Olaparib With or Without Durvalumab for DDR Gene Mutated Biliary Tract Cancer Following Platinum-based Chemotherapy (OPTIMUM)

This is an interventional treatment trial for Biliary Tract Cancer Read More

Inclusion Criteria:

Inclusion Criteria:

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Age 19 years and older
• Eastern Cooperative Oncology Group (ECOG) performance status 0 ~ 1
• Patients must have a life expectancy ≥ 16 weeks.
• Histologically confirmed adenocarcinoma of biliary tract (intrahepatic, extrahepatic cholangiocarcinoma, or gallbladder carcinoma).
• Locally advanced unresectable, recurrence after curative surgery or metastatic disease
• At least 16 weeks of continuous first-line platinum-based chemotherapy for unresectable or metastatic disease
• Somatic or germline mutation of at least one the DNA damage repair gene including ATM, ATR, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, GEN1, FANCA, FANCD2, POLE, MLH1, MSH2, MSH6, MRE11A, NBN, PALB2, PMS2, RAD50, RAD51, RAD51C, RAD51D, and XRCC2 confirmed by targeted exome sequencing
• Measurable disease is not necessarily needed for enrollment.
• No active uncontrolled infection, except chronic viral hepatitis under antiviral therapy.
• Normal organ and bone marrow function measured within 28 days prior to administration of study treatment including haemoglobin ≥10.0 g/dL with no blood transfusion in the past 28 days, platelets ≥ 100 x 109/L, neutrophils ≥ 1.5 x 109/L, creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test ,serum total bilirubin ≤ 1.5 x ULN and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 x ULN
• No other malignant disease apart from adequately treated non-melanotic skin cancer, curatively treated carcinoma in situ of the uterine cervix, localized prostate or papillary thyroid cancer, or any other cancer where treated with curative intent > 5 years previously without evidence of relapse
• Written, informed consent to the study
• Body weight >30kg
• 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:

Exclusion Criteria:

• Participation in another clinical study with an investigational product during the last 6 months.
• 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.
• Medical or psychiatric conditions that compromise the patient's ability to give informed consent or to complete the protocol or a history of non-compliance
• Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting study treatment is 2 weeks.
• Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
• Obstruction of gastrointestinal tract
• Active gastrointestinal bleeding
• Myocardial infarction within 6 months prior to the study medication, and other clinically significant heart disease (e.g., unstable angina, congestive heart failure or uncontrolled hypertension)
• Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the study or which would jeopardise compliance with the protocol
• Combined hepatocellular carcinoma/cholangiocarcinoma is excluded.
• ECG abnormalities including 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), resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
• Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.
• Patients with leptomeningeal carcinomatosis or symptomatic uncontrolled brain metastases.
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia and vitiligo
• 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.
• History of allogenic organ transplantation or double umbilical cord blood transplantation.
• Active or prior documented autoimmune or inflammatory disorders.
• History of active primary immunodeficiency.
• 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.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
• 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.
• Concomitant use of known strong or moderate CYP3A inhibitors/inducers, unless with adequate washout period prior to starting olaparib.