A Phase 2 Study of Tremelimumab (Day 1 only), Durvalumab (MEDI4736) and Trans-arterial catheter chemoembolization (TACE)in patients with advanced Hepatocellular Carcinoma (HCC)

Prior treatment

• Patients who have had standard of care chemotherapy, large field radiotherapy, or major surgery must wait 4 weeks prior to entering the study.
• Patients who have undergone prior liver transplantation are ineligible.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
• Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent
• 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. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening. Participants with a past or resolved HBV infection (defined as the presence of anti‑HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Adjust wording as necessary and consider evaluating at screening for studies with known hepatotoxicity or other relevant requirements.
• 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 (see section 4.1 and 4.2) 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. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or180 days after the last dose of durvalumab and tremelimumab combination therapy
• Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
• Patients with unhealed surgical wounds for more than 30 days.

Other illness

• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consentHistory 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.
• 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.
• Diverticulitis either active or history of within the past 2 years. Note that diverticulosis is permitted.
• Active or history of inflammatory bowel disease (colitis, Crohn’s). Active or history of systemic lupus erythematosus or Wegener’s granulomatosis.
• ● Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)Patients should not be vaccinated with live attenuated vaccines within 30 days of starting durvalumab or tremelimumab treatment.
• History of hypersensitivity reaction to human or mouse antibody products.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

Other

• 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.

• Patients must have histopathological confirmation of hepatocellular carcinoma (HCC) 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. Fibrolamellar variant is also allowed. No prior systemic therapy for advanced HCC is permitted, though investigator discretion is allowed for patients who discontinued sorafenib/lenvatinib for tolerability reasons
• Body weight >30kg
• Patients must have normal organ and marrow function as defined below: o Haemoglobin ≥9.0 g/dL o Absolute neutrophil count (ANC ≥1.0 × 109 /L) o Platelet count ≥75 × 109/L o Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). <> o AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN o Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine clearance CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
• ● Patients must have recovered from any acute toxicity related to prior therapy, including surgery. Toxicity should be ≤ grade 1 or returned to baseline.
• Men and women of all races and ethnic groups are eligible for this trial.
  • ● 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).
  • Patient must be able to understand and willing to sign a written informed consent document
  • 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 ≥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
  • Patients must have HCC with evidence of extrahepatic disease that is not amenable to potentially curative resection, transplantation or ablation. Staging as per BCLC group C.
  • Disease must be technically amenable to transhepatic arterial chemoembolization (TACE) and the provision of TACE must be considered to be a reasonable intervention as decided at the GI MDT at the Mater Misericordiae University Hospital (MMUH). Each prospective case will be discussed at this tumor board with interventional radiology and a unanimous consensus across the disciplines of medical oncology, hepatology and interventional radiology must be reached as to the suitability of each patient for this protocol based on the distribution of their disease.
  • If liver cirrhosis is present, patient must have a Child-Pugh A/B7 classification.
  • Age >18 years
  • ECOG performance status 0-1 with a life expectancy of at least 12 weeks