NSABP B-46-I - "A Phase III Clinical Trial Comparing the Combination of TC Plus Bevacizumab to TC Alone and to TAC for Women with Node-Positive or High-Risk Node-Negative, HER2-Negative Breast Cancer"

NOTE:  This is an INDUSTRY TRIAL receiving funds, not credits.  Participation is limited - only certain investigators are currently approved.

Treatment Plan    (Supplied Drug:  Bevacizumab)

RANDOMIZATION - See protocol for pre-medication & supportive regimens.  Begin w/i 2 wks following randomiz.

Group 1 (TAC) - Q 21 days x 6 cycles.  Administer drugs in order listed.

Doxorubicin (A):  50mg/m2, via sidearm thru running IV over 5-15 mins, Day 1

Cyclophosphamide (C):  500mg/m2, IV over 15-30 mins, Day 1

Docetaxel (T):  75mg/m2, IV over 60 mins, Day 1

Pegfilgrastim (preferred):  6mg, SC, Day 2 (administer on Day 3 or 4 at investigator's discretion)

OR

Filgrastim:  5mcg/kg, Days 2-10

Group 2 (TC) - Q 21 days x 6 cycles.  Administer drugs in order listed.

Docetaxel (T):  75mg/m2, IV over 60 mins, Day 1

Cyclophosphamide (C):  600mg/m2, IV over 15-30 mins, Day 1

Group 3 (TCB) - Q 21 days x 6 cycles.  Start therapy a minimum of 28 days following most recent surgery.  Central venous access strongly recommended.

Docetaxel (T):  75mg/m2, IV over 60 mins, Day 1

Cyclophosphamide (C):  600mg/m2, IV over 15-30 mins, Day 1

Bevacizumab (B) (1st dose):  15mg/kg, IV over 90 mins, Day 1 (Cycle 1 only - give after chemo)

Bevacizumab (B) (2nd dose):  15mg/kg, IV over 60 mins, Day 1 (Cycle 2)

Bevacizumab (B) (all subsequent doses):  15mg/kg, IV over 30 mins, Day 1 (Cycles 3-6)

    â

Bevacizumab (B):  15mg/kg, IV over 30 mins, Day 1, q 21 days (until 1 yr following 1st Bevacizumab dose)

Eligibility

• Female, age >18 & <70.

• ECOG perf status 0-1.

• Unilateral invasive breast adenocarcinoma on histol exam.

• HER2(-) based on current ASCO/CAP guidelines.  If result of in situ hybridization testing (FISH, CISH, or other) is equivocal, pt is eligible if HER2-targeted therapy is not planned.

• All of following must be met:

  • By path eval, primary tumor pT1-3

  • By path eval, ipsilateral nodes pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN3a, or pN3b.  If pN0, >1 of following must be met:

    • ER(-) and PgR(-)

    • Path tumor size >2.0cm

    • T1c (path tumor size >1.0cm but <2.0cm) and ER(+) (PgR status may be positive or negative) and either grade 3 histology or Oncotype DX Recurrence Score >25.

• Undergone either total mastectomy or breast-conserving surgery (lumpectomy).

• For lumpectomy pts, margins of resected specimen must be histol free of invasive tumor & DCIS (by local pathologist).  If path exam finds tumor at resection line, additional surgery must be performed to obtain clear margins.  If tumor still present at resected margin after re-excision(s), pt must undergo total mastectomy to be eligible.  Pts w/margins positive for LCIS are eligible w/o additional resection.

• For mastectomy pts, margins must be histol free of invasive tumor & DCIS.

• Must have completed one of following for eval of path nodal status:

  • Sentinel lymphadenectomy alone if path nodal staging based on sentinel lymphadenectomy is pN0, pN1mi, or pN1b

  • Sentinel lymphadenectomy followed by removal of additional non-sentinel nodes if SN is positive

  • Axillary lymphadenectomy w/o SN isolation procedure

• >28 days & <84 days between last surgery for breast cancer (tx or staging) and randomiz.

• Must have ER analysis performed on primary tumor pre-randomiz.  If ER(-), then PgR analysis must be performed (either core bx or surgical resection can be used for ER/PgR testing).

• Most recent post-op counts, within 6 wks pre-randomiz:  ANC >1200/mm3; platelets >100,000/mm3; Hgb >10g/dL; total bili <ULN*; alk phos <2.5x ULN**; SGOT <1.5x ULN**. 

  *     Unless >ULN to 1.5x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bili

  **   Alk phos & SGOT may not both be >ULN.

• SGOT or alk phos >ULN is allowed if liver imaging (CT, MRI, PET-CT, or PET w/i 90 days pre-randomiz) does not show mets disease and blood parameters above are met.

• Alk phos >ULN but <2.5x ULN is allowed if bone scan, PET-CT, or PET w/i 90 days pre-randomiz does not show mets disease.

• Most recent post-op serum creat <ULN.

