NSABP B-41 - "A Randomized Phase III Trial of Neoadjuvant Therapy for Patients with Palpable and Operable HER2-Positive Breast Cancer Comparing the Combination of Trastuzumab Plus Lapatinib to Trastuzumab and to Lapatinib Administered with Weekly Paclitaxel Following AC Accompanied by Correlative Science Studies to Identify Predictors of Pathologic Complete Response"

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:  Lapatinib)

SEE PROTOCOL FOR PRE-MEDICATION REGIMEN

GROUP 1

Doxorubicin:  60mg/m2, IV over 15 mins, Day 1, q 21 days, Cycles 1-4

Cyclophosphamide:  600mg/m2, IV over 30 mins, Day 1, q 21 days, Cycles 1-4

Initiate 21 days after last dose of AC:

Paclitaxel:  80mg/m2, IV over 60 mins, Days 1, 8, & 15, q 28 days, Cycles 5-8

Trastuzumab:  (1st dose) 4mg/kg, IV over 90 mins, weekly (begin Day 1 of 1st Paclitaxel cycle), x 16+ wks (until 1-7 days b/f surg)

Trastuzumab:  (Subsequent doses) 2mg/kg, IV over 30 mins, weekly (begin Day 1 of 1st Paclitaxel cycle), x 16+ wks (until 1-7 days b/f surg)

             â

SURGERY (Lumpectomy or Mastectomy & Axillary Staging)

             â

Trastuzumab:  6mg/kg, IV over 30-60 mins, q 3 wks (begin 1-6 wks post-surg), complete 1 yr of targeted therapy

Post-op Trastuzumab should end 1 yr from 1st pre-op Trastuzumab dose, regardless of any missed doses.

GROUP 2

Doxorubicin:  60mg/m2, IV over 15 mins, Day 1, q 21 days, Cycles 1-4

Cyclophosphamide:  600mg/m2, IV over 30 mins, Day 1, q 21 days, Cycles 1-4

Initiate 21 days after last dose of AC:

Paclitaxel:  80mg/m2, IV over 60 mins, Days 1, 8, & 15, q 28 days, Cycles 5-8

Lapatinib:  1250mg, PO, QD (6 tabs at same time daily, >1 hr b/f >1 hr after meal) - begin Day 1 of 1st Paclitaxel cycle, continue daily until 1 day b/f surg

             â

SURGERY (Lumpectomy or Mastectomy & Axillary Staging)

             â

Trastuzumab:  (1st dose) 8mg/kg, IV over 90 mins, q 3 wks (begin 1-6 wks post-surg), complete 1 yr of targeted therapy

Trastuzumab:  (Subsequent doses) 6mg/kg, IV over 30-60 mins, q 3 wks (begin 1-6 wks post-surg), complete 1 yr of targeted therapy

Post-op Trastuzumab should end 1 yr from 1st pre-op Lapatinib dose, regardless of any missed doses.

GROUP 3

Doxorubicin:  60mg/m2, IV over 15 mins, Day 1, q 21 days, Cycles 1-4

Cyclophosphamide:  600mg/m2, IV over 30 mins, Day 1, q 21 days, Cycles 1-4

Initiate 21 days after last dose of AC:

Paclitaxel:  80mg/m2, IV over 60 mins, Days 1, 8, & 15, q 28 days, Cycles 5-8

Trastuzumab:  (1st dose) 4mg/kg, IV over 90 mins, weekly (begin Day 1 of 1st Paclitaxel cycle), x 16+ wks (until 1-7 days b/f surg)

Trastuzumab:  (Subsequent doses) 2mg/kg, IV over 30 mins, weekly (begin Day 1 of 1st Paclitaxel cycle), x 16+ wks (until 1-7 days b/f surg)

Lapatinib:  750mg, PO, QD (4 tabs at same time daily, >1 hr b/f >1 hr after meal) - begin Day 1 of 1st Paclitaxel cycle, continue daily until 1 day b/f surg

             â

SURGERY (Lumpectomy or Mastectomy & Axillary Staging)

             â

Trastuzumab:  6mg/kg, IV over 30-60 mins, q 3 wks (begin 1-6 wks post-surg), complete 1 yr of targeted therapy

Post-op Trastuzumab should end 1 yr from 1st pre-op targeted therapy dose (Trastuzumab or Lapatinib), regardless of any missed doses.

Eligibility

• Must consent to release of the required block from the diagnostic core bx for the correlative studies.  Local path dept must agree to release the block pre-study entry.  Submit block w/i 30 days following randomiz.

• Female, age >18.

• ECOG perf status 0-1.

• Prim breast tumor must be palpable and >2.0cm by PE.

• Dx of invasive breast adenocarcinoma by core needle bx.

• HER2+ pre-study entry.  Assays using FISH or CISH require gene amplification.  Assays using IHC require strongly postive (3+) staining score.

