| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Advanced ovarian cancer patients who have:
Cohort 1 – platinum resistant disease and are PARP inhibitor naïve;
Cohort 2 – had at least 2 prior lines of therapy which must include at least 1 line of platinum-based chemotherapy followed by PARP inhibitor maintenance |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 2A:
To investigate the efficacy of EP0057 in combination with Olaparib in the indicated patient populations
To explore the safety and tolerability of EP0057 when combined with Olaparib in the indicated patient populations
Phase 2B:
To investigate the efficacy of EP0057 in combination with Olaparib vs SoC chemotherapy (TBC) |
|
| E.2.2 | Secondary objectives of the trial |
Phase 2A:
To further investigate the efficacy of EP0057 in combination with Olaparib
Pharmacokinetics
Phase 2B:
To further investigate the efficacy of EP0057 in combination with Olaparib vs SoC chemotherapy
To explore the safety of EP0057 when combined with Olaparib in the indicated patient populations versus SOC chemotherapy
Patient Quality of Life |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all the following inclusion criteria to be eligible for inclusion in the study:
1. Patients age ≥18 years of age at the time of informed consent
2. Ability to understand and provide written informed consent prior to undergoing any study procedures
3. Life expectancy of > 3 months, as estimated by the investigator
4. Histologically confirmed diagnosis (cytology alone excluded) with highgrade serous ovarian cancer or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer
5. BRCA mutational status is known (germline and somatic). (For Patients in Phase 2A, status does not need to be known prior to enrolment)
6. HRD status is known. (For Patients in Phase 2A, status does not need to be known prior to enrolment)
7. At least 1 measurable lesion to assess response by RECIST v1.1 criteria
8. Archival tumour sample must be available. In the absence of an archival tumour biopsy, a tumour tissue biopsy will need to be collected prior to enrolment
9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 at Screening
10. Normal organ and bone marrow function:
Haemoglobin ≥ 9.0 g/dL
Absolute neutrophil count (ANC) ≥ 1.5 x 109
Lymphocyte count ≥ 0.5 x 109
Platelet count ≥ 100 x 109
Total bilirubin ≤ 1.5 institutional upper limit normal (ULN)
Serum albumin ≥ 2.5 g/dL
AST and ALT ≤ 2.5 x ULN, unless liver metastases are present in which case they must be ≤ 5 x ULN
Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance >50mL/min (calculated using the Cockroft-Gault formula) for patients with creatinine levels above institutional normal
Patients not receiving anti-coagulant medication must have an INR of ≤ 1.5 and an aPTT ≤ 1.5 x ULN
11. In the opinion of the investigator, all other relevant medical conditions must be well-managed and stable for at least 28 days prior to first administration of study drug
12. Willing and able to participate in all required evaluations and procedures in this study protocol
13. Contraception. Each female subject of childbearing potential must agree to use a highly effective method of contraception (i.e., a method with less than 1% failure rate per year [e.g., sterilisation, hormone implants, hormone injections, some intrauterine devices, vasectomized partner, or combined birth control pills]) from screening until 120 days after the last dose of EP0057. Females of childbearing potential must have a negative serum pregnancy test at Screening and a negative serum or urine pregnancy test within 24 hours prior to EP0057 dosing on Day 1 of each Cycle (and must not be lactating). Each female subject will be considered to be of childbearing potential unless she has been surgically sterilised by hysterectomy or bilateral tubal ligation/salpingectomy or has been postmenopausal for at least 1 year.
Cohort 1 patients (Phase 2A and 2B) must be/have:
14. PARP inhibitor naïve
15. Received no more than 1 prior line of therapy which must be platinum based chemotherapy
16. Either: Stable disease (SD) following treatment with first line platinum-based
chemotherapy OR Primary platinum resistant disease defined by progressive disease (PD) within ≥ 1 and ≤ 6 months after completion of first line platinum-based chemotherapy
Cohort 2 patients (Phase 2A and 2B) must have:
18. Received at least 2 prior lines of treatment, 1 of which must be platinum-based chemotherapy
19. Received a PARP inhibitor in the maintenance setting as their most recent treatment following a confirmed response by RECIST1.1 (CR or PR) to the last regimen which must be a platinum-based chemotherapy, with maintenance of response by PARP inhibitor lasting ≥6 and up to 12 months, with subsequent confirmed disease progression as defined by RECIST v1.1 criteria
|
|
| E.4 | Principal exclusion criteria |
1. Non-epithelial tumour of the ovary, the fallopian tube or the peritoneum
2. Ovarian tumours of low malignant potential or low grade
3. Prior treatment with a topoisomerase I inhibitor
4. Potent inhibitors or inducers of CYP3A4
5. Concurrent treatment with Coumadin (warfarin)
6. History of stroke, transient ischemic attack (TIA), or myocardial infarction, within 6 months prior to C1D1
7. Brain and/or leptomeningeal metastases that are symptomatic or untreated or that require current therapy. Brain imaging must not be older than 12 weeks (at the start of screening). Results with
abnormal/unexpected findings of brain MRI should be discussed with the Medical Monitor as part of the screening process
8. Systemic anti-cancer therapy for the disease under study within 3 weeks, or 5 half-lives, whichever is longer, of the first dose of study drug
9. Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 2 toxicities, which in the opinion of the Investigator should not exclude the patient. Ongoing Grade 1 toxicities should be discussed with and approved by the Medical Monitor prior to inclusion
10. Patients considered at higher baseline risk for new onset cystitis should be discussed by the Investigator and Medical Monitor prior to enrolment
11. Patients with a history, or features suggestive, of bone marrow dysplasia or myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML)
12. Confirmed QTcF > 470 msec on screening ECG or congenital long QT syndrome
