| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| This is a multicenter, randomized, placebo controlled, double blind study including patients with patients with histologically confirmed, advanced (FIGO stage IIIB, IIIC, or IV of the 2014 FIGO classification) high grade serous or high grade endometrioid (based on local histopathological findings) ovarian cancer, fallopian tube cancer, primary peritoneal cancer and clear cell carcinoma of the ovary in first line therapy. |
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| E.1.1.1 | Medical condition in easily understood language |
| A study including patients with advanced endometrioid ovarian cancer, fallopian tube cancer, primary peritoneal cancer and clear cell carcinoma of the ovary in first line therapy. |
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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 aim of this study is to determine the efficacy of the PARP-inhibitor Rucaparib as maintenance therapy following a previous maintenance therapy with the anti-VEGF bevacizumab compared to placebo in BRCA negative patients.
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| E.2.2 | Secondary objectives of the trial |
Secondary aims of this study are the determination of PFS2, the evaluation of quality of life, Determination of time to next medical intervention, the time to next subsequent therapy, assessment of safety and overall survival (OS) for patients who receive Rucaparib compared to placebo.
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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 |
The biological clock (circadian clock) regulates physiology and behaviour via molecular mechanisms and plays a vital role in human health. Circadian rhythm disruption is associated to several diseases including diabetes, Alzheimer's disease, obesity, depression and cancer. Published studies have reported a role for clock dysregulation in cancer. Thus, it is crucial to characterize the individual's internal circadian rhythm. This information can be used as a monitoring mechanism to enhance health, but also to optimize the time for medicine intake based on the individual's internal timing. We will measure the circadian rhythmicity based on the mRNA expression levels of four core-clock genes and compare their expression phenotypes as a reaction to the therapy at the times (Time 0-Time 5) as listed below. Circadian rhythmicity will be analysed as described below. This data will allow to obtain valuable information regarding the circadian clock of the patient and how it is affected by the therapy, contributing to explain possible secondary effects (e.g. sleep disturbances) and may help to find ways to minimize those by
enhancing oscillations (e.g. via light exposure). |
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| E.3 | Principal inclusion criteria |
1. Written informed consent and obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
2. Age ≥ 18.
3. Patients with histologically confirmed, advanced (FIGO stage IIIB, IIIC, or IV of the 2014 FIGO classification) high grade serous or high grade endometrioid (based on local histopathological findings) ovarian cancer, fallopian tube cancer, primary peritoneal cancer and clear cell carcinoma of the ovary in first line therapy.
4. Availability of archival tumor tissue for central NGS analysis and Patient must be BRCA negative based on these results
5. Treatment with Bevacizumab or respective biosimilar for 12 to 15 months, independent of dosage.
6. Patients who have completed first line platinum-taxane chemotherapy and at least stable disease after treatment with Bevacizumab before randomization.
7. Patients must be randomized at least 3 weeks and no more than 9 weeks after their last dose of Bevacizumab (last dose is the day of the last infusion) and all major toxicities from the previous chemotherapy must have resolved to CTC AE grade 1 or better (except alopecia and peripheral neuropathy).
8. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
9. Patients must have normal organ and bone marrow function:
a. Hemoglobin ≥ 9.0 g/dL independent of transfusion ≤ 14 days prior to screening hemoglobin assessment
b. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
c. Platelet count ≥ 100 x 109/L
d. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN); < 2 × ULN if hyperbilirubinemia is due to Gilbert’s syndrome
e. Aspartate aminotransferase /Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT)) and Alanine aminotransferase /Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) ≤ 3 x ULN, unless liver metastases are present in which case they must be ≤ 5 x ULN
f. Serum creatinine ≤ 1.5 x institutional ULN and creatinine clearance > 30 mL/min
g. Patients not receiving anticoagulant medication who have an International Normalized Ratio (INR) ≤1.5 and an Activated ProThrombin Time (aPTT) ≤1.5 x ULN.
10. Postmenopausal or evidence of non-childbearing status for women of childbearing potential prior to the first dose of study treatment. Female patients of childbearing potential must have a negative serum pregnancy test result ≤3 days prior to administration of the first dose of study treatment.
Patients are considered to be of childbearing potential unless 1 of the following applies:
a) Considered to be permanently sterile. Permanent sterilization includes hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy; or
b) Is postmenopausal, defined as no menses for at least 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level consistently in the postmenopausal range (30 mIU/mL or higher) may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy; however, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to confirm a postmenopausal state.
Female patients of reproductive potential must practice highly effective methods (failure rate < 1% per year) of contraception with their partners, if of reproductive potential, during treatment and for 6 months following the last dose of rucaparib or longer if requested by local authorities. Highly effective contraception includes: Ongoing use of progesterone only injectable or implantable contraceptives; Placement of an intrauterine device (IUD) or intrauterine system (IUS); Bilateral tubal occlusion; Sexual abstinence as defined as complete or true abstinence, acceptable only when it is the usual and preferred lifestyle of the patient; periodic abstinence (eg, calendar, symptothermal, post-ovulation methods) is not acceptable; or Sterilization of the male partner, with appropriate post-vasectomy documentation of absence of sperm in ejaculate. |
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| E.4 | Principal exclusion criteria |
1. Non-epithelial origin of the ovary, the fallopian tube or the peritoneum (i.e. germ cell tumors) and Ovarian tumors of low malignant potential (e.g. borderline tumors), or low grade serous ovarian cancer, or low grade endometrioid ovarian cancer, or mucinous carcinoma.
3. Patients receiving radiotherapy within 6 weeks prior to study treatment.
4. Major surgery within 4 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
5. use of any other PARP-Inhibitor in first line therapy
6. Administration of other simultaneous chemotherapy drugs, any other anti-cancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period (hormonal replacement therapy is permitted as are steroidal antiemetics).
9. History or evidence of hemorrhagic disorders within 6 months prior to randomization.
10. Evidence of bleeding diathesis or significant coagulopathy (in the absence of coagulation).
11. History or or evidence for brain metastases or spinal cord compression.
12. History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures).
13. Significant traumatic injury during 4 weeks prior to randomization.
14. Non-healing wound, active ulcer or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require 3 weekly wound examinations.
15. Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease.
16. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment related complications.
17. Pregnant or lactating women, women of child-bearing potential who do not agree to the usage of highly effective contraception methods (see inclusion criteria).
18. Participation in another clinical study with an investigational product immediately prior to randomization.
19. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
20. Patients with a known hypersensitivity to Rucaparib or any of the recipients of the product.
21. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or history of chronic hepatitis B or C.
22. Other active malignancy requiring treatment.
23. Patient who might be dependent on the sponsor, CRO, site or the investigator.
24. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression free survival in BRCA negative patients (PFS, time from randomization until disease progression or death)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Will be evaluated from randomisation until end of study. |
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| E.5.2 | Secondary end point(s) |
• PFS2 (time from randomization to second progression or death)
• Quality of life
o PRO's (EORTC QLQ-C30, EORTC QLQ-OV28, FSI, SF-12, Everyday Memory Questionnaire, PRO-CTCAE
o Daily activity at least two years and beyond progression (max one year after)
• Determination of time to next medical intervention (e.g. bowel obstruction, Ascites puncture)
• Time to next subsequent therapy e.g. chemotherapy
• Safety assessment, includes AEs/SAEs, laboratory evaluations, vital signs and physical examination
• Overall survival (OS) defined as time from Randomization to death by any cause |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Will be evaluated from randomisation until end of study. |
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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 | No |
| 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) | 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 | 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 | 24 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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