Health Condition 1: C220- Liver cell carcinoma Health Condition 2: null- Men and women =18 years of age with Unresectable Hepatocellular Carcinoma.
Conditions
Interventions
Intervention1: MEDI4736 monotherapy,
MEDI4736 plus Tremelimumab
combination therapy
: Drug: Durvalumab
Drug: Tremelimumab (Regimen 1)
Drug: Tremelimumab (Regimen 2)
Drug: Durvalumab (Regimen 1)
Sponsors
AstraZeneca AB
Eligibility
Inclusion criteria
Inclusion criteria: 1. Age greater than or equal to 18 years at the time of screening 2. Body weight >30 kg 3. Written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. 4. Confirmed HCC based on histopathological findings from tumor tissues 5. Must not have received prior systemic therapy for HCC 6. Must not be eligible for locoregional therapy for unresectable HCC. For patients who progressed after locoregional therapy for HCC, locoregional therapy must have been completed =28 days prior to the baseline scan for the current study 7. Barcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for locoregional therapy) or stage C 8. Child-Pugh Score class A 9. ECOG performance status of 0 or 1 at enrollment 10. Patients with HBV infection (as characterized by positive hepatitis B surface antigen [HBsAg], detectable HBV DNA, or hepatitis B core antibodies [anti HBc Ab]) and are eligible for inclusion must be treated with antiviral therapy, per institutional practice, to ensure adequate viral suppression (HBV DNA =2000 IU/mL) prior to enrollment. Note: HBV-positive patients must remain on antiviral therapy for the study duration and must continue therapy for 6 months after the last dose of study medication. 11. Patients with HCV infection must have confirmed diagnosis of HCV characterized by the presence of detectable HCV RNA or anti-HCV antibody upon enrollment (management of this disease is per local institutional practice). 12. At least 1 measurable lesion, not previously irradiated, that can be accurately measured at baseline as =10 mm in the longest diameter (except lymph nodes, which must have a short axis =15 mm) with CT or MRI, and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines 13. Adequate organ and marrow function, as defined below. Criteria “a, ? “b, ? “c, ? and “f ? cannot be met with transfusions, infusions, or growth factor support administered within 14 days of starting the first dose a. Hemoglobin =9 g/dL b. Absolute neutrophil count =1000/µL c. Platelet count =75000/µL d. Total bilirubin (TBL) =2.0×ULN e. AST and ALT =5×ULN f. Albumin =2.8 g/dL g. International normalized ratio (INR) =1.6 h. Calculated creatinine clearance =50 mL/minute as determined by Cockcroft Gault (using actual body weight) or 24 hour urine creatinine clearance a. Hemoglobin =9 g/dL b. Absolute neutrophil count =1000/µL c. Platelet count =75000/µL d. Total bilirubin (TBL) =2.0×ULN e. AST and ALT =5×ULN f. Albumin =2.8 g/dL g. International normalized ratio (INR) =1.6 h. Calculated creatinine clearance =50 mL/minute as determined by Cockcroft Gault (using actual body weight) or 24 hour urine creatinine clearance 14. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal as described in Section 3.8
Exclusion criteria
Exclusion criteria: 1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) 2. Previous study drug(s) assignment in the present study. 3. Concurrent enrollment in another clinical study, unless it is an observational (non interventional) clinical study or during the follow-up period of an interventional study. 4. Have received an investigational product within 28 days prior to the first dose of study drug(s) 5. Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Grade =2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria: - Patients with Grade =2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. - Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician. 6. Any concurrent chemotherapy, study drug, or biologic or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable. 7. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. 8. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 28 days of the first dose of study drug(s). 9. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of study drug(s). Note: Local surgery of isolated lesions for palliative intent is acceptable 10. History of allogeneic organ transplantation (eg, liver transplant). 11. History of hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy (eg, no lactulose, rifaximin, etc if used for purposes of hepatic encephalopathy). 12. Ascites that require ongoing paracentesis, within 6 weeks prior to the first scheduled dose, to control symptoms. 13. Main portal vein thrombosis present on imaging 14. Active or prior documented GI variceal bleed or history of upper GI bleeding, ulcers, or esophageal varices with bleeding within 12 months; adequate endoscopic therapy according to institutional standards is required for patients with history of esophageal variceal bleeding or assessed as high risk for esophageal variceal by the treating investigator 15. Patient currently exhibits symptomatic or uncontrolled hypertension defined as diastolic blood pressure >90 mmHg or systolic blood pressure >140 mmHg 16. Any condition interfering with swallowing pills, uncontrolled diarrhea, or other contraindication to oral therapy. 17. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis, Graves isease, rheumatoid arthritis, hypophysitis, uveitis, etc)). Patients without active disease in the last 5 years are excluded unless discussed with the Study Physician and considered appropriate for study participation The following are exceptions to this criterion: - Patients with vitiligo or alopecia - Patients with hypothyroidism (eg, following Has
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To assess the efficacy of durvalumab plus tremelimumab arm compared with sorafenib arm: Overall Survival (Timepoint)Timepoint: Overall Survival | — |
Secondary
| Measure | Time frame |
|---|---|
| To assess disease-related symptoms, impacts, and health-related quality of life (HRQoL) in Durvalumab Monotherapy vs. Sorafenib and Durvalumab plus tremelimumab vs SorafenibTimepoint: Overall Survival;To assess PFS from rechallenge in the durvalumab plus tremelimumab combination arm and to assess PFS from first post-discontinuation therapy in Durvalumab Monotherapy, Durvalumab plus tremelimumab, and Sorafenib armTimepoint: Overall Survival (OS) (Time frame-Approximately 4 years);To assess the efficacy of Durvalumab Monotherapy and Durvalumab plus tremelimumab in patients with an opportunity for 32 weeks of follow-up.Timepoint: ORR, BoR, DOR as per RECIST 1.1;To assess the efficacy of Durvalumab Monotherapy vs. Sorafenib and Durvalumab plus tremelimumab vs Sorafenib armTimepoint: Overall Survival & Progression free survival;To assess the efficacy of Durvalumab Monotherapy vs. Sorafenib and Durvalumab plus tremelimumab vs Sorafenib arm by PD-L1 expression.Timepoint: Overall Survival;To assess the efficacy of Durvalumab Monotherapy vs. Sorafenib arm (for non-inferiority)Timepoint: Overall Survival;To assess the efficacy of Durvalumab Monotherapy vs. Sorafenib arm (for superiority)Timepoint: Overall Survival;To assess the efficacy of Durvalumab Monotherapy vs. Sorafenib arm and Durvalumab plus tremelimumab vs Sorafenib arm using immune-related Response Evaluation Criteria in solid tumors (irRECIST) and modified Response Evaluation Criteria in Solid Tumors (mRECIST) for HCC.Timepoint: Progression free survival & Overall survival;To assess the safety and tolerability profile across all treatment armsTimepoint: Overall Survival;To assess the safety and tolerability profile of all immunotherapy arms with sorafenib arm Timepoint: Overall Survival;To evaluate the population pharmacokinetics (PK) and pharmacodynamics of Durvalumab Monotherapy vs. Durvalumab plus tremelimumab armTimepoint: Overall Survival;To evaluate the population PK and pharmacodynamics of all immunotherapy | — |
Countries
Brazil, Canada, China, France, Germany, Hong Kong, India, Italy, Japan, Republic of Korea, Russian Federation, Spain, Taiwan, Thailand, Ukraine, United States of America, Viet Nam
Contacts
Public ContactMr Sandeep AV
AstraZeneca Pharma India Limited
Outcome results
None listed