| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adjuvant Breast Cancer: Node positive or high risk node negative and HER 2 negative |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 14.1 |
| 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) |
|
| 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 TC regimen (TCB) improves invasive disease-free survival (IDFS) relative to TC alone. |
|
| E.2.2 | Secondary objectives of the trial |
Invasive Dosease Free Survival-(IDFS):To determine whether the regimen of TCB improves IDFS relative to the TAC chemotherapy regimen.
Disease Free Survival-(DFS-DCIS): To determine whether the regimen of TCB improves DFS-DCIS relative to the TAC regimen.
Overall Survival-(OS): To determine whether the regimen of TCB improves OS relative to the TC alone regimen. To determine whether the regimen of TCB improves OS relative to the TAC regimen. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-The patient must have signed and dated an approved consent form
-Patients must be female.
-patient must be ≥ 18 and ≤ 70 years old.
- ECOG performance status of 0 or 1 (see Appendix B).
- tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
- HER2-negative breast cancer based on current ASCO/CAP Guideline
Recommendations
the following staging criteria must be met according to AJCC criteria:
• By pathologic evaluation,
primary tumor must be pT1-3;
•, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b,pN1c), pN2a, pN3a, or pN3b
If pN0, at least one of the following criteria must be met:
− ER negative and PgR negative; or
− Pathologic tumor size > 2.0 cm; or
− T1c (pathologic tumor size > 1.0 cm but ≤ 2.0 cm) and ER positive (PgR status
may be positive or negative) and either grade 3 histology or Oncotype DX®
Recurrence Score of ≥ 25.
-Patients must have undergone either a total mastectomy or breast-conserving surgery(lumpectomy)
- 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- For patients who undergo mastectomy, margins must be histologically free of invasive tumor and DCIS.
-Patients must have completed one of the following procedures for evaluation of
pathologic nodal status:
• Sentinel lymphadenectomy alone if pathologic nodal staging based on sentinel
lymphadenectomy is pN0, pN1mi, or pN1b;
• Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph
nodes if the sentinel node (SN) is positive; or
• Axillary lymphadenectomy without SN isolation procedure.
-The interval between the last surgery for breast cancer (treatment or staging) and
randomization must be at least 28 days but no more than 84 days.
(-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. (Either a core
biopsy or surgical resection specimen can be used for ER/PgR testing.)
-The most recent postoperative blood counts, performed within 6 weeks prior to
randomization, must meet the following criteria:
• ANC must be ≥ 1200/mm3;
• platelet count must be ≥ 100,000/mm3; and
• hemoglobin must be ≥ 10 g/dL.
-The following criteria for evidence of adequate hepatic function must be met based on the results of the most recent postoperative tests 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. For example, if the
alkaline phosphatase is > the ULN but ≤ 2.5 x ULN, then the AST must be ≤ the
ULN. If the AST is > the ULN but ≤ 1.5 x ULN, then the alkaline phosphatase must
be ≤ ULN.
Note: If ALT is performed instead of AST (per institution's standard practice), the ALT
value must be ≤ 1.5 x ULN; if both were performed, the AST must be ≤ 1.5 x ULN.
NSABP B-46-I/USOR 07132 – Page 14
-Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the study if liver imaging (CT, MRI, PET-CT, or PET scan performed within 90 days prior to
randomization) does not demonstrate metastatic disease and the requirements in criterion are met.
- Patients with 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
90 days prior to randomization does not demonstrate metastatic disease.
- The most recent postoperative serum creatinine performed within 6 weeks prior to
randomization must be ≤ ULN for the lab.
- A urine sample must be tested for proteinuria by the dipstick method. Eligibility must be based on the most recent postoperative test result(s) performed within 6 weeks prior to
randomization. Urine dipstick must indicate 0-1+ protein. If dipstick reading is ≥ 2+, a
24-hour urine specimen must be collected and must demonstrate < 1 gram of protein.
- LVEF assessment by 2-D echocardiogram or MUGA scan must be performed within
90 days prior to randomization. The LVEF must be ≥ 50% regardless of the facility’s
LLN. (If the facility performing the assessment has not reported the LVEF as a whole
number, decimals reported as ≥ 5 should be rounded up and decimals reported as
< 5 should be rounded down.)
|
|
| E.4 | Principal exclusion criteria |
T4 tumors including inflammatory breast cancer.
Definitive clinical or radiologic evidence of metastatic disease. (Chest imaging
[mandatory for all patients] and other imaging within 90 days prior to randomization.)
Synchronous or metachronous contralateral invasive breast cancer. (Patients with
synchronous and/or metachronous contralateral DCIS are eligible.)
Any history of ipsilateral invasive breast cancer or ipsilateral DCIS.
History of non-breast malignancies within 5 years prior to randomization, except for the
following: carcinoma in situ of the cervix, colorectal carcinoma in situ, melanoma in situ,
and basal cell and squamous cell carcinomas of the skin.
