Clinical trial NCT02049957: 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
Official title: A Phase 1b/2 Study of Safety and Efficacy of MLN0128 (Dual TORC1/2 Inhibitor) in Combination With Exemestane or Fulvestrant Therapy in Postmenopausal Women With ER+/HER2- Advanced or Metastatic Breast Cancer That Has Progressed on Treatment With Everolimus in Combination With Exemestane or Fulvestrant
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: Sapanisertib
MLN0128
Lead sponsor: Calithera Biosciences, Inc
Sponsor class: INDUSTRY
First posted: 2014-01-30
Enrollment: 118
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria

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

Phase 1b and Phase 2

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

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

   Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression.
4. Have a history of brain metastasis are eligible for the study provided that all the following criteria are met:

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

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

    Phase 1b Only: In addition to the previously mentioned inclusion criteria, each patient must meet the following inclusion criterion to be enrolled in the phase 1b portion of the study:
11. Patients may have SD or disease progression during their most recent treatment with exemestane or fulvestrant, or everolimus in combination with either exemestane (any country) or fulvestrant (US only). Exemestane or fulvestrant in combination with MLN0128 can also be initiated as a new line of therapy.

    Phase 2 Only: In addition to the previously mentioned inclusion criteria, each patient must meet all of the following inclusion criteria to be enrolled in the phase 2 portion of the study:
12. Measurable disease defined as follows:

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

Exclusion Criteria

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

Phase 1b and Phase 2

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

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

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

    Phase 1b Only: In addition to the previously mentioned exclusion criteria, patients meeting the following exclusion criterion are not to be enrolled in the phase 1b portion of the study:
12. More than 3 prior chemotherapy regimens for locally advanced or metastatic disease.

    Phase 2 Only: In addition to the previously mentioned exclusion criteria, patients meeting the following exclusion criterion are not to be enrolled in the phase 2 portion of the study:
13. More than 1 prior chemotherapy regimen for locally advanced or metastatic disease.

Primary outcomes:
measure: Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: First dose of study drug through 30 days after the last dose (Up to 52 months)
measure: Phase 2: Clinical Benefit Rate at 16 Weeks (CBR-16)
timeFrame: Week 16
Secondary outcomes:
measure: Phase 2: Clinical Benefit Rate at 24 Weeks (CBR-24)
timeFrame: Week 24
measure: Phase 2: Overall Response Rate (ORR)
timeFrame: 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)
measure: Phase 2: Progression-Free Survival (PFS)
timeFrame: 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)
measure: Phase 2: Overall Survival (OS)
timeFrame: Up to 24 months
measure: Phase 2: Best Percent Change From Baseline in Tumor Size
timeFrame: Baseline to Month 24
measure: Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib
timeFrame: Cycle 1 Day 15 and Cycle 2 Day 1 pre-dose and multiple timepoints (Up to 8 hours) post-dose
measure: Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib
timeFrame: Cycle 1 Day 15 and Cycle 2 Day 1 pre-dose and multiple timepoints (Up to 8 hours) post-dose
measure: Phase 1: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for Sapanisertib
timeFrame: Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose, extrapolated to 24 hours post-dose
measure: 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
timeFrame: Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose, extrapolated to last timepoint
measure: Phase 1: Terminal Elimination Half-life (T1/2) for Sapanisertib
timeFrame: Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Los Angeles Hematology
state: California
city: San Francisco
country: United States
facility: University of California at San Francisco (PARENT)
state: California
city: Santa Barbara
country: United States
facility: Santa Barbara Hematology Oncology Medical Group, Inc.
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Lakewood
country: United States
facility: Rocky Mountain Cancer Centers, LLP
state: Colorado
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center
state: Florida
city: Plantation
country: United States
facility: Florida Cancer Research Institute
state: Florida
city: Westwood
country: United States
facility: University of Kansas Medical Center Research Institute, Inc.
state: Kansas
city: Silver Spring
country: United States
facility: Holy Cross Hospital
state: Maryland
city: Novi
country: United States
facility: Henry Ford Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Bronx
country: United States
facility: Eastchester Center for Cancer Care / BRANY
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College New York Presbyterian Hospital
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati Physicians Company, LLC
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals of Cleveland
state: Ohio
city: Chattanooga
country: United States
facility: Erlanger Medical Center
state: Tennessee
city: Beaumont
country: United States
facility: Texas Oncology, P.A. - Beaumont
state: Texas
city: Dallas
country: United States
facility: Texas Oncology, P.A.
state: Texas
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: Millennium Oncology
state: Texas
city: Plano
country: United States
facility: Texas Health Physicians Group
state: Texas
city: San Antonio
country: United States
facility: Cancer Care Network of South Texas - SAT&BC
state: Texas
city: Tyler
country: United States
facility: Texas Oncology, P.A. - Tyler
state: Texas
city: Chesapeake
country: United States
facility: Virginia Oncology Associates - Hampton
state: Virginia
city: Salem
country: United States
facility: Oncology and Hematology Assoc. of SW VA, Inc.
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: Antwerpen
country: Belgium
facility: UZ Antwerpen
city: Bruxelles
country: Belgium
facility: Institut Jules Bordet
city: Bruxelles
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Charleroi
country: Belgium
facility: GHdC Notre Dame
city: Libramont
country: Belgium
facility: Centre Hospitalier de l'Ardenne
city: Wilrijk
country: Belgium
facility: GZA Ziekenhuizen - Campus Sint-Augustinus
city: Caen Cedex 05
country: France
facility: Centre Francois Baclesse
state: Calvados
city: Nantes
country: France
facility: Centre Catherine de Sienne
state: Loire Atlantique
city: Le Mans Cedex 02
country: France
facility: Clinique Victor Hugo - Centre Jean Bernard
state: Sarthe
city: Avignon
country: France
facility: Institut Sainte Catherine
state: Vaculuse
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: 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.