| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ErbB2 Positive Locally Recurrent or 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 | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 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 compare the investigator assessed progression-free survival
following treatment with neratinib in combination with paclitaxel versus
trastuzumab plus paclitaxel in subjects who have not received previous
treatment for erbB-2-positive locally recurrent or metastatic breast
cancer. |
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| E.2.2 | Secondary objectives of the trial |
- To compare investigator assessed clinical activity between treatment
arms by measuring overall survival, objective response rate, duration of
response, and clinical benefit rate (complete response + partial response
+ stable disease ≥ 24 weeks).
- To compare safety (adverse events and serious adverse events) between treatment arms.
- To compare the frequency of and time to symptomatic or progressive central nervous system lesions in both treatment arms. |
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| 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 |
A pharmacogenetic sub-study will be conducted under this protocol:
Upon separate consent, original tumor biopsy sample will be studied for: P95HER2 levels via an antibody-based assay, PIK3CA mutations in hotspots (ie, exons 9,20 via gene sequencing), PIK3CA amplification (q-PCR or FISH), PTEN loss and erbB family members (erbB-1, erbB-2, erbB-3, and erbB-4) (IHC), c-Myc amplification (q-PCR or FISH). Blood samples will be taken at baseline; cycle 1, day 15; and cycle 2, day 1 for assessment of serum HER2/ECD.
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| E.3 | Principal inclusion criteria |
1. Female subjects aged 18 years or older.
2. Subjects must have histologically and/or cytologically confirmed diagnosis of breast cancer.
3. Subjects must have locally recurrent or metastatic breast cancer that is not amenable to curative surgery and/or radiation.
4. Documentation of erbB-2 gene amplification by FISH (as defined by a ratio >2.2) or chromogenic in situ hybridization (CISH, as defined by the manufacturer’s kit instruction) or documentation of erbB-2-overexpression by IHC (defined as IHC3+, or IHC2+ with FISH or CISH confirmation) based on local laboratory or initial diagnostic results utilizing one of the sponsor-approved assays. If erbB-2 status is unavailable or was determined using a test other than a sponsor-approved assay (as defined in the protocol) and cannot be assessed using one of these assays prior to randomization, testing and study eligibility must be obtained from the sponsor-identified central laboratory prior to randomization.
5. All subjects must have tumor tissue (ie, most recent archived formalin fixed-paraffin embedded tissue [block or unstained slides])available for central review of erbB-2 expression levels by FISH testing performed by a sponsor identified central laboratory.
6. Documentation of ER/PgR status (positive or negative) based on local laboratory or initial diagnostic results must be available before study entry. If results are unavailable, tumor tissue may be sent to the sponsor-identified central vendor for assessment prior to study entry as per investigator’s discretion.
7. Subjects must have at least 1 measurable lesion as defined by modified Response Evaluation Criteria in Solid Tumors (RECIST 1.0) criteria (specifically, no ascites, pleural or pericardial effusions, osteoblastic bone metastases, or carcinomatous lymphangitis of the lung as only lesion).
8. Subjects must have Eastern Cooperative Oncology Group (ECOG) status of 0 to 2 (not declining within 2 weeks prior to the first does of investigational product).
9. Subjects must have left ventricular ejection fraction (LVEF) within institutional range of normal as measured by multiple gated acquisition (MUGA) or echocardiogram (ECHO).
10. Screening laboratory values must be within the following parameters:
- Absolute neutrophil count (ANC) ≥1.5 x 109 /L (1500/mm3)
- Platelet count ≥100 x 109/L (100,000/mm3)
- Hemoglobin ≥9.0 g/dL (90 g/L)
- Serum creatinine ≤1.5 x upper limit of normal (ULN)
- Total bilirubin ≤1.5 x ULN (<3 ULN if Gilbert’s disease)
- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT
≤2.5 x ULN (≤5 x ULN if liver metastases are present)
11. Subjects must have recovered (to grade 1 or baseline) from all clinically significant acute adverse effects of prior therapies (excluding alopecia).
12. All subjects who are not surgically sterile or postmenopausal must agree and commit to the use of a reliable method of birth control starting 2 weeks prior to the administration of the first dose of investigational product until 28 days after the last dose of investigational product. A woman of childbearing potential is one who is biologically capable of becoming pregnant. This includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives
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| E.4 | Principal exclusion criteria |
1. Prior systemic anti-cancer therapy (including cytotoxic chemotherapy, signal transduction inhibitors [eg, lapatinib], biologic [eg, trastuzumab]), or other investigational anticancer therapy) for locally recurrent or metastatic disease. Prior endocrine therapy in any setting is allowed.
2. Prior treatment with an erbB-2 inhibitor, other than trastuzumab, lapatinib, or the combination of the two in the neoadjuvant or adjuvant setting.
