Brain Mets - Capecitabine and WBRT

Central nervous system (CNS) metastases is the most common type of brain malignancy, and
breast cancer is the second most common type of malignancy to cause CNS metastases. Although
the incidence of CNS metastases is less common than bone or visceral metastases, it is
associated with poorer prognosis and is relatively unresponsive to systemic therapies. The
incidence of CNS metastases in breast cancer has been estimated as 1-16% in clinical series,
with higher rates (18-30%) in autopsy series. Recently a trend towards increasing CNS
relapse has been noted, up to 25-34%. This may be partly explained by the increasing use of
contrast-enhanced magnetic resonance imaging (MRI), heightened awareness by patient or
clinicians, or an alteration in the natural history of breast cancer with improvements in
systemic therapies, resulting in a prolongation of survival. Therefore, with improvements in
treatments, metastases are better controlled, resulting in the CNS becoming a sanctuary for
residual disease. The treatment of CNS metastases in breast cancer remains challenging.
Surgical resection of tumor will prolong survival only in patients with a single lesion and
with well controlled systemic disease. For patients with multiple lesions, whole brain
radiotherapy (WBRT) remains the backbone in the management of CNS metastases. Recently the
use of stereotactic radiosurgery alone or in combination with WBRT has been explored.
Although better local control was achieved with the combination therapy, minimal overall
survival benefit was seen. This may be secondary to the competing risk of death from
systemic (extra-CNS) progression. The use of systemic agents including chemotherapy and
hormonal therapy has been generally disappointing. This is often attributed to the
impermeability of the blood-brain and blood-tumor barriers. Furthermore, P-glycoprotein
(Pgp), a drug efflux pump encoded by the multidrug resistance gene, mdR1, is expressed in
brain endothelial cells. Therefore, agents such as doxorubicin, cyclophosphamide,
5-fluorouracil, paclitaxel, docetaxel and vinorelbine, which are active against breast
cancer, may either penetrate CNS poorly, or be transported out of the CNS environment.
However, the blood brain barrier may be more leaky and permeable than previously thought in
patients with CNS metastases, and these agents may achieve therapeutic concentrations in the
CNS. As evidence for this, patients without prior exposure to agents such as
cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and doxorubicin, can have
significant objective responses in the CNS metastases. Today, most patients would have
received these agents in the adjuvant setting, thus emphasizing the importance of both
chemo-sensitivity together with CNS penetration, in the treatment of CNS metastases.

This is a single arm, open label, phase II drug study. This study will be conducted at the
Breast Care Center at Baylor College of Medicine and its affiliated hospital, and at Ben
Taub General Hospital in Houston. Patients who were diagnosed with CNS metastases (brain +/-
leptomeningeal disease) will be identified prospectively. All eligible patients will receive
capecitabine concurrently with WBRT followed by combination capecitabine with sunitinib.
WBRT will be administered at 30 Gy in 10 fractions together with capecitabine to be given on
the first day of WBRT at 1000 mg/m2/day and continued daily for 14 days. After a 7 days rest
period, capecitabine will be restarted at 2000mg/m2/day for 14 days followed by a 7 days
rest period. This will be given together with sunitinib at 37.5 mg daily. This is the dosing
determined by the phase I study with capecitabine and sunitinib. Dose reduction and/or
treatment postponement will be done for significant toxicity. Capecitabine with sunitinib
will be administered until disease progression in either CNS and/or non-CNS sites. Efficacy
assessments will be performed on all subjects via imaging studies in the CNS and extra-CNS
sites 8 weeks after starting study, then every 12 weekly. Neurological examination will be
performed at baseline, 3 weeks after starting treatment, then every 6 weekly. Assessment of
treatment toxicity will be performed at baseline, 3 weeks after starting treatment, then
every 3 weekly using the NCI Common Toxicity grading system. Clinical and laboratory
parameters will be assessed until disease progression or withdrawal from study (due to
unacceptable toxicity or withdrawal of consent). Subjects with progression of CNS and / or
extra-CNS disease will be considered progressors. Subjects withdrawn from treatment will be
followed for survival until death.

