Sapanisertib in Combination With Fulvestrant in Women With Advanced or Metastatic Breast Cancer After Aromatase Inhibitor Therapy

Phase 2

Completed

Conditions: Breast Neoplasms

Interventions: Drug: Fulvestrant
Drug: Sapanisertib

Registration Number: NCT02756364

Lead Sponsor: Calithera Biosciences, Inc

Brief Summary: The primary purpose of this study is to compare the progression free survival (PFS) of participants treated with the combination of fulvestrant plus daily sapanisertib and fulvestrant plus weekly sapanisertib versus participants treated with single-agent fulvestrant.

Detailed Description: The drug being tested in this study is called sapanisertib. Sapanisertib is being tested to treat postmenopausal women with advanced or metastatic estrogen receptor (ER) positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer that has progressed during or after aromatase inhibitor (AI) therapy. This study will evaluate the efficacy and safety of combination of fulvestrant + daily sapanisertib and fulvestrant + weekly sapanisertib compared with fulvestrant alone.

The study will enroll approximately 153 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* Fulvestrant 500 mg

* Fulvestrant 500 mg + Sapanisertib 4 mg

* Fulvestrant 500 mg + Sapanisertib 30 mg

All participants will receive either fulvestrant 500 mg intramuscularly (IM), fulvestrant 500 mg + sapanisertib 4 mg daily or fulvestrant 500 mg + sapanisertib 30 mg weekly.

This multicenter trial will be conducted Spain and the USA. Participants will make multiple visits to the clinic, and end of treatment (EOT) visit which will occur 30 to 40 days after receiving their last dose of study drug or before the start of any subsequent anticancer therapy. After EOT, participants will be followed for progression free survival (PFS) and overall survival (OS).

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 141

Inclusion Criteria

Female participants aged 18 years or older who are postmenopausal.
Histologically proven diagnosis of breast cancer with evidence of metastatic disease or locoregional recurrence.
Histological confirmation and documentation of estrogen receptor (ER)-positive status (≥1% positive stained cells).
Histological or cytological confirmation and documentation of human epidermal growth factor receptor-2 (HER2)-negative status by local laboratory testing using criteria in the American Society of Oncology (ASCO)/College of American Pathologists (CAP) Clinical Practice Guideline update.
Measurable disease defined as either of the following:
- At least 1 extra-osseous lesion that could be accurately measured in at least 1 dimension.
- The lesion must have measured ≥20 mm with conventional imaging techniques or ≥10 mm with spiral CT or MRI. Lymph nodes must be ≥1.5 cm in the short axis to be considered measurable.
- Bone lesions (lytic or mixed [lytic plus sclerotic]) in the absence of measurable disease as defined above. Note: Participants with sclerotic/osteoblastic bone lesions only, in the absence of measurable disease, were not eligible.
Progressive Disease (PD) during prior aromatase inhibitor (AI) therapy.
Have a history of brain metastasis provided that all of the following criteria are met:
- Brain metastases have been treated.
- No evidence of PD for ≥3 months before the first dose of study drug.
- No hemorrhage after treatment.
- Off dexamethasone treatment for ≥4 weeks before the first dose of study drug.
- No ongoing requirement for dexamethasone or anti-epileptic drugs.
Eastern cooperative oncology group (ECOG) performance status of 0 or 1.
Clinical laboratory values as specified below within 4 weeks before the first dose of study drug:
- Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥1.5*10^9/L; platelet count ≥100*10^9/L; hemoglobin (Hgb) ≥9 g/dL.
- Total bilirubin ≤1.5*the upper limit of the normal range (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5*ULN (≤5*ULN if liver metastases are present).
- Creatinine clearance ≥40 mL/min based 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.

Exclusion Criteria

Prior therapy with mechanistic target of rapamycin (mTOR), phosphoinositide-3-kinase (PI3K), or dual PI3K-mTOR inhibitors, serine/threonine-specific protein kinase (AKT) inhibitors, or fulvestrant.
Prior treatment with >1 line of chemotherapy for metastatic breast cancer or for locoregional recurrence that was not amenable to resection or radiation therapy with curative intent.
Experienced PD on >2 endocrine therapies for metastatic breast cancer or for locoregional recurrence that was not amenable to resection or radiation therapy with curative intent.
Life-threatening metastatic visceral disease (defined as extensive hepatic involvement or symptomatic pulmonary lymphangitic spread).
Poorly controlled diabetes mellitus defined as hemoglobin A1c (glycosylated hemoglobin; HbA1c) >7%; participants with a history of transient glucose intolerance due to corticosteroid administration may be eligible if all other inclusion/exclusion criteria are met.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fulvestrant 500 mg	Fulvestrant	Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks).
Fulvestrant 500 mg + Sapanisertib 4 mg	Fulvestrant	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).
Fulvestrant 500 mg + Sapanisertib 30 mg	Fulvestrant	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).
Fulvestrant 500 mg + Sapanisertib 4 mg	Sapanisertib	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).
Fulvestrant 500 mg + Sapanisertib 30 mg	Sapanisertib	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	Up to 40 months	PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Up to 40 months	ORR was defined as the percentage of participants who achieve a best response of complete response (CR) or partial response (PR) according to RECIST v1.1 criteria. CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
Clinical Benefit Rate (CBR)	Up to 40 months	CBR was defined as the percentage of participants who achieved a best response of CR, PR, or stable disease (SD) of any duration. CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Percentage of Participants Who Experienced at Least One Treatment-emergent Adverse Event (TEAE)	Up to 164 weeks	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Overall Survival (OS)	Up to 164 weeks	OS was defined as the time from the date of randomization to the date of death.
Time to Progression (TTP)	Up to 40 months	TTP was defined as the time from the date of randomization to the date of first documentation of progression. Per RECIST v1.1, PD was defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Trial Locations

