| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Maintenance Treatment in [A] Patients with Epithelial Ovarian Cancer (EOC) in Complete Remission Following First-Line Chemotherapy and [B] Patients with EOC in Second Remission |
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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 | 17.0 |
| 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) |
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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 |
Part A
To assess the efficacy, in terms of overall survival (OS), of Cvac compared with placebo for the maintenance treatment of patients with epithelial ovarian cancer (EOC) in complete remission (CR) following first-line chemotherapy.
Recruitment has been completed and a total of 76 patients were recruited and randomized at 24 centers in Europe, North America, and Australia.
Part B
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)
Up to 210 patients will be recruited and randomized at up to 70 centers. |
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| E.2.2 | Secondary objectives of the trial |
Part A
• To assess the time to next treatment (TTNT) in patients after treatment with Cvac compared with placebo
• To assess the efficacy, in terms of progression-free survival (PFS), of Cvac compared with placebo for the maintenance treatment of patients with EOC in CR following first line chemotherapy
• To assess the safety and tolerability of Cvac compared with placebo
• To assess health-related quality of life (QoL) related to Cvac treatment compared with placebo
Part B
• 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
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part A Screening Inclusion Criteria
Patients may be enrolled in and randomized to the study only if they meet all of the following criteria at screening:
1. Females ≥ 18 years of age at screening with a confirmed diagnosis of Stage III or IV epithelial ovarian, primary peritoneal, or fallopian tube cancer
2. Have undergone or will undergo optimal debulking surgery, defined as ≤ 1 cm of residual tumor
3. Eligible for, and plan to undergo standard platinum and taxane first-line chemotherapy
4. Signed an informed consent form (ICF)
5. Willing and able to complete study procedures within the study timelines
6. Mucin 1-positive tumor as determined by central immunohistopathology
7. Adequate renal function in the opinion of the investigator based on serum creatinine and/or glomerular filtration rate
8. Adequate liver function: serum glutamic oxaloacetic transaminase/aspartate aminotransferase (SGOT/AST) and serum glutamic pyruvic transaminase/alanine aminotransferase (SGPT/ALT) ≤ 2 × upper limit of normal (ULN) and serum bilirubin ≤ 1.5 × ULN unless Gilbert’s syndrome has previously been confirmed for the patient.
9. 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
10. Life expectancy of at least 12 months at the time of screening as judged by the investigator
11. 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.
Part A Baseline Inclusion and Exclusion Criteria
Patients must meet the following baseline criteria in order to continue to dosing and follow up stages of the study:
1. Have achieved complete remission as evidenced by the baseline radiological scan ≤ 32 weeks after randomization; complete remission is defined as no detectable lesion, no relevant abnormalities on physical examination, and a normal CA 125 level
2. Have completed at least 3 cycles of platinum- and taxane-based first-line chemotherapy, with or without concurrent bevacizumab
3. Have not withdrawn consent from study participation
4. Remain willing and able to complete study procedures within the study timelines
5. Adequate bone marrow function: WBCs ≥ 3.0 K/µL, ANC ≥ 1.5 × 109/L, hemoglobin ≥ 9 g/dL, and platelets ≥ 100 × 109/L
6. Adequate renal function in the opinion of the investigator based on serum creatinine and/or glomerular filtration rate
7. Adequate liver function: SGOT/AST and SGPT/ALT ≤ 2 × ULN and serum bilirubin ≤ 1.5 × ULN
8. 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.
9. Have not developed another type of malignancy, except carcinoma in-situ of the cervix or basal cell and squamous cell carcinomas of the skin that have been adequately treated
10. Have not been treated with any investigational product (for any condition) between screening and baseline
11. No concurrent systemic treatment with steroids or other immunosuppressant agents at a dose considered by the investigator to be higher than a standard physiological dose
12. No other health condition or reason that would preclude participation in the study in the judgment of the principal investigator.
Part B Inclusion Criteria
Refer to the Protocol Section 7.1 Part B
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| E.4 | Principal exclusion criteria |
Part A Screening Exclusion Criteria
Patients are to be excluded from the study at the time of screening for any of the following reasons:
1. Non-epithelial ovarian cancer, including ovarian germ cell, sarcoma, mixed Müllerian tumors, or mucinous carcinoma of the peritoneum
2. Malignancy other than EOC, except those that have been in CR for a minimum of 3 years, and except carcinoma in-situ of the cervix or basal cell and squamous cell carcinomas of the skin that have been adequately treated
3. Treatment with any investigational product (for any condition) within 4 weeks of screening
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. Clinically significant abnormalities as measured by ECG
7. Active uncontrolled infection
8. Uncontrolled hypertension
9. Diagnosed immunodeficiency or autoimmune disorder
10. Infection with human immunodeficiency virus (HIV) or hepatitis C virus (HCV), or active and infectious hepatitis B virus (HBV) infection
11. Pregnant or lactating
12. Evidence or history of central nervous system metastasis
13. Known hypersensitivity to any of the components of the study agent
14. Active or latent infection with Mycobacterium tuberculosis in any body tissue (especially renal and/or lung)
15. Any other health condition that would preclude participation in the study in the judgment of the principal investigator.
Part B 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
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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A
OS will be measured as the number of days between baseline (Week 0) and the date of death from any cause. OS data will be censored at the date of the data cut-off for the OS analysis for surviving patients, or at the date of last contact for lost-to-follow-up patients, whichever occurs first.
Part B
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 |
Each patient will be assessed for PD every 12 weeks beginning at baseline, 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.
For Part A, the original protocol provided for up to 1000 patients to be randomised so that approx. 800 would achieve CR upon completion of first-line chemotherapy and thus proceed to the treatment phase. 76 patients were randomised prior to termination of enrolment in Nov 2013. Only 40 patients achieved CR following first-line chemotherapy and advanced to the treatment phase to receive Cvac or placebo, and thus efficacy and safety data will be descriptively analysed. |
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| E.5.2 | Secondary end point(s) |
Part A
TTNT is defined as the time from baseline (Week 0) to the date when a next treatment for EOC is started.
PFS is defined as the time from baseline (Week 0) to the date of the radiological scan used to determine PD or date of death from any cause (PFS event). The analysis of the secondary PFS endpoint will be based on PD evaluations by the local site radiologist and assessments conducted approximately every 12 weeks after baseline.
Part B
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.
A secondary analysis of TTNT and PFS will use the baseline visit as the reference starting date.
Each patient will be assessed for PD every 12 weeks beginning at baseline, until PD is determined by the investigator, or until death, or until the end of the study, whichever occurs first for the patient.
The investigator shall continue with PD evaluations until determination of either unequivocal PD or confirmed equivocal PD.
Safety and tolerability will be assessed by the following:
• Adverse events evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4
• Clinically relevant changes from baseline in vital signs
• Clinically relevant changes from baseline in 12-lead electrocardiogram (ECG)
• Clinically relevant changes from baseline in physical examinations
• Clinically relevant changes from baseline in safety laboratory assessments (hematology with differential count, biochemistry, and urinalysis)
• Clinically relevant autoantibody laboratory assessments.
Quality of life will be assessed by 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 endpoints:
• Change in ECOG performance status from baseline
• Human leukocyte antigen (HLA) genotyping and breast cancer gene (BRCA) status from patients where data are available
• Immunological assays
Part B only:
•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: Schedule of assessments
Each patient will be assessed for PD every 12 weeks beginning at baseline, until PD is determined by the investigator, or until death, or until the end of the study, whichever occurs first for the patient.
The investigator shall continue with PD evaluations until determination of either unequivocal PD or confirmed equivocal PD. |
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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 | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Part A (Randomised Double Blind Placebo Controlled) and Part B (Randomized Open Label Controlled) |
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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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Part A is placebo controlled; Part B is "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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 36 |
| 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 |
| 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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Follow-up visits will be made every 12 weeks until PD and then
telephone contacts until, death or end of study, 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 | 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 |
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