Clinical Trials List
Protocol Number1280.4
NCT Number(ClinicalTrials.gov Identfier)NCT02123823
2015-09-01 - 2018-03-01
Phase II
Terminated4
ICD-10C50
Malignant neoplasm of breast
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
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Trial Applicant
Boehringer Ingelheim
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Sponsor
Boehringer Ingelheim
-
Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- 金光亮 Division of General Surgery
- 林永慧 Division of General Surgery
- 邱仁輝 Division of General Surgery
- Chun-Yu Liu Division of General Surgery
- Ta-Chung Chao Division of General Surgery
- Yi-Fang Tsai Division of General Surgery
The Actual Total Number of Participants Enrolled
3 Stop recruiting
Audit
None
Co-Principal Investigator
- 甘蓉瑜 Division of Gastroenterological Surgery
- Fang-Ming Chen Division of Gastroenterological Surgery
- Chieh-Han Chuang Division of Gastroenterological Surgery
- Ming-Feng Hou Division of Gastroenterological Surgery
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
- Huey-En Tzeng Division of Hematology & Oncology
- 李芳儀 Division of Hematology & Oncology
- 蔡志文 Division of Hematology & Oncology
- ZHENG-WEI ZHOU Division of Hematology & Oncology
- Chih-Chiang Hung Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
- 郭文宏 Division of General Surgery
- SUNG-HSIN KUO Division of General Surgery
- MING-YANG WANG Division of General Surgery
- YEN-SHEN LU Division of General Surgery
- 林柏翰 Division of General Surgery
- Wei-Wu Chen Division of General Surgery
- 林璟宏 Division of General Surgery
- 張允中 Division of General Surgery
- 羅喬 Division of General Surgery
- 蔡立威 Division of General Surgery
- 張端瑩 Division of General Surgery
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Audit
None
Condition/Disease
Locally Advanced or Metastatic Breast Cancer
Objectives
Phase I part: To determine the maximum tolerated dose (MTD), and recommended
Phase II dose of BI 836845 in combination with exemestane and everolimus in
women with HR+/HER2 locally advanced or metastatic breast cancer
Phase II part: To evaluate the anti-tumor activity of BI 836845 in combination with
exemestane and everolimus versus exemestane and everolimus alone in women with
HR+/HER2 locally advanced or metastatic breast cancer
In addition, safety will be assessed
Pharmacokinetics (PK), pharmacogenomics and exploratory biomarkers will be
investigated in both Phase I and Phase II parts
Test Drug
BI 836845
Active Ingredient
fully human IgG1 monoclonal antibody (mAb)
Dosage Form
Injection
Dosage
200
Endpoints
The primary endpoint of the phase II part of this study is progression-free survival, as
determined by RECIST 1.1.
Secondary endpoints are:
• Time to progression
• Objective response (CR, PR)
• Time to objective response
• Duration of objective response
• Disease control (CR + PR + SD6m24w+ Non-CR/NonPD6m24w)
• Duration of disease control
determined by RECIST 1.1.
Secondary endpoints are:
• Time to progression
• Objective response (CR, PR)
• Time to objective response
• Duration of objective response
• Disease control (CR + PR + SD6m24w+ Non-CR/NonPD6m24w)
