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A Randomised Phase II Study of Carboplatin With or Without the Addition of the ETAR Inhibitor ZD4054 as Treatment for Patients With Metastatic Breast Cancer

Phase 2
18 Years
Not Enrolling
Metastatic Breast Cancer

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Trial Information

A Randomised Phase II Study of Carboplatin With or Without the Addition of the ETAR Inhibitor ZD4054 as Treatment for Patients With Metastatic Breast Cancer

In the UK about 41,000 patients are diagnosed with breast cancer each year. More and more
patients are surviving breast cancer, mostly due to the earlier detection and improvements
in treatment. Nevertheless, in about 6% of patients the cancer has already spread to other
parts of the body when they are first diagnosed; in a further 30% of patients the cancer
comes back elsewhere in their body after initial treatment. Once it has spread to other
parts of the body, breast cancer is incurable, with patients living, on average, a further
24 months. The aims when treating patients with metastatic breast cancer are to prolong and
improve their day to day life. A number of different chemotherapy drugs are available for
treatment of metastatic breast cancer. There is, however, still a need to develop new
treatments. The aim of this trial is to use a new drug called ZD4054 combined with an
established chemotherapy drug (carboplatin) to see whether this prolongs the period for
which patients live with the cancer kept under control.

ZD4054 is a new, oral drug which may help to slow down cancer growth. It works by blocking
growth that is controlled by specific proteins on cancer cells called endothelins.

Endothelins act by binding to their endothelin receptors, presence of these receptors have
been found in about 45% of breast cancer cases. ZD4054 is an endothelin receptor blocker.
We hope to show that adding this new drug increases the effectiveness of carboplatin. We
know from trials in other cancers that similar drugs may be able to slow down the growth of

Metastatic breast cancer (MBC) remains incurable and there has been little change in long
term outcomes. Chemotherapy is used to improve symptoms and prolong survival in patients
with advanced breast cancer. Nevertheless, most tumours inevitably progress and the clinical
response rates to subsequent chemotherapy agents are disappointing. There is, therefore, a
need for continued clinical research into new strategies to enhance the effectiveness of
currently available chemotherapy agents to improve survival.

The endothelin pathway has been implicated in a number of oncogenic pathways. ET-1 and ETAR
are frequently over-expressed in breast cancers and are prognostic for poor outcome.
Inhibition of the endothelin pathway enhances cytotoxicity when combined with chemotherapy
agents such as carboplatin in pre-clinical models. ZD4054 is a specific inhibitor of ETAR
and represents a novel therapeutic target in breast cancer.

This study investigates whether ZD4054, an oral endothelin A receptor (ETAR) inhibitor, in
combination with carboplatin chemotherapy, has sufficient activity to warrant a future Phase
III trial in patients with advanced/metastatic breast cancer.

Inclusion Criteria:

- Patients aged over 18

- Histological or cytological diagnosis of metastatic breast cancer, or previous
histological diagnosis of breast cancer and evidence of metastatic or locally
advanced disease unsuitable for local therapy

- No more than 2 prior lines of chemotherapy treatment for metastatic breast cancer

- Life expectancy greater than 12 weeks

- Patients must have previously received or be ineligible for a taxane

- Informed written consent

- Adequate bone marrow and hepatic function

- Haemoglobin ≥ 9.0 g/dl (if no prior transfusion or transfusion more than 4 weeks
previously) or ≥ 10.0 g/dl (transfusion within last 4 weeks), absolute neutrophil
count ≥ 1.5 x 109/L, platelets ≥100 x 109/L

- Total bilirubin < 1.5 x upper normal limit

- AST and ALT ≤ 2.5 x upper normal limit (or ≤ 5x UNL in the presence of liver

- Adequate renal function

- GFR ≥ 60 mls/min calculated using Wright Formula or measured by EDTA plasma clearance
At least one measurable lesion on CT scanning. Disease measurable by other RECIST
v1.1 compatible imaging (e.g. MRI, CXR) or clinically measurable will be allowed as
long as the same assessment method is used throughout the trial

- ECOG performance status ≤ 2

Exclusion Criteria:

- Previous treatment with platinum based chemotherapy

- Known brain or leptomeningeal metastases

- Any co-existing medical conditions that, in the Investigator's judgement, may
substantially increase the risk associated with the patient's participation in the
study or potentially hamper compliance with the study protocol and follow-up schedule

- Concomitant medication unsuitable for combination with trial medication

- Concomitant administration of potent CYP3A inhibitors, specifically: Protease
inhibitors (atanazavir, indinavir, nelfinavir, ritonavir, saquinavir), Macrolide
antibiotics (clarithromycin, telithromycin), Azole antifungals (ketoconazole,
itraconazole, voriconazole), nefazodone

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

PFS (time to event)

Outcome Description:

PFS (time to event) based on Response Evaluation Criteria in Solid Tumours (RECIST v1.1). Time from enrolment to any progression and/or death. Those progression-free and alive will be censored at time of last follow-up visit.

Outcome Time Frame:

18 weeks of treatment

Safety Issue:



United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:




Start Date:

September 2010

Completion Date:

August 2013

Related Keywords:

  • Metastatic Breast Cancer
  • Breast Neoplasms