Overview

This is a multi-center, prospective, open-label, phase II trial. Patients with suspected advanced ovarian cancer planned to undergo diagnostic laparoscopy for histologic confirmation and evaluation of disease spread will be registered into the trial after providing a 1st written informed consent.

Eligibility

Inclusion Criteria:

WoO pre-treatment (screening phase):

1. Patients with presumed and previously untreated advanced stage ovarian cancer planned to undergo laparoscopy for histologic diagnosis and treatment planning
2. Patients willing and able to comply with the study protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
3. Patients able and willing to provide fresh frozen biopsy samples from laparoscopy as well as primary debulking for translational endpoints as well as serial liquid biopsies
4. Patients able and willing to provide formaldehyde-fixed paraffin embedded (FFPE) tissue samples from laparoscopy and primary debulking surgery
5. Patients aged ≥18 years
6. Patients must be 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
7. Provision of signed and dated, written ICF for the mandatory biomarker and genetic re-search as well as the clinical/therapeutic part of the study prior to any mandatory study specific procedures, sampling, and analyses
8. Eastern cooperative oncology group (ECOG) performance status 0-1 (see Appendix 1)
9. Patients must have a life expectancy ≥16 weeks
10. Ability to take oral medication
11. Postmenopausal or evidence of non-childbearing status for women of childbearing potential (WOCBP): negative serum pregnancy test within 28 days of study treatment and confirmed neagtive urine or serum pregnancy test prior to treatment on day 1.

    Postmenopausal is defined as:

    • Amenorrheic 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)
12. Women of childbearing potential (WOCBP) and their partners, who are sexually active,

    must agree to the use of 2 highly effective forms of contraception in combination. This should be started from the signing of the informed consent and continue throughout the period of taking study treatment and for at least 6 months after last dose of study drug(s), or they must totally/truly abstain from any form of sexual intercourse.

    WoO treatment phase:

13. Confirmed advanced (FIGO IIB/III/IV) high-grade, non-mucinous, non-clear cell epithelial ovarian, fallopian tube or primary peritoneal cancer or known (BReast CAncer) BRCA mutation and any histologic type
14. Planned primary debulking surgery after confirmation of diagnosis and disease evaluation during laparoscopy
15. Body weight >30kg
16. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
    • Haemoglobin ≥10.0 g/dL with no blood transfusion in the past 28 days
    • Absolute neutrophil count (ANC) ≥1.5×10^9/L
    • Platelet count ≥100×10^9/L
    • Total bilirubin ≤1.5 × institutional upper limit of normal (ULN)
    • Aspartate aminotransferase (AST), serum glutamic oxaloacetic transaminase (SGOT) / alanine aminotransferase (ALT), serum glutamic pyruvate transaminase (SGPT) ≤2.5 × institutional upper limit of normal unless liver metastases are present in which case they must be ≤5×ULN. (cave: patients with intrahepatic metastases affecting liver function test might not be candidates for primary debulking surgery)
    • Patients must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test:

