NSABP B-44-I - "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"

NOTE:  This is an INDUSTRY TRIAL receiving funds, not credits.  Participation is limited - only St. Luke's Hospital is currently approved.

Treatment Plan    (Supplied Drug:  Bevacizumab)

RANDOMIZATION

Group 1A  

Begin 2 wks post-randomiz.  Central venous access strongly recommended.

Docetaxel:  75mg/m2, IV over 60 mins, Day 1 q 3 wks (Cycles 1-6)

Carboplatin:  AUC=6mg/mL/min, IV over 30-60 mins, Day 1 q 3 wks (Cycles 1-6)

Trastuzumab (1st dose):  8mg/kg, IV over 90 mins, Day 1 (Cycle 1 only)

Trastuzumab (subseq. doses):  6mg/kg, IV over 30-60 mins, Day 1 q 3 wks (Cycles 2-6)

Continue targeted therapy following completion of chemo/targeted therapy cycles

Trastuzumab:  6mg/kg, IV over 30-60 mins, Day 1 q 3 wks (until 1 yr following 1st Trastuzumab dose regardless of any missed doses)

Group IB

Begin 2 wks post-randomiz.  Central venous access strongly recommended.

Cycle 1 only, Bevacizumab must be given after chemo & Trastuzumab.

Docetaxel:  75mg/m2, IV over 60 mins, Day 1 q 3 wks (Cycles 1-6)

Carboplatin:  AUC=6mg/mL/min, IV over 30-60 mins, Day 1 q 3 wks (Cycles 1-6)

Trastuzumab (1st dose):  8mg/kg, IV over 90 mins, Day 1 (Cycle 1 only)

Trastuzumab (subseq. doses):  6mg/kg, IV over 30-60 mins, Day 1 q 3 wks (Cycles 2-6)

Bevacizumab (1st dose):  15mg/kg, IV over 90 mins, Day 1 q 3 wks (Cycles 1-6)

Bevacizumab (2nd dose):  15mg/kg, IV over 60 mins, Day 1 q 3 wks (Cycles 1-6)

Bevacizumab (subseq. doses):  15mg/kg, IV over 30 mins, Day 1 q 3 wks (Cycles 1-6)

Flush IV line

Continue targeted therapy following completion of chemo/targeted therapy cycles

Trastuzumab:  6mg/kg, IV over 30-60 mins, Day 1 q 3 wks (until 1 yr following 1st Trastuzumab dose regardless of any missed doses)

Bevacizumab:  15mg/kg, IV over 30 mins, Day 1 q 3 wks (until 1 yr following 1st Bevacizumab dose regardless of any missed doses)

Flush IV line

Eligibility

• Female, >18 yrs old.
• ECOG perf status 0-1.
• Must be unilateral invasive breast adenocarcinoma on histol exam.
• HER2+ based on test results:
  • Local testing (if available) should show tumor is IHC 2+ or 3+ or is considered HER2+ for gene amplification by FISH, CISH, or other ISH method.  If local ISH test results are equivocal, tumor can be submitted for central HER2 testing.
  • Central testing (required for ALL pts) must show tumor is HER2+ (defined as FISH+ &/or IHC 3+).
• All of following must be met:
  • Prim tumor:  pT1-3 by path eval
  • Ipsilateral nodes:  pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN3a, or pN3b
  • If pN0, at least 1 of following must be met:
    • Path tumor size >2.0cm
    • ER negative & PgR negative
    • Histol &/or nuclear Grade 2 (intermediate) or 3 (high)
    • Age <35 yrs
• Must have undergone total mastectomy or breast conserving surgery (lumpectomy).
• Pts who undergo lumpectomy:  Margins of resected specimen must be histol free of invasive tumor and DCIS.  If path exam shows tumor at line of resection, additional operative procedures may be performed to obtain clear margins.  If tumor still present after re-excision(s), pt must undergo total mastectomy to be eligible.  Pts w/margins positive for LCIS are eligible w/o additional resection.
• Pts who undergo mastectomy:  Margins must be free of gross residual tumor.  Pts w/microscopic positive margins are eligible (see protocol for RT requirements).
• Must have completed 1 of following for eval of path nodal status:
  • Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes if SN+
  • Sentinel lymphadenectomy alone if path nodal staging based on sentinel lymphadenectomy is pN0, pN1mi, or pN1b
  • Axillary lymphadenectomy w/o SN isolation procedure
  • >28 days & <84 days between last breast cancer surgery (tx or staging) & randomiz
• Must have ER analysis performed on prim tumor pre-randomiz.  If ER-, then PgR analysis must be performed.

• From most recent post-op tests w/i 6 wks pre-randomiz:   ANC >1200/mm3; platelets >100,000/mm3; Hgb >10g/dL; total bili <ULN for lab*; alk phos <2.5x ULN for lab**; SGOT <1.5x ULN for lab**; serum creat <ULN for lab; meas or calc CrCl >60mL/min; urine dipstick 0 - 1+ protein***. 

  *      Unless bili elevated >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.

  ***  If >2+, collect 24-hr urine specimen (must be <1.0g protein/24 hrs)

• SGOT or alk phos >ULN is allowed if liver imaging (CT, MRI, or PET w/i 3 mos pre-randomiz) r/o mets disease and hepatic requirements are met.

• Alk phos >ULN but <2.5x ULN is allowed if bone scan or PET (w/i 3 mos pre-randomiz) r/o mets disease.

