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

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)