Assessment of efficacy of AZD2281 in Platinum Sensitive Serous Ovarian Cancer

Conditions: platinum sensitive serous ovarian cancer
MedDRA version: 18.1Level: PTClassification code 10033128Term: Ovarian cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2008-003439-18-GB

Lead Sponsor: AstraZeneca AB

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: Female

Target Recruitment: 250

Inclusion Criteria

1.Provision of fully informed consent prior to any study specific procedures.
2.Patients must be > 18 years of age.
3.Female patients with histologically diagnosed serous ovarian cancer or recurrent serous ovarian cancer with a histology type of serous, or a serous component (including primary peritoneal and fallopian tube cancer). This includes patients who have developed recurrent ovarian cancer with macroscopic peritoneal metastases outside the pelvis or distant metastases. Patients with spinal cord compression may be considered if they have received definitive treatment for this and evidence of clinically stable disease for 28 days.
4.Patients must have completed at least 2 previous courses of platinum containing therapy (e.g. carboplatin or cisplatin):
b.For the penultimate platinum based chemotherapy course prior to enrolment on the study:
-A patient must have been defined as platinum sensitive after this treatment; defined as disease progression greater than 6 months after completion of their last dose of platinum chemotherapy.
b. For the last chemotherapy course prior to enrolment on the study:
- Patients must have received a platinum containing regimen.
- Patients must have demonstrated an objective stable maintained response (partial or complete response) and this response needs to be maintained to permit entry into the study.
• This response can be confirmed as per RECIST, (note the assessment does not need to be confirmed >4 weeks later) and/or a CA-125 GCIG confirmed response (at least a 50% reduction in CA-125 levels from the last pre-treatment sample, confirmed 28 days later).
-Patients must be treated on the study within 8 wks of completion of their final dose of the platinum containing regimen.
-Chemotherapy course must have consisted of a minimum of 4 treatment cycles.
Note: The two platinum regimens determining eligibility do not necessarily have to be sequential. For example if a patient received topotecan between the penultimate and last platinum based chemotherapy they could be eligible provided the criteria specified above are satisfied.
5.Formalin fixed, paraffin embedded tumour sample from the primary or recurrent cancer must be available for central testing. If there is not written confirmation of the availability of an archived tumour sample prior to enrolment the patient is not eligible for the study.
6.Pre-treatment CA-125 measurements must meet criterion specified below:
-If the 1st value is within ULN the patient is eligible to enter the study and a second sample is not required
-If the 1st value is greater than ULN a second assessment must be performed at least 7 days after the 1st. If the second assessment is = 15% more than the first the patient is not eligible
7.Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
-Haemoglobin = 9.0 g/dL
-Absolute neutrophil count (ANC) = 1.5 x 109/L
-White blood cells (WBC) > 3x109/L
-Platelet count = 100 x 109/L
-Total bilirubin = 1.5 x institutional upper limit of normal
-AST (SGOT)/ALT (SGPT) = 2.5 x institutional upper limit of normal unless liver metastases are present in which case it must be = 5x ULN
-Serum creatinine = 1.5 x institutional upper limit of normal (ULN)
8.ECOG performance status = 2 (see Appendix F)
9.Patients must have a life expectancy = 16 weeks.
10.Evidence of non-childbearing status: negative urine or serum pre

Exclusion Criteria

1.Patients with low grade ovarian carcinoma. (Grade 1)
2.Patients who have had drainage of their ascites during the final 2 cycles of their last chemotherapy regimen prior to enrolment on the study.
3.Previous treatment with PARP inhibitors including AZD2281.
4.Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, Ductal Carcinoma in Situ (DCIS), stage 1 grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for = 5 years.
5.Patients receiving any chemotherapy, radiotherapy (except for palliative reasons), within 2 weeks from the last dose prior to study entry (or a longer period depending on the defined characteristics of the agents used). Patients may continue the use of corticosteroids, provided the dose is stable during the study and has been started at least 4 weeks prior to enrolment.
6.Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required.
7.Major surgery within 2 weeks of starting the study and patients must have recovered from any effects of any major surgery.
8.Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
9.Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication (eg, partial bowel obstruction or malabsorption).
10.Patients requiring treatment with potent inhibitors or inducers of CYP3A4 (see Section 6.4.1 for guidelines and wash out periods).
11.Pregnant or breast feeding women.
12.Immunocompromised patients, eg, patients who are known to be serologically positive for human immunodeficiency virus (HIV).
13.Patients with known hepatic disease (ie, Hepatitis B or C).
14.Persistent toxicities (grade 2 or greater) caused by previous cancer therapy (excluding alopecia).
15.Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
16.Previous randomisation to treatment in the present study.
17.Treatment with any investigational product during the last 28 days (or a longer period depending on the defined characteristics of the agents used).
18.Patients with a known hypersensitivity to AZD2281 or any of the excipients of the product.
19.Patients currently experiencing seizures or who were currently being treated with only anti-epileptics for seizures (use of anti-epileptic drugs to control pain is allowed in patients not suffering from seizures unless drug is excluded due to CYP3A4 induction - phenytoin, carbamazepine, phenobarbitone, see Section 6.4.1.
20.Optional pharmacogenetics sample only:
·previous allogeneic bone marrow transplant
·blood transfusion in the last 120 days prior to entry to the study

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of this study is:<br>·To determine the efficacy (assessed by Progression Free Survival [PFS]) of AZD2281 compared to placebo in the overall population.;Secondary Objective: The secondary objectives of this study are:<br>·To determine the efficacy of AZD2281 compared to placebo by assessment of overall survival (OS), best overall response, duration of response, Cancer Antigen (CA)-125 response (Gynecologic Cancer InterGroup [GCIG] criteria), time to progression by CA-125 (GCIG criteria), or RECIST. <br>··To determine the safety and tolerability of AZD2281 compared to placebo.<br>·To determine the effects of AZD2281 compared to placebo on disease related symptoms.<br>·To determine the quality of life of patients treated with AZD2281 compared to placebo.<br>;Primary end point(s): Primary outcome variable<br>-PFS as evaluated by RECIST<br>;Timepoint(s) of evaluation of this end point: 137 progression events (primary analysis)

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Secondary outcome variables<br>-Efficacy: OS, best overall response, duration of response, CA-125 response (GCIG criteria), time to progression by CA-125 (GCIG criteria) or RECIST, Quality of Life (QoL) and disease related symptoms. <br>-Safety: AEs, physical examination, vital signs including BP, pulse, ECG and laboratory findings including clinical chemistry, haematology and urinalysis.<br>;Timepoint(s) of evaluation of this end point: The final anlaysis of OS is scheduled to take place when there are a similar number of OS events as PFS events in the primary analysis. All other efficacy secondary andpoints at primary analysis. Safety secondary endpoints at primary and final analysis.