CTRI/2021/01/030856 [Registered on: 29/01/2021] Trial Registered Prospectively
Last Modified On:
31/07/2025
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Randomized, Parallel Group, Multiple Arm Trial
Public Title of Study
A global study in adjuvant setting in patients with hepatocellular carcinoma
Scientific Title of Study
A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multi-center Study of Durvalumab Monotherapy or in Combination with Bevacizumab as Adjuvant Therapy in Patients With Hepatocellular Carcinoma Who Are at High Risk of Recurrence After Curative Hepatic Resection or Ablation (EMERALD-2)
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
D910DC00001 Version 2.0 dated 20 DEC 2019
Protocol Number
NCT03847428
ClinicalTrials.gov
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Senior Director, Oncology Country Head Site Management and Monitoring – India
Affiliation
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road, Bangalore
Bangalore KARNATAKA 560045 India
Phone
91-9845079472
Fax
91-8067748857
Email
Sandeep.AV@astrazeneca.com
Source of Monetary or Material Support
AstraZeneca AB
151 85 Sodertalje, Sweden
Primary Sponsor
Name
AstraZeneca AB
Address
151 85 Sodertalje, Sweden
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
AstraZeneca Pharma India Ltd
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road, Bangalore – 560045
Countries of Recruitment
Australia Austria Brazil Canada China France Germany Hong Kong India Italy Japan Peru Philippines Poland Republic of Korea Russian Federation Taiwan Thailand Turkey United States of America Viet Nam
AIG Hospitals (a unit of Asian Institute of Gastroenterology)
No 136, Plot No 2/3/4/5 Survey,
136/1, Mindspace Road, Gachibowli,
Pin Code 500032, Hyderabad TELANGANA
9959778112
drmvkrishnaonco@gmail.com
Dr Vijay Agarwal
Aster CMI Hospital
Dept. of Medical Oncology
#43/2 New Airport Road, NH-7 Sahakara Nagar
Hebbal , PIN 560092 Bangalore KARNATAKA
8971072222
drvijay.agarwal@asterhospital.com
Dr Satheesh CT
Healthcare Global Enterprises Ltd (HCG)
Healthcare Global Enterprises Ltd
HCG Towers # 8 , P. Kalinga Rao Road
Sampangi Ram Nagar
PIN -560027
Bangalore KARNATAKA
9242698750
drsatheeshct@gmail.com
Dr Dipanjan Panda
Indraprastha Apollo Hospital, Sarita Vihar
Consultant Medical Oncologist
Delhi-Mathura Road, Sarita Vihar
PIN 110076 New Delhi DELHI
954094693 1126823629 dipanjan.panda@gmail.com
Dr Sandeep Batra
Max Super Speciality Hospital, Saket
Associate Director,
Dept. of Medical Oncology,
Max Super Speciality Hospital,
Saket, (A unit of Devki Devi Foundation),
2, Press Enclave Road, Saket, PIN 110017, New Delhi DELHI
9811035061
Sandeep.Batra@maxhealthcare.com
Dr Sumit Goyal
Rajiv Gandhi Cancer Institute and Research Centre
Dept. of Medical Oncology
Senior Consultant and Unit Head Medical Oncology
Sector-5 Rohini PIN-110085 New Delhi DELHI
8447274181 01147022222 drsumittrials@gmail.com
Dr Lokesh KN
Shettys Hospital
Dept. of Medical Oncology
Kaveri Nagar, Kodichikkanahalli,
Bommanhalli, PIN 560068
Bangalore KARNATAKA
8971609070 8025732887 knloki@gmail.com
Dr Satheesh C T
Sri Venkateshwara Hospitals
Dept. of Medical Oncology
27, 29th Main Road, Rashtra Kuvempu Nagara,
BTM 2nd stage, BTM layout,
PIN-560076,
Bangalore KARNATAKA
9242698750 08040416700 drsatheeshct@gmail.com
Dr Arnab Bhattacharjee
Tata Medical Centre, Kolkata
Consultant Medical Oncologist
14-Mar, E-W, New Town Rajarahat PIN-700160 Kolkata WEST BENGAL
7980672007 03366057000 arnab1572@gmail.com
Dr Vikas SureshChand Ostwal
Tata Memorial Hospital
3rd Floor, Homibaba, Building, Room no: 323, Dr. Ernest Borges Marg, Parel, PIN 400012 Mumbai MAHARASHTRA
Institutional Ethics Committee- Devki Devi Foundation
Approved
Institutional Review Board Rajiv Gandhi Cancer Institute and Research Centre
Approved
Institutional Review Board Tata Medical Centre, Kolkata
Approved
Shetty’s Hospital Ethics Committee
Submittted/Under Review
Sri Venkateshwara Hospital Ethics Committee
Approved
Tata Memorial Hospital Institutional Ethics Committee
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: C220||Liver cell carcinoma,
Intervention / Comparator Agent
Type
Name
Details
Intervention
Durvalumab
Arm A: 1120 mg (Q3W) + Bevacizumab 15mg/kg (Q3W) for upto maximum of 12 months (18 doses or cycles)
Comparator Agent
Durvalumab Monotherapy or in Combination with Bevacizumab
Arm B: Durvalumab 1120 mg (Q3W) + Bevacizumab Placebo 15mg/kg (Q3W) for upto maximum of 12 months (18 doses or cycles)
Comparator Agent
Placebo
Arm C: Durvalumab Placebo (Q3W) + Bevacizumab Placebo (Q3W) for upto maximum of 12 months (18 doses or cycles)
Inclusion Criteria
Age From
18.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
1. Provision of signed and dated written informed consent form (ICF) and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the US, EU Data Privacy Directive in the EU) obtained from the patient prior to any mandatory study-specific procedures, sampling, and analyses, including screening evaluations.
