| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with presumed and previously untreated advanced stage ovarian cancer planned to undergo laparoscopy for histologic diagnosis and treatment planning. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with presumed and previously untreated advanced stage ovarian cancer planned to undergo laparoscopy for histologic diagnosis and treatment planning |
|
| 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057529 |
| E.1.2 | Term | Ovarian cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10070906 |
| E.1.2 | Term | Ovarian cancer stage II |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10070907 |
| E.1.2 | Term | Ovarian cancer stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10070908 |
| E.1.2 | Term | Ovarian cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016182 |
| E.1.2 | Term | Fallopian tube cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10016180 |
| E.1.2 | Term | Fallopian tube cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016185 |
| E.1.2 | Term | Fallopian tube cancer stage II |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016186 |
| E.1.2 | Term | Fallopian tube cancer stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016187 |
| E.1.2 | Term | Fallopian tube cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 proof the feasibility of a window-of-opportunity treatment with Olaparib alone in patients with newly diagnosed high-grade ovarian cancer planned for primary debulking surgery
• To proof the feasibility of a window-of-opportunity treatment with Olaparib in combination with Durvalumab in patients with newly diagnosed high-grade ovarian cancer planned for primary debulking surgery |
|
| E.2.2 | Secondary objectives of the trial |
• To proof the safety of a window-of-opportunity treatment with Olaparib alone in patients with newly diagnosed high-grade ovarian cancer planned for primary debulking surgery
• To proof the safety of a window-of-opportunity treatment with Olaparib in combination with Durvalumab in patients with newly diagnosed high-grade ovarian cancer planned for primary debulking surgery
• To evaluate the utility of early ctDNA dynamics (cohort A + B) as clinically useful biomarker for response to therapy administered during a 3-4 weeks window-of-opportunity prior to interval debulking, based on tumor specific mutant ctDNA changes from baselines.
• ctDNA will be analyzed using 2 alternative platforms (1. ROCHE Diagnostics AVENIO ctDNA Analysis assay; 2. to be determined, depending on expected advances in technology)
- The methods are described in detail in the laboratory Manual |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 research 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
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 negative 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 TWO highly effective forms of contraception in combination (as described in Appendix 5 of the CIP. 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 (as described in Appendix 5 of the CIP).
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 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) ≥1.5×109/L
- Platelet count ≥100×109/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 |
|
| E.4 | Principal exclusion criteria |
1. Significant uncontrolled concomitant disease or illness that could affect compliance with the study protocol
3. Other malignancy unless curatively treated with no evidence of disease for ≥5 years except
4. 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
5. Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML
6. Brain metastases or spinal cord compression, Evidence of central nervous system (CNS) or leptomeningeal metastases
8. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection
10. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
11. History of active primary immunodeficiency
12. ECOG performance status (PS) ≥2 or general condition that might interfere with the compliance with the study protocol
Prior / concomitant therapy
13. Prior antineoplastic therapy for ovarian, fallopian tube or primary peritoneal cancer
14. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
15. 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
16. Patients planned for neoadjuvant chemotherapy or deemed unresectable at laparoscopy
17. Concomitant use of known strong CYP3A inhibitors
18. Concomitant use of known strong or moderate CYP3A inducers
19. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
20. Prior treatment with Olaparib or any other PARP inhibitor
31. Patients who are pregnant or breastfeeding 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)
Additional Durvalumab specific exclusion criteria for cohort B
21. 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 PK properties of an agent, a longer wash-out period will be required
22. 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 Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Coordinating Investigator.
b. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with Durvalumab may be included only after consultation with the Coordinating Investigator.
23. Any concurrent chemotherapy, 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.
24. 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
25. History of allogenic organ transplantation
26. History of leptomeningeal carcinomatosis
27. 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
28. 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 (known positive 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-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.
29. Current or prior use of immunosuppressive medication within 14 days before the first dose of Durvalumab.
30. 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.
32. Prior randomisation or treatment in a previous Durvalumab clinical study regardless of treatment arm assignment or other immunotherapies
33. (Sub)ileus or signs of malignant bowel obstruction. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The feasibility of window-of-opportunity administration of Olaparib or Olaparib plus Durvalumab will be assessed by:
• The successful completion of planned window-of-opportunity therapy defined as:
- Relative dose intensity (RDI) of ≥80%
- No treatment-related surgical delays (defined as >14 days from preplanned date of surgery)
- Any treatment or study-procedure related complications that in the judgement of the investigator or surgeon could significantly adversely impact perioperative morbidity or mortality, that leads to a delay in the planned operative date
- Adherence to therapeutic strategy (no treatment- or study procedure-related change from primary debulking surgery to neoadjuvant chemotherapy or surgery >7 days ahead of schedule)
- Withdrawal of informed consent, patients wish or logistic reasons, do not count in this respect. In addition, patients that require a change in therapeutic strategy because of non-treatment or study-related reasons will not count in the feasibility analysis and will be replaced
- Lack of clinical progression prior to primary debulking surgery
- No treatment-related toxicities of any grade that in the judgment of the investigator or surgeon significantly interfered with the subject’s optimal perioperative management
- Patients withdrawing consent before breaching any of the above-mentioned criteria are non-evaluable and will be replaced |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Safety:
• Proportion of patients who experience any adverse event (CTCAE v5.0), of a grade ≥3 between registration into the trial until 60 days after surgery or 60 days after the originally planned surgery date in case of switch of therapeutic strategy (e.g. from primary debulking to neoadjuvant or palliative chemotherapy) (assessed at the time intervals outlined in the Schedule of Assessments). It will be analyzed in the safety analysis population.
- Dose reductions, surgical delays, or interruptions due to WoO therapy
- Frequency of serious adverse events (SAEs) from registration into the study until 60 days after surgery or 60 days after the originally planned surgery date in case of switch of therapeutic strategy (e.g. from primary debulking to neoadjuvant or palliative chemotherapy)
- Frequency of abnormalities of clinical laboratory tests by worst toxicity grade (assessed at the time intervals outlined in the Schedule of Assessments)
ctDNA Dynamics:
- Proportion of ctDNA mutation positive patients at baseline above a predefined a cut-off (copies/ml)
- Circulating DNA ratio at day 21 (CDR21), defined as the ratio of mutation abundance at treatment day 21 relative to baseline of the mutant ctDNA allele with the highest abundance (mutant copies/ml).
- The median CDR21 will be used to distinguish between responders and non-responders
- Alternative cut-offs for response as well as time points will be explored
- The tumor specific mutation with the highest allele frequency (clonal mutations) within the tumor (corrected for germline mutations) will alternatively be used to investigate early ctDNA dynamics if detected at reasonable frequency in ctDNA by the respective platform.
Qualification for further investigation of this approach will be accepted if response status can be determined by ctDNA dynamics at baseline and day 21 in 75% of patients, with either platform. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.5 | Efficacy | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Feasibility of window-of-opportunity administration of Olaparib (cohort A) or Olaparib plus Durvalumab (cohort B). |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 15 |
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