Cancer
Conditions
Keywords
Neoplasms, Breast
Brief summary
This is a randomized, parallel-arm, open-label, multi-centre, Phase II study to determine the efficacy and safety of lapatinib in combination with vinorelbine or capecitabine in women with ErbB2 overexpressing metastatic breast cancer (MBC) who have received no more than one chemotherapeutic regimen in the metastatic setting.
Detailed description
Approximately 105 subjects will be enrolled in the study and randomized 2:1 to one of the following regimens Arm A (n=70): Lapatinib 1250 mg orally once daily continuously plus Vinorelbine 20mg/m2 intravenously (IV) on day 1 and 8, every third week, or Arm B (n=35): Lapatinib 1250 mg orally once daily (QD) continuously plus Capecitabine 2000 mg/m2/day orally in 2 doses 12 hours apart on days 1-14 every third week. Randomization will be stratified according to the following variables: 1) Prior receipt of therapy for metastatic breast cancer (Yes or No), and 2) Site of metastatic disease (Visceral/Soft tissue or Bone-only). Subjects will receive randomized study treatment until disease progression or discontinuation of study treatment due to unacceptable toxicity, withdrawal of consent, lost to follow up, or death. All subjects who discontinue study treatment without documented progression will continue to be followed for progression according to protocol-schedule until new anti-cancer therapy is initiated and/or progression or death is documented. Survival data will be collected for all subjects to ensure a minimum of 18 months survival data. This study will include a safety run-in phase for approximately the first 30 subjects (20 randomized to lapatinib and vinorelbine; 10 to lapatinib and capecitabine).
Interventions
DRUGVinorelbine
Vinorelbine
DRUGLapatinib
Lapatinib
DRUGCapecitabine
Capecitabine
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
After disease progression in the Randomized Phase (in which participants received lapatinib plus vinorelbine), participants were given the option of crossing over to the alternative treatment arm (lapatinib plus capecitabine), and continuing in a post-progression Cross-over Phase.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
: * Signed informed consent prior to registration. * Considered by the investigator to have a life expectancy of ≥12 weeks. * Subjects must be female and have histologically - confirmed invasive breast cancer with Stage IV disease at primary diagnosis or at relapse after curative - intent surgery. * Documented overexpression of ErbB2 * Subjects should have progressive disease following prior therapy which may include anthracyclines, taxanes, and trastuzumab. * Females aged ≥18 years * Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1. * Subjects must have adequate organ and marrow function * Subjects must have a cardiac ejection fraction of at least 50% and within the institutional range of normal. * Radiotherapy prior to initiation of study medication is allowed to a limited area ( e . g . , palliative therapy ) , if it is not the sole site of disease. * Subjects with stable central nervous system (CNS) metastases are permitted. * Subject must be free of gastrointestinal diseases or any other conditions that impede swallowing, retaining, and absorption of oral medications. * Bisphosphonate therapy for bone metastases is allowed; however, treatment must be initiated prior to the first dose of study medication. Prophylactic use of bisphosphonates in subjects without bone disease, except for the treatment of osteoporosis, is not permitted.
Exclusion criteria
* Subjects taking prohibited medications are not eligible for the study. * Therapy with lapatinib, vinorelbine, or capecitabine prior to randomization into this study. * Prior therapy with more than one chemotherapeutic regimen for metastatic breast cancer. * Concurrent anticancer or concomitant radiotherapy treatment. * History of uncontrolled or symptomatic angina; history of arrhythmias requiring medications ; clinically significant myocardial infarction \< 6 months from study entry; uncontrolled or symptomatic congestive heart failure; ejection fraction below the institutional normal limit; or any other cardiac condition, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient. * Have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment). * Use of an investigational drug within 30 days or 5 half - lives, whichever is longer, preceding the first dose of investigational treatment, or, concurrent treatment with an investigational agent or participation in another clinical trial involving investigational agents. * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the agents used in this study or their excipients that in the opinion of the investigator or GSK Medical Monitor contraindicates their participation. * Known deficiency for the enzyme dihydropyrimidine dehydrogenase (DPD). * Known history of uncontrolled inter - current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness / social situations that would limit compliance with study requirements. * 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. * Pregnant or lactating females at any time during the study (due to the potential teratogenic or abortifacient effects of lapatinib and breastfeeding). * Subjects with diseases affecting gastrointestinal function resulting in an inability to take oral medication , including ; malabsorption syndrome, disease significantly affecting gastrointestinal function , or resection of the stomach , small bowel , or colon. Subjects with inflammatory bowel disease or ulcerative colitis are also excluded. * Peripheral neuropathy of Grade 2 or greater. * Unresolved or unstable, serious toxicity from prior administration of another investigational drug and / or of prior cancer treatment. * 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 |
