| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2+ Metastatic Breast Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
Breast cancer with a specific mutation (HER2)
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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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000020826 |
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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 |
The co-primary objectives of this study are:
• to compare independently adjudicated progression free survival (PFS) following treatment with neratinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2-positive (HER2+) MBC who have received two or more prior HER2- directed regimens in the metastatic setting.
• to compare overall survival (OS) following treatment with neratinib plus capecitabine versus lapatinib plus capecitabine in this population.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to compare between the two treatment groups:
• Investigator-assessed PFS.
• Objective response rate (ORR), duration of response (DOR) and clinical benefit (CBR) (complete response [CR] or partial response [PR] or stable disease [SD] ≥24 weeks).
• Time to intervention for symptomatic metastatic central nervous system (CNS) disease.
• Safety (adverse events [AEs], serious adverse events [SAEs]).
• Health outcomes assessments.
Exploratory objective:
• To assess the population pharmacokinetics (PK) of neratinib when administered in combination with capecitabine.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Aged ≥18 years at signing of informed consent.
2. Histologically confirmed MBC, current stage IV.
3. Documented HER2 overexpression or gene-amplified tumor (immunohistochemistry [IHC] 3+ or IHC 2+ with confirmatory fluorescence in situ hybridization [FISH]+). (Note: Patients who are IHC 0 or 1+ are not eligible to participate in the study). Tumor samples will be evaluated for HER2 expression by IHC (Herceptest™) and if required for gene amplification by FISH analysis (IQFISH pharmDx™).
4. Prior treatment with at least two (2) HER2-directed regimens for metastatic breast cancer. A new regimen is defined as a modification in a planned course of therapy to include other treatment agents (alone or in combination) as a result of disease progression, relapse, or toxicity. A new regimen also starts when a planned period of observation off therapy is interrupted by a need for additional treatment for the disease.
5. At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
6. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
7. Eastern Cooperative Oncology Group (ECOG) status of 0 to 1.
8. Negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after menopause.
9. Women of childbearing potential must agree and commit to the use of a highly effective method of contraception, as determined to be acceptable by the Investigator, from the time of informed consent until 28 days after the last dose of the investigational products. Men must agree and commit to use a barrier method of contraception while on treatment and for 3 months after last dose of investigational products.
10. Provide written, informed consent to participate in the study and follow the study procedures. |
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| E.4 | Principal exclusion criteria |
1. Received previous therapy with capecitabine, neratinib, lapatinib, or any other HER2-directed tyrosine kinase inhibitor.
2. Received prior therapy resulting in a cumulative epirubicin dose >900 mg/m2 or cumulative doxorubicin dose >450 mg/m2. If another anthracycline or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of 450 mg/m2 doxorubicin.
3. Any major surgery ≤28 days prior to the initiation of investigational products, or received anti-cancer therapy (including chemotherapy, biological therapy, hormonal therapy, investigational agents, or other anti-cancer therapy) administered ≤21 days prior to the initiation of investigational products.
4. Received radiation therapy ≤14 days prior to initiation of investigational products.
5. Symptomatic or unstable brain metastases. (Note: Asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days prior to randomization are eligible to participate in the study).
6. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia.
7. QTc interval >0.450 seconds or known history of QTc prolongation or Torsades de Pointes.
8. Screening laboratory assessments outside the following limits:
Laboratory endpoint : Required limit for exclusion
8a. Absolute neutrophil count (ANC) : <1500/μL (1.5 x 10^9 /L)
8b. Platelet count : <100,000/μL
8c. Hemoglobin (Hb) : <8 g/dL (transfusions allowed).Transfusions must be at least 14 days prior to baseline.
8d. Total bilirubin : >1.5 x institutional upper limit of normal (ULN)
8e. Aspartate aminotransferase (AST) and/or Alanine aminotransferase (ALT) : >3 x institutional ULN (>5 x ULN if liver metastases are present).
