E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer |
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E.1.1.1 | Medical condition in easily understood language |
Ovarian, Fallopian Tube, or Primary Peritoneal 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 | 10061269 |
E.1.2 | Term | Malignant peritoneal neoplasm |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10016181 |
E.1.2 | Term | Fallopian tube neoplasms malignant |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1.To determine PFS in patients with relapsed platinum-sensitive ovarian cancer classified into molecularly-defined subgroups by a prospectively defined HRD signature (Part 1) 2.To estimate ORR in heavily pre-treated patients with relapsed ovarian cancer classified into molecularly-defined subgroups by a prospectively defined HRD signature (Part 2) |
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E.2.2 | Secondary objectives of the trial |
1. To estimate the overall response rate (ORR) (Part 1) 2. To estimate ORR including CA-125 response criteria 3. To evaluate duration of response (DOR) 4. To determine PFS (Part 2) 5. To evaluate survival (Part 2) 6. To evaluate the safety and tolerability of rucaparib 7. To evaluate the steady state trough level pharmacokinetics (PK) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved informed consent form prior to any study-specific evaluation 2. Be ≥18 years of age at the time the informed consent form is signed 3. Have a histologically confirmed diagnosis of high-grade serous or Grade 2 or Grade 3 endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer − If mixed histology, >50% of the primary tumor must be confirmed to be high-grade serous or endometrioid upon re-review by local pathology - Patients with a histology other than serous or endometrioid are also eligible for Part 2 of the study if they are known to harbor a deleterious/pathogenic BRCA mutation (germline or somatic) 4. Have relapsed/progressive disease as confirmed by radiologic assessment 5. Part 1: Received prior platinum-based therapy and have platinum-sensitive disease a. Received ≥1 prior platinum-based treatment regimen; AND b. Received a platinum-based regimen as their last treatment; continuous or switch maintenance treatment as part of this regimen is permitted (hormonal treatment may be permitted following the last platinum regimen with advance approval from the Sponsor); AND c. Was sensitive to the last platinum regimen. Platinum-sensitive disease is defined as documented radiologic progression ≥6 months after the last dose of platinum administered in the treatment setting. Part 2: Received at least 3, but no more than 4, prior chemotherapy regimens and had documented treatment-free interval of ≥6 months following 1st chemotherapy regimen received a.Hormonal agents (eg. tamoxifen, letrozole, etc), anti-angiogenic agents (eg. bevacizumab, pazopanib, cediranib, nintedanib, trebananib, etc), and other non-chemotherapy agents administered as single agent treatement will not be counted as a chemotherapy regimen for the purpose of determing patient eligibility b.Agents administered in the maintenance setting will not be counted as a separate regimen 6. Part 1 only: If <55 years of age at diagnosis, or has prior history of breast cancer, or has close relative (first or second degree) with ovarian cancer or early onset (<age 50) breast cancer, must have been previously tested for gBRCA mutation; after 15 patients harboring the gBRCA mutation are enrolled, no additional patients with a known gBRCA mutation will be allowed to enroll. 7. Have undergone a biopsy of tumor tissue prior to first dose of study drug and had the tumor tissue confirmed by the central laboratory as being of adequate quality (at least 20% tumor content with a minimum of 80% nucleated cellular content). Note: biopsy is optional for Part 2 patients known to harbor a deleterious gBRCA mutation. - If tumor tissue obtained from the biopsy is deemed inadequate, and the patient is unwilling or unable to have another biopsy, the patient may be considered for enrollment if archival tumor tissue is provided and deemed of adequate quality. This must occur prior to any treatment with rucaparib. a. Biopsy must be of solid tumor tissue; ascites is not acceptable. b. Biopsy must be of sufficient yield for planned analyses. 8. Have sufficient archival FFPE tumor tissue available for planned analyses; cytospin blocks from ascites are not acceptable. − The most recently obtained tumor tissue that is of adequate quality (at least 20% tumor content with a minimum of 80% nucleated cellular content) should be submitted 9. Have measurable disease as defined by RECIST v1.1 in addition to the lesion planned for biopsy; a single RECIST target lesion will suffice if, in the Investigator’s opinion, it is of sufficient size that the biopsy will not affect post-dose RECIST evaluations. 10. Have adequate organ function confirmed by the following laboratory values obtained within 14 days prior to the first dose of rucaparib: a. Bone Marrow Function i. Absolute neutrophil count (ANC) ≥1.5 × 109/L ii. Platelets >100 × 109/L iii. Hemoglobin ≥9 g/dL b. Hepatic Function i. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN); if liver metastases, then ≤5 × ULN ii. Bilirubin ≤1.5 × ULN (<2 × ULN if hyperbilirubemia is due to Gilbert’s syndrome) iii. Serum albumin ≥30g/L (3 g/dL) (Part 2 only) c. Renal Function i. Serum creatinine ≤1.5 × ULN or estimated glomerular filtration rate (GFR) ≥45 mL/min using the Cockcroft Gault formula 11. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 |
