Neoplasms, Breast
Conditions
Keywords
Advanced Metastatic Breast Cancer, HER2 positive, HER2+, breast cancer, lapatinib, TYVERB, TYKERB, Capecitabine
Brief summary
Local study in China and Hong Kong to evaluate safety and efficacy in lapatinib + capecitabine in women with Human epidermal growth factor receptor 2 (HER2) positive advanced or metastatic breast cancer.
Detailed description
The Primary objective of the study was to evaluate the overall clinical benefit response (CBR) rate. This was a single arm, open-label, multi-center study of lapatinib plus capecitabine in women from mainland China and Hong Kong who had advanced or metastatic breast cancer that progressed on prior chemotherapies with or without trastuzumab. Participants received study treatment until disease progression, unacceptable toxicity, or withdrawal for any other reasons.
Interventions
DRUGlapatinib
Lapatinib ditosylate monohydrate tablets, 250 mg, are oval, biconvex, orange, film-coated tablets taken orally.
DRUGcapecitabine
Capecitabine is supplied as a biconvex, oblong, light peach and peach colored, film-coated tablets for oral administration.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent; * Female ≥18 years; * Pathology that has histologically confirmed invasive breast cancer with stage IIIb/c or stage IV disease; • If recurrent disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology or histology. * Documented overexpression of Her2 (ErbB2) of IHC 3+ or FISH positive, in primary or metastatic tumor tissue is required for enrollment into the study; by local testing or central laboratory testing determined by country of residence. NB. Approximately, 51 subjects will be enrolled in a single stage design to test for efficacy in women from China and Hong Kong. Due to the fact that trastuzumab is not commonly prescribed in China and Hong Kong, the current study allows up to 40% of subjects who are trastuzumab naïve to be enrolled. * Prior therapies must include at minimum a taxane and/or anthracycline and may include trastuzumab if available; other prior regimens are not limited except capecitabine and Erbb2 inhibitors other than trastuzumab. Chemo regimen requirements are as follows: * Taxane containing regimen for at least 4 cycles or \<4 cycles provided disease progression or treatment limiting toxicity occurred while on taxane * Anthracycline containing regimen for at least 4 cycles or \<4 cycles provided disease progression or treatment limiting toxicity occurred while on anthracycline * Taxanes and Anthracyclines may have been administered concurrently or separately * Prior treatment may have contained trastuzumab alone or in combination with other chemotherapy in the adjuvant, locally advanced or metastatic setting and patient must have failed the treatment * Prior treatment with capecitabine is not permitted unless 6 months have elapsed since the last dose of capecitabine and the subject is free of any capecitabine related toxicity * Prior therapy with an ErbB1 and/or ErbB2 inhibitor, other than trastuzumab is not permitted * Other prior chemo-regimens not listed above are unlimited. * For those subjects whose disease is ER+ and/or PR+ one of following criteria should be met. * Subjects who received hormonal therapy and are no longer benefiting from this therapy and the hormonal treatment must have been stopped before the first dose of investigational treatment * Subjects with visceral disease that requires chemotherapy (eg., subjects with liver or lung metastases) * Rapidly progressing or life threatening disease, as determined by the investigator * Subjects with stable CNS metastases (asymptomatic and off systemic steroids and anticonvulsants for at least 3 months) are eligible * Measurable lesion(s) according to RECIST (Response Evaluation Criteria in Solid Tumors); * Radiotherapy as palliative treatment for painful metastatic disease is permitted but must have been stopped within 2 weeks prior to initiation of any investigational treatment. All subjects must have recovered from all radiotherapy related toxicities prior to initiation of any investigational treatment. The site of radiotherapy must not be used as a site of measurable disease; * Cardiac ejection fraction within institutional range of normal as measured by echocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive; * ECOG Performance Status of 0 to 1; * Life expectancy of ≥ 12 weeks; * Able to swallow and retain oral medication; * Women with potential to have children must be willing to practice acceptable methods of birth control during the study; * Willing to complete all screening assessments as outlined in the protocol; * Adequate organ function as defined by the Table of Baseline Laboratory Values
Exclusion criteria
