A global study in adjuvant setting in patients with hepatocellular carcinoma

Phase 3

Recruiting

• Conditions: Liver cell carcinoma,

• Registration Number: CTRI/2021/01/030856
• Lead Sponsor: AstraZeneca AB

Brief Summary

The purposeof this Phase 3 study is to evaluate the preliminary efficacy and safety ofDurvalumab Monotherapy or in Combination with Bevacizumab as Adjuvant Therapyin Patients With Hepatocellular Carcinoma Who Are at High Risk of RecurrenceAfter Curative Hepatic Resection or Ablation.

 In current study Approximately 888 patients will berandomized in a 1:1:1 ratio in 3 treatment arm

 The crossover between different groups is not possible in this group. All the patientsrandomized into study will be followed for survival follow up

 The patientswill be stratified based on following parameters

 a)    Evidence of microvascular invasion (Yes Vs Novs Unknown)

b)    Geographic region (China vs Asia without Chinaand Japan) vs (Japan +Rest of the world)

 Tumor evaluation usingRECIST 1.1 will be conducted at screening (within 28 days prior torandomization); thereafter every 12 weeks (q12w) ±1 week (after randomization)for the first 24-months and then 24 weeks (q24w) ±1 week, until RECIST1.1-defined radiological PD, consent withdrawal, or death

Detailed Description

Not available

Study Timeline

• Study Start: 2021-01-02
• Last Update Posted: 2024-03-18

Recruitment & Eligibility

• Status: Open to Recruitment
• Sex: All
• Target Recruitment: 888

Inclusion Criteria

• 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.
• 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.
• 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.
• Platelet count ≥ 75000/ µL iv.
• Total bilirubin (TBL) ≤ 2.0 x the upper limit of normal (ULN).
• 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.

Exclusion Criteria

• 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.
• 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.
• 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.
• 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.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
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 Measures

Name	Time	Method
To investigate the immunogenicity of Arm A vs Arm B	Presence of ADA for Durvalumab and Bevacizumab
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
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 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
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
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
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 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 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
To assess patients overall impression of severity of cancer symptoms	PGIS
To assess physical functioning using PROMIS	PROMIS

Trial Locations

Locations (10)

AIG Hospitals (a unit of Asian Institute of Gastroenterology); 🇮🇳 Hyderabad, TELANGANA, India

Aster CMI Hospital; 🇮🇳 Bangalore, KARNATAKA, India

Healthcare Global Enterprises Ltd (HCG); 🇮🇳 Bangalore, KARNATAKA, India

Indraprastha Apollo Hospital, Sarita Vihar; 🇮🇳 Delhi, DELHI, India

Max Super Speciality Hospital, Saket; 🇮🇳 Delhi, DELHI, India

Rajiv Gandhi Cancer Institute and Research Centre; 🇮🇳 Delhi, DELHI, India

Shettys Hospital; 🇮🇳 Bangalore, KARNATAKA, India

Sri Venkateshwara Hospitals; 🇮🇳 Bangalore, KARNATAKA, India

Tata Medical Centre, Kolkata; 🇮🇳 Kolkata, WEST BENGAL, India

Tata Memorial Hospital; 🇮🇳 Mumbai, MAHARASHTRA, India

AIG Hospitals (a unit of Asian Institute of Gastroenterology)

🇮🇳Hyderabad, TELANGANA, India

Dr Vamshi Krishna M

Principal investigator

9959778112

drmvkrishnaonco@gmail.com