Advanced Breast Carcinoma, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, HER2-positive Breast Cancer, HER2-Positive Breast Carcinoma
Conditions
Brief summary
This phase II trial studies how well FASN inhibitor TVB-2640, paclitaxel, and trastuzumab work in treating patients with HER2 positive breast cancer that has spread to other places in the body (metastatic). FASN inhibitor TVB-2640 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Trastuzumab is a form of targeted therapy because it attaches itself to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the body's immune system. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Estrogen can cause the growth of breast cancer cells. Drugs used in endocrine therapy either lower the amount of estrogen made by the body or blocks the use of estrogen by the tumor cells. This may help stop the growth of tumor cells that need estrogen to grow. Giving FASN inhibitor TVB-2640 and trastuzumab in combination with paclitaxel or endocrine therapy may help control the disease in patients with HER2 positive breast cancer.
Detailed description
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.
Interventions
DRUGAnastrozole
Given PO
DRUGDenifanstat
Given PO
DRUGExemestane
Given PO
DRUGFulvestrant
Given IM
PROCEDUREEchocardiography
Undergo ECHO
DRUGLetrozole
Given PO
DRUGPaclitaxel
Given IV
BIOLOGICALTrastuzumab
Given IV
PROCEDUREComputed Tomography
Undergo CT
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
PROCEDUREBiospecimen Collection
Undergo blood sample collection
PROCEDUREBiopsy
Undergo biopsy
Sponsors
Mayo Clinic
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* PRE-REGISTRATION INCLUSION CRITERIA * Age \>=18 years * 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 =\< six (6) prior chemotherapy regimens in the metastatic setting * Cohort A one of the following must be true: * Distant disease progression during administration of combination therapy with taxane based chemotherapy and anti-HER2 therapy (trastuzumab or pertuzumab) for metastatic disease * Note: patients who began treatment with this combination and discontinued taxane-based chemotherapy due to intolerability before distant disease progression are eligible * Distant disease progression during administration or within 180 days of discontinuing combination therapy with taxane based chemotherapy and anti-HER2 therapy (trastuzumab or pertuzumab) in the adjuvant disease * Note: patients who began treatment with this combination and discontinued taxane-based chemotherapy due to intolerability before distant disease progression are eligible * For patient who received taxane based chemotherapy and anti-HER2 therapy (trastuzumab or pertuzumab) in the neo-adjuvant setting and underwent surgical resection of primary breast disease: distant disease progression during or within 180 days of discontinuing anti-HER2 therapy (trastuzumab or pertuzumab) in the adjuvant setting * Cohort B (one of the following must be true): * Distant disease progression during administration of combination therapy with endocrine therapy and anti-HER2 therapy (trastuzumab or pertuzumab) for metastatic disease; permissible endocrine therapies include an aromatase inhibitor or fulvestrant * NOTE: Tamoxifen is not permissible * Distant disease progression during administration of combination therapy with endocrine therapy and anti-HER2 therapy (trastuzumab or pertuzumab) in the adjuvant setting; permissible endocrine therapies include an aromatase inhibitor or fulvestrant * NOTE: Tamoxifen is not permissible * Willingness to provide mandatory tumor tissue specimens for correlative research * NOTE: If insufficient or no tissue is obtained by the pre-registration biopsy, an archival tissue specimen (preferably from a metastatic site) from procedure performed =\< 5 years prior to pre-registration must be available to submit for Central Laboratory review prior to registration * Exception: If there is no medically safe site for biopsy, Study Chair (Dr. Haddad) may waive this requirement * 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-expression (immunohistochemistry \[IHC\] 1-3+) on pre-registration biopsy. (HER2+ is defined by 2018 American Society of Clinical Oncology/College of American Pathologists \[ASCO/CAP\] guidelines) * NOTE: If pre-registration biopsy is HER2- by ASCO/CAP guidelines then both of the following must be true: * The patient's most recent prior biopsy (prior to the pre-registration biopsy) must be HER2+, AND * The managing provider must be planning to treat the patient with anti-HER2 therapy * For Cohort B only: Histologic confirmation of ERalpha positive disease (\>= 1% expression) * Hemoglobin \>= 9.0 g/dL (obtained =\< 14 days prior to registration) * Absolute neutrophil count (ANC) \>= 1500/mm\^3 (obtained =\< 14 days prior to registration) * Platelet count \>= 100,000/mm\^3 (obtained =\< 14 days prior to registration) * Direct bilirubin =\< 1.5 x upper limit of normal (ULN) (obtained =\< 14 days prior to registration) * Aspartate transaminase (AST) =\< 3 x ULN (=\< 5 x ULN for patients with liver involvement) (obtained =\< 14 days prior to registration) * Calculated creatinine clearance \>= 45 ml/min using the Cockcroft-Gault formula (obtained =\< 14 days prior to registration) * Cardiac ejection fraction (left ventricular ejection fraction \[LVEF\]) \>= 50% by echocardiogram =\< 28 days prior to 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | 14 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | 14 months | 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 times will be estimated using the Kaplan-Meier approach. |
| Clinical Benefit Rate | 41 months | 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. |
| Progression Free Survival | 41 months | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORTufia C. Haddad, M.D.
Mayo Clinic in Rochester
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 57.3 Years STANDARD_DEVIATION 11.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 0 |
| other Total, other adverse events | 15 / 15 | 0 / 0 |
| serious Total, serious adverse events | 7 / 15 | 0 / 0 |
Outcome results
None listed