* Pregnant or lactating females at anytime during the study * Subjects with only non-measurable metastatic sites of disease per RECIST, (e.g. bone metastases, pleural effusion, or ascites, etc.); * Planned concurrent anti-cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy) while taking investigational treatment; * Unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment; * Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded; * History of other malignancy. However, subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma, are eligible; * Concurrent disease or condition that would make the subject inappropriate for study participation, or any serious medical disorder that would interfere with the subject's safety; * Uncontrolled infection; * Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate (CBR) | Baseline; every 6 weeks for the first 36 weeks and then every 12 weeks until disease progression. The maximum time participants were followed was approx. 90 months | CBR is defined by the percentage of participants achieving either a confirmed tumor response of complete response (CR) or partial response (PR) or stable disease (SD) for at least 24 weeks. Response Criteria in Solid Tumors (RECIST) is a system for measuring tumor shrinkage or progression in terms of the longest dimensions of the tumor on imaging scans such as computerized tomography (CT). A partial response requires a decrease of 30% or more, complete response requires all target lesions disappear, Progression requires an increase of at least 20%, and Stable disease falls in between these two. All responses have a repeat assessment to confirm the response. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Baseline; every 6 weeks for the first 36 weeks and then every 12 weeks until disease progression. The maximum time participants were followed was 90.38 months. | PFS is defined as the time from first dose date until the date of disease progression or death due to any reason, whichever occurs first. |
| Six Months Progression-Free Survival | at Baseline and every 6 weeks for the first 36 weeks and then every 12 weeks until disease progression. The maximum time participants were followed up to 90.38 months, with 6 months PFS reported. | Six Months Progression-Free Survival is defined as the percentage of surviving participants who are progression-free longer than six months (greather than 180 days) after the first start date of study treatment. |
| Time to Response (TTR) | Baseline; every 6 weeks for the first 36 weeks and then every 12 weeks until disease progression. The maximum time participants were followed was approx. 14.78 months | Time to response is defined as the time from first dose date until first documentation of disease response. TTR only applied to participants for whom best overall response was complete response (CR), partial response (PR) or stable disease (SD). Participants who had not had a partial response, complete response or stable disease at the cut-off date for this endpoint analysis were censored for time to response. |
| Duration of Response (DOR) | Baseline; every 6 weeks for the first 36 weeks and then every 12 weeks until disease progression. The maximum time participants were followed was 88.80 months. | Duration of response (complete response, partial response or stable disease) is defined as the time of first documentation of disease response until the date of disease progression or death due to breast cancer, whichever occurs first. DOR only applied to participants for whom best overall response was complete response (CR), partial response (PR) or stable disease (SD). Participants who had not had a partial response, complete response or stable disease at the cut-off date for this endpoint analysis were censored for duration of response. |
| Number of Participants With Central Nervous System (CNS) as First Site of Relapse | Baseline; every 6 weeks for the first 36 weeks and then every 12 weeks until disease progression. The maximum time participants were followed was 90 months | Number of participants who had Central Nervous System metastasis as the first site of relapse. CT, Magnetic Resonance Imaging, etc. were used for the assessment. |
Countries
China, Hong Kong
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lapatinib + Capecitabine Daily oral lapatinib (1250 mg/day) in combination with capecitabine (2000 mg/m2/day on Days 1-14 every 21 Days); m2 = Square meter: Body Surface Area | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
| Overall Study | Death | 7 |
| Overall Study | Disease progression | 32 |
| Overall Study | Missing | 3 |
| Overall Study | Subject received new anti-cancer chemotherapy/traditional Chinese medicine | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Lapatinib + Capecitabine |
|---|---|
| Age, Continuous | 48.8 years STANDARD_DEVIATION 10.61 |
| Race/Ethnicity, Customized Chinese | 52 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 | 2 / 52 |
| other Total, other adverse events | 49 / 52 |
| serious Total, serious adverse events | 4 / 52 |
Outcome results
Primary
Clinical Benefit Rate (CBR)
CBR is defined by the percentage of participants achieving either a confirmed tumor response of complete response (CR) or partial response (PR) or stable disease (SD) for at least 24 weeks. Response Criteria in Solid Tumors (RECIST) is a system for measuring tumor shrinkage or progression in terms of the longest dimensions of the tumor on imaging scans such as computerized tomography (CT). A partial response requires a decrease of 30% or more, complete response requires all target lesions disappear, Progression requires an increase of at least 20%, and Stable disease falls in between these two. All responses have a repeat assessment to confirm the response.
