TVB-2640 and Trastuzumab With Paclitaxel or Endocrine Therapy for Treatment of HER2 Positive Metastatic 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. 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. 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 A and cohort B. CORRELATIVE RESEARCH 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 are assigned to 1 of 2 cohorts. COHORT A: 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, and optionally every 21 days after 3 cycles and paclitaxel is discontinued. Cycles repeat every 28 days in the absence of disease progression or unexpected toxicity. Patients also undergo echocardiography (ECHO) and computed tomography (CT) or magnetic resonance imaging (MRI) at screening and on study and undergo collection of blood samples and biopsy on study. COHORT B: Patients receive FASN inhibitor TVB-2640 PO QD on days 1-28 and trastuzumab IV over 30-90 minutes on days 1, 8, 15, and 22 and optionally every 21 days after 3 cycles and paclitaxel is discontinued. Patients also continue endocrine therapy of either anastrozole PO QD, exemestane PO QD, fulvestrant intramuscularly (IM) on days 1 and 14 of cycle 1 and day 1 of subsequent cycles, or letrozole PO QD. Cycles repeat every 28 days in the absence of disease progression or unexpected toxicity. Patients also undergo ECHO and CT or MRI at screening and on study and undergo collection of blood samples and biopsy on study. After completion of study treatment, patients are followed up every 6 months for up to 3 years.