NSABP B-40 - "A Randomized Phase III Trial of Neoadjuvant Therapy in Patients with Palpable and Operable Breast Cancer Evaluating the Effect on Pathologic Complete Response (pCR) of Adding Capecitabine or Gemcitabine to Docetaxel when Administered Before AC with or without Bevacizumab and Correlative Science Studies Attempting to Identify Predictors of High Likelihood for pCR with Each of the Regimens"

Treatment Plan    (Supplied Drugs:  Bevacizumab, Capecitabine, Gemcitabine)

1)  REQUIRED TISSUE COLLECTION (4 core needle bx samples collected pre-randomiz)

2)  RANDOMIZATION

See protocol for premedication regimens & REQUIRED cytokine support.  Administer drugs in order listed.  Central venous access strongly recommended.

Group 1A (Docetaxel à AC):  q 21 days x 4 cycles

Docetaxel:  100mg/m2, IV over 60 mins, Day 1

21 days after Day 1 of last cycle of Docetaxel

Doxorubicin:  60mg/m2, IV over 15 mins, Day 1

Cyclophosphamide:  600mg/m2, IV over 30 mins, Day 1

Group 1B (Docetaxel + Bevacizumab à  AC + Bevacizumab):  q 21 days x 4 cycles

Bevacizumab:  15mg/kg, IV over 90 mins (1st dose - see protocol for subsequent doses), Day 1

Docetaxel:  100mg/m2, IV over 60 mins (flush IV line after Bevacizumab), Day 1

21 days after Day 1 of last cycle of Docetaxel

Bevacizumab:  15mg/kg, IV over 30 mins, Day 1 (only w/AC cycles 1 & 2)

Doxorubicin:  60mg/m2, IV over 15 mins, Day 1 (flush IV line after Bevacizumab)

Cyclophosphamide:  600mg/m2, IV over 30 mins, Day 1

Group 2A (Docetaxel + Capecitabine à AC):  q 21 days x 4 cycles

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

Capecitabine:  825mg/m2, PO, BID, Days 1-14

21 days after Day 1 of last cycle of Docetaxel + Capecitabine

Doxorubicin:  60mg/m2, IV over 15 mins, Day 1

Cyclophosphamide:  600mg/m2, IV over 30 mins, Day 1

Group 2B (Docetaxel + Capecitabine + Bevacizumab à  AC + Bevacizumab):  q 21 days x 4 cycles

Bevacizumab:  15mg/kg, IV over 90 mins (1st dose - see protocol for subsequent doses), Day 1

Docetaxel:  75mg/m2, IV over 60 mins (flush IV line after Bevacizumab), Day 1

Capecitabine:  825mg/m2, PO, BID, Days 1-14

21 days after Day 1 of last cycle of Docetaxel + Capecitabine

Bevacizumab:  15mg/kg, IV over 30 mins, Day 1 (only w/AC cycles 1 & 2)

Doxorubicin:  60mg/m2, IV over 15 mins, Day 1 (flush IV line after Bevacizumab)

Cyclophosphamide:  600mg/m2, IV over 30 mins, Day 1

Group 3A (Docetaxel + Gemcitabine à AC):  q 21 days x 4 cycles

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

Gemcitabine:  1000mg/m2, IV over 30 mins, Days 1 & 8

21 days after Day 1 of last cycle of Docetaxel + Capecitabine

Doxorubicin:  60mg/m2, IV over 15 mins, Day 1

Cyclophosphamide:  600mg/m2, IV over 30 mins, Day 1

Group 3B (Docetaxel + Gemcitabine + Bevacizumab à  AC + Bevacizumab):  q 21 days x 4 cycles

Bevacizumab:  15mg/kg, IV over 90 mins (1st dose - see protocol for subsequent doses), Day 1

Docetaxel:  75mg/m2, IV over 60 mins (flush IV line after Bevacizumab), Day 1

Gemcitabine:  1000mg/m2, IV over 30 mins, Days 1 & 8

21 days after Day 1 of last cycle of Docetaxel + Capecitabine

Bevacizumab:  15mg/kg, IV over 30 mins, Day 1 (only w/AC cycles 1 & 2)

Doxorubicin:  60mg/m2, IV over 15 mins, Day 1 (flush IV line after Bevacizumab)

Cyclophosphamide:  600mg/m2, IV over 30 mins, Day 1

3)  SURGERY (As soon as possible following recovery from chemo, final LVEF asmt b/f surgery, & final clinical response asmt.  Group 1B, 2B, & 3B pts who complete 4 cycles of AC, should have surgery >9 wks following last dose of Bevacizumab.  See protocol for important notes re:  timing of surgery.)

Lumpectomy or Mastectomy & Eval of Axilla  (see protocol for instructions)

Hormonal therapy at investigator's discretion.  ER+ &/or PgR+ tumor pts should receive minimum 5 yrs hormonal therapy.

4)  POST-OP THERAPY FOR GROUPS 1B, 2B, & 3B ONLY

Bevacizumab:  15mg/kg, IV over 30 mins, q 21 days, x 10 cycles (start >28 days post-surg) - RT (if given) may be delivered concurrently

5)  POST-OP RT

RT must be given post-lumpectomy.  Post-mastectomy RT at physician's discretion.

Eligibility

• Female, age >18.

