) prior to entering this study OR histopathological
                  confirmation of carcinoma in the setting of clinical and radiological
                  characteristics which, together with the pathology, are highly suggestive of a
                  diagnosis of HCC (or biliary tract carcinoma). Fibrolamellar variant is also
                  allowed. The term BTC includes intra or extrahepatic cholangiocarcinoma,
                  gallbladder cancer or ampullary cancer.

               2. Patients must have disease that is not amenable to potentially curative
                  resection, transplantation or ablation. HCC patients must have progressed on,
                  been intolerant to, or refused prior sorafenib therapy. Patients with BTC must
                  have received, been intolerant of or refused at least one line of chemotherapy.

               3. Patients must have multiple tumor lesions (at least 2): one for the ablation
                  procedure and another for evaluation located outside the proposal ablation zone.

               4. Disease must be technically amenable to transhepatic arterial chemoembolization
                  (TACE) (HCC patients only), radiofrequency ablation (RFA), or cryoablation. Each
                  case will be discussed at gastrointestinal (GI) tumor board with interventional
                  radiology. Patients must have evaluable disease.

               5. If liver cirrhosis is present, patient must have a Child-Pugh A/B7 classification

               6. Age 18 years or older

               7. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

               8. Patients must have normal organ and marrow function as defined below:

          -  leukocytes greater than or equal to 3,000/mcL

          -  absolute neutrophil count greater than or equal to 1,000/mcL

          -  platelets greater than or equal to 60,000/mcL

          -  total bilirubin If cirrhosis present: Part of Child Pugh requirement; If no cirrhosis:
             bilirubin should be less than or equal to 2 x upper limit of normal (ULN)

          -  serum albumin If cirrhosis present: Part of Child Pugh requirement; If no cirrhosis:
             albumin should be less than or equal to 2.5g/dl

          -  patients are eligible with alanine aminotransferase (ALT) or aspartate
             aminotransferase (AST) up to 5 x ULN.

          -  creatinine < 1.5x institution upper limit of normal OR creatinine clearance greater
             than or equal to 45 mL/min/1.73 m^2 for patients with creatinine levels above
             institutional normal

             9. Patients must have recovered from any acute toxicity related to prior therapy,
             including surgery. Toxicity should be less than or equal to grade 1 or returned to
             baseline.

             10. Patients must not have other invasive malignancies within the past 5 years (with
             the exception of non-melanoma skin cancers, non-invasive bladder cancer or localized
             prostate cancer for whom systemic therapy is not required).

             11. Patient must be able to understand and willing to sign a written informed consent
             document.

             12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
             female pre-menopausal patients. Women will be considered post-menopausal if they have
             been amenorrheic for 12 months without an alternative medical cause. The following
             age-specific requirements apply:

          -  Women <50 years of age would be considered post-menopausal if they have been
             amenorrheic for 12 months or more following cessation of exogenous hormonal treatments
             and if they have luteinizing hormone and follicle-stimulating hormone levels in the
             post-menopausal range for the institution or underwent surgical sterilization
             (bilateral oophorectomy or hysterectomy).

          -  Women greater than or equal to 50 years of age would be considered post-menopausal if
             they have been

        amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments,
        had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced
        menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral
        oophorectomy, bilateral salpingectomy or hysterectomy. Subject is willing and able to
        comply with the protocol for the duration of the study including undergoing treatment and
        scheduled visits and examinations including follow up.

        13. Body weight greater than 30kg

        EXCLUSION CRITERIA:

          1. Patients who have had standard of care chemotherapy, large field radiotherapy, or
             major surgery must wait 2 weeks prior to entering the study. For recent experimental
             therapies a 28 day period of time must elapse before treatment.

          2. Patients who have undergone prior liver transplantation are ineligible.

          3. Patients with known brain metastases will 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.

          4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             systemic infection, symptomatic congestive heart failure, unstable angina pectoris,
             cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia)
             or psychiatric illness/social situations that would limit compliance with study
             requirements.

          5. History of chronic autoimmune disease (e.g., Addison's disease, multiple sclerosis,
             Graves disease, Hashimoto's thyroiditis, rheumatoid arthritis, hypophysitis, etc.)
             with symptomatic disease within the 3 years before randomization. Note: Active
             vitiligo or a history of vitiligo will not be a basis for exclusion.

          6. Dementia or significantly altered mental status that would prohibit the understanding
             or rendering of Information and Consent and compliance with the requirements of the
             protocol.

          7. Diverticulitis either active or history of within the past 2 years. Note that
             diverticulosis is permitted.

          8. Active or history of inflammatory bowel disease (colitis, Crohn's), irritable bowel
             disease, celiac disease, or other serious, chronic, gastrointestinal conditions
             associated with diarrhea. Active or history of systemic lupus erythematosus or
             Wegener's granulomatosis. Currently receiving immunosuppressive doses of steroids or
             other immunosuppressive medications (inhaled and topical steroids are permitted)

          9. History of sarcoidosis syndrome

         10. Patients should not be vaccinated with live attenuated vaccines within 30 days of
             starting durvalumab or tremelimumab treatment.

         11. Has a known history of Human Immunodeficiency Virus (HIV). HIV-positive patients
             receiving anti-retroviral therapy are excluded from this study due to the possibility
             of pharmacokinetic interactions between antiretroviral medications and tremelimumab.
             HIV positive patients not receiving antiretroviral therapy are excluded due to the
             possibility that tremelimumab may worsen their condition and the likelihood that the
             underlying condition may obscure the attribution of adverse events.

         12. History of hypersensitivity reaction to human or mouse antibody products.

         13. Pregnancy and breast feeding are exclusion factors. The effects of tremelimumab on the
             developing human fetus are unknown. Enrolled patients must agree to use adequate
             contraception prior to study entry, the duration of study participation and 6 months
             after the end of the treatment. Should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this study, she should inform
             her treating physician immediately.

         14. Patients with unhealed surgical wounds for more than 30 days.