Breast Neoplasms
Conditions
Brief summary
The main objective of the trial is to assess the efficacy of xentuzumab in combination with everolimus and exemestane over everolimus and exemestane in patients with HR+/ HER2- advanced or metastatic breast cancer and non-visceral disease.
Interventions
DRUGXentuzumab
Intravenous infusion
DRUGPlacebo
Intravenous infusion
DRUGEverolimus
Tablet
DRUGExemestane
Tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented histologically confirmed breast cancer with ERand/ or PgR-positive and HER2-negative status * Locally advanced or metastatic breast cancer not deemed amenable to curative surgery or curative radiation therapy * Archival tumour sample available at the time of informed consent and provided to the central laboratory around the time of randomisation. Patients must provide a formalin-fixed paraffin embedded (FFPE) tissue biopsy sample preferably taken at the time of presentation with recurrent or metastatic disease (provision of a biopsy sample taken from the bone is not acceptable). * Patients must satisfy the following criteria for prior therapy: * Disease progression during treatment or within 12 months of completion of endocrine adjuvant therapy or * Disease progression while on or within 1 month after the end of prior endocrine therapy for advanced/metastatic breast cancer (Note: the endocrine therapy does not have to be the treatment immediately prior to trial entry). * Patients must have * At least one measurable non-visceral lesion according to RECIST version 1.1 in either lymph nodes, soft tissue, skin and/or * At least one measurable non-visceral lesion according to RECIST version 1.1 as lytic or mixed (lytic + blastic) in bone and/or * At least one non-measurable (lytic, mixed lytic + blastic, or blastic) bone lesion according to RECIST version 1.1 * Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1. * Fasting glucose \<8.9 mmol/L (\<160 mg/dL) and HbA1c \<8.0% * Adequate organ function
Exclusion criteria
* Previous treatment with agents targeting the IGF pathway, AKT, or 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) * Evidence of visceral metastasis/es (i.e. liver, lung, peritoneal, pleural metastases, malignant pleural effusions, malignant peritoneal effusions) at screening. NOTE: Patients with a past history of visceral metastases are eligible if visceral metastases have completely resolved at least 3 months * History or evidence of metastatic disease to the brain * Leptomeningeal carcinomatosis * More than 1 prior line of chemotherapy for HR+ HER2- metastatic breast cancer * Radiotherapy within 4 weeks prior to the start of study treatment * Use of concomitant systemic sex hormone therapy * History or presence of cardiovascular abnormalities * Known pre-existing interstitial lung disease * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | From randomisation until the earliest of disease progression, death or the time point of primary PFS analysis, up to 892 days. | Progression-free survival (PFS) defined as the time from randomisation until progressive disease (PD) according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) in combination with modified MD Anderson Criteria (for bone lesion assessment), based on blinded independent assessment or death from any cause, whichever occurred earlier. As per RECIST, PD is defined as at least a 20% increase in the sum of diameters of target lesions, unequivocal progression of non-target lesions or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomisation until death from any cause, up to 995 days. | Overall survival (OS) defined as the time from randomisation until death from any cause. For patients with 'event' as an outcome for OS: OS\[days\] = date of outcome - date of randomisation + 1. For patients with 'censored' as an outcome for OS: OS (censored)\[days\] = date of outcome - date of randomisation + 1. |
| Number of Patients With Disease Control (DC) | From randomisation until the earliest of progressive disease or death from any cause, up to 892 days. | Disease control (DC) was defined as a best overall response (BOR) of either complete response (CR), partial response (PR), stable disease (SD) or Non-CR/No-PD. SD and Non-CR/Non-PR must have been observed up until at least week 24 tumor assessment. BOR was defined according to RECIST v1.1 in combination with modified MD Anderson Criteria (for bone lesion assessment) based on all evaluable tumor assessments from randomisation until the earliest of PD, start of subsequent anti-cancer therapy, loss to follow-up, withdrawal of consent or death. To be aligned with the primary endpoint derivation, tumor assessments after two or more consecutively misses assessments were not considered. DC was assessed by independent reviewers. |
