FASN Inhibitor TVB-2640, Paclitaxel, and Trastuzumab in Treating Patients With HER2 Positive Advanced Breast Cancer

PRIMARY OBJECTIVES:

I. To estimate the overall tumor response rate (ORR i.e. complete response [CR]+partial
response [PR]) of the combination of FASN inhibitor TVB-2640 (TVB-2640) with paclitaxel and
trastuzumab in patients with taxane and trastuzumab-resistant, advanced HER2-positive breast
cancer who have had prior exposure to trastuzumab emtansine (T-DMI) in the metastatic breast
cancer setting.

II. To estimate the ORR of the combination of TVB-2640 with paclitaxel and trastuzumab in
patients with taxane and trastuzumab-resistant, advanced HER2-positive breast cancer who have
not had prior exposure to T-DMI in the metastatic breast cancer setting.

SECONDARY OBJECTIVES:

I. For each patient cohort, to evaluate the safety profile of the combination of TVB-2640
with paclitaxel and trastuzumab.

II. For each patient cohort, to assess the clinical benefit rate (CBR), duration of response,
and progression free survival of the combination of TVB-2640 with paclitaxel and trastuzumab.

III. To obtain a point and interval estimate of the difference in RR as well as the
difference in CBR between cohort 1 and cohort 2.

TERTIARY OBJECTIVES:

I. For each patient cohort, to assess the changes in FASN, phosphorylation (p)AKT, and pS6
expression in tumor tissue after the first cycle of the combination of TVB-2640 with
paclitaxel and trastuzumab from pre-treatment levels.

II. For each patient cohort, to assess the changes in levels of cellular apoptosis in tumor
tissue after the first cycle of the combination of TVB-2640 with paclitaxel and trastuzumab
from pre-treatment levels.

III. For each patient cohort, to assess the changes in serum FASN after the first cycle of
the combination of TVB-2640 with paclitaxel and trastuzumab from pre-treatment levels.

OUTLINE:

Patients receive FASN inhibitor TVB-2640 orally (PO) once daily (QD) on days 1-28, paclitaxel
intravenously (IV) over 1-96 hours on days 1, 8, and 15, and trastuzumab IV over 30-90
minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease
progression or unexpected toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 3
years.

Inclusion Criteria:

- PRE-REGISTRATION INCLUSION CRITERIA

- Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)
criteria that is:

- A non-nodal lesion is considered measurable if its longest diameter can be
accurately measured as >= 1.0 cm with computed tomography (CT) scan, CT component
of a positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI)
and/or

- A malignant lymph node is considered measurable if its short axis is > 1.5 cm
when assessed by CT scan (CT scan slice thickness recommended to be no greater
than 5 mm)

- Note: tumor lesions in a previously irradiated area are not considered measurable
disease; disease that is measurable by physical examination only is not eligible

- Received =< four (4) prior chemotherapy regimens in the metastatic setting

- One of the following must be true:

- Progressed on taxane-based chemotherapy in the metastatic setting OR

- Metastatic disease was diagnosed during or =< 12 months after last dose of
neoadjuvant or adjuvant taxane-based chemotherapy

- One of the following must be true:

- Progressed on trastuzumab and pertuzumab in the metastatic setting OR

- Metastatic disease was diagnosed during or =< 6 months after last dose of
neoadjuvant or adjuvant HER2-directed therapy

- Unlimited prior endocrine therapy for hormone receptor positive disease

- Willingness to provide mandatory tumor tissue specimens for correlative research

- REGISTRATION INCLUSION CRITERIA

- Registration must be completed =< 28 days of pre-registration

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

- Histological confirmation of HER2-positive advanced breast cancer; HER2+ is defined by
2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP)
guidelines

- Hemoglobin >= 9.0 g/dL

- Absolute neutrophil count (ANC) >= 1500/mm^3

- Platelet count >= 100,000/mm^3

- Direct bilirubin =< 1.5 x upper limit of normal (ULN)

- Aspartate transaminase (AST) =< 3 x ULN (=< 5 x ULN for patients with liver
involvement)

- Calculated creatinine clearance >= 45 ml/min using the Cockcroft-Gault formula

- Cardiac ejection fraction (left ventricular ejection fraction [LVEF]) >= 50% by
echocardiogram =< 30 days of registration

- Provide written informed consent

- Willing to return to enrolling institution for follow-up (during the active monitoring
phase of the study)

