| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced HER2-positive breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Breast cancer which is spreading locally |
|
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072740 |
| E.1.2 | Term | Locally advanced 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 |
| To determine the pathologic complete response rate in breast and axillary lymph nodes (pCR breast and nodes) for patients with HER2-positive locally advanced breast cancer (LABC) following neoadjuvant therapy. |
|
| E.2.2 | Secondary objectives of the trial |
To determine the pathologic complete response (pCR) rate in breast in patients with locally advanced breast cancer (LABC);
To determine the clinical complete response (cCR) rate in patients with LABC who present with palpable disease;
To determine 2-year recurrence-free interval (RFI);
To determine 2-year overall survival (OS);
To determine toxicities of the FB-7 regimens.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The patient must have consented to participate and must have signed and dated an appropriate IRB/IEC-approved consent form to enter the study, for the optional procurement of tumor samples by a core biopsy procedure prior to randomization, and for submission of tumor and blood samples required for the FB-7 correlative science studies (see Section 7.1).
2. Patients must be female.
3. Patients must be ≥ 18 years old.
4. The European Cooperative Oncology Group (ECOG) performance status must be 0 or 1.
5. Patients must have the ability to swallow oral medication.
6. The diagnosis of invasive adenocarcinoma of the breast must have been made by core needle biopsy or by limited incisional biopsy.
7. Patients must have estrogen receptor (ER) analysis performed on the primary tumor prior to randomization. If ER analysis is negative, then progesterone receptor (PgR) analysis must also be performed. Patients are eligible with either hormone receptor-positive or hormone receptor-negative tumors.
8. Breast cancer must be determined to be HER2-positive prior to randomization. Assays using FISH or CISH require gene amplification. Assays using IHC require a strongly positive (3+) staining score.
9. Clinical staging, based on the assessment by physical exam, must be AJCC stage IIB, IIIA, IIIB, or IIIC:
- cT2 and cN1;
- cT3 and cN0 or cN1;
- Any cT and cN2 or cN3; or
- cT4.
10. The patient must have a mass in the breast or axilla measuring ≥ 2.0 cm by physical exam, unless the patient has inflammatory breast cancer, in which case measurable disease by physical exam is not required.
11. At the time of randomization, blood counts performed within 4 weeks prior to randomization must meet the following criteria:
- Absolute neutrophil count (ANC) must be ≥ 1200/mm3;
- Platelet count must be ≥ 100,000/mm3;
- Hemoglobin must be ≥ 10 g/dL;
12. The following criteria for evidence of adequate hepatic function performed within 4 weeks prior to randomization must be met:
- total bilirubin must be ≤ upper limit of normal (ULN) for the lab unless the patient has a bilirubin elevation > ULN to 1.5 x ULN due to Gilbert’s disease or similar syndrome involving slow conjugation of bilirubin; and
- alkaline phosphatase must be ≤ 2.5 x ULN for the lab; and
- aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be ≤ 1.5 x ULN for the lab.
13. Patients with alkaline phosphatase > ULN but ≤ 2.5 x ULN are eligible for inclusion in the study if liver imaging (Computerized Tomography [CT], Magnetic Resonance Imaging [MRI], Positron Emission Tomography [PET], or PET-CT scan) performed within 4 weeks prior to randomization does not demonstrate metastatic disease and the requirements in Section 4.2.12 are met.
14. Patients with either unexplained skeletal pain or alkaline phosphatase that is ULN but ≤ 2.5 x ULN are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan performed within 4 weeks prior to randomization does not demonstrate metastatic disease. Patients with suspicious findings on bone scan or PET scan are eligible if suspicious findings are determined to be benign by x-ray, MRI, or biopsy.
15. Serum creatinine performed within 4 weeks prior to randomization must be ≤ 1.5 x ULN for the lab.
16. The LVEF assessment by 2-D echocardiogram or MUGA scan performed within 90 days prior to randomization must be ≥ 50% regardless of the facility's lower limit of normal (LLN). Note: Since the pre-entry LVEF serves as the baseline for comparing subsequent LVEF assessments to determine if targeted therapy can be administered, it is critical that this baseline study be an accurate assessment of the patient's LVEF. If the baseline LVEF is ≥ 70%, the investigator is encouraged to have the accuracy of the initial LVEF result confirmed and to consider repeating the study if the accuracy is uncertain.
17. 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.
