BI 836845 in Estrogen Receptor Positive Metastatic Breast Cancer

A Phase Ib/II Randomized Study of BI 836845 in Combination With Exemestane and Everolimus Versus Exemestane and Everolimus Alone in Women With Locally Advanced or Metastatic Breast Cancer

Phase Ib / II study to determine the Maximum Tolerated Dose and Recommended Phase II Dose, and to evaluate the safety and antitumour activity, of BI 836845 and everolimus in combination with exemestane in women with HR+/HER2- advanced breast cancer

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: Everolimus; Drug: Exemestane; Drug: BI 836845

• Study Type: Interventional
• Enrollment (Actual): 164
• Phase: Phase 1

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • Medical University of Graz State Hospital - University Hospital Graz
  • Wien, Austria, 1160
    • Wilhelminenspital
• Belgium
  • Brussel, Belgium, 1090
    • Brussels - UNIV UZ Brussel
  • Bruxelles, Belgium, 1200
    • Brussels - UNIV Saint-Luc
  • Charleroi, Belgium, 6000
    • Charleroi - HOSP Grand Hôpital de Charleroi
  • Edegem, Belgium, 2650
    • Edegem - UNIV UZ Antwerpen
  • Leuven, Belgium, 3000
    • UZ Leuven
  • Liège, Belgium, 4000
    • Centre hospitalier universitaire de Liege
  • Liège, Belgium, 4000
    • Liège - HOSP St-Joseph
  • Namur, Belgium, 5000
    • CHU UCL Namur - Site De Sainte-Elisabeth
• France
  • Besançon, France, 25030
    • HOP Jean Minjoz
  • Marseille, France, 13009
    • INS Paoli-Calmettes
  • Nantes, France, 44202
    • CTR Catherine de Sienne
  • Paris, France, 75248
    • INS Curie
  • Paris, France, 75015
    • HOP Européen G. Pompidou
  • Plerin Sur Mer, France, 22190
    • Ctr Cario
• Ireland
  • Dublin 4, Ireland, D04 T6F4
    • St. Vincent'S University Hospital
• Korea, Republic of
  • Goyang, Korea, Republic of, 10408
    • National Cancer Center
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center
  • Seoul, Korea, Republic of, 110-744
    • Seoul National University Hospital
• Netherlands
  • Maastricht, Netherlands, 6229 HX
    • Maastricht University
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Vall d'Hebron
  • Lleida, Spain, 25198
    • Hospital Arnau de Vilanova
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal
  • Madrid, Spain, 28033
    • MD Anderson Cancer Center Madrid
  • Sevilla, Spain, 41013
    • Hospital Virgen del Rocío
  • Valencia, Spain, 46010
    • Hospital Clinico de Valencia
• Sweden
  • Stockholm, Sweden, 171 76
    • Centrummottagningen
• Taiwan
  • Kaohsiung, Taiwan, 8807
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Taichung, Taiwan, 40705
    • Taichung Veterans General Hospital
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
  • Taipei, Taiwan, 112
    • Taipei Veterans General Hospital
• United Kingdom
  • Dundee, United Kingdom, DD1 9SY
    • Ninewells Hospital & Medical School
  • London, United Kingdom, EC1M 6BQ
    • St Bartholomew's Hospital
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
    • Freeman Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• Histologically-confirmed locally advanced (aBC) or metastatic breast cancer (mBC) not deemed amenable to curative surgery or curative radiation therapy
• Tumors are positive for estrogen-receptor (ER) and/or progesterone receptor (PgR).
• Tumors must be negative for HER2 per local lab testing.
• Must have adequate archival tumor tissue from surgery or biopsy.
• Postmenopausal female patients aged >=18 years old.
• Objective evidence of recurrence or progressive disease on or after the last line of systemic therapy for breast cancer prior to study entry
• The patient is disease refractory to non-steroidal aromatase inhibitor (letrozole and/or anastrozole)
• Patients must have: a) Measurable lesion according to RECIST version 1.1 (R09-0262) or b) Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable lesion as defined above
• Eastern Cooperative Oncology Group performance score <= 2.
• Life expectancy of >= 6 months in the opinion of the investigator
• Fasting plasma glucose < 8.9 mmol/L (< 160 mg/dL) and HbA1c < 8.0%
• Adequate organ function
• Recovered from any previous therapy related toxicity to <= Grade 1 at study entry (except for stable sensory neuropathy <=Grade 2 and alopecia)
• Written informed consent that is consistent with ICH-GCP guidelines and local regulations

