Letrozole and Imatinib Mesylate in Treating Postmenopausal Participants With Estrogen or Progesterone Positive Metastatic Breast Cancer

Study Overview
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Brief Summary
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This phase II trial studies the side effects and how well letrozole and imatinib mesylate work in treating postmenopausal participants with estrogen or progesterone positive breast cancer that has spread to other places in the body. Letrozole is an antihormonal drug used in the standard treatment of hormonal sensitive breast cancer. Imatinib mesylate is a drug that binds to certain proteins on the tumor cells and prevents them from further growth. Imatinib mesylate is thought to prevent the potential resistance to letrozole, which may make the letrozole more effective. Giving letrozole and imatinib mesylate may work better in treating participants with breast cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the efficacy of letrozole plus imatinib mesylate in patients with estrogen receptor (ER) and or progesterone receptor (PgR) positive metastatic breast cancer. II. To determine the safety and tolerability of letrozole plus imatinib mesylate in patients with metastatic breast cancer. III. To determine the time to disease progression and overall survival in patients with metastatic breast cancer who are treated with letrozole plus imatinib mesylate. OUTLINE: Participants receive imatinib mesylate orally (PO) twice daily (BID) and letrozole PO once daily (QD) for 8 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up at 1 and 4 weeks and at 2, 4, 6, 9, and 12 months.

Official Title
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Phase II Study of Letrozole (Femara) Plus Imatinib Mesylate (Gleevec) for Postmenopausal Patients With ER and/or PR Positive Metastatic Breast Cancer

Conditions
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Anatomic Stage IV Breast Cancer AJCC v8, Estrogen Receptor Positive, KIT Positive, PDGFR Positive, Postmenopausal, Progesterone Receptor Positive, Prognostic Stage IV Breast Cancer AJCC v8

Intervention / Treatment
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* Drug: Imatinib Mesylate
* Drug: Letrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal women able to comply with the protocol requirements with metastatic breast cancer, whose tumors are estrogen (ER) and/or progesterone (PgR) positive, defined by core biopsy immunohistochemistry with greater than 10% positive malignant epithelial cells Patients must have documented expression of either PDGFR or CD117 (c-kit) by immunohistochemistry Patients may have received tamoxifen in the adjuvant/neoadjuvant or setting. Patients may have previously received chemotherapy in the adjuvant/ neoadjuvant setting, though this is not required. Prior chemotherapy for metastatic breast cancer is allowed. Concomitant bisphosphonates are allowed for patients with bone metastases and who have another site of measurable disease Post menopausal status defined by one of the following: no spontaneous menses for at least 1 year, in women greater than or equal to 55 years spontaneous menses within the past 1 year in women greater than or equal to 55 years with postmenopausal gonadotrophin levels (luteinizing hormone [LH] and follicle stimulating hormone [FSH] levels greater than 40 IU/L ) or postmenopausal estradiol levels (less than 5 mg/dl) or according to the definition of postmenopausal range for the laboratory involved bilateral oophorectomy Performance status, Eastern Cooperative Oncology Group (ECOG) greater than or equal to 2 Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal to 10 mm with conventional techniques. Bone disease only will not be accepted as measurable disease. Pleural or peritoneal effusions will not be accepted as measurable disease Absolute neutrophil count (ANC) = 1.5 x 10 to the 9th power/L Platelets greater than or equal to 100.0 x 10 to the 9th power/L Hemoglobin greater than 10.0 g/dL Creatinine less than 1.5 mg/dl Total (T.) bilirubin less than 1.5 x normal Aspartate aminotransferase (AST) less than 2.5 x normal A life expectancy of at least 6 months Localized radiotherapy, which does not influence the signal of evaluable lesion, is allowed prior to the initiation of imatinib mesylate. Patients must have recovered from the myelosuppressive effects of previous radiotherapy (at least 2-4 weeks) Ability to understand and the willingness to sign a written informed consent Exclusion Criteria: Prior treatment with Femara or Gleevec Uncontrolled endocrine disorders such as diabetes mellitus, confirmed hypo- or hyperthyroidism, Cushing's syndrome, Addison's disease (treated or untreated) Patients with unstable angina, or uncontrolled cardiac disease (e.g. class III or IV New York Heart Association's functional classification) Other concurrent malignant disease with the exception of cone-biopsied in situ carcinoma of the cervix uteri, or adequately treated basal or squamous cell carcinoma of the skin, or other curable cancers e.g. Hodgkin's disease or non-Hodgkin lymphoma (NHL), provided 5 years have elapsed from completion of therapy, and there has been no recurrence Concomitant treatment with steroids, e.g. glucocorticoids for indications other than cancer, except aerosol for obstructive airways diseases and steroid injection to the joints for treatment of inflammation Other investigational drugs within the past 3 weeks and the concomitant use of investigational drugs History of non-compliance to medical regimens and patients who are considered potentially unreliable Patients with known brain metastasis Patients with known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis) Patients with known diagnosis of human immunodeficiency virus (HIV) infection Patients who received chemotherapy within 4 weeks (6 weeks for nitrosourea or mitomycin-C) prior to study entry, unless the disease is rapidly progressing Patients who previously received radiotherapy to greater than or equal to 25% of the bone marrow Patients who had a major surgery within 2 weeks prior to study entry
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (imatinib mesylate, letrozole)<br>Participants receive imatinib mesylate PO BID and letrozole PO QD for 8 weeks in the absence of disease progression or unacceptable toxicity. | Drug: Imatinib Mesylate<br>* Given PO<br>* Other names: STI571;Drug: Letrozole<br>* Given PO<br>* Other names: Femara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Among participants with CR or PR as the best overall response, duration of response (DOR) was defined as the time from which measurement criteria were met for CR or PR until the date of progression. Progression-free survival (PFS) was defined as the time from study enrollment to disease progression or death from any cause, whichever occurred first. PFS data were censored at the time of removal from study. Overall survival (OS) was defined as the time from study registration to death from any cause. Information on vital status was collected following study completion through July 23, 2018 and was used in the determination of OS. Among patients with SD as the best overall response, duration of SD was defined as the time from study enrollment to disease progression or removal from study. | From the registration until disease progression, death, unacceptable toxicity, or withdraw of study consent, whichever occurred first assessed up to 182 months | 
| Overall Survival of Participants | This sample size would provide an estimate of the objective response rate (ORR) 95% confidence intervals for the ORR and CBR were calculated using the exact binomial method. Among patients with CR or PR as the best overall response, duration of response (DOR) was defined as the time from which measurement criteria were met for CR or PR until the date of progression. Progression-free survival (PFS) was defined as the time from study enrollment to disease progression or death from any cause, whichever occurred first. PFS data were censored at the time of removal from study. Overall survival (OS) was defined as the time from study registration to death from any cause. Information on vital status was collected following study completion through July 23, 2018 and was used in the determination of OS. Among patients with SD as the best overall response, duration of SD was defined as the time from study enrollment to disease progression or removal from study. | From the registration until disease progression, death, unacceptable toxicity, or withdraw of study consent, whichever occurred first assessed up to 182 months |