Clinical Trials List
Protocol NumberD419CC00002
NCT Number(ClinicalTrials.gov Identfier)NCT03298451
Active
2017-11-01 - 2027-12-31
Phase III
Recruiting1
Terminated9
ICD-10C22
Malignant neoplasm of liver and intrahepatic bile ducts
ICD-10C22.0
Liver cell carcinoma
A Randomized, Open-label, Multi-center Phase III Study of Durvalumab and Tremelimumab as First-line Treatment in Patients With Advanced Hepatocellular Carcinoma
-
Trial Applicant
-
Sponsor
AstraZeneca
-
Trial scale
Multi-Regional Multi-Center
-
Update
2026/02/01
Investigators and Locations
Co-Principal Investigator
- Ming-Huang Chen Division of Hematology & Oncology
- Yee Chao Division of Hematology & Oncology
- Chung-Pin Li Division of Hematology & Oncology
- Rheun-Chuan Lee Division of Hematology & Oncology
- Yi-Hsiang Huang Division of Hematology & Oncology
- Yi-Ping Hung Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
9 Completed
Audit
None
Co-Principal Investigator
- 簡世杰 Digestive System Department
- Shang-Yin Wu Division of Hematology & Oncology
- Chiu Hung Chiu Digestive System Department
- Yih-Jyh Lin Division of General Surgery
- 劉奕廷 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Completed
Co-Principal Investigator
- Chien-Hung Chen Digestive System Department
- YU-YUN SHAO Division of Hematology & Oncology
- Chiun Hsu Division of Hematology & Oncology
- 呂理駿 Division of Hematology & Oncology
- Chih-Hung Hsu Division of Hematology & Oncology
- Ying-Chun Shen Division of Hematology & Oncology
- 林宗哲 Division of Hematology & Oncology
- 梁逸歆 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Completed
Co-Principal Investigator
- Chen-Chun Lin Digestive System Department
- 呂嘉偉 Division of Radiology
- Chia-Hsun Hsieh Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Completed
The Actual Total Number of Participants Enrolled
0 Completed
The Actual Total Number of Participants Enrolled
0 Completed
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Completed
Co-Principal Investigator
- 許家豪 Division of General Surgery
- Hsueh-Chou Lai Digestive System Department
- Li-Yuan Bai Division of Hematology & Oncology
- Po-Heng Chuang Digestive System Department
The Actual Total Number of Participants Enrolled
0 Completed
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Completed
The Actual Total Number of Participants Enrolled
0 Recruiting
Condition/Disease
Hepatocellular Carcinoma (HCC)
Objectives
Primary objective:
To assess the efficacy of durvalumab 1500 mg
plus tremelimumab 75 mg×4 doses compared
with sorafenib 400 mg BID
Key secondary objectives:
-To assess the efficacy of durvalumab 1500 mg
plus tremelimumab 300 mg×1 dose combination
therapy compared with sorafenib 400 mg BID
-To assess the efficacy of durvalumab 1500 mg
monotherapy compared with sorafenib 400 mg
BID
Test Drug
Durvalumab/ Tremelimumab
Active Ingredient
Humanized anti-CTLA-4 mAb
Humanized anti-PD-L1 mAb
Humanized anti-PD-L1 mAb
Dosage Form
injection
Dosage
20
50
50
Endpoints
Primary Outcome Measures :
Overall Survival (OS) [ Time Frame: From the date of randomization until death due to any cause, assessed up to 4 years. ]
Secondary Outcome Measures :
Time to Progression (TTP) [ Time Frame: From randomization until objective tumor progression, assessed up to 4 years. ]
Progression-free survival (PFS) [ Time Frame: From date of randomization until the date of objective disease progression or death, assessed up to 4 years. ]
Objective response rate (ORR) [ Time Frame: Until progression, assessed up to 4 years. ]
Disease control rate (DCR) [ Time Frame: Until progression, assessed up to 4 years. ]
Duration of response (DoR) [ Time Frame: From the date of first documented response (RECIST 1.1.) until the first date of documented progression or death in the absence of disease progression, assessed up to 4 years. ]
Other Outcome Measures:
Adverse events [ Time Frame: From the time of signature of informed consent, throughout the treatment period, and up to the follow-up period, assessed up to 4 years ]
Overall Survival (OS) [ Time Frame: From the date of randomization until death due to any cause, assessed up to 4 years. ]
Secondary Outcome Measures :
Time to Progression (TTP) [ Time Frame: From randomization until objective tumor progression, assessed up to 4 years. ]
Progression-free survival (PFS) [ Time Frame: From date of randomization until the date of objective disease progression or death, assessed up to 4 years. ]
Objective response rate (ORR) [ Time Frame: Until progression, assessed up to 4 years. ]
Disease control rate (DCR) [ Time Frame: Until progression, assessed up to 4 years. ]
Duration of response (DoR) [ Time Frame: From the date of first documented response (RECIST 1.1.) until the first date of documented progression or death in the absence of disease progression, assessed up to 4 years. ]
Other Outcome Measures:
Adverse events [ Time Frame: From the time of signature of informed consent, throughout the treatment period, and up to the follow-up period, assessed up to 4 years ]
Inclution Criteria
Inclusion criteria
For inclusion in the study, patients should fulfill the following criteria:
1. Age ≥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
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.
