E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-positive metastatic breast cancer who have received trastuzumab and endocrine therapy in the neoadjuvant and/or adjuvant setting |
|
E.1.1.1 | Medical condition in easily understood language |
Advanced/Metastatic Breast Cancer |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER-2 positive breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 |
The primary objective is to demonstrate superiority of lapatinib/trastuzumab/AI
combination (Treatment Group A) vs. trastuzumab/AI combination (Treatment Group B) for overall survival. |
|
E.2.2 | Secondary objectives of the trial |
To compare OS in Treatment Group B (trastuzumab/AI) vs. Treatment Group C
(lapatinib/AI) and Treatment Group A (trastuzumab/lapatinib/AI) vs. Treatment
Group C (lapatinib/AI)
• To compare progression free survival (PFS) in Treatment Group A
(lapatinib/trastuzumab/AI) vs. Treatment Group B (trastuzumab/AI) and
Treatment Group C ( lapatinib/AI) vs. Treatment Group B (trastuzumab/AI)
• To compare overall response rate (complete or partial response), time to
response, and duration of response in Treatment Group A
(lapatinib/trastuzumab/AI) vs. Treatment Group B (trastuzumab/AI) and
Treatment Group C (lapatinib/AI) vs. Treatment Group B (trastuzumab/AI)
• To compare clinical benefit (complete response, partial response, or stable
disease for at least 6 months) in Treatment Group A (lapatinib/trastuzumab/AI)
vs. Treatment Group B (trastuzumab/AI) and Treatment Group C (lapatinib/AI)
vs. Treatment Group B (trastuzumab/AI)
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Signed written informed consent
2. Post-menopausal female subjects ≥18 years of age. Post-menopausal as defined
by any of the following:
• Age > 60 years
• Age ≥ 45 years with amenorrhea > 12 months with an intact uterus
• Having undergone a bilateral oophorectomy or radiation castration with
amenorrhea for at least 6 months
• FSH and estradiol levels in postmenopausal range (utilizing ranges from the
local laboratory facility). In subjects who have previously been treated with
an GnRH/LHRH analogue, the last injection must have been administered >
4 months prior to randomization and menses must not have restarted
3. Histologically confirmed Stage IV invasive breast cancer
• Subjects may have either measurable or non-measurable disease per Response
Evaluation Criteria in Solid Tumors (RECIST 1.1) [Eisenhauer, 2009]
4. Tumors that are ER+ and/or PgR+ by local laboratory
5. Documentation of HER2 overexpression or gene amplification, in the invasive
component of either the primary tumor or metastatic disease site as defined as:
• 3+ by Immunohistochemistry (IHC)
and/or
• HER2/neu gene amplification by fluorescence, chromogenic or silver in situ
hybridization [FISH, CISH or SISH; >6 HER2/neu gene copies per nucleus
or a FISH, CISH or SISH test ratio (HER2 gene copies to chromosome 17
signals) of ≥2.0]
6. Subject must have received prior neoadjuvant and/or adjuvant trastuzumab
7. Subject must have received prior neoadjuvant and/or adjuvant endocrine therapy
8. Subjects who have a life expectancy of > 6 months as assessed by the treating
investigator
9. Have baseline of Left Ventricular Ejection Fraction (LVEF) ≥50% measured by
echocardiography (ECHO) or multi-gated acquisition scan (MUGA)
10. ECOG performance status of 0-1 (Section 12.2, Appendix 2)
11. All prior treatment related toxicities must be CTCAE (Version 4.0) ≤ Grade 1
[NCI, 2009] at the time of randomization
12. Completion of screening assessments
13. Adequate baseline organ function defined by: (Refer to page 26 of Protocol)
French subjects: In France, a subject will be eligible for inclusion in this study only if
either affiliated to or a beneficiary of a social security category. |
|
E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. History of another malignancy.
Exception: 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.