• Duration of disease control
Inclution Criteria
Inclusion criteria
1. Histologically-confirmed locally advanced (aBC) or metastatic breast cancer (mBC)
not deemed amenable to curative surgery or curative radiation therapy
2. Tumors are positive for estrogen-receptor (ER) and/or progesterone receptor (PgR).
Tumors must be negative for HER2 per local lab testing. ER, PgR and HER2 status
previously assessed by local lab is acceptable
3. Must have adequate archival tumor tissue from surgery or biopsy (refer to
Section 5.3.3 and Section 5.6.3.3 for details). If multiple surgeries/biopsies are
available for individual patient, the most recent and/or the most appropriate tissue
material is requested
4. Postmenopausal female patients aged ≥18 years old. Postmenopausal status is
defined either by:
a. Age ≥ 55 years and one year or more of amenorrhea
b. Age < 55 years and one year or more of amenorrhea, with an estradiol assay <
20 pg/ml
c. Surgical menopause with bilateral oophorectomy
5. Objective evidence of recurrence or progressive disease on or after the last line of
systemic therapy for breast cancer prior to study entry
6. The patient is disease refractory to non-steroidal aromatase inhibitor (letrozole and/or
anastrozole): defined as recurrence during or within 12 months after the end of
adjuvant treatment or progression during or within 1 month after the end of aromatase
inhibitor treatment for locally advanced or metastatic disease
Note: Letrozole or anastrozole do not have to be the most recent treatment. Prior
anticancer therapy, e.g. tamoxifen, fulvestrant are allowed
7. Patients must have
a. Measurable lesion according to RECIST version 1.1 (R09-0262) or
b. Bone lesions only: lytic or mixed (lytic + sclerotic) in the absence of
measurable lesion as defined above
8. Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score ≤ 2.
Refer to APPENDIX 10.2
9. Life expectancy of ≥ 6 months in the opinion of the investigator
10. Fasting plasma glucose < 8.9 mmol/L (< 160 mg/dL) and HbA1c < 8.0%
11. Adequate organ function, defined as all of the following:
a) Absolute neutrophil count (ANC) ≥ 1500/mm3
b) Platelet count ≥100,000/mm3
c) International Normalized Ratio (INR) ≤ 2.0
d) Serum creatinine ≤ 1.5 times ULN.
e) Total Bilirubin ≤ 1.5 times upper limit of institutional normal (patients with
Gilbert syndrome total bilirubin must be < 4 times institutional upper limit of
normal)
f) Aspartate amino transferase (AST) and alanine amino transferase (ALT) ≤ three
times the upper limit of institutional normal (ULN) (if related to liver metastases ≤
five times ULN)
g) Fasting triglycerides ≤300 mg/dL or 3.42 mmol/L
h) Hemoglobin (Hgb) ≥ 9.0 g/dL
12. Recovered from any previous therapy related toxicity to ≤ Grade 1 at study entry
(except for stable sensory neuropathy ≤Grade 2 and alopecia)
13. Written informed consent that is consistent with ICH-GCP guidelines and local
regulations
Optional fresh biopsy substudy for the Phase II part:
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)
1. Histologically-confirmed locally advanced (aBC) or metastatic breast cancer (mBC)
not deemed amenable to curative surgery or curative radiation therapy
2. Tumors are positive for estrogen-receptor (ER) and/or progesterone receptor (PgR).
Tumors must be negative for HER2 per local lab testing. ER, PgR and HER2 status
previously assessed by local lab is acceptable
3. Must have adequate archival tumor tissue from surgery or biopsy (refer to
Section 5.3.3 and Section 5.6.3.3 for details). If multiple surgeries/biopsies are
available for individual patient, the most recent and/or the most appropriate tissue
material is requested
4. Postmenopausal female patients aged ≥18 years old. Postmenopausal status is
defined either by:
a. Age ≥ 55 years and one year or more of amenorrhea
b. Age < 55 years and one year or more of amenorrhea, with an estradiol assay <
20 pg/ml
c. Surgical menopause with bilateral oophorectomy
5. Objective evidence of recurrence or progressive disease on or after the last line of
systemic therapy for breast cancer prior to study entry
6. The patient is disease refractory to non-steroidal aromatase inhibitor (letrozole and/or
anastrozole): defined as recurrence during or within 12 months after the end of
adjuvant treatment or progression during or within 1 month after the end of aromatase
inhibitor treatment for locally advanced or metastatic disease
Note: Letrozole or anastrozole do not have to be the most recent treatment. Prior
anticancer therapy, e.g. tamoxifen, fulvestrant are allowed
7. Patients must have
a. Measurable lesion according to RECIST version 1.1 (R09-0262) or
b. Bone lesions only: lytic or mixed (lytic + sclerotic) in the absence of
measurable lesion as defined above
8. Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score ≤ 2.
