E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Maintenance treatment in patients with epithelial ovarian cancer (EOC) with no evidence of disease (NED) following second remission defined as after response to second-line platinum-based therapy. |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of ovarian cancer |
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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 | 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) |
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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 efficacy, in terms of overall survival (OS), of Cvac compared with observational standard of care following second remission in epithelial ovarian cancer (EOC). |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives • To assess the time to next treatment (TTNT) in patients after treatment with Cvac compared with observational standard of care • To assess the efficacy, in terms of progression-free survival (PFS), of Cvac compared with observational standard of care following second remission • To assess the safety and tolerability of Cvac compared with observational standard of care • To assess health-related quality of life (QoL) related to Cvac treatment compared with observational standard of care Exploratory Objectives • Investigate the utility of biomarkers as predictors or prognostic factors of clinical outcomes of Cvac • Investigate histopathology of tumor samples for potential markers of predictive clinical efficacy of Cvac • Evaluate immunologic response to Cvac administration • Assess the effect of Cvac on changes in ECOG performance status from baseline visit (defined as the visit within 2 weeks of the 1st dose) compared with observational standard of care
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients may be enrolled in and randomized to the study only if they meet all of the following criteria at screening and the baseline visit (defined as the visit within 2 weeks of the first dose): 1. Females ≥ 18 years of age at screening with a confirmed diagnosis of epithelial ovarian, fallopian tube, or peritoneal cancer 2. Underwent standard cytoreductive surgery and first-line chemotherapy containing platinum before first relapse and were in complete remission for at least 6 months prior to relapse 3. Relapsed once and then underwent standard platinum-based second line chemotherapy (at least 3 cycles is required) with or without a second bulk-reducing surgery 4. Second remission defined as: a. No definitive evidence of disease (NED) on CT or MRI of the abdomen and pelvis; b. CA-125 ≤ upper limit of normal (ULN) or 90% reduction in CA-125 since start of second-line chemotherapy; c. Negative physical exam (i.e., no clinical signs) 5. Life expectancy ≥ 3 months in the opinion of the investigator 6. Signed an informed consent form (ICF) 7. Willing and able to complete study procedures within the expected study timelines 8. Mucin 1-positive tumor as determined by central immunohistopathology 9. Histologically documented EOC, fallopian tube, or peritoneal cancer (patients with pseudomyxoma, mesothelioma, unknown primary tumor, sarcoma, or neuroendocrine histology, with borderline ovarian cancer, i.e., patients with low malignant potential tumors, and with clear cell or mucinous histology are excluded) 10. Adequate end-organ and hematological function as defined by: a. Adequate bone marrow function: white blood cells (WBCs) ≥ 3.0 K/µL, absolute neutrophil count (ANC) ≥ 1.5 × 109/L, hemoglobin ≥ 9 g/dL, and platelets ≥ 100 × 109/L b. Adequate renal function: serum creatinine ≤ 1.5 × ULN c. Adequate liver function: serum glutamic oxaloacetic transaminase/aspartate aminotransferase (SGOT/AST) and serum glutamic pyruvic transaminase/alanine aminotransferase (SGPT/ALT) ≤ 2 × ULN and serum bilirubin ≤ 1.5 × ULN 11. Generally well-controlled blood pressure with systolic blood pressure ≤ 140 mmHg and diastolic blood pressure ≤ 90 mmHg prior to randomization (antihypertensive medications are permitted). Low-dose chronic hormonal or steroidal treatments are also permitted. 12. Not pregnant, and if of childbearing potential, agrees to use a highly effective method of birth control (implanted, injectable, or oral combination hormonal method alone or in possible combinations, intrauterine device, vasectomized partner, or abstinence) prior to study entry, for the duration of the study, and for 3 months after the last dose of study agent. Male partners of a study patient must use a condom in addition to the acceptable method of contraception for the female partner as specified above 13. ECOG status of 0 or 1 (applicable at the baseline visit only).
