E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Recurrent high grade serous ovarian carcinoma |
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E.1.1.1 | Medical condition in easily understood language |
Recurrent high grade serous ovarian carcinoma |
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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 | LLT |
E.1.2 | Classification code | 10033131 |
E.1.2 | Term | Ovarian carcinoma |
E.1.2 | System Organ Class | 100000004864 |
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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 make an assessment of the efficacy of a combined APR-246 and carboplatin/PLD chemotherapy regimen in patients with platinum sensitive recurrent HGSOC with mutated TP53. |
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E.2.2 | Secondary objectives of the trial |
• To assess the safety profile of the combined APR-246 and carboplatin/PLD chemotherapy regimen compared with carboplatin/PLD chemotherapy regimen alone. • To evaluate potential biomarkers. • To assess the biological activity in tumor and surrogate tissues. • To compare quality of life of patients treated with these regimens.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Archived sections from the original FFPE sample reviewed by a gynecological pathologist confirming High Grade Serous Ovarian Cancer, High Grade Serous Peritoneal Cancer or Primary Fallopian Tube Cancer, and positive IHC staining for p53 assessed according to defined standard (as detailed in the laboratory manual). Cases that do not show p53 staining will not be included. 2. Radiologically-confirmed Disease Progression between six and twenty-four (6-24) months after a first or second platinum based regimen. 3. At least a single (RECIST v1.1) measurable lesion. 4. Adequate organ function prior to registration: a) Bone Marrow Reserve: Absolute neutrophil count (ANC) ≥ 1.5 x109/L, Platelets ≥ 100 x109/L, Hemoglobin ≥ 9 g/dL. b) Hepatic: Total bilirubin level < 1.5 x ULN, ALT and AST < 2.5 x ULN. c) Renal: Calculated creatinine clearance > 30mL/min. d) Electrolytes Potassium within institutional normal ranges. 5. Toxicities from previous cancer therapies, excluding alopecia, must have recovered to grade 1 (defined by CTCAE 4.0). Chronic stable grade 2 peripheral neuropathy secondary to neurotoxicity from prior therapies may be considered on a case by case basis by the Principal Investigator. 6. If of childbearing potential, negative pre-treatment serum pregnancy test. 7. If of childbearing potential, willing to use an effective form of contraception (see below) during chemotherapy treatment and for at least six months thereafter. Such methods include: (if using hormonal contraception this method must be supplemented with a barrier method, preferably male condom). combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: o oral o intravaginal o transdermal progestogen-only hormonal contraception associated with inhibition of ovulation: o oral o injectable o implantable intrauterine device (IUD) intrauterine hormone-releasing system ( IUS) bilateral tubal occlusion vasectomised partner true sexual abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception. Male condom with spermicide (female condom and male condom should not be used together) 8. ECOG performance status of 0 to 1 (Appendix I). 9. ≥ 18 years of age. 10. Written informed consent obtained prior to any screening procedures and in accordance with federal, local, and institutional guidelines. 11. Patient has exhausted all available treatments, including surgery, and is considered a suitable candidate to receive carboplatin/PLD. |
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E.4 | Principal exclusion criteria |
1. Prior exposure to cumulative doses of doxorubicin >400 mg/m2 or epirubicin >720 mg/m2. 2. Confirmed cardiac history of any of the following: a) Myocardial infarct within six months prior to registration, b) New York Heart Association Class II or worse heart failure (Appendix II), c) A history of familial long QT syndrome, d) Clinically significant pericardial disease, e) Electrocardiographic evidence of acute ischemia, f) Symptomatic atrial or ventricular arrhythmias not controlled by medications. g) QTc ≥ 480 msec calculated from a single ECG reading or a mean of 3 ECG readings using Fridericia’s correction (QTcF = QT/RR0.33) h) Bradycardia (<40bpm) i) Left ventricular ejection fraction (LVEF) < the institution lower limit of normal as assessed by ECHO 3. Major abdominal surgery or peritonitis within six weeks prior to study treatment. 4. Unresolved bowel obstruction, sub-occlusive disease or the presence of brain metastases. 5. History of uncontrolled allergic reactions to carboplatin, platinum containing compounds or mannitol and/or hypersensitivity to PLD or to any of the excipients. 6. Unable to undergo imaging by either CT scan or MRI. 7. Evidence of any other medical conditions (such as psychiatric illness, infectious diseases, neurological conditions, physical examination or laboratory findings) that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment related complications. 8. Breast feeding. 9. Concurrent malignancy requiring therapy (excluding non-invasive carcinoma or carcinoma in situ). 10. Patients requiring or undergoing concurrent treatment with live vaccines 11. Patients requiring or undergoing concurrent treatment with phenytoin. 12. Known HIV positive status, active hepatitis B or C status. 13. Is taking any concurrent (or within 4 week prior to registration) anti-cancer therapy, immunotherapy, radiotherapy or any ancillary anti-cancer therapy; or any therapy that is considered to be investigational (i.e., used for non-approved indications(s) and in the context of a research investigation). Supportive care measures are allowed. 14. Patients unable to be regularly followed for any reason (geographic, familiar, social, psychological, housed in an institution e.g., prison because of a court agreement or administrative order). Patients who are dependent on the sponsor/CRO or investigational site as well as on the Investigator. 15. Use of concomitant treatment with QT/QTc prolonging drugs. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Progression-free survival (PFS) based on Blinded Independent Central Review (BICR) is the primary endpoint and is defined as the number of days from the date of randomization to the date of objective disease progression or relapse (according to RECIST v1.1 only) or death due to any cause, whichever occurs first. If neither event occurs, PFS will be censored at the date of the last evaluable tumor assessment. Symptomatic deterioration is not objective disease progression. All patients will be monitored for events until 12 months after the last patient is enrolled. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Please refer to the study protocol. |
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E.5.2 | Secondary end point(s) |
• Best overall response and overall response rate (according to RECIST v1.1 and GCIG criteria) • Duration of response (complete or partial response) • PFS by assessment of CA-125 (according to GCIG Criteria) • Overall survival • Safety profile based on AEs and laboratory assessments • Evaluation of biomarkers and tumor activity based on CA-125 • Quality of Life assessment using EORTC Ovarian (QLQ-OV28) and the Functional Assessment of Cancer Therapy-Ovarian (FACT-O)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to the study protocol. |
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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 | Yes |
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 | 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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
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 |
Belgium |
France |
Netherlands |
Spain |
Sweden |
United Kingdom |
United States |
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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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The end of the study is defined as the date of the last visit of the last patient taking part in the study. |
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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 | 4 |
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 | 4 |
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 |