HCC
Conditions
Keywords
HCC, TACE, SBRT, immunotherapy, hepatocellular carcinoma, liver cancer, unresectable, large liver tumour
Brief summary
This study is a prospective phase II, single arm mono-institutional study conducted in Queen Mary Hospital (Hong Kong) assessing the efficacy and safety of the sequential administration of trans-arterial chemo-embolization (TACE) and stereotactic body radiotherapy (SBRT) with immune checkpoint inhibitors in unresectable hepatocellular carcinoma (HCC) patients.
Detailed description
Hepatocellular carcinoma (HCC) is a serious global health problem. It ranks the fifth in incidence and third in cancer-related mortality at Hong Kong in 2015. The disease has high mortality rate, and surgery is the only curative therapy although only 30% of patients are diagnosed early enough to undergo liver resection or transplantation or radiofrequency ablation (RFA). For inoperable patients with disease limited to liver, trans-arterial chemo-embolization (TACE) is the most commonly used therapy. Previous randomized studies have demonstrated its survival benefit, however it rarely cures the disease; also its efficacy is very limited in patients with sizable tumor or multi-focal diseases. Efforts have been made to improve the response of treatment, but none has consistently demonstrated the benefit. As a result, over the past decade, there is no major advancement in the treatment strategy for intermediate stage HCC patients. Recently, stereotactic body radiotherapy (SBRT) has emerged as one of the promising local therapy of HCC. This advanced radiotherapy technique allows killing of cancer cells by delivering a potent dose of radiation with excellent geometric precision. Data have demonstrated its favorable local control rate and toxicity profile in locally advanced HCC. Further, recent studies, including our series, indicated that combining SBRT and TACE is therapeutically superior. As such, it is postulated that combined TACE+SBRT is a more potent local therapy than TACE in preventing tumor progression, and it may potentially translate into survival benefit. The recent discovery in immune-oncology represents another breakthrough in management of HCC. Pre-clinical data showed that there is high expression of immunosuppressive cells and up-regulation of programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoints in the HCC microenvironment; it provides the rationale for immunotherapy to be used in this setting. This premise was supported by several early phase clinical studies, in which anti-PD-1/programmed death ligand 1 (PD-L1) therapy resulted in a durable response and favorable survival. More intriguingly, there are scientific and clinical data in supporting the synergy between immune checkpoint inhibitors (ICI) and SBRT for both local tumor regression and distant control (out-of-the-field abscopal) effect. For high risk HCC, such approach may warrant further exploration. Based on all these, a hypothesis is made that combined TACE+SBRT followed by immunotherapy is a promising strategy in treating unresectable HCC. In this single-arm prospective phase II study, it is aimed at evaluating the efficacy and safety of this treatment regime.
Interventions
PROCEDURETACE
Procedure of TACE will be standardized.
RADIATIONSBRT
SBRT screening and planning will be performed by radiation therapists, medical physicists, and oncologists.
DRUGDurvalumab
1500mg Durvalumab administered IV over 60 minutes on Day 1 of each immunotherapy treatment every 4 weeks until disease progression (PD)
DRUGTremelimumab
300mg Tremelimumab administered over 60 minutes on Day 1 of cycle 1.
