| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly Diagnosed Advanced Epithelial Ovarian Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced Epithelial Ovarian Cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the antitumour activity according to RECIST 1.1 criteria of paclitaxel + carboplatin with or without Debio 1143 at the end of neoadjuvant treatment (prior to interval debulking surgery) in patients with newly diagnosed epithelial ovarian cancer. |
|
| E.2.2 | Secondary objectives of the trial |
To determine the rate of optimal surgical cytoreduction at interval debulking surgery
To determine the rate of radiological complete response at the end of neoadjuvant treatment and after debulking surgery/ the rate of complete pathological response
To assess tumour response to paclitaxel+carboplatin with or without Debio1143 as measured by CA125 tumour marker during the neoadjuvant treatment and after debulking surgery/ the safety and tolerability of Debio1143 when given in combination with paclitaxel+carboplatin/ the duration of surgical intervention and the rate of perioperative morbidity
To determine the rate of postoperative mortality/ the discharge time from hospital
To investigate the Exposure/Response relationship of Debio 1143 when combined with paclitaxel and carboplatin, based on PK disposition relationship with any pharmacological, safety, and/or efficacy markers
To confirm that paclitaxel exposure in the Debio 1143 treatment group is comparable to the control group |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Women ≥ 18 years ≤ 70 years.
2. Patient with newly diagnosed, histologically confirmed (cytology alone excluded) high-grade serous ovarian cancer and high-grade endometrioid ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma.
For patients with endometrioid cancer, only grade 3 defined by morphological features and immunohistochemical staining42 are eligible.
3. Documented FIGO stage IIIC-IV confirmed by laparoscopy (or mini-laparotomy) and imaging AND unsuitable for primary complete cytoreductive surgery.
4. Medically fit to undergo surgical cytoreduction after 4 cycles of neoadjuvant chemotherapy.
5. Eligible for carboplatin and paclitaxel chemotherapy.
6. Tumour biopsy sample for exploratory analysis.
7. ECOG performance score 0-2.
8. Life expectancy of at least 6 months in the best judgement of the investigator.
9. Minimum of one measurable tumour lesion, according to the RECIST 1.1 criteria (measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or > 10 mm with calipers by clinical exam. Lymph nodes with a short axis ≥ 15 mm are considered to be measurable and assessable as target lesions).
10. Adequate bone marrow, renal and liver function: calculated creatinine clearance ≥ 50 mL/min as determined by the modified Cockcroft method; absolute neutrophil count ≥ 1500/μL, platelets ≥ 100000/μL, haemoglobin ≥ 9 g/dL, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 4 × ULN; total bilirubin ≤ 2.0 mg/dL.
11. Serum albumin level ≥ lower limit normal (LLN).
12. Women of child-bearing potential must
o Have a negative serum pregnancy test at screening.
o Agree to use appropriate contraception method from time of study entry to surgery or up to 6 months after the last day of treatment.
13. No active rheumatoid arthritis, active inflammatory bowel disease, chronic infections, or any other disease or condition associated with chronic inflammation.
14. QTcF interval ≤ 480 milliseconds.
15. Able to take oral medication and has no condition or prior surgical procedure affecting absorption.
16. Able to understand and voluntarily sign an informed consent form. |
|
| E.4 | Principal exclusion criteria |
1. History of another active malignancy within the preceding 3 years, except for adequately treated carcinoma in situ of the cervix, breast, and non-melanomatous skin.
2. Mucinous, clear cell, and carcinosarcoma histologies.
3. Clinical evidence of brain or leptomeningeal metastases.
4. Serious disabling disease contraindicating cytoreductive surgery such as, but not limited to, New York Heart Association (NYHA) grade 3/4 congestive heart failure and severe pulmonary disease.
5. Major surgery within 28 days prior to the first dose of study treatment and not fully recovered to baseline or to a stable clinical status.
6. Human immunodeficiency virus (HIV) infection (testing required)
7. Known history of HBV or HCV (testing not required in the absence of clinical findings or suspicion).
8. Pre-existing sensory or motor neuropathy NCI-CTCAE v 4.03 ≥ 2.
9. Any psychological familial, sociological or geographical condition potentially preventing compliance with the study protocol schedule.
10. Prior treatment with an inhibitor of apoptosis protein (IAP) inhibitors.
11. Known allergic reaction triggered by Debio 1143 or its excipients.
12. Use or requirement for use of aspirin or aspirin-containing products with > 160 mg of aspirin per day.
13. Concurrent treatment with prohibited medications |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Response Rate (RR) according to RECIST 1.1 criteria at the end of 4 cycles of neoadjuvant treatment and prior to interval debulking surgery as determined by central independent radiology committee |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At the end of 4 cycles of neoadjuvant treatment and prior to interval debulking surgery |
|
| E.5.2 | Secondary end point(s) |
-Rate of complete cytoreduction (sCR), defined as no macroscopic residual tumour at time of interval debulking surgery
-Rate of radiological CR as assessed by RECIST 1.1 at the end of neoadjuvant treatment (prior to interval debulking surgery) and after debulking surgery
-Rate of response rate at the end of neoadjuvant treatment and after interval debulking surgery (EOS)
-Rate of complete pathological response (pCR) defined as no residual invasive cancer at the time of debulking
-Response rate measured by CA-125 tumour marker during the neoadjuvant treatment and after debulking surgery as assessed by GCIG criteria
-Incidence of AEs and SAEs according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03 criteria and extent of treatment exposure
-Safety and tolerability of Debio 1143 when given in combination with paclitaxel + carboplatin as assessed by laboratory values, vital signs, ECG, and ECOG PS
-Rate of perioperative serious complications within the first 28 days such as grade 3 to 5 hemorrhage/bleeding during surgery or postoperative requiring at least 2 units transfusion of red blood cells, vascular events (thrombosis/embolism), infections requiring IV antibiotics/antifungal or antiviral intervention, gastrointestinal fistula, urine fistula, etc
-Rate of postoperative death (< 28 days)
-Duration of hospitalisation for debulking surgery (from day of surgery to day of discharge)
-Duration of surgical intervention.
-Pharmacokinetic analyses
o Debio 1143 (including Debio 1143-MET1) PK parameters relevant for exposure description (e.g., AUC, Cmax, trough plasma concentration (Ctrough), average plasma concentration [Cavg]) and for exploratory analysis (e.g., apparent clearance [CL/F], V/F, t1/2, MRAUC).
o Paclitaxel (including 6αOH-paclitaxel as appropriate) PK parameters: AUC, TC>0.05, total body clearance (CL), and any other PK parameter as deemed appropriate. Adequate paclitaxel exposure will be evaluated by comparing AUC and TC>0.05 between both study arms, notably in the PK subset of 8 and 15 consecutive patients approximately by treatment arm.19
o Carboplatin PK parameter: AUC of free platinum and any other PK parameter as deemed
appropriate.
-Exposure/Response relationship based on the exposure measure (i.e., parameter characterizing drug input into the body) and the response measure (i.e. direct measures of the pharmacological effect of the drug by PDy marker (MCP1, CK-M30), efficacy marker, safety marker) (per ICH E4, EMA, and FDA guidelines). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoint(s) of evaluation of secondary end points are described in protocol section 9.1.2 where applicable. |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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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