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Safety and Efficacy Study of Sapanisertib in Combination With Exemestane or Fulvestrant in Postmenopausal Women With Estrogen Receptor Positive/Human Epidermal Growth Factor Receptor 2 Negative (ER+/HER2-) Metastatic Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02049957
Recruitment Status : Completed
First Posted : January 30, 2014
Results First Posted : January 27, 2020
Last Update Posted : January 5, 2021
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Brief Summary:
This is a phase 1b/2 study of the safety and efficacy of sapanisertib (MLN0128) in combination with exemestane or fulvestrant therapy in women with estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) advanced or metastatic breast cancer who progressed on treatment with everolimus in combination with exemestane or fulvestrant.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Sapanisertib Drug: Fulvestrant Drug: Exemestane Phase 2

Detailed Description:

The drug being tested in this study is called sapanisertib (MLN0128). Sapanisertib is being tested in women with estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) advanced or metastatic breast cancer who progressed on treatment with everolimus. This study will look at the safety and efficacy of sapanisertib when given in combination with exemestane or fulvestrant.

The study enrolled 118 patients. This study has two phases: phase 1 and phase 2. Phase 1 has 2 parts. In part 1 of phase 1, unmilled active pharmaceutical ingredient (API) capsules were administered, while in part 2, capsules based on milled API were administered.

  • Phase 1 (Part 1): sapanisertib 5 mg (unmilled) + exemestane
  • Phase 1 (Part 1): sapanisertib 5 mg (unmilled) + fulvestrant
  • Phase 1 (Part 2): sapanisertib 3 mg (milled) + exemestane
  • Phase 1 (Part 2): sapanisertib 3 mg (milled) + fulvestrant
  • Phase 1 (Part 2): sapanisertib 4 mg (milled) + exemestane

In phase 2, participants were enrolled into one of 2 parallel cohorts, depending on the quality and/or duration of their prior response to everolimus in combination with either exemestane (any country) or fulvestrant (US only).

Everolimus-Resistant Cohort: patients who had progressed on treatment with everolimus in combination with either exemestane (any country) or fulvestrant (US only) without achieving an objective response (CR or PR) or after achieving stable disease for <6 months as their best response.

Everolimus-Sensitive Cohort: participants who had progressed on treatment after achieving a CR or PR of any duration, or stable disease for ≥6 months with prior everolimus treatment in combination with either exemestane (any country) or fulvestrant (US only). Participants were to receive MLN0128 in combination with the same dose of the previously administered treatment (exemestane [any country] or fulvestrant [US only]).

This multi-center trial will be conducted worldwide. The overall time to participate in this study was 52 months. Participants made multiple visits to the clinic and were contacted by telephone every 3 months for a follow-up assessment.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 118 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Study of Safety and Efficacy of MLN0128 (Dual TORC1/2 Inhibitor) in Combination With Exemestane or Fulvestrant Therapy in Postmenopausal Women With ER+/HER2- Advanced or Metastatic Breast Cancer That Has Progressed on Treatment With Everolimus in Combination With Exemestane or Fulvestrant
Actual Study Start Date : February 13, 2014
Actual Primary Completion Date : June 29, 2018
Actual Study Completion Date : June 29, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane
Sapanisertib 5 mg, unmilled active pharmaceutical ingredient (API) capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 12 cycles).
Drug: Sapanisertib
Sapnisertib capsules
Other Name: MLN0128

Drug: Exemestane
Exemestane tablets.

Experimental: Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant
Sapanisertib 5 mg, unmilled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection, intramuscularly (IM), once on Day 1 of each cycle (Up to 57 cycles).
Drug: Sapanisertib
Sapnisertib capsules
Other Name: MLN0128

Drug: Fulvestrant
Fulvestrant IM injection.

Experimental: Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane
Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 8 cycles).
Drug: Sapanisertib
Sapnisertib capsules
Other Name: MLN0128

Drug: Exemestane
Exemestane tablets.

Experimental: Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant
Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle up to 14 cycles plus fulvestrant 500 mg, injection, IM, once on Day 1 of each cycle (Up to 14 cycles).
Drug: Sapanisertib
Sapnisertib capsules
Other Name: MLN0128

Drug: Fulvestrant
Fulvestrant IM injection.

