Overview
A single-arm, interventional study combining Immunotherapy and propranolol with/without chemotherapy and propranolol
- 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.
- 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.
- 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.
Eligibility
Inclusion Criteria:
1. Patients must be 18 years of age or older.
2. Body Weight \>30kg
3. Life expectancy of at least 12 weeks
4. 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.
5. Radiation therapy (palliative or curative) must have been completed at least 4 weeks prior to first study treatment and patients must have toxicities recovered to grade 1 or less.
6. Patients must be capable of providing consent to enrolment and treatment.
7. Patients with a performance status of ECOG 0-2(15) will be eligible for enrolment (see Appendix 1).
8. Measurable disease must be present according to RECIST criteria V1.1(16) (see Appendix 3).
9. Women of child-bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test at the time of screening. WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy or bilateral salpingectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 50 years in the absence of other biological or physiological causes.
10. Patients (men and women) of childbearing / reproductive potential should use highly effective birth control methods, as defined by the investigator, during the study treatment period and for a period of 6 months after the last dose of study drug. A highly effective method of birth control is defined as those that result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
11. Female patients who are breast-feeding should discontinue nursing prior to the first dose of study treatment and until 90 days after the last dose of durvalumab monotherapy or 180 days after the last does of durvalumab + tremelimumab combination therapy.
12. Male patients should agree to not donate sperm during the study and for a period of at least 6 months after last dose of study drug.
13. Absence of any condition hampering compliance with the study protocol and follow- up schedule; those conditions should be discussed with the patient before registration in the trial.
14. The following adequate organ function laboratory values must be met:
Hematological:
• Absolute neutrophil count (ANC) \>1.5 x109/L
* For the Hepatocellular cohort Platelet count \>/ 1.0 x109/L is adequate • Platelet count \>100 x109/L
* For the Hepatocellular cohort Platelet count \>/ 65 x109/L is adequate • Hemoglobin \>9 g/dL (may have been transfused)
Renal:
• Estimated creatinine clearance ≥ 45 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)
Hepatic:
* Total serum bilirubin \<1.5x ULN
o For the HCC cohort bilirubin ≤ 2 x ULN
* AST and ALT \<2.5x ULN (or ≤ 5 x ULN for patients with documented metastatic disease to the liver)
Exclusion Criteria:
1. Patients who have received prior palliative systemic treatment for their advanced cancer.
2. History of pneumonitis requiring treatment with steroids.
3. History of active interstitial lung disease.
4. For HCC patients they must have a Child Pugh status of A.
5. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
6. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
7. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart) \<\
