Sequential TransArterial Chemoembolization and Stereotactic RadioTherapy Followed by Durvalumab (MEDI4736) and Tremelimumab for Downstaging Hepatocellular Carcinoma for Hepatectomy
Overview
- Phase
- Phase 2
- Status
- Recruiting
- Sponsor
- The University of Hong Kong
- Enrollment
- 33
- Locations
- 2
- Primary Endpoint
- Downstaging for hepatectomy
Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •For inclusion in the study, patients should fulfill the following criteria:
- •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.
- •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.
- •Adult male or female aged \>18 years at time of study entry
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
- •Body weight \>30kg
- •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:
- •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).
Exclusion Criteria
- •Patients should not enter the study if any of the following exclusion criteria are fulfilled:
- •Participation in another clinical study with an investigational product within 4 weeks prior to the first dose of study treatment
- •Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study
- •Any unresolved toxicity NCI 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.
- •Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
- •Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
- •Prior radiotherapy to the region of liver or selective internal radiotherapy
- •Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
Arms & Interventions
Durvalumab + Tremelimumab
1500mg Durvalumab administered IV over 60 minutes on Day 1 of each immunotherapy treatment every 4 weeks until disease progression (PD) and 300mg Tremelimumab administered over 60 minutes on Day 1 of cycle 1.
Intervention: TACE (Procedure)
Durvalumab + Tremelimumab
1500mg Durvalumab administered IV over 60 minutes on Day 1 of each immunotherapy treatment every 4 weeks until disease progression (PD) and 300mg Tremelimumab administered over 60 minutes on Day 1 of cycle 1.
Intervention: SBRT (Radiation)
Durvalumab + Tremelimumab
1500mg Durvalumab administered IV over 60 minutes on Day 1 of each immunotherapy treatment every 4 weeks until disease progression (PD) and 300mg Tremelimumab administered over 60 minutes on Day 1 of cycle 1.
Intervention: Durvalumab (Drug)
Durvalumab + Tremelimumab
1500mg Durvalumab administered IV over 60 minutes on Day 1 of each immunotherapy treatment every 4 weeks until disease progression (PD) and 300mg Tremelimumab administered over 60 minutes on Day 1 of cycle 1.
Intervention: Tremelimumab (Drug)
Outcomes
Primary Outcomes
Downstaging for hepatectomy
Time Frame: 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 Outcomes
- 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)
- Toxicity tolerability measurement in treatment related procedure(From the date of screening to 90 days after last treatment, around 3 years and 90 days)
- 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)
- 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)
- Overall survival (OS)(From the date of first study treatment to the date of death from any cause, assessed up to 5 years)
- 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)
- 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)