A Phase I/II randomised, double-blind, multi-centre study to assess the efficacy of AZD2281 when given in combination with paclitaxel in the 1st or 2nd line treatment of patients with metastatic Triple Negative Breast Cancer

• Register: EUCTR
• Last refreshed on: 21 May 2018
• Main ID: EUCTR2008-002608-25-BE
• Date of registration: 31/07/2008
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca AB
• Public title: A Phase I/II randomised, double-blind, multi-centre study to assess the efficacy of AZD2281 when given in combination with paclitaxel in the 1st or 2nd line treatment of patients with metastatic Triple Negative Breast Cancer
• Scientific title: A Phase I/II randomised, double-blind, multi-centre study to assess the efficacy of AZD2281 when given in combination with paclitaxel in the 1st or 2nd line treatment of patients with metastatic Triple Negative Breast Cancer
• Date of first enrolment: 11/08/2008
• Target sample size: 270
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-002608-25
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): Therapeutic use (Phase IV):

Countries of recruitment

Austria, Belgium, Czech Republic, Denmark

Key inclusion & exclusion criteria

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 or cytologically diagnosed metastatic triple-negative breast cancer
- Oestrogen, progesterone and HER2 negative advanced adenocarcinoma of the breast defined as:
§ For ER, PR status: Allred<3 or ER, PR IHC 0 and
§ For HER2 status: IHC 0 or 1+ or FISH negative; if IHC 2+, need negative FISH confirmation.
4. Phase II only - At least one lesion, not irradiated within 12 weeks of the first administration of study treatment, that can be accurately measured as ³ 10 mm in the longest diameter with spiral computed tomography (CT) scan or as ³ 20 mm with conventional techniques according to RECIST (Conventional CT, MRI) and which is suitable for accurate repeated measurements.
5. Patients must have normal organ and bone marrow function measured within 7 days prior to administration of study treatment as defined below:
- Haemoglobin = 9.0 g/dL
- Absolute neutrophil count (ANC) = 1500 x 106/L
- White blood cells (WBC) > 3x109/L
- Platelet count = 100, 000 x 106/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 it must be = 5x ULN
- Creatinine clearance (Cockcroft-Gault) within normal range (> 60 mL/min).
- Serum creatinine = 1.5 x institutional upper limit of normal (ULN)
6. ECOG performance status = 2 for breast (see Appendix F)
7. Patients must have a life expectancy = 16 weeks.
8. Evidence of non-childbearing status: negative urine or serum pregnancy test within 7 days of study treatment for women of childbearing potential, or postmenopausal status
Postmenopausal is defined by any one of the following:
§ natural menopause with last menses >1 year ago;
§ radiation-induced oophorectomy with last menses >1 year ago,
§ chemotherapy-induced menopause with >1 year interval since last menses,
§ serum follicle stimulating hormone, lutenising hormone and plasma oestradiol levels in the post menopausal range for the institution,
§ or surgical sterilisation (bilateral oophorectomy or hysterectomy).
9. 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. Formalin fixed, paraffin embedded tumour sample from the primary or recurrent cancer must be available for central testing. If an archived tumour sample is not available the patient will not be eligible for the study.
For inclusion in genetic research, patients must fulfil the following criterion:
1. Provision of informed consent for genetic research
If a patient declines to participate in the genetic research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this Clinical Study Protocol, so long as they consent to that part.

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. Any previous treatment with a PARP inhibitor, including AZD2281, in the past or any treatment with paclitaxel within the last 12 months
2. Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for = 5 years.
3. 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). The patient can receive a stable dose of bisphosphonates for bone metastases, before and during the study as long as these were started at least 4 weeks prior to enrolment.
4. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to enrolment.
5. More than one prior chemotherapy for advanced disease and/or extensive irradiation leading to bone marrow deficiency. Extensive radiotherapy would be that involving 30% of the bone marrow e.g. whole pelvis or half spine.
6. Major surgery within 4 weeks of starting the study and patients must have recovered from any effects of any major surgery.
7. Pre-existing peripheral neuropathy > grade 1.
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 (e.g. partial bowel obstruction or malabsorption)
10. Patients requiring treatment with inhibitors or inducers of CYP3A4 (see Section 6.4.1 for guidelines and wash out periods).
11. Patients requiring treatment with inhibitors or inducers of CYP2C8 (see Section 6.4.2 for guidelines and wash out periods).
12. Pregnant or breastfeeding women.
13. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
14. Patients with known hepatic disease (i.e., Hepatitis B or C).
15. Persistent toxicities (grade 2 or greater) from any cause, except fpr alopecia.
16. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
17. Previous randomisation to treatment in the present study
18. Treatment with any investigational product during the last 14 days (or a longer period depending on the defined characteristics of the agents used)
19. Patient with a history of hypersensitivity reactions to paclitaxel or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil)
20. Patients with a known hypersensitivity to AZD2281 or any of the excipients of the product.
21. 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

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

Health Condition(s) or Problem(s) studied

Metastatic Triple Negative Breast Cancer
MedDRA version: 9.1 Level: LLT Classification code 10055113 Term: Breast cancer metastatic

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
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Capsule*
Route of administration of the placebo: Oral use

Product Name: paclitaxel
Pharmaceutical Form: Intravenous infusion
Other descriptive name: paclitaxel
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 6-

Primary Outcome(s)

Secondary Objective: The secondary objective of Phase I:
· To identify any toxicities of AZD2281 in combination with paclitaxel.
The secondary objectives of Phase II:
· To determine the efficacy of AZD2281 in combination with paclitaxel compared to paclitaxel alone by assessment of overall survival (OS), objective response rate (ORR), duration of response, changes in Cancer Antigen (CA)-153 and Carcinoembryonic Antigen (CEA).
· To determine the safety and tolerability of AZD2281 in combination with paclitaxel compared to paclitaxel alone.
· To determine the effects of AZD2281 in combination with paclitaxel compared to paclitaxel alone on disease related symptoms Functional Assessment of Cancer Treatment- Breast Cancer questionnaire (FACT-B).
· To determine the quality of life of patients treated with AZD2281 in combination with paclitaxel compared to paclitaxel alone.

Primary end point(s): Phase I
· Primary outcome variable
- Safety: Adverse events (AEs), physical examination, vital signs including blood pressure (BP), pulse, electrocardiogram (ECG) and laboratory findings including clinical chemistry, haematology and urinalysis.
Phase II
· Primary outcome variable
- PFS as evaluated by RECIST

Main Objective: The primary objective of the Phase I part of this study is:
· To establish the appropriate doses of paclitaxel and AZD2281 in combination, based on safety and tolerability (for use in the randomised Phase II part of the study).
The primary objective of the Phase II part of this study is:
· To determine the efficacy (assessed by Progression Free Survival [PFS]) of AZD2281 in combination with paclitaxel compared to paclitaxel alone in this patient population.

Secondary ID(s)

2008-002608-25-AT

D0810C00011