Refer to APPENDIX 10.2
9. Life expectancy of ≥ 6 months in the opinion of the investigator
10. Fasting plasma glucose < 8.9 mmol/L (< 160 mg/dL) and HbA1c < 8.0%
11. Adequate organ function, defined as all of the following:
a) Absolute neutrophil count (ANC) ≥ 1500/mm3
b) Platelet count ≥100,000/mm3
c) International Normalized Ratio (INR) ≤ 2.0
d) Serum creatinine ≤ 1.5 times ULN.
e) Total Bilirubin ≤ 1.5 times upper limit of institutional normal (patients with
Gilbert syndrome total bilirubin must be < 4 times institutional upper limit of
normal)
f) Aspartate amino transferase (AST) and alanine amino transferase (ALT) ≤ three
times the upper limit of institutional normal (ULN) (if related to liver metastases ≤
five times ULN)
g) Fasting triglycerides ≤300 mg/dL or 3.42 mmol/L
h) Hemoglobin (Hgb) ≥ 9.0 g/dL
12. Recovered from any previous therapy related toxicity to ≤ Grade 1 at study entry
(except for stable sensory neuropathy ≤Grade 2 and alopecia)
13. Written informed consent that is consistent with ICH-GCP guidelines and local
regulations
Optional fresh biopsy substudy for the Phase II part:
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
Exclusion criteria
Phase I part:
1. 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 (sirolimus, temsirolimus, etc.)
2. 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)
3. Known hypersensitivity to monoclonal antibody, mTOR inhibitors (e.g. sirolimus), or
to the excipients of any study drugs
4. Ovarian suppression by ovarian radiation or treatment with a luteinizing hormonereleasing hormone (LH-RH) agonist (goserelin acetate or leuprolide acetate)
5. Less than one week after receiving immunization with attenuated live vaccines prior
to study treatment
6. 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
7. 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)
8. Hormonal treatment for breast cancer within 2 weeks prior to start of study treatment
9. 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
10. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids
use except in cases outlined below:
a. Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways
diseases), eye drops or local injections (e.g. intra-articular) are allowed
b. Patients on stable low dose of corticosteroids for at least two weeks before
study entry are allowed
11. Chronic hepatitis B infection (defined as presence of HBsAg and/ or HBV- DNA),
chronic hepatitis C infection (defined as presence of anti-HCV Ab and/or HCV-RNA)
and/or known HIV carrier
12. QTcF prolongation > 470 ms or QT prolongation deemed clinically relevant by the
investigator (e.g., congenital long QT syndrome).The QTcF will be calculated as the
mean of the 3 ECGs taken at screening
13. 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 (subjects who are intended
for urgent chemotherapy)
14. History of brain or other CNS metastases
15. Bilateral diffuse lymphangitic carcinomatosis
16. Hypokalemia of Grade >1
17. 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
18. Family history of long QT syndrome
19. 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) such as:
a) History or presence of clinically relevant cardiovascular abnormalities such as
uncontrolled hypertension, congestive heart failure, New York Heart Association
(NYHA, refer to Appendix 10.1) functional classification of 3 or 4, unstable angina
or poorly controlled arrhythmia, including any type of atril fibriliation. Myocardial
infarction within 6 month prior to the study entry
b) Impairment of gastrointestinal function or who have gastrointestinal disease that
may significantly alter the absorption of study drugs (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome) , or any GI
disorders of Grade > 1
c) Active skin, mucosa or ocular disorders of Grade > 1
d) Significant symptomatic deterioration of lung function. If clinically indicated,
pulmonary function tests including measures of predicted lung volumes, DLco, O2
saturation at rest on room air should be considered to exclude restrictive pulmonary
disease, pneumonitis or pulmonary infiltrates
20. Patients being treated with drugs recognized as being strong or moderate CYP3A4
and/or P-glycoprotein (PgP) inhibitors and/or strong CYP3A4 inducers within 2
weeks (or use of amiodarone within 6 months) prior to study entry. Refer to Section
10.3
21. Patients unwilling or unable to comply with study and follow-up procedures in the
opinion of the investigator
22. Patients received more than two lines of chemotherapy for locally advanced or
metastatic breast cancer
Note: A chemotherapy line in advanced/metastatic disease is an anticancer regimen(s)
that contains at least 1 cytotoxic chemotherapy agent and given for 21 days or longer.
