| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2 positive Metastatic Breast Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 changes in the expression of biomarkers associated with HER family, immunomodulation, apoptosis, and ABC transporters within each treatment arm between the pre-treatment biopsy and the disease progression biopsy. |
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| E.2.2 | Secondary objectives of the trial |
•To describe, ORR, CBR, and PFS on study treatment and OS in subjects treated with trastuzumab in combination with lapatinib or chemotherapy.
•To describe PFS on first next line (PFS-NL) and subsequent lines of anti-cancer therapies.
•To explore association between changes in biomarkers and PFS, PFS-NL and OS.
•To describe the safety and tolerability of trastuzumab in combination with lapatinib and of trastuzumab in combination with chemotherapy.
•To explore changes in molecular subtype determined by PAM50 assay at time of disease progression.
•To describe changes of Patient Reported Outcomes (PRO)(Health Related Quality of Life (HRQOL)) within the study population and to describe the differences of PRO/HRQOL between treatment groups.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed written informed consent
2. Female Greater than 18 years
3. Histologically or cytologially confirmed invasive breast cancer with distant metastasis
4. Subjects must have at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [Eisenhauer, 2009]
Note: Biopsied lesions should not be used as target lesions.
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 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 OR HER2/chromosome 17 ratio less than 2.0 with average HER2 copy number ≥6 signals/cell nucleus];
6. Centrally determined HER2-positive, hormone receptor status, breast molecular subtype by PAM50 on the pre-treatment biopsy of metastatic lesion obtained during screening
Note: Biopsied lesions should not be used as target lesions.
7. Progression on at least 2 lines of anti-HER2-targeted therapies for MBC
8. Documented radiological disease progression during the most recent treatment regimen for metastatic disease
9. Most recent treatment regimen for metastatic disease must include trastuzumab and chemotherapy.
Note: Trastuzumab emtansine (T-DM1) is considered acceptable as prior trastuzumab/chemotherapy regimen
10. Agreement to provide 2 tumor biopsies
11. Prior treatment with pertuzumab, lapatinib, and/or trastuzumab emtansine is allowed; however, the last treatment for MBC must not include trastuzumab in combination with pertuzumab.
12. Subjects with radiographically stable CNS metastases, defined as radiographically stable on the previous 2 brain imaging scans, asymptomatic, and off systemic steroids and anticonvulsants for at least 1 month are eligible; treatment with prophylactic anticonvulsants is permitted unless listed under Prohibited Medications (Section 6)
13. Discontinuation of all prior chemotherapy, immunotherapy, or biological therapy at least 3 weeks prior to the first dose of investigational product is required.
Note: Discontinuation of trastuzumab is not necessary.
14. All treatment related toxicities, except alopecia, must have recovered to Grade 1 or better (Common Terminology Criteria for Adverse Events (CTCAE); version 4.0) prior to administration of the first dose of study treatment.
15. Baseline LVEF ≥50% as measured by ECHO or MUGA and above the testing institution’s lower limit of normal
16. QTc <450 msec or QTc <480 msec for patients with bundle branch block. The QTc is the QT interval corrected for heart rate according to either Bazett’s formula (QTcB), Fridericia’s formula (QTcF), or another method, machine or manual overread.
For subject eligibility and withdrawal, QT correction formula QTcB will be used.
For purposes of this data analysis, Bazett's formula will be used as the primary method of calculating the corrected QT interval. The QTc should be based on either a single ECG or an average of 3 sequential ECGs obtained within 24 hours of each other. The QTc should be based on single or averaged QTc values of triplicate ECGs obtained over a brief recording period.
17. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment and agree to use effective contraception, as defined in Section 7.4.7, during the study and for 30 days following the last dose of study treatment.
