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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)

PHRR210310-003410

D910DC00001

2020-CT0582

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

This is a Phase III, randomized, double-blind, placebo-controlled, multi-center, global study to assess the efficacy and safety of durvalumab in combination with bevacizumab or durvalumab monotherapy or placebo as adjuvant therapy. This study will be conducted in patients with HCC who are at high risk of recurrence after curative hepatic resection or ablation.

Regime Classification Priority
2017 - 2022 Global competitiveness and innovation in health Drug Discovery and Development
Start Date Duration in Months Target Completion Date Actual Completion Date
2021-03-01 51 2025-06-01 0000-00-00

Ongoing

Institution Classification Region LTO #
AstraZeneca AB Private Business Sweden LTO-3000002234602
Institution Region
AstraZeneca AB Sweden
Name E-Mail Institution and Institution Address
Mark Joseph Grajo markjoseph.grajo@astrazeneca.com 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippines
Name E-Mail Institution and Institution Address
Mark Joseph Grajo markjoseph.grajo@astrazeneca.com 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippines
Name Expertise Affiliation
Corazon Ngelangel, MD Oncology Asian Hospital and Medical Center
Janus P. Ong, MD, MPH Oncology The Medical City
Jennifer Sandoval-Tan, MD Oncology Philippine General Hospital
Project Location Institutional Ethics Review Board
Asian Hospital and Medical Center Asian Hospital and Medical Center Institutional Review Board
The Medical City The Medical City - Institutional Review Board
Philippine General Hospital Philippine General Hospital Ethics Review Board

Patients With Hepatocellular Carcinoma Who Are at High Risk of Recurrence After Curative Hepatic Resection or Ablation

Recurrence-free survival (RFS) using Blinded independent central review (BICR) assessments according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

  • Recurrence-free survival at 24 months (RS24) and Time to recurrence (TTR) using BICR assessments according to RECIST 1.1
  • Overall survival analysis at 36 months after first patient randomized (OS36), Overall survival analysis at 48 months after first patient randomized (OS48)
  • Recurrence on the next therapy(RFS2)/Progression on the next therapy(PFS2) as assessed by the Investigator according to local standard clinical practice
  • Association of Programmed cell death ligand-1 (PD-L1) expression level with the following:
    • RFS and TTR using BICR assessments according to RECIST 1.1
    • Overall survival (OS)
  • Presence of Antidrug antibody (ADA) for durvalumab and bevacizumab
  • Durvalumab and bevacizumab concentrations and PK parameters
  • EORTC QLQ-C30 and EORTC QLQ-HCC18: Time to deterioration in symptoms (eg, abdominal pain, fatigue, appetite loss, nausea), functioning (eg, physical), and global health status/QoL
  • AEs, physical examination, vital signs, ECG, laboratory findings, Eastern Cooperative Oncology Group Performance status (ECOG PS), and Child-Pugh score
  • Exploratory biomarker analysis, which may include (but is not limited to) the following:
    • Somatic mutations and tumor mutational burden
    • Gene expression profiles within the peripheral and/or tumor, microsatellite stability index, expression and activity of immune-rated pathways and/or genes, viral antigens, RNA, or DNA
    • Plasma circulating tumor DNA by captured-base targeted next-generation sequencing assay
    • Number, phenotype, and expression profile of immune cells such as T cells

Pending

  • Australia
  • Austria
  • Bassas da India
  • Brazil
  • Canada
  • China
  • Egypt
  • France
  • Germany
  • Hong Kong
  • Italy
  • Japan
  • Peru
  • Philippines
  • Poland
  • Russia
  • Singapore
  • South Korea
  • Taiwan
  • Thailand

Clinical Trial

D910DC00001

2020-CT0582

2021-02-24

0000-00-00

10

Unspecified

Unspecified

01 Mar 2021

INCLUSION CRITERIA

Informed consent
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.
The ICF process is described in Appendix A-3.

Age
2 Age ≥18 years at the time of screening. For patients aged


Type of patient and disease characteristics
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 must be randomized within 12 weeks of completion of curative hepatic resection, or final curative ablation procedure.
5 Imaging to confirm 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 (9 Patients with HCV infection (as characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody) must 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. A definition of post-menopausal is provided in Section 5.3.
11 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 × upper limit of normal (ULN)
(e) Aspartate aminotransferase (AST) and ALT ≤5 × ULN
(f) Albumin ≥2.8 g/dL
(g) International normalized ratio ≤1.6 (for patients receiving Warfarin, please consult with the study physician)
(h) Urine protein 2+ or less
(i) 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

Males:
Creatinine CL (mL/min) = WT (kg) × (140 - Age)
                                     72 × serum creatinine (mg/dL)


Females:
Creatinine CL (mL/min) = WT (kg) × (140 - Age) × 0.85
                                     72 × serum creatinine (mg/dL)

Sex
12 Male and female

 

EXCLUSION CRITERIA

Patients are eligible to be included in the study only if none of the exclusion criteria for this study are met. Under no circumstances can there be exceptions to this rule.

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 “significant”) 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.

(a) 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:

(a) 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
(b) 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
(c) Adequately treated non-melanoma skin cancer or lentigo malignant without evidence of disease
(d) 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 (Patients with a capped aneurysm may be included but only after consultation with the Study Physician) Prior/concomitant therapy
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 (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:

(a) Intranasal, inhalational, topical steroids, or local steroid injections (eg, intra-articular injection)
(b) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
(c) Steroids as pre-medication for hypersensitivity reactions (eg, CT-scan premedication)

Other exclusions
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. 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 Judgment 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.


Genetics research study (optional)
31 Exclusion criteria for participation in the optional (DNA) genetics research component of the study include the following:

(a) Previous allogeneic bone marrow transplant
(b) Non-leukocyte-depleted whole-blood transfusion in 120 days of genetic sample

Interventional

Durvalumab, Bevacizumab

This study will screen 1110 patients at 175 sites in 16 countries to achieve a global enrollment target of 888 patients who will be randomized in a 1:1:1 ratio to one of the following treatment groups:

  • Arm A: Durvalumab 1120 mg (Q3W) + bevacizumab 15 mg/kg (Q3W)
  • Arm B: Durvalumab 1120 mg (Q3W) + bevacizumab placebo (Q3W)
  • Arm C: Durvalumab placebo (Q3W) + bevacizumab placebo (Q3W)

None

Randomized

Double Blind

Unspecified

Parallel

to assess the efficacy and safety of durvalumab in combination with bevacizumab or durvalumab monotherapy or placebo as adjuvant therapy.

Phase III

Utilization Utilization Info
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