|---|---|---|
| Progression Free Survival (PFS) in the Randomized Phase | From randomization until disease progression, death, or discontinuation from the study (average of 27 study weeks) | PFS is defined as the time from randomization until the earliest date of disease progression (PD) or death due to any cause, if sooner. PD is defined as at least a 20 % increase in the sum of the longest diameter (LD) of target lesions, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of \>=1 new lesion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From the date of randomization until death (average of 55 study weeks) | OS is defined as the time from randomization to the date of death due to any cause. Participants who had not died were censored at the date of the last adequate tumor assessment at the time of the cut-off. |
| Duration of Response (DOR) in the Randomized Phase | From the time of the first documented confirmed complete or partial response until disease progression or death, if sooner (average of 27 study weeks) | DOR is defined as the time from the first documented evidence of response (CR or PR) until the first documented sign of disease progression (a \>=20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of \>=1 new lesion) or death, if sooner. CR=the disappearance of all TLs. PR=a \>=30% decrease in the sum of the LD of target lesions, taking as a reference the Baseline sum LD. |
| Time to Response in the Randomized Phase | From randomization until the time of the first documented confirmed CR or PR (average of 27 study weeks) | Time to response is defined as the time from randomization until the first documented evidence of CR (the disappearance of all TLs) or PR (a \>=30% decrease in the sum of the LD of the TLs, taking as a reference the basline sum LD) (whichever status is recorded first). When tumor response was confirmed at a repeat assessment, the time to response was taken to be the first time that the response was observed. |
| Number of Participants With Overall Response (OR), as Assessed by the Investigator in the Randomized Phase | From randomization until disease progression, death, or discontinuation from the study (average of 27 study weeks) | OR is defined as the number of participants achieving either a confirmed complete response (CR: the disappearance of all target lesions \[TLs\]) or partial response (PR: a \>=30% decrease in the sum of the longest diameter \[LD\] of the TLs, taking as reference the baseline sum LD) as assessed by the investigator as the best OR. |
| Area Under the Concentration-time Curve Over the Dosing Interval (AUC-tau) for Vinorelbine | Days 1 and 8; 0 to 24 hours post-dose | AUC-tau is defined as the area under the concentration-time curve over a dosing interval at steady state, where tau is the length of the dosing interval. The AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. Pharmacokinetic (PK) parameters were to be assessed in an optional sub-study. No participants were enrolled in this optional sub-study; thus, no PK data are available. |
| Maximum Concentration (Cmax) for Vinorelbine | Days 1 and 8; 0 to 24 hours post-dose | Cmax is defined as the maximum observed plasma or serum concentration after administration of the drug. PK parameters were to be assessed in an optional sub-study. No participants were enrolled in this optional sub-study; thus, no PK data are available. |
| Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | From randomization until disease progression, death, or discontinuation from the study (average of 55 study weeks) | An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grades: 0 = no AE or within normal limits; 1 = mild AE; 2 = moderate AE; 3 = severe and undesirable AE; 4 = life-threatening or disabling AE; 5 = death related to AE. |
| Number of Participants With Clinical Benefit (CB) in the Randomized Phase | From randomization until disease progression, death, or discontinuation from the study (average of 27 study weeks) | CB is defined as the the number of participants achieving either a confirmed CR or PR or having stable disease (SD) for at least 24 weeks (i.e., approximately 6 months). CR=the disappearance of all TLs. PR=a \>=30% decrease in the sum of the LD of TLs, taking as a reference the Baseline sum LD. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD=at least a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of \>=1 new lesion). Participants with unknown or missing responses were treated as non-responders. |
Countries
Bulgaria, Chile, France, Germany, Greece, Italy, Mexico, Poland, Serbia, Spain
Participant flow
Pre-assignment details
In the Randomized Phase (RP), participants were treated until disease progression (PD) or discontinuation of treatment due to unacceptable toxicity, withdrawal of consent, lost to follow-up, or death. After PD in the RP, participants were given the option of crossing over to the alternative treatment arm in a post-progression Cross-over Phase (CP).