Previous therapy with anthracyclines, taxanes, or bevacizumab for any malignancy.
Chemotherapy administered for the currently diagnosed breast cancer prior to
randomization.
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.) Any sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy
Patients are eligible if these medications are discontinued prior to
randomization.
Known active hepatitis B or hepatitis C with abnormal liver function tests.
Cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens.
-Uncontrolled hypertension defined as systolic BP > 150 mmHg or diastolic BP
> 90 mmHg, with or without anti-hypertensive medication. Patients with initial BP
elevations are eligible if initiation or adjustment of BP medication lowers pressure to
meet eligibility requirements.
History of hypertensive crisis or hypertensive encephalopathy.
History of TIA or CVA.
History of any arterial thrombotic event within 12 months prior to randomization.
Symptomatic peripheral vascular disease.
Intrinsic lung disease resulting in dyspnea.
Unstable diabetes mellitus.
Active infection or chronic infection requiring suppressive antibiotics.
History of a major organ allograft or condition requiring chronic immunosuppression,
e.g., kidney, liver, lung, heart, bone marrow transplant, or autoimmune diseases.
(Patients who have received corneal transplants, cadaver skin, or bone transplants are
eligible.)
Any significant bleeding within 180 days prior to randomization, exclusive of
menorrhagia in premenopausal women.
Non-healing wound, skin ulcers, or incompletely healed bone fracture.
Major surgical procedure, open biopsy, or significant traumatic injury within
28 days prior to the planned start of study therapy. (Note: Placement of a vascular access
device is not considered a major surgical procedure. See Section 7.3 for instructions
regarding initiation of therapy after placement for Group 3 patients.)
NSABP B-46-I/USOR 07132 – Page 16
Anticipation of need for major surgical procedures during study therapy and for at least
90 days following completion of bevacizumab. (See Section 7.9 regarding the timing of
surgery to replace the tissue expanders with permanent implants for patients who have
had breast reconstruction and other elective surgery.)
Gastroduodenal ulcer(s) documented by endoscopy to be active within 180 days before
randomization.
History of GI perforation, abdominal fistulae, or intra-abdominal abscess.
Known bleeding diathesis or coagulopathy.
Requirement for therapeutic doses of coumadin or equivalent.
Sensory/motor neuropathy ≥ grade 2, as defined by the NCI CTCAE v3.0.
Conditions that would prohibit administration of corticosteroids.
Chronic daily treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone
equivalent) (excluding inhaled steroids).
History of hypersensitivity reaction to drugs formulated with polysorbate 80.
Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing must be
performed within 2 weeks prior to randomization according to institutional standards
for women of childbearing potential.)
Other non-malignant systemic disease that would preclude the patient from receiving
study treatment or would prevent required follow-up.
Psychiatric or addictive disorders or other conditions that, in the opinion of the
investigator, would preclude the patient from meeting the study requirements.
Use of any investigational product within 4 weeks prior to randomization. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
IDFS, 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, melanoma in situ, carcinoma in situ of the cervix, colorectal carcinoma in situ, or lobular carcinoma in situ of the breast), or death from any cause prior to recurrence or second primary cancer |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| It is estimated that it will take 32 months to accrue 3900 patients (1300 for each arm), and it will take another 34 months of follow-up to reach the required number of events to test the primary hypothesis. So, allowing an additional 6 months for data lock and report development, the total time to the initial release of findings will be about 6 years.There will be three interim analyses. The first interim analysis will take place at the first regularly scheduled meeting of the NSABP Data Safety Monitoring Committee (DSMC) after 95 events have occurred in total on the TCB + TC arms. |
|
| E.5.2 | Secondary end point(s) |
| Secondary endpoints include IDFS for the comparison of TCB vs. TAC. Other secondary endpoints for the comparison of TCB vs. TC and TCB vs. TAC include disease-free survival (DFS-DCIS), overall survival (OS), and recurrence-free interval (RFI). DFS-DCIS is defined as time to local recurrence following mastectomy, local recurrence in the ipsilateral breast following lumpectomy (invasive or non-invasive), regional recurrence, distant recurrence, contralateral breast cancer (invasive or non-invasive), second primary cancer (other than squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, colorectal carcinoma in situ, or lobular carcinoma in situ of the breast), or death from any cause prior to recurrence or second primary cancer. OS is defined as time from randomization until death from any cause. RFI is defined as time from randomization until local, regional, or distant recurrence. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| No timepoints specified for secondary endpoints. |
|
| 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) | 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 | 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 | 14 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
-patient develops a serious side effect that she cannot tolerate or that cannot be controlled with other medciations.
-the patients health gets worse
-the patient is unable to meet the study requirements or
-new information about the study drugs or other treatmnets fro breast cancer becomes available
-patient withdraws consent |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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