• ECOG perf status 0-1.

• Invasive breast adenocarcinoma dx by core needle bx.

• Prim breast tumor palpable & >2cm on PE.

• LVEF by MUGA or echo w/i 3 mos pre-study entry & >LLN for cardiac imaging facility (see protocol for details).

• EKG w/i 3 mos pre-study entry.

• At randomiz:  ANC >1200/mm3; platelets >100,000/mm3; Hgb >10g/dL; total bili <ULN* and alk phos** <2.5x ULN  and SGOT <1.5x ULN**. 

  *   Unless Grade 1 bili elevation (>ULN to 1.5x ULN) from Gilbert's disease or similar syndrome due to slow conjugation of bili.

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

• Either skeletal pain or alk phos >ULN but <2.5x ULN is allowed if bone scans do not show mets.  Confirm suspicious findings as benign by xray, MRI, or bx.

• SGOT or alk phos >ULN is allowed if liver imaging does not show mets and requirements above are met.

• Serum creat <ULN; calc CrCl >50mL/min; UPC ratio <1.0.

• Able to swallow oral meds.

• No tumor that is strongly HER2+ by IHC (3+) or by FISH (positive for gene amplification).

• No excisional or incisional bx for prim breast tumor.

• No surgical axillary staging prior to study entry.  Exceptions:  1) FNA or core bx of an axillary node is permitted for any pt; & 2) a pre-neoadjuv therapy sentinal node bx for pts w/clinically negative axillary nodes is permitted (NOT RECOMMENDED).

• No T4 tumors.

• No ipsilateral cN2b or cN3 disease (cN1 or cN2a is allowed).

• No definitive clinical or radiologic evidence of mets.

• No synchronous bilat breast cancer (invasive or DCIS).

• No tx for currently diagnosed breast cancer pre-study entry including RT, chemo, biotherapy, &/or hormonal therapy.

• No sex hormonal therapy (unless DC'd pre-randomiz).

• No therapy w/any hormonal agent either for osteoporosis or breast cancer prevention (unless DC'd pre-randomiz).

• No hx of breast cancer, including DCIS (LCIS is allowed).

• No prior therapy w/anthracyclines, taxanes, capecitabine, 5-FU, gemcitabine, or bevacizumab for any malignancy.

• No other malignancies unless disease-free >5 yrs and at low risk for recurrence (physician's opinion).  Following cancers are allowed if diagnosed and treated w/i past 5 yrs:  in situ  cervical cancer, colon cancer, or melanoma and non-melanoma skin cancer.

• No cardiac disease to preclude use of anthracyclines. 

• No hx of MI documented by elevated cardiac enzymes or persistent regional wall abnormalities on LV function asmt.

• No hx of TIA or CVA.

• No hx of other arterial thrombotic event w/i 12 mos pre-study entry.

• No symptomatic perip vascular disease.

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

• No gastroduodenal ulcer determined active by endoscopy.

• No major surgical procedure, open bx, or significant traumatic injury w/i 28 days prior to start of study therapy (does not include placement of vascular access device).  No anticipation of major surgical procedures (other than required breast surgery) during course of study.

• No known bleeding diathesis or coagulopathy (warfarin pts w/in-range INR [usually 2-3] are allowed).

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

• No other non-malignant systemic disease to preclude tx w/any study regimen or prevent follow-up.

• No counter-indication to corticosteroids.

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

• No use of any investigational agent w/i 30 days pre-study entry.

• No pregnant or lactating women at randomiz.

• PRESTUDY REQUIREMENTS (w/i 4 wks unless otherwise indicated):

  • H&P, perf status (w/i 3 mos)

  • Ht, wt, BP, anti-HTN meds asmt, cardiac hx

  • Tumor asmt by clinical exam (include prim tumor and palpable regional lymph nodes)

  • Msmt of target lesions

  • CBC/diff/platelets

  • Serum creat

  • Calc CrCl

  • UPC ratio

  • Bili/SGOT/alk phos

  • Serum bhCG (if applicable, w/i 2 wks)

  • Chest CT or CXR (PA & Lat)* - w/i 3 mos

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

  • Bone scan* (required if alk phos >ULN or unexplained bone pain)

  • MUGA or echo** (w/i 3 mos; use same method throughout study)

  • EKG (w/i 3 mos)

  • Bilat breast imaging (Ipsilateral w/i 6 mos; contralateral w/i 12 mos.  MRI [not US] is permitted as a substitute for mammogram at baseline.)

  • Ultrasound of ipsilateral axilla*** (b/f or after entry but b/f therapy begins)

  • Marking of prim tumor site# (b/f or after entry but b/f therapy begins)

  • Core bx tissue for submission (prim tumor)##

  • Blood/Serum collection (w/pt's consent; after entry - b/f therapy begins)

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

  **     If LVEF >75%, investigator should have result reviewed pre-study entry.

  ***   Strongly recommended for planning axillary staging procedure.  If abnormal, FNA is recommended.

  #      Clip placement, tattoo, etc. to mark prim tumor site.

  ##    1 core in formalin, 1 core in RNAlater, 2 cores in shipping medium for Precision Therapeutics (contact KCCOP for kit).  Process per protocol and ship all 4 samples to Precision Therapeutics.

• Signed informed consent.