3. Prior treatment with neoadjuvant or adjuvant anthracyclines with a cumulative dose of doxorubicin of >400 mg/m2, epirubicin dose >800 mg/m2, or the equivalent dose for other anthracyclines or derivatives (eg, 72 mg/m2 of mitoxantrone).
4. Subjects with recurrence or progression of disease within 12 months after completion of adjuvant or neoadjuvant systemic anticancer therapy (including cytotoxic chemotherapy, signal transduction inhibitors [eg, lapatinib], biologic [eg, trastuzumab], or other investigational anticancer therapy), other than endocrine therapy, for early breast cancer.
5. Subjects with bone or skin as the only site of measurable disease. Subjects with skin lesions measurable by computed tomography (CT) scans or magnetic resonance imaging (MRI) as only site of measurable disease are allowed.
6. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other cancer therapy within 2 weeks before the administration of the first dose of investigational product.
7. Subjects with active uncontrolled or symptomatic central nervous system (CNS) metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Subjects with a history of CNS metastases or cord compression are eligible if they have been definitively treated and are off anticonvulsants and steroids for at least 4 weeks before first dose of investigational product. Subjects with newly detected asymptomatic CNS metastases must be definitively treated (eg. radiotherapy, stereotactic surgery) before being considered for the trial.
8. Subjects with active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥3), unstable angina, and myocardial infarction (within 12 months of study entry).
9. Subjects with inadequately controlled hypertension (ie, systolic blood pressure [BP] > 180 mm Hg or diastolic BP > 100 mm Hg).
10. Subjects with family or personal history of congenital long or short QT syndrome, Brugada syndrome or QTc interval > 0.45 second or known history of QTc prolongation or torsade de pointe (TdP).
11. Subject with significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn’s disease, malabsorption, or grade ≥2 diarrhea of any etiology at baseline).
12. Subject with preexisting grade 2 or greater motor or sensory neuropathy.
13. Subjects with history of life-threatening hypersensitivity reaction to taxanes, trastuzumab or their excipients.
14. Subjects with clinical contraindication to steroids preventing their use as part of paclitaxel premedication.
15. Women who are pregnant, breast-feeding or women of child bearing potential who are not using effective contraception during participation in the study and do not agree to do so for at least 28 days after final dose of investigational product.
16. Subjects with inability or unwillingness to swallow oral medications.
17. Immunocompromised subjects, including known seropositivity for human immunodeficiency virus (HIV), or current or chronic hepatitis B and/or hepatitis C infection (as detected by positive testing for hepatitis B surface antigen [HbsAg] or antibody to hepatitis C virus [anti HCV] with confirmatory testing). (Note: testing is not mandatory to be eligible for the study. However, if a subject is at risk for having undiagnosed HCV [due to history of injection drug use or due to geographic location for example], testing at screening should be considered.)
18. Subjects with any other cancer, including contralateral breast cancer, within 5 years prior to screening with the exception of adequately treated ductal carcinoma in situ, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin.
19. Evidence of significant medical illness or abnormal laboratory finding that, in the investigator’s judgment, will substantially increase the risk associated with the subject’s participation in, and completion of, the study, or could preclude the evaluation of the subject’s response. Examples include, but are not limited to, serious active infection (ie, requiring IV antibiotic or antiviral agent), uncontrolled major seizure disorder, significant pulmonary disorder (eg, interstitial pneumonitis, pulmonary hypertension), or psychiatric disorder that would interfere with the subject safety or informed consent.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression Free Survival (PFS)
PFS is the interval from the date of randomization until the first date on which recurrence or progression, or death due to any cause, is documented, censored at the last assessable evaluation or at the initiation of new anticancer therapy. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS: every 8 weeks from first dose of investigational product. |
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| E.5.2 | Secondary end point(s) |
1) To compare investigator assessed clinical activity between treatment arms by measuring: OS, ORR, duration of response (DOR), and clinical benefit rate (CBR; CR + PR + stable disease [SD] ≥ 24 weeks).
2) To compare safety (AEs; serious adverse events [SAEs]) between treatment arms.
3) To compare the frequency of and time to symptomatic or progressive central nervous system (CNS) lesions in both treatment arms.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS: every 3 months after last dose of investigational product
ORR/DOR/CBR/CNS met. evaluation: Every 8 weeks from first dose of investigational product
Safety: weekly assessment
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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 | Yes |
| 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 57 |
| 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 |
| Bahamas |
| Belarus |
| Belgium |
| Bulgaria |
| Canada |
| China |
| Croatia |
| Denmark |
| France |
| Germany |
| Greece |
| Hong Kong |
| Hungary |
| India |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Latvia |
| Lithuania |
| Malaysia |
| Malta |
| Poland |
| Portugal |
| Serbia |
| Singapore |
| South Africa |
| Spain |
| Switzerland |
| Taiwan |
| Turkey |
| Ukraine |
| 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
|
| Trial will end approximately one year after the last of the 304 PFS events required for PFS analysis have been observed. The last study subject visit will define the end of 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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