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

  • STATUS
    Recruiting
  • End date
    Oct 30, 2024
  • participants needed
    62
  • sponsor
    Asan Medical Center
Updated on 19 April 2022

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.

Details
Condition Biliary Tract Cancer, DNA Damage Repair Deficiency
Treatment durvalumab, olaparib
Clinical Study IdentifierNCT05222971
SponsorAsan Medical Center
Last Modified on19 April 2022

Eligibility

Yes No Not Sure

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
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