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

Sponsor

Asan Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT05222971

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Biliary Tract Cancer DNA Damage Repair Deficiency	Drug: Durvalumab Drug: Olaparib	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

62 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Randomized Open-labeled Phase 2 Study of Maintenance Olaparib With or Without Durvalumab for DDR Gene Mutated Advanced Biliary Tract Cancer Following Platinum-based Chemotherapy

Actual Study Start Date :

Apr 1, 2022

Anticipated Primary Completion Date :

Oct 30, 2023

Anticipated Study Completion Date :

Oct 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Olaparib plus durvalumab Olaparib 300 mg twice daily Durvalumab 1,500 mg IV on Day 1 Every 4 weeks	Drug: Durvalumab Durvalumab 1,500 mg IV on Day 1 Every 4 weeks Drug: Olaparib Olaparib 300 mg twice daily Every 4 weeks
Active Comparator: Olaparib Olaparib 300 mg twice daily Every 4 weeks	Drug: Olaparib Olaparib 300 mg twice daily Every 4 weeks

Arm

Intervention/Treatment

Experimental: Olaparib plus durvalumab

Olaparib 300 mg twice daily Durvalumab 1,500 mg IV on Day 1 Every 4 weeks

Drug: Durvalumab

Durvalumab 1,500 mg IV on Day 1 Every 4 weeks

Drug: Olaparib

Olaparib 300 mg twice daily Every 4 weeks

Active Comparator: Olaparib

Olaparib 300 mg twice daily Every 4 weeks

Drug: Olaparib

Olaparib 300 mg twice daily Every 4 weeks

Outcome Measures

Primary Outcome Measures

6-month progression-free survival rate [6 months]
Time interval between randomization and tumor progression or death of any cause

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Asan Medical Center	Seoul		Korea, Republic of	05505

Sponsors and Collaborators

Asan Medical Center

Investigators

Principal Investigator: Changhoon Yoo, Asan Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

Changhoon Yoo, Associate professor, Asan Medical Center

ClinicalTrials.gov Identifier:

NCT05222971

Other Study ID Numbers:

OPTIMUM

First Posted:

Feb 3, 2022

Last Update Posted:

Apr 12, 2022

Last Verified:

Apr 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Undecided

Plan to Share IPD:

Undecided

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Biliary Tract Neoplasms

Durvalumab

Olaparib

Study Results

No Results Posted as of Apr 12, 2022