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
NCT ID: NCT02049957
Last Updated: 2023-02-08
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
118 participants
INTERVENTIONAL
2014-02-13
2018-06-29
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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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).
Sapanisertib
Sapnisertib capsules
Exemestane
Exemestane tablets.
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).
Sapanisertib
Sapnisertib capsules
Fulvestrant
Fulvestrant IM injection.
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).
Sapanisertib
Sapnisertib capsules
Exemestane
Exemestane tablets.
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).
Sapanisertib
Sapnisertib capsules
Fulvestrant
Fulvestrant IM injection.
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).
Sapanisertib
Sapnisertib capsules
Exemestane
Exemestane tablets.
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.
Sapanisertib
Sapnisertib capsules
Exemestane
Exemestane tablets.
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.
Sapanisertib
Sapnisertib capsules
Fulvestrant
Fulvestrant IM injection.
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.
Sapanisertib
Sapnisertib capsules
Exemestane
Exemestane tablets.
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.
Sapanisertib
Sapnisertib capsules
Fulvestrant
Fulvestrant IM injection.
Interventions
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Sapanisertib
Sapnisertib capsules
Fulvestrant
Fulvestrant IM injection.
Exemestane
Exemestane tablets.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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.
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.
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
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.
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.
12. More than 3 prior chemotherapy regimens for locally advanced or metastatic disease.
13. More than 1 prior chemotherapy regimen for locally advanced or metastatic disease.
18 Years
FEMALE
No
Sponsors
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Calithera Biosciences, Inc
INDUSTRY
Responsible Party
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Principal Investigators
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Medical Monitor
Role: STUDY_DIRECTOR
Millennium Pharmaceuticals, Inc.
Locations
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Los Angeles Hematology
Los Angeles, California, United States
University of California at San Francisco (PARENT)
San Francisco, California, United States
Santa Barbara Hematology Oncology Medical Group, Inc.
Santa Barbara, California, United States
University of Colorado Cancer Center
Aurora, Colorado, United States
Rocky Mountain Cancer Centers, LLP
Lakewood, Colorado, United States
Mount Sinai Medical Center
Miami Beach, Florida, United States
Florida Cancer Research Institute
Plantation, Florida, United States
University of Kansas Medical Center Research Institute, Inc.
Westwood, Kansas, United States
Holy Cross Hospital
Silver Spring, Maryland, United States
Henry Ford Medical Center
Novi, Michigan, United States
University of Minnesota
Minneapolis, Minnesota, United States
Mayo Clinic
Rochester, Minnesota, United States
Roswell Park Cancer Institute
Buffalo, New York, United States
Herbert Irving Comprehensive Cancer Center
New York, New York, United States
Weill Cornell Medical College New York Presbyterian Hospital
New York, New York, United States
Eastchester Center for Cancer Care / BRANY
The Bronx, New York, United States
University of Cincinnati Physicians Company, LLC
Cincinnati, Ohio, United States
University Hospitals of Cleveland
Cleveland, Ohio, United States
Erlanger Medical Center
Chattanooga, Tennessee, United States
Texas Oncology, P.A. - Beaumont
Beaumont, Texas, United States
Texas Oncology, P.A.
Dallas, Texas, United States
UT Southwestern Medical Center
Dallas, Texas, United States
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Millennium Oncology
Houston, Texas, United States
Texas Health Physicians Group
Plano, Texas, United States
Cancer Care Network of South Texas - SAT&BC
San Antonio, Texas, United States
Texas Oncology, P.A. - Tyler
Tyler, Texas, United States
Virginia Oncology Associates - Hampton
Chesapeake, Virginia, United States
Oncology and Hematology Assoc. of SW VA, Inc.
Salem, Virginia, United States
West Virginia University
Morgantown, West Virginia, United States
UZ Antwerpen
Antwerp, , Belgium
Institut Jules Bordet
Brussels, , Belgium
Universitair Ziekenhuis Brussel
Brussels, , Belgium
GHdC Notre Dame
Charleroi, , Belgium
Centre Hospitalier de l'Ardenne
Libramont, , Belgium
GZA Ziekenhuizen - Campus Sint-Augustinus
Wilrijk, , Belgium
Centre Francois Baclesse
Caen, Calvados, France
Centre Catherine de Sienne
Nantes, Loire Atlantique, France
Clinique Victor Hugo - Centre Jean Bernard
Le Mans, Sarthe, France
Institut Sainte Catherine
Avignon, Vaculuse, France
Countries
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References
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Lim B, Potter DA, Salkeni MA, Silverman P, Haddad TC, Forget F, Awada A, Canon JL, Danso M, Lortholary A, Bourgeois H, Tan-Chiu E, Vincent S, Bahamon B, Galinsky KJ, Patel C, Neuwirth R, Leonard EJ, Diamond JR. Sapanisertib Plus Exemestane or Fulvestrant in Women with Hormone Receptor-Positive/HER2-Negative Advanced or Metastatic Breast Cancer. Clin Cancer Res. 2021 Jun 15;27(12):3329-3338. doi: 10.1158/1078-0432.CCR-20-4131. Epub 2021 Apr 5.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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2014-001921-34
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
U1111-1195-3894
Identifier Type: REGISTRY
Identifier Source: secondary_id
C31001
Identifier Type: -
Identifier Source: org_study_id
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