Sponsors
The University of Hong Kong
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For inclusion in the study, patients should fulfill the following criteria: 1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. 2. Diagnosis of unresectable HCC confirmed pathologically or made according to American Association for the Study of Liver Diseases (AASLD) practice guideline 2010: patients with cirrhosis of any etiology and patients with chronic hepatitis B (HBV) who may not have fully developed cirrhosis, the presence of liver nodule \>1cm and demonstrated in a single contrast-enhanced dynamic imaging \[either computed tomography (CT) or magnetic resonance imaging (MRI)\] of intense arterial uptake and washout in portal venous and delayed phases. 3. Adult male or female aged \>18 years at time of study entry 4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 5. Body weight \>30kg 6. 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 months without an alternative medical cause. The following age-specific requirements apply: 7. 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 or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). 8. 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, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 9. Must have a life expectancy of at least 12 weeks 10. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. 11. Tumor size 5-25cm and number of lesions ≤3 12. Portal vein involvement (Vp1-3) is allowed: Vp1, presence of a tumor thrombus distal to, but not within, the second-order branches of the portal vein; Vp2, presence of a tumor thrombus in the second-order branches of the portal vein; Vp3, presence of a tumor thrombus in the first-order branches of the portal vein. 13. Liver volume minus gross tumor volume (GTV) \> 700cc 14. Child-Pugh liver function class A-B7 15. No prior immunotherapy 16. Subjects with confirmed concomitant HBV infection (defined as HBsAg positive or HBV DNA detectable) that are eligible for inclusion must be treated with antiviral therapy (per local institutional practice) prior to enrollment to ensure adequate viral suppression (HBV DNA \< 2000 IU/mL), must remain on antiviral therapy for the study duration, and continue therapy for 6 months after the last dose of investigational product(s) 17. At least one measurable lesion according to RECIST v1.1. Adequate normal organ and marrow function as defined below: * Haemoglobin ≥ 9.0 g/dL * Absolute neutrophil count (ANC ≥1.5 (or 1.0) x (\> 1500 per mm\^3) * Platelet count ≥ 75 x 109/L (\>75,000 per mm\^3) * Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). * AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN * Measured creatinine clearance (CL) \>45 mL/min or Calculated creatinine clearance CL\>45 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
Exclusion criteria
Patients should not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Downstaging for hepatectomy | From the date of first study treatment to the date of last study treatment, an average of 3 years | To assess the number of patients amendable to curative surgical interventions (resection or radiofrequency ablation) after successful down-sizing of tumor(s) by intervention in HCC patients treated with combined TACE and SBRT followed by Durvalumab plus Tremelimumab |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to progression (TTP) | From the date of first study treatment to radiographically documented progression according to mRECIST 1.1, assessed up to 3 years | measured from the date of first study treatment to radiographically documented progression according to mRECIST 1.1. This does not include death from any cause. |
| Progression-free survival (PFS) | From the date of first study treatment to radiographically documented progression according to mRECIST 1.1 or death from any cause, whichever occurs first, assessed up to 3 years | measured from the date of first study treatment to radiographically documented progression according to mRECIST 1.1 or death from any cause (whichever occurs first). Participants alive and without disease progression or lost to follow-up will be censored at the date of their last radiographic assessment. |
| Overall survival (OS) | From the date of first study treatment to the date of death from any cause, assessed up to 5 years | measured from date of first study treatment to the date of death from any cause |
| Response rate measured by mRECIST criteria | From the date of screening to radiographically documented progression according to mRECIST 1.1, assessed up to 3 years | Complete response (CR): Disappearance of any intra-tumoral arterial enhancement in all target lesions Partial response (PR): At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions Stable disease (SD): Any cases that do not qualify for either partial response or progressive disease Progressive disease (PD): An increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started |
| Questionnaire based Quality of Life (QoL) assessment | From the date of screening to radiographically documented progression according to mRECIST 1.1, an average of 3 years | To evaluate the patient-reported quality of life (QoL) treated with combined TACE and SBRT followed by Durvalumab plus Tremelimumab. Questionnaires EORTC-QLQ-C30 and FACT Hep will be used |
| Pathological response | From the date of first study treatment to amendable to surgery after receiving combined TACE and SBRT followed by Durvalumab plus Tremelimumab, whichever occurs first, assessed up to 5 years | Defined as the percentage of surface with non-viable cancer cells (represented by necrosis or fibrosis, the ultimate stage of necrosis) in relation to the total tumor area and will be equal to: 100% - viable cancer cells (%). If there are multiple tumors, the mean percentage will be used. Pathological complete response (pCR) is defined by the absence of viable tumor cells in any nodule. |
| Toxicity tolerability measurement in treatment related procedure | From the date of screening to 90 days after last treatment, around 3 years and 90 days | To measure the toxicities in HCC patients treated with combined TACE and SBRT followed by Durvalumab plus Tremelimumab. Dosage used will be recorded each time together with the response of patients. If any adverse event happens, the highest dosage will be noted down. |
Countries
Hong Kong
Contacts
Primary ContactAlbert CHAN
Outcome results
None listed