- Negative urine pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only

- NOTE: If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required

- Patient and his/her partner agree to use adequate contraception after providing
written informed consent through 3 months after the last dose of TVB-2640, as follows:

- For women: Compliant with a medically-approved contraceptive regimen during and
for 3 months after the treatment period or documented to be surgically sterile or
postmenopausal

- For men: Compliant with a medically-approved contraceptive regimen during and for
3 months after the treatment period or documented to be surgically sterile; men
whose sexual partners are of child-bearing potential must agree to use 2 methods
of contraception prior to study entry, during the study, and for 3 months after
the treatment period

- Willingness to provide mandatory tumor tissue and/or blood specimens for correlative
research

Exclusion Criteria:

- PRE-REGISTRATION EXCLUSION CRITERIA

- Patients who previously discontinued trastuzumab due to unacceptable cardiac toxicity

- Patients with a history of LVEF decline to below 50% during or after prior trastuzumab
or other HER2 directed therapy

- Patients with any class of New York Heart Association (NYHA) congestive heart failure
(CHF) or heart failure with preserved ejection fraction (HFPEF)

- Patients with a history of known coronary artery disease or a myocardial infarction
within 12 months prior to pre-registration

- Patients with persistently uncontrolled hypertension (systolic blood pressure [BP] >
160 mm Hg or diastolic BP > 100 mm Hg) despite optimal medical therapy

- Patients with known unstable angina pectoris

- Patients with a known history of serious cardiac arrhythmias requiring treatment
(exception: controlled atrial fibrillation, paroxysmal supraventricular tachycardia)

- Patients with a prolonged corrected QT interval (QTc) interval (>= 450 ms)

- Leptomeningeal disease or uncontrolled brain metastasis

- NOTE: Metastases treated by surgery and/or radiotherapy such that patient is
neurologically stable and off steroids >=12 weeks prior to preregistration are
eligible

- Failure to recover from acute, reversible effects of prior therapy regardless of
interval since last treatment

- EXCEPTION: Grade 1 peripheral (sensory) neuropathy that has been stable for at
least 3 months since completion of prior treatment

- Tumors involving spinal cord or heart

- Visceral crisis or lymphangitic spread

- NOTE: Visceral crisis is not the mere presence of visceral metastases, but
implies severe organ dysfunction as assessed by symptoms and signs, laboratory
studies, and rapid progression of disease

- Uncontrolled intercurrent non-cardiac illness including, but not limited to,

- Ongoing or active infection

- Psychiatric illness/social situations

- Dyspnea at rest due to complications of advanced malignancy or other disease that
requires continuous oxygen therapy

- Or any other conditions that would limit compliance with study requirements

- Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
positive and currently receiving antiretroviral therapy

- NOTE: Patients known to be HIV positive, but without clinical evidence of an
immunocompromised state, are eligible for this trial

- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm

- History of myocardial infarction =< 6 months, or congestive heart failure requiring
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

- Prior history of hypersensitivity, drug or radiation-induced, or other immune-mediated
pneumonitis

- Patient is unable to swallow oral medications or has impairment of gastrointestinal
(GI) function or GI disease that may significantly alter drug absorption (e.g. active
inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption
syndrome); concomitant therapy with proton pump inhibitors and/or H2-receptor
antagonists is permissible

- Patient has a history of clinically significant dry eye (xerophthalmia) or other
corneal abnormality, or if a contact lens wearer, does not agree to abstain from
contact lens use from baseline through the last TVB-2640 dose

- Patients with a history of intolerance to trastuzumab (i.e. a grade 3 or 4 infusion
reaction) are excluded; Note: patients with a history of mild infusion reaction to
trastuzumab who have previously been successfully re-challenged after an infusion
reaction with or without prophylactic medication are allowed

- Other active malignancy =< 5 years prior to pre-registration

- EXCEPTIONS: Non-melanoma skin cancer or carcinoma-in-situ of the cervix which has
been adequately treated

- NOTE: If there is a history of prior malignancy, patients must not be receiving
other treatment for their cancer and the disease must be inactive/stable

- REGISTRATION EXCLUSION CRITERIA

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Any of the following therapies prior to registration:

- Chemotherapy =< 3 weeks

- Immunotherapy =< 3 weeks

- Biologic therapy =< 3 weeks

- Hormonal therapy =< 2 weeks

- Monoclonal antibodies =< 3 weeks

- Radiation therapy =< 2 weeks

- CDK 4/6 inhibitors =< 4 weeks

- mTOR inhibitors =< 4 weeks