2. Age ≥18 years at the time of screening. .
3. Histologically or cytologically, newly diagnosed, confirmed HCC and successfully completed curative therapy (resection or ablation).
a. Hepatic resection and have the following pathologic and/or radiologic findings from surgery:
(i) Any size with microvascular invasion (clear pathologic assessment on microvascular invasion: Yes or No) or satellite tumor
(ii) 3 or less tumors, with at least one >5 cm
(iii) 4 or more tumors, ≤5 cm each
b. Ablation (radiofrequency or microwave, cryoablation, or PEI per institutional standard. Embolisation (e.g. TACE/TAE) is acceptable so long as it is part of the local planned ablative process) where all curative procedures are completed within a 12 week window, and have the following radiologic findings prior to ablation:
(i) Solitary tumor, 3 to 5 cm
(ii) 2 to 4 tumors, ≤5 cm each
(iii) Exclude patients with 5 or more tumors.
4. Patients to be randomized within 12 weeks of completion of curative hepatic resection, or final curative ablation procedure.
5. Imaging confirmed disease-free status within 28 days prior to randomization.
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1 at enrollment.
7. Child-Pugh score of 5 or 6.
8. Patients with HBV infection (as characterized by positive hepatitis B virus surface antigen [HBsAg] and/or anti-hepatitis B core antibodies (HBcAbs) with detectable HBV deoxyribonucleic acid (DNA) [≥10 IU/mL or above the limit of detection per local laboratory]) must receive antiviral therapy at least after enrollment (sign of ICF) per institutional practice to ensure adequate viral suppression (HBV DNA ≤2000 IU/mL) prior to randomization. Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment. Patients who test positive for anti HBcAb with undetectable HBV DNA (<10 IU/mL or under the limit of detection per local laboratory) do not require antiviral therapy. These patients will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥10 IU/mL or above the limit of detection per local laboratory). Patients with detectable HBV DNA during the study must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment.
9. Patients with HCV infection (as characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody) to be managed per local institutional practice for the study and for 6 months after the last dose of study treatment.
10. 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 month without alternative medical cause. The following age-specific requirements apply:
11. 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.
12. 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, or had chemotherapy-induced menopause with last menses >1 year ago.
13. Women who are surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) are eligible.
14. Adequate organ and marrow function, as defined below. Please note: 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. Please record screening lab values and units below:
i. Hemoglobin ≥ 9g/dL
ii. Absolute neutrophil count ≥ 1000/µL
iii. Platelet count ≥ 75000/ µL
iv. Total bilirubin (TBL) ≤ 2.0 x the upper limit of normal (ULN).
v. ALT and AST ≤ 5 x ULN;
vi. Albumin ≥2.8 g/dL
vii. International normalized ratio ≤1.6 (for patients receiving warfarin, please consult study physician)
viii. Urine protein 2+ or less
ix. Tested blood urea nitrogen or creatinine ≤1.5 × ULN or calculated creatinine clearance (CL) ≥51 mL/min as determined by the Cockcroft Gault formula (using actual WT) or 24-hour urine creatinine CL
ExclusionCriteria
Details
Medical conditions
1. History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered “significantâ€) during the 3 months prior to randomization.
2. History of significant bleeding disorders, vasculitis, or a significant bleeding episode from the GI tract within 3 months prior to study randomization.
