T-DM1 Alone Versus T-DM1 and Metronomic Temozolomide in Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases Following Stereotactic Radiosurgery

Background:

- Breast cancer is the most common cancer in women. In the HER2+ subtype, brain metastases
can occur in up to 25-40% of patients.

- The standard therapy for brain metastases continues to be surgery or stereotactic
radiosurgery (SRS) and/or whole brain radiation therapy (WBRT).

- Currently, independently of localized or systemic treatment modality, once brain
metastases are established, options for treatment are limited, and the disease almost
invariably progresses, limiting not only survival but also quality of life in most
patients.

- Preclinical literature suggests the hypothesis that preventing the formation of a
metastasis by a drug may be more efficacious than attempting to shrink an established
lesion.

- Our group has shown in vitro and in vivo in animal models injected with a brain tropic
MGMT+ cell line, that even in very low doses temozolomide (TMZ) administered in a
prophylactic, metronomic fashion can significantly prevent development of brain
metastases.

- We propose a secondary-prevention clinical trial with oral TMZ given to HER2+ breast
cancer patients with brain metastases after recent local treatment (SRS or surgical
resection) in combination with the anti-HER2 agent T-DM1 for systemic control of
disease.

Objectives:

- Phase I (run in): to identify the maximum tolerated dose (MTD) of TMZ when used in
combination with T-DM1.

- Phase II: to determine if the combination regimen of T-DM1 and temozolomide improves the
freedom from distant new brain metastases following stereotactic radiosurgery or
surgical resection in HER2-positive breast cancer brain metastases at one year as
compated to T-DM1 alone.

Eligibility:

Phase I:

- Histologically confirmed HER2+ breast cancer.

- ECOG performance status 0-2 and adequate organ and marrow function.

- Brain metastases, treated within 12 weeks of study entry with SRS, resection or WBRT.

- Patients with leptomeningeal metastatic disease are ineligible.

- Patients that are unable to complete a brain MRI with contrast are ineligible.

- Patients with breast tissue expanders must have those removed before enrollment.

- HBV, HCV or HIV-positive patients are ineligible.

- Patient with impaired cardiac function or clinically significant cardiac disease are
ineligible.

- Corticosteroids will be allowed at enrollment and during the first month of treatment
with T-DM1 after SRS, up to a dose of no more than 10mg of dexamethasone daily or
equivalent. Patients that need to continue corticosteroids after the initial month will
not be allowed to increase the dose after that period, and will be taken off protocol.

Phase II:

- Histologically confirmed HER2+ breast cancer.

- ECOG performance status 0-2 and adequate organ and marrow function.

- 1-10 brain metastases, by contrast MRI, treated within 12 weeks of study entry with SRS
and/or resection.

- Patients with leptomeningeal metastatic disease are ineligible.

- Patients with history of WBRT are ineligible.

- Patients that are unable to complete a brain MRI with contrast are ineligible.

- Patients with breast tissue expanders must have those removed before enrollment.

- HBV, HCV or HIV-positive patients are ineligible.

- Patient with impaired cardiac function or clinically significant cardiac disease are
ineligible.

- Corticosteroids will be allowed at enrollment and during the first month of treatment
with T-DM1 after SRS, up to a dose of no more than 10mg of dexamethasone daily or
equivalent. Patients that need to continue corticosteroids after the initial month will
not be allowed to increase the dose after that period, and will be taken off protocol.

Design:

- This is a Phase I/II open label study that will evaluate the potential benefit of TMZ in
prevention of new brain metastases in patients with limited brain metastases from HER2+
breast cancer, previously treated with SRS or surgical resection of brain metastases.

- All patients will receive the standard second-line therapy for HER2+ metastatic breast
cancer: T-DM1. During phase II patients will be randomized between T-DM1 plus TMZ versus
T-DM1 alone.

- Phase I run in: T-DM1 3.6 mg/kg IV every 21 days plus TMZ 30, 40 or 50 mg/m^2 daily.

- Phase II: T-DM1 3.6 mg/kg versus T-DM1 3.6mg/kg plus TMZ at recommended phase 2 dose
(RP2D).

- Phase I will follow a standard 3+3 design. Thus, with 3 dose levels, up to 18 patients
may be included in the initial safety evaluation.

- In the phase II portion of the trial, a total of 49 evaluable subjects per arm (98
total) will need to be randomized over a 3-year period and followed for an additional 2
years from the date of entry of the last patient, with occurrence of 79 total relapses
in both arms combined, in order to have 80% power to compare the curves.