Time frame: Baseline; every 6 weeks for the first 36 weeks and then every 12 weeks until disease progression. The maximum time participants were followed was approx. 90 months
Population: Intent-to-Treat (ITT) Population: all participants who received at least one dose of investigational product
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lapatinib + Capecitabine | Clinical Benefit Rate (CBR) | 57.7 Percentage of participants |
Secondary
Duration of Response (DOR)
Duration of response (complete response, partial response or stable disease) is defined as the time of first documentation of disease response until the date of disease progression or death due to breast cancer, whichever occurs first. DOR only applied to participants for whom best overall response was complete response (CR), partial response (PR) or stable disease (SD). Participants who had not had a partial response, complete response or stable disease at the cut-off date for this endpoint analysis were censored for duration of response.
Time frame: Baseline; every 6 weeks for the first 36 weeks and then every 12 weeks until disease progression. The maximum time participants were followed was 88.80 months.
Population: Intent-to-Treat (ITT) Population: all participants who received at least one dose of investigational product. DOR only applied to participants for whom best overall response is complete response (CR) or partial response (PR) or stable disease (SD).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lapatinib + Capecitabine | Duration of Response (DOR) | 8.18 Months |
Secondary
Number of Participants With Central Nervous System (CNS) as First Site of Relapse
Number of participants who had Central Nervous System metastasis as the first site of relapse. CT, Magnetic Resonance Imaging, etc. were used for the assessment.
Time frame: Baseline; every 6 weeks for the first 36 weeks and then every 12 weeks until disease progression. The maximum time participants were followed was 90 months
Population: Intent-to-Treat (ITT) Population: all participants who received at least one dose of investigational product
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lapatinib + Capecitabine | Number of Participants With Central Nervous System (CNS) as First Site of Relapse | Participants with any site of relapse | 17 participants |
| Lapatinib + Capecitabine | Number of Participants With Central Nervous System (CNS) as First Site of Relapse | Participants with CNS disease as first site of relapse | 2 participants |
Secondary
Progression-Free Survival (PFS)
PFS is defined as the time from first dose date until the date of disease progression or death due to any reason, whichever occurs first.
Time frame: Baseline; every 6 weeks for the first 36 weeks and then every 12 weeks until disease progression. The maximum time participants were followed was 90.38 months.
Population: Intent-to-Treat (ITT) Population: all participants who received at least one dose of investigational product
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lapatinib + Capecitabine | Progression-Free Survival (PFS) | 6.34 Months |
Secondary
Six Months Progression-Free Survival
Six Months Progression-Free Survival is defined as the percentage of surviving participants who are progression-free longer than six months (greather than 180 days) after the first start date of study treatment.
Time frame: at Baseline and every 6 weeks for the first 36 weeks and then every 12 weeks until disease progression. The maximum time participants were followed up to 90.38 months, with 6 months PFS reported.
Population: Intent-to-Treat (ITT) Population: all participants who received at least one dose of investigational product
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lapatinib + Capecitabine | Six Months Progression-Free Survival | 53.55 Percentage of participants |
Secondary
Time to Response (TTR)
Time to response is defined as the time from first dose date until first documentation of disease response. TTR only applied to participants for whom best overall response was complete response (CR), partial response (PR) or stable disease (SD). Participants who had not had a partial response, complete response or stable disease at the cut-off date for this endpoint analysis were censored for time to response.
Time frame: Baseline; every 6 weeks for the first 36 weeks and then every 12 weeks until disease progression. The maximum time participants were followed was approx. 14.78 months
Population: Intent-to-Treat (ITT) Population: all participants who received at least one dose of investigational product. TTR only applied to participants for whom best overall response was complete response (CR) or partial response (PR) or stable disease.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lapatinib + Capecitabine | Time to Response (TTR) | 4.07 Months |
Post Hoc
All Collected Deaths
On treatment deaths were collected from the start of treatment up to 30 days after study drug discontinuation, for a maximum duration of 4276 days (treatment duration ranged from 13 - 4246 days) for Lapatinib and 3384 days (treatment duration ranged form 8 - 3354 days) for Capecitabine. Total deaths was collected from study start to study end (LPLV).
Time frame: up to 4276 days for Lapatinib/up to 3384 days for Capecitabine (on-treatment), approx. 12 years (all collected deaths)
Population: Clinical Database Population: all treated participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lapatinib + Capecitabine | All Collected Deaths | Total Deaths | 11 Participants |
| Lapatinib + Capecitabine | All Collected Deaths | On-treatment Deaths | 2 Participants |