E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Platinum Sensitive Ovarian Cancer |
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E.1.1.1 | Medical condition in easily understood language |
Platinum Sensitive 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 | 20.0 |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate efficacy of niraparib as maintenance therapy in patients who have platinum sensitive ovarian cancer as assessed by the prolongation of progression-free survival (PFS). |
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E.2.2 | Secondary objectives of the trial |
(1) concordance of a candidate companion BRACanalysis diagnostic test compared to the centralized BRCA mutation test used in this study, if needed;
(2) Concordance of a candidate companion HRD diagnostic test compared to the HRD test used in this study, if needed;
(3) to evaluate additional measures of clinical benefit including patient reported outcomes (PROs), time to first subsequent treatment (TFST), time to second subsequent treatment (TSST), time from treatment randomization to the earlier date of assessment of progression on the next anticancer therapy following study treatment or death by any cause (progression-free survival 2; PFS2), chemotherapy-free interval (CFI), and overall survival (OS);
(4) to evaluate the safety and tolerability of niraparib compared to placebo in the indicated target population;
(5) to evaluate QTc in a subset of niraparib-treated ovarian cancer patients |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Food effect substudy, Version 1.0, date 03-May-2013
Objective: To assess the effect of a high fat meal on the PK of a single 300 mg dose of niraparib in patients with ovarian cancer. |
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E.3 | Principal inclusion criteria |
1. Female, age at least 18 years
2. Patient agrees to undergo analysis of their gBRCA status. (Testing must be completed prior to randomization. The sample may be submitted at any time prior to the screening period if it appears patient is likely to meet other eligibility requirements. To facilitate early testing, a separate informed consent form [ICF] specific for genotyping will be available to be signed prior to gBRCA status testing.)
3. Histologically diagnosed ovarian cancer, fallopian tube cancer, or primary peritoneal cancer
4. High grade (or Grade 3) serous or high grade predominantly serous histology or known to have gBRCAmut
5. Patients must have completed at least 2 previous courses of platinum-containing therapy (eg, carboplatin, oxaliplatin, or cisplatin):
a. For the penultimate (next to last) platinum-based chemotherapy course prior to enrollment on the study:
i. A patient must have platinum sensitive disease after this treatment; defined as achieving a response (CR or PR) and disease progression > 6 months after completion of their last dose of platinum therapy (document 6-12 months or > 12 months). (Source documentation required and may include physician or clinic notes.)
b. For the last chemotherapy course prior to being randomized in the study:
i. Patients must have received a platinum-containing regimen for a minimum of 4 cycles
ii. Patients must have achieved a partial or complete tumor response
iii. Following the last regimen, patients must have either
1. CA-125 in the normal range OR
2. CA-125 decrease by more than 90% during their last platinum regimen which is stable for at least 7 days (ie, no increase > 15%) iv. Following the last regimen, patients must not have any measurable lesion > 2 cm at the time of study entry
c. Patients must be randomized within 8 weeks after completion of their final dose of the platinum-containing regimen.
Note: The last platinum regimen does not necessarily have to immediately follow the next to last (penultimate) platinum regimen. For example, if a patient received a non-platinum regimen between the penultimate platinum regimen and last platinum regimen, they could be eligible, so long as they meet all entry criteria
6. The patient agrees to complete PROs during study treatment and at 1 additional time point 8 weeks following study treatment discontinuation. It is estimated that completion of PROs will take less than 20 minutes at each time point. Since these are questionnaires, their completion will not interfere with, or preclude, future treatment or clinical studies
7. Formalin fixed, paraffin-embedded archival tumor available from the primary or recurrent cancer required for all patients
8. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
9. Adequate organ function
a. Absolute neutrophil count (ANC) ≥ 1,500/μL
b. Platelets ≥ 100,000/μL
c. Hemoglobin ≥ 9 g/dL
d. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min using Cockcroft-Gault equation
e. Total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ 1 x ULN
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN unless liver metastases are present, in which case they must be ≤ 5 x ULN
10. Able to take oral medications
11. Women of childbearing potential must use adequate birth control for the duration of study participation
Additional Inclusion Criteria for Food Effect Sub-Study
With the exception of inclusion criteria 2, 4, 5, 6, 7, and 8 (above), all main study inclusion criteria apply. In addition, the following inclusion criteria apply to the FE sub-study only:
1. Entry criteria are broadened to include patients with ovarian cancer regardless of platinum sensitivity and burden of disease as long as no standard therapy exists or the patient has refused standard therapy.