18. ECOG performance status of 0 or 1 (Section 12.3)
19. Completion of screening and baseline assessments
20. Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
21. At least 4 weeks must have elapsed since the last surgery and 2 weeks must have elapsed since radiotherapy
22. Adequate baseline organ function as defined in Table 2 (Please see protocol P50)
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. |
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| E.4 | Principal exclusion criteria |
1. Lactating female
Note: Women with potential to have children must be willing to practice acceptable methods of birth control during the study
2. Bone-only disease and/or disease that cannot be biopsied.
3. Unstable CNS metastases or leptomeningeal carcinomatosis not considered radiographically stable (as defined above in inclusion criterion 12)
Note: Subjects with radiographically stable central nervous system (CNS) metastases are defined as radiographically stable on the previous 2 brain imaging studies, asymptomatic, and off systemic steroids and anticonvulsants for at least 1 month; treatment with prophylactic anticonvulsants is permitted unless listed under Prohibited Medications
4. Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions including concurrent disease that could interfere with subject’s safety, obtaining informed consent, or compliance with the study procedures.
5. Serious cardiac illness or medical condition including but not confined to:
-Uncontrolled arrhythmias (e.g. ventricular tachycardia, high-grade atrioventricular (AV)-block, supraventricular arrhythmias which are not adequately rate-controlled);
- Angina pectoris requiring antianginal medication;
- History of congestive heart failure or systolic dysfunction (LVEF <50%);
- Documented myocardial infarction <6 months from study entry;
- Evidence of transmural infarction on ECG;
- Poorly controlled hypertension (e.g. systolic >160mm Hg or diastolic >100mm Hg);
- Clinically significant valvular heart disease.
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. Any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels as well as subjects with ulcerative colitis are also excluded
8. Any prohibited medication as described in Section 6.2
9. Prior treatment with trastuzumab in combination with lapatinib or prior treatment with an irreversible inhibitor of the intracellular domain of the HER2 receptor such as neratinib
10. Last treatment for metastatic disease including trastuzumab in combination with pertuzumab
11. Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment
12. A known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the study drugs or their excipients that, in the opinion of the investigator or GSK medical monitor, contraindicates participation
French subjects must not have participated in any study using an investigational drug during the previous 30 days |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Changes in gene and/or protein expression profile within each arm on a prespecified set of biomarkers associated with HER family, immunomodulation, apoptosis, and ABC transporters compared between the pre-treatment biopsy and disease progression biopsy. The HER2-enriched and Non-HER2-enriched cohorts will be analyzed separately. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis of changes in biomarker expressions and evaluation of PFS and PFS-NL will be performed approximately 12 months after the last subject is randomized. |
|
| E.5.2 | Secondary end point(s) |
• OS defined as the interval of time between randomization and death due to any cause; investigator-assessed PFS defined as the interval of time between randomization and disease progression or death due to any cause; investigator-assessed ORR defined as percentage of subjects with a CR or PR; and CBR defined as percentage of subjects with a CR, PR, or SD for at least 6 months
• PFS on all subsequent lines of anti-cancer therapies defined as the interval of time between start of next-line anticancer therapy and disease progression or discontinuation of that next-line therapy for any cause
• Determine if a change at disease progression in biomarker correlates with PFS, PFS-NL or OS
• Summary AE profile for both treatment arms
• Molecular subtype at study entry (HER2-enriched) compared with molecular subtype at PD
• Summarize the results of the Functional Assessment of Cancer Therapy – Breast (FACT-B) and Multidimensional Assessment of Fatigue (MAF) Scalefor each arm
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will also be reported to compliment the primary analysis. The second and final analysis for OS will be performed at the time when
•75% of the subjects have died
•100% of subjects have completed study treatment;
•all subjects who go onto first next line therapy have completed first next line therapy.
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| 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 | 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) | 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 | No |
| 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
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 |
| Austria |
| Brazil |
| Hong Kong |
| Italy |
| Mexico |
| Peru |
| Philippines |
| Russian Federation |
| Spain |
| Thailand |
| United States |
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| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
| 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 |
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