18. Women of child bearing potential (WOCBP) must agree and commit to 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 any investigational product.
|
|
| E.4 | Principal exclusion criteria |
1. Fine needle aspiration (FNA) alone to diagnose the primary breast cancer.
2. Excisional biopsy or lumpectomy performed prior to randomization.
3. Surgical axillary staging procedure prior to randomization. Procedures that are permitted prior to study entry include: 1) FNA or core biopsy of an axillary node for any patient, and 2) although not recommended, a pre-neoadjuvant therapy sentinel node (SN) biopsy for patients with clinically negative axillary nodes.
4. Definitive clinical or radiologic evidence of metastatic disease. Chest imaging [mandatory for all patients] and other imaging [if required] must have been performed within 90 days prior to randomization.
5. History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral ductal carcinoma in situ (DCIS) treated with radiation therapy (RT). Patients with a history of lobular carcinoma in situ (LCIS) are eligible.
6. Contralateral invasive breast cancer at any time. Patients with contralateral DCIS or LCIS are eligible.
7. History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to randomization.
8. Known metastatic disease from any malignancy (solid tumor or hematologic).
9. Previous therapy with anthracyclines, taxanes, cyclophosphamide, trastuzumab, or neratinib for any malignancy.
10. Treatment including RT, chemotherapy, and/or targeted therapy, administered for the currently diagnosed breast cancer prior to randomization.
11. Continued endocrine therapy such as raloxifene or tamoxifen (or other selective estrogen receptor modulator [SERM]) or an aromatase inhibitor. Patients are eligible if these medications are discontinued prior to randomization.
12. Any continued sex hormonal therapy, e.g., birth control pills and ovarian hormone replacement therapy. Patients are eligible if these medications are discontinued prior to randomization.
13. Active hepatitis B or hepatitis C with abnormal liver function tests.
14. Intrinsic lung disease resulting in dyspnea.
15. Active infection or chronic infection requiring chronic suppressive antibiotics.
16. Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease or condition significantly affecting gastrointestinal function.
17. Persistent ≥ grade 2 diarrhea regardless of etiology.
18. Sensory or motor neuropathy ≥ grade 2, as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE v3.0).
19. Conditions that would prohibit intermittent administration of corticosteroids for paclitaxel premedication.
20. Chronic daily treatment with corticosteroids with a dose of ≥ 10 mg/day methylprednisolone equivalent (excluding inhaled steroids).
21. Uncontrolled hypertension defined as a systolic blood pressure (BP) > 150 mmHg or diastolic BP > 90 mmHg, with or without anti-hypertensive medications. Patients with hypertension that is well-controlled on medication are eligible.
22. Cardiac disease (history of and/or active disease) that would preclude the use of any of the drugs included in the treatment regimen. This includes but is not confined to:
Active cardiac disease:
- symptomatic angina pectoris within the past 180 days that required the initiation of or increase in anti-anginal medication or other intervention;
- ventricular arrhythmias except for benign premature ventricular contractions;
- supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication;
- conduction abnormality requiring a pacemaker;
- valvular disease with documented compromise in cardiac function; and
- symptomatic pericarditis.
History of cardiac disease:
- myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular function;
- history of documented congestive heart failure (CHF); and
- documented cardiomyopathy.
23. Other nonmalignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up.
24. Pregnancy or lactation at the time of randomization. Pregnancy testing should be performed within 14 days prior to randomization documented by negative serum hCG test for women of child bearing potential.
25. The investigator should assess the patient to determine if she has any psychiatric or addictive disorder or other condition that, in the opinion of the investigator, would preclude her from meeting the study requirements.
26. Use of any investigational agent within 4 weeks prior to randomization.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Pathologic complete response rate (pCR) in breast and nodes. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At the time of surgery, approximately 7 months from randomization. |
|
| E.5.2 | Secondary end point(s) |
Pathologic complete response (pCR) in breast;
Clinical complete response (cCR) assessed by physical exam at the completion of paclitaxel (before AC);
cCR assessed by physical exam at the completion of AC (before surgery);
Events for analysis of recurrence-free interval (RFI) include inoperable progressive disease and local, regional, and distant recurrence during the 2 years from randomization;
Time from randomization until death from any cause;
Reported toxicities, including cardiotoxicity, as defined by Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE v3.0). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
2 years from randomization;
Time from randomization until death from any cause. |
|
| 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 | No |
| 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 | No |
| 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
| 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 | 41 |
| 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 |
| France |
| Italy |
| Portugal |
| Spain |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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 |
Print