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E.4 | Principal exclusion criteria |
1. Active second malignancy, i.e., patient known to have potentially fatal cancer present for which she may be (but not necessarily) currently receiving treatment a. Patients with a history of malignancy that has been completely treated, with no evidence of that cancer currently, are permitted to enroll in the trial provided all chemotherapy was completed >6 months prior and/or bone marrow transplant (BMT) >2 years prior to first dose of rucaparib 2. Prior treatment with any PARP inhibitor, including oral or intravenous rucaparib. Patients who previously received iniparib are eligible 3. Symptomatic and/or untreated central nervous system (CNS) metastases. Patients with asymptomatic previously treated CNS metastases are eligible provided they have been clinically stable for at least 4 weeks 4. Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of rucaparib 5. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or history of chronic hepatitis B or C 6. Pregnant or breast feeding. Women of childbearing potential must have a negative serum pregnancy test <3 days prior to first dose of rucaparib. 7. Received treatment with chemotherapy, radiation, antibody therapy or other immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or experimental drugs ≤14 days prior to first dose of rucaparib and/or ongoing adverse effects from such treatment > NCI CTCAE Grade 1 (ongoing Grade 2 non-hematologic toxicity related to most recent treatment regimen may be permitted with prior advanced approval from Sponsor). 8. Received administration of strong CYP1A2 or CYP3A4 inhibitors ≤7 days prior to first dose of rucaparib or have on-going requirements for these medications 9. Non-study related minor surgical procedure ≤5 days, or major surgical procedure ≤21 days, prior to first dose of rucaparib; in all cases, the patient must be sufficiently recovered and stable before treatment administration 10. Presence of any other condition that may increase the risk associated with study participation or may interfere with the interpretation of study results, and, in the opinion of the investigator, would make the patient inappropriate for entry into the study 11.Diagnosis of low-grade serous or Grade 1 endometrioid ovarian cancer 12.Part 2 Only: Hospitalization for bowel obstruction within 3 months prior to enrollment |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Disease progression (RECIST v1.1) as assessed by investigator, or death from any cause in molecularly-defined subgroups identified by a prospectively defined HRD signature 2.ORR by RECIST v1.1 in molecularly-defined subgroups identified by a prospectively defined HRD signature |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Tumor assessments will be performed at Screening, at the end of every 8weeks (±4 days), and post-treatment (if patient discontinued treatment for any reason other than radiologically confirmed disease progression) until radiologically confirmed disease progression, death or initiation of subsequent treatment. Patients who have been on treatment at least 18months, may decrease the frequency of tumor assessments to every 16 (±2) weeks. Tumor assessments should be done at the time of treatment discontinuation if it has been ≥8 weeks since the last assessment. A confirmatory scan should be performed at least 4 weeks after an initial response of PR or CR is observed. CA-125 will be collected at Screening, on Day 1 of each cycle, and at End of Treatment visit and as clinically indicated. |
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E.5.2 | Secondary end point(s) |
1.ORR by RECIST v1.1 2.ORR by RECIST v1.1 and GCIG CA-125 criteria 3.DOR by RECIST v1.1 4.Disease progression (RECIST v1.1) as assessed by investigator, or death from any cause 5. Overall survival 6. The incidence of adverse events (AEs), clinical laboratory abnormalities, and dose modifications 7. Trough (Cmin) level rucaparib concentrations |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.DOR assessments will be as per tumor assessments for primary endpoint 2.PFS will be assessed as per tumor assessments for primary endpoint 3.ORR by RECIST will be assessed as per tumor assessments for primary endpoint 4.ORR by GCIG CA-125 criteria will be assessed as per CA-125 assessments for primary endpoint 5.AEs will be recorded at Screening, on Day 1 of each cycle, at end of treatment, and end of study visit (28±3 days after last dose). Ongoing SAEs will be followed to resolution. Clinical laboratory abnormalities will be recorded at Screening, on Day 1 of each cycle, and at end of treatment (urinalysis performed at Screening). Dose modifications to be recorded as needed 6.Samples for rucaparib PK to be taken prior to dosing on Day 15 of Cycle 1 and Day 1 of Cycles 2, 3, and 4 |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
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 | No |
E.8.1.1 | Randomised | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 |
Australia |
Canada |
France |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 trial will close when the required number of PFS events has been observed. Upon formal closure of the study, individual patients who arecontinuing to receive benefit from treatment at the time of study closure, and who do not meet any of the criteria for withdrawal, will have the option of entering an extension protocol in which they can continue to receive rucaparib |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 2 |