2. Subjects with extensive symptomatic visceral disease including hepatic
involvement and pulmonary lymphangitic spread of tumor, or the disease is
considered by the investigator to be rapidly progressing or life threatening
(subjects who are intended for chemotherapy)
3. Subjects who received prior chemotherapy, hormonal therapy, immunotherapy,
biologic therapy, or anti-HER2 therapy for advanced or metastatic disease
4. Serious cardiac illness or medical condition including but not confined to:
• Uncontrolled arrhythmias
• Uncontrolled or symptomatic angina
• History of congestive heart failure (CHF)
• Documented myocardial infarction <6 months from study entry
5. Known history of, or clinical evidence of, central nervous system (CNS)
metastases or leptomeningeal carcinomatosis
6. Current active hepatic or biliary disease (with exception of subjects with Gilbert's
syndrome, asymptomatic gallstones, liver metastases or stable chronic liver
disease per investigator assessment)
7. Concurrent disease or condition that may interfere with study participation, or any
serious medical disorder that would interfere with the subject’s safety (for
example, active or uncontrolled infection or any psychiatric condition prohibiting
understanding or rendering of informed consent)
8. Have any clinically significant gastrointestinal abnormalities that may alter
absorption such as malabsorption syndrome or major resection of the stomach or
bowels
9. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to
drugs chemically related to any of the study agents or their excipients that, in the
opinion of the Investigator or GSK medical monitor, contraindicates their
participation
10. Any prohibited medication as described in Section 6.2.
11. Administration of an investigational drug within 30 days or 5 half-lives,
whichever is longer, preceding the first dose of study treatment. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is overall survival assessed for
lapatinib/trastuzumab/AI combination (Treatment Group A) vs. trastuzumab/AI
combination (Treatment Group B). Overall Survival is defined as the time from
randomization until death due to any cause. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time point of primary end point - Q2 2018 |
|
E.5.2 | Secondary end point(s) |
OS in Treatment Group B (trastuzumab/AI) vs. Treatment Group C
(lapatinib/AI) and Treatment Group A (trastuzumab/lapatinib/AI) vs. Treatment
Group C (lapatinib/AI) defined as the time from randomization until death due
to any cause.
• Progression free survival (PFS) in Treatment Group A
(lapatinib/trastuzumab/AI) vs. Treatment Group B (trastuzumab/AI) and
Treatment Group C (lapatinib/AI) vs. Treatment Group B (trastuzumab/AI)
which is defined as the interval of time (in weeks) between the date of
randomization and the earlier of date of disease progression or date of death due
to any cause as assessed by the investigator.
• Overall response rate (complete or partial response) which is defined as the
percentage of subjects achieving either a CR or PR as per RECIST 1.1 criteria in
Treatment Group A (lapatinib/trastuzumab/AI) vs. Treatment Group B
(trastuzumab/AI) and Treatment Group C (lapatinib/AI) vs. Treatment Group B
(trastuzumab/AI) as assessed by the investigator.
• Time to response which is defined as the time from randomization until first
documented evidence of PR or CR (whichever status is recorded first) as per
RECIST 1.1 criteria in Treatment Group A (lapatinib/trastuzumab/AI) vs.
Treatment Group B (trastuzumab/AI) and Treatment Group C (lapatinib/AI) vs.
Treatment Group B (trastuzumab/AI) as assessed by the investigator.
• Duration of response which is defined, for the subset of subjects who achieve a
CR or PR, to be the time from first documented evidence of PR or CR until the
first documented sign of disease progression or death due to breast cancer, if
sooner as per RECIST 1.1 criteria in Treatment Group A
(lapatinib/trastuzumab/AI) vs. Treatment Group B (trastuzumab/AI) and
Treatment Group C (lapatinib/AI) vs. Treatment Group B (trastuzumab/AI) as
assessed by the investigator.
• Clinical benefit in Treatment Group A (lapatinib/trastuzumab/AI) vs. Treatment
Group B (trastuzumab/AI) and Treatment Group C (lapatinib/AI) vs. Treatment
Group B (trastuzumab/AI) which is defined as the percentage of subjects with
evidence of CR, PR, or SD for at least 6 months as per RECIST 1.1 criteria as
assessed by the investigator. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time point of secondary endpoints - 2Q 2018 |
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
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 |
|
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 124 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Belgium |
Brazil |
Bulgaria |
Croatia |
Germany |
Hong Kong |
Hungary |
India |
Ireland |
Korea, Republic of |
Lithuania |
Norway |
Poland |
Portugal |
Romania |
Russian Federation |
Taiwan |
Ukraine |
United Kingdom |
United States |
|
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
|
Collection of all study data will continue until: at least 75% of subjects have reached an event (death) or at most 25% subjects are censored AND the last subject has discontinued study treatment. The primary endpoint is Overall survival so when the events for the analysis have been reached that will be the final analysis |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |