Overview

This prospective, multicenter, open-label, randomized phase II maintenance study is evaluating the efficacy of UV1-olaparib-durvalumab combination as maintenance therapy after platinum combination therapy for BRCAwt patients with relapsed ovarian cancer.

Eligibility

Inclusion Criteria:

1. 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.
2. Histologically diagnosed epithelial ovarian, fallopian tube or primary peritoneal cancer.
3. Radiological or histological confirmation of relapse disease ≥ 6 month after last chemotherapy
4. Patients who are non-gBRCAmut or tBRCAwt
5. Have completed at least two lines, but no more than 4 lines, of platinum-containing chemotherapy, which means that patients at first,second or third relapse with treatment free interval of more than 6 months is eligible.
   1. Subjects must have completed at least 4 cycles of the last platinum-containing chemotherapy
6. Be either:
   1. PARPi naive
   2. Earlier treated with PARPi and not progressed during 6 months of PARPi therapy
7. Must have, in the opinion of the investigator, CR or PR on the post-treatment scan and

   no evidence of rising CA-125 level, following completion of the last chemotherapy course.

8. Patient consents to Myriad myChoice® HRD test.
9. Must be included in the study within 10 weeks of completion of the final dose of platinum-containing chemotherapy.
10. Age ≥18 years
11. Body weight >30 kg
12. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Appendix 3)
13. Must have a life expectancy ≥ 16 weeks.
14. 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 (6,2 mmol/L) with no blood transfusion in the past 28 days
    • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
    • Platelet count ≥ 100 x 10^9/L
    • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
    • Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5x ULN
    • Must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test : i. Estimated creatinine clearance = Estimated creatinine clearance = [[140 - age(yr)] x weight(kg)] / [72 x serum Cr (mg/dL)] (multiply by 0.85 for women)
15. Ability to swallow oral medications (tablets) without chewing, breaking, crushing,

    opening or otherwise altering the product formulation.

16. Post-menopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed 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)

Exclusion Criteria:

1. Previous immunotherapy (for example anti-PD-1/L1, including durvalulmab).
2. 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.
3. 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.
4. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.
5. 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.
6. 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.
7. Disease progression during or within 4 weeks after PARPi therapy.
8. Subject has received > 2 lines of chemotherapy for relapse
9. Concomitant treatment with bevacizumab within the last 3 weeks.
10. Concomitant therapy with any other anticancer therapy or chronic use of systemic corticosteroids of more than 10mg prednisolone daily.
11. 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 study treatment is 2 weeks.
12. 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 study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
13. Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation
14. Subjects being considered at poor medical condition due to a serious, uncontrolled medical disorder or non-malignant systemic disease.
15. Major surgery or significant traumatic injury within 28 days of run-in
16. Immunocompromised subjects e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV), patients with active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C.

    Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti- HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.

17. Pregnancy, lactation or intention to become pregnant during the study or/and within 1 month after the last dose of olaparib. If the patient can become pregnant, the patient must be on acceptable birth control listed in Appendix 5.
18. Participation in a clinical study within 28 days or 5 half-lives of the drug, whichever is longest.
19. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
20. Patients with a history of allergy or hypersensitivity to any of the study drugs (including human granulacyte-macrophage colony stimulating factor), yeast-derived products or any constituent of the products have to be excluded from study participation.
21. 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 Study Physician.
    2. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
22. 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

23. 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 AEs or compromise the ability of the patient to give written informed consent

24. 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). A single ECG ≥ 470 ms is sufficient.
25. History of active primary immunodeficiency
26. Active infection including tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice) are eligible.
27. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
28. Has active infection with SARS-CoV-2 (antigen test).
29. Patients unable to be regularly followed for any reason (geographic, familiar, social, psychologic, housed in an institution e.g. prison because of a court agreement or administrative order according § 40 Abs. 1 S. 3 Nr. 4 AMG.).
30. Subjects that are depending on the sponsor/CRO or investigational site as well as on the investigator.