• LVEF asmt w/i 3 mos pre-randomiz (2D echo preferred, but MUGA may be substituted).  LVEF must be >55% regardless of facility's LLN (use same method & facility throughout the study).  If baseline LVEF >70%, have accuracy of initial LVEF confirmed & repeat if uncertain.

• ECG w/i 3 mos pre-randomiz and not showing:  ventricular arrhythmias (except benign PVCs); supraventricular & nodal arrhythmias requiring a pacemaker or not controlled w/meds; or conduction abnormality requiring a pacemaker.

• No inflammatory breast cancer.

• No definitive clinical or radiologic evidence of mets.  Chest imaging (mandatory) & other imaging (if required) w/i 3 mos pre-randomiz.

• No hx of ipsilateral invasive breast cancer regardless of tx or ipsilateral DCIS treated w/excision & RT.

• No hx of non-breast malignancies w/i 5 yrs pre-study entry, except carcinoma of cervix, colon, or melanoma (all in situ), or non-melanoma skin cancer.

• No previous therapy w/anthracyclines, taxanes, Carboplatin, Trastuzumab, or Bevacizumab for any malignancy.

• No RT, chemo, &/or targeted therapy administered for currently diagnosed breast cancer pre-randomiz.

• No continued therapy w/any hormonal agent or aromatase inhibitor.  Pts are eligible if these meds DC'd pre-randomiz.

• No sex hormonal therapy.  Pts are eligible if these meds DC'd pre-randomiz.

• No cardiac disease to preclude use of drugs in tx regimens.  Includes, but not confined to:

  Active cardiac disease

  • angina pectoris requiring use of anti-anginal meds

  • ventricular arrhythmias except benign PVC

  • supraventricular & nodal arrhythmias requiring pacemaker or not controlled w/meds

  • conduction abnormality requiring pacemaker

  • valvular disease w/documented compromise in cardiac function

  • symptomatic pericarditis

  Hx of cardiac disease

  • MI documented by elevated cardiac enzymes or persistent regional wall abnormalities on LV asmt

  • hx of documented CHF

  • documented cardiomyopathy

• No uncontrolled HTN (systolic >150 mmHg or diastolic >90 mmHg w/o anti-HTN meds (w/i 28 days pre-randomiz).  Pts w/initial BP elevations are eligible if BP med lowers pressure to meet entry criteria.

• No hx of hypertensive crisis or hypertensive encephalopathy.

• No hx of TIA or CVA.

• No hx of 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 chronic infection requiring suppressive antibiotics.

• No significant bleeding w/i 6 mos pre-randomiz, exclusive of menorrhagia in premenopausal women.

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

• No major surgical procedure, open bx, or significant traumatic injury w/i 28 days prior to planned start of study therapy.  Placement of vascular access device is not major surgery.

• No anticipation of need for major surgery during study therapy & <3 mos following completion of Bevacizumab.

• No documented gastroduodenal ulcer by endoscopy w/i 6 mos pre-randomiz.

• No hx of GI perforation, abdominal fistula, or intra-abdominal abscess.

• No known bleeding diathesis or coagulopathy.

• No therapeutic doses of Coumadin or equiv.

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

• No conditions to prohibit use of corticosteroids.

• No chronic daily tx w/corticosteroids (>10mg/day methylprednisolone equiv) - excluding inhaled steroids.

• No hx of hypersensitivity to drugs formulated w/polysorbate 80.

• No pregnant or nursing women.  Pregnancy test w/i 14 days pre-randomiz is required [if applicable]).

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

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

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

• PRE-STUDY REQUIREMENTS (See protocol for Pre-Randomization Requirements)

  • Consent form for pre-entry HER2 testing (b/f tumor is submitted)

  • Tumor sample submission for central HER2 testing (MANDATORY)*

  • Determination of hormone receptor status

  • H&P, perf status, concomitant meds, BP, ht, wt#

  • Menopausal status (estradiol level prn)#

  • CBC/diff/platelets$

  • Serum creat$

  • CrCl (calc or meas)$

  • Urine dipstick for protein (if >2+ protein by dipstick, obtain a 24-hr urine protein)$

  • Pregnancy test (w/i 14 days, if applicable; use institutional standards)

  • Chest CT or CXR** %

  • Liver imaging (if alk phos or SGOT >ULN)**&

  • Bone nuclear imaging (if alk phos >ULN or unexplained bone pain)**&

  • 2D echo or MUGA (2D echo preferred - use same method & facility throughout tx)***%

  • ECG%

  • Bilat breast imaging (MRI permitted as substitute for mammogram b/f entry [US is not].  Unilateral for mastectomy pts w/ or w/o reconstruction.)@

  • Serum/Plasma for biomarkers (w/pt's consent - after randomiz, but b/f study therapy begins)!

  *       Tumor block (or 20 unstained sections).  Allow adequate time to receive test results w/i 84 days from surgery until randomiz.  Tissue will also be used for translational research (in consenting pts).

  **     PET-CT permitted as alternative to CT of chest & abdomen, and bone scan to r/o mets

  ***   If baseline LVEF >70%, have accuracy of initial LVEF confirmed & repeat if uncertain.

  #      Within 4 wks pre-randomiz

  $      Within 6 wks pre-randomiz (most recent post-op test results)

  %    Within 3 mos pre-randomiz

  &     Within 3 mos pre-randomiz (if required)

  @    Within 6 mos pre-randomiz

  !        Contact KCCOP for kits.  Samples to be centrifuged & stored at -70^oC (max 6 mos) until shipment on dry ice to Roche.

• Signed informed consent for study.