A Phase II, Open-Label, Randomised, Comparative, International Multicentre Study to Compare the Safety and Efficacy of Two Different Doses of AZD2281 Given Orally Twice Daily Versus Intravenous Liposomal Doxorubicin Given Monthly in Patients With Advanced BRCA1- or BRCA2-Associated Ovarian Cancer Who Have Failed Previous Platinum-Based Chemotherapy

• Register: EUCTR
• Last refreshed on: 4 December 2018
• Main ID: EUCTR2007-007622-22-DE
• Date of registration: 12/11/2008
• Prospective Registration: No
• Primary sponsor: AstraZeneca AB
• Public title: A Phase II, Open-Label, Randomised, Comparative, International Multicentre Study to Compare the Safety and Efficacy of Two Different Doses of AZD2281 Given Orally Twice Daily Versus Intravenous Liposomal Doxorubicin Given Monthly in Patients With Advanced BRCA1- or BRCA2-Associated Ovarian Cancer Who Have Failed Previous Platinum-Based Chemotherapy
• Scientific title: A Phase II, Open-Label, Randomised, Comparative, International Multicentre Study to Compare the Safety and Efficacy of Two Different Doses of AZD2281 Given Orally Twice Daily Versus Intravenous Liposomal Doxorubicin Given Monthly in Patients With Advanced BRCA1- or BRCA2-Associated Ovarian Cancer Who Have Failed Previous Platinum-Based Chemotherapy
• Date of first enrolment: 08/05/2008
• Target sample size: 90
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-007622-22
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: yes; Other specify the comparator: Caelyx (liposomal doxorubicin)
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Germany, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Female, aged 18 years or older.
2. Histologically or cytologically confirmed advanced ovarian cancer, stage IIIB/IIIC/IV (see Appendix D) or recurrent ovarian cancer. Patients with spinal cord compression may be considered if they have received definitive treatment for this and evidence of clinically stable disease for at least 28 days. In addition, patients with primary peritoneal carcinoma or fallopian tube carcinoma may be considered for the study, as long as they are confirmed as being BRCA1 or BRCA2.
3. Confirmed BRCA1 or BRCA2 status (with a pre existing genetic report & sequence scan). Please note: if there is a strong family history suggesting BRCA (+/-) status but it is unknown, then patients must not be randomised or receive study drug/comparator until a confirmatory genetic test report is received (see Section 5.2.1 for further details). Patients must have BRCA1/2 mutations known to cause loss of gene function (clinical deleterious or suspected deleterious mutations).
4. One or more measurable lesions, at least 10 mm in the longest diameter (LD) by spiral CT scan, or 20 mm with conventional techniques, according to RECIST criteria, not irradiated within 12 weeks of the first administration of study drug/comparator.
5. ECOG performance status of 0 2 (see Appendix E).
6. Estimated life expectancy of at least 16 weeks.
7. Progressive or recurrent disease after platinum-based chemotherapy. (Note: for patients with recurrence within 12 months of completion of most recent platinum chemotherapy ie, patients considered resistant or, at best, partially sensitive to platinum, this recurrence does not need to be within 12 months of entering this study. The most recent treatment prior to study entry therefore need not comprise a platinum-based regime. Cases where patients whose recurrence has occurred greater than 12 months from completion of most recent platinum chemotherapy, may only be considered for this study if there is a documented medical contra-indication to further platinum chemotherapy and must be discussed and agreed with the Sponsor prior to consent).
8. Adequate bone marrow, hepatic and renal function, defined as:
- Haemoglobin =9.0 g/dL,
- White blood cells >3x109/L,
- Absolute neutrophil count =1.5x109/L,
- Platelets =100x109/L,
- Total bilirubin =1.5 x upper limit of normal (ULN),
- Aspartate transaminase (AST) (SGOT) and alanine transaminase (ALT) (SGPT) =2.5 x ULN (or =5x ULN in the presence of liver metastases),
- Serum creatinine =1.5 x ULN.
9. The patient is willing and able to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations.
10. The patient has given written informed consent prior to any study related procedure not constituting part of the standard care for the condition, with the understanding that said consent may be withdrawn at any time, without prejudice to any future medical care.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Less than 28 days from active therapy (ie, any treatment used to treat the disease) or high dose radiotherapy (patients may continue concomitant use of bisphosphonates if started prior to commencing study treatment and patients may receive palliative radiotherapy for bone disease during the study).
2. Prior treatment with liposomal doxorubicin
3. Prior treatment with anthracyclines as a treatment for ovarian cancer.
Patients who have received anthracyclines (non-liposomal doxorubicin or epirubicin) for the treatment of breast cancer are eligible provided the
lifetime cumulative dose has not exceeded 240 mg/m2 or 480 mg/m2
respectively at screening.
4. Patients requiring treatment with inhibitors or inducers of CYP3A4 (see Section 3.5.1 for guidelines and wash-out periods).
5. Patients with known brain metastases.
6. Any other malignancy which has been active or treated within the past 5 years, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions or endometrial carcinoma stage 1A grade 1. Patients with a history of breast cancer are not eligible if the disease was diagnosed within the past 5 years except for adequately treated stage I or II breast cancer without evidence of recurrent disease. Patients with a history of breast cancer who received definitive treatment can participate even if they received adjuvant treatment during the 5 years prior to screening.
7. Persistent CTC grade 2 or greater toxicities (excluding alopecia) caused by prior therapy.
8. Patients currently experiencing seizures or who are currently being treated with any anti epileptic 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 3.5.1).
9. Major thoracic and/or abdominal surgery in the four weeks prior to the start of study treatment.
10. Left ventricular ejection fraction below 50%.
11. 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.
12. Presence of gastrointestinal disorders that, in the Investigator’s opinion, are likely to interfere with the absorption of AZD2281 or with the patients ability to take regular oral medication.
13. Patients who are unable to swallow orally administered medication.
14. Patients who are immunocompromised, eg, patients known to be serologically positive for human immunodeficiency virus (HIV).
15. A positive pregnancy test. Pregnant or breast-feeding women, or women of childbearing potential unless effective methods of contraception are used (lack of childbearing potential is met by being post-menopausal or being surgically sterile. Patients of childbearing potential and their partners, who are sexually active, must agree to use two highly effective forms of contraception throughout their participation in the study and for 3 months after the last dose of study drug(s).
Acceptable Non-hormonal birth control methods include
• Total sexual abstinence. Abstinence must be for the total duration

Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

Advanced BRCA1 or BRCA2 associated ovarian cancer whose disease has progressed or recurred after platinum based chemotherapy
MedDRA version: 9.1 Level: LLT Classification code 10033128 Term: Ovarian cancer

Intervention(s)

Product Name: AZD2281 (KU-0059436)
Pharmaceutical Form: Capsule*
INN or Proposed INN: olaparib
CAS Number: 763113-22-0
Current Sponsor code: AZD2281 (KU-0059436)
Other descriptive name: 4-(3-{[4-(Cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)phthalazin-1(2H)-one
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Trade Name: Caelyx
Pharmaceutical Form: Intravenous infusion
Other descriptive name: pegylated liposomal doxorubicin hydrochloride
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-

Primary Outcome(s)

Primary end point(s): The primary objective of this study is to compare the efficacy of AZD2281 with liposomal doxorubicin. This objective will be assessed by the primary variable of PFS and secondary variables of ORR, duration of response, CA 125 level and tumour size.

Secondary Objective: The secondary objectives of the study are:
· To compare the safety and tolerability profile of two different dose levels of AZD2281 versus liposomal doxorubicin in the study population.
· To determine AZD2281 exposure at the 2 different dose levels following oral administration.
· To conduct a preliminary assessment of Quality of Life (QoL) as measured by the Functional Assessment of Cancer Therapy – Ovarian Cancer (FACT-O) questionnaire

Main Objective: To compare the efficacy of 3 different dose levels of AZD2281 with liposomal doxorubicin in patients with advanced BRCA1 or BRCA2 associated ovarian cancer. This will be assessed by the following:
primary variable
· progression free survival (PFS)
secondary variables
· objective response rate (complete response (CR) and partial response (PR)) at various timepoints and overall
· overall duration of response
· tumour size
· CA 125 levels
· Overall survival (OS)

Secondary ID(s)

2007-007622-22-GB

D0810C00012