CALGB 40603 - "Randomized Phase II 2 x 2 Factorial Trial of the Addition of Carboplatin +/- Bevacizumab to Neoadjuvant Weekly Paclitaxel Followed by Dose-Dense AC in Hormone Receptor-Poor/HER2-Negative Resectable Breast Cancer"

Treatment Plan    (Supplied Drug:  Bevacizumab)

RANDOMIZATION

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CORE NEEDLE OR INCISIONAL BIOPSIES (MANDATORY - strongly suggested that they are image-guided & obtained at time of clip placement)

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Group 1:  Paclitaxel (P) à ddAC

Paclitaxel:  80mg/m2, IV, weekly x 12 wks

Doxorubicin:  60mg/m2, IV, q 2 wks, x 4 cycles

Cyclophosphamide:  600mg/m2, IV, q 2 wks, x 4 cycles (w/CSF support)

Group 2:  Paclitaxel (P) à ddAC (Bevacizumab concurrent w/Paclitaxel & ddAC)

Paclitaxel:  80mg/m2, IV, weekly x 12 wks

Doxorubicin:  60mg/m2, IV, q 2 wks, x 4 cycles

Cyclophosphamide:  600mg/m2, IV, q 2 wks, x 4 cycles (w/CSF support)

Bevacizumab:  10mg/kg, x 9 doses (w/weekly Paclitaxel on Wks 1, 3, 5, 7, 9, 11 & w/AC during Cycles 1, 2, 3)

Group 3:  Paclitaxel (P) w/concurrent Carboplatin à ddAC

Paclitaxel:  80mg/m2, IV, weekly x 12 wks

Doxorubicin:  60mg/m2, IV, q 2 wks, x 4 cycles

Carboplatin:  AUC=6, IV, q 3 wks, x 4 doses (beginning w/Paclitaxel on Wk 1)

Cyclophosphamide:  600mg/m2, IV, q 2 wks, x 4 cycles (w/CSF support)

Group 4:  Paclitaxel (P) w/concurrent Carboplatin à ddAC (Bevacizumab concurrent w/Paclitaxel & ddAC)

Paclitaxel:  80mg/m2, IV, weekly x 12 wks

Doxorubicin:  60mg/m2, IV, q 2 wks, x 4 cycles

Carboplatin:  AUC=6, IV, q 3 wks, x 4 doses (beginning w/Paclitaxel on Wk 1)

Cyclophosphamide:  600mg/m2, IV, q 2 wks, x 4 cycles (w/CSF support)

Bevacizumab:  10mg/kg, x 9 doses (w/weekly Paclitaxel on Wks 1, 3, 5, 7, 9, 11 & w/AC during Cycles 1, 2, 3)

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SURGERY

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POST-PROTOCOL ADJUVANT THERAPY (at physician's discretion - see protocol for recommendations)

Eligibility

• Invasive breast cancer, dxd by core needle or incisional bx (excisional bx not permitted).

• Hormone-receptor poor (both ER & PgR negative or staining present in <10% of invasive cells by IHC).

• HER2-negative (IHC 0-1+ or FISH ratio [HER2 gene copy/chromosome 17] of <2.0 if IHC 2+).

• Resectable, clinical Stg II-III (T2, N0 - T3, N0 or T1-3, N1-2a).  No T4, N2b-3, or M1 disease.  Staging to r/o mets is recommended for Stg III pts.  Multicentric or bilat disease is allowed if target lesion meets eligibility criteria.

• Must undergo pre-tx research bx.

• No prior chemo, hormone therapy, or RT w/therapeutic intent for this cancer.

• Target lesion >1cm, clinically or radiographically.  Palpable or radiographically measurable axillary adenopathy will be recorded, but will not serve as meas disease for prim endpoint.  No axillary disease only (no identifiable tumor in breast that is >1cm on PE or radiographic study).

• No significant hx of bleeding w/i 6 mos pre-regist; no serious or non-healing wound, skin ulcer, or bone fx; no abdominal fistula, GI perforation, or intra-abdominal abscess w/i past 6 mos; no major surgical procedure w/i 28 days pre-randomiz; & no anticipated need for major surgery during study.  The following are NOT considered major surgical procedures that are prohibited in 28 days prior to or following randomiz:  Obtaining required research needle bxs; placement of radiopaque clip to localize tumor(s) for subsequent surgical resection; placement of port for central venous access; FNA of prominent or suspicious axillary lymph node; needle bx of clinically or radiographically detected lesion to r/o mets disease; or pre-tx sentinel LN sampling.

• No baseline neuropathy >Grade 2.

• Women or men age >18.

• Zubrod 0-1.

• No pregnant or nursing women.  Women of reproductive potential must have negative pregnancy test at baseline & agree to use effective, non-hormonal contraception during study tx.

• No CHF, MI, or unstable angina pectoris; arterial thrombotic event, stroke, or TIA w/i past 12 mos; uncontrolled HTN (systolic >160 or diastolic >90); uncontrolled or symptomatic arrhythmia; or >Grade 2 perip vascular disease.

• Pre-tx MUGA or echo w/LVEF > institutional LLN.

• Granulocytes >1000/mcl; platelets >100,000/mcl; total bili <1.5x ULN; calc or meas CrCl >30ml/min; urine protein <1+ or UPC ratio <1*; serum SGPT <2.5x ULN; Serum ßHCG negative (if applicable); PT/INR <1.5x ULN**.

  *   If urine protein on UA is 1+, pt must have either urine protein:creat ratio <1 or 24-hr urine protein <1gm/24 hrs.

  ** If pt is on therapeutic doses of warfarin, must have INR <3 on stable dose of warfarin, no active bleeding, & no path condition associated w/high risk of bleeding.

• PRE-STUDY REQUIREMENTS:

  Within 16 days pre-regist:  All bloodwork; baseline H&P

  Within 28 days pre-regist:  Mammogram, US, or breast MRI (if used for tumor msmt); serum pregnancy test (if applicable)

  Within 42 days pre-regist:  Bone or PET/CT, CT chest & abdomen, LVEF (MUGA or ECHO)

  • H&P, progress notes, ht, wt

  • Clinical tumor msmts (MRI strongly recommended)

  • LVEF (MUGA or Echo)

  • CBC/diff/platelets

  • Creat, bili, SGPT

  • Serum ßHCG (if applicable)

  • Urine protein or UPC ratio

  • Bone or PET scan*

  • CT chest & abdomen*

  • Radiographic tumor msmts (by MRI, mammogram, or US; MRI strongly recommended)

  • Whole blood for pharmacogenomics (w/pt's consent)**

  • Image-guided core bxs (MANDATORY - strongly suggested that they are image-guided & obtained at time of clip placement)***

  *       Recommended for Stg III & Stg II (at investigator's discretion) to r/o mets.

  **     10mL EDTA purple-top tube.  Refrigerate until shipped.  Send Mon-Fri only on cold pack via overnight delivery to:  CALGB Path Coordinating Office; Columbus, OH.  Contact KCCOP for CALGB's FedEx account number.

  ***   2 core bxs in RNAlater & 2 core bxs in 10% neutral buffered formalin.  Also 2 additional core bxs in OCT (if site is able to get frozen specimens & dry ice).  Contact KCCOP for kit.  Send Mon-Fri only via overnight delivery to:  CALGB Path Coordinating Office; Columbus, OH.

• Signed informed consent.