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


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Primary Outcome Measures:

  • Overall response rate [ Time Frame: Up to 3 years ]

    Will be defined as the number of patients whose disease meets the Response Evaluation Criteria in Solid Tumors criteria for a partial or complete response on two consecutive evaluations at least 8 weeks apart divided by the total number of patients in that cohort who started protocol treatment. For each cohort, a two-stage Simon minimax design with a safety run-in period will be used to test the null hypothesis that the true tumor response rate is at most 5% against the alternative it is at least 20%.

Secondary Outcome Measures:

  • Clinical benefit rate [ Time Frame: Up to 3 years ]

    Will be defined as the proportion of patients who have completed 6 cycles of treatment without disease progression (that is, their objective disease status is a complete response, partial response, or stable for 6 cycles or more). A point and interval estimate of the response rate as well as the clinical benefit rate will be constructed using the Duffy-Santner approach to take into account the sequential nature of the study design. The distribution of response times and progression-free survival times will be estimated using the Kaplan-Meier approach.

  • Duration of response [ Time Frame: Up to 3 years ]

    Will be defined as the time from the first radiologic finding of a partial response or complete response to disease progression among those patients whose disease meets the Response Evaluation Criteria in Solid Tumors criteria for complete response or partial response on 2 consecutive evaluations approximately 8 weeks apart. A point and interval estimate of the response rate as well as the clinical benefit rate will be constructed using the Duffy-Santner approach to take into account the sequential nature of the study design. The distribution of response times and progression-free survival tim

  • Progression free survival [ Time Frame: Up to 3 years ]

    Will be defined as time from randomization to the first of these disease events: local/regional or distant breast recurrence, ductal breast carcinoma in situ or invasive breast disease in contralateral breast, non-breast second primary, or death due to any cause. A point and interval estimate of the response rate as well as the clinical benefit rate will be constructed using the Duffy-Santner approach to take into account the sequential nature of the study design. The distribution of response times and progression-free survival times will be estimated using the Kaplan-Meier approach.

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.