| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the preliminary efficacy of maintenance treatment with olaparib (arm A) to that of olaparib plus durvalumab and UV1 (arm C) |
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| E.2.2 | Secondary objectives of the trial |
• 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 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.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. The consent must be signed before the time of inclusion.
2. Histologically diagnosed with epithelial ovarian, fallopian tube or primary peritoneal cancer, excluding mucinous or low-grade serous histology.
3. Radiological or histological confirmation of relapse disease ≥ 6 months after penultimate chemotherapy.
4. Patients who are non-gBRCAmut or tBRCAwt.
5. Have completed at least two lines, but no more than 3 lines, of chemotherapy, which means that patients at first or second relapse with treatment free interval of more than 6 months on penultimate chemotherapy are eligible. See Figure 3, section 5.
a. Patients must have completed at least 4 cycles of the latest platinum-containing chemotherapy.
6. Be either:
a. PARPi naive.
b. Earlier treated with PARPi and not progressed during 6 months of PARPi therapy.
7. Must not, in the opinion of the investigator, have progressed on, or after, latest platinum- containing chemotherapy. This means that patients with CR, PR, or SD or no evidence of disease are eligible. It should be documented CR or PR on the post-treatment scan following completion of the last chemotherapy course.
8. Patient consents to HRD test (Acceptable HRD tests: Myriad myChoice® CDx, Leuven HRD test, NOGGO GISv1, and TSO 500 HRD).
9. Must be randomized 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 /L.
- Platelet count ≥ 100 x 10 /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 urine test:
o 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. |
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| E.4 | Principal exclusion criteria |
1. Previous use of immune checkpoint inhibitors.
a. In case the patient has participated in an immune checkpoint inhibitor blinded study, the patient may be enrolled without unblinding.
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 (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation ≥ 470 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
4. Patients with myelodysplastic syndrome/acute myeloid leukemia 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 if 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.
7. Concomitant treatment with bevacizumab within the last 3 weeks.
8. Concomitant therapy with any other anticancer therapy or chronic use of systemic corticosteroids of more than 10mg prednisolone daily.
9. Concomitant use of known strong CYP3A inhibitors [...] or moderate CYP3A inhibitors [...]. The required washout period prior to starting study treatment is 2 weeks.
10. Concomitant use of known strong CYP3A inducers [...] or moderate CYP3A inducers [...]. The required washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
11. Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation.
12. Major surgery or significant traumatic injury within 28 days of randomization.
13. Immunocompromised patients, e.g., [...], patients with active hepatitis B [...] 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.
[...]
15. Participation in a clinical study within 28 days or 5 half-lives of the drug, whichever is longest.
16. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
17. Patients with a history of allergy or hypersensitivity to any of the study drugs (including human granulocyte-macrophage colony stimulating factor), yeast-derived products or any constituent of the products.
18. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy except for alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
[...]
19. Active or prior documented autoimmune or inflammatory disorders [...]. The following are exceptions to this criterion:
[...]
20. 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, [...].
21. 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.
22. History of active primary immunodeficiency.
23. Active infection including tuberculosis (TB) [...].
24. 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.
[...]
27. Patients that are depending on the sponsor/CRO or investigational site as well as on the investigator. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Progression-free survival (PFS) arm A versus C |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• PFS arm B versus arm C
• Assessment of PROs
• PFS assessed by blinded independent central review (BICR)
• Efficacy according to stratification factors
• Efficacy according to PD-L1 status
• Overall survival (OS)
• Time to first subsequent therapy (TFST)
• Subsequent progression (PFS2)
• Time to second subsequent therapy (TSST)
• Objective Response Rate (ORR)
• Disease Control Rate (DCR)
• Safety analysis
Exploratory endpoint
• Evaluation of changes in genetic, molecular and immunological markers of response and/or resistance over time
• Correlation between changes in genetic, molecular and immunological markers and efficacy in defined subgroups
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 60 months for all endpoints |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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60 months from the last patient entered into the trial.
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|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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