Neoplasms, Breast
Conditions
Keywords
VEGF, Tyrosine kinase, ErbB2, Her2-neu, metastatic breast cancer, EGFR, ErbB1, bevacizumab, lapatinib, breast carcinoma, breast cancer, breast lump, breast cancer positive for human epidermal growth factor receptor 2 (HER2), HER2 positive metastatic breast cancer, breast cancer progression, estrogen-receptor (ER) positive(+) breast cancer, Paget's disease
Brief summary
This study will examine the efficacy and safety of lapatinib and bevacizumab in patients with ErbB2-overexpressing breast cancer.
Interventions
DRUGlapatinib
1500 mg oral lapatinib (once daily)
DRUGbevacizumab
10 mg/kg intravenous bevacizumab (every two weeks)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Females that are at least 18 years of age. * Women of childbearing potential must have a negative serum pregnancy test at screening. * Documented evidence of HER2-overexpressing unresectable or metastatic breast cancer. Disease may/may not have been treated in metastatic setting. * Subjects are permitted (but not required) to have previously-treated brain metastases that are stable and asymptomatic. * Adequate hepatic, renal and cardiac function * ECOG score 0-1 and a life expectancy of at least 12 weeks. * Able to swallow oral medication * Signed informed consent
Exclusion criteria
* Pregnancy * Unstable or symptomatic CNS metastases * Major surgery within 28 days of enrollment (minor surgery within 7 days). * Prior anti-cancer treatment within 14 days of enrollment, or unresolved treatment-related toxicities. * A serious non-healing wound, ulcer, or bone fracture at baseline. * Class II, III or IV heart failure as defined by the NYHA functional classification system * History of significant vascular disease, arterial thrombosis, unstable INR, hypertensive crisis, or uncontrolled hypertension. * History of myocardial infarction, stenting procedure, or angioplasty within 6 months of enrollment. * History of abdominal fistulae, gastrointestinal perforation, or intra-abdominal abscess within 6 months of enrollment. * History of malabsorption syndrome, ulcerative colitis, or bowel obstruction. * Proteinuria * Requires concurrent anti-cancer treatment or investigational treatment. * Known hypersensitivity to either study medication * Received investigational treatment within 28 days or 5 half-lives, whichever is longer * Concurrent disease or circumstances that would lead the investigator would consider the subject an inappropriate candidate for the study * Requires medication that has been excluded during study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-evaluated Crude Progression-free Survival Rate After 12 Weeks of Study Treatment | up to week 12 | The PFS rate is defined as the percentage of subjects who have shown no evidence of disease progression or death from any cause following 12 weeks of treatment. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Since there is no independent reviewer, only the investigator response was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Tumor Response Rate Per Investigator Assessment (RECIST) | This endpoint was defined in the original protocol but was cancelled per Amendment 3, which was implemented Nov 2015. The timeframe therefore is from treatment start to Nov 2015, with a maximum timeframe of approx. 8.7 years. | Overall Tumor Response Rate is defined as the percentage of subjects achieving either a confirmed complete (CR) or partial (PR) tumor response by investigator and per the Response Evaluation Criteria in Solid Tumors (RECIST). For each subject, the best tumor response during the study are considered the 'Overall Tumor Response.' Subjects with unknown or missing response are treated as non-responders; i.e. they are included in the denominator when calculating the percentage. |
| Investigator-Assessed Clinical Benefit Response Rate (%) (RECIST) | This endpoint was defined in the original protocol but was cancelled per Amendment 3, which was implemented Nov 2015. The timeframe therefore is from treatment start to Nov 2015, with a maximum timeframe of approx. 8.7 years. | Clinical Benefit Rate is defined as the percentage of subjects with evidence of confirmed complete or partial tumor responses at any time or stable disease for at least 24 weeks per the Response Evaluation Criteria in Solid Tumors (RECIST). Subjects with unknown or missing response are treated as non-responders (i.e. not Complete response (CR), Partial response (PR) or Stable Disease (SD)). |
| Overall Tumor Response - Best Response Per Investigator Assessment (RECIST) | This endpoint was defined in the original protocol but was cancelled per Amendment 3, which was implemented Nov 2015. The timeframe therefore is from treatment start to Nov 2015, with a maximum timeframe of approx. 8.7 years. | Overall Tumor Response - Best Response per Investigator Assessment Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by image including CT, MRI or bone scan: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. For each subject, the best tumor response during the study was considered to be the 'Overall Tumor Response' per the Response Evaluation Criteria in Solid Tumors (RECIST). |
| Progression-free Survival - Kaplan-Meier Estimates for Progression-free Survival (Weeks) - Median | This endpoint was defined in the original protocol but was cancelled per Amendment 3, which was implemented Nov 2015. The timeframe therefore is from treatment start to Nov 2015, with a maximum timeframe of approx. 8.7 years. | Progression-free survival (PFS) = time from treatment start date until the first documented sign of disease progression, as defined by the investigator, or death due to any cause. For participants who did not progress or die at the time of reporting, PFS data were censored at the time of the last radiological assessment. Greenwood's formula was used to calculate the standard error of the estimates from the Kaplan-Meier curve. |
| Progression-free Survival - Kaplan-Meier Estimates for Progression-free Survival (Weeks) - 1st and 3rd Quartile | This endpoint was defined in the original protocol but was cancelled per Amendment 3, which was implemented Nov 2015. The timeframe therefore is from treatment start to Nov 2015, with a maximum timeframe of approx. 8.7 years. | Progression-free survival (PFS) = time from treatment start date until the first documented sign of disease progression, as defined by the investigator, or death due to any cause. For participants who did not progress or die at the time of reporting, PFS data were censored at the time of the last radiological assessment. Greenwood's formula was used to calculate the standard error of the estimates from the Kaplan-Meier curve. |
| Progression-free Survival | This endpoint was defined in the original protocol but was cancelled per Amendment 3, which was implemented Nov 2015. The timeframe therefore is from treatment start to Nov 2015, with a maximum timeframe of approx. 8.7 years. | Progression-free survival (PFS) = time from treatment start date until the first documented sign of disease progression, as defined by the investigator, or death due to any cause. For participants who did not progress or die at the time of reporting, PFS data were censored at the time of the last radiological assessment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lapatinib + Bevacizumab Lapatinib (1500 mg once daily taken orally) and bevacizumab (10 mg/kg intravenously \[IV\] every two weeks) | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Physician Decision | 5 |
| Overall Study | progressive disease | 1 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Lapatinib + Bevacizumab |
|---|---|
| Age, Continuous | 52.5 years STANDARD_DEVIATION 10.2 |
| Race/Ethnicity, Customized African American/African Heritage | 7 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Asian and White | 1 Participants |
| Race/Ethnicity, Customized White/Caucasian/European Heritage | 42 Participants |
| Sex: Female, Male Female | 52 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 52 |
| other Total, other adverse events | 52 / 52 |
| serious Total, serious adverse events | 13 / 52 |
Outcome results
Primary
Investigator-evaluated Crude Progression-free Survival Rate After 12 Weeks of Study Treatment
The PFS rate is defined as the percentage of subjects who have shown no evidence of disease progression or death from any cause following 12 weeks of treatment. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Since there is no independent reviewer, only the investigator response was reported.
Time frame: up to week 12
Population: Intent-to-Treat (ITT) Population: all enrolled participants, regardless of whether or not they received any study medication
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lapatinib + Bevacizumab | Investigator-evaluated Crude Progression-free Survival Rate After 12 Weeks of Study Treatment | No disease progression by Week 12 | 36 Participants |
| Lapatinib + Bevacizumab | Investigator-evaluated Crude Progression-free Survival Rate After 12 Weeks of Study Treatment | Disease progression or death by Week 12 | 16 Participants |
95% CI: [54.9, 81.3]
Secondary
Investigator-Assessed Clinical Benefit Response Rate (%) (RECIST)
Clinical Benefit Rate is defined as the percentage of subjects with evidence of confirmed complete or partial tumor responses at any time or stable disease for at least 24 weeks per the Response Evaluation Criteria in Solid Tumors (RECIST). Subjects with unknown or missing response are treated as non-responders (i.e. not Complete response (CR), Partial response (PR) or Stable Disease (SD)).
Time frame: This endpoint was defined in the original protocol but was cancelled per Amendment 3, which was implemented Nov 2015. The timeframe therefore is from treatment start to Nov 2015, with a maximum timeframe of approx. 8.7 years.
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lapatinib + Bevacizumab | Investigator-Assessed Clinical Benefit Response Rate (%) (RECIST) | 38.5 Percentage of participants |
Secondary
Overall Tumor Response - Best Response Per Investigator Assessment (RECIST)
Overall Tumor Response - Best Response per Investigator Assessment Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by image including CT, MRI or bone scan: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. For each subject, the best tumor response during the study was considered to be the 'Overall Tumor Response' per the Response Evaluation Criteria in Solid Tumors (RECIST).
Time frame: This endpoint was defined in the original protocol but was cancelled per Amendment 3, which was implemented Nov 2015. The timeframe therefore is from treatment start to Nov 2015, with a maximum timeframe of approx. 8.7 years.
Population: ITT Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lapatinib + Bevacizumab | Overall Tumor Response - Best Response Per Investigator Assessment (RECIST) | Stable disease | 26 Participants |
| Lapatinib + Bevacizumab | Overall Tumor Response - Best Response Per Investigator Assessment (RECIST) | Unknown | 8 Participants |
| Lapatinib + Bevacizumab | Overall Tumor Response - Best Response Per Investigator Assessment (RECIST) | Complete response | 0 Participants |
| Lapatinib + Bevacizumab | Overall Tumor Response - Best Response Per Investigator Assessment (RECIST) | Partial response | 7 Participants |
| Lapatinib + Bevacizumab | Overall Tumor Response - Best Response Per Investigator Assessment (RECIST) | Progressive Disease | 11 Participants |
Secondary
Overall Tumor Response Rate Per Investigator Assessment (RECIST)
Overall Tumor Response Rate is defined as the percentage of subjects achieving either a confirmed complete (CR) or partial (PR) tumor response by investigator and per the Response Evaluation Criteria in Solid Tumors (RECIST). For each subject, the best tumor response during the study are considered the 'Overall Tumor Response.' Subjects with unknown or missing response are treated as non-responders; i.e. they are included in the denominator when calculating the percentage.
Time frame: This endpoint was defined in the original protocol but was cancelled per Amendment 3, which was implemented Nov 2015. The timeframe therefore is from treatment start to Nov 2015, with a maximum timeframe of approx. 8.7 years.
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lapatinib + Bevacizumab | Overall Tumor Response Rate Per Investigator Assessment (RECIST) | 13.5 Percentage of participants |
Secondary
Progression-free Survival
Progression-free survival (PFS) = time from treatment start date until the first documented sign of disease progression, as defined by the investigator, or death due to any cause. For participants who did not progress or die at the time of reporting, PFS data were censored at the time of the last radiological assessment.
Time frame: This endpoint was defined in the original protocol but was cancelled per Amendment 3, which was implemented Nov 2015. The timeframe therefore is from treatment start to Nov 2015, with a maximum timeframe of approx. 8.7 years.
Population: ITT Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lapatinib + Bevacizumab | Progression-free Survival | Progressed or Died (event) | 39 Participants |
| Lapatinib + Bevacizumab | Progression-free Survival | Censored, Follow-up ended | 13 Participants |
Secondary
Progression-free Survival - Kaplan-Meier Estimates for Progression-free Survival (Weeks) - 1st and 3rd Quartile
Progression-free survival (PFS) = time from treatment start date until the first documented sign of disease progression, as defined by the investigator, or death due to any cause. For participants who did not progress or die at the time of reporting, PFS data were censored at the time of the last radiological assessment. Greenwood's formula was used to calculate the standard error of the estimates from the Kaplan-Meier curve.
Time frame: This endpoint was defined in the original protocol but was cancelled per Amendment 3, which was implemented Nov 2015. The timeframe therefore is from treatment start to Nov 2015, with a maximum timeframe of approx. 8.7 years.
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lapatinib + Bevacizumab | Progression-free Survival - Kaplan-Meier Estimates for Progression-free Survival (Weeks) - 1st and 3rd Quartile | Estimates for progression-free survival 3rd Quartile (weeks) | 35.6 weeks |
| Lapatinib + Bevacizumab | Progression-free Survival - Kaplan-Meier Estimates for Progression-free Survival (Weeks) - 1st and 3rd Quartile | Estimates for progression-free survival 1st Quartile (weeks) | 12.9 weeks |
Secondary
Progression-free Survival - Kaplan-Meier Estimates for Progression-free Survival (Weeks) - Median
Progression-free survival (PFS) = time from treatment start date until the first documented sign of disease progression, as defined by the investigator, or death due to any cause. For participants who did not progress or die at the time of reporting, PFS data were censored at the time of the last radiological assessment. Greenwood's formula was used to calculate the standard error of the estimates from the Kaplan-Meier curve.
Time frame: This endpoint was defined in the original protocol but was cancelled per Amendment 3, which was implemented Nov 2015. The timeframe therefore is from treatment start to Nov 2015, with a maximum timeframe of approx. 8.7 years.
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lapatinib + Bevacizumab | Progression-free Survival - Kaplan-Meier Estimates for Progression-free Survival (Weeks) - Median | 24.7 weeks |