Experimental: Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 18 cycles).
Drug: Sapanisertib
Sapnisertib capsules
Other Name: MLN0128

Drug: Exemestane
Exemestane tablets.

Experimental: Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)
Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 14 cycles) in everolimus sensitive participants.
Drug: Sapanisertib
Sapnisertib capsules
Other Name: MLN0128

Drug: Exemestane
Exemestane tablets.

Experimental: Phase 2:Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)
Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 17 cycles) in everolimus sensitive participants.
Drug: Sapanisertib
Sapnisertib capsules
Other Name: MLN0128

Drug: Fulvestrant
Fulvestrant IM injection.

Experimental: Phase 2: Sapanisertib 4 mg+Exemestane (Everolimus Resistant)
Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus once daily in a 28-day cycle (Up to 12 cycles) in everolimus resistant participants.
Drug: Sapanisertib
Sapnisertib capsules
Other Name: MLN0128

Drug: Exemestane
Exemestane tablets.

Experimental: Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
Sapanisertib 4 mg, milled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 9 cycles) in everolimus resistant participants.
Drug: Sapanisertib
Sapnisertib capsules
Other Name: MLN0128

Drug: Fulvestrant
Fulvestrant IM injection.




Primary Outcome Measures :
  1. Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: First dose of study drug through 30 days after the last dose (Up to 52 months) ]

    An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. This includes any newly occurring event, or a previous condition that has increased in severity or frequency since the administration of study drug.

    A SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug will be determined by the Investigator.


  2. Phase 2: Clinical Benefit Rate at 16 Weeks (CBR-16) [ Time Frame: Week 16 ]
    CBR-16 was defined as the percentage of participants who achieved confirmed complete response (CR) or partial response (PR) of any duration or had confirmed stable disease (SD) as best response and the first 2 or more post baseline scans had PR/SD and the duration of SD was >112 days. Disease response was assessed for target lesions by computed tomography (CT) or magnetic resonance imaging (MRI) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. CR is disappearance of all target lesions. PR is >=30% decrease in the sum of the longest diameter of target lesions. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression (PD).


Secondary Outcome Measures :
  1. Phase 2: Clinical Benefit Rate at 24 Weeks (CBR-24) [ Time Frame: Week 24 ]
    CBR-24 was defined as the percentage of participants who achieved confirmed CR or PR at any time or had confirmed SD as best response and the first 2 or more post baseline scans had PR/SD and the duration of stable disease was >168 days. Disease response was assessed for target lesions by CT or MRI according to RECIST version 1.1 guidelines. CR is disappearance of all target lesions. PR is >=30% decrease in the sum of the longest diameter of target lesions. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

  2. Phase 2: Overall Response Rate (ORR) [ Time Frame: Baseline then every 2 cycles from Cycles 2 through 6, and every 3 cycles thereafter in a 28-day cycle up to End of Treatment (EOT) (Up to 24 months) ]
    ORR is defined as the percentage of participants with confirmed CR or PR as per RECIST version1.1 guidelines. CR is disappearance of all target lesions. PR is >=30% decrease in the sum of the longest diameter of target lesions.

  3. Phase 2: Progression-Free Survival (PFS) [ Time Frame: Baseline then every 2 cycles from Cycles 2 through 6, and every 3 cycles thereafter in a 28-day cycle, then every 3 months after EOT until disease progression or death (Up to 24 months) ]
    PFS is defined as the time in months from the date of first dose of study treatment to the date of the first documented disease progression or death. Disease progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; or the appearance of one or more new lesions.

  4. Phase 2: Overall Survival (OS) [ Time Frame: Up to 24 months ]
    OS is the time in months from start of study treatment to date of death due to any cause. Data for the analysis of OS included the censored data at the timepoint that the participant was last known to be alive.

