Clinical trial NCT02756364: Sapanisertib in Combination With Fulvestrant in Women With Advanced or Metastatic Breast Cancer After Aromatase Inhibitor Therapy
Official title: An Open-Label Phase 2 Study of MLN0128 (A TORC1/2 Inhibitor) in Combination With Fulvestrant in Women With ER-Positive/HER2-Negative Advanced or Metastatic Breast Cancer That Has Progressed During or After Aromatase Inhibitor Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Neoplasms
Keywords: Drug Therapy
Lead sponsor: Calithera Biosciences, Inc
Sponsor class: INDUSTRY
First posted: 2016-04-29
Enrollment: 141
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility criteria: Inclusion Criteria:

1. Female participants aged 18 years or older who are postmenopausal.
2. Histologically proven diagnosis of breast cancer with evidence of metastatic disease or locoregional recurrence.
3. Histological confirmation and documentation of estrogen receptor (ER)-positive status (≥1% positive stained cells).
4. 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.
5. 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.
6. Progressive Disease (PD) during prior aromatase inhibitor (AI) therapy.
7. 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.
8. Eastern cooperative oncology group (ECOG) performance status of 0 or 1.
9. 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:

1. 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.
2. 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.
3. 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.
4. Life-threatening metastatic visceral disease (defined as extensive hepatic involvement or symptomatic pulmonary lymphangitic spread).
5. 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.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Up to 40 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to 164 weeks
measure: Time to Progression (TTP)
timeFrame: Up to 40 months
measure: Objective Response Rate (ORR)
timeFrame: Up to 40 months
measure: Clinical Benefit Rate (CBR)
timeFrame: Up to 40 months
measure: Percentage of Participants Who Experienced at Least One Treatment-emergent Adverse Event (TEAE)
timeFrame: Up to 164 weeks
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Southern Cancer Center, PC
state: Alabama
city: Bakersfield
country: United States
facility: CBCC Global Research 6501 Truxtun Avenue Bakersfield, CA
state: California
city: Fullerton
country: United States
facility: St. Jude Hospital Yorba Linda DBA St. Joseph Heritage Healthcare
state: California
city: La Jolla
country: United States
facility: UCSD Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Hematology/Oncology David Geffen School of Medicine
state: California
city: Oceanside
country: United States
facility: North County Oncology
state: California
city: Redondo Beach
country: United States
facility: Torrance Health Association
state: California
city: San Luis Obispo
country: United States
facility: PHC-SLO Oncology and Hematology
state: California
city: Santa Barbara
country: United States
facility: Cancer Center of Santa Barbara With Sansum Clinic
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center-Anschutz Cancer Pavilion (ACP)
state: Colorado
city: Grand Junction
country: United States
facility: St. Mary'S Hospital Regional Cancer Center
state: Colorado
city: Lakewood
country: United States
facility: Rocky mountain cancer centers LLP
state: Colorado
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital- Bienes Cancer Center
state: Florida
city: Hollywood
country: United States
facility: Memorial Healthcare System
state: Florida
city: Orlando
country: United States
facility: Orlando Health Inc.
state: Florida
city: Fort Wayne
country: United States
facility: Ft. Wayne Medical Oncology and Hematology, Inc
state: Indiana
city: Scarborough
country: United States
facility: New England Cancer Specialists
state: Maine
city: Saint Louis Park
country: United States
facility: Health Partners Institute Park Nicollet Frauenshuh Cancer Center
state: Minnesota
city: Henderson
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Brick
country: United States
facility: New Jersey Hematology & Oncology Associates
state: New Jersey
city: Mount Kisco
country: United States
facility: Northern Westchester Hospital Cancer Treatment & Wellness Center
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Austin
country: United States
facility: Texas Oncology, P.A.
state: Texas
city: Dallas
country: United States
facility: Texas Oncology - Presbyterian Hospital
state: Texas
city: Dallas
country: United States
facility: Texas Oncology, P.A.
state: Texas
city: McAllen
country: United States
facility: Texas Oncology- South Second Street
state: Texas
city: San Antonio
country: United States
facility: Cancer Care Centers of South Texas
state: Texas
city: Tyler
country: United States
facility: Texas Oncology,PA. Tyler TX, 75702
state: Texas
city: Leesburg
country: United States
facility: Virginia Cancer Specialist PC
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University School of Medicine
state: West Virginia
city: Terrassa
country: Spain
facility: Consorci Sanitari de Terrassa
state: Barcelona
city: San Sebastian
country: Spain
facility: Onkologikoa
state: Guipuzcoa
city: Palma de Mallorca
country: Spain
facility: Hospital Universitari Son Espases
state: Islas Baleares
city: Palma de Mallorca
country: Spain
facility: Hospital Son Llatzer
state: Islas Baleares
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta del Hierro
state: Madrid
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
state: Navarra
city: Reus
country: Spain
facility: Hospital Universitario Sant Joan de Reus
state: Tarragona
city: A Coruna
country: Spain
facility: Complejo Hospitalario Universitario A Coruna
city: A Coruna
country: Spain
facility: Centro Oncologico de Galicia
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial
city: Barcelona
country: Spain
facility: Hospital De la Santa Creu i Sant Pau
city: Caceres
country: Spain
facility: Hospital San Pedro de Alcantara
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova de Lleida
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Murcia
country: Spain
facility: Hospital General Universitario Morales Messeguer
city: Murcia
country: Spain
facility: Hospital Clinico Universitario Virgen de la Arrixaca
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen de la Macarena
city: Valencia
country: Spain
facility: Fundacion Instituto Valenciano de Oncologia
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References: