CTSU N063D - "ALTTO - Adjuvant Lapatinib &/or Trastuzumab Treatment Optimisation Study:  A Randomized, Multi-Centre, Open-Label, Phase III Study of Adjuvant Lapatinib, Trastuzumab, Their Sequence and Their Combination in Patients with HER2/ErbB2 Positive Primary Breast Cancer"

Treatment Plan    (Supplied Drug:  Lapatinib)

NOTE:  Pts can be enrolled concurrently on CTSU IBCSG 25-02.

DESIGN 2 w/PACLITAXEL

Randomiz <6 wks from Day 1 of last chemo cycle.  Study tx begins <14 days after randomiz.

Surgery & complete (neo-)adjuv chemo (select from approved list)

    â

LVEF >50%

    â

RANDOMIZATION

Each Arm:  Total Duration = 1 yr (52 wks)

Arm 1

Paclitaxel:  80mg/m2, IV, q week x 12 doses

Trastuzumab:  4mg/kg, IV (loading dose on Day 1)

Trastuzumab:  2mg/kg, IV, q week x 12 wks

After finishing Paclitaxel, continue Trastuzumab (w/RT if indicated)

Trastuzumab:  6mg/kg, IV, q 3 wks x 40 wks

Arm 2

Paclitaxel:  80mg/m2, IV, q week x 12 doses

Lapatinib:  1500mg, PO, QD, x 12 wks

After finishing Paclitaxel, continue Lapatinib (w/RT if indicated)

Lapatinib:  1500mg, PO, QD, x 40 wks

Arm 3

Paclitaxel:  80mg/m2, IV, q week, x 12 doses

Trastuzumab:  4mg/kg, IV (loading dose on Day 1)

Trastuzumab:  2mg/kg, IV, q week x 12 wks (follow by 6-wk washout period, then by Lapatinib)

Lapatinib:  1500mg, PO, QD, x 34 wks

Arm 4

Paclitaxel:  80mg/m2, IV, q week x 12 doses

Lapatinib:  750mg, PO, QD, x 12 wks w/Paclitaxel (given concomitantly w/Paclitaxel)

Lapatinib:  1000mg, PO, QD, x 40 wks (starting Day 1 of Wk 13)

Trastuzumab:  4mg/kg, IV (loading dose at Day 1)

Trastuzumab:  2mg/kg, IV, q week x 12 wks

Trastuzumab:  6mg/kg, IV, q 3 wks (w/RT if indicated)  x 40 wks

DESIGN 2 w/DOCETAXEL

Randomiz <6 wks from Day 1 of last chemo cycle.  Study tx begins <14 days after randomiz.

Surgery & complete (neo-)adjuv chemo (select from approved list)

    â

LVEF >50%

    â

RANDOMIZATION

Each Arm:  Total Duration = 1 yr (52 wks)

Arm 1

Docetaxel:  75mg/m2, IV, q 3 wks x 4 doses

Trastuzumab:  4mg/kg, IV (loading dose at Day 1)

Trastuzumab:  2mg/kg, IV, q week x 12 wks

After finishing Docetaxel, continue Trastuzumab (w/RT if indicated)

Trastuzumab:  6mg/kg, IV, q 3 wks x 40 wks

Arm 2

Docetaxel:  75mg/m2, IV, q 3 wks x 4 doses

Lapatinib:  1250mg, PO, QD x 12 wks

After finishing Docetaxel, continue Lapatinib (w/RT if indicated)

Lapatinib:  1500mg, PO, QD, x 40 wks

G-CSF:  Mandatory prophylaxis x 12 wks w/Docetaxel (freq/dose/route at investigator's discretion)

Arm 3

Docetaxel:  75mg/m2, IV, q 3 wks x 4 doses

Trastuzumab:  4mg/kg, IV (loading dose at Day 1)

Trastuzumab:  2mg/kg, IV, q week x 12 wks

Follow by 6-wk washout period, then by Lapatinib

Lapatinib:  1500mg, PO, QD, x 34 wks

Arm 4

Docetaxel:  75mg/m2, IV, q 3 wks x 4 doses

Lapatinib:  1000mg, PO, QD, x 12 wks w/Docetaxel (given concomitantly w/Docetaxel)

Lapatinib:  1000mg, PO, QD, x 40 wks (starting Day 1 of Wk 13)

Trastuzumab:  4mg/kg, IV (loading dose at Day 1)

Trastuzumab:  2mg/kg, IV, q week x 12 wks

Trastuzumab:  6mg/kg, IV, q 3 wks (w/RT if indicated)  x 40 wks

G-CSF:  Mandatory prophylaxis x 12 wks w/Docetaxel (freq/dose/route at investigator's discretion)

DESIGN 2B

Randomiz <8 wks from definitive surgery.  Study tx begins <14 days after randomiz.

Surgery

    â

LVEF >50%

    â

RANDOMIZATION

Each Arm:  Total Duration = 1 yr (52 wks)

Arm 1

Docetaxel:  75mg/m2, IV, q 3 wks x 6 doses

Carboplatin:  AUC=6, IV, q 3 wks x 6 doses

Trastuzumab:  4mg/kg, IV (loading dose at Day 1)

Trastuzumab:  2mg/kg, IV, q week x 18 wks (w/Docetaxel & Carboplatin)

Trastuzumab:  6mg/kg, IV (w/o loading dose), q 3 wks x 34 wks (starting Day 1 of Wk 19)

G-CSF:  Mandatory prophylaxis x 18 wks during chemo & targeted therapy (freq/dose/route at investigator's discretion)

Arm 2

Docetaxel:  75mg/m2, IV, q 3 wks x 6 doses

Carboplatin:  AUC=6, IV, q 3 wks x 6 doses

Lapatinib:  1000mg, PO, QD x 18 wks (w/Docetaxel & Carboplatin)

Lapatinib:  1500mg, PO, QD x 34 wks (starting Day 1 of Wk 19)

G-CSF:  Mandatory prophylaxis x 18 wks during chemo & targeted therapy (freq/dose/route at investigator's discretion)

Arm 3

Docetaxel:  75mg/m2, IV, q 3 wks x 6 doses

Carboplatin:  AUC=6, IV, q 3 wks x 6 doses

Trastuzumab:  4mg/kg, IV (loading dose at Day 1)

Trastuzumab:  2mg/kg, IV, q week x 18 wks (w/Docetaxel & Carboplatin)

G-CSF:  Mandatory prophylaxis x 18 wks during chemo & targeted therapy (freq/dose/route at investigator's discretion)

Follow by 6-wk washout period, then by Lapatinib

Lapatinib:  1500mg, PO, QD, x 28 wks (starting from Wk 7 of washout period)

Arm 4

Docetaxel:  75mg/m2, IV, q 3 wks x 6 doses

Carboplatin:  AUC=6, IV, q 3 wks x 6 doses

Trastuzumab:  4mg/kg, IV (loading dose at Day 1)

Trastuzumab:  2mg/kg, IV, q week x 18 wks (w/Docetaxel & Carboplatin)

Trastuzumab:  6mg/kg, IV (w/o loading dose), q 3 wks x 34 wks (starting Day 1 of Wk 19)

Lapatinib:  1000mg, PO, QD x 18 wks (w/Docetaxel)

Lapatinib:  1000mg, PO, QD x 34 wks (starting Day 1 of Wk 19)

G-CSF:  Mandatory prophylaxis x 18 wks during chemo & targeted therapy (freq/dose/route at investigator's discretion)

Eligibility

• Age >18.

• ECOG perf status 0-1.

• Non-mets operable primary invasive breast adenocarcinoma that meets following criteria:

  • Histol-confirmed

  • Adequately excised (exceptions:  Pts w/"non-resectable" deep margin invasion are eligible if they have or will receive RT encompassing the region concerned.  Pts w/histol-documented skin infiltration [pT4] are eligible if they have or will receive RT encompassing tumor bed.)

  • Axilla dissected.  SN sampling allowed if axillary dissection follows confirmation of positive SN.  SN sampling alone is NOT acceptable after neoadjuv chemo (in pts receiving neoadjuv chemo, node status will be considered unknown, regardless of results of post-chemo axillary dissection).

  • Axillary node+ pt OR node- pt w/tumor >1.0cm in greatest diameter.  ITC are considered pN0 & micrometastases are considered pN1.

• Known hormone receptor status (ER/PgR or ER alone).

• Designs 1 & 2:  Must have received >4 cycles of approved anthracycline-based (neo-)adjuv chemo regimen or listed as an exception in protocol:

  • For Design 1:  Randomiz <12 wks from Day 1 of last chemo cycle after obtaining post-chemo LVEF >50.  Start study tx <14 days post-randomiz.

  • For Design 2:  Randomiz <6 wks from Day 1 of last anthracycline-containing chemo cycle after obtaining post-chemo LVEF >50.  Start study tx <14 days post-randomiz & must be concurrent w/taxanes.

  • For Design 2B:  Randomiz <8 wks from definitive surgery.  Non-anthracycline platinum containing regimen (Docetaxel & Carboplatin) and study tx must start concomitantly & <14 days post-randomiz.

• Baseline LVEF >50% by echo or MUGA.  For Designs 1 & 2, must be done after completion of all anthracycline-based (neo-)adjuv chemo and prior to targeted therapy(ies).  For Design 2B, must be done prior to targeted therapy(ies) and chemo (Docetaxel & Carboplatin).

