Breast Cancer
Conditions
Keywords
Sapanisertib, MLN0128
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.
Interventions
DRUGSapanisertib
Sapnisertib capsules
DRUGFulvestrant
Fulvestrant IM injection.
DRUGExemestane
Exemestane tablets.
Sponsors
Calithera Biosciences, Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| Phase 2: Best Percent Change From Baseline in Tumor Size | Baseline to Month 24 | — |
| 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: 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 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 1: Terminal Elimination Half-life (T1/2) for Sapanisertib | Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose | — |
| 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 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. |
Countries
Belgium, France, United States
Participant flow
Recruitment details
Participants took part in the study at 40 investigative sites in Belgium, France and the United States from 13 February 2014 to 03 July 2018.
Pre-assignment details
Postmenopausal women with estrogen receptor positive/human epidermal growth factor receptor-2 negative advanced/metastatic breast cancer who progressed with everolimus (everolimus sensitive-achieved CR/PR of any duration/stable disease for ≥6 months; resistant-without CR/PR/SD \< 6 months) were enrolled to receive MLN0128+exemestane/fulvestrant.
Participants by arm
| Arm | Count |
|---|---|
| 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). | 6 |
| 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). | 6 |
| 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). | 3 |
| 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). | 3 |
| 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). | 6 |
| 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. | 43 |
| 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. | 8 |
| Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant) 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 12 cycles) in everolimus resistant participants. | 35 |
| 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. | 8 |
| Total | 118 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 | 0 | 0 | 5 | 0 | 6 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Progressive Disease | 5 | 4 | 2 | 2 | 6 | 35 | 7 | 26 | 6 |
| Overall Study | Study Terminated by Sponsor | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 3 | 1 |
Baseline characteristics
| Characteristic | Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant | Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | Total | Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant) | Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant) | Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive) | Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive) | Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane | Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 56.2 years | 61.3 years | 57.31 years | 58.5 years | 58.8 years | 52.1 years | 58.9 years | 59.5 years | 52.3 years | 54.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 103 Participants | 7 Participants | 29 Participants | 8 Participants | 36 Participants | 5 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 11 Participants | 1 Participants | 6 Participants | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 165.7 cm | 167.1 cm | 165.02 cm | 163.7 cm | 164.5 cm | 165.7 cm | 163.5 cm | 161.1 cm | 170.8 cm | 167.0 cm |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 4 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 7 Participants | 0 Participants | 1 Participants | 0 Participants | 4 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 0 Participants | 6 Participants | 0 Participants | 5 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 6 Participants | 98 Participants | 8 Participants | 25 Participants | 8 Participants | 36 Participants | 6 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Belgium | 0 Participants | 0 Participants | 16 Participants | 0 Participants | 7 Participants | 0 Participants | 9 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment France | 0 Participants | 0 Participants | 7 Participants | 0 Participants | 3 Participants | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 6 Participants | 6 Participants | 95 Participants | 8 Participants | 25 Participants | 8 Participants | 30 Participants | 6 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 118 Participants | 8 Participants | 35 Participants | 8 Participants | 43 Participants | 6 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Weight | 69.45 kg | 69.18 kg | 70.37 kg | 82.10 kg | 71.60 kg | 67.45 kg | 72.10 kg | 63.63 kg | 64.34 kg | 70.57 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 3 | 0 / 3 | 1 / 6 | 0 / 43 | 0 / 35 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 3 / 3 | 3 / 3 | 6 / 6 | 43 / 43 | 35 / 35 | 8 / 8 | 8 / 8 |
| serious Total, serious adverse events | 1 / 6 | 2 / 6 | 0 / 3 | 0 / 3 | 2 / 6 | 11 / 43 | 5 / 35 | 3 / 8 | 2 / 8 |
Outcome results
Primary
Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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.
Time frame: First dose of study drug through 30 days after the last dose (Up to 52 months)
Population: Safety Population included participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 6 Participants |
| Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant | Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant | Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 6 Participants |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 3 Participants |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 3 Participants |
| Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane | Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 6 Participants |
| Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane | Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
Primary
Phase 2: Clinical Benefit Rate at 16 Weeks (CBR-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).