        Estimated creatinine clearance=((140-age [years])weight (kg))/(serum creatinine
        (mg/dL)72)(* 0,85) 17. Patients must have successfully contributed blood and tissue
        samples as per requirements.
        Exclusion Criteria:
        Medical conditions:
          1. Disease requiring urgent surgical intervention
          2. Evidence of significant uncontrolled concomitant disease that could affect compliance
             with the study protocol
          3. Significant uncontrolled symptom burden (e.g. but not necessarily limited to large
             volume ascites, shortness of breath on exertion, pain requiring opioid medication,
             signs of (sub)ileus
          4. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, recent (within 3 months) myocardial
             infarction, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia,
             interstitial lung disease, uncontrolled major seizure disorder, unstable spinal cord
             compression, superior vena cava syndrome, serious chronic gastrointestinal conditions
             associated with diarrhea, or psychiatric illness/social situations that would limit
             compliance with study requirement, substantially increase risk of incurring AEs or
             compromise the ability of the patient to give written informed consent.
          5. 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. Patients with a history of localized triple negative breast cancer may be
             eligible, provided they completed their adjuvant chemotherapy more than three years
             prior to registration, and that the patient remains free of recurrent or metastatic
             disease (optional criteria that is dependent on the patient population under
             investigation).
          6. Resting electrocardiography (ECG) indicating uncontrolled, potentially reversible
             cardiac conditions, as judged by the investigator (eg., unstable ischemia,
             uncontrolled symptomatic arrhythmia, conges-tive heart failure, QTcF prolongation >500
             ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
          7. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
             criteria
             a. Patients with irreversible toxicity not reasonably expected to be exacerbated by
             treatment with olaparib, durvalumab or the combination may be included only after
             consultation with the coordinating investigator.
          8. Patients with myelodysplastic syndrome/acute myeloid leukemia or with features
             suggestive of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML).
          9. Brain metastases or spinal cord compression. Patients with suspected brain metastases
             at screening should have an MRI (preferred) or CT each preferably with IV contrast of
             the brain prior to study entry
         10. 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.
         11. Evidence of central nervous system (CNS) or leptomeningeal metastases.
         12. Patients considered a 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.
         13. Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders or any status that might interfere with resorption of the
             respective study drugs, e.g. parenteral nutrition, short bowel syndrome likely to
             interfere with absorption of the study medication.
         14. Immunocompromised patients, e.g., patients who are known to be serologically positive
             for human immunodeficiency virus (HIV).
         15. History of active primary immunodeficiency
         16. 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 or hepatitis C.
               1. Active HBV is defined by a known positive 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.
               2. Patients positive for HCV antibody are eligible only if polymerase chain reaction
                  is negative for HCV RNA
         17. ECOG performance status (PS) ≥2 or general condition that might interfere with the
             compliance with the study protocol
         18. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients.
             Prior / concomitant therapy:
         19. Prior antineoplastic therapy for ovarian, fallopian tube or primary peritoneal cancer
         20. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
             reasons) within 3 weeks prior to study treatment
         21. Any concurrent chemotherapy, investigational medicinal product (IMP), biologic, or
             hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for
             non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable
         22. Patients planned for neoadjuvant chemotherapy or deemed unresectable at laparoscopy
         23. Concomitant use of known strong cytochrome P450 3A (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.
         24. 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 olaparib is 5 weeks for enzalutamide or phenobarbital and 3
             weeks for other agents
         25. Major surgery within 2 weeks of starting study treatment and patients must have
             recovered from any effects of any major surgery
         26. History of allogenic organ transplantation
         27. Previous allogenic bone marrow transplant or double umbilical cord blood
             transplantation (dUCBT).
         28. Patients with a known hypersensitivity to olaparib or any of the excipients of the
             product.
         29. Prior treatment with olaparib or any other poly [ADP-ribose] polymerase (PARP)
             inhibitor
         30. Whole blood transfusions in the last 120 days prior to entry to the study (packed red
             blood cells and platelet transfusions are acceptable, for timing refer to inclusion
             criteria no. 16)
             Other exclusions:
         31. Patients who are pregnant or breast-feeding or patients of reproductive potential who
             are not willing to employ effective birth control from screening to 6 months after the
             last dose of study drug(s).
         32. Involvement in the planning and/or conduct of the study
         33. Participation in another interventional clinical study with an investigational product
             during the last with the last 3 months.
         34. 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.
         35. Previous enrolment in the present study.
         36. Judgement by the investigator that the patient is unsuitable to participate in the
             study and the patient is unlikely to comply with study procedures, restrictions and
             requirements.
             Additional Durvalumab-specific exclusion criteria for cohort B:
         37. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine
             therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
             antibodies) ≤28 days prior to the first dose of study drug. If sufficient wash-out
             time has not occurred due to the schedule or pharmacokinetic (PK) properties of an
             agent, a longer wash-out period will be required.
         38. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
             criteria
               1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
                  consultation with the coordinating investigator.
               2. Patients with irreversible toxicity not reasonably expected to be exacerbated by
                  treatment with durvalumab may be included only after consultation with the
                  coordinating investigator.
         39. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
             Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
             replacement therapy) is acceptable.
         40. 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.
         41. History of allogenic organ transplantation.
         42. Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
             the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome,
             or wegener syndrome [granulomatosis with polyangiitis, graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
             criterion:
               1. Patients with vitiligo or alopecia
               2. Patients with hypothyroidism (e.g., following hashimoto syndrome) stable on
                  hormone replacement
               3. Any chronic skin condition that does not require systemic therapy
               4. Patients without active disease in the last 5 years may be included but only
                  after consultation with the study physician
               5. Patients with celiac disease controlled by diet alone
         43. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
             gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
             situations that would limit compliance with study requirement, substantially increase
             risk of incurring (Adverse Events) AEs or compromise the ability of the patient to
             give written informed consent.
         44. History of another primary malignancy except for
               1. Malignancy treated with curative intent and with no known active disease ≥5 years
                  before the first dose of IMP and of low potential risk for recurrence
               2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease
               3. Adequately treated carcinoma in situ without evidence of disease
         45. History of leptomeningeal carcinomatosis
         46. Brain metastases or spinal cord compression. Patients with suspected brain metastases
             at screening should have an MRI (preferred) or CT each preferably with IV contrast of
             the brain prior to study entry.
         47. 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)
         48. Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and tuberculosis testing in
             line with local practice), hepatitis B (known positive hepatitis B virus (HBV) surface
             antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV infection
             (defined as the presence of hepatitis B core antibody [anti-hepatitis-B-core (HBc)]
             and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody
             are eligible only if polymerase chain reaction is negative for HCV RNA.
         49. Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab. The following are exceptions to this criterion:
               1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g.,
                  intra-articular injection)
               2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent
               3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)
         50. Receipt of live attenuated vaccine within 30 days prior to the first dose of IMP.
             Note: patients, if enrolled, should not receive live vaccine whilst receiving IMP and
             up to 30 days after the last dose of IMP.
         51. Prior randomisation or treatment in a previous durvalumab clinical study regardless of
             treatment arm assignment or other immunotherapies
         52. Patients who have received prior anti-programmed cell death-protein 1(PD-1), anti
             PD-L1 or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4):
               1. Must not have experienced a toxicity that led to permanent discontinuation of
                  prior immunotherapy.
               2. All AEs while receiving prior immunotherapy must have completely resolved or
                  resolved to baseline prior to screening for this study.
               3. Must not have experienced a ≥grade 3 immune related AE or an immune related
                  neurologic or ocular AE of any grade while receiving prior immunotherapy. Note:
                  Patients with endocrine AE of ≤grade 2 are permitted to enroll if they are stably
                  maintained on appropriate replacement therapy and are asymptomatic.
               4. Must not have required the use of additional immunosuppression other than
                  corticosteroids for the management of an AE, not have experienced recurrence of
                  an AE if rechallenged, and not currently require maintenance doses of >10 mg
                  prednisone or equivalent per day.
         53. Patients planned for neoadjuvant chemotherapy (e.g. but not exclusively due to extend
             of disease spread or poor general condition etc.).
         54. (sub)ileus or signs of malignant bowel obstruction.