Evaluation of Olaparib and Durvalumab in Metastatic Pancreatic Cancer with DNA Damage Repair Gene Alterations

Trial ID: 2024-510970-26-00
Protocol: TTD-20-04
Sponsor: Asociacion Grupo Tratamiento De Tumores Digestivos

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Diseases & Conditions

Colorectal cancer metastatic

Objectives

The primary objective of this study is to evaluate the efficacy of **olaparib** in combination with **durvalumab** by assessing the overall response rate (ORR) in patients with metastatic pancreatic cancer and DNA damage repair gene alterations. This is clinically relevant as it aims to determine the potential therapeutic benefit of this combination therapy in improving response rates in a population with limited treatment options.

Secondary objectives include:

Evaluating the efficacy of the combination by assessing progression-free survival (PFS).
Evaluating the efficacy by assessing overall survival (OS).
Evaluating the efficacy by assessing the duration of response (DoR).
Evaluating the efficacy by assessing the disease control rate (DCR).
Evaluating the safety and tolerability of the combination across subjects included in this trial.

Participants

The clinical trial involves participants diagnosed with **metastatic pancreatic cancer**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a body weight greater than 30 kg and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial population was selected based on specific criteria, including prior receipt of platinum-based chemotherapy with a beneficial response, normal organ and bone marrow function, and a life expectancy of at least 16 weeks. Participants must have measurable disease as per RECIST version 1.1 guidelines and must not have progressed while on platinum-based chemotherapy. The trial includes individuals with histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas, with alterations in DNA damage repair genes. Both male and female participants are required to adhere to specific contraceptive measures during and after the trial. The sponsor has not provided information regarding the total number of participants. Participants must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures, and must provide written informed consent. The trial also involves a vulnerable population, as indicated by the inclusion of individuals with specific health conditions. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **olaparib** in combination with **durvalumab** in patients with metastatic pancreatic cancer and alterations in DNA damage repair genes. This is a Phase II, randomized, double-blind, controlled trial. The trial aims to assess the overall response rate (ORR) as the primary endpoint, with secondary endpoints including progression-free survival (PFS), overall survival (OS), duration of response (DoR), and disease control rate (DCR). The trial is expected to run from December 2022 to July 2025, with a maximum treatment period of six months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, prior chemotherapy response, and organ function. Following successful screening, participants will be randomized to receive either the investigational treatment or a control. Study visits will occur regularly to monitor treatment response and safety, including assessments of adverse events graded by NCI CTCAE v5.0, vital signs, and laboratory parameters. The end-of-study visit will conclude the participant's involvement, with final evaluations of treatment efficacy and safety.

Participant involvement is expected to last up to six months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. Participants must comply with scheduled visits, treatment plans, and other trial procedures to remain in the study. The trial will ensure that all participants provide written informed consent before any study-specific procedures are conducted.

Treatment

The clinical trial involves the administration of **durvalumab**, an experimental medication classified under the ATC code L01FF03. Durvalumab is a monoclonal antibody, specifically a protein of other origin, known by the synonym MEDI4736. It is administered via **intravenous infusion**. The pharmaceutical form is designated as PHF00230MIG. The maximum daily dose of durvalumab is 1500 mg, with a total maximum dose of 9000 mg over a treatment period of up to 6 months. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

In conjunction with durvalumab, the trial also includes the administration of **olaparib**, a chemical substance and a PARP inhibitor, classified under the ATC code L01XX46. Olaparib is administered **orally** in the pharmaceutical form PHF00082MIG. The maximum daily dose is 600 mg, with a total maximum dose of 109500 mg over a 6-month treatment period. The dosing schedule is structured to optimize therapeutic efficacy while monitoring participant compliance to ensure accurate adherence to the prescribed regimen.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this trial. The focus is on evaluating the efficacy of the combination of olaparib and durvalumab in patients with metastatic pancreatic cancer and DNA damage repair gene alterations. The trial's main objective is to assess the overall response rate (ORR) of this combination therapy.

Efficacy

The efficacy of the combination of **olaparib** and **durvalumab** in patients with metastatic pancreatic cancer and DNA damage repair gene alterations will be assessed primarily through the Overall Response Rate (ORR). ORR is defined as the percentage of patients achieving a complete response (CR) or partial response (PR) as evaluated by investigators using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary efficacy endpoints include Progression-Free Survival (PFS), Overall Survival (OS), Duration of Response (DoR), and Disease Control Rate (DCR). PFS is measured from the initial date of study treatment to the date of objective disease progression or death, whichever occurs first. OS is defined as the time from the initial date of study treatment to the date of death from any cause. DoR is the time from the first objective response to disease progression or death, with censoring at the last evaluable disease assessment date for patients who have not progressed or died. DCR is the percentage of patients achieving CR, PR, or stable disease.

Assessments will be conducted according to the RECIST 1.1 criteria, and adverse events will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. The trial will also monitor vital signs and evaluate laboratory parameters to ensure comprehensive safety and efficacy profiling. The study is designed to provide a robust evaluation of the therapeutic potential of the drug combination in the specified patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Males and females ≥18 years of age (at the time consent is obtained).
Written informed consent provided.
Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale (Appendix A).
Subject must have archival tumour tissue available for central laboratory testing of alterations in DDR genes or willing to undergo a fresh tumour biopsy.
Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas.
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. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.
Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas with alterations in DNA damage repair genes.
Presence of alterations in DDR genes in tumour tissue or blood (somatic) or blood and saliva (germinal) sample previously determined by a local assay at any time prior to Screening or by the central laboratory.
Patients must have received a minimum of 1 line of chemotherapy for metastatic disease and a maximum of 2 lines. Patients who have received adjuvant treatment and have recurrence within 6 months of completion of the adjuvant or neoadjuvant treatment, is counted as first line chemotherapy.
Patients must have received platinum-based chemotherapy and must have benefit of it and not progressed while on platinum. Benefit is defined as partial or complete response or PFS  6 months.
Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment
Body weight >30 kg
ECOG performance status 0-1 within 14 days before enrolment (Appendix A).
Measurable disease as defined by RECIST version 1.1 guidelines.
Patients must have a life expectancy ≥ 16 weeks.
Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 7 days of study treatment.
Male patients must use a condom during treatment and for 3 months after the last dose of study drug 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 5.3.1) if they are of childbearing potential. Male patients should not donate sperm throughout the period of taking study drug and for 3 months following the last dose of study drug.
Resolution of all toxic effects of prior treatments, except alopecia, to Grade 0 or 1, by NCI CTCAE version 5.0.
Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures

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Exclusion Criteria

Other malignancy unless curatively treated with no evidence of disease for ≥5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS).
Uncontrolled, clinically significant, symptomatic cardiovascular disease within 6 months before enrolment, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication.
Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
Persistent toxicities (≥Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia.
Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.
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.
Patients considered a poor medical condition due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
Patients with an active infection.
Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
Patients with known active hepatitis (i.e., Hepatitis B or C).
Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent.
Any pre-existing medical condition of sufficient severity to prevent full compliance with the study.
Have received previously treatment with PARP inhibitors or PDL-1 inhibitors (including durvalumab).
Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment.
Concomitant chemotherapy, hormonal therapy, immunotherapy, or any other form of cancer treatment.
Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. Significant traumatic injury within 4 weeks of the first dose of study intervention.
Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
Concurrent treatment or treatment within 4 weeks of study entry with any other investigational agent.
Patients with a known hypersensitivity to olaparib, durvalumab or any of the excipients of the product.
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.
Female patients who are lactating and breastfeeding or have a positive pregnancy test during the Screening Period.