An uMbrella Study of BIomarker-driven Targeted Therapy In Patients With Platinum-resistant Recurrent OvariaN Cancer(AMBITION)

Inclusion Criteria:

• Histologically confirmed high-grade serous or high-grade endometrioid ovarian, primaryperitoneal, or fallopian tube cancers.
• Disease progression within 6 months of completing platinum-based chemotherapy
• Who had received ≥ two lines of chemotherapy
• Provision of informed consent prior to any study specific procedures
• Female aged 20 years older at time of study entry
• Body weight >30kg
• Patients must have normal organ and bone marrow function measured within 28 days priorto administration of study treatment as defined below: 1) Haemoglobin ≥ 10.0 g/dL withno blood transfusion in the past 28 days, 2) Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, 3) Platelet count ≥ 100 x 109/L, 4) Total bilirubin ≤ 1.5 x institutional upperlimit of normal (ULN), 5) Aspartate aminotransferase (AST) (Serum Glutamic OxaloaceticTransaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic PyruvateTransaminase (SGPT)) ≤ 3 x institutional upper limit of normal unless liver metastasesare present in which case they must be ≤ 5x ULN, 6) Patients must have creatinineclearance estimated using the Cockcroft-Gault equation of ≥50 mL/min: Estimatedcreatinine clearance = (140-age [years]) x weight (kg) (x F)a serum creatinine (mg/dL)x 72, 7) a where F=0.85 for females and F=1 for males, 8) Urine protein: creatinineratio (UPC) ≤1 OR ≤2+ proteinuria on two consecutive dipsticks taken no less than 1week apart. Patients with 2+ proteinuria on dipstick must also have UPC <0.5 on 2consecutive samples. 9) Adequately controlled blood pressure (systolic blood pressure (SBP) ≤140 mmHg; diastolic blood pressure (DBP) ≤ 90mmHg) on maximum of 3antihypertensive medications. Patients must have a blood pressure (BP) of ≤ 140/90mmHg taken in the clinic setting by a medical professional within 2 weeks prior tostarting study. It is strongly recommended that patients who are on threeantihypertensive medications be followed by a cardiologist or a primary care physicianfor management of BP while on study. 10) Adequately controlled thyroid function, withno symptoms of thyroid dysfunction
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Patients must have a life expectancy ≥ 16 weeks.
• Postmenopausal or evidence of non-childbearing status for women of childbearingpotential: negative urine or serum pregnancy test within 28 days of study treatmentand confirmed prior to treatment on day 1. Postmenopausal is defined as: 1)Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments,

2. Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the postmenopausal range for women under 50, 3) radiation-induced oophorectomy with lastmenses >1 year ago, 4) chemotherapy-induced menopause with >1 year interval since lastmenses, 5) surgical sterilisation (bilateral oophorectomy or hysterectomy)

• Patients is willing and able to comply with the protocol for the duration of the studyincluding undergoing treatment and scheduled visits and examinations.
• Patients must have evaluable disease - define as one of the following: 12.1 RECIST 1.1measurable disease OR, 12.2 Evaluable disease (defined as solid and cysticabnormalities on radiographic imaging that do not meet RECIST 1.1 definitions fortarget lesions OR ascites and/or pleural effusion that has been pathologicallydemonstrated to be disease-related) in the setting of a CA125 > 2 times ULN.
• Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary cancer must beavailable for central testing. If there is not written confirmation of theavailability of an archived tumour sample prior to enrolment the patient is noteligible for the study. For inclusion in i) the optional exploratory genetic researchand ii) the optional biomarker research, patients must fulfil the following criteria:

1. Provision of informed consent for genetic research, 2) Provision of informedconsent for biomarker research

• If a patient declines to participate in the optional exploratory genetic research orthe optional biomarker research, there will be no penalty or loss of benefit to thepatient. The patient will not be excluded from other aspects of the study.

Exclusion Criteria:

• Involvement in the planning and/or conduct of the study (applies to both AstraZenecastaff and/or staff at the study site)
• Previous enrollment or randomization in the present study
• Participation in another clinical study with an investigational product during thelast 60 months
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of aninterventional study
• Any previous treatment with poly ADP ribose polymerase(PARP) inhibitor (includingolaparib), anti-PD-1, PD-L1, CTLA-4 (including durvalumab and tremelimumab).
• Other malignancy within the last 5 years except: adequately treated non-melanoma skincancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma, or other solid tumours includinglymphomas (without bone marrow involvement) curatively treated with no evidence ofdisease for ≥5 years. Patients with a history of localised triple negative breastcancer may be eligible, provided they completed their adjuvant chemotherapy more thanthree years prior to registration, and that the patient remains free of recurrent ormetastatic disease
• Resting ECG with Corrected QT Interval(QTc) > 470 msec on 2 or more time points withina 24 hour period or family history of long QT syndrome
• Patients receiving any systemic chemotherapy or radiotherapy (except for palliativereasons) within 3 weeks prior to study treatment
• Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrinetherapy, targeted therapy, biologic therapy, tumour embolization, monoclonalantibodies) ≤21 days prior to the first dose of study drug If sufficient wash-out timehas not occurred due to the schedule or Pharmacokinetics(PK) properties of an agent, alonger wash-out period will be required, as agreed by AstraZeneca/MedImmune and theinvestigator
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormonereplacement therapy) is acceptable.
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field ofradiation within 4 weeks of the first dose of study drug
• 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 washoutperiod prior to starting olaparib is 2 weeks.
• Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ) ormoderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washoutperiod prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3weeks for other agents.
• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria : 1) Patients with Grade ≥2 neuropathy will be evaluated on a case-by-casebasis after consultation with the Principal Investigator. 2) Patients withirreversible toxicity not reasonably expected to be exacerbated by treatment withdurvalumab or tremelimumab may be included only after consultation with the PrincipalInvestigator.
• Patients with myelodysplastic syndrome/acute myeloid leukaemia or with featuressuggestive of Myelodysplastic syndrome/Acute myeloid leukemia(MDS/AML).
• Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absenceof brain metastases is not required. The patient can receive a stable dose ofcorticosteroids before and during the study as long as these were started at least 4weeks prior to treatment. Patients with spinal cord compression unless considered tohave received definitive treatment for this and evidence of clinically stable diseasefor 28 days.