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
- Conditions
- Breast Cancer
- Interventions
- Registration Number
- NCT02049957
- Lead Sponsor
- Calithera Biosciences, 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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 118
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant Sapanisertib 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). Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive) Sapanisertib 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. Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant 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). Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane Sapanisertib 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). Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane 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). Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane 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). Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant 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). Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane Sapanisertib 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). Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane 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). Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant Sapanisertib 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). Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane Sapanisertib 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). Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive) 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 14 cycles) in everolimus sensitive participants. Phase 2:Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive) Fulvestrant 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. Phase 2:Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive) Sapanisertib 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. Phase 2: Sapanisertib 4 mg+Exemestane (Everolimus Resistant) Exemestane 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. Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant) Sapanisertib 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. Phase 2: Sapanisertib 4 mg+Exemestane (Everolimus Resistant) Sapanisertib 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. Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant) Fulvestrant 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.
- Primary Outcome Measures
Name Time Method Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) 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.Phase 2: Clinical Benefit Rate at 16 Weeks (CBR-16) 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
Name Time Method Phase 1: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Sapanisertib 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.
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 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.
Phase 2: Clinical Benefit Rate at 24 Weeks (CBR-24) 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.
Phase 2: Progression-Free Survival (PFS) 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.
Phase 2: Overall Response Rate (ORR) 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.
Phase 2: Overall Survival (OS) 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.
Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib Cycle 1 Day 15 and Cycle 2 Day 1 pre-dose and multiple timepoints (Up to 8 hours) post-dose Phase 2: Best Percent Change From Baseline in Tumor Size Baseline to Month 24 Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib Cycle 1 Day 15 and Cycle 2 Day 1 pre-dose and multiple timepoints (Up to 8 hours) post-dose Phase 1: Terminal Elimination Half-life (T1/2) for Sapanisertib Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose
Trial Locations
- Locations (40)
Henry Ford Medical Center
🇺🇸Novi, Michigan, United States
Texas Oncology, P.A. - Tyler
🇺🇸Tyler, Texas, United States
Institut Sainte Catherine
🇫🇷Avignon, Vaculuse, France
University of Cincinnati Physicians Company, LLC
🇺🇸Cincinnati, Ohio, United States
Millennium Oncology
🇺🇸Houston, Texas, United States
The University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
UZ Antwerpen
🇧🇪Antwerpen, Belgium
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
University of Kansas Medical Center Research Institute, Inc.
🇺🇸Westwood, Kansas, United States
Rocky Mountain Cancer Centers, LLP
🇺🇸Lakewood, Colorado, United States
University of California at San Francisco (PARENT)
🇺🇸San Francisco, California, United States
GHdC Notre Dame
🇧🇪Charleroi, Belgium
Los Angeles Hematology
🇺🇸Los Angeles, California, United States
Santa Barbara Hematology Oncology Medical Group, Inc.
🇺🇸Santa Barbara, California, United States
Florida Cancer Research Institute
🇺🇸Plantation, Florida, United States
Mount Sinai Medical Center
🇺🇸Miami Beach, Florida, United States
Holy Cross Hospital
🇺🇸Silver Spring, Maryland, United States
Eastchester Center for Cancer Care / BRANY
🇺🇸Bronx, New York, United States
Weill Cornell Medical College New York Presbyterian Hospital
🇺🇸New York, New York, United States
Herbert Irving Comprehensive Cancer Center
🇺🇸New York, New York, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
UT Southwestern Medical Center
🇺🇸Dallas, Texas, United States
University Hospitals of Cleveland
🇺🇸Cleveland, Ohio, United States
Texas Oncology, P.A. - Beaumont
🇺🇸Beaumont, Texas, United States
Texas Oncology, P.A.
🇺🇸Dallas, Texas, United States
Erlanger Medical Center
🇺🇸Chattanooga, Tennessee, United States
Cancer Care Network of South Texas - SAT&BC
🇺🇸San Antonio, Texas, United States
Texas Health Physicians Group
🇺🇸Plano, Texas, United States
Virginia Oncology Associates - Hampton
🇺🇸Chesapeake, Virginia, United States
Oncology and Hematology Assoc. of SW VA, Inc.
🇺🇸Salem, Virginia, United States
Institut Jules Bordet
🇧🇪Bruxelles, Belgium
Universitair Ziekenhuis Brussel
🇧🇪Bruxelles, Belgium
Centre Hospitalier de l'Ardenne
🇧🇪Libramont, Belgium
GZA Ziekenhuizen - Campus Sint-Augustinus
🇧🇪Wilrijk, Belgium
Centre Francois Baclesse
🇫🇷Caen Cedex 05, Calvados, France
Clinique Victor Hugo - Centre Jean Bernard
🇫🇷Le Mans Cedex 02, Sarthe, France
Centre Catherine de Sienne
🇫🇷Nantes, Loire Atlantique, France
West Virginia University
🇺🇸Morgantown, West Virginia, United States
University of Colorado Cancer Center
🇺🇸Aurora, Colorado, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States