Overview

This is a Phase II, non-randomized, multicenter, unblinded open-label study of Olaparib in monotherapy in participants with advanced (locally advanced/metastatic) PALB2-related pancreatic cancer that have progressed after at least one treatment for advanced disease.

Eligibility

Inclusion Criteria:

• Has a histologically or cytologically confirmed pancreatic adenocarcinoma
• Has advanced (unresectable or metastatic) pancreatic cancer by American Joint Committee on Cancer 8th Edition
• Has documented mutation in PALB2 gene (germline or somatic) that is predicted to be deleterious or suspected deleterious.
• Has at least one lesion (measurable) that can be accurately assessed at baseline by CT scan (or MRI, if the subject is allergic to CT contrast media) and is suitable for repeated assessment according to RECIST Version 1.1 criteria.
• Has a life expectancy ≥16 weeks.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1, as assessed within 3 days of the treatment initiation.
• Has received at least one systemic treatment for advanced disease (locally advanced or metastatic disease).
• Has adequate organ function as defined in Table 2; all screening laboratory tests should be performed within 10 days prior to initiation of study intervention.
• Is male or female, who is at least 18 years of age at the time of signing the informed consent.

        Male Participants Contraceptive use by men should be consistent with local regulations
        regarding the methods of contraception for those participating in clinical studies.
          -  A male participant must agree to use contraception ad detailed in Appendix D of this
             protocol during the treatment period and for at least 3 months following the last dose
             of Olaparib when having sexual intercourse with pregnant woman or with a WOPBP. Female
             partners of male patients should also use a highly effective form of contraception
             ([see appendix D for acceptable methods]) if they are of childbearing potential Male
             patients should not donate sperm throughout the period of taking olaparib and for 3
             months following the last dose of olaparib.
        Female Participants Contraceptive use by women should be consistent with local regulations
        regarding the methods of contraception for those participating in clinical studies.
          -  11. A female participant is eligible to participate if she is not pregnant* (Appendix
             D), not breastfeeding and at least 1 of the following conditions applies:
               1. Not a WOCBP as defined in Appendix D
                  OR
               2. A WOCBP who agrees to follow the contraceptive guidance in Appendix D during
                  treatment period and for least one month after the last dose of study
                  intervention.
        Postmenopausal is defined as:
          -  Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments
          -  Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post
             menopausal range for women under 50
          -  radiation-induced oophorectomy with last menses >1 year ago
          -  chemotherapy-induced menopause with >1 year interval since last menses
          -  surgical sterilisation (bilateral oophorectomy or hysterectomy)
               -  evidence of non-childbearing status for women of childbearing potential is
                  defined with negative urine or serum pregnancy test within 28 days of study
                  treatment and confirmed prior to treatment on day 1 (within 24 hours) and before
                  every cycles.
        Informed Consent
          -  Has (or legally acceptable representative if applicable) provided written informed
             consent for the study. The participant may also provide consent/assent for future
             biomedical research. However, the participant may participate in the main trial
             without participating in the FBR.
        Exclusion Criteria:
          -  Has a known additional malignancy that is progressing or requires active treatment.
             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), Stage 1, grade 1 endometrial
             carcinoma.
          -  Has myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of
             MDS/AML.
          -  3. Patients with symptomatic uncontrolled brain metastases and/or carcinomatous
             meningitis. Subject with previously treated brain metastasis may participate proved
             they are stable (without evidence of progression by imaging for at leat four weeks
             prior to the first dose of trial treatment and any neurological symptoms have returned
             to baseline), no evidence of new or enlarging brain metastases. 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.
          -  4. Has a documented weigh loss > 10% from baseline during screening and/or decline in
             ECOG PS to >1 between visit and within 73 hours prior to first dose of therapy.
          -  Has an active infection requiring systemic therapy.
          -  Has a known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.
          -  Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2)
             caused by previous cancer therapy, excluding alopecia. Patients previously treated
             with Oxaliplatinum who experienced a ≤ G2 neuropathy can be included after
             consultation with the study physician
          -  Patients considered at poor medical risk 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.
          -  Is unable to swallow orally administered medication or patients with gastrointestinal
             disorders likely to interfere with absorption of the study medication.
          -  Is a immunocompromised patients, e.g., patients who are known to be serologically
             positive for human immunodeficiency virus (HIV).
          -  Has a known active hepatitis (i.e. Hepatitis B or C).
               -  Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen
                  (HBsAg) result. Patients with a past or resolved HBV infection (defined as the
                  presence of hepatitis B core antibody and absence of HBsAg) are eligible.
               -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if
                  polymerase chain reaction is negative for HCV RNA.
        Prior/concomitant therapy
          -  Any previous treatment with PARP inhibitor, including Olaparib.
          -  Has prior systemic chemotherapy, targeted small molecule therapy or radiotherapy
             (except for palliative reasons) within 3 weeks prior to study treatment.
          -  Has received prior therapy with an anti-monoclonal antibody within 4 weeks or who has
             not recovered (i.e. <= G1 or at baseline) from adverse events due to agents
             administered more than 4 weeks earlier.
          -  15. Bone as only site of metastatic disease from pancreatic cancer (bone only disease)
          -  16. Major surgery within 2 weeks of starting study treatment and patients must have
             recovered from any effects of any major surgery.
          -  17. Is currently receiving 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 olaparib is 2 weeks.
          -  18. Is currently receiving 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 olaparib is 5 weeks for enzalutamide or phenobarbital and 3
             weeks for other agents.
          -  19. Has received previous allogenic bone marrow transplant or double umbilical cord
             blood transplantation (dUCBT).
          -  20. Has received a whole blood transfusions in the last 120 days prior to entry to the
             study. Packed red blood cells and platelet transfusions are acceptable, if not
             performed within 28 days of the first dose of study intervention.
        Prior/concurrent clinical study experience
          -  21. Patients that is currently participating or has participated in another clinical
             study with an investigational product administered in the last 4 weeks
          -  22. Patients with a known hypersensitivity to olaparib or any of the excipients of the
             product.
        Diagnostic assessments
          -  23. Has resting ECG indicating uncontrolled, potentially reversible cardiac
             conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled
             symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms,
             electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
          -  24. Has a history or current evidence of any condition, therapy or laboratory
             abnormality that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.
        Other exclusions
          -  Has a benign variant of PALB2 gene or variant of uncertain (or unknown) significance
             (VUS)
          -  Has a histology other than pancreatic adenocarcinoma (for example, neuroendocrine,
             adenosquamous etc.)
          -  Involvement in the planning and/or conduct of the study
          -  Judgment by the investigator that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions and
             requirements.
          -  Is pregnant or breastfeeding,or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 30-90 days after the last dose of trial treatment.