| Eligibility |
Inclusion Criteria:
1. Written informed consent and any locally-required authorization obtained from the
subject prior to performing any protocol-related procedures, including screening
evaluations
2. Age > 20 years at time of study entry
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
4. Life expectancy of > 16weeks
5. Histologically proven BTC, including intrahepatic cholangiocarcinoma, extrahepatic
bile duct cancer, gallbladder cancer, ampulla of vater cancer
6. Unresectable or recurrent
7. Failed immunotherapy for their advanced BTC (the patient may have also received
chemotherapy in the 1 or 2L)
8. At least one measurable lesion that can be accurately assessed at baseline by computed
tomography (CT) (magnetic resonance imaging [MRI] where CT is contraindicated) and is
suitable for repeated assessment as per RECIST 1.1.
9. Body weight >30kg
10. Adequate normal organ and marrow function measured within 28 days prior to
administration of study treatment as defined below :
- Haemoglobin =9.0 g/dL
- Absolute neutrophil count (ANC) = 1.5 x 109/L
- Platelet count = 100x 109/L
- Serum bilirubin =1.5 x institutional upper limit of normal (ULN). (This will not
apply to patients with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis
or hepatic pathology), who will be allowed only in consultation with their
physician.)
- AST (SGOT)/ALT (SGPT) =2.5 x institutional upper limit of normal unless liver
metastases are present, in which case it must be =5x ULN
- Patients must have creatinine clearance estimated of =51 mL/min using the
Cockcroft-Gault equation or based on a 24 hour urine test :
Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)a serum
creatinine (mg/dL) x 72 a where F=0.85 for females and F=1 for males.
11. Postmenopausal or evidence of non-childbearing status for women of childbearing
potential: negative urine or serum pregnancy test within 28 days of study treatment
and confirmed prior to treatment on day 1.
Postmenopausal is defined as:
- Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
- Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post
menopausal range for women under 50
- radiation-induced oophorectomy with last menses >1 year ago
- chemotherapy-induced menopause with >1 year interval since last menses
- surgical sterilisation (bilateral oophorectomy or hysterectomy) 12. Male patients must
use a condom during treatment and for 6 months after the last dose of AZD6738 when
having sexual intercourse with a pregnant woman or with a woman of childbearing
potential. Female partners of male patients should also use a highly effective form of
contraception ([see appendix H for acceptable methods]) if they are of childbearing
potential 13. Patient is willing and able to comply with the protocol for the duration
of the study including undergoing treatment and scheduled visits and examinations
including follow up.
Exclusion Criteria:
1. Participation in another clinical study with an investigational product during the
last 3 weeks
2. Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
medication.
3. Any previous treatment with ATR inhibitor
4. 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
5. Receipt of the last dose of anti-cancer therapy (chemotherapy, endocrine therapy,
targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other
investigational agent) within 21 days of the first dose of study drug .2 The minimum
washout period for immunotherapy is 42 days
6. Mean QT interval:
Mean resting corrected QT interval (QTc) >470 msec for females and >450 for men,
obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart using the Fredericia
formula
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
such as congestive heart failure, unstable angina pectoris, acute myocardial
infarction, hypokalaemia, congenital long QT syndrome, immediate family history of
long QT syndrome or unexplained sudden death under 40 years of age, conduction
abnormality not controlled with pacemaker or medication.
7. Current or prior use of immunosuppressive medication within 28 days before the first
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid. The following are exceptions to this
criterion
The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (e.g., 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 (e.g., CT scan
premedication)
8. 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 may be included only after consultation with the Study
Physician.
9. 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.
10. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
radiation within 4 weeks of the first dose of study drug
11. 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.
Patients must have recovered from any effects of any major surgery
12. History of allogenic organ transplantation.
13. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., 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:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only
after consultation with the study physician
- Patients with celiac disease controlled by diet alone
14. 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
15. 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 IP and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
- Adequately treated carcinoma in situ without evidence of disease
16. History of leptomeningeal carcinomatosis
17. Brain metastases or spinal cord compression. Patients with symptomatic uncontrolled
brain metastases. A scan to confirm the absence of brain metastases is not required.
The patient can receive a stable dose of corticosteroids before and during the study
as long as these were started at least 4 weeks prior to treatment. Patients with
spinal cord compression unless considered to have received definitive treatment for
this and evidence of clinically stable disease for 28 days.
18. History of active primary immunodeficiency
19. Active infection or immunocompromised patients including tuberculosis (clinical
evaluation that includes clinical history, physical examination and radiographic
findings, and TB testing in line with local practice), hepatitis B , hepatitis C, or
human immunodeficiency virus (positive HIV 1/2 antibodies). Subjects with simple HBV
carrier, a past or resolved HBV infection (defined as the presence of hepatitis B core
antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
for HCV RNA.
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. Female patients who are pregnant or breastfeeding
22. Male or female patients of reproductive potential who are not willing to employ
effective birth control from screening to 6 months after the last dose of AZD6738 or
durvalumab monotherapy. (including sperm donation for male patients)
23. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.
24. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required
steroid treatment, or any evidence of clinically active interstitial lung disease.
Concomitant use of known potent (eg. phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort)
inhibitors or CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required
washout period prior to starting study treatment is five half-lives, except for
St-Johns' wort, which is 3 weeks.
25. Diagnosis of ataxia telangiectasia.
26. Refractory nausea and vomiting, chronic gastrointestinal diseases or previous
significant bowel resection, with clinically significant sequelae that would preclude
adequate absorption of AZD6738.
27. Haematuria: +++ on microscopy or dipstick.
28. Hypotension (<100/60 mmHg) or clinically relevant orthostatic hypotension, including a
fall in blood pressure of >20 mmHg.
29. Judgment by the investigator that the patient is unsuitable to participate in the
study and the patient is unlikely to comply with study procedures, restrictions and
requirements.
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