| Duration of Disease Control (DC) | From randomisation until the earliest of progressive disease or death from any cause, up to 892 days. | Duration of disease control (DC), defined as the time from randomisation until the earliest of disease progression (according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) in combination with modified MD Anderson Criteria (for bone lesion assessment) or death from any cause, among patients with DC. Duration of DC was assessed by independent reviewers. The duration of DC was calculated as followed: For patients with disease progression or death: Duration of DC \[days\] = date of outcome - date of randomisation + 1 For patients without disease progression or death: Duration of DC (censored) \[days\] = date of outcome - date of randomisation + 1 |
| Number of Participants With Objective Response (OR) | From randomisation until end of treatment, up to 892 days. | Number of participants with objective response (OR) by independent assessment. OR is defined as a best overall response of complete response (CR) or partial response (PR). Best overall response is defined according to RECIST v1.1 in combination with modified MD Anderson Criteria (for bone lesion assessment) and will consider all tumor assessments from randomisation until the earliest of PD, start of subsequent anti-cancer therapy, loss to follow-up, withdrawal of consent or death. To be aligned with the primary endpoint derivation, tumor assessments after two or more consecutively misses assessments were not considered. |
| Time to Pain Progression or Intensification of Pain Palliation | From randomisation until the earliest of pain progression, intensification of pain palliation, death or the time point of progression free survival analysis, up to 843 days. | Time to pain progression or intensification of pain palliation was defined as the time from randomisation until the earliest of: * 2 point increase from baseline in the Brief Pain Inventory - Short Form (BPI-SF), Item 3 (worst pain), without a decrease (of ≥1 point) from baseline analgesics use (via the 8-point Analgesic Quantification Algorithm \[AQA\]), or * 2 point increase from baseline in the AQA, or Death. |
Countries
Australia, Belgium, Canada, France, Germany, Greece, Italy, Portugal, Spain, United Kingdom, United States
Participant flow
Recruitment details
A multi-centre, double-blind, placebo-controlled, randomised trial which assess the efficacy of of xentuzumab in combination with everolimus and exemestane over everolimus and exemestane in patients with Hormon Receptor+ (HR+)/ Human epidermal growth factor receptor 2 (HER2)- advanced or metastatic breast cancer and non-visceral disease.
Pre-assignment details
All patients were screened for eligibility prior to participation in the trial. Patients were screened from 53 investigational sites in 11 countries, to ensure that they (the patients) strictly met all inclusion and none of the exclusion criteria. Screening could occur 1-28 days prior to randomisation to study treatment, patients were not to be randomised if any of the entry criteria were violated. Re-screening was allowed but only once per patient.
Participants by arm
| Arm | Count |
|---|---|
| 1000 mg Xentuzumab + 10 mg Everolimus + 25 mg Exemestane 1000 mg concentrate for solution for infusion of Xentuzumab (BI 836845) (10mg/mL supplied in 20mL vials (200mg/vial)) was administered once weekly as intravenous infusion over 1 hour on day 1, 8, 15 and 22 of 28-days cycles and on day 1, 8, 15, 22, 29, 36, 43 and 50 of 56-day cycles and tablets of 10 mg of Everolimus (Afinitor®) and tablets of 25 mg Exemestane (Aromasin®) were administered orally once per day at approximately the same time of day, after a meal. | 52 |
| Placebo + 10 mg Everolimus + 25 mg Exemestane Concentrate for solution for infusion of Placebo was administered once weekly as intravenous infusion of 1 hour on day 1, 8, 15 and 22 of 28-days cycles and on day 1, 8, 15, 22, 29, 36, 43 and 50 of 56-day cycles and tablets of 10 mg of Everolimus (Afinitor®) and tablets of 25 mg Exemestane (Aromasin®) were administered orally once per day at approximately the same time of day, after a meal. | 51 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 6 |
| Overall Study | Covid-19 related | 1 | 1 |
| Overall Study | Lack of clinical benefit | 0 | 1 |
| Overall Study | Not treated | 2 | 0 |
| Overall Study | Progressive disease | 37 | 31 |
| Overall Study | Sponsor decision/recommendation | 3 | 2 |
| Overall Study | Study closure | 2 | 2 |
| Overall Study | Switched to other drug/therapy | 2 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 6 |
Baseline characteristics
| Characteristic | Placebo + 10 mg Everolimus + 25 mg Exemestane | Total | 1000 mg Xentuzumab + 10 mg Everolimus + 25 mg Exemestane |
|---|---|---|---|
| Age, Continuous | 60.3 Years STANDARD_DEVIATION 9.6 | 60.6 Years STANDARD_DEVIATION 10.5 | 60.9 Years STANDARD_DEVIATION 11.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants | 84 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 14 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants | 15 Participants | 6 Participants |
| Race (NIH/OMB) White | 41 Participants | 85 Participants | 44 Participants |
| Sex: Female, Male Female | 51 Participants | 103 Participants | 52 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 52 | 10 / 51 |
| other Total, other adverse events | 48 / 50 | 50 / 51 |
| serious Total, serious adverse events | 13 / 50 | 18 / 51 |
Outcome results
Primary
Progression Free Survival (PFS)
Progression-free survival (PFS) defined as the time from randomisation until progressive disease (PD) according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) in combination with modified MD Anderson Criteria (for bone lesion assessment), based on blinded independent assessment or death from any cause, whichever occurred earlier. As per RECIST, PD is defined as at least a 20% increase in the sum of diameters of target lesions, unequivocal progression of non-target lesions or the appearance of new lesions.
Time frame: From randomisation until the earliest of disease progression, death or the time point of primary PFS analysis, up to 892 days.
Population: Randomised Set (RS): The randomised set included all randomised patients, regardless of whether they received treatment or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1000 mg Xentuzumab + 10 mg Everolimus + 25 mg Exemestane | Progression Free Survival (PFS) | 12.7 Months |
| Placebo + 10 mg Everolimus + 25 mg Exemestane | Progression Free Survival (PFS) | 11.0 Months |
Comparison: Cox proportional hazards model stratified for presence of baseline bone-only metastases, prior cyclin-dependent kinase (CDK) 4/6 inhibitor treatment and menopause status.p-value: 0.653495% CI: [0.55, 2.59]Log-rank test
Secondary
Duration of Disease Control (DC)
Duration of disease control (DC), defined as the time from randomisation until the earliest of disease progression (according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) in combination with modified MD Anderson Criteria (for bone lesion assessment) or death from any cause, among patients with DC. Duration of DC was assessed by independent reviewers. The duration of DC was calculated as followed: For patients with disease progression or death: Duration of DC \[days\] = date of outcome - date of randomisation + 1 For patients without disease progression or death: Duration of DC (censored) \[days\] = date of outcome - date of randomisation + 1
Time frame: From randomisation until the earliest of progressive disease or death from any cause, up to 892 days.
Population: Randomised Set (RS): The randomised set included all randomised patients, regardless of whether they received treatment or not. Only participants with disease control are reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1000 mg Xentuzumab + 10 mg Everolimus + 25 mg Exemestane | Duration of Disease Control (DC) | 14.6 Months |
| Placebo + 10 mg Everolimus + 25 mg Exemestane | Duration of Disease Control (DC) | 18.4 Months |
Secondary
Number of Participants With Objective Response (OR)
Number of participants with objective response (OR) by independent assessment. OR is defined as a best overall response of complete response (CR) or partial response (PR). Best overall response is defined according to RECIST v1.1 in combination with modified MD Anderson Criteria (for bone lesion assessment) and will consider all tumor assessments from randomisation until the earliest of PD, start of subsequent anti-cancer therapy, loss to follow-up, withdrawal of consent or death. To be aligned with the primary endpoint derivation, tumor assessments after two or more consecutively misses assessments were not considered.
Time frame: From randomisation until end of treatment, up to 892 days.
Population: Randomised Set (RS): The randomised set included all randomised patients, regardless of whether they received treatment or not.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1000 mg Xentuzumab + 10 mg Everolimus + 25 mg Exemestane | Number of Participants With Objective Response (OR) | 6 Participants |
| Placebo + 10 mg Everolimus + 25 mg Exemestane | Number of Participants With Objective Response (OR) | 5 Participants |
p-value: 0.775995% CI: [0.34, 4.43]Regression, Logistic
Secondary
Number of Patients With Disease Control (DC)
Disease control (DC) was defined as a best overall response (BOR) of either complete response (CR), partial response (PR), stable disease (SD) or Non-CR/No-PD. SD and Non-CR/Non-PR must have been observed up until at least week 24 tumor assessment. BOR was defined according to RECIST v1.1 in combination with modified MD Anderson Criteria (for bone lesion assessment) based on all evaluable tumor assessments from randomisation until the earliest of PD, start of subsequent anti-cancer therapy, loss to follow-up, withdrawal of consent or death. To be aligned with the primary endpoint derivation, tumor assessments after two or more consecutively misses assessments were not considered. DC was assessed by independent reviewers.
Time frame: From randomisation until the earliest of progressive disease or death from any cause, up to 892 days.
Population: Randomised Set (RS): The randomised set included all randomised patients, regardless of whether they received treatment or not.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1000 mg Xentuzumab + 10 mg Everolimus + 25 mg Exemestane | Number of Patients With Disease Control (DC) | 29 Participants |
| Placebo + 10 mg Everolimus + 25 mg Exemestane | Number of Patients With Disease Control (DC) | 25 Participants |
p-value: 0.493295% CI: [0.6, 2.86]Regression, Logistic
Secondary
Overall Survival (OS)
Overall survival (OS) defined as the time from randomisation until death from any cause. For patients with 'event' as an outcome for OS: OS\[days\] = date of outcome - date of randomisation + 1. For patients with 'censored' as an outcome for OS: OS (censored)\[days\] = date of outcome - date of randomisation + 1.
Time frame: From randomisation until death from any cause, up to 995 days.
Population: Randomised Set (RS): The randomised set included all randomised patients, regardless of whether they received treatment or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1000 mg Xentuzumab + 10 mg Everolimus + 25 mg Exemestane | Overall Survival (OS) | NA Months |
| Placebo + 10 mg Everolimus + 25 mg Exemestane | Overall Survival (OS) | NA Months |
Comparison: Cox proportional hazards model stratified for presence of baseline bone-only metastases, prior cyclin-dependent kinase (CDK) 4/6 inhibitor treatment and menopause status.p-value: 0.179795% CI: [0.18, 1.4]Log rank test
Secondary
Time to Pain Progression or Intensification of Pain Palliation
Time to pain progression or intensification of pain palliation was defined as the time from randomisation until the earliest of: * 2 point increase from baseline in the Brief Pain Inventory - Short Form (BPI-SF), Item 3 (worst pain), without a decrease (of ≥1 point) from baseline analgesics use (via the 8-point Analgesic Quantification Algorithm \[AQA\]), or * 2 point increase from baseline in the AQA, or Death.
Time frame: From randomisation until the earliest of pain progression, intensification of pain palliation, death or the time point of progression free survival analysis, up to 843 days.
Population: Randomised Set (RS): The randomised set included all randomised patients, regardless of whether they received treatment or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1000 mg Xentuzumab + 10 mg Everolimus + 25 mg Exemestane | Time to Pain Progression or Intensification of Pain Palliation | 5.6 Months |
| Placebo + 10 mg Everolimus + 25 mg Exemestane | Time to Pain Progression or Intensification of Pain Palliation | 3.0 Months |
Comparison: Cox proportional hazards model stratified for presence of baseline bone-only metastases, prior cyclin-dependent kinase (CDK) 4/6 inhibitor treatment and menopause status.p-value: 0.927995% CI: [0.54, 1.76]Log Rank