Participants by arm
| Arm | Count |
|---|---|
| Lapatinib + Capecitabine in RP; Lapatinib + Vinorelbine in CP Participants received a daily dose of 5 tablets of lapatinib (1250 milligrams \[mg\]) continuously at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received capecitabine 2000 mg per meters squared (mg/m\^2) per day, divided and administered orally twice daily, 12 hours apart, for 14 days, every 21 days. Capecitabine was taken with food or within 30 minutes after food with approximately 200 milliliters (mL) of water. After disease progression in the Randomized Phase (in which participants received lapatinib plus vinorelbine), participants were given the option of crossing over to the alternative treatment arm (lapatinib plus capecitabine), and continuing in a post-progression Cross-over Phase. | 37 |
| Lapatinib + Vinorelbine in RP; Lapatinib + Capecitabine in CP Participants received a daily dose of 5 tablets of lapatinib (1250 mg) at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received an intravenous (IV) infusion of vinorelbine 20 mg/m\^2 over the course of 5 to 10 minutes on Days 1 and 8 of a 21-day treatment cycle. After disease progression in the Randomized Phase (in which participants received lapatinib plus capecitabine), participants were given the option of crossing over to the alternative treatment arm (lapatinib plus vinorelbine), and continuing in a post-progression Cross-over Phase. | 75 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 5 |
| Overall Study | Missing | 2 | 1 |
| Overall Study | Ongoing: Study records not completed | 0 | 2 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | study close / terminated : done in error | 2 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 10 |
Baseline characteristics
| Characteristic | Lapatinib + Capecitabine in RP; Lapatinib + Vinorelbine in CP | Lapatinib + Vinorelbine in RP; Lapatinib + Capecitabine in CP | Total |
|---|---|---|---|
| Age, Continuous | 57.5 Years STANDARD_DEVIATION 10.9 | 57.7 Years STANDARD_DEVIATION 10.23 | 57.6 Years STANDARD_DEVIATION 10.41 |
| Race/Ethnicity, Customized African American/African Heritage | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander & White | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 36 Participants | 74 Participants | 110 Participants |
| Sex: Female, Male Female | 37 Participants | 75 Participants | 112 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 32 / 37 | 72 / 75 | 27 / 37 | 15 / 17 |
| serious Total, serious adverse events | 4 / 37 | 25 / 75 | 3 / 37 | 4 / 17 |
Outcome results
Primary
Progression Free Survival (PFS) in the Randomized Phase
PFS is defined as the time from randomization until the earliest date of disease progression (PD) or death due to any cause, if sooner. PD is defined as at least a 20 % increase in the sum of the longest diameter (LD) of target lesions, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of \>=1 new lesion.
Time frame: From randomization until disease progression, death, or discontinuation from the study (average of 27 study weeks)
Population: ITT Population: participants who were randomized to study treatment, regardless of whether they actually received study medication
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lapatinib Plus Capecitabine | Progression Free Survival (PFS) in the Randomized Phase | 6.2 months |
| Lapatinib Plus Vinorelbine | Progression Free Survival (PFS) in the Randomized Phase | 6.2 months |
95% CI: [0.53, 1.35]
Secondary
Area Under the Concentration-time Curve Over the Dosing Interval (AUC-tau) for Vinorelbine
AUC-tau is defined as the area under the concentration-time curve over a dosing interval at steady state, where tau is the length of the dosing interval. The AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. Pharmacokinetic (PK) parameters were to be assessed in an optional sub-study. No participants were enrolled in this optional sub-study; thus, no PK data are available.
Time frame: Days 1 and 8; 0 to 24 hours post-dose
Secondary
Duration of Response (DOR) in the Randomized Phase
DOR is defined as the time from the first documented evidence of response (CR or PR) until the first documented sign of disease progression (a \>=20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of \>=1 new lesion) or death, if sooner. CR=the disappearance of all TLs. PR=a \>=30% decrease in the sum of the LD of target lesions, taking as a reference the Baseline sum LD.
Time frame: From the time of the first documented confirmed complete or partial response until disease progression or death, if sooner (average of 27 study weeks)
Population: ITT Population. Only participants with a confirmed CR or PR were assessed for duration of response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lapatinib Plus Capecitabine | Duration of Response (DOR) in the Randomized Phase | 10.8 months |
| Lapatinib Plus Vinorelbine | Duration of Response (DOR) in the Randomized Phase | 6.7 months |
Secondary
Maximum Concentration (Cmax) for Vinorelbine
Cmax is defined as the maximum observed plasma or serum concentration after administration of the drug. PK parameters were to be assessed in an optional sub-study. No participants were enrolled in this optional sub-study; thus, no PK data are available.
Time frame: Days 1 and 8; 0 to 24 hours post-dose
Secondary
Number of Participants With Clinical Benefit (CB) in the Randomized Phase
CB is defined as the the number of participants achieving either a confirmed CR or PR or having stable disease (SD) for at least 24 weeks (i.e., approximately 6 months). CR=the disappearance of all TLs. PR=a \>=30% decrease in the sum of the LD of TLs, taking as a reference the Baseline sum LD. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD=at least a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of \>=1 new lesion). Participants with unknown or missing responses were treated as non-responders.
