E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-positive metastatic breast cancer who have received prior trastuzumab and endocrine therapies |
|
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 | 16.1 |
E.1.2 | Level | PT |
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 rate (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 |
Refer to the authorized prescribing information for lapatinib [TYKERB Package Insert, 2010], trastuzumab [HERCEPTIN Package Insert, 2009], letrozole [FEMARA Package Insert, 2010], anastrozole [ARIMIDEX Package Insert, 2009], and exemestane [AROMASIN Package Insert, 2008] for specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the study treatment(s) that may impact subject eligibility.
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Signed written informed consent. In Korea and Japan, subjects who are between ≥18 and <20 years of age must also have a legal representative sign the written informed consent.
2. Post-menopausal female subjects ≥18 years of age. Post-menopausal as defined by any of the following:
•Subjects at least 60 years of age.
•Subjects under 60 years of age and amenorrhic for at least 12 consecutive months AND follicle-stimulating hormone (FSH) and estradiol levels in postmenopausal range (utilizing ranges from the local laboratory facility).
•Prior bilateral oophorectomy.
•Prior radiation castration with amenorrhea for at least 6 months
3. Subjects must have a history of histologically confirmed breast cancer, with a clinically confirmed diagnosis of metastatic disease [confirmed by histology, cytology or other clinical means (e.g. CT, MRI)]. 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 at least one prior regimen containing trastuzumab in combination with chemotherapy for breast cancer:.
•Subject has ONLY received prior trastuzumab in combination with chemotherapy as neoadjuvant and/or adjuvant treatment.
OR
•Subject has received ONE prior trastuzumab-containing regimen for metastatic disease (and has progressed), and may or may not have received prior trastuzumab in combination with chemotherapy as neoadjuvant and/or adjuvant treatment.
7. Subject must have received prior endocrine therapy (such as aromatase inhibitors or selective estrogen receptor modulators).
8. Subjects who have a life expectancy of > 6 months as assessed by the treating investigator
9. Subjects must have baseline Left Ventricular Ejection Fraction (LVEF) ≥50% measured by echocardiography (ECHO) or multi-gated acquisition scan (MUGA)
10. Subject must have an 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 Protocol page 27)
14. Subjects must meet all of the following criteria:
•QTc <450msec or
•QTc <480msec for subjects with bundle branch block
The QTc is the QT interval corrected for heart rate according to either Bazett’s formula (QTcB) or to Fridericia’s formula (QTcF), machine or manual over read, for males and females. The specific formula that will be used in a protocol should be determined prior to initiation of the study, and the formula used to determine inclusion and discontinuation should be the same throughout the study. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period
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. 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
4. Known history of, or clinical evidence of, central nervous system (CNS)
metastases or leptomeningeal carcinomatosis
5. Have acute or currently active/requiring anti-viral therapy hepatic or biliary
disease (with the exception of subjects with Gilbert's syndrome, asymptomatic
gallstones, liver metastases or stable chronic liver disease per investigator
assessment)
6. Have a 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)
7. Have any clinically significant gastrointestinal abnormalities that may alter
absorption such as malabsorption syndrome or major resection of the stomach or bowels
8. 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
9. Any prohibited medication as described in Section 6.2.
10. 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 |
The time point of primary end point, overall survival will be assessed at
the end of study - Q2 2018 |
|
E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints of this study are:
- 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 B (trastuzumab/AI) vs. Treatment Group C
(lapatinib/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 B (trastuzumab/AI) vs. Treatment Group C (lapatinib/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 B (trastuzumab/AI) vs. Treatment Group C (lapatinib/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 B (trastuzumab/AI) vs. Treatment Group C
(lapatinib/AI) as assessed by the investigator.
- Clinical benefit rate in Treatment Group A (lapatinib/trastuzumab/AI)
vs. Treatment Group B (trastuzumab/AI) and Treatment Group B (trastuzumab/AI) vs. Treatment Group C (lapatinib/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 |
The time point of the secondary end points: overall survival and progression free survival will be assessed at the end of study - Q2 2018. Lesion assessments assessed by Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) will be performed every 12 weeks and at study conclusion.
|
|
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 | No |
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.8.5 | 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 |
Belgium |
Bulgaria |
France |
Ireland |
Japan |
Croatia |
Norway |
Portugal |
Romania |
Argentina |
Australia |
Brazil |
Colombia |
Germany |
Hong Kong |
Hungary |
India |
Korea, Republic of |
Lithuania |
Spain |
Israel |
Peru |
Philippines |
Poland |
Russian Federation |
Singapore |
Taiwan |
Ukraine |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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 |