2. ECOG 0-2
3. Must be able to eat a high fat meal and fast for 12 hours |
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E.4 | Principal exclusion criteria |
1. Drainage of ascites during last 2 cycles of last chemotherapy
2. Palliative radiotherapy within 1 week encompassing > 20% of the bone marrow
3. Persistent > Grade 2 toxicity from prior cancer therapy
4. Symptomatic uncontrolled brain or leptomeningeal metastases. (To be considered “controlled”, central nervous system (CNS) disease must have undergone treatment [eg, radiation or chemotherapy] at least 1 month prior to study entry. The patient must not have any new or progressive signs or symptoms related to the CNS disease and must be taking a stable dose of steroids or no steroids.) A scan to confirm the absence of brainmetastases is not required. Patients with spinal cord compression may be considered if they have received definitive treatment for this and evidence of clinically stable disease (SD) for 28 days.
5. Known hypersensitivity to the components of niraparib
6. Major surgery within 3 weeks of starting the study or patient has not recovered from any effects of any major surgery
7. Diagnosis, detection or treatment of invasive cancer other than ovarian cancer ≤ 2 years prior to randomization (except basal or squamous cell carcinoma of the skin that has been definitively treated)
8. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
9. History or current evidence of any condition, therapy, or lab abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study treatment, or is not in the best interest of the patient to participate
• Patients must not have received a transfusion (platelets or red blood cells) within 4 weeks of the first dose of study treatment
10. Patient is pregnant or breast feeding, or expecting to conceive children within the projected duration of the study treatment
11. Immunocompromised patients (Note: patients with splenectomy are allowed.)
12. Patients with known active hepatic disease (ie, Hepatitis B or C)
13. Prior treatment with a known PARP inhibitor
14. Patients with a baseline QT prolongation > 470 milliseconds
15. Patients are receiving concomitant medications that prolong QTc and are unable to discontinue use for the duration of the study
Additional Exclusion Criteria for Food Effect Sub-Study:
With the exception of exclusion criteria 1 and 13 (above), all main study exclusion criteria apply. In addition, the following exclusion criteria apply to the FE sub-study only:
1. Chemotherapy within 3 weeks of study start
2. Patient taking a proton pump inhibitor, antacids, or H2 blocker within 48 hours of dose
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-Free Survival |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Date of first documentation of objective progression or death by any cause in the absence of documented objective progression whichever occurs first. |
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E.5.2 | Secondary end point(s) |
1. Concordance of a candidate companion BRACanalysis diagnostic test compared to the centralized BRCA mutation test used in this study, if needed
2. Concordance of a candidate companion HRD diagnostic test compared to the HRD test used in this study, if needed
3. Observed changes from baseline in the following PROs:
a. FOSI
b. EQ-5D-5L
c. Neuropathy questionnaire
4. Outcomes for the next anticancer therapy following study treatment (best response, dose limiting toxicities, and date of progression) will be collected using source documentation.
5. PFS2 is defined as the time from treatment randomization to the earlier date of assessment of progression on the next anticancer therapy following study treatment or death by any cause. Determination of progression will be by site physician clinical and radiographic assessment (clinic and radiology notes may serve as source documentation).
6. Time to first subsequent therapy (TFST) is defined as the date of randomization in the current study to the start date of the first subsequent anticancer therapy.
7. Time to second subsequent therapy (TSST) is defined as the date of randomization in the current study to the start date of the second subsequent anticancer therapy.
8. Chemotherapy-free interval (CFI) the time from last platinum dose until initiation of next anticancer therapy (excluding maintenance therapy). CFI relative to CFI from prior chemotherapy regimens will be evaluated (clinic notes may serve as source documentation).
9. OS as measured from the date of randomization to the date of death by any cause
10. Time to CA-125 progression from time of randomization
11. Evaluation of the effects of food on the PK of niraparib |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
(1) Concordance of a candidate companion BRACanalysis diagnostic test compared to the centralized BRCA mutation test used in this study, if needed
(2) Concordance of a candidate companion HRD diagnostic test compared to the HRD test used in this study, if needed
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 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) | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 66 |
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 |
Austria |
Belgium |
Canada |
Denmark |
France |
Germany |
Hungary |
Israel |
Italy |
Norway |
Poland |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 18 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
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 |