| Eligibility |
Inclusion Criteria:
1. Participant must be = 18 years at the time of screening.
2. Histologically confirmed, unresectable advanced or metastatic BTC including
cholangiocarcinoma (intrahepatic or extrahepatic), gallbladder carcinoma.
3. Participants with previously untreated disease are eligible if presented with
unresectable or metastatic BTC at initial diagnosis.
4. Prior curative intent treatment (surgery and, if given in the adjuvant setting,
chemotherapy and/or radiation) is permitted, with recurrent disease >6 months. This
includes participants with residual disease after surgery, who received chemotherapy,
chemoembolization, or radiotherapy.
5. A WHO/ECOG PS of 0 to 2.
6. At least one lesion that qualifies as a RECIST 1.1 TL at baseline.
7. Participants with HBV infection (as characterised by positive HBsAg and/or anti-HBcAb
with detectable HBV DNA, as per local laboratory standards) must be treated with
antiviral therapy, as per institutional practice, to ensure adequate viral suppression
(as per local laboratory standards) prior to enrolment. Participants must remain on
antiviral therapy for the study duration and for 6 months after the last dose of study
intervention. Participants who test positive for anti-HBc with undetectable HBV DNA
(as per local laboratory standards) do not require antiviral therapy prior to
enrolment. These participants will be tested at every cycle to monitor HBV DNA levels
and initiate antiviral therapy if HBV DNA is detected (as per local laboratory
standards). HBV DNA detectable participants must initiate and remain on antiviral
therapy for the study duration and for 6 months after the last dose of study
intervention.
8. Adequate organ and marrow function, as defined below.
- Haemoglobin = 9 g/dL
- Absolute neutrophil count = 1.5 × 109/L
- Platelet count = 100 × 109/L
- Serum bilirubin = 2.0 × ULN; this will not apply to participants with confirmed
Gilbert's syndrome. Any clinically significant biliary obstruction should be
resolved before enrolment.
- ALT and AST = 2.5 × ULN. For participants with hepatic metastases, ALT and AST =
5 × ULN.
- Calculated creatinine clearance > 50 mL/minute as determined by Cockcroft-Gault
(using actual body weight) or 24-hour urine creatinine clearance. For
chemotherapy regimens including carboplatin, oxaliplatin, or gemcitabine as
monotherapy, the recommended threshold for calculated creatinine clearance is >
40 mL/minute as determined by Cockcroft-Gault (using actual body weight) or
24-hour urine creatinine clearance.
9. Must have a life expectancy of at least 12 weeks.
10. Body weight of > 30 kg.
11. Male or female.
12. Negative pregnancy test (serum) for women of childbearing potential.
13. Female participants must be one year post-menopausal (amenorrhoeic for 12 months
without an alternative medical cause), surgically sterile, or using one highly
effective form of birth control (a highly effective method of contraception is defined
as one that can achieve a failure rate of less than 1% per year when used consistently
and correctly). Women of childbearing potential must agree to use one highly effective
method of birth control (see Appendix H for a complete list of highly effective birth
control methods). They should have been stable on their chosen method of birth control
from the time of screening throughout the total duration of the study and the drug
washout period (90 days after the last dose of study intervention with durvalumab or
180 days after the last dose of durvalumab and gemcitabine-based therapy).
- Non-sterilised male partners of a woman of childbearing potential must use a male
condom plus spermicide (condom alone in countries where spermicides are not approved)
throughout this period. Cessation of birth control after this point should be
discussed with a responsible physician. Periodic abstinence, as well as the rhythm and
withdrawal methods are not acceptable methods of birth control.
14. Male participants who intend to be sexually active with a female partner of
childbearing potential must be surgically sterile or using an acceptable method of
contraception (see Appendix H) from the time of screening throughout the total
duration of the study and the drug washout period (90 days after the last dose of
study intervention with durvalumab or 180 days after the last dose of durvalumab and
gemcitabine-based therapy) to prevent pregnancy in a partner. Male participants must
not donate or bank sperm during this same time period.
- Female partners (of childbearing potential) of male participants must also use a
highly effective method of contraception throughout this period.
15. Participant is capable of giving signed informed consent as described in Appendix A,
Section A3 which includes compliance with the requirements and restrictions listed in
the ICF and in this protocol.
16. Written informed consent from the participant has been obtained prior to any
study-related procedures.
