Biliary Tract Cancer, DNA Damage Repair Deficiency
Conditions
Brief summary
First-line gemcitabine plus cisplatin chemotherapy is the standard first-line treatment for unresectable or metastatic advanced biliary tract cancer and the optimal duration of the treatment is not mentioned in current clinical guidelines. In the pivotal phase 3 ABC-02 trial, patients received up to 6 to 8 cycles of treatment and stopped without maintenance and our retrospective study shows no significant benefit of continuing gemcitabine plus cisplatin beyond 6 to 8 cycles. However, the survival outcomes of patients who completed 6 to 8 cycles of gemcitabine plus cisplatin without progression are dismal with progression-free survival from the last dose of the treatment of median 5.2 months in a prior retrospective study. Indeed, there is an unmet clinical need in terms of maintenance therapy for advanced biliary tract cancer without progression to first-line gemcitabine plus cisplatin chemotherapy. Durvalumab with/without tremelimumab, anti-CTLA4 inhibitor, showed encouraging results in recently presented study for treatment of advanced biliary tract cancer combination with gemcitabine plus cisplatin. Combination of olaparib and durvalumab showed promising results for metastatic HER-2 negative BRCA mutated breast cancer. For DDR gene mutated advanced biliary tract cancer, olaparib plus durvalumab combination may show synergistic effect with better efficacy than olaparib monotherapy. Both olaparib and durvalumab are relatively well tolerated compared to other cytotoxic chemotherapeutic agents. Olaparib may have some degree of myelosuppression, most patients are expected to well tolerate. Although combination of durvalumab and olaparib may cause additional adverse events, these also might be tolerable, considering that there are no overlapping toxicities between durvalumab and olaparib and the safety data for the combination of durvalumab with olaparib. Considering poor prognosis in patients with advanced biliary tract cancer and lack of maintenance treatment following scheduled first-line GemCis, clinical benefits with maintenance olaparib or olaparib plus durvalumab weigh more than the potential risks.
Interventions
DRUGDurvalumab
Durvalumab 1,500 mg IV on Day 1 Every 4 weeks
DRUGOlaparib
Olaparib 300 mg twice daily Every 4 weeks
Sponsors
Asan Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6-month progression-free survival rate | 6 months | Time interval between randomization and tumor progression or death of any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival | 1 year | Time interval between randomization and death of any cauase |
| Toxicity profile | 6 months | Any toxicities graded by National Cancer Institute Common Terminology Criteria version 5 |
| Response rates | 6 months | objective response rates graded by Response Evaluation Criteria in Solid tumor version 1.1 |
| Progression-free survival | 1 year | Time interval between randomization and tumor progression or death of any cause |
Countries
South Korea
Contacts
Primary ContactChanghoon Yoo
Outcome results
None listed