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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Sapanisertib
* Drug: Fulvestrant
* Drug: Exemestane


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Each patient must meet all of the following inclusion criteria to be enrolled in the study: Phase 1b and Phase 2 Advanced or metastatic breast cancer. 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. 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. 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 Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. 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 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). 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. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and suitable venous access for the study-required blood sampling. 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: 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: 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 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 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. 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. 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). Previous treatment with dual PI3K/mTOR inhibitors or TORC1/2 inhibitors. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of MLN0128. 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. 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. Known human immunodeficiency virus infection. 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 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) 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: 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: More than 1 prior chemotherapy regimen for locally advanced or metastatic disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane<br>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<br>* Sapnisertib capsules<br>* Other names: MLN0128;Drug: Exemestane<br>* Exemestane tablets.<br>|
| Experimental: Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant<br>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<br>* Sapnisertib capsules<br>* Other names: MLN0128;Drug: Fulvestrant<br>* Fulvestrant IM injection.<br>|
| Experimental: Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane<br>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<br>* Sapnisertib capsules<br>* Other names: MLN0128;Drug: Exemestane<br>* Exemestane tablets.<br>|
| Experimental: Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant<br>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<br>* Sapnisertib capsules<br>* Other names: MLN0128;Drug: Fulvestrant<br>* Fulvestrant IM injection.<br>|
| Experimental: Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane<br>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<br>* Sapnisertib capsules<br>* Other names: MLN0128;Drug: Exemestane<br>* Exemestane tablets.<br>|
| Experimental: Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)<br>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<br>* Sapnisertib capsules<br>* Other names: MLN0128;Drug: Exemestane<br>* Exemestane tablets.<br>|
| Experimental: Phase 2:Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)<br>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<br>* Sapnisertib capsules<br>* Other names: MLN0128;Drug: Fulvestrant<br>* Fulvestrant IM injection.<br>|
| Experimental: Phase 2: Sapanisertib 4 mg+Exemestane (Everolimus Resistant)<br>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<br>* Sapnisertib capsules<br>* Other names: MLN0128;Drug: Exemestane<br>* Exemestane tablets.<br>|
| Experimental: Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)<br>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<br>* Sapnisertib capsules<br>* Other names: MLN0128;Drug: Fulvestrant<br>* Fulvestrant IM injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | First dose of study drug through 30 days after the last dose (Up to 52 months) | 
| 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). | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 24 | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | Up to 24 months | 
| 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 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: 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. | Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose, extrapolated to 24 hours post-dose | 
| 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. | Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose, extrapolated to last timepoint | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sapanisertib, MLN0128