| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced BRCA1 or BRCA2 associated ovarian cancer whose disease has progressed or recurred after platinum based chemotherapy |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To compare the efficacy of 2 different dose levels of AZD2281 versus 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)
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
· To assess the safety and tolerability profile of 2 different dose levels of AZD2281 versus liposomal doxorubicin in the study population.
· To determine AZD2281 exposure at 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
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
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| E.4 | Principal 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).
16. Simultaneous participation in any other study involving an investigational medicinal product, or having participated in a study less than 28 days prior to the start of study treatment.
17. Known hypersensitivity to any of the excipients in the AZD2281 or a conventional formulation of Doxorubicin HCl.
18. Previous treatment with AZD2281 or other drug with similar mode of action.
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| E.5 End points |
| E.5.1 | 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, tumour size and overall survival. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Caelyx (liposomal doxorubicin) |
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| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| 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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| The end of this study is defined as the date of the last visit of the last patient, occurring when all patients have completed study therapy. |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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