For inclusion in the study, patients should fulfill the following criteria:
1. Age ≥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
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
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
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 [eg, colitis or Crohn's disease], diverticulitis [with the
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease,
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 Hashimoto syndrome) stable on
hormone replacement
Any chronic skin condition that does not require systemic therapy
Patients with celiac disease controlled by diet alone
18. Confirmed HBV infection must not be co-infected with HCV (as indicated by the
absence of anti-HCV antibodies) or hepatitis D virus (HDV; as indicated by the
absence of anti-HDV antibodies).
19. Confirmed HCV infection must not be co-infected with HBV as defined by negative
HBsAg. Patients with confirmed HCV infection who are negative for HBsAg, but
positive for anti-HBc with detectable HBV DNA, are eligible but must be started on
active antiviral therapy (for HBV) prior to enrollment to ensure adequate viral
suppression (HBV DNA ≤2000 IU/mL).
20. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, ILD, serious chronic GI conditions associated
with diarrhea, or psychiatric illness/social situations that would limit compliance
with study requirement, substantially increase the risk of incurring AEs, or
compromise the ability of the patient to give written informed consent.
21. History of another primary malignancy except for:
Malignancy treated with curative intent and with no known active disease
≥5 years before the first dose of study drug(s) and of low potential risk for
recurrence
Adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease
Adequately treated carcinoma in situ without evidence of disease
22. History of leptomeningeal carcinomatosis.
23. Brain metastases or spinal cord compression. Patients with suspected brain
metastases at screening should have an MRI (preferred) or CT, each preferably with
IV contrast of the brain prior to study entry.
24. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and
HCC.
25. History of active primary immunodeficiency.
26. Active infection including tuberculosis (TB) (clinical evaluation that includes
clinical history, physical examination and radiographic findings, and TB testing in
line with local practice), or human immunodeficiency virus (positive human HIV
1/2 antibodies).
27. Current or prior use of immunosuppressive medication within 14 days before the
first dose of study drug(s). The following are exceptions to this criterion:
Intranasal, inhaled, topical steroids, or local steroid injections (eg,
intra-articular injection)
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent
Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication)
28. Receipt of live attenuated vaccine within 30 days prior to the first dose of study
drug(s). Note: Patients, if enrolled, should not receive live vaccine while receiving
study drug(s) and up to 30 days after the last dose of study drug(s).
29. 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 or 180 days
after the last dose of durvalumab plus tremelimumab combination therapy. Not
engaging in sexual activity, as per the patient’s preferred and usual lifestyle, for the
total duration of the treatment and washout periods is an acceptable practice.
30. Prior randomization or treatment in a previous durvalumab and/or tremelimumab
clinical study regardless of treatment arm assignment.
31. Patients who have received anti-PD-1, anti PD-L1, or anti CTLA-4 prior to the first
dose of study drug(s)
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
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 [eg, colitis or Crohn's disease], diverticulitis [with the
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease,
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 Hashimoto syndrome) stable on
hormone replacement
Any chronic skin condition that does not require systemic therapy
Patients with celiac disease controlled by diet alone
18. Confirmed HBV infection must not be co-infected with HCV (as indicated by the
absence of anti-HCV antibodies) or hepatitis D virus (HDV; as indicated by the
absence of anti-HDV antibodies).
19. Confirmed HCV infection must not be co-infected with HBV as defined by negative
HBsAg. Patients with confirmed HCV infection who are negative for HBsAg, but
positive for anti-HBc with detectable HBV DNA, are eligible but must be started on
active antiviral therapy (for HBV) prior to enrollment to ensure adequate viral
suppression (HBV DNA ≤2000 IU/mL).
20. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, ILD, serious chronic GI conditions associated
with diarrhea, or psychiatric illness/social situations that would limit compliance
with study requirement, substantially increase the risk of incurring AEs, or
compromise the ability of the patient to give written informed consent.
21. History of another primary malignancy except for:
Malignancy treated with curative intent and with no known active disease
≥5 years before the first dose of study drug(s) and of low potential risk for
recurrence
Adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease
Adequately treated carcinoma in situ without evidence of disease
22. History of leptomeningeal carcinomatosis.
23. Brain metastases or spinal cord compression. Patients with suspected brain
metastases at screening should have an MRI (preferred) or CT, each preferably with
IV contrast of the brain prior to study entry.
24. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and
HCC.
25. History of active primary immunodeficiency.
26. Active infection including tuberculosis (TB) (clinical evaluation that includes
clinical history, physical examination and radiographic findings, and TB testing in
line with local practice), or human immunodeficiency virus (positive human HIV
1/2 antibodies).
27. Current or prior use of immunosuppressive medication within 14 days before the
first dose of study drug(s). The following are exceptions to this criterion:
Intranasal, inhaled, topical steroids, or local steroid injections (eg,
intra-articular injection)
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent
Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication)
28. Receipt of live attenuated vaccine within 30 days prior to the first dose of study
drug(s). Note: Patients, if enrolled, should not receive live vaccine while receiving
study drug(s) and up to 30 days after the last dose of study drug(s).
29. 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 or 180 days
after the last dose of durvalumab plus tremelimumab combination therapy. Not
engaging in sexual activity, as per the patient’s preferred and usual lifestyle, for the
total duration of the treatment and washout periods is an acceptable practice.
30. Prior randomization or treatment in a previous durvalumab and/or tremelimumab
clinical study regardless of treatment arm assignment.
31. Patients who have received anti-PD-1, anti PD-L1, or anti CTLA-4 prior to the first
dose of study drug(s)
The Estimated Number of Participants
-
Taiwan
120 participants
-
Global
1310 participants