Primary endpoint: 1. To determine progression free survival. Progression will be defined by
progression in either CNS or extra-CNS metastases. Secondary endpoint: 1. To assess the
toxicities associated with the regimen 2. To determine the overall objective response in CNS
disease 3. To determine the overall objective response in extra-CNS disease 4. To determine
the overall survival.

Inclusion Criteria:

1. Signed inform consent.

2. Patients must be age 18 or older.

3. Histological or cytologically confirmed invasive breast cancer, with Stage IV
disease.

4. Patient must have evidence of radiographically measurable CNS metastases (greater
than or equal to 10mm on T1-weighted gadolinium-enhanced MRI) within 2 weeks prior to
starting treatment. Patients without known extra-CNS disease are eligible.

5. All patients must have metastases in the brain. Patients with concurrent
leptomeningeal carcinomatosis are eligible for the study. Local radiation to sites of
meningeal involvement in the spine is allowed.

6. No prior whole brain radiation.

7. Patients who had previous stereotactic brain irradiation are eligible, provided they
have new measurable brain lesions (which has not been radiated previously) and will
receive WBRT at 30Gy over 10 fractions.

8. Patients may undergo surgical resection of CNS metastases if clinically indicated,
but must have remaining measurable disease in the brain after surgery.

9. No prior treatment with capecitabine in the adjuvant or metastatic settings. Patients
may have completed 5-fluorouracil based treatment in the adjuvant setting or
metastatic setting more than one year prior.

10. Patients who had previous trastuzumab therapy will be eligible but treatment will be
discontinued prior to enrollment.

11. Cardiac ejection fraction within institutional range of normal as measure by
echocardiogram or MUGA scans at baseline.

12. Hematological adequacy as indicated by:

- ANC greater than or equal to 1000mg/mm3

- Hemoglobin greater than or equal to 9gm/dL

- Platelets greater than or equal to 50,000/mm3.

13. Hepatic adequacy as indicated by:

- Bilirubin less than or equal to 2.0 times upper limit of normal

- AST and ALT less than or equal to 5 times upper limit of normal.

14. Renal adequacy as indicated by:

- Creatinine less than or equal to 1.5 times upper limit of normal

15. Patients must have recovered from toxicity of prior chemotherapy with laboratory
values as specified above. Concurrent treatment with bisphosphonates is permitted.

16. Performance status of ECOG 0-1.

17. Life expectancy of at least 12 weeks.

18. At least 3 weeks since major surgical procedures.

19. Able to swallow and retain oral medication.

Exclusion Criteria:

1. Patients who are pregnant or breast feeding.

2. Known allergy to capecitabine or 5-fluorouracil.

3. Known to have dihydropyrimidine dehydrogenase (DPD) deficiency.

4. Patients who have leptomeningeal carcinomatosis as the only site of CNS metastases.

5. Patients taking concomitant medications which are CYP3A4 inhibitors or inducers.

6. Patients who will receive intrathecal chemotherapy for leptomeningeal disease.

7. Patients with psychiatric or addictive disorders that would adversely effect
compliance with oral medication.

8. Life expectancy less than 3 months.

9. Patients with symptomatic lymphangitic spread to lung.

10. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel.

11. History of immediate or delayed hypersensitivity reaction to gadolinium contrast
agents, or other contraindication or gadolinium contrast.

12. Other known contraindication to MRI, such as a cardiac pacemaker, implanted cardiac
defibrillator, brain aneurysm clips, cochlear implant, ocular foreign body, or
shrapnel,

13. Vascular disease within 12 months prior to enrollment, defined as one or more of the
following:

- history of documented myocardial infarction (including severe/unstable angina)

- Coronary/peripheral artery bypass graft

- Symptomatic heart failure (CHF)

- Cerebrovascular accident or transient ischemic attack

- Pulmonary embolism,

14. Uncontrolled infection

15. History of other malignancy, except for curatively treated basal cell carcinoma or
squamous cell carcinoma of the skin, or carcinoma in situ of the cervix. Subjects
with other malignancies who have been disease-free for at least 5 years are eligible