• LVEF by MUGA or echo w/i 3 mos pre-randomiz.  Must be >50% regardless of facility's LLN.  If baseline LVEF 65%, it should be reviewed for accuracy pre-study entry (used as baseline comparison).

• At randomiz:   ANC >1200/mm3; platelets >100,000/mm3; Hgb >10g/dL; serum creat <ULN for lab; total bili <ULN for lab*; alk phos <2.5x ULN for lab; SGOT <1.5x ULN for lab.   * Unless bili elevated >ULN to 1.5x ULN due to Gilbert's disease or similar syndrome due to slow conjugation of bili.

• Pts w/skeletal pain or alk phos >ULN (but <2.5x ULN) are eligible if bone scan or PET does not show mets disease.  Suspicious findings must be determined benign by xray, MRI, or bx.

• Pts w/SGOT or alk phos >ULN are eligible if liver CT, MRI, or PET does not show definitive mets and above requirements for hepatic function are met.

• Able to swallow PO meds.

• No FNA alone to diagnose prim tumor.

• No excisional bx or lumpectomy pre-randomiz.

• No surgical axillary staging pre-randomiz.  Exceptions:  1) FNA or core bx of axillary node for any pt, & 2) pre-neoadjuv therapy SN bx for pts w/clinically negative axillary nodes (not recommended).

• No T4 tumors.

• No ipsilateral cN2b or cN3 disease.

• No definitive clinical or radiologic evidence of mets.

• No synchronous bilat invasive breast cancer.

• No requirement for chronic use of any med or substance specified in protocol.  Pts are eligible if these meds &/or substances can be DC'd within protocol's specified timeframe.

• No tx for currently diagnosed breast cancer pre-randomiz.

• No sex hormonal therapy (pt eligible if therapy is DC'd pre-randomiz).

• No continued therapy w/any hormonal agent (pt eligible is med is DC'd pre-randomiz).

• No hx of ipsilateral or contralateral invasive breast cancer (regardless of tx) or ipsilateral DCIS treated w/RT.

• No prior therapy w/anthracyclines, taxanes, Trastuzumab, or Lapatinib for any malignancy.

• No other malignancies (except in situ  cervical or colon cancer, in situ  melanoma, or non-melanoma skin cancer) unless pt disease-free >5 yrs pre-randomiz and at low risk for recurrence (physician's opinion).

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

          Active cardiac disease

  • Angina pectoris requiring use of anti-anginal meds

  • Ventricular arrhythmias except benign premature ventricular contractions controlled by meds

  • Conduction abnormality requiring a pacemaker

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

  • Clinically significant valvular disease

          Hx of cardiac disease

  • MI documented by elev cardiac enzymes or persistent regional wall abnormalities on asmt of LV function

  • Documented CHF

  • Documented cardiomyopathy

• No uncontrolled HTN (BP >150/90 mm/Hg on antihypertensive therapy).  HTN that is well-controlled on meds is allowed.

• No hx or current symptomatic interstitial pneumonitis of pulmonary fibrosis or  definitive evidence of such on CT or CXR in asymptomatic pts.

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

• No malabsorption syndrome, ulcerative colitis, resection of stomach of small bowel, or other disease significantly affecting GI function.

• No other non-malignant systemic disease to preclude any of the tx regimens or follow-up.

• No conditions to prohibit administration of corticosteroids.

• No administration of any investigational agent w/i 30 days pre-randomiz.

• No pregnancy or lactation at regist.

• PRESTUDY REQUIREMENTS (w/i 4 wks pre-randomiz unless otherwise noted):

  • H&P, ht, wt, menopausal status

  • Asmt of BP meds

  • Asmt of tumor by PE (prim tumor & palpable regional lymph nodes)

  • Msmt of target lesion(s)

  • CBC/diff/platelets

  • Serum creat

  • Bili/SGOT/alk phos

  • Pregnancy test (if applicable)

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

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

  • Bone imaging w/nuclear scan or PET (if alk phos >ULN or unexplained bone pain)

  • MUGA or Echo (w/i 3 mos; use same method & facility [if possible] throughout tx; if LVEF >65% have LVEF result reviewed pre-randomiz)

  • EKG (w/i 3 mos)

  • Bilat breast imaging (ipsilateral w/i 3 mos; contralateral w/i 12 mos)*

  • US of ipsilateral axilla (b/f or after study entry; strongly recommended for axillary staging; if abnormal, FNA or core bx is recommended)

  • Marking of prim tumor site (b/f or after study entry; clip, tattoo, or other marking method b/f therapy begins)

  • Tumor block from dx core bx (REQUIRED) - request b/f study entry & local path dept must agree to release block**

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

  *      MRI (not ultrasound) is permitted as a substitute for mammogram at baseline & b/f surg.

  **     Submit block to NSABP Biostat Ctr w/i 30 days of randomiz.  Block is strongly preferred.  If path dept will not release a block, contact NSABP Div. of Pathology immediately for permission to submit alternative tissue & submission instructions.

• Signed informed consent.