| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Advanced or Metastatic Breast Cancer positive for estrogen-receptor (ER) and/or progesterone receptor (PgR) and negative for HER2 which is refractory to non-steroidal aromatase inhibitor (letrozole and/or anastrozole) |
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| E.1.1.1 | Medical condition in easily understood language |
| advanced breast cancer overexpressing hormone receptors (like estrogen) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10070575 |
| E.1.2 | Term | Estrogen receptor positive breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I part: To determine the Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) of BI 836845 and everolimus in combination with exemestane in women with HR+/HER2- advanced breast cancer.
Phase II part: To evaluate the antitumor activity of BI 836845 in combination with exemestane and everolimus compared to exemestane and everolimus alone in women with HR+/HER2- advanced breast cancer.
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| E.2.2 | Secondary objectives of the trial |
| To determine the safety of BI 836845 in combination with exemestane and everolimus in HR+/HER2- advanced breast cancer patients. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 women aged > or = 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 measurable lesion according to RECIST version 1.1 or 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
Optional collection of fresh tumour biopsies was discontinued alongside xentuzumab discontinuation as per sponsor decision, from 28th October 2016. |
|
| E.4 | Principal 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 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
- 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) |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1: Progression-free survival (PFS)
2: occurrence of Dose Limiting Toxicity (DLT) and MTD - phase I part
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1: After the decision of the sponsor to stop recruitment and Xentuzumab treatment, it was decided to not perform the primary analysis with the 90 PFS reached. The analyses for the primary endpoint of PFS will be based on data obtained until 25th November 2016 (4 weeks after communication of xentuzumab discontinuation).
2: up to 28 days
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|
| E.5.2 | Secondary end point(s) |
1: Time to progression (TTP), defined as the duration of time from the date of randomization until the date of the first objective tumor progression acording to RECIST 1.1
2: Objective response (OR), defined as best overall response of complete response (CR) or partial response (PR) (CR + PR), where best overall response is determined according to RECIST 1.1 from date of randomisation until the earliest of disease progression, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy.
3: Time to objective response, defined as the time from randomisation until first documented CR or PR.
4: 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.
5: 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, where best overall response is defined according to RECIST 1.1 from date of randomisation until the earliest of disease progression, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy.
6: Duration of disease control, defined as the time from randomisation until the earliest of disease progression or death, among patients with disease control.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For endpoints 1 to 6 detailed in section E.5.2 the timepoint of evaluation is the following: As for PFS, analyses of other RECIST based endpoints will also only utilize data obtained from assessments scheduled until 25th November 2016
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| France |
| Ireland |
| Korea, Republic of |
| Netherlands |
| Spain |
| Sweden |
| Taiwan |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 11 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
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