Locations (52): New England Cancer Specialists
🇺🇸
Scarborough, Maine, United States
Texas Oncology, P.A.
🇺🇸
Dallas, Texas, United States
St. Jude Hospital Yorba Linda DBA St. Joseph Heritage Healthcare
🇺🇸
Fullerton, California, United States
Southern Cancer Center, PC
🇺🇸
Mobile, Alabama, United States
UCSD Moores Cancer Center
🇺🇸
La Jolla, California, United States
UCLA Hematology/Oncology David Geffen School of Medicine
🇺🇸
Los Angeles, California, United States
North County Oncology
🇺🇸
Oceanside, California, United States
New Jersey Hematology & Oncology Associates
🇺🇸
Brick, New Jersey, United States
Virginia Cancer Specialist PC
🇺🇸
Leesburg, Virginia, United States
Holy Cross Hospital- Bienes Cancer Center
🇺🇸
Fort Lauderdale, Florida, United States
Memorial Healthcare System
🇺🇸
Hollywood, Florida, United States
Rocky mountain cancer centers LLP
🇺🇸
Lakewood, Colorado, United States
St. Mary'S Hospital Regional Cancer Center
🇺🇸
Grand Junction, Colorado, United States
Health Partners Institute Park Nicollet Frauenshuh Cancer Center
🇺🇸
Saint Louis Park, Minnesota, United States
Comprehensive Cancer Centers of Nevada
🇺🇸
Henderson, Nevada, United States
Texas Oncology - Presbyterian Hospital
🇺🇸
Dallas, Texas, United States
Northern Westchester Hospital Cancer Treatment & Wellness Center
🇺🇸
Mount Kisco, New York, United States
Hospital Universitario Sant Joan de Reus
🇪🇸
Reus, Tarragona, Spain
Hospital Clinic i Provincial
🇪🇸
Barcelona, Spain
Hospital Son Llatzer
🇪🇸
Palma de Mallorca, Islas Baleares, Spain
West Virginia University School of Medicine
🇺🇸
Morgantown, West Virginia, United States
Clinica Universidad de Navarra
🇪🇸
Pamplona, Navarra, Spain
Hospital Universitari Son Espases
🇪🇸
Palma de Mallorca, Islas Baleares, Spain
Hospital Universitari Vall d'Hebron
🇪🇸
Barcelona, Spain
Texas Oncology,PA. Tyler TX, 75702
🇺🇸
Tyler, Texas, United States
Hospital Universitario Puerta del Hierro
🇪🇸
Majadahonda, Madrid, Spain
Hospital De la Santa Creu i Sant Pau
🇪🇸
Barcelona, Spain
Onkologikoa
🇪🇸
San Sebastian, Guipuzcoa, Spain
Complejo Hospitalario Universitario A Coruna
🇪🇸
A Coruna, Spain
Hospital San Pedro de Alcantara
🇪🇸
Caceres, Spain
Hospital Clinico Universitario de Valencia
🇪🇸
Valencia, Spain
Hospital Universitario Miguel Servet
🇪🇸
Zaragoza, Spain
Centro Oncologico de Galicia
🇪🇸
A Coruna, Spain
Hospital General Universitario Morales Messeguer
🇪🇸
Murcia, Spain
Hospital Clinico Universitario Virgen de la Arrixaca
🇪🇸
Murcia, Spain
Fundacion Instituto Valenciano de Oncologia
🇪🇸
Valencia, Spain
Hospital General Universitario Gregorio Maranon
🇪🇸
Madrid, Spain
Hospital Universitari Arnau de Vilanova de Lleida
🇪🇸
Lleida, Spain
Hospital Universitario Virgen de la Macarena
🇪🇸
Sevilla, Spain
Hospital Universitario Ramon y Cajal
🇪🇸
Madrid, Spain
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
University of Colorado Cancer Center-Anschutz Cancer Pavilion (ACP)
🇺🇸
Aurora, Colorado, United States
Cancer Care Centers of South Texas
🇺🇸
San Antonio, Texas, United States
CBCC Global Research 6501 Truxtun Avenue Bakersfield, CA
🇺🇸
Bakersfield, California, United States
PHC-SLO Oncology and Hematology
🇺🇸
San Luis Obispo, California, United States
Cancer Center of Santa Barbara With Sansum Clinic
🇺🇸
Santa Barbara, California, United States
Torrance Health Association
🇺🇸
Redondo Beach, California, United States
Ft. Wayne Medical Oncology and Hematology, Inc
🇺🇸
Fort Wayne, Indiana, United States
Texas Oncology- South Second Street
🇺🇸
McAllen, Texas, United States
Consorci Sanitari de Terrassa
🇪🇸
Terrassa, Barcelona, Spain
Hospital Clinico San Carlos
🇪🇸
Madrid, Spain
Orlando Health Inc.
🇺🇸
Orlando, Florida, United States