8f. Creatinine clearance : <50 mL/min (as calculated by Cockroft and Gault formula or Modification of Diet in Renal Disease [MDRD] formula).
9. Active infection or unexplained fever >38.5°C (>101.3°F).
10. Other malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or vulva; c) prostate cancer of Gleason Score 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas.
11. Currently breast-feeding.
12. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn’s disease, malabsorption, or Grade ≥2 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 4.0 [CTCAE v.4.0] diarrhea of any etiology at screening).
13. Active infection with hepatitis B or hepatitis C virus.
14. Known dihydropyrimidine dehydrogenase deficiency.
15. Known hypersensitivity to 5 fluorouracil or to any component of the investigational products or compounds of similar chemical composition.
16. Unable or unwilling to swallow tablets.
17. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that would, in the Investigator’s judgment, make the patient inappropriate for this study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
There are 2 co-primary endpoints: independently adjudicated PFS and OS. All patients randomized will be evaluated.
1. PFS is defined as disease progression (radiographic or other appropriate modality) or death due to any cause.
2. Overall survival, defined as the time from randomization to death due to any cause.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Efficacy assessment for PFS will be assessed by a blinded, independent, central review of tumor assessments for all patients at screening, and then after every 6 weeks from first dose of investigational product, regardless of treatment schedule modification (e.g., dose delay), until documented disease progression or death due to any cause. Progressive disease (PD) will be independently assessed using RECIST v1.1.
2. Survival data will be collected throughout the active treatment phase and during the long term follow-up phase. Survival follow-up after patient discontinuation of investigational product will be conducted approximately every 12 weeks to assess for survival until patient death or withdrawal of consent. |
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| E.5.2 | Secondary end point(s) |
1. Comparison of clinically relevant improvements in breast cancer patients with respect to radiographic changes or changes in other appropriate modalities, including:
o “Investigator-assessed” PFS, assessed by tumor assessments that will occur for all patients at screening, and then after every 6 weeks from first dose of investigational product, regardless of treatment schedule modification (e.g., dose delay), until documented disease progression or death due to any cause;
o Objective response rate, defined as the proportion of patients demonstrating either a CR or PR during the study;
o Duration of response is measured from the time at which response criteria were met for CR or PR (whichever status was recorded first) until the first date of recurrence or PD or death;
o Clinical benefit rate, defined as the proportion of patients who achieved overall tumor response (CR or PR) or SD for at least 24 weeks.
2. Time to intervention for symptomatic metastatic CNS disease, defined as date of initiation of intervention or therapy for symptomatic CNS disease determined by the investigator to be due to CNS metastasis. This may include brain, leptomeningeal and epidural metastases including epidural spinal cord compression arising from tumor growth in the epidural space.
3. Safety Assessments: Patients receiving at least 1 dose of investigational product will be evaluable for safety.
4. Health Outcomes Assessment:
The following health outcomes assessments will be completed by patients:
• European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30), version 3
• EORTC QLQ-BR23 (breast cancer-specific questionnaire)
• The EuroQol (EQ-5D-5L) multi-dimensional health status questionnaire
Exploratory endpoint:
5. Pharmacokinetics:
A population PK study with sparse sampling will be included in the study to assess the variability of neratinib concentration when administered in combination with capecitabine among individuals in the target patient population. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 & 2: Time points of evaluation for secondary endpoints 1 & 2 are detailed above.
3. AEs and SAEs will be reported until 28 days after the last dose of investigational product(s) and will be followed until resolution or until condition stabilizes. Should an Investigator be made aware of any SAE occurring any time after the reporting period, it must be promptly reported.
4. Health outcomes assessments will be performed at screening, every 6 weeks during the active treatment period and at treatment discontinuation.
Exploratory endpoint:
5. PK samples will be collected from approximately 100 patients in the neratinib plus capecitabine arm (Arm A) at Cycle 1, on Days 1 and 15.
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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 | 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) | 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 | 2 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Hong Kong |
| Ireland |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| Portugal |
| Russian Federation |
| Singapore |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 17 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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