Cabazitaxel Plus Lapatinib as Therapy for HER2-Positive Metastatic Breast Cancer Patients With Intracranial Metastases

This is an open-label, non-randomized, Phase II study with a lead-in safety cohort. Through
the safety lead-in portion of this trial we will define the optimal dose of cabazitaxel when
given in combination with lapatinib for patients with HER2-positive MBC and CNS metastases.
The Phase II portion will further assess intracranial response rate in patients with
HER2-positive MBC and CNS metastases. Toxicity and progression free survival (PFS) will be
obtained and evaluated. The trial will be conducted at multiple study sites by SCRI
Development Innovations.

Inclusion Criteria:

1. Patients with HER2-positive MBC and unequivocal evidence of brain metastases.

2. Documented HER2-positive tumor status at study entry defined as:

- Immunohistochemical (IHC) score 3+ or

- IHC score 1-2+ and confirmed as FISH (Fluorescence in situ hybridization)
positive (based on ASCO-CAP guidelines 2013) or

- FISH or SISH (Silver in situ hybridization) positive (based on ASCO-CAP
guidelines 2013)

3. Patient must have at least one measurable brain lesion (defined as any lesion ≥ 5mm
cm in the longest dimension), on T1 weighted, gadolinium enhanced MRI. Patients may
have had surgical excisions of brain metastases provided at least one lesions meets
the following criteria:

- Patients with brain metastases previously untreated with any intra-cranial
radiation (i.e. no whole brain radiation therapy [WBRT]/partial brain radiation
or stereotactic radiosurgery [SRS]) must have at least one intra-cranial tumor
lesion that is ≥ 5mm.

- Patients with brain metastases previously untreated with any intracranial
radiation (i.e., no whole brain radiation therapy [WBRT]/partial brain radiation
or stereotactic radiosurgery [SRS]) must have at least one intracranial tumor
lesion that is ≥ 5mm.

- Patients with brain metastases previously treated with WBRT/partial brain
radiation only must have at least one intracranial tumor lesion ≥ 5mm and must
have evidence of intracranial progressive disease

- Patients previously treated with WBRT/partial brain radiation and SRS must have
at least one intracranial tumor lesion ≥ 5mm that was not treated with SRS and
must have intracranial disease.

- Patients previously treated with SRS must either demonstrate disease progression
≥ 12 weeks after completing SRS with a lesion measuring ≥ 5mm or must have at
least one intracranial tumor lesion ≥ 5mm that was not treated with SRS.

4. Patients who have received WBRT/partial brain radiation for intra-cranial metastases
are eligible if treatment was completed ≥28 days prior to the first dose of study
drug.

5. Estrogen receptor (ER) and progesterone receptor (PR) status in the primary or most
recent tumor assessment must be known or pending at the time of study registration.
Patient's ER/PR status (i.e., positive or negative) does not influence enrollment but
is a requirement.

6. Patient must have received prior treatment with HER2-directed therapy such as
trastuzumab, either in the adjuvant or metastatic setting.

7. Prior treatment with lapatinib in the (neo)adjuvant and metastatic setting.

8. Patients without prior chemotherapy for MBC are eligible provided the patients
relapsed during adjuvant therapy with trastuzumab or ≤6 months following completion
of adjuvant therapy. Otherwise, there is no specific minimum or maximum number of
previous chemotherapy regimens for MBC.

9. Patients must have completed cytotoxic chemotherapy ≥21 days (for an every 3-week
regimen) or ≥14 days (for an every 2-week or weekly regimen) and have recovered from
or come to a new chronic or stable baseline from all treatment-related toxicities in
order to be eligible for study treatment.

- Patient must have completed biologic therapy ≥3 weeks or 5-half lives whichever
is shorter.

- Patient must be discontinued from hormonal therapy a minimum of 1 day prior to
the first dose of study treatment.

- Patients receiving palliative radiation to bone, soft tissue or any other
disease sites must have completed this ≥1 week prior to the first dose of study
treatment.