Time frame: From randomization until disease progression, death, or discontinuation from the study (average of 27 study weeks)
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lapatinib Plus Capecitabine | Number of Participants With Clinical Benefit (CB) in the Randomized Phase | 18 participants |
| Lapatinib Plus Vinorelbine | Number of Participants With Clinical Benefit (CB) in the Randomized Phase | 29 participants |
95% CI: [0.63, 3.58]
Secondary
Number of Participants With Grade 4 and Grade 5 Adverse Events (AE)
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grades: 0 = no AE or within normal limits; 1 = mild AE; 2 = moderate AE; 3 = severe and undesirable AE; 4 = life-threatening or disabling AE; 5 = death related to AE.
Time frame: From randomization until disease progression, death, or discontinuation from the study (average of 55 study weeks)
Population: Safety Population: participants who received at least one dose of study medication, based on the actual treatment received
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lapatinib Plus Capecitabine | Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | Leukopenia, Grade 4 | 0 participants |
| Lapatinib Plus Capecitabine | Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | Mucosal inflammation, Grade 4 | 0 participants |
| Lapatinib Plus Capecitabine | Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | Neutropenia, Grade 4 | 0 participants |
| Lapatinib Plus Capecitabine | Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | Pulmonary embolism, Grade 4 | 0 participants |
| Lapatinib Plus Capecitabine | Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | Febrile neutropenia, Grade 4 | 0 participants |
| Lapatinib Plus Capecitabine | Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | Intestinal obstruction, Grade 5 | 0 participants |
| Lapatinib Plus Capecitabine | Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | Helicobacter gastritis, Grade 4 | 1 participants |
| Lapatinib Plus Vinorelbine | Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | Intestinal obstruction, Grade 5 | 1 participants |
| Lapatinib Plus Vinorelbine | Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | Helicobacter gastritis, Grade 4 | 0 participants |
| Lapatinib Plus Vinorelbine | Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | Neutropenia, Grade 4 | 9 participants |
| Lapatinib Plus Vinorelbine | Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | Leukopenia, Grade 4 | 1 participants |
| Lapatinib Plus Vinorelbine | Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | Febrile neutropenia, Grade 4 | 1 participants |
| Lapatinib Plus Vinorelbine | Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | Mucosal inflammation, Grade 4 | 1 participants |
| Lapatinib Plus Vinorelbine | Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | Pulmonary embolism, Grade 4 | 1 participants |
Secondary
Number of Participants With Overall Response (OR), as Assessed by the Investigator in the Randomized Phase
OR is defined as the number of participants achieving either a confirmed complete response (CR: the disappearance of all target lesions \[TLs\]) or partial response (PR: a \>=30% decrease in the sum of the longest diameter \[LD\] of the TLs, taking as reference the baseline sum LD) as assessed by the investigator as the best OR.
Time frame: From randomization until disease progression, death, or discontinuation from the study (average of 27 study weeks)
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lapatinib Plus Capecitabine | Number of Participants With Overall Response (OR), as Assessed by the Investigator in the Randomized Phase | 13 participants |
| Lapatinib Plus Vinorelbine | Number of Participants With Overall Response (OR), as Assessed by the Investigator in the Randomized Phase | 15 participants |
Secondary
Overall Survival (OS)
OS is defined as the time from randomization to the date of death due to any cause. Participants who had not died were censored at the date of the last adequate tumor assessment at the time of the cut-off.
Time frame: From the date of randomization until death (average of 55 study weeks)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lapatinib Plus Capecitabine | Overall Survival (OS) | 19.4 months |
| Lapatinib Plus Vinorelbine | Overall Survival (OS) | 24.3 months |
Secondary
Time to Response in the Randomized Phase
Time to response is defined as the time from randomization until the first documented evidence of CR (the disappearance of all TLs) or PR (a \>=30% decrease in the sum of the LD of the TLs, taking as a reference the basline sum LD) (whichever status is recorded first). When tumor response was confirmed at a repeat assessment, the time to response was taken to be the first time that the response was observed.
Time frame: From randomization until the time of the first documented confirmed CR or PR (average of 27 study weeks)
Population: ITT Population. Only participants with a confirmed CR or PR were assessed for time to response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lapatinib Plus Capecitabine | Time to Response in the Randomized Phase | 9.3 weeks |
| Lapatinib Plus Vinorelbine | Time to Response in the Randomized Phase | 9.4 weeks |