| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ovarian, Primary Peritoneal or Fallopian Tube Cancer |
|
| 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 | 21.0 |
| 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) |
|
| 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 | 10061328 |
| E.1.2 | Term | Ovarian epithelial cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10016180 |
| E.1.2 | Term | Fallopian tube cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 evaluate progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST), as assessed by the investigator, in molecularly-defined homologous recombination deficiency (HRD) subgroups
|
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate patient-reported outcome (PRO) of disease-related symptoms utilizing the disease-related symptoms – physical (DRS–P) subscale of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index 18 (FOSI-18)
2. To evaluate PRO utilizing the complete FOSI-18
3. To evaluate survival benefit
4. To evaluate PFS by RECIST, as assessed by independent radiology review (IRR), in molecularly-defined HRD subgroups
5. To evaluate safety
6. To determine the population pharmacokinetics (PK) of rucaparib
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have signed an Institutional Review Board/Independent Ethics Committee-approved informed consent form prior to any study-specific evaluation
2. Be ≥ to 18 years of age when the informed consent form is signed
3. Have a histologically confirmed diagnosis of high-grade (Grade 2 or 3) serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer
-For mixed histology, >50% of the primary tumor must be confirmed to be high-grade serous or endometrioid
-Grade 2 tumors classified under a 3-tier system should be re-reviewed by local pathology and confirmed as high-grade under the 2-tier system
4. Received prior platinum based (PB) therapy and have platinum sensitive disease (i.e. documented radiologic disease progression >6 mths following the last dose of the penultimate platinum administered)
-Received ≥2 prior platinum-based treatment regimens, including platinum-based regimen that must have been administered immediately prior to maintenance therapy in this trial. In addition, up to 1 non-platinum chemotherapy regimen is permitted.
-Prior hormonal therapy is permitted; this treatment will not be counted as a non-platinum regimen.
-There is no upper limit on the number of prior PB regimens that have been received, but the patient must have been sensitive to the penultimate PB regimen administered.
-If both neoadjuvant and adjuvant treatment were administered pre/post any debulking surgery, this will be considered 1 treatment regimen
-Prior maintenance therapy following a prior treatment regimen is permitted, with the exception of the regimen received immediately prior to maintenance in this study. No anticancer therapy is permitted to be administered as maintenance treatment in the interval period between completion of the most recent PB therapy and initiation of study drug in this trial.
5. Achieved best response of either complete response (CR) or partial response (PR) to the most recent platinum-based regimen administered and is randomized to study treatment within 8 wks of the last dose of platinum received.
-The most recent platinum-based regimen must have been a chemotherapy doublet. The choice of the platinum and the 2nd chemotherapy agent is per investigator’s discretion.
-A minimum of 4 cycles of platinum chemotherapy must have been administered. There is no cap on the maximum number of cycles; however, additional cycles of treatment administered following completion of therapy for the specific purpose of enabling patient eligibility and randomization within 8 weeks of the last platinum dose is not permitted.
-A CR is defined as a complete radiologic response per RECIST v1.1, i.e. absence of any detectable disease and CA-125 <ULN
-A PR is defined as either a partial response per RECIST v1.1 (if disease was measurable prior to chemotherapy) or a serologic response per GCIG CA-125 response criteria (if disease was not measurable according to RECIST v1.1)
-CA-125 must also be <ULN for all responses classified as a PR
-R0 surgery (no visible tumor) or R1 surgery (residual disease < 1 cm) as a component of the most recent treatment regimen is not permitted. The response assessment must be determined solely in relation to the chemotherapy regimen administered. The presence of measurable disease or CA-125 > 2 x ULN immediately prior to the chemotherapy regimen is required.
-Responses must have been maintained through the completion of chemotherapy and during the interval period between completion of chemotherapy and entry in the study
-All disease assessments performed prior to and during this chemotherapy regimen must be adequately documented in the patient’s medical record
6. Have sufficient archival formalin-fixed paraffin-embedded (FFPE) tumor tissue (1 x 4 µm section for hematoxylin and eosin [H&E] stain and approximately 8 to 12 x 10 µm sections, or equivalent) available for planned analyses.
-The most recently collected tumor tissue should be provided, if available
-Submission of a tumor block is preferred; if sections are provided, these must all be from the same tumor sample.