  5. Phase 2: Best Percent Change From Baseline in Tumor Size [ Time Frame: Baseline to Month 24 ]
  6. Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib [ Time Frame: Cycle 1 Day 15 and Cycle 2 Day 1 pre-dose and multiple timepoints (Up to 8 hours) post-dose ]
  7. Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib [ Time Frame: Cycle 1 Day 15 and Cycle 2 Day 1 pre-dose and multiple timepoints (Up to 8 hours) post-dose ]
  8. Phase 1: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Sapanisertib [ Time Frame: Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose, extrapolated to 24 hours post-dose ]
    AUC(0-24) is the area under the plasma concentration-time curve of the samples collected up to 8 hours and extrapolated up to 24 hours.

  9. Phase 1: AUC(0-last): Area Under the Plasma Concentration-time Curve From Time 0 to Last Extrapolated Concentration Over the Dosing Interval for Sapanisertib [ Time Frame: Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose, extrapolated to last timepoint ]
    AUC(0-last) is the area under the plasma concentration-time curve of the samples collected up to 8 hours and extrapolated up to last time point.

  10. Phase 1: Terminal Elimination Half-life (T1/2) for Sapanisertib [ Time Frame: Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Postmenopausal Women With ER/PR+ Metastatic Breast Cancer.
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Each patient must meet all of the following inclusion criteria to be enrolled in the study:

Phase 1b and Phase 2

  1. Advanced or metastatic breast cancer.
  2. Histological or cytological confirmation of ER+ status (defined as > 1% positive tumor cells), and histological or cytological confirmation of HER2-negative (HER2-) status by local laboratory testing using criteria in the American Society of Oncology (ASCO)/College of American Pathologists (CAP) Clinical Practice Guideline update.
  3. Female patients 18 years of age or older who are postmenopausal for at least 1 year before the Screening visit, where menopause is defined by: Age ≥ 55 years and 1 year or more of amenorrhea. Surgical menopause with bilateral oophorectomy

    Age < 55 years and 1 year or more of amenorrhea, with an estradiol assay < 20 pg/mL

    Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression.

  4. Have a history of brain metastasis are eligible for the study provided that all the following criteria are met:

    Brain metastases which have been treated

    • No evidence of disease progression for ≥ 3 months or hemorrhage after treatment
    • Off-treatment with dexamethasone for 4 weeks before administration of the first dose of MLN0128
    • No ongoing requirement for dexamethasone or anti-epileptic drugs
  5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
  6. Clinical laboratory values as specified below within 4 weeks before the first dose of MLN0128:

    • Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; platelet count ≥ 100 x 10^9/L; hemoglobin ≥ 9 g/dL
    • Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present)
    • Creatinine clearance ≥ 50 mL/min based either on Cockcroft-Gault estimate or based on a 12- or 24-hour urine collection
    • Fasting serum glucose ≤ 130 mg/dL and fasting triglycerides ≤ 300 mg/dL
  7. Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of institutional standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks before the first dose of MLN0128 (ie, if the institutional standard of normal is 50%, LVEF may be as low as 45% to be eligible for the study).
  8. Able to provide paraffin blocks or a minimum of 10 unstained slides of available archival tumor tissues (paraffin blocks are preferred). If archival tumor tissue is not available, a tumor biopsy may be performed before the patient begins treatment with MLN0128. If fewer than 10 slides are available or the tumor content/area requirements are not met, study eligibility will be determined upon discussion with the sponsor.
  9. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and suitable venous access for the study-required blood sampling.
  10. Voluntary written consent must be given before the performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

    Phase 1b Only: In addition to the previously mentioned inclusion criteria, each patient must meet the following inclusion criterion to be enrolled in the phase 1b portion of the study:

  11. Patients may have SD or disease progression during their most recent treatment with exemestane or fulvestrant, or everolimus in combination with either exemestane (any country) or fulvestrant (US only). Exemestane or fulvestrant in combination with MLN0128 can also be initiated as a new line of therapy.

