Phase II, open label, single arm study to investigate anti-tumor effect of ixabepilone in patients with locally recurrent or metastatic breast cancer (mBC) selected by the ixabepilone Drug Response Prediction (DRP) after failure of an anthracycline and a taxane

Ixabepilone is approved by FDA for use in patients with with metastatic or
locally advanced breast cancer. Ixabepilone has documented treatment effect
both in combination with capecitabine and as monotherapy (see current SmPC for
Ixempra). Since there are few treatment options for patients resistant to
anthracylines, taxanes and capecitabine, ixabepilone is an alternative
treatment option for these late stage breast cancer patients. Ixabepilone given
as monotherapy has a documented ORR that varies between 11.5 to 42% (26). With
this relatively low response rate a relatively high amount of patients will be
exposed to treatment without having an effect, and thereby also exposed to the
side effects of the product. Therefore, a Drug Response Prediction methodology
(see below) has been introduced in the current study. Patients expected to
respond to treatment will be selected according to a tumor biopsy mRNA
expression profiling, leading to a DRP score and only patients having a DRP
score > 33% will be considered as possible positive responders and included in
the study.

The rationale for using DRP-Ixempra-Breast > 33% was based on retrospective
analysis of archival biopsies from the study on neo-adjuvant treatment of
breast cancer. Briefly, gene expression was measured in archival biopsies
before treatment with 4 series of cyclophosphamide and doxorubicine followed by
treatment with Ixabepilone. Based on this archival biopsy, the
DRP-Ixempra-Breast was able to correctly predict response to Ixabepilone, and
the response above a cutoff of 33 was 31% while the response below cut off 33
was 13%. It is concluded that the DRP-Ixempra-Breast is able to predict
response based on an archival biopsy. If the prediction changes during
anticancer treatment, the prediction will be even more accurate with a new
biopsy.

Between half and two thirds of the patients are expected to have a positive DRP
score (above > 33%) and can be offered therapy with ixabepilone.

Primary:
• To evaluate the clinical benefit rate (CBR) of ixabepilone

Secondary:
• To evaluated progression free survival (PFS)
• To evaluate overall survival (OS)
• To evaluate objective response rate (ORR) defined as Complete Response (CR)
and Partial Response (PR)
• To evaluate the safety profile of ixabepilone in patient with locally
recurrent or metastatic breast cancer
• To further establish the clinical validation of the use of the
DRP-Ixempra-Breast in selecting patients with locally recurrent or metastatic
breast
cancer
• Assess difference in prediction based on archival and fresh biopsy from same
patient (percent agreement in binary prediction, and difference in
primary and secondary endpoints with archival versus fresh biopsies)

This study is a multi-center, open-label, non-randomized, phase II study of
ixabepilone as treatment in patients with locally recurrent or metastatic
breast cancer. Previous chemotherapies (neoadjuvant, adjuvant or in the
metastatic setting) must have included a taxane and an anthracycline unless
anthracycline therapy is not indicated. The patients should have received a
maximum of three (3) prior chemotherapies in the metastatic setting.
Patients will be screened with the DRP-Ixempra-Breast. If the DRP score is
above >33% the patient can be included in the clinical study, if all the other
eligibility criteria are fulfilled.

Patients will be screened with the DRP-Ixempra-Breast. If the DRP score is
above >33% the patient can be included in the clinical study, if all the other
eligibility criteria are fulfilled. Archival biopsy is used for determining the
DRP-Ixempra-Breast (if obtainable biopsy should be taken after the last
anticancer treatment has been stopped for determining any change in
DRP-Ixempra-Breast). If such biopsy is not available it has to be done during
the screening (first 2 weeks, if possible). The biopsy can be taken from any
lesion, and the sample will be used to obtain the DRP score.

The dose of ixabepilone is 40 mg/m2 infused intravenously over 3 hours every 3
weeks.

Potential participants will attend a screening visit that will take 2-3 hours
to confirm eligibility for the study. This will include taking a biopsy of
their tumor if there is not a suitable one already available.

If a participant is enrolled they will remain in on IMP until tumour
progression or they have unacceptable side effects. After this they will be
followed up every 3 months for for up to 2 years.

IMP is administered every 3 weeks and will be administered as a continuous
3-hour intravenous infusion on Day 1 in each cycle. Before each infusion,
participants will also receive pre-medication to reduce the chance of them
having a hypersensitivity reaction to the study treatment. During each cycle
participants will be asked to attend visits on Day 8 and Day 15.

The following assessments will be carried out during study visits (the full
schedule can be found in section 6.2 of the protocol):

• At screening -Tumour biopsy and the DRP analysis; if a biopsy was taken after
the last anti-cancer treatment had stopped, this tissue may be used for DRP
assessment. However, if a biopsy is not available it may be done during the 4
weeks screening period. The biopsy may be image guided by a CT (Computerized
Tomography) scan or by an ultrasound scan to help locate the tumour. This
sample will then be used for DRP assessment.
• Medical history,
• Physical examination
• Vital Signs, including height (baseline only), weight, blood pressure,
temperature, respiratory rate and heart rate.
• Electrocardiogram
• CT scan or MRI (Magnetic Resonance Imaging) scans. In some cases a chest
X-ray may be required.
• Routine blood tests, including Haematology and Chemistry,
• Pregnancy urine or blood test, if you are a woman and can become pregnant
• A neurotoxicity questionnaire

Participants that stop treatment without tumor progression, well receive CT or
MRI scans every 9 weeks until week 24 and then every 3 months until progression
and thereafter followed every 3 months until death.

Participants that stop treatment due to tumor progression will be followed up
every 3 months until death.

Study participants could respond to the study medication (i.e a reduction in
tumor size or temporary halt of growth), however it is possible that there will
be no direct benefit to participants.