3. History of GI perforation and/or fistulae within 6 months prior to randomization.
4. Any history of nephrotic or nephritic syndrome.
5. Evidence of symptomatic congestive heart failure (New York Heart Association II to IV) or symptomatic or poorly controlled cardiac arrhythmia.
6. History of arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization.
7. Uncontrolled arterial hypertension defined by a systolic pressure ≥150 mm Hg or diastolic pressure ≥90 mm Hg despite standard medical management.
8. Serious or non-healing wound, peptic ulcer, or bone fracture within 28 days prior to randomization
9. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
10. Evidence, by Investigator assessment, of varices at risk of bleeding on upper endoscopy or contrast-enhanced cross-sectional imaging undertaken at the screening visit, or within 6 months (24 weeks) of randomization.
11. Evidence of distant metastasis (except regional lymph node metastases related to the disease under study, per Appendix F), co-existing malignant disease or macrovascular invasion on baseline imaging
12. History of hepatic encephalopathy within 12 months prior to randomization or requirement for medications to prevent or control encephalopathy (no lactulose, rifaximin, etc, if used for purposes of hepatic encephalopathy).
13. Evidence of portal vein thrombosis, visible on baseline/eligibility imaging, and patients with Vp1, Vp2, Vp3 and Vp4.
14. Clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (eg, paracentesis) to maintain symptomatic control, within 6 months prior to the first dose of study treatment. (Note:Patients with ascites who have required pharmacologic intervention (eg, diuretics) and who have been on stable doses of diuretics for ascites for ≥2 months before randomization are eligible)
15. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn s disease], diverticulitis [except for diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [eg, granulomatosis with polyangiitis, Graves disease, rheumatoid arthritis, hypophysitis, and uveitis]). The following are exceptions to this criterion:
a. Patients with vitiligo or alopecia
b. Patients with hypothyroidism (eg, following Hashimoto syndrome), stable on hormone replacement
c. Any chronic skin condition that does not require systemic therapy
d. Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician
e. Patients with celiac disease controlled by diet alone
16. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease (ILD), serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase the risk of incurring AEs or compromise the ability of the patient to give written informed consent.
17. History of another primary malignancy except for the following:
i. Prostate cancer of pathologic stage less than or equal to T2cN0M0 determined from a prior prostatectomy without biochemical recurrence and who, in the opinion of the Investigator, are not deemed to require active intervention, or patients with incidental histologic findings of prostate cancer that has not been treated prior to the study and who do not require specific therapy for prostate cancer beyond the surgery described in the Clinical Study Protocol and also are considered to be at low risk for recurrence per the Investigator
ii. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study treatment and of low potential risk for recurrence
ii. Adequately treated non-melanoma skin cancer or lentigo malignant without evidence of disease
iv. Adequately treated carcinoma in situ without evidence of disease
18. Active infection, including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice) or human immunodeficiency virus (HIV; positive for HIV 1/2 antibodies).
19. Active co-infection with both HBV and HCV, or co-infected with HBV and hepatitis D virus.
20. Known allergy or hypersensitivity to any of the study treatments or any of the study treatment excipients.
21. History of aneurysm (Note: Patients with a capped aneurysm may be included but only after consultation with the Study Physician)
22. Major surgery (as defined by the Investigator) within 28 days prior to randomization, or central venous access device placement within 7 days prior to randomization (Note: biopsy from any type of surgery within 28 days is not an exclusion criteria, nor are procedures to treat varices).
23. Receipt of routine treatment for chronic condition with nonsteroidal anti-inflammatory agents (eg, indomethacin, ibuprofen, naproxen, or similar agents) or other anti-platelet agents (eg, clopidogrel, ticlopidine, dipyridamole, or anagrelide). Require minimum washout period of 5 days prior to randomization.
24. Receipt of prior systemic anticancer therapy for HCC.
25. History of allogeneic organ transplantation or those who are on a waiting list for liver transplantation.
26. Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment. Note: Patients, if enrolled, should not receive live vaccine while receiving study treatment and up to 90 days after the last dose of study treatment.
27. Current or prior use of immunosuppressive medication within 14 days before the first dose of study treatment. The following are exceptions to this criterion:
i. Intranasal, inhalational, topical steroids, or local steroid injections (eg, intra-articular injection)
ii. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
iii. Steroids as pre-medication for hypersensitivity reactions (eg, CT-scan premedication)
28. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 6 months after the last dose of study treatment. (Note:Not engaging in sexual activity, per the patient s preferred and usual lifestyle, for the total duration of the treatment and 6 months after the last dose of study treatment is an acceptable practice.)
29. Judgement by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
30. Involvement in the planning and/or conduct of the study for both AstraZeneca staff and/or staff at the study site.
Genetic Research Study (Optional)
31. Exclusion criteria for participation in the optional (DNA) genetics research component of the study include the following:
(a) Previous allogenic bone marrow transplant
Non-leukocyte-depleted whole-blood transfusion in 120 days of genetic sample collection
Method of Generating Random Sequence
Stratified block randomization
Method of Concealment
Centralized
Blinding/Masking
Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded
Primary Outcome
Outcome
TimePoints
To assess the efficacy of Arm B versus Arm C
TRFS using BICR assessments according to RECIST 1.1 (Time frame-Approximately 2 years)
Secondary Outcome
Outcome
TimePoints
To assess the efficacy of Arm A versus Arm C
RFS using BICR assessments according to RECIST 1.1 (Time frame-Approximately 2 years)
To assess the efficacy of Arm A versus Arm C and Arm B versus Arm C
RFS (Recurrence Free Survival) at 24 months and TTR using BICR assessment according to RECIST 1.1
Overall survival at 36 months & Overall survival 48 months
RFS2 PFS2 as assessed by the investigator according to local standard clinical practice
To investigate the relationship between a patient baseline PDL-1 expression and efficacy outcome with Durvalumab by comparing Arm A versus Arm C and Arm B vs Arm C
According to PDL-1 Expression level with the following
• RFS at 24 months and TTR using BICR assessment according to RECIST 1.1
• Overall survival
To assess the efficacy of Arm A versus Arm C and Arm B versus Arm C by evidence of microvascular invasion (Yes vs No or Unknown) and geographic region (China vs [Asia without China and Japan] vs [Japan PLUS Rest of the world)
RFS at 24 months and TTR using BICR assessment according to RECIST 1.1
• Overall survival
To investigate the immunogenicity of Arm A vs Arm B
Presence of ADA for Durvalumab and Bevacizumab
To evaluate the population PK of Arm A vs Arm B
Durvalumab and Bevacizumab concentration of PK parameters
To assess the disease related symptoms impacts, and HRQoL in patients treated in Arm A vs Arm C and Arm B vs Arm C
EORTC-QLQ-30 and EORTC-QLQ HCC 18 time to deterioration in symptoms (abdominal pain , fatigue, appetite loss and nausea), functioning (eg physical) and global health status/QoL
Safety objective
To assess the safety and tolerability of all treatment groups
AEs, physical examinations, vital signs, ECGs, and laboratory findings ECOG PS and Child PUGH Score
To collect blood and tissue sample for analysis of biomarkers and to explore potential biomarkers in residual biological sample that may influence the progression of cancer (prognostic biomarkers) &/or identify the patients likely to have treatment benefit (predictive biomarkers)
Exploratory biomarker analysis which may include
• Somatic Mutations and tumor mutational burdens
• Gene expression profiles within peripheral &.or tumor microsatellite stability index , expression and activity of immune rated pathways &/or genes , viral antigens, RNA or DNA
• Plasma circulating tumor DNA by capture based targeted next generation sequencing assay
To assess patient reported treatment tolerability and global assessment of treatment tolerability
Collection of PROCTCAE symptoms via an electronic device solution (pre-selected items based on treatment groups) and PGI-TT
To assess patients overall impression of severity of cancer symptoms
PGIS
To explore the impact of treatment and disease state on health state utility using EQ-5D-5L
Health state utility based on the EQ-5D-5L health state utility index
To explore the impact of treatment and disease state on health care resource use
Key healthcare resource use beyond mandated visits based on the HOSPAD module
To assess physical functioning using PROMIS
PROMIS
Target Sample Size
Total Sample Size="888" Sample Size from India="30" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
The purpose
of this Phase 3 study is to evaluate the preliminary efficacy and safety of
Durvalumab Monotherapy or in Combination with Bevacizumab as Adjuvant Therapy
in Patients With Hepatocellular Carcinoma Who Are at High Risk of Recurrence
After Curative Hepatic Resection or Ablation.
In current study Approximately 888 patients will be
randomized in a 1:1:1 ratio in 3 treatment arm
The cross
over between different groups is not possible in this group. All the patients
randomized into study will be followed for survival follow up
The patients
will be stratified based on following parameters
a)Evidence of microvascular invasion (Yes Vs No
vs Unknown)
b)Geographic region (China vs Asia without China
and Japan) vs (Japan +Rest of the world)
Tumor evaluation using
RECIST 1.1 will be conducted at screening (within 28 days prior to
randomization); thereafter every 12 weeks (q12w) ±1 week (after randomization)
for the first 24-months and then 24 weeks (q24w) ±1 week, until RECIST
1.1-defined radiological PD, consent withdrawal, or death