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E.4 | Principal exclusion criteria |
Patients are to be excluded from the study at the time of screening and the baseline visit (defined as the visit within 2 weeks of the first dose) for any of the following reasons: 1. More than 2 previous lines of chemotherapy for EOC, fallopian tube, or peritoneal cancer 2. Primary platinum-refractory or platinum-resistant disease (i.e., patients who progress prior to cessation of induction therapy [platinum refractory] or recur within 6 months after cessation [platinum resistant]) 3. Treatment with any investigational product (for any condition) within 4 weeks of screening. Enrolled in or has not completed at least 28 days (prior to screening) since ending another investigational device or drug treatment, or currently receiving other investigational treatments 4. Concurrent systemic treatment with steroids or other immunosuppressant agents at a dose considered by the investigator to be higher than a standard physiological dose 5. Evidence of severe or uncontrolled cardiac disease, including myocardial infarction or unstable angina within 6 months of screening, congestive heart failure, or ventricular arrhythmias requiring medication 6. Diagnosed immunodeficiency or autoimmune disorder 7. Infection with human immunodeficiency virus (HIV) or hepatitis C virus (HCV), or active and infectious hepatitis B virus (HBV) infection 8. Pregnant or lactating/breastfeeding 9. Evidence or history of central nervous system metastasis 10. Known hypersensitivity to any of the components of the study agent 11. Any unresolved persistent toxicities from prior systemic therapy that are either Grade 3 or Grade 4 (except alopecia) per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 12. Intent to treat patient with both an anti-angiogenesis therapy (such as bevacizumab) and a PARP inhibitor as part of maintenance therapy. Only one or the other are permitted while the patient is on study and must be started between the baseline visit and Visit 1 if it will be used as part of the patient’s maintenance therapy regimen 13. Prior malignant diseases, unless the patient has been in full remission for a minimum of 2 years, except carcinoma in situ of the cervix or basal cell and squamous cell carcinomas of the skin (note: rationale for contraindication for existing and prior malignant diseases unless the patient has been in complete remission for an entire 2 years unless exceptions for in situ carcinoma or the cervix or basal cell or squamous cell carcinoma or the skins is provided in the investigator’s brochure) 14. Active, uncontrolled, ongoing infection.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint for this study is overall survival (OS). OS is defined as the number of days elapsed between the randomization date and the date of death (regardless of cause). A secondary analysis of OS will use the baseline visit as the reference starting date. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Approximately 210 patients will be recruited and randomized into the trial. Upon either completing or discontinuing the treatment phase of the study, patients will then be followed for OS and PFS. OS will be monitored every 24 weeks after confirmation of progressive disease (PD). PFS will be radiologically assessed at intervals of approximately 12 weeks at the site until PD, death, or until the end of the study if a patient does not progress or die during the study. Radiological scans will be evaluated at the site for determination of progression, and must be kept for potential later evaluation by an independent radiologist.
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E.5.2 | Secondary end point(s) |
Time to next treatment (TTNT) is defined as the number of days from the randomization date to the date when a next treatment for EOC is started.
Progression free survival (PFS) is defined as the number of days from the randomization date to the earliest of documented disease progression or death without prior progression.
Each patient will be assessed for progressive disease (PD) every 12 weeks beginning at the baseline visit, until PD is determined by the investigator, or until death, or until the end of the study, whichever occurs first.
The investigator shall continue with PD evaluations until determination of either unequivocal PD or confirmed equivocal PD (see definitions in Section 9.2 of the protocol).
A secondary analysis of TTNT and PFS will use the baseline visit as the reference starting date.
Safety and tolerability will be assessed by the following: • Adverse events evaluated according to the National Cancer Institute (NCI) CTCAE version 4 • Clinically relevant changes from the baseline visit in vital signs • Clinically relevant changes from the baseline visit in 12-lead electrocardiogram (ECG) • Clinically relevant changes from the baseline visit in physical examinations • Clinically relevant changes from the baseline visit in safety laboratory assessments (hematology with differential count, biochemistry, and urinalysis) • Clinically relevant autoantibody laboratory assessments.
Quality of life will be assessed using the following: • European Organisation for Research and Treatment of Cancer–Quality of Life Questionnaire (EORTC QLQ-C30, version 3) • OV28 Module to EORTC QLQ • EuroQol Group EQ-5D-3L.
Other and exploratory analyses: • Change in ECOG performance status from the baseline visit • Human leukocyte antigen (HLA) genotyping and breast cancer gene (BRCA) status from patients where data are available • Immunological assays • Assess the utility of biomarkers as predictors of PFS and/or OS.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
See Protocol Table 1 for Schedule of Assessments. Each patient will be assessed for PD at the clinical site at intervals of approx. 12 weeks, until PD is determined, or until death, or study end, whichever occurs first for the patient. Radiological scans should be performed using the same technique (CT or MRI) throughout the entire study, if possible. As all patients must be deemed to have no evidence of disease at baseline to continue on study, disease progression thereafter will be defined as any measurable new lesion(s) that can be accurately measured in at least one dimension. A secondary analysis of TTNT and PFS will use the baseline visit date as the reference starting date. QoL will be assessed at baseline, after each dose of study agent, and at PFS Follow-Up Visits. |
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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 | 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 | 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 | 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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Observational standard of care |
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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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 28 |
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 |
Belarus |
Belgium |
Bulgaria |
Germany |
Latvia |
Lithuania |
Poland |
Ukraine |
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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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12 weeks after Visit 7 (± 1 week), and every 12 weeks thereafter (± 1 week), until unequivocal PD or death, or until the end of study (whichever occurs first), patients will attend a PFS Follow-Up Visit. After PD, investigators will continue to contact patients or caretakers to assess overall survival approximately every 24 weeks until death or the end of 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 | 5 |
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 | 5 |
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 |