A single-arm, interventional study combining Immunotherapy and propranolol with/without chemotherapy and propranolol
1. Pancreatic Cancer Durvalumab will be administered once every 4 weeks, in combination with gemcitabine + nab-paclitaxel (day 1/8/15) and continuous propranolol. Tremelimumab will be given on day 1 of cycle 1, which may be repeated at the time of progression in eligible patients. 2. HCC Durvalumab will be administered once every 4 weeks in combination with continuous propranolol. Tremelimumab will be given on day 1 of cycle 1, which may be repeated at the time of progression in eligible patients. 3. Biliary Tract Cancer (BTC, Cholangiocarcinoma of the gallbladder or bile ducts) Durvalumab will be administered once every 3 weeks, in combination with cisplatin + gemcitabine (day 1/8) and continuous propranolol. Tremelimumab will be given on day 1 of cycle 1, which may be repeated at the time of progression in eligible patients.
Patients must be 18 years of age or older.
Body Weight >30kg
Life expectancy of at least 12 weeks
Patients must have a diagnosis of histologically documented advanced pancreatic adenocarcinoma, hepatocellular carcinoma, or BTC not amenable to curative intent local therapy or surgery. For the histologies there must only one histology type present ie not mixed cholangiocarcinoma/HCC. For the HCC cohort if tissue biopsy if histological diagnosis is not possible, diagnosis can be made clinically by American Association for the study of liver diseases (AASLD) criteria in cirrhotic patients.
Patients who have received prior palliative systemic treatment for their advanced cancer.
History of pneumonitis requiring treatment with steroids.
History of active interstitial lung disease.
For HCC patients they must have a Child Pugh status of A.
Single group
Durvalumab
Biological/VaccineIt is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of programmed cell death ligand 1 with the PD-1. Durvalumab is known as a checkpoint inhibitor drug
Gemcitabine
DrugGemcitabine is a nucleoside analog and a chemotherapeutic agent. As a prodrug, gemcitabine is transformed into its active metabolites that work by replacing the building blocks of nucleic acids during DNA elongation, arresting tumour growth and promoting apoptosis of malignant cells
Nab paclitaxel
DrugNanoparticle albumin-bound (nab) paclitaxel is a form of paclitaxel which works as an antimicrotubule agent. Paclitaxel, the active ingredient in nab-paclitaxel promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This interferes with the normal dynamic reorganization of the microtubule network required for interphase and mitotic functions
Tremelimumab
Biological/VaccineTremelimumab is a fully human monoclonal antibody against CTLA-4. It is an immune checkpoint blocker.
Propranolol
DrugCompetitively blocks both β1 and β2 adrenergic receptors.
Cisplatin
Drugcisplatin has been associated with ability to crosslink with the urine bases on the DNA to form DNA adducts, preventing repair of the DNA leading to DNA damage and subsequently induces apoptosis within cancer cells.
Investigating and establishing the efficacy of propranolol in boosting the effects of immunotherapy in pancreatic adenocarcinoma
combination of gemcitabine+nab-paclitaxel+propranolol+durvalumab+tremelimumab's objective response rate is greater than or equal to 50%
Investigating and establishing the efficacy of propranolol in boosting the effects of immunotherapy in hepatocellular carcinoma
propranolol + durvalumab + tremelimumab objective response rate is greater than 45%
Investigating and establishing the efficacy of propranolol in boosting the effects of immunotherapy in biliary tract tumors
To demonstrate in unresectable BTC (gallbladder, cholangiocarcinoma of the biliary tracts including ampullary carcinomas) that the combination of gemcitabine + cisplatin + propranolol + durvalumab + tremelimumab's objective response rate is greater than 50%
Feasibility of study therapy
The number of participants who complete at least 2 cycles of therapy for the treatment of advanced hepato-pancreatobiliary cancers, over the total duration of study.
Safety/tolerability
Treatment related and non-related adverse events per CTCAE v.5.0 of for the treatment of advanced hepato-pancreatobiliary tumors. Incidence of adverse events, the number of dose modifications and discontinuations due to adverse events, including immune-related adverse events.
Progression-free survival
associated with therapy (defined as the time between the date of treatment initiation and the date of disease progression or death (whatever the cause, whichever occurs first)
Overall Survival
associated with therapy. (Defined as the time between the date of treatment initiation and the date of death)
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