Clinical trial NCT02123823: BI 836845 in Estrogen Receptor Positive Metastatic Breast Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2014-04-28
Enrollment: 164
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


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

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)

Primary outcomes:
measure: Progression-free survival (PFS)
timeFrame: up to 11 months
measure: Occurrence of Dose Limiting Toxicity (DLT) - phase I part
timeFrame: up to 28 days
measure: Maximum Tolerated Dose (MTD) - phase I part
timeFrame: up to 15 months
Secondary outcomes:
measure: Objective response (OR), defined as complete response (CR) or partial response (PR) (CR + PR)
timeFrame: up to 11 months
measure: Time to progression (TTP), defined as the duration of time from the date of randomization until the date of the first objective tumor progression
timeFrame: up to 11 months
measure: Disease control (DC), 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 (CR + PR + SD24w + Non-CR/Non-PD24w)
timeFrame: up to 11 months
measure: Time to objective response, defined as the time from randomisation until first documented CR or PR
timeFrame: up to 11 months
measure: Duration of objective response, defined as the time from first documented CR or PR until the earliest of disease progression or death among patients with OR
timeFrame: up to 11 months
measure: Duration of disease control, defined as the time from randomisation until the earliest of disease progression or death, among patients with disease control
timeFrame: up to 11 months
Other outcomes:
Locations:
city: Graz
country: Austria
facility: LKH-Univ. Hospital Graz
city: Wien
country: Austria
facility: Wilhelminenspital
city: Brussel
country: Belgium
facility: Brussels - UNIV UZ Brussel
city: Bruxelles
country: Belgium
facility: Brussels - UNIV Saint-Luc
city: Charleroi
country: Belgium
facility: Charleroi - HOSP Grand Hôpital de Charleroi
city: Edegem
country: Belgium
facility: Edegem - UNIV UZ Antwerpen
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liège
country: Belgium
facility: Centre Hospitalier Universitaire de Liège
city: Liège
country: Belgium
facility: Liège - HOSP St-Joseph
city: Namur
country: Belgium
facility: CHU UCL Namur - Site De Sainte-Elisabeth
city: Besançon
country: France
facility: HOP Jean Minjoz
city: Marseille
country: France
facility: INS Paoli-Calmettes
city: Nantes
country: France
facility: CTR Catherine de Sienne
city: Paris
country: France
facility: HOP Européen G. Pompidou
city: Paris
country: France
facility: INS Curie
city: Plerin Sur Mer
country: France
facility: Ctr Cario
city: Dublin 4
country: Ireland
facility: St Vincent's University Hospital
city: Goyang
country: Korea, Republic of
facility: National Cancer Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht University
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Lleida
country: Spain
facility: Hospital Arnau de Vilanova
city: Madrid
country: Spain
facility: MD Anderson Cancer Center Madrid
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital Clínico de Valencia
city: Stockholm
country: Sweden
facility: Centrummottagningen
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Dundee
country: United Kingdom
facility: Ninewells Hospital & Medical School
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: 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.