The main scope of this trial is to determine progression free survival in patients treated
with Rucaparib as maintenance therapy vs. Placebo after receiving Bevacizumab for 12 to 15
months.
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 12 weeks thereafter.
During treatment, clinical visits (blood cell counts, detection of toxicity) occur every 4
weeks. Physical examinations and tumor assessments 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 patients in 24
months.
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 IIIA, IIIB, IIIC, or IV
of the 2014 FIGO classification) 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 next-generation sequencing (NGS)
Analysis and no Detection BRCA mutation (BRCAnegative).
5. Treatment with Bevacizumab 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 CTCAE 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:
1. Hemoglobin ≥ 10.0 g/dL independent of transfusion ≤ 14 days prior to Screening
hemoglobin assessment
2. Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L
3. Platelet count ≥ 100 x 109 /L
4. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN); < 2 × ULN if
hyperbilirubinemia is due to Gilbert's syndrome
5. 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
6. Serum creatinine ≤ 1.5 x institutional ULN and creatinine clearance > 30 mL/min
7. 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 rucaparib.
Patients are considered to be of childbearing potential unless 1 of the following applies:
1. Considered to be permanently sterile. Permanent sterilization includes hysterectomy,
bilateral salpingectomy, and/or bilateral oophorectomy; or
2. 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:
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 mucinous carcinoma.
2. Patients with myelodysplastic syndrome/acute myeloid leukemia history.
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. Previous allogeneic bone marrow transplant.
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).
7. Clinically significant (e.g. active) cardiovascular disease.
8. Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or
Sub-Arachnoids Hemorrhage (SAH) within 6 months prior to randomization.
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 clinical suspicion of brain metastases or spinal cord compression. CT/MRI
of the brain is mandatory (within 4 weeks prior to randomization) in case of suspected
brain metastases. Spinal MRI is mandatory (within 4 weeks prior to randomization) in
case of suspected 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, Clinical Research Organization (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 Arzneimittelgesetz (AMG).