Inclusion criteria for the biopsy substudy are identical to the main study of the phase II part except for the following two inclusion criteria:

• Fresh tumor biopsy should be taken when deemed safe and feasible by the investigator and upon informed consent by the patient. Bone lesion is not recommended for biopsy
• Patients eligible to undergo tumor biopsy should have normal coagulation parameters (INR and PTT within normal range)

Exclusion criteria:

• Previous treatment with agents targeting on IGF pathway, phosphoinositide 3-kinase (PI3K) signaling pathway, protein kinase B (AKT), or mammalian target of rapamycin (mTOR) pathways
• Prior treatment with exemestane (except adjuvant exemestane stopped >12 months prior to start of study treatment as long as the patient did not recur during or within 12 months after the end of adjuvant exemestane)
• Known hypersensitivity to monoclonal antibody, mTOR inhibitors (e.g. sirolimus), or to the excipients of any study drugs
• Ovarian suppression by ovarian radiation or treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist
• Less than one week after receiving immunization with attenuated live vaccines prior to study treatment
• Radiotherapy within 4 weeks prior to the start of the study treatment, except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture which can then be completed within two weeks prior to study treatment
• Chemotherapy, biological therapy (other than bevacizumab), immunotherapy or investigational agents within 5 half-life of the drug or within two weeks prior to the start of study treatment, whichever is longer; bevacizumab treatment within 4 weeks prior to start of study treatment (this criterion concerns anti-cancer therapy only)
• Hormonal treatment for breast cancer within 2 weeks prior to start of study treatment
• Major surgery in the judgement of the investigator within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study
• Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use except Topical applications, inhaled sprays, eye drops or local injections or Patients on stable low dose of corticosteroids for at least two weeks before study entry
• Chronic hepatitis B infection, chronic hepatitis C infection and/or known HIV carrier
• QTcF prolongation > 470 ms or QT prolongation deemed clinically relevant by the investigator
• Disease that is considered by the investigator to be rapidly progressing or life threatening such as extensive symptomatic visceral disease including hepatic involvement and pulmonary lymphangitic spread of tumor
• History or current presence of brain or other CNS metastases
• Bilateral diffuse lymphangitic carcinomatosis (in lung)
• Hypokalemia of Grade >1
• History of another primary malignancy within 5 years, with the exception of adequately treated in-situ carcinoma of the cervix, uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer
• Family history of long QT syndrome
• Any concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety and anti-tumor activity of the test drug(s)
• Patients being treated with drugs recognized being strong or moderate CYP3A4 and/or PgP inhibitors and/or strong CYP3A4 inducers within 2 weeks prior to study entry
• Patients received more than two lines of chemotherapy for locally advanced or metastatic breast cancer (For the Phase II: more than one line)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: everolimus 10 mg + exemestane 25 mg - Phase II; Subjects received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting on Day 1 continously until disease progression, intolerable AEs or other reason necessitating withdrawal.	Drug: Everolimus; 10mg dose; Drug: Exemestane; Fixed dose at 25mg
Experimental: xentuzumab (BI 836845) 1000 mg + everolimus 10 mg + exemestane 25 mg - Phase II; Subjects received a single dose of 1000 milligram (mg) BI 836845 (xentuzumab) as a 1 hour (h) intravenous infusion once a week on Day 1, 8, 15 and 22 in a 28-day course until disease progression, intolerable AEs or other reason necessitating withdrawal. Subjects also received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting on Day 1 continously until disease progression, intolerable AEs or other reason necessitating withdrawal. Administration of xentuzumab was stopped after 28th October 2016, and participants in this group who remained in the trial could continue with everolimus 10 mg + exemestane 25 mg.	Drug: Everolimus; 10mg dose; Drug: Exemestane; Fixed dose at 25mg; Drug: BI 836845; 1000 mg, recommended dose per Phase Ib part. Human monoclonal antibody. Dose escalation in Phase Ib. 2 dose levels (high or low) depending on the dose cohort explored; Other Names: xentuzumab
Experimental: xentuzumab (BI 836845) 750 mg + everolimus 10 mg + exemestane 25 mg - Phase Ib; Subjects received a single dose of 750 milligram (mg) BI 836845 (xentuzumab) as a 1 hour (h) intravenous infusion once a week on Day 1, 8, 15 and 22 in a 28- day course until disease progression, intolerable AEs or other reason necessitating withdrawal. Subjects also received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting 7 days before first administration of BI 836845 (xentuzumab) continously until disease progression, intolerable AEs or other reason necessitating withdrawal.	Drug: Everolimus; 10mg dose; Drug: Exemestane; Fixed dose at 25mg; Drug: BI 836845; 1000 mg, recommended dose per Phase Ib part. Human monoclonal antibody. Dose escalation in Phase Ib. 2 dose levels (high or low) depending on the dose cohort explored; Other Names: xentuzumab
