Advanced Breast Cancer, Breast Cancer
Conditions
Keywords
HER2, ErbB2, metastatic, neratinib, lapatinib, capecitabine, HKI-272, Nerlynx, PB-272
Brief summary
This is a study of an experimental drug (neratinib) versus a combination of drugs (lapatinib and capecitabine) in women who have erbB-2 (HER-2) positive metastatic or locally advanced breast cancer. The goal of this study is to compare the two regimens in shrinking tumors and extending the lives of women with erbB2 (HER2) positive breast cancer. The study will also compare the safety of the two regimens and to compare quality of life of patients taking the two regimens.
Interventions
DRUGNeratinib
Tablets 240 mg orally once per day until disease progression or unacceptable toxicity
DRUGLapatinib
Tablets 1250 mg orally once per day until disease progression or unacceptable toxicity.
DRUGCapecitabine
Tablets 2000 mg/m² given orally in two evenly divided daily doses for first 14 days of each 21 day cycle. Given until disease progression or unacceptable toxicity.
Sponsors
Puma Biotechnology, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Stage IIIB, IIIC, or IV erbB2 (HER2) positive breast cancer * Prior use of Herceptin (trastuzumab), and a taxane * Adequate cardiac and renal function
Exclusion criteria
* More than 2 prior Herceptin (trastuzumab) regimens or prior use of Xeloda (capecitabine) and / or Tykerb (lapatinib) \[Tyverb\] * Bone as the only site of disease * Active central nervous system metastases (subjects should be stable and off anticonvulsants and steroids) * Significant gastrointestinal disorder with diarrhea as major symptom
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From randomization date to progression or death, assessed up to 69 months | Progression Free Survival, Measured in Months, for Subjects Randomized. Investigator assessment. The time interval from the date of randomization until the earliest date of progression per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) or death due to any cause. For subjects without death or progression, censorship was at the last valid tumor assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR). | From randomization date to progression or last tumor assessment, assessed up to 69 months | Objective Response Rate, investigator assessment. The ORR was defined as the percentage of participants demonstrating a confirmed objective response, either Complete Response (CR) or Partial Response (PR) during the study per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; and Non-PD for non-target lesions, and no new lesions. |
| Clinical Benefit Rate | From randomization date to progression or last tumor assessment, assessed up to 69 months | Clinical benefit rate (CR, PR, or SD = 24 weeks) for women For ErbB2 Positive Advanced Breast Cancer. Clinical benefit rate was the percentage of subjects who achieved overall tumor response per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Clinical Benefit (CB) = CR + PR + SD \>= 24 weeks. |
| Overall Survival (OS) | From randomization date to death, assessed up to 69 months | Overall Survival (OS) was defined as the time from randomization to death due to any cause. Subjects last known to be alive were censored at the last date of last contact or the data cutoff employed for the analysis, whichever was earlier. |
| Frequency of CNS Metastases (Frequency) | From randomization date to first CNS symptom or lesions | The percent of patients with symptomatic or progressive CNS lesions was the proportion of subjects who had PD considering CNS lesions only, according to RECIST criteria. |
| Time to CNS Metastases | From randomization date to first CNS symptom or lesions | Time to symptomatic or progressive Central nervous system (CNS) lesions. Time to symptomatic or progressive CNS lesions was the time from the date of randomization until the date of progressive disease (PD) considering CNS lesions only (ie, appearance of newly diagnosed CNS lesions or progressive CNS lesions). |
| Duration of Response | From start date of response to first PD, assessed up to 69 months after the first subject was randomized. | Duration of response was measured from the time at which response criteria were met for complete response (CR) or partial response (PR) (whichever status was recorded first) until the first date of recurrence or progressive disease (PD) or death. For subjects without death or progression, censorship was at the last valid tumor assessment per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Croatia, Czechia, France, Germany, Greece, Hong Kong, Hungary, Italy, Japan, Jordan, Mexico, Poland, Puerto Rico, Romania, Russia, Serbia, Singapore, Slovenia, South Africa, South Korea, Spain, Switzerland, Taiwan, Thailand, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Neratinib Neratinib
Neratinib: Tablets, 240mg once per day until disease progression or unacceptable toxicity | 117 |
| Lapatinib+Capecitabine Lapatinib plus Capecitabine
Lapatinib: Tablets 1250mg once per day until disease progression or unacceptable toxicity.