- INCLUSION CRITERIA:

Phase 1 Inclusion Criteria

- Patients must have histologically confirmed HER2-positive breast cancer for which
standard curative measures do not exist or are no longer effective. HER2 testing must
have been performed in a laboratory accredited by the College of American Pathologists
(CAP) or another accrediting entity.

- Patients must have brain metastases, treated within 12 weeks of study entry with SRS,
resection or WBRT. A minimum interval of 3 weeks between completion of brain SRS
and/or resection and 6 weeks for WBRT and the start of treatment in this trial will be
observed to allow proper healing. The presence of concomitant extracranial metastatic
disease is allowed for enrollment.

- Corticosteroids will be allowed at enrollment and during the first month of treatment

with T-DM1 after SRS, up to a dose of no more than 10mg of dexamethasone daily or
equivalent. Patients that need to continue corticosteroids after the initial month will be
allowed to continue in the protocol treatment if no further increase in dose is necessary.
Patients that need increase in dose of corticosteroid after initial month will be taken off
protocol treatment.

- Age greater than or equal to18 years. Because breast cancer is not commonly found in
pediatric population and no dosing or adverse event data are currently available on
the use of temozolomide in combination with T-DM1 in patients <18 years of age,
children are excluded from this study, but will be eligible for future pediatric
trials.

- ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to
60%)

- Patients must have normal organ and marrow function as defined below:

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,000/mcL

- platelets greater than or equal to 100,000/mcL

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) <3.0 X institutional upper limit of normal

- creatinine up to 1.5 upper institutional limits, OR

- creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients
with creatinine levels above institutional normal.

- Alkylating agents as well as other therapeutic agents used in this trial are known to
be teratogenic, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry, for the duration of study participation and for 7 months (women) or 4 months
(men) after treatment completion. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately.

- Ability of subject to understand and the willingness to sign a written informed
consent document.

Phase 2 Inclusion Criteria

- Patients must have histologically confirmed HER2-positive breast cancer for which
standard curative measures do not exist or are no longer effective. HER2 testing must
have been performed in a laboratory accredited by the College of American Pathologists
(CAP) or another accrediting entity.

- Patients must have 1-10 brain metastases, by contrast MRI, treated within 12 weeks of
study entry with SRS and/or resection. A minimum interval of 3 weeks between
completion of brain SRS and/or resection and the start of treatment in this trial will
be observed to allow proper healing. The presence of concomitant extracranial
metastatic disease is allowed for enrollment.

- Corticosteroids will be allowed at enrollment and during the first month of treatment
with T-DM1 after SRS, up to a dose of no more than 10mg of dexamethasone daily or
equivalent. Patients that need to continue corticosteroids after the initial month
will be allowed to continue in the protocol treatment if no further increase in dose
is necessary. Patients that need increase in dose of corticosteroid after initial
month will be taken off protocol treatment.

- Age greater than or equal to 18 years. Because breast cancer is not commonly found in
pediatric population and no dosing or adverse event data are currently available on
the use of temozolomide in combination with T-DM1 in patients <18 years of age,
children are excluded from this study, but will be eligible for future pediatric
trials.

- ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to
60%)

- Patients must have normal organ and marrow function as defined below:

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,000/mcL

- platelets greater than or equal to 100,000/mcL

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) <3.0 X institutional upper limit of normal

- creatinine up to 1.5 upper institutional limits, OR

- creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients
with creatinine levels above institutional normal.

- Alkylating agents as well as other therapeutic agents used in this trial are known to
be teratogenic, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry, for the duration of study participation and for 7 months (women) or 4 months
(men) after treatment completion. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately.

- Ability of subject to understand and the willingness to sign a written informed
consent document.

EXCLUSION CRITERIA:

Phase 1 Exclusion Criteria

- Patients who are receiving any other investigational agents.

- Patients unable to speak or understand English, since they cannot complete
neurocognitive evaluation.

- Patients with known leptomeningeal metastatic disease.

- Patients with major symptoms or impairments related to brain metastases, such as
aphasia or severe confusion, will be excluded per PI discretion when those symptoms
preclude proper neurocognitive evaluation during the study treatment.

- Patients who have received previous treatment with T-DM1 and had systemic progression
of disease while on it, are ineligible. Patients receiving treatment with T- DM1 whose
only site of disease progression was brain are allowed to enroll in this trial.

- Patients who have received chemotherapy in the previous 3 weeks (6 weeks for
nitrosoureas or mitomycin).

- HBV (HBs Ag positive) or HCV (anti-HCV positive) patients are ineligible because of
potential reactivation of hepatitis virus with temozolomide use.

