ABCSG 30/BETH Details

A multicenter, phase III, randomized trial of adjuvant therapy for patients with HER2-positive node-positive or high risk node-negative breast cancer comparing chemotherapy plus trastuzumab with chemotherapy plus trastuzumab plus bevacizumab

Start:
09/2008

Contact ABCSG-Trial office

E-mail: info@abcsg.at
Phone: +43 1 408 92 30
Fax: +43 1 409 09 90

Design


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Primary objectives:

  • The primary objective is to determine whether the regimens of chemotherapy + trastuzumab + bevacizumab improve invasive disease-free survival (IDFS) relative to the regimens of chemotherapy + trastuzumab.

Secondary objectives:

To determine whether:

  • the TCH®H regimen + bevacizumab improves IDFS relative to the TCH®H regimen alone
  • the TH®FEC®H regimen + bevacizumab improves IDFS relative to the TH®FEC®H regimen alone
  • the regimens of chemotherapy + trastuzumab + bevacizumab improve disease-free survival (DFS) relative to the regimens of chemotherapy + trastuzumab
  • the regimen of TCH®H + bevacizumab improves DFS relative to the regimen of TCH®H alone
  • the regimen of TH®FEC®H + bevacizumab improves DFS relative to the regimen of TH®FEC®H alone
  • the regimens of chemotherapy + trastuzumab + bevacizumab improve overall survival (OS) relative to the regimens of chemotherapy + trastuzumab
  • the TCH®H regimen + bevacizumab improves OS relative to the TCH®H regimen alone
  • the TH®FEC®H regimen + bevacizumab improves OS relative to the TH®FEC®H regimen alone
  • the regimens of chemotherapy + trastuzumab + bevacizumab improve recurrence-free interval (RFI) relative to the regimens of chemotherapy + trastuzumab
  • the TCH®H regimen + bevacizumab improves RFI relative to the TCH®H regimen alone
  • the TH®FEC®H regimen + bevacizumab improves RFI relative to the TH®FEC®H regimen alone
  • the regimens of chemotherapy + trastuzumab + bevacizumab improve distant recurrence-free interval (DRFI) relative to the regimens of chemotherapy + trastuzumab
  • the TCH®H regimen + bevacizumab improves DRFI relative to the TCH®H regimen alone
  • the TH®FEC®H regimen + bevacizumab improves DRFI relative to the TH®FEC®H regimen alone

To evaluate:

  • cardiac toxicity associated with each of the regimens
  • non-cardiac toxicity associated with each of the regimens

To identify biomarkers (from tumor or serum and/or plasma) predictive of toxicity and the level of benefit from the addition of bevacizumab to standard adjuvant systemic treatment

Inclusion criteria:

Patient Selection Guidelines

The following considerations should be weighed carefully as they may make a patient an unsuitable candidate for participation in the BETH Trial.

  1. Patients should have a life expectancy of at least 10 years, excluding their diagnosis of breast cancer (Comorbid conditions should be taken into consideration, but not the diagnosis of breast cancer.)
  2. Submission of tissue samples from the breast surgery for central HER2 testing is required for all patients prior to enrollment in the BETH Trial. For patients who have consented, these samples will also be utilized for the BETH Trial translational research. Therefore, the local pathology department policy regarding release of blocks must be considered early in the screening process
  3. Women who have had breast reconstruction utilizing tissue expanders must be in agreement with not having expansion performed within 2 weeks before the first bevacizumab dose, during bevacizumab, and until 6 weeks following the last dose of bevacizumab
  4. Women of reproductive potential must agree to use an effective non-hormonal method of contraception during therapy and for at least 6 months after the last dose of bevacizumab and/or trastuzumab

Patient-Specific and General Inclusion Criteria

  1. The patient must have consented to participate and must have signed and dated both IRB-approved consent forms that conform to the guidelines of the local regulatory authority and the institution. 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 ³ 18 years old. (The minimum age for eligibility can be older than 18 years if required by local regulatory authority.)
  4. The patient must have an ECOG performance status of 0 or 1

Disease-Specific Inclusion Criteria

  1. The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination
  2. 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
  3. 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
  4. Patients must have undergone either a total mastectomy or breast conserving surgery (lumpectomy)
  5. The interval between the last surgery for breast cancer (treatment or staging) and randomization must be no more than 84 days and not less than 28 days
  6. 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. If pathologic examination demonstrates tumor at the line of resection, additional operative procedures may be performed to obtain clear margins. If tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible. (Patients with margins positive for LCIS are eligible without additional resection.)
  7. For patients who undergo mastectomy, margins must be free of gross residual tumor. Patients with microscopic positive margins are eligible.

Clinical and Pathologic Staging Criteria Requirements

Primary Tumor

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
    1. Bone Marrow Function (most recent postoperative test performed within 6 weeks prior to randomization)

      ANC must be ³ 1200/mm3

      Platelet count must be ³ 100,000/mm3 and

      Hemoglobin must be ³ 10 g/dL

    2. 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 ³ 2+, collect a 24-hour urine specimen, which must demonstrate < 1.0 g of protein per 24 hours

    3. 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. 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

    4. Cardiac Function

      LVEF must be performed within 3 months prior to randomization. It is preferred that LVEF assessment be performed by 2-D echocardiogram; however, MUGA scan may be substituted for 2-D echocardiogram based on institutional preferences. The same LVEF method should be used throughout the study. We strongly advise that all echocardiography or MUGAs be performed at the same cardiac imaging facility used at baseline. The LVEF must be ³ 55% regardless of the institution’s LLN

      Note: Since the pre-entry LVEF serves as the baseline for comparing subsequent LVEF assessments to determine if trastuzumab and bevacizumab 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 test if the accuracy is uncertain.

      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

Exclusion criteria:

  1. Inflammatory breast cancer
  2. Synchronous contralateral breast cancer (invasive or non-invasive)
  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.)
  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
  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.)
  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:
    • 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
    • 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 ³ 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
  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
  33. History of hypersensitivity reaction to drugs formulated with polysorbate 80
  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