| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Resected node-positive or high risk node-negative, invasive HER2-positive breast cancer. |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10006291 |
| E.1.2 | Term | Breast neoplasms malignant and unspecified (incl nipple) |
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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 determine whether the addition of bevacizumab to the two designated regimens of chemotherapy + trastuzumab (TCHB->HB; THB->FEC->HB) will improve invasive disease-free survival (IDFS) relative to the two designated regimens of chemotherapy + trastuzumab (TCH->H; TH->FEC->H). |
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| E.2.2 | Secondary objectives of the trial |
Please refer to protocol section 3.2 for the list of secondary objective related to
1. Invasive disease-free survival (IDFS) within chemotherapy cohorts
2. Disease-free survival (DFS)
3. Overall survival (OS)
4. Recurrence-free interval (RFI)
5. Distant recurrence-free interval (DRFI)
6. Cardiac toxicity
7. Non-cardiac toxicity
8. Molecular predictors of efficacy and cardiac dysfunction |
|
| 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 |
See protocol section 7.0 for a description of all sub-studies.
1. Correlative studies: optional donation of tumor tissue and serum samples for DNA exploratory studies (objective: testing of additional biomarkers and somatic genetic alterations in order to aid in the identification of clinical benefit in certain subsets of populations or even in the identification of anticancer therapies to target the marker).
2. Cardiovascular substudies: optional provision of serum and plasma samples (objective: examination of genetic and biochemical markers to 1. develop pretreatment screening tools to identify patients at high risk of developing LV dysfunction and 2. to allow early detection of ventricular dysfunction)
3. BETH Ancillary Study (with separate protocol and ICF) |
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| E.3 | Principal inclusion criteria |
See Section 4 of protocol and Annex A for full details:
1. The patient must have consented to participate and must have signed and dated both EC-approved consent forms. The pre-entry central HER2 testing consent form must be signed before tumor material is sent to the central laboratory for HER2 testing
2. Patients must be female
3. The patient must be >=18 years old.
4. The patient must have an ECOG performance status of 0 or 1.
5. The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
6. The breast cancer must be HER2-positive based on test results as follows:
*Local testing (if available) should demonstrate that the tumor is IHC 2+ or 3+ or is considered to be HER2-positive for gene amplification by FISH, CISH, or other in situ hybridization method. (If local IHS test results are considered equivocal, the tumor can be submitted for central HER2 testing.)
*Central testing (a requirement for ALL patients) must demonstrate that the tumor is HER2-positive which is defined as IHC 3+ and/or FISH-positive.
7.Patients must have ER analysis performed on the primary tumor prior to randomization. If ER analysis is negative, then PgR analysis must also be performed.
8.Patients must have undergone either a total mastectomy or lumpectomy.
9.The interval between the last surgery for breast cancer and randomization must be no more than 84 days and not less than 28 days.
10. For patients who undergo lumpectomy, the margins of the resected specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist.
11. For patients who undergo mastectomy, margins must be free of gross residual tumor. Patients with microscopic positive margins are eligible.
12. All of the following staging criteria (according to the 6th edition of the AJCC Cancer Staging Manual) must be met:
* By pathologic evaluation, primary tumor must be pT1-3;
* By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN3a, or pN3b
* If pN0, must also meet at least one of the following criteria:
* Pathologic tumor size > 2.0 cm;
* ER negative and PgR negative;
* Histologic and/or nuclear grade 2 (intermediate) or 3 (high); or
* Age < 35 years
13. Patients must have completed one of the following procedures for evaluation of pathologic nodal status:
* Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes if SN is positive;
* Sentinel lymphadenectomy alone if pathologic nodal staging based on sentinel lymphadenectomy is pN0, pN1mi or pN1b; or
* Axillary lymphadenectomy without SN isolation procedure.
14. Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the study if liver imaging (CT, MRI, or PET scan), performed within 3 months prior to randomization, does not demonstrate metastatic disease and meets other testing parameters as described in Criterion 16 below.
15. Patients with alkaline phosphatase that is > ULN but <= 2.5 x ULN are eligible for inclusion in the study if a bone scan or PET scan, performed within 3 months prior to randomization, does not demonstrate metastatic disease.
16. The following organ specific criteria (according to the local laboratory facility) must be met to provide evidence of adequate organ function, at the time of study entry :
Bone Marrow Function (most recent postoperative test performed within 6 weeks prior to randomization)
*ANC must be >= 1200/mm3;
*Platelet count must be >= 100,000/mm3;
*Hemoglobin must be >= 10 g/dL.
Renal Function (most recent postoperative test performed within 6 weeks prior to randomization)
*Serum creatinine must be <= ULN for the lab.
