Olaparib, Durvalumab and UV1 in Relapsed Ovarian Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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STUDY DESIGN 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. Number of total subjects to be included in the trial: 184 patients will be enrolled in the study. Patients are randomized into one of the three treatment arms, (A:B:C), in a 1:1:2 randomization: Arm A (olaparib): 46 subjects Arm B (olaparib plus durvalumab): 46 subjects Arm C (olaparib plus durvalumab plus UV1): 92 subjects Patients are stratified according to: HRD status Previous use of PARP inhibitor (yes/no) Primary objective: • To compare the preliminary efficacy of maintenance treatment with olaparib (arm A) to that of olaparib plus durvalumab and UV1 (arm C) Secondary objectives: To compare the preliminary efficacy of maintenance treatment with olaparib plus durvalumab (arm B) to that of olaparib plus durvalumab and UV1 (arm C) To compare the preliminary efficacy of maintenance treatment with olaparib plus durvalumab to that of olaparib plus durvalumab and UV1 according to stratification factors To evaluate Patient Reported Outcomes (PROs) in treatment arms To compare the preliminary efficacy of maintenance treatment according to PD-L1 status To evaluate safety in treatment arms Exploratory objectives: To describe genetic, molecular, and immunological mechanisms in blood and tumor of maintenance treatment. To explore the efficacy of maintenance treatment in the molecular subgroups based on homologous recombination deficiency (HRD) status.

Official Title
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A Randomized Clinical Trial Investigating Olaparib, Durvalumab (MEDI4736) and UV1 as Maintenance Therapy in BRCAwt Patients With Recurrent Ovarian Cancer

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: Olaparib + durvalumab + UV1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Histologically diagnosed epithelial ovarian, fallopian tube or primary peritoneal cancer. Radiological or histological confirmation of relapse disease ≥ 6 month after last chemotherapy Patients who are non-gBRCAmut or tBRCAwt 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. a. Subjects must have completed at least 4 cycles of the last platinum-containing chemotherapy Be either: PARPi naive Earlier treated with PARPi and not progressed during 6 months of PARPi therapy 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. Patient consents to Myriad myChoice® HRD test. Must be included in the study within 10 weeks of completion of the final dose of platinum-containing chemotherapy. Age ≥18 years Body weight >30 kg Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Appendix 3) Must have a life expectancy ≥ 16 weeks. 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) Ability to swallow oral medications (tablets) without chewing, breaking, crushing, opening or otherwise altering the product formulation. 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: Previous immunotherapy (for example anti-PD-1/L1, including durvalulmab). 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. 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. 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 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. Disease progression during or within 4 weeks after PARPi therapy. Subject has received > 2 lines of chemotherapy for relapse Concomitant treatment with bevacizumab within the last 3 weeks. Concomitant therapy with any other anticancer therapy or chronic use of systemic corticosteroids of more than 10mg prednisolone daily. 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. 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 Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation Subjects being considered at poor medical condition due to a serious, uncontrolled medical disorder or non-malignant systemic disease. Major surgery or significant traumatic injury within 28 days of run-in 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. 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. Participation in a clinical study within 28 days or 5 half-lives of the drug, whichever is longest. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. 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. 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 Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician. 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: Patients with vitiligo or alopecia Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement Any chronic skin condition that does not require systemic therapy Patients without active disease in the last 5 years may be included but only after consultation with the study physician Patients with celiac disease controlled by diet alone 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 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. History of active primary immunodeficiency 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. 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. Has active infection with SARS-CoV-2 (antigen test). 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.). Subjects that are depending on the sponsor/CRO or investigational site as well as on the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label randomized phase 2 trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: (A) Olaparib<br>Olaparib 300 mg tablets twice daily until progressive disease or unacceptable toxicity. | Drug: Olaparib + durvalumab + UV1<br>* The subjects are randomized 1:1:2 to receive treatment until progression of disease or untorable toxicity.<br>* Other names: Olaparib (active comparator);|
| Experimental: (B) Olaparib + durvalumab<br>Olaparib 300 mg tablets twice daily until progressive disease or unacceptable toxicity. Durvalumab 1500 mg IV every 4 weeks for 24 months or until disease progression or unacceptable toxicity. | Drug: Olaparib + durvalumab + UV1<br>* The subjects are randomized 1:1:2 to receive treatment until progression of disease or untorable toxicity.<br>* Other names: Olaparib (active comparator);|
| Experimental: (C) Olaparib + durvalumab + UV1<br>Olaparib 300 mg tablets twice daily until disease progression or unacceptable toxicity. Durvalumab 1500 mg IV every 4 weeks for 24 months or until disease progression or unacceptable toxicity. Eight UV1 vaccinations during the first 5 month: Four UV1 vaccinations 300 μg (+ 75 μg of sargramostim) during the first 10 days with a minimum of 2 days apart. From cycle 2-5 subjects will receive one UV1 (+ sargramostim) vaccination every 4th week. | Drug: Olaparib + durvalumab + UV1<br>* The subjects are randomized 1:1:2 to receive treatment until progression of disease or untorable toxicity.<br>* Other names: Olaparib (active comparator);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | PFS is compared between arm A versus C | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | PFS is compared between arm B versus C | 36 months | 
| PFS assessed by blinded independent central review (BICR) | PFS is compared in each arm | 36 months | 
| Overall survival (OS) | OS is compared in each arm | 36 months | 
| Patient reported outcomes (PROs) - QLQ-OV28 | Quality of life measured by EORTC QLQ - OV28;These are the validated questionnaires to be answered by patients. Results to be reported as descriptive and on a scale of 1-10 | 36 months | 
| Patient reported outcomes (PROs) - QLQ-C30 | Quality of life measured by EORTC QLQ - C30;These are the validated questionnaires to be answered by patients. Results to be reported as descriptive and on a scale of 1-10 | 36 months |