Experimental: xentuzumab (BI 836845) 1000 mg + everolimus 10 mg + exemestane 25 mg - Phase Ib; Subjects received a single dose of 1000 milligram (mg) BI 836845 (xentuzumab) as a 1 hour (h) intravenous infusion once a week on Day 1, 8, 15 and 22 in a 28-day course until disease progression, intolerable AEs or other reason necessitating withdrawal. Subjects also received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting 7 days before first administration of BI 836845 (xentuzumab) continously until disease progression, intolerable AEs or other reason necessitating withdrawal.	Drug: Everolimus; 10mg dose; Drug: Exemestane; Fixed dose at 25mg; Drug: BI 836845; 1000 mg, recommended dose per Phase Ib part. Human monoclonal antibody. Dose escalation in Phase Ib. 2 dose levels (high or low) depending on the dose cohort explored; Other Names: xentuzumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) - Phase II Part	Progression-free survival (PFS) in the phase II part is presented. Progression-free survival (PFS) was defined as the time from randomisation until radiological tumour progression according to RECIST 1.1, or death from any cause, whichever occurred earlier. Clinical disease progression was not considered for determination of a PFS event, unless the outcome of the progression was death. The cut-off date was 25th November 2016. At cut-off date, xentuzumab was discontinued in all patients in the experimental arm per sponsor decision, recruitment was also terminated. Patients who discontinued xentuzumab treatment continued with everolimus 10 mg + exemestane 25 mg treatment.	From randomisation until radiological tumour progression according to RECIST 1.1, or death from any cause or data cut-off (25Nov2016), up to 30 months.
Number of Patients With Dose Limiting Toxicity (DLT) - Phase Ib Part	Number of patients with dose limiting toxicity (DLT) in phase Ib part is presented.	From first administration of study treatment until end of first treatment cycle, up to 28 days.
Maximum Tolerated Dose (MTD) - Phase Ib Part	The Maximum Tolerated Dose (MTD) in this study was defined as the highest dose level examined of trial medication, at which no more than 1 out of 6 patients experienced a DLT during the MTD evaluation period. The MTD evaluation period was defined as the time from the first administration of xentuzumab up to start of cycle 2. A "3+3" Phase Ib dose finding phase was performed to determine the MTD.	up to 28 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Objective Response (OR) - Phase II Part	Objective response (OR) - phase II part is presented. Objective response (OR), defined as best overall response of complete response (CR) or partial response (PR), where best overall response was determined according to RECIST 1.1 from date of randomisation until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy.	From randomisation until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy or data cut-off (25Nov2016), up to 30 months.
Time to Progression (TTP) - Phase II Part	Time to progression (TTP) is presented. Time to progression (TTP), defined as the time from the date of randomization until the date of the first objective tumour progression according to RECIST 1.1.	From randomisation until the date of the first objective tumour progression according to RECIST 1.1. or data cut-off (25Nov2016), up to 30 months.
Number of Patients With Disease Control (DC) - Phase II Part	Disease control is defined as best overall response of complete response (CR) or partial response (PR), or stable disease (SD) >= 24 weeks, or Non-CR/Non-PD for >= 24 weeks. PD=Progressive disease.	From randomisation until data cut-off (25Nov2016), up to 30 months.
Time to Objective Response - Phase II Part	Time to objective response is presented. Time to objective response is defined as the time from randomisation until first documented complete response (CR) or partial response (PR).	From randomisation until first documented complete response (CR) or partial response (PR) or data cut-off (25Nov2016), up to 30 months.
Duration of Objective Response - Phase II Part	Duration of objective response is presented. Duration of objective response is defined as the time from first documented complete response (CR) or partial response (PR) until the earliest of disease progression or death among patients with objective response (OR).	From randomisation until the earliest of disease progression or death or data cut-off (25Nov2016), up to 30 months.
Duration of Disease Control - Phase II Part	Duration of disease control is presented. Duration of disease control is defined as the time from randomisation until the earliest of disease progression or death, among patients with disease control.	From randomisation until the earliest of disease progression or death or data cut-off (25Nov2016), up to 30 months.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Investigators: Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Publications and helpful links