Exclusion Criteria:
1. Ampullary carcinoma.
2. As judged by the investigator, any evidence of diseases (such as severe or
uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding
diseases, active infection, active ILD/pneumonitis, serious chronic gastrointestinal
conditions associated with diarrhoea, psychiatric illness/social situations), history
of allogenic organ transplant, which, in the investigator's opinion, makes it
undesirable for the participant to participate in the study or that would jeopardise
compliance with the protocol.
3. Active or prior documented autoimmune or inflammatory disorders including inflammatory
bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of
diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener
syndrome [granulomatosis with polyangiitis], Graves' disease, rheumatoid arthritis,
hypophysitis, uveitis, etc). The following are exceptions to this criterion:
- Participants with vitiligo or alopecia.
- Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on
hormone replacement.
- Any chronic skin condition that does not require systemic therapy.
- Participants without an active disease in the last 5 years may be included but
only after consultation with the study physician.
- Participants with celiac disease controlled by diet alone.
- Participants with = Grade 2 lymphopenia will be evaluated on a case-by- case
basis after consultation with the study physician
4. History of another primary malignancy, except for malignancy treated with curative
intent and with no known active disease = 5 years before the first dose of study
intervention and of low potential risk for recurrence, basal cell carcinoma of the
skin, squamous cell carcinoma of the skin or lentigo maligna that has undergone
potentially curative therapy, or adequately treated carcinoma in situ without evidence
of disease.
5. History of leptomeningeal carcinomatosis.
6. History of active primary immunodeficiency.
7. Known to have tested positive for HIV (positive HIV 1/2 antibodies) or active
tuberculosis infection (clinical evaluation that may include clinical history,
physical examination and radiographic findings, or tuberculosis testing in line with
local practice).
8. Participants co-infected with HBV (presence of HBsAg and/or anti-HBcAb with detectable
HBV DNA, as per local laboratory standards) and HCV (presence of anti-HCV antibodies),
or coinfected with HBV and HDV (presence of anti-HDV antibodies).
9. Persistent toxicities (CTCAE Grade > 2) caused by previous anticancer therapy;
alopecia and vitiligo are excluded toxicities.
- Participants with Grade = 2 neuropathy will be evaluated on a case-by-case basis
after consultation with the study physician.
- Participants with irreversible toxicity not reasonably expected to be exacerbated
by treatment with durvalumab may be included only after consultation with the
study physician.
10. History of previous or current, brain metastases or spinal cord compression (including
asymptomatic and adequately treated disease). Participants with suspected brain
metastases at screening should have an MRI (preferred) or CT scan, each preferably
with IV contrast of the brain prior to study entry.
11. Known allergy or hypersensitivity to any of the study intervention or any of the study
intervention excipients.
12. Any concurrent chemotherapy, other than the one allowed in the study, IP, biologic, or
hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for
non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
13. Palliative radiotherapy with a limited field of radiation within 2 weeks of the first
dose of study intervention, or radiotherapy with a wide field of radiation or
radiotherapy affecting more than 30% of the bone marrow within 4 weeks before the
first dose of study intervention. Prior locoregional therapy, such as
radioembolization, is allowed as long as done more than 2 weeks prior.
14. Receipt of live attenuated vaccine within 30 days prior to the first dose of study
intervention (see Appendix J). Enroled participants should not receive live vaccine
while receiving study intervention and up to 30 days after the last dose of IP.
15. Major surgical procedure (as defined by the investigator) within 28 days prior to the
first dose of IP. Minor surgery of isolated lesions for palliative intent is
acceptable if performed more than 14 days prior to the first dose of IP.
16. Prior exposure to immune-mediated therapy including, but not limited to, other
anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic
anticancer vaccines.
17. Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab. The following are exceptions to this criterion:
- Intranasal, inhaled, or topical steroids or local steroid injections (eg,
intra-articular injection).
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent.
- Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication).
18. Receipt of the last dose of anticancer therapy (chemotherapy, targeted therapy,
biologic therapy, or mAbs) within 28 days prior to the first dose of study
intervention or 5 half-lives of the respective study intervention, whichever is
longer.
19. Participation in another clinical study with a study intervention administered in the
last 3 months.
20. Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study, or during the follow-up period of an
interventional study.
21. Prior randomisation or study intervention in a previous durvalumab clinical study,
regardless of study intervention arm assignment.
22. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).
23. Female participants who are pregnant or breastfeeding or male or female participants
of reproductive potential who are not willing to use effective birth control from
screening to 90 days after the last dose of study intervention with durvalumab or 180
days after the last dose of durvalumab and gemcitabine-based therapy.
24. Judgement by the investigator that the participant should not participate in the study
if the participant is unlikely to comply with study procedures, restrictions, and
requirements.
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