E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Women with recurrent platinum-resistant or refractory epithelial ovarian cancer and low HER3 mRNA expression. |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066697 |
E.1.2 | Term | Ovarian cancer recurrent |
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 |
Part 1: Safety Run-in Phase
The primary objective for Part 1 of this study is as follows:
-To determine the safety and tolerability of pertuzumab in combination with either topotecan or paclitaxel.
Part 2:
The primary objective for Part 2 of this study is as follows:
-To determine if pertuzumab plus chemotherapy is superior to placebo plus chemotherapy as measured by progression-free survival (PFS). |
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E.2.2 | Secondary objectives of the trial |
The secondary objective for Part 1 of this study is as follows:
-To descriptively evaluate the progression-free survival (PFS) of pertuzumab in combination with either topotecan or paclitaxel.
The secondary objectives for Part 2 of this study are as follows:
-To determine if pertuzumab plus chemotherapy is superior to placebo plus chemotherapy with respect to:
-Overall survival (OS).
-Objective response rate (ORR).
-Biological progression-free interval (PFIBIO).
-Safety and tolerability.
-Quality of life (QoL). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed written informed consent approved by the relevant IEC/IRB.
2. Female patients aged 18 years or older.
3. Low HER3 mRNA expression levels (concentration ratio equal or lower than 2.81, as assessed by qRT-PCR on a cobas z480 instrument).
4. Histologically or cytologically confirmed and documented epithelial ovarian cancer that is platinum-resistant or refractory (defined as progression within 6 months from completion of a minimum of 4 platinum therapy cycles or progression during platinum therapy).
5. At least one measurable lesion and/or non measurable disease according to RECIST version 1.1, or cancer antigen-125 (CA-125) assessable disease according to Gynecologic Center Intergroup (GCIG) criteria. The following histological types are eligible:
• Adenocarcinoma not otherwise specified.
• Clear cell adenocarcinoma.
• Endometrioid adenocarcinoma.
• Malignant Brenner's tumor.
• Mixed epithelial carcinoma including malignant mixed Müllerian tumors.
• Mucinous adenocarcinoma.
• Serous adenocarcinoma.
• Transitional cell carcinoma.
• Undifferentiated carcinoma.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
7. LVEF greater than or equal to 55%.
8. Negative serum pregnancy test in women of childbearing potential (WOCBP; premenopausal or less than 12 months of amenorrhea post-menopause, and who have not undergone surgical sterilization).
9. For WOCBP who are sexually active, agreement to use a highly effective, non hormonal form of contraception or two effective forms of non hormonal contraception during and for at least 6 months post trial treatment (a highly effective non-hormonal form of contraception, such as surgical sterilization, or two effective non-hormonal forms of contraception, such as a barrier method of contraception in conjunction with spermicidal jelly).
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E.4 | Principal exclusion criteria |
1. Non-epithelial tumors.
2. Ovarian tumors with low malignant potential (i.e. borderline tumors).
3. History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or basal cell carcinoma, except for tumors with a negligible risk for metastasis or death, such as adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix or breast.
4. Serious uncontrolled concomitant disease that would contraindicate the use of any of the investigational drugs used in this study or that would put the patient at high risk for treatment-related complications.
5. Previous treatment with more than 2 chemotherapy regimens, . If a patient has previously been treated with topotecan, paclitaxel, or gemcitabine as second-line therapy, the patient will not be retreated with the same agent.
6. Any prior radiotherapy to the pelvis or abdomen.
7. History or evidence on physical/neurological examination of central nervous system disease unrelated to cancer, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures).
8. Pre-exisiting peripheral neuropathy ≥ CTC grade 2.
9. Inadequate organ function, evidenced by the following laboratory results:
• Absolute neutrophil count <1,500 cells/mm3.
• Platelet count <100,000 cells/mm3.
• Hemoglobin <9 g/dL.
• Total bilirubin greater than 1.5 ×upper limit of normal (ULN) (unless the patient has documented Gilbert’s syndrome).
• Serum alkaline phosphatase, aspartate aminotransferase (AST; SGOT) or alanine aminotransferase (ALT; SGPT) >2.5 × ULN (or > 5 × ULN in the presence of liver metastases)
• Serum creatinine >2.0 mg/dL or >177 μmol/L.
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) >1.5 × ULN (unless on therapeutic anti-coagulation).
10. Uncontrolled hypertension (systolic >150 mm Hg and/or diastolic >100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: cerebrovascular accident (CVA)/stroke or myocardial infarction within 6 months prior to first study medication, unstable angina, congestive heart failure (CHF) of New York Heart Association (NYHA) Grade II or higher, or serious cardiac arrhythmia requiring medication.
11. Current known infection with HIV, HBV, or HCV.
12. Dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy.
13. Major surgical procedure or significant traumatic injury within 28 days prior to first study drug administration or anticipation of need for major surgery during the course of study treatment.
14. Receipt of intravenous antibiotics for infection within 14 days prior to first study drug administration.
15. Current chronic daily treatment with corticosteroids (dose equivalent to or greater than 10 mg/day methylprednisolone), excluding inhaled steroids.
16. Known hypersensitivity to any of the trial drugs or excipients.
17. History of receiving any investigational treatment within 28 days prior to first study drug administration, including prior enrollment into Part 1 of the trial.
18. Concurrent participation in any clinical trial.
19. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1 (safety run-in phase): primary objective will be safety and tolerability (analyses will be descriptive).
Part 2
The primary efficacy endpoint is PFS. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1: The main safety analysis will occur when all patients have received three cycles of pertuzumab with chemotherapy (i.e. topotecan or paclitaxel) and will be assessed by an Independent Data Monitoring Committee (IDMC). This is expected to happen approximately 6.5 months after FPI for Part 1.
Part 2:
The analysis of the primary efficacy endpoint (PFS) in Part 2 of the study will be performed when 109 events have occurred, approximately 12 months after randomization of the first patient. |
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E.5.2 | Secondary end point(s) |
Part 2:
Efficacy: OS, ORR, PFIBIO
Safety:
-Incidence, nature, and severity of all adverse events (AEs), serious adverse events (SAEs), and AEs that caused premature withdrawal from study medication.
-Premature withdrawal from the study and study treatment.
-Cardiac disorders / incidence of congestive heart failure.
-Laboratory test abnormalities.
-LVEF and electrocardiograms (ECGs) over the course of the study.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 2: A first analysis of OS will be performed with the final analysis of PFS. The final analysis of OS will take place once all patients have been followed up for at least 12 months after the last patient randomized has received their last dose of study drug, unless they have been lost to follow-up, withdrawn consent, or died, or the Sponsor prematurely terminates the trial, whichever occurs first. There will be no interim efficacy analysis for Part 2 of the trial. |
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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 | No |
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 | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Patient-reported outcome measures, biomarkers |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
Study comprises 2 parts. Part 1: non-randomized, open-l., safety run-in. Part 2 as in section E.8.1 |
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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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 96 |
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 |
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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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Part 1: see protocol section 3.2
Part 2: The end of Part 2 of the study is defined as the date when all patients have been followed up for at least 12 months after the last patient randomized has received their last dose of study drug, unless they have been lost to follow-up, withdrawn consent, or died, or if the trial is prematurely terminated by the Sponsor, whichever occurs first. |
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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 | 3 |
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 | 3 |
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 |