- Grade greater than or equal to 3 peripheral neuropathy according to (NCI CTCAE)
version 4.0.

- Cerebral Vascular Accident (CVA) or Transitory Ischemic Attack (TIA) in the year
before enrollment, or presence of residual symptoms from CVA that happened more than a
year before.

- Pulmonary Embolism (PE) in the 3 months before enrollment. Anticoagulation is
permitted.

- Impaired cardiac function or clinically significant cardiac disease including the
following:

- New York Heart Association grade III or IV congestive heart failure.

- Myocardial infarction within the last 12 months.

- Subjects with impaired LVEF (<50%).

- Patients with inability to complete brain MRI studies with contrast.

- Patients with breast tissue expanders must have those removed before enrollment.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to temozolomide or T-DM1.

- Patients receiving medications that are strong CYP3A4 inhibitors or inducers are
ineligible. In vitro studies indicate that DM1, the cytotoxic component of T-DM1, is
metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5. Concomitant use of
strong CYP3A4 inhibitors with T-DM1 should be avoided due to the potential for an
increase in DM1 exposure and toxicity. Consider an alternate medication with no or
minimal potential to inhibit CYP3A4.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, that would limit compliance with study requirements.

- Pregnant women are excluded from this study because temozolomide is an alkylating
agent with the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with temozolomide and/or T-DM1, breastfeeding should be
discontinued if the mother is treated with either of those agents. These potential
risks may also apply to other agents used in this study.

- HIV-positive patients are excluded because these patients are at increased risk of
lethal infections when treated with marrow-suppressive therapy.

- Patients with any other concomitant invasive malignancies are ineligible. Prior
invasive cancers treated with curative intent, and with no evidence of recurrent
disease, may be eligible after PI evaluation. Patients with treated limited stage
basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the breast
or cervix are eligible.

Phase 2 Exclusion Criteria

- Patients who are receiving any other investigational agents.

- Patients unable to speak or understand English, since they cannot complete
neurocognitive evaluation.

- Patients with known leptomeningeal metastatic disease.

- Patients previously treated with whole brain radiation therapy (WBRT).

- Patients with major symptoms or impairments related to brain metastases, such as
aphasia or severe confusion, will be excluded per PI discretion when those symptoms
preclude proper neurocognitive evaluation during the study treatment.

- Patients who have received previous treatment with T-DM1 and had systemic progression
of disease while on it, are ineligible. Patients receiving treatment with T- DM1 whose
only site of disease progression was brain are allowed to enroll in this trial.

- Patients who have received chemotherapy in the previous 3 weeks (6 weeks for
nitrosoureas or mitomycin).

- HBV (HBs Ag positive) or HCV (anti-HCV positive) patients are ineligible because of
potential reactivation of hepatitis virus with temozolomide use.

- Grade greater than or equal to 3 peripheral neuropathy according to (NCI CTCAE)
version 4.0.

- Cerebral Vascular Accident (CVA) or Transitory Ischemic Attack (TIA) in the year
before enrollment, or presence of residual symptoms from CVA that happened more than a
year before.

- Pulmonary Embolism (PE) in the 3 months before enrollment. Anticoagulation is
permitted.

- Impaired cardiac function or clinically significant cardiac disease including the
following:

- New York Heart Association grade III or IV congestive heart failure.

- Myocardial infarction within the last 12 months.

- Subjects with impaired LVEF (<50%).

- Patients with inability to complete brain MRI studies with contrast.

- Patients with breast tissue expanders must have those removed before enrollment.

- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to temozolomide or T-DM1.

- Patients receiving medications that are strong CYP3A4 inhibitors or inducers are
ineligible. In vitro studies indicate that DM1, the cytotoxic component of T-DM1, is
metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5. Concomitant use of
strong CYP3A4 inhibitors with T-DM1 should be avoided due to the potential for an
increase in DM1 exposure and toxicity. Consider an alternate medication with no or
minimal potential to inhibit CYP3A4.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, that would limit compliance with study requirements.

- Pregnant women are excluded from this study because temozolomide is an alkylating
agent with the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with temozolomide and/or T-DM1, breastfeeding should be
discontinued if the mother is treated with either of those agents. These potential
risks may also apply to other agents used in this study.

- HIV-positive patients are excluded because these patients are at increased risk of
lethal infections when treated with marrow-suppressive therapy.

- Patients with any other concomitant invasive malignancies are ineligible. Prior
invasive cancers treated with curative intent, and with no evidence of recurrent
disease, may be eligible after PI evaluation.