Time frame: Week 16
Population: Response-Evaluable Population included participants who received at least 1 dose of study drug and had measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | Phase 2: Clinical Benefit Rate at 16 Weeks (CBR-16) | 44 percentage of participants |
| Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant | Phase 2: Clinical Benefit Rate at 16 Weeks (CBR-16) | 50 percentage of participants |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | Phase 2: Clinical Benefit Rate at 16 Weeks (CBR-16) | 23 percentage of participants |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | Phase 2: Clinical Benefit Rate at 16 Weeks (CBR-16) | 25 percentage of participants |
Secondary
Phase 1: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Sapanisertib
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.
Time frame: Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose, extrapolated to 24 hours post-dose
Population: Participants from PK Population included participants with sufficient dosing and PK data to reliably estimate PK parameters. PK data was not available for Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant arm group at Cycle 1 Day 15. Number analyzed is the number of participants with data available for analyses at the given timepoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | Phase 1: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Sapanisertib | 577.081 h*ng/mL | Standard Deviation 331.9813 |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | Phase 1: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Sapanisertib | 178.063 h*ng/mL | Standard Deviation 46.1416 |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | Phase 1: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Sapanisertib | 332.618 h*ng/mL | Standard Deviation 228.5641 |
| Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane | Phase 1: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Sapanisertib | 277.626 h*ng/mL | Standard Deviation 64.0661 |
Secondary
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
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.
Time frame: Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose, extrapolated to last timepoint
Population: PK Population included participants with sufficient dosing and PK data to reliably estimate PK parameters. PK data was not available for Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant arm group at Cycle 1 Day 15. Number analyzed is the number of participants with data available for analyses at the given timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | 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 | 577.081 h*ng/mL | Standard Deviation 331.9813 |
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | 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 2 | 101.599 h*ng/mL | Standard Deviation 51.0248 |
| Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant | 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 2 | 109.496 h*ng/mL | Standard Deviation 82.3968 |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | 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 2 | 89.576 h*ng/mL | Standard Deviation 15.0117 |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | 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 | 164.123 h*ng/mL | Standard Deviation 52.6287 |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | 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 | 332.618 h*ng/mL | Standard Deviation 228.5641 |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | 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 2 | 109.548 h*ng/mL | Standard Deviation 52.85 |
| Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane | 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 | 251.165 h*ng/mL | Standard Deviation 83.7121 |
| Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane | 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 2 | 116.557 h*ng/mL | Standard Deviation 8.6059 |
Secondary
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
Population: Pharmacokinetic (PK) Population included participants with sufficient dosing and PK data to reliably estimate PK parameters. PK data was not available for Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant arm group at Cycle 1 Day 15. Number analyzed is the number of participants with data available for analyses at the given timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib | Cycle 1 Day 15 | 57.72 ng/mL | Standard Deviation 9.927 |
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib | Cycle 2 Day 1 | 38.68 ng/mL | Standard Deviation 20.551 |
| Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant | Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib | Cycle 2 Day 1 | 44.96 ng/mL | Standard Deviation 34.459 |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib | Cycle 2 Day 1 | 43.47 ng/mL | Standard Deviation 0.874 |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib | Cycle 1 Day 15 | 47.40 ng/mL | Standard Deviation 6.583 |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib | Cycle 1 Day 15 | 50.90 ng/mL | Standard Deviation 23.476 |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib | Cycle 2 Day 1 | 45.30 ng/mL | Standard Deviation 16.235 |
| Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane | Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib | Cycle 1 Day 15 | 45.37 ng/mL | Standard Deviation 9.644 |
| Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane | Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib | Cycle 2 Day 1 | 44.68 ng/mL | Standard Deviation 8.636 |
Secondary
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
