| 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) <<for durvalumab
monotherapy and durvalumab + tremelimumab combination studies this criterion can be
removed. For durvalumab ±tremelimumab in combination with an agent with pro-arrhythmic
potential or where effect of the combination on QT is not known if this criterion
should be retained.
8. History of another malignancy or a concurrent malignancy;
• Exceptions include patients who have been disease-free for 3 years, or patients with
a history of completely resected non-melanoma skin cancer or successfully treated in
situ carcinoma are eligible, for example cervical cancer in situ. As well patients
with a resected malignancy that did not require systemic therapy post-surgery are
allowed.
9. Active brain metastases or leptomeningeal disease.
• Patients with treated brain metastases that have been treated, are off steroids and
anticonvulsants and have imaging documenting stability of brain metastases for 6 weeks
post treatment will be eligible for enrolment.
10. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal,
inhaled, topical steroids, or local steroid injection (e.g., intra-articular
injection); b. Systemic corticosteroids at physiologic doses = 10 mg/day of prednisone
or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT
scan premedication).
11. Prior organ transplantation including allogeneic stem-cell transplantation.
12. Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory
agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid
diseases not requiring immunosuppressive treatment are eligible.
13. Active infection requiring systemic therapy or Active infection including tuberculosis
(clinical evaluation that includes clinical history, physical examination and
radiographic findings, and TB testing in line with local practice), hepatitis B (known
positive HBV surface antigen (HBsAg) result), hepatitis C, Patients with a past or
resolved HBV infection (defined as the presence of hepatitis B core antibody
[anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV)
antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
Patients known positive for HIV.
14. Known prior severe hypersensitivity to investigational product or any component in its
formulations, including known severe hypersensitivity reactions to monoclonal
antibodies (CTCAE v5.0 Grade = 3).
15. Other severe acute or chronic medical conditions including inflammatory bowel disease,
immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent
(within the past year) or active suicidal ideation or behavior; or laboratory
abnormalities that may increase the risk associated with study participation or study
treatment administration or may interfere with the interpretation of study results
and, in the judgment of the investigator, would make the patient inappropriate for
entry into this study.
16. Persisting toxicity related to prior therapy (NCI CTCAE v. 5.0 grade > 1); however,
alopecia, sensory neuropathy = grade 2, or other toxicities = grade 2 not constituting
a safety risk based on investigator's judgment are acceptable.
17. Enrollment in any other clinical protocol or investigational study with an
interventional agent or assessments that may interfere with study procedures.
18. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of durvalumab monotherapy or 180 days after
the last dose of durvalumab + tremelimumab combination therapy.
19. 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.
20. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
30 days after the last dose of IP.
21. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical
study regardless of treatment arm assignment.
22. Asthma requiring corticosteroid inhalers and having been admitted within the last year
for an asthma exacerbation
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