    Phase 2 Only: In addition to the previously mentioned inclusion criteria, each patient must meet all of the following inclusion criteria to be enrolled in the phase 2 portion of the study:

  12. Measurable disease defined as follows:

    • At least 1 extra-osseous lesion that can be accurately measured in at least 1 dimension. The lesion must measure ≥ 20 mm with conventional imaging techniques or ≥ 10 mm with spiral computed tomography (CT) or magnetic resonance imaging (MRI), or
    • Bone lesions (lytic or mixed [lytic plus sclerotic]) in the absence of measurable disease as defined above
  13. Patients must have had disease progression during treatment with everolimus in combination with either exemestane (any country) or fulvestrant (US only) (duration of treatment ≥ 4 weeks) and must have tolerated everolimus treatment in combination with exemestane (any country) or fulvestrant (US only) adequately according to the treating physician's judgment. Everolimus in combination with exemestane or fulvestrant is not required to be the most recent treatment before enrollment, but progression on the most recent anticancer therapy is required for enrollment.

Exclusion Criteria

Patients meeting any of the following exclusion criteria are not to be enrolled in the study:

Phase 1b and Phase 2

  1. Prior anticancer therapy or other investigational therapy within 2 weeks before administration of the first dose of MLN0128 (except for exemestane or fulvestrant, which should be continued). Treatment with everolimus must be discontinued 2 weeks before administration of the first dose of MLN0128.
  2. Chronic concomitant therapy with bisphosphonates or denosumab for the prevention of bone metastases. Concomitant treatment with bisphosphonates or denosumab is permitted for treatment of osteoporosis or management of existing bone metastases if initiated at least 4 weeks before administration of the first dose of MLN0128.
  3. Initiation of treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids (either IV or oral steroids, excluding inhalers) within 1 week before administration of the first dose of MLN0128 (patients already receiving erythropoietin on a chronic basis for ≥ 4 weeks are eligible).
  4. Previous treatment with dual PI3K/mTOR inhibitors or TORC1/2 inhibitors.
  5. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of MLN0128.
  6. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) > 7%; patients with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in this study if all other inclusion/exclusion criteria are met.
  7. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise participation of the patient in the study.
  8. Known human immunodeficiency virus infection.
  9. History of any of the following within the last 6 months before administration of the first dose of MLN0128:

    • Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures
    • Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures
    • Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia)
    • Placement of a pacemaker for control of rhythm
    • New York Heart Association Class III or IV heart failure
    • Pulmonary embolism
  10. Significant active cardiovascular or pulmonary disease before administration of the first dose of MLN0128, including:

    • Uncontrolled hypertension (ie, systolic blood pressure > 180 mm Hg; diastolic blood pressure > 95 mm Hg)
    • Pulmonary hypertension
    • Uncontrolled asthma or oxygen saturation < 90% by arterial blood gas analysis or pulse oximetry on room air
    • Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention; or history of valve replacement
    • Medically significant (symptomatic) bradycardia
    • History of arrhythmia requiring an implantable cardiac defibrillator
    • Baseline prolongation of the rate-corrected QT interval (QTc; eg, repeated demonstration of QTc interval > 480 ms, or history of congenital long QT syndrome, or torsades de pointes)
  11. Diagnosed or treated for another malignancy within 2 years before administration of the first dose of MLN0128 or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.

    Phase 1b Only: In addition to the previously mentioned exclusion criteria, patients meeting the following exclusion criterion are not to be enrolled in the phase 1b portion of the study:

  12. More than 3 prior chemotherapy regimens for locally advanced or metastatic disease.

    Phase 2 Only: In addition to the previously mentioned exclusion criteria, patients meeting the following exclusion criterion are not to be enrolled in the phase 2 portion of the study:

  13. More than 1 prior chemotherapy regimen for locally advanced or metastatic disease.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02049957


Locations
Show Show 40 study locations
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
Layout table for investigator information
Study Director: Medical Monitor Millennium Pharmaceuticals, Inc.
  Study Documents (Full-Text)

Documents provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Study Protocol  [PDF] October 26, 2017
Statistical Analysis Plan  [PDF] July 23, 2018

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02049957    
Other Study ID Numbers: C31001
2014-001921-34 ( EudraCT Number )
U1111-1195-3894 ( Registry Identifier: WHO )
First Posted: January 30, 2014    Key Record Dates
Results First Posted: January 27, 2020
Last Update Posted: January 5, 2021
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
URL: https://vivli.org/ourmember/takeda/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Sapanisertib
MLN0128
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Fulvestrant
Exemestane
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action