• Over expression &/or amplification of HER2 in invasive component of prim tumor (for neoadjuv tx, tissue sample used for HER2 testing should be collected b/f neoadjuv tx starts).  Must meet 1 of following definitions and be confirmed by central lab pre-randomiz:

  • 3+ over expression by IHC (>30% of invasive tumor cells)

  • 2+ or 3+ (in <30% neoplastic cells) over expression by IHC and in situ hybridization (FISH/CISH) demonstrating HER2 gene amplification

  • HER2 gene amplification by FISH/CISH (>6 HER2 gene copies per nucleus, or FISH ratio [HER2 gene copies to chromosome 17 signals] >2.2).

  Pts w/negative or equivocal overall result (FISH test ratio <2.2, <6.0 HER2 gene copies per nucleus) and staining scores of 0, 1+, 2+, or 3+ (in <30% neoplastic cells) by IHC are ineligible.  Equivocal results may be submitted for final determination by central lab.

• No hx of ipsi- &/or contralateral invasive breast cancer.

• No past (<10 yrs) or current malig neoplasms, except curatively treated non-melanoma skin cancer or in situ cervical cancer.  NOTE:  Pts w/prior malignancy diagnosed >10 yrs past who have been curatively treated w/surgery only, without RTor systemic therapy (chemo or endocrine) are eligible.  No prior invasive breast cancer or melanoma at any time.

• No clinically staged T4 tumor, including inflammatory breast cancer.

• No bilat tumors.

• No max cumulative dose of doxorubicin >360mg/m² or max curative dose of epirubicin >720mg/m² or any prior anthracyclines unrelated to present breast cancer.

• No (neo-)adjuv chemo using perip stem cell or BM stem cell support.

• No prior mediastinal RT except internal mammary node RT for present breast cancer.

• No positive or suspicious internal mammary nodes identified by SN technique which have or will not be irradiated, or pts w/supraclavicular node involvement (confirmed by FNA or bx).

• No prior use of anti-HER2 therapy for any reason or other prior biologic or immunotherapy for breast cancer.

• No concurrent anti-cancer tx, except hormonal therapy.

• No concurrent anti-cancer tx in another investigational trial w/hormone or immunotherapy.

• No serious cardiac illness or medical condition.

• No other concurrent serious disease that may interfere w/planned tx (such as severe pulmonary condition/illness).

• None of following immediately prior to randomiz:  Serum total bili >2.0x ULN; SGOT or SGPT >2.5x ULN; alk phos >2.5x ULN; serum creat >2.0x ULN; total WBC <2.5x 10⁹/L; ANC <1.5x 10⁹/L; platelets <100x 10⁹/L.

• Unresolved or unstable serious adverse events from prior adjuv chemo or RT.

• No malabsorption syndrome or any disease significantly affecting GI function, stomach or small bowel resection, or inability to swallow oral meds.  No ulcerative colitis.

• No pregnant or lactating women.  If childbearing potential, must have a negative pregnancy test (urine or serum) w/i 7 days pre-randomiz (irrespective of method of contraception used, including tubal ligation).

• No women/men of reproductive potential (including women whose last menstrual period was <12 mos ago [unless surgically sterile] who are unable or unwilling to use adequate contraception [IUD, barrier methods used w/spermicidal jelly, or total abstinence] during study tx).  No oral, injectable, or implant hormonal contraceptives.

• No concomitant use of CYP3A4 inhibitors or inducers.

• PRESTUDY REQUIREMENTS:

  • Central Path Review (includes HER2 determination & ER/PgR status) - MANDATORY*

  • Blood Kit submission (contact KCCOP for kit) - MANDATORY@

  • Demographics, medical hx, PE**

  • CXR or chest CT (w/i 6 mos pre-randomiz)

  • Mammogram or breast MRI (w/i 1 yr pre-randomiz)

  • Pregnancy test (w/i 7 days pre-randomiz)

  • Cardiac monitoring**:  ECG, LVEF***, signs/symptoms

  • Hematology & Biochemistry**#

  • Menopausal status

  • SAE

  • Pharmacogenetic research blood (w/pt's consent)

  • QOL (optional)

  *       Submit:  2 FFPE blocks (1 tumor [preferably same block used for orig breast cancer dx] & 1 normal), H&E stained slides, op report, & path report.  Send to NCCTG Operations Office; Rochester, MN. 

  **    Within 14 days pre-randomiz

  ***    LVEF results must be available prior to administration of Trastuzumab or Lapatinib.

  #      Include Hgb, total WBC, ANC, platelets, serum creat, BUN, SGOT, SGPT, alk phos, bili

  @    Draw & ship blood on same day (<8 hrs after drawn).  Ship Mon-Thurs only via overnight delivery to Mayo Medical Laboratories.

• Signed informed consent.