General Publications

• Schmid P, Sablin MP, Bergh J, Im SA, Lu YS, Martinez N, Neven P, Lee KS, Morales S, Perez-Fidalgo JA, Adamson D, Goncalves A, Prat A, Jerusalem G, Schlieker L, Espadero RM, Bogenrieder T, Huang DC, Crown J, Cortes J. A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer. Breast Cancer Res. 2021 Jan 15;23(1):8. doi: 10.1186/s13058-020-01382-8.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2014
• Primary Completion (Actual): November 25, 2016
• Study Completion (Actual): December 14, 2021

Study Registration Dates

• First Submitted: April 22, 2014
• First Submitted That Met QC Criteria: April 24, 2014
• First Posted (Estimated): April 28, 2014

Study Record Updates

• Last Update Posted (Actual): July 15, 2025
• Last Update Submitted That Met QC Criteria: June 26, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: MTOR Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Enzyme Inhibitors; Protein Kinase Inhibitors; Steroid Synthesis Inhibitors; Hormone Antagonists; Estrogen Antagonists; Aromatase Inhibitors; Everolimus; Exemestane
• Other Study ID Numbers: 1280.4; 2013-001110-15 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

After the study is completed and the primary manuscript is accepted for publishing, researchers can use this following link https://www.mystudywindow.com/msw/datasharing to request access to the clinical study documents regarding this study, and upon a signed "Document Sharing Agreement".

Also, Researchers can use the following link https://www.mystudywindow.com/msw/datasharing to find information in order to request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined in the website.

The data shared are the raw clinical study data sets.

• IPD Sharing Time Frame: After all regulatory activities are completed in the US and EU for the product and indication, and after the primary manuscript has been accepted for publication.
• IPD Sharing Access Criteria: For study documents - upon signing of a 'Document Sharing Agreement'. For study data - 1. after the submission and approval of the research proposal (checks will be performed by both the independent review panel and the sponsor, including checking that the planned analysis does not compete with sponsor's publication plan); 2. and upon signing of a 'Data Sharing Agreement'.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR