| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Breast Cancer (with ErbB2 Overexpressing Metastatic Breast Cancer) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To evaluate progression-free survival (PFS) in women with ErbB2-overexpressing
MBC treated with lapatinib in combination with vinorelbine or lapatinib in
combination with capecitabine, who have received no more than 1 prior
chemotherapeutic regimen in the metastatic setting. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the two treatment arms for the following:
• Overall response rate (ORR) [complete response (CR) and partial response
(PR)]
• Overall survival (OS)
• Duration of response
• Time to response
• Clinical Benefit Rate (CBR)
• Qualitative and quantitative toxicities
• To characterize the PK of vinorelbine alone and in combination with lapatinib in a
subgroup of subjects (at selected sites) receiving this combination
Exploratory Objectives
• For patients who experience disease progression on their randomized treatment arm
and elect to continue in the post-progression cross-over phase, time to second
progression following cross-over will be evaluated as an exploratory objective.
• This study will collect pharmacogenetics samples for exploratory research, as
described in Appendix 3 of the protocol. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| An optional PK sub-study will be performed as part of Cycle 1 of the lapatinib and vinorelbine arm only, at centres with experience and capability to perform intensive PK assessments. The objective is to have a minimum of 12-16 subjects participate in this PK sub-study, but the overall study recruitment will not be extended to complete this sub-study. Following completion of the PK sub-study, subsequent study procedures will be identical to the main protocol. Subjects who participate in the sub-study will receive vinorelbine alone on Day 1, delaying the start of lapatinib to Day 2. Lapatinib will be administered alone on Days 2-7, and both drugs administered on Day 8. The objective is to assess the effect of lapatinib on vinorelbine pharmacokinetics to supplement similar data being obtained in other ongoing studies of this combination. Additional details are available in Section 6.5 and Table 12 of the protocol. |
|
| E.3 | Principal inclusion criteria |
1. Signed informed consent prior to registration.
2. Considered by the investigator to have a life expectancy of ≥12 weeks.
3. 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. Where the disease is restricted to a solitary lesion, the neoplastic nature of the lesion should be confirmed by cytology or histology.
4. Documented overexpression of ErbB2 by 3+ immunohistochemistry or a positive
score by fluorescence in situ hybridization (FISH) or chromogenic in situ
hybridisation (CISH) using a local laboratory result on a specimen from the primary
tumour or visceral metastatic site. Verification by a central laboratory is not
required.
5. Subjects should have progressive disease following prior therapy which may include anthracyclines, taxanes, and trastuzumab. Subjects who have not received prior treatment for MBC must fulfill one or more of the following conditions: 1) Relapse following receipt of trastuzumab-based therapy in the adjuvant setting, 2)
Contraindication to receiving trastuzumab or documented medical reason for
trastuzumab not being appropriate, as determined by the study investigator, or 3)
Unsuitable for taxane-based chemotherapy as determined by the study investigator.
6. All prior chemotherapy, immunotherapy, biologic therapy, or surgery (except for
minor surgical procedures) must be discontinued or completed at least 4 weeks prior
to first dose of randomized study medication. Hormonal therapy must be
discontinued at least 1 week prior to first dose. Prior treatment with trastuzumab is
permitted provided that at least 6 weeks has elapsed since the last dose of therapy
and all treatment-related adverse events are ≤ Grade 1 at the time of randomization.
7. Prior diagnosis of non-breast cancer is allowed as long as the subject is free of
disease and has not received treatment for prior malignancies for at least 5 years.
Subjects with completely resected basal or squamous cell skin cancer or successfully
treated cervical carcinoma in situ will be allowed if it has been 1 year or longer since
definitive and curative surgery.
8. Females aged ≥18 years with any menopausal status:
• Non-child-bearing potential (i.e., women with functioning ovaries who have a
current documented tubal ligation or hysterectomy, or women who are
postmenopausal).
• Child-bearing potential (i.e., women with functioning ovaries and no
documented impairment of oviductal or uterine function that would cause
sterility): This category includes women with oligomenorrhea (severe), women
who are perimenopausal, and young women who have begun to menstruate.
These subjects must have a negative serum pregnancy test at screening and
agree to one of the following:
• Complete abstinence from intercourse from 2 weeks prior to
administration of the first dose of study medication until 28 days after
the final dose of study medication; or
• Consistent and correct use of one of the following acceptable methods of
birth control: male partner who is sterile prior to the female subject’s
entry into the study and is the sole sexual partner for that female subject;
any intrauterine device or contraceptive method with a documented
failure rate of less than 1% per year
9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1.
10. Subjects must have adequate organ and marrow function as defined view protocol for further information.
11. Subjects must have a cardiac ejection fraction of at least 50% (as measured by
echocardiogram [ECHO] or multigated acquisition scan [MUGA]) and within the
institutional range of normal.
12. 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 must have completed radiation treatment and recovered from all acute radiation treatment-related toxicities (e.g., bone marrow suppression) prior to commencement of combination treatment.
13. Subjects with stable central nervous system (CNS) metastases are permitted.
14. Subject must be free of gastrointestinal diseases or any other conditions that impede swallowing, retaining, and absorption of oral medications.
15. 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.
|
|
| E.4 | Principal exclusion criteria |
1. Subjects taking medications listed in Section 5.9.2 of the protocol are not eligible for the study.
This includes human immunodeficiency virus-positive subjects receiving combination anti-retroviral therapy because of possible pharmacokinetic interactions with lapatinib.
2. Therapy with lapatinib, vinorelbine, or capecitabine prior to randomization into this
study.
3. Prior therapy with more than one chemotherapeutic regimen for metastatic breast
cancer.
4. Concurrent anticancer or concomitant radiotherapy treatment.
5. 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.
6. 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).
7. 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.
8. 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.
9. Known deficiency for the enzyme dihydropyrimidine dehydrogenase (DPD).
10. 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.
11. 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.
12. Pregnant or lactating females at any time during the study (due to the potential
teratogenic or abortifacient effects of lapatinib and breastfeeding).
13. 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.
14. Peripheral neuropathy of Grade 2 or greater.
15. Unresolved or unstable, serious toxicity from prior administration of another
investigational drug and/or of prior cancer treatment.
16. Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy analysis will be based on PFS. PFS is the primary endpoint and is defined as the interval between the date of randomization and the date of objective disease progression or death from any cause. Disease progression will be based on the assessments from the investigator review of objective evidence of progression (e.g., radiological scans and medical photographs).
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| The study will compare lapatinib+vinorelbine with lapatinib+capecitabine |
|
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 48 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of trial is achieved when LSLV is reached |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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