*Creatinine clearance (calculated or measured) must be >60 mL/min.
*Urine dipstick indicating 0-1+ protein. If dipstick reading is >= 2+, collect a
24-hour urine specimen, which must demonstrate <1.0 g of protein per 24 hours.
Liver Function (most recent postoperative test performed within 6 weeks prior to randomization)
*total bilirubin must be <= 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
*AST must be <= 1.5 x ULN for the lab.
*Alkaline phosphatase and AST may not both be > the ULN.
Cardiac Function
*LVEF must be performed within 3 months prior to randomization.
*The ECG (performed within 3 months prior to randomization) must not have demonstrated any of the following conditions:
•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.
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|
| E.4 | Principal exclusion criteria |
See Section 4 of protocol and Annex A for full details:
Disease-specific :
1. Inflammatory breast cancer.
2. Synchronous contralateral breast cancer (invasive or non-invasive).
Clinical Staging :
3. Definitive clinical or radiologic evidence of metastatic disease. (Chest imaging [mandatory for all patients] and other imaging [if required] must have been performed within 3 months prior to randomization.)
Cancer History :
4.History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral DCIS treated with excision and RT.
5. History of non-breast malignancies within the 5 years prior to study entry, except for the following: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.
6. Previous therapy with anthracyclines, taxanes, carboplatin, trastuzumab, or bevacizumab for any malignancy.
7. Treatment including RT, chemotherapy, and/or targeted therapy, administered for the currently diagnosed breast cancer prior to randomization.
Endocrine Therapy :
8. Continued therapy with any hormonal agent such as raloxifene or tamoxifen (or other SERM) or an aromatase inhibitor. (Patients are eligible if these medications are discontinued prior to randomization.)
Medical History :
9. Cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens. This includes but is not confined to:
* Active cardiac disease :
** angina pectoris that requires the use of anti-anginal medication;
** 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 LV function;
** history of documented CHF; and
** documented cardiomyopathy.
10. Uncontrolled hypertension defined as systolic BP > 150 mmHg or diastolic BP > 90 mmHg, with or without anti-hypertensive medication. (BP must be assessed within 28 days prior to randomization.) Patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria.
11. History of hypertensive crisis or hypertensive encephalopathy.
12. History of TIA or CVA.
13. History of any arterial thrombotic event within 12 months before randomization.
14. Symptomatic peripheral vascular disease.
15. Intrinsic lung disease resulting in dyspnea.
16. Unstable diabetes mellitus.
17. Active infection or chronic infection requiring suppressive antibiotics.
18. Any significant bleeding within 6 months before randomization, exclusive of menorrhagia in premenopausal women.
19. Known bleeding diathesis or coagulopathy.
20. Requirement for therapeutic doses of coumadin or equivalent.
21. Gastroduodenal ulcer(s) documented by endoscopy to be active within 6 months of randomization.
22. History of GI perforation, abdominal fistulae, or intra-abdominal abscess.
23. Non-healing wound, skin ulcers, or incompletely healed bone fracture.
24. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to planned start of study therapy. (Note: Placement of a vascular access device is not considered a major surgical procedure.
25. Anticipation of need for major surgical procedures during study therapy and for at least 3 months following completion of bevacizumab.
26. Conditions that would prohibit administration of corticosteroids.
27. Sensory/motor neuropathy >= grade 2, as defined by the NCI's CTCAE v3.0.
28. Other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up.
29. Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements.
Current Medication :
30. Any sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy, etc. Patients are eligible if these medications are discontinued prior to randomization.
31. Chronic daily treatment with corticosteroids (dose of > 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).
32. Use of any investigational agent within 4 weeks prior to enrollment in the study.
Allergies :
33. History of hypersensitivity reaction to drugs formulated with polysorbate 80.
Pregnancy :
34. Pregnancy or lactation at the time of study entry. Pregnancy testing must be performed within
14 days prior to randomization according to institutional standards for women of child-bearing potential.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Invasive disease-free survival, defined as time to local recurrence following mastectomy, invasive local recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, invasive contralateral breast cancer, second primary cancer (other than squamous or basal cell carcinoma of the skin, carcinoma in situ of the cervix, colon carcinoma in situ, or lobular carcinoma in situ of the breast), or death from any cause prior to recurrence or second primary cancer. |
|
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Regimens of chemotherapy + Herceptin + Avastin will be compared to chemotherapy + Herceptin |
|
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 246 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
| All randomized patients will be followed until death or at least until 10 years after study entry. The trial will end 10 years after the last patient was randomized. |
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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 | 13 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 13 |
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