10. Patients must have recovered (>2 week recovery is mandated) from any acute
neurosurgical intervention for metastatic CNS disease (e.g., resection, shunt
placement) and must be clinically stable. These patients must have residual
measurable CNS lesion(s) following the surgical procedure if this site is to serve as
the target lesion.

11. Patients must be neurologically stable, and if receiving steroids, must be on stable
or decreasing doses of corticosteroids and/or anticonvulsants for defined as being on
stable low doses of corticosteroids ≥ 5 days prior to the first dose of study
treatment.

12. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 2.

13. Adequate hematologic, renal, and hepatic function.

14. Adequate coagulation parameters.

15. Other laboratory testing:

- Serum magnesium ≥ the institutional lower limit of normal (LLN)

- Serum potassium ≥ the institutional LLN

16. Male patients willing to use adequate contraceptive measures.

17. Female patients who are not of child-bearing potential, and female patients of
child-bearing potential who agree to use adequate contraceptive measures, who are not
breastfeeding, and who have a negative serum or urine pregnancy test within 72 hours
prior to start of treatment.

18. Life expectancy ≥12 weeks.

19. Ability to swallow oral medications.

20. Willingness and ability to comply with trial and follow-up procedures.

21. Ability to understand the nature of this trial and give written informed consent.

22. Willingness and ability to comply with trial and follow-up procedures.

23. Ability to understand the nature of the trial and give written informed consent.

Exclusion Criteria:

1. Previous treatment with cabazitaxel.

2. CNS disease requiring immediate neurosurgical intervention (e.g., resection, shunt
placement, etc.).

3. Leptomeningeal metastases as the only site of CNS metastases. Patients with
parenchymal brain metastases and leptomeningeal metastases are eligible provided they
meet all other eligibility criteria.

4. Peripheral neuropathy ≥Grade 2 (CTCAE v4.0).

5. Concurrent treatment with radiation therapy, hormonal therapy, biologic therapy or
chemotherapy is not allowed. Low dose corticosteroids (≤30 mg/day prednisone or its
equivalent) are allowed.

6. Concurrent treatment with drugs known to be moderate and strong inhibitors or
inducers of isoenzyme CYP3A that cannot be discontinued or switched to different
medication prior to starting study drug.

7. Concurrent use of St. John's wort and grapefruit/grapefruit juice ≤7 days prior to
starting study drug is not allowed.

8. Presence of active gastrointestinal (GI) disease or other condition that in the
opinion of the investigator will interfere significantly with the absorption,
distribution, metabolism, or excretion of oral therapy (e.g. ulcerative disease,
uncontrolled nausea, or vomiting).

9. Known diagnosis of human immunodeficiency virus (HIV), Hepatitis B (HBV) or Hepatitis
C (HCV).

10. Presence of other active cancers, or history of treatment for invasive cancer ≥3
years. Patients with stage I cancer who have received definitive local treatment with
curative intent at least 3 years previously, and are considered unlikely to recur are
eligible. All patients with previously treated in situ carcinoma (i.e. non-invasive)
are eligible, as are patients with history of non-melanoma skin cancer.

11. Any severe and/or uncontrolled medical conditions or other conditions that could
affect participation in the study such as:

- Symptomatic congestive heart failure (CHF) of New York Heart Association Class
III or IV.

- QTc > 480 ms on screening ECG (using the Fredericia formula)

- Poorly controlled or clinically significant atherosclerotic vascular disease
including cerebrovascular accident (CVA), transient ischemic attack (TIA),
angioplasty, cardiac or vascular stenting in the past 6 months

- Active (acute or chronic) or uncontrolled severe infections.

- Active hepatic or biliary disease (except for patients with Gilbert's syndrome,
asymptomatic gallstones, liver metastases, or stable chronic liver disease per
investigator assessment).

12. Known hypersensitivity to cabazitaxel or other drugs formulated with polysorbate 80.

13. Psychological, familial, sociological, or geographical conditions that do not permit
compliance with the protocol.

14. Inability or unwillingness to comply with study and/or follow-up procedures outlined
in the protocol.