If a cytotoxic chemotherapy regimen was discontinued for a reason other than disease
progression and lasted less than 21 days, then this regimen does not count as a "prior
line of chemotherapy".
Phase II Part:
Exclusion criteria for the Phase II part are identical to the Phase I part except that exclusion
criteria number 22 of the Phase I part is replaced with the following exclusion criteria:
Patients received more than one line of chemotherapy for locally advanced or
metastatic breast cancer
Phase I part:
1. 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 (sirolimus, temsirolimus, etc.)
2. 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)
3. Known hypersensitivity to monoclonal antibody, mTOR inhibitors (e.g. sirolimus), or
to the excipients of any study drugs
4. Ovarian suppression by ovarian radiation or treatment with a luteinizing hormonereleasing hormone (LH-RH) agonist (goserelin acetate or leuprolide acetate)
5. Less than one week after receiving immunization with attenuated live vaccines prior
to study treatment
6. 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
7. 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)
8. Hormonal treatment for breast cancer within 2 weeks prior to start of study treatment
9. 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
10. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids
use except in cases outlined below:
a. Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways
diseases), eye drops or local injections (e.g. intra-articular) are allowed
b. Patients on stable low dose of corticosteroids for at least two weeks before
study entry are allowed
11. Chronic hepatitis B infection (defined as presence of HBsAg and/ or HBV- DNA),
chronic hepatitis C infection (defined as presence of anti-HCV Ab and/or HCV-RNA)
and/or known HIV carrier
12. QTcF prolongation > 470 ms or QT prolongation deemed clinically relevant by the
investigator (e.g., congenital long QT syndrome).The QTcF will be calculated as the
mean of the 3 ECGs taken at screening
13. 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 (subjects who are intended
for urgent chemotherapy)
14. History of brain or other CNS metastases
15. Bilateral diffuse lymphangitic carcinomatosis
16. Hypokalemia of Grade >1
17. 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
18. Family history of long QT syndrome
19. 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) such as:
a) History or presence of clinically relevant cardiovascular abnormalities such as
uncontrolled hypertension, congestive heart failure, New York Heart Association
(NYHA, refer to Appendix 10.1) functional classification of 3 or 4, unstable angina
or poorly controlled arrhythmia, including any type of atril fibriliation. Myocardial
infarction within 6 month prior to the study entry
b) Impairment of gastrointestinal function or who have gastrointestinal disease that
may significantly alter the absorption of study drugs (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome) , or any GI
disorders of Grade > 1
c) Active skin, mucosa or ocular disorders of Grade > 1
d) Significant symptomatic deterioration of lung function. If clinically indicated,
pulmonary function tests including measures of predicted lung volumes, DLco, O2
saturation at rest on room air should be considered to exclude restrictive pulmonary
disease, pneumonitis or pulmonary infiltrates
20. Patients being treated with drugs recognized as being strong or moderate CYP3A4
and/or P-glycoprotein (PgP) inhibitors and/or strong CYP3A4 inducers within 2
weeks (or use of amiodarone within 6 months) prior to study entry. Refer to Section
10.3
21. Patients unwilling or unable to comply with study and follow-up procedures in the
opinion of the investigator
22. Patients received more than two lines of chemotherapy for locally advanced or
metastatic breast cancer
Note: A chemotherapy line in advanced/metastatic disease is an anticancer regimen(s)
that contains at least 1 cytotoxic chemotherapy agent and given for 21 days or longer.
If a cytotoxic chemotherapy regimen was discontinued for a reason other than disease
progression and lasted less than 21 days, then this regimen does not count as a "prior
line of chemotherapy".
Phase II Part:
Exclusion criteria for the Phase II part are identical to the Phase I part except that exclusion
criteria number 22 of the Phase I part is replaced with the following exclusion criteria:
Patients received more than one line of chemotherapy for locally advanced or
metastatic breast cancer
The Estimated Number of Participants
-
Taiwan
20 participants
-
Global
171 participants