-Sample must be received at the central laboratory at least 3 weeks prior to planned start of treatment in order to enable stratification for randomization
7. Have CA-125 measurement <ULN
8. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
9. Have adequate organ function confirmed by the following laboratory values obtained within 14 days of the first dose of study drug:
a. Bone Marrow Function
-Absolute neutrophil count (ANC) ≥1.5 × 109/L
-Platelets >100 × 109/L
-Hemoglobin ≥9 g/dL
b. Hepatic Function
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × ULN; if liver metastases, then ≤5 × ULN
-Bilirubin ≤1.5 × ULN (<2 x ULN if hyperbilirubinemia is due to Gilbert’s syndrome)
c. Renal Function
-Serum creatinine ≤1.5 × ULN or estimated glomerular filtration rate (GFR) ≥45 mL/min using the Cockcroft Gault formula |
|
| E.4 | Principal exclusion criteria |
1. History of a prior malignancy except:
a. Curatively treated non-melanoma skin cancer
b. Breast cancer treated curatively >3 years ago, or other solid tumor treated curatively >5 years ago, without evidence of recurrence
c. Synchronous endometrioid endometrial cancer (Stage 1A G1/G2)
2. Prior treatment with any poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, including oral or intravenous rucaparib. Patients who previously received iniparib are eligible.
3. Required drainage of ascites during the final 2 cycles of the last platinum-based regimen and/or during the period between the last dose of chemotherapy of that regimen and randomization to maintenance treatment in this study
4. 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.
5. Pre-existing, duodenal stent and/or any gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of study drug
6. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or history of chronic hepatitis B or C.
7. Pregnant or breast feeding. Women of childbearing potential must have a negative serum pregnancy test ≤ 3 days prior to first dose of study drug
8. 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 study drug and/or ongoing adverse effects from such treatment > National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) (NCI CTCAE) Grade 1, with the exception of Grade 2 non-hematologic toxicity such as alopecia, peripheral neuropathy and related effects of prior chemotherapy that are unlikely to be exacerbated by treatment with study drug
-Ongoing hormonal treatment for previously treated breast cancer is permitted
-Refer also to inclusion criteria #4 for guidelines pertaining to prior maintenance therapy
9. Received administration of strong CYP1A2 or CYP3A4 inhibitors ≤7 days prior to first dose of study drug or have on-going requirements for these medications (Appendix F)
10. Non-study related minor surgical procedure ≤5 days, or major surgical procedure ≤21 days, prior to first dose of study drug; in all cases, the patient must be sufficiently recovered and stable before treatment administration
11. Presence of any other condition that may increase the risk associated with study participation or interfere with the interpretation of study results, and, in the opinion of the investigator, would make the patient inappropriate for the study
No waivers of these inclusion or exclusion criteria will be granted by the investigator and the sponsor or its designee for any patient enrolled into the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Disease progression according to RECIST Version 1.1 (v1.1), as assessed by the investigator, or death from any cause (invPFS), in molecularly defined subgroups |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Disease assessment/tumor scans at the end of every 12 weeks after start of treatment on day 1 of cycle 1.
Patients who have been on study at least 18 months may decrease the frequency of disease assessments to every 16 (±2) weeks. |
|
| E.5.2 | Secondary end point(s) |
1. Time to a 4-point decrease in the disease-related symptoms – physical (DSR-P subscale) of the FACT-Ovarian Symptom Index 18 (FOSI-18)
2. Time to an 8-point decrease in the total score of the FOSI-18
3. Overall Survival (OS)
4. Disease progression according to RECIST v1.1, as assessed by IRR, or death from any cause (irrPFS), in molecularly defined subgroups
5. Incidence of AEs, clinical laboratory abnormalities, and dose modifications
6. Individual model parameter estimates of rucaparib and covariates identification |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. FOSI-18 & EQ-5D instruments are required at Screening, on Day 1 of each treatment cycle, at discontinuation, and at the 28 day post-treatment discontinuation follow-up visit.
2. The FOSI-18 and EQ-5D instruments must be completed prior to other scheduled study procedures and dosing (if applicable) at Screening, on Day 1 of each treatment cycle, at treatment discontinuation, and at the 28-day post-treatment discontinuation follow-up visit for all patients
3. Every 12 weeks until death, loss to follow-up, withdrawal of consent from study, or closure of the study.
4. As point 3
5. AEs that occur after first dose through to 28 days after last dose of study drug will be recorded
6. Day 15 of Cycle 1, on Day 1 of Cycle 2, on Day 15 of Cycle 2, and on Day 1 of Cycle 4 and Cycle 7. |
|
| 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 | 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) | 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 | 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 | 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 | 47 |
| 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 |
| Belgium |
| Canada |
| France |
| Germany |
| Israel |
| Italy |
| New Zealand |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| The trial is monitored on an ongoing basis by an IDMC for the number of PFS events required for the primary endpoint and for safety signals. An unblinding of treatment assignment might be performed when the study is still ongoing if the IDMC recommends it. However, the study is not anticipated to close until all patients are off treatment and sufficient OS follow up has occurred. Upon study end, eligible patients have the option of entering an extension protocol to continue rucaparib treatment. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
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