Population: Participants from PK Population, participants with sufficient dosing and PK data to reliably estimate PK parameters. PK data was not available for Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant arm group at Cycle 1 Day 15.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | Phase 1: Terminal Elimination Half-life (T1/2) for Sapanisertib | 6.639 hour | Standard Deviation 1.2176 |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | Phase 1: Terminal Elimination Half-life (T1/2) for Sapanisertib | 3.161 hour | Standard Deviation 1.6585 |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | Phase 1: Terminal Elimination Half-life (T1/2) for Sapanisertib | 7.777 hour | Standard Deviation 2.9177 |
| Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane | Phase 1: Terminal Elimination Half-life (T1/2) for Sapanisertib | 5.370 hour | Standard Deviation 1.4638 |
Secondary
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
Population: PK Population included participants with sufficient dosing and PK data to reliably estimate PK parameters. PK data was not available for Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant arm group at Cycle 1 Day 15. Number analyzed is the number of participants with data available for analyses at the given timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib | Cycle 1 Day 15 | 3.005 hour |
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib | Cycle 2 Day 1 | 2.280 hour |
| Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib | Cycle 2 Day 1 | 3.500 hour |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib | Cycle 1 Day 15 | 0.600 hour |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib | Cycle 2 Day 1 | 0.980 hour |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib | Cycle 1 Day 15 | 1.035 hour |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib | Cycle 2 Day 1 | 1.000 hour |
| Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib | Cycle 2 Day 1 | 2.000 hour |
| Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib | Cycle 1 Day 15 | 2.000 hour |
Secondary
Phase 2: Best Percent Change From Baseline in Tumor Size
Time frame: Baseline to Month 24
Population: Participants from Safety Population included participants who received at least 1 dose of study drug and provided both baseline and at least one post-baseline disease response.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | Phase 2: Best Percent Change From Baseline in Tumor Size | -0.46 percentage change in tumor size | Standard Deviation 34.89 |
| Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant | Phase 2: Best Percent Change From Baseline in Tumor Size | 0.96 percentage change in tumor size | Standard Deviation 38.98 |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | Phase 2: Best Percent Change From Baseline in Tumor Size | 1.76 percentage change in tumor size | Standard Deviation 31.14 |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | Phase 2: Best Percent Change From Baseline in Tumor Size | -18.91 percentage change in tumor size | Standard Deviation 19.71 |
Secondary
Phase 2: Clinical Benefit Rate at 24 Weeks (CBR-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.
Time frame: Week 24
Population: Response-Evaluable Population included participants who received at least 1 dose of study drug and had measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | Phase 2: Clinical Benefit Rate at 24 Weeks (CBR-24) | 28 percentage of participants |
| Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant | Phase 2: Clinical Benefit Rate at 24 Weeks (CBR-24) | 38 percentage of participants |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | Phase 2: Clinical Benefit Rate at 24 Weeks (CBR-24) | 23 percentage of participants |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | Phase 2: Clinical Benefit Rate at 24 Weeks (CBR-24) | 25 percentage of participants |
Secondary
Phase 2: Overall Response Rate (ORR)
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.
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)
Population: Response-Evaluable Population included participants who received at least 1 dose of study drug and had measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | Phase 2: Overall Response Rate (ORR) | 7 percentage of participants |
| Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant | Phase 2: Overall Response Rate (ORR) | 13 percentage of participants |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | Phase 2: Overall Response Rate (ORR) | 0 percentage of participants |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | Phase 2: Overall Response Rate (ORR) | 13 percentage of participants |
Secondary
Phase 2: Overall Survival (OS)
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.
Time frame: Up to 24 months
Population: Safety Population included participants who received at least 1 dose of study drug. Participants without documentation of death at the time of analysis were censored at the date last known to be alive.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | Phase 2: Overall Survival (OS) | 15.9 months |
| Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant | Phase 2: Overall Survival (OS) | 20.7 months |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | Phase 2: Overall Survival (OS) | 14.0 months |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | Phase 2: Overall Survival (OS) | 13.0 months |
Secondary
Phase 2: Progression-Free Survival (PFS)
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.
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)
Population: Safety Population included participants who received at least 1 dose of study drug. For a participant whose disease had not progressed and was last known to be alive, PFS was censored at the last response assessment that was stable disease or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane | Phase 2: Progression-Free Survival (PFS) | 4.1 months |
| Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant | Phase 2: Progression-Free Survival (PFS) | 5.5 months |
| Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane | Phase 2: Progression-Free Survival (PFS) | 3.3 months |
| Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant | Phase 2: Progression-Free Survival (PFS) | 5.4 months |