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

Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02049957
• Other study ID #: C31001
• Secondary ID: 2014-001921-34U1
• Status: Completed
• Phase: Phase 2
• Start date: February 13, 2014
• Est. completion date: June 29, 2018

Study information

• Verified date: February 2023
• Source: Calithera Biosciences, Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 118
• Est. completion date: June 29, 2018
• Est. primary completion date: June 29, 2018
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Sapanisertib
Sapnisertib capsules
• Fulvestrant
Fulvestrant IM injection.
• Exemestane
Exemestane tablets.

Locations

Country	Name	City	State
Belgium	UZ Antwerpen	Antwerpen
Belgium	Institut Jules Bordet	Bruxelles
Belgium	Universitair Ziekenhuis Brussel	Bruxelles
Belgium	GHdC Notre Dame	Charleroi
Belgium	Centre Hospitalier de l'Ardenne	Libramont
Belgium	GZA Ziekenhuizen - Campus Sint-Augustinus	Wilrijk
France	Institut Sainte Catherine	Avignon	Vaculuse
France	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
United States	University of Colorado Cancer Center	Aurora	Colorado
United States	Texas Oncology, P.A. - Beaumont	Beaumont	Texas
United States	Eastchester Center for Cancer Care / BRANY	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Erlanger Medical Center	Chattanooga	Tennessee
United States	Virginia Oncology Associates - Hampton	Chesapeake	Virginia
United States	University of Cincinnati Physicians Company, LLC	Cincinnati	Ohio
United States	University Hospitals of Cleveland	Cleveland	Ohio
United States	Texas Oncology, P.A.	Dallas	Texas
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Millennium Oncology	Houston	Texas
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Rocky Mountain Cancer Centers, LLP	Lakewood	Colorado
United States	Los Angeles Hematology	Los Angeles	California
United States	Mount Sinai Medical Center	Miami Beach	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	West Virginia University	Morgantown	West Virginia
United States	Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Weill Cornell Medical College New York Presbyterian Hospital	New York	New York
United States	Henry Ford Medical Center	Novi	Michigan
United States	Texas Health Physicians Group	Plano	Texas
United States	Florida Cancer Research Institute	Plantation	Florida
United States	Mayo Clinic	Rochester	Minnesota
United States	Oncology and Hematology Assoc. of SW VA, Inc.	Salem	Virginia
United States	Cancer Care Network of South Texas - SAT&BC	San Antonio	Texas
United States	University of California at San Francisco (PARENT)	San Francisco	California
United States	Santa Barbara Hematology Oncology Medical Group, Inc.	Santa Barbara	California
United States	Holy Cross Hospital	Silver Spring	Maryland
United States	Texas Oncology, P.A. - Tyler	Tyler	Texas
United States	University of Kansas Medical Center Research Institute, Inc.	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Calithera Biosciences, Inc

Countries where clinical trial is conducted

United States,  Belgium,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	First dose of study drug through 30 days after the last dose (Up to 52 months)
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).	Week 16
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.	Week 24
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.	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)
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.	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)
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.	Up to 24 months
Secondary	Phase 2: Best Percent Change From Baseline in Tumor Size		Baseline to Month 24
Secondary	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
Secondary	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
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.	Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose, extrapolated to 24 hours post-dose
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.	Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose, extrapolated to last timepoint
Secondary	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