BI 836845 in Estrogen Receptor Positive Metastatic Breast Cancer

NCT ID: NCT02123823

Last Updated: 2025-07-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 164 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-05-15
• Study Completion Date: 2021-12-14

Brief Summary

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

Conditions

Neoplasms

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Everolimus

Intervention Type: DRUG

10mg dose

Exemestane

Intervention Type: DRUG

Fixed dose at 25mg

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.

Group Type: EXPERIMENTAL

Everolimus

Intervention Type: DRUG

10mg dose

Exemestane

Intervention Type: DRUG

Fixed dose at 25mg

BI 836845

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Everolimus

Intervention Type: DRUG

10mg dose

Exemestane

Intervention Type: DRUG

Fixed dose at 25mg

BI 836845

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Everolimus

Intervention Type: DRUG

10mg dose

Exemestane

Intervention Type: DRUG

Fixed dose at 25mg

BI 836845

Intervention Type: DRUG

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

Interventions

Everolimus

10mg dose

Intervention Type: DRUG

Exemestane

Fixed dose at 25mg

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

xentuzumab

Eligibility Criteria

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

• 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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Boehringer Ingelheim

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Boehringer Ingelheim

Role: STUDY_CHAIR

Boehringer Ingelheim

Locations

Medical University of Graz State Hospital - University Hospital Graz

Graz, , Austria

Wilhelminenspital

Vienna, , Austria

Brussels - UNIV UZ Brussel

Brussels, , Belgium

Brussels - UNIV Saint-Luc

Brussels, , Belgium

Charleroi - HOSP Grand Hôpital de Charleroi

Charleroi, , Belgium

Edegem - UNIV UZ Antwerpen

Edegem, , Belgium

UZ Leuven

Leuven, , Belgium

Centre Hospitalier Universitaire de Liège

Liège, , Belgium

Liège - HOSP St-Joseph

Liège, , Belgium

CHU UCL Namur - Site De Sainte-Elisabeth

Namur, , Belgium

HOP Jean Minjoz

Besançon, , France

INS Paoli-Calmettes

Marseille, , France

CTR Catherine de Sienne

Nantes, , France

HOP Européen G. Pompidou

Paris, , France

INS Curie

Paris, , France

Ctr Cario

Plerin Sur Mer, , France

St. Vincent's University Hospital

Dublin, , Ireland

Maastricht University

Maastricht, , Netherlands

National Cancer Center

Goyang, , South Korea

Seoul National University Hospital

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Hospital Vall d'Hebron

Barcelona, , Spain

Hospital Clínic de Barcelona

Barcelona, , Spain

Hospital Arnau de Vilanova

Lleida, , Spain

MD Anderson Cancer Center Madrid

Madrid, , Spain

Hospital Ramón y Cajal

Madrid, , Spain

Hospital Clínico San Carlos

Madrid, , Spain

Hospital Universitario 12 de Octubre

Madrid, , Spain

Hospital Virgen del Rocío

Seville, , Spain

Hospital Clínico de Valencia

Valencia, , Spain

Centrummottagningen

Stockholm, , Sweden

Kaohsiung Medical University Chung-Ho Memorial Hospital

Kaohsiung City, , Taiwan

Taichung Veterans General Hospital

Taichung, , Taiwan

National Taiwan University Hospital

Taipei, , Taiwan

Taipei Veterans General Hospital

Taipei, , Taiwan

Ninewells Hospital & Medical School

Dundee, , United Kingdom

St Bartholomew's Hospital

London, , United Kingdom

Freeman Hospital

Newcastle upon Tyne, , United Kingdom

Countries

Austria; Belgium; France; Ireland; Netherlands; South Korea; Spain; Sweden; Taiwan; United Kingdom

References

Dercle L, McGale J, Zhao B, Schmitt J, Peltzer A, Schwartz LH, Amend M. Artificial intelligence and radiomics biomarkers for treatment response prediction in advanced HER2-negative breast cancer. Breast. 2025 Sep 3;84:104571. doi: 10.1016/j.breast.2025.104571. Online ahead of print.

Reference Type: DERIVED

PMID: 40974664 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33451345 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://www.mystudywindow.com

Related Info

Other Identifiers

2013-001110-15

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1280.4

Identifier Type: -

Identifier Source: org_study_id