Capecitabine: Tablets 2000mg/m2 given in two evenly divided daily doses for first 14 days of each 21 day cycle. Given until disease progression or unacceptable toxicity. | 116 |
| Total | 233 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 48 | 43 |
| Overall Study | Discontinuation of Study by Sponsor | 1 | 0 |
| Overall Study | Failed to Return | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Withdrawal by Subject | 11 | 6 |
Baseline characteristics
| Characteristic | Neratinib | Lapatinib+Capecitabine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 13 Participants | 16 Participants | 29 Participants |
| Age, Categorical Between 18 and 65 years | 104 Participants | 100 Participants | 204 Participants |
| Age, Continuous | 53.1 years STANDARD_DEVIATION 10.11 | 54.7 years STANDARD_DEVIATION 13.8 | 54.3 years STANDARD_DEVIATION 12.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 32 Participants | 46 Participants | 78 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 6 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) White | 77 Participants | 64 Participants | 141 Participants |
| Sex: Female, Male Female | 117 Participants | 116 Participants | 233 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 | — / — | — / — |
| other Total, other adverse events | 113 / 116 | 114 / 115 |
| serious Total, serious adverse events | 31 / 116 | 24 / 115 |
Outcome results
Primary
Progression Free Survival
Progression Free Survival, Measured in Months, for Subjects Randomized. Investigator assessment. The time interval from the date of randomization until the earliest date of progression per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) or death due to any cause. For subjects without death or progression, censorship was at the last valid tumor assessment.
Time frame: From randomization date to progression or death, assessed up to 69 months
Population: Intent to Treat population, includes all subjects who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neratinib | Progression Free Survival | 4.53 months |
| Lapatinib+Capecitabine | Progression Free Survival | 6.83 months |
p-value: 0.23195% CI: [0.89, 1.6]Log Rank
Secondary
Clinical Benefit Rate
Clinical benefit rate (CR, PR, or SD = 24 weeks) for women For ErbB2 Positive Advanced Breast Cancer. Clinical benefit rate was the percentage of subjects who achieved overall tumor response per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Clinical Benefit (CB) = CR + PR + SD \>= 24 weeks.
Time frame: From randomization date to progression or last tumor assessment, assessed up to 69 months
Population: Intent to Treat population, includes all subjects who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neratinib | Clinical Benefit Rate | 44.4 percentage of participants |
| Lapatinib+Capecitabine | Clinical Benefit Rate | 63.8 percentage of participants |
Secondary
Duration of Response
Duration of response was measured from the time at which response criteria were met for complete response (CR) or partial response (PR) (whichever status was recorded first) until the first date of recurrence or progressive disease (PD) or death. For subjects without death or progression, censorship was at the last valid tumor assessment per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions.
Time frame: From start date of response to first PD, assessed up to 69 months after the first subject was randomized.
Population: No. of Subjects with either complete or partial response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neratinib | Duration of Response | 12.48 months |
| Lapatinib+Capecitabine | Duration of Response | 7.98 months |
Secondary
Frequency of CNS Metastases (Frequency)
The percent of patients with symptomatic or progressive CNS lesions was the proportion of subjects who had PD considering CNS lesions only, according to RECIST criteria.
Time frame: From randomization date to first CNS symptom or lesions
Population: Intent to Treat population, includes all subjects who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Frequency of CNS Metastases (Frequency) | 9.4 percentage of participants |
| Lapatinib+Capecitabine | Frequency of CNS Metastases (Frequency) | 12.9 percentage of participants |
Secondary
Objective Response Rate (ORR).
Objective Response Rate, investigator assessment. The ORR was defined as the percentage of participants demonstrating a confirmed objective response, either Complete Response (CR) or Partial Response (PR) during the study per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; and Non-PD for non-target lesions, and no new lesions.
Time frame: From randomization date to progression or last tumor assessment, assessed up to 69 months
Population: Intent to Treat population, includes all subjects who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Objective Response Rate (ORR). | 29.1 percentage of participants |
| Lapatinib+Capecitabine | Objective Response Rate (ORR). | 40.5 percentage of participants |
Secondary
Overall Survival (OS)
Overall Survival (OS) was defined as the time from randomization to death due to any cause. Subjects last known to be alive were censored at the last date of last contact or the data cutoff employed for the analysis, whichever was earlier.
Time frame: From randomization date to death, assessed up to 69 months
Population: Intent to Treat population, includes all subjects who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neratinib | Overall Survival (OS) | 19.74 months |
| Lapatinib+Capecitabine | Overall Survival (OS) | 23.62 months |
Secondary
Time to CNS Metastases
Time to symptomatic or progressive Central nervous system (CNS) lesions. Time to symptomatic or progressive CNS lesions was the time from the date of randomization until the date of progressive disease (PD) considering CNS lesions only (ie, appearance of newly diagnosed CNS lesions or progressive CNS lesions).
Time frame: From randomization date to first CNS symptom or lesions
Population: Intent to Treat population, includes all subjects who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neratinib | Time to CNS Metastases | 19.68 months |
| Lapatinib+Capecitabine | Time to CNS Metastases | NA months |