13. Receiving an investigational anti-cancer treatment concurrently or within 3 weeks or 5 half-lives of either the parent drug or any active metabolite, whichever is longer, prior to the first dose of study drug
14. Any evidence of severe or uncontrolled systemic conditions (e.g., severe hepatic impairment) or current unstable or uncompensated respiratory or cardiac conditions which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol
15. Hypersensitivity to EP0057 or any of its excipients
16. Known history of human immunodeficiency virus infection (HIV) (testing is not required), active infection with SARS-CoV-2, hepatitis B virus (HBV) or hepatitis C virus (HCV) per institutional protocol. Testing for HBV or HCV status is not necessary unless clinically indicated or the patient has a history of HBV or HCV infection. All patients should be tested for an active SARS-CoV-2 infection with an approved diagnostic test kit
17. Malignant disease other than that being treated in this study, with the following exceptions:
Malignancies that were treated curatively and have not recurred within 2 years prior to study treatment
Completely resected basal cell and squamous cell skin cancers
Any malignancy considered to be indolent and that has never required therapy
Completely resected carcinoma in situ of any type
18. Any medical condition that would, in the investigator’s judgment, prevent the patient’s participation in the clinical study due to safety concerns, compliance with clinical study procedures, or interpretation of study results
19. Any major surgical procedure (in the investigator’s judgement) within 2 weeks of the first dose of study drug
20. Pregnant, likely to become pregnant, or lactating women (where pregnancy is defined as the state of a female after conception and until the termination of gestation)
21. Palliative radiotherapy (e.g., for pain or bleeding) within 6 weeks prior to randomization or patients who have not completely recovered (Grade ≥2) from the effects of previous radiotherapy
22. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
Note: Patients with indwelling catheters (e.g., PleurX) are allowed
23. Hypersensitivity or intolerance (due to safety or other reasons) to PARP inhibitors
Cohort 1 patients (Phase 2A and 2B) who:
24. Have primary platinum refractory disease defined as progression during first line treatment with 4 - 6 cycles of platinum-based chemotherapy
25. Have had prior treatment with Bevacizumab
Cohort 2 patients (Phase 2A and 2B) who:
26. Progress within ≥ 1 and < 6 months during PARP inhibitor maintenence treatment
27. Progress after treatment with PARP inhibitor maintenance treatment lasting > 12 months |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 2A:
Overall Response Rate (ORR) as measured using RECIST1.1
Safety and tolerability; AEs, SAEs, dose interruptions and reductions, withdrawals due to treatment related toxicities, duration of treatment, vital signs, haematology, clinical chemistry and ECGs.
Phase 2B:
The following endpoints for patients treated with EP0057 plus Olaparib will be compared with those for patients treated with SoC for both Cohorts 1 and 2:
Progression-free Survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For Phase 2A, the efficacy data will be assessed for futility analysis after approximately 15 patients are enrolled into each cohort. There will be an initial data cut-off to assess the primary endpoint of ORR approximately 4 months after the last patient has commenced treatment within each Cohort.
Data for Cohorts 1 and 2 will be presented side-by-side in summaries and maybe summarised at different timepoints.
For Phase 2B, the data cut-off to assess the primary endpoint of PFS will occur when the required
number of PFS events have occurred in each cohort. Patients may continue to be followed for Overall Survival (OS). |
|
| E.5.2 | Secondary end point(s) |
Phase 2A:
PFS
PFS by BRCA (germline and somatic) and HRD status
OS
OS by BRCA (germline and somatic) and HRD status
Duration of response
Duration of response by BRCA (germline and somatic) and HRD status
ORR by BRCA (germline and somatic) and HRD status
Pharmacokinetics parameters:
Maximum plasma concentration (Cmax), time to Cmax (tmax), terminal plasma half-life (t½λz), area under the plasma concentrationtime curve from zero to infinity (AUCSS), oral plasma clearance (CL/F), oral volume of distribution during terminal phase (Vz/F), mean residence time (MRT).
Phase 2B:
The following endpoints for patients treated with EP0057 plus Olaparib will be compared with those for patients treated with SoC for both Cohorts 1 and 2:
OS
Safety and tolerability; AEs, SAEs, vital signs, haematology and clinical chemistry, ECGs, dose interruptions and reductions, withdrawals due to treatment related toxicities, duration of treatment
OS by BRCA (germline and somatic) and HRD status
PFS by BRCA (germline and somatic) and HRD status
ORR
ORR by BRCA (germline and somatic) and HRD status
Duration of response
Duration of response by BRCA (germline and somatic) and HRD status
QoL EORTC Quality-of-Life Questionnaire (QLQ-C30) and the ovarian cancer module (QLQ-OV28) and EQ-5D |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For Phase 2A, there will be an initial data cut-off to assess the secondary endpoints including safety, PFS and OS will also be summarised.
Patients will continue to be followed for PFS and OS.
Data for Cohorts 1 and 2 will be presented side-by-side in summaries and maybe summarised at different timepoints.
For Phase 2B:
Efficacy data will be summarised and analysed on an intention-to-treat basis using the full analsis set
and based on randomised treatment assignment. Additonal data presentations with longer term follow up for safety, PFS and OS may also be reported when the study has completed
PFS will be compared when the required number of events has been reached. PFS at 6, 12 and 24 months will be derived from Kaplan Meier survival estimates. |
|
| 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 | Yes |
| 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 | 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| Czech Republic |
| Hungary |
| Italy |
| Poland |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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