• Urine must be tested for proteinuria by dipstick (followed by UPC ratio if needed) or by UPC ratio alone.  Most recent post-op test result(s) w/i 6 wks pre-randomiz must be either UPC <1.0 or urine dipstick 0-1+ protein (if >2+, a subsequent UPC must be <1.0).

• LVEF by 2D echo or MUGA w/i 90 days pre-randomiz.  LVEF must be >50% regardless of facility's LLN (see protocol for details).

• No T4 tumors including inflammatory breast cancer.

• No definitive clinical or radiologic evidence of mets.  Chest imaging (mandatory) and other imaging (prn) performed w/i 90 days pre-randomiz.

• No synchronous or metachronous contralateral invasive breast cancer.  Synchronous &/or metachronous contralateral DCIS is allowed.

• No prior ipsilateral invasive breast cancer or ipsilateral DCIS.

• No non-breast malignancies w/i 5 yrs pre-randomiz except in situ cervical carcinoma, in situ colorectal carcinoma, melanoma in situ, or non-melanoma skin cancer.

• No prior anthracyclines, taxanes, or bevacizumab for any malignancy.

• No chemo administered for currently diagnosed breast cancer pre-randomiz.

• No continued use of hormonal agent(s) or aromatase inhibitors.  Pts are eligible if these are discontinued pre-randomiz.

• No sex hormonal therapy.  Pts are eligible if these are discontinued pre-randomiz.

• No known active Hep B or Hep C w/abnormal liver function tests.

• No cardiac disease (prior &/or active) to preclude use of study drugs.

• No uncontrolled HTN (systolic >150mmHg or diastolic >90mmHg) w/ or w/o BP meds.  Initial BP elevation is allowed if initiation or adjustment of BP med lowers pressure to meet requirements.

• No prior hypertensive crisis or hypertensive encephalopathy.

• No prior TIA or CVA.

• No prior arterial thrombotic event w/i 12 mos pre-randomiz.

• No symptomatic perip vascular disease.

• No intrinsic lung disease resulting in dyspnea.

• No unstable diabetes mellitus.

• No active or infection or chronic infection requiring suppressive antibiotics.

• No prior major organ allograft or condition requiring chronic immunosuppression.  Corneal transplants, cadaver skin, or bone transplants are allowed.

• No significant bleeding w/i 180 days pre-randomiz (except menorrhagia in premenopausal women).

• No non-healing wound, skin ulcer, or incompletely healed bone fx.

• No major surgery, open bx, or significant traumatic injury w/i 28 days prior to start of study therapy.  Placement of vascular access device is allowed.

• No need for major surgery during study therapy & >90 days post-completion of Bevacizumab.

• No active gastroduodenal ulcer(s) by endoscopy w/i 180 days pre-randomiz.

• No prior GI perforation, abdominal fistulae, or intra-abdominal abscess.

• No known bleeding diathesis or coagulopathy.

• No need for therapeutic doses of coumadin or equivalent.

• No sensory/motor neuropathy >Grade 2 (NCI CTCAE v3.0).

• No conditions prohibiting use of corticosteroids.

• No chronic daily tx w/corticosteroids (>10mg/day methtylpredisolone equivalent), excluding inhaled steroids.

• No prior hypersensitivity reaction to drugs formulated w/polysorbate 80.

• No pregnant or lactating women.  Pregnancy test w/i 2 wks pre-randomiz for women of childbearing potential.

• No other non-malignant systemic disease to preclude study tx or follow-up.

• No psychiatric or addictive disorder or other condition to preclude study tx or follow-up (investigator's opinion).

• No use of any investigational product w/i 4 wks pre-randomiz.

• PRESTUDY REQUIREMENTS:

  • Hormone receptor status*

  • Complete H&P, perf status, BP, ht, wt**

  • Menopausal status**

  • CBC/diff/platelets***

  • Bili/SGOT/alk phos***

  • Serum creat***

  • Urine dipstick for protein &/or UPC ratio***

  • Pregnancy test (if applicable, w/i 2 wks pre-randomiz)

  • 2D echo or MUGA#

  • Chest CT or CXR (PET & PET-CT scans are also permitted)#

  • Liver imaging (CT, MRI, PET-CT, or PET to r/o mets disease; required only if alk phos or SGOT >ULN)#

  • Bone nuclear imaging (PET or PET-CT also allowed; required only if bone pain or if alk phos >ULN)#

  • Bilat breast imaging (w/i 180 days pre-randomiz)##

  • Tumor sample submission (paraffin block; MANDATORY w/i 3 mos POST-randomiz)

  *       Performed on prim tumor.  If ER(-), then PgR analysis must also be done.  Core bx or surgical resection specimen can be used.

  **     Within 4 wks pre-randomiz

  ***   Within 6 wks pre-randomiz (must be post-op testing)

  #       Within 90 days pre-randomiz

  ##    MRI or mammogram allowed (not US).  May be unilateral for mastectomy pts w/ or w/o reconstruction.  Not required for bilat mastectomy pts.

• Signed informed consent.