Rucaparib MAintenance After Bevacizumab Maintenance Following Carboplatin Based First Line Chemotherapy in Ovarian Cancer Patients

The main scope of this trial is to determine progression free survival in BRCA negative patients treated with Rucaparib as maintenance therapy vs. Placebo after receiving Bevacizumab for 12 to 15 months.

BRCA negative patients will be stratified according to time point of surgery (adjuvant vs. neoadjuvant), result of surgery (tumor free vs. not tumor free resection), study site and response (complete response (CR) vs. partial response (PR)/SD) and randomized 2:1 to receive either Rucaparib (Arm A) or Placebo (Arm B).

In both of the arms, tumor assessments (CT or MRI) are performed before randomization, and every 6 months thereafter.

During treatment, clinical visits (blood cell counts, detection of toxicity) occur every 4 weeks. Physical examinations will take place every 12 weeks. Safety will be monitored continuously by careful monitoring of all adverse events (AEs) and serious adverse events (SAEs).

About 30 sites in Germany will participate in this study to recruit 190 BRCA negative patientsin 24 months.

Inclusion criteria

• Written informed consent and obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
• Age ≥ 18.
• Patients with histologically confirmed, advanced (FIGO stage IIIA, 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.
• Availability of archival tumor tissue for central next-generation sequencing (NGS) Analysis and no Detection BRCA mutation (BRCAnegative).
• Treatment with Bevacizumab or respective biosimilar for 12 to 15 months, independent of dosage.
• Patients who have completed first line platinum-taxane chemotherapy and at least stable disease after treatment with Bevacizumab before randomization.
• 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 CTCAE grade 1 or better (except alopecia and peripheral neuropathy).
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Patients must have normal organ and bone marrow function:

• Hemoglobin ≥ 10.0 g/dL independent of transfusion ≤ 14 days prior to Screening hemoglobin assessment
• Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L
• Platelet count ≥ 100 x 109 /L
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN); < 2 × ULN if hyperbilirubinemia is due to Gilbert's syndrome
• 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
• Serum creatinine ≤ 1.5 x institutional ULN and creatinine clearance > 30 mL/min
• Patients not receiving anticoagulant medication who have an International Normalized Ratio (INR) ≤1.5 and an Activated ProThrombin Time (aPTT) ≤1.5 x ULN.
• 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 rucaparib.

Patients are considered to be of childbearing potential unless 1 of the following applies:

• Considered to be permanently sterile. Permanent sterilization includes hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy; or
• 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 milli International Units/milliliter (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.

Exclusion criteria

• 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.
• Patients with myelodysplastic syndrome/acute myeloid leukemia history.
• Patients receiving radiotherapy within 6 weeks prior to study treatment.
• Major surgery within 4 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
• Previous allogeneic bone marrow transplant.
• Use of any other PARP-inhibitor in first line therapy.
• 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).
• Clinically significant (e.g. active) cardiovascular disease.
• Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub-Arachnoids Hemorrhage (SAH) within 6 months prior to randomization.
• History or evidence of hemorrhagic disorders within 6 months prior to randomization.
• Evidence of bleeding diathesis or significant coagulopathy (in the absence of coagulation).
• History or evidence for brain metastases or spinal cord compression.
• History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures).
• Significant traumatic injury during 4 weeks prior to randomization.
• 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.
• Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease.
• 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.
• Pregnant or lactating women, women of child-bearing potential who do not agree to the usage of highly effective contraception methods (see inclusion criteria).
• Participation in another clinical study with an investigational product immediately prior to randomization.
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
• Patients with a known hypersensitivity to Rucaparib or any of the recipients of the product.
• Known human immunodeficiency virus (HIV) or acquired immunodeficiency Syndrome (AIDS)-related illness, or history of chronic hepatitis B or C.
• Other active malignancy requiring treatment.
• Patient who might be dependent on the sponsor, Clinical Research Organization (CRO), site or the investigator.
• Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 Arzneimittelgesetz (AMG).