Phase I/II Study of Neoadjuvant Lapatinib in Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      RATIONALE: Drugs used in chemotherapy, such as docetaxel, fluorouracil, epirubicin, and
      cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing
      the cells or by stopping them from dividing. Lapatinib may stop the growth of tumor cells by
      blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as
      trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells
      to grow and spread. Others find tumor cells and help kill them or carry tumor-killing
      substances to them. Giving these treatments before surgery may make the tumor smaller and
      reduce the amount of normal tissue that needs to be removed. Giving trastuzumab after surgery
      may kill any tumor cells that remain after surgery.

      PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of
      docetaxel and lapatinib when given with or without combination chemotherapy and to see how
      well they work in treating women with locally advanced, inflammatory, or resectable breast
      cancer.
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  Determine the maximum tolerated dose of neoadjuvant therapy comprising docetaxel and
           lapatinib ditosylate before or after fluorouracil, epirubicin hydrochloride, and
           cyclophosphamide (FEC chemotherapy) in patients with HER2-positive locally advanced,
           inflammatory, or large resectable breast cancer. (Phase I)

        -  Determine the safety of this regimen in these patients. (Phase I)

        -  Determine the pathological complete response rate in patients treated with neoadjuvant
           docetaxel and lapatinib ditosylate followed by FEC chemotherapy, and with neoadjuvant
           docetaxel and trastuzumab (Herceptin®) followed by FEC chemotherapy. (Phase II)

      Secondary

        -  Determine the biological activity (i.e., changes in apoptosis and proliferation markers
           [PTEN mutation and function, pAkt, mTOR, and associated proteins]) of neoadjuvant
           docetaxel and lapatinib ditosylate in these patients. (Phase I)

        -  Determine adverse events or biological modifications. (Phase I)

        -  Determine the tolerability of these regimens in these patients. (Phase II)

        -  Determine the clinical activity of these regimens. (Phase II)

        -  Identify genes that may predict response in patients treated with docetaxel and
           lapatinib ditosylate. (Phase II)

      OUTLINE: This is a multicenter, open-label, phase I dose-escalation study of docetaxel and
      lapatinib ditosylate followed by a randomized phase II study. Patients enrolled in the phase
      II portion of the study are stratified by institution and disease status (locally advanced
      disease vs large operable tumor).

        -  Phase I (completed as of 5/26/2010): Patients receive docetaxel IV over 1 hour on day 1
           and oral lapatinib ditosylate once daily on days 1-21. Treatment repeats every 3 weeks
           for 4 courses. Two additional courses may be given at the discretion of the physician.

             -  Cohorts of 3-6 patients receive escalating doses of docetaxel and lapatinib
                ditosylate until the maximum tolerated dose (MTD) is determined. The MTD is defined
                as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience
                dose-limiting toxicity (DLT).

        -  Phase I bridge step (completed as of 5/26/2010): Patients receive FEC chemotherapy
           comprising fluorouracil IV over 15 minutes, epirubicin hydrochloride IV over 60 minutes,
           and cyclophosphamide IV over 60 minutes on day 1. Treatment repeats every 3 weeks for 3
           courses. Patients also receive docetaxel and lapatinib ditosylate as in phase I at the
           MTD for up to 3 courses.

             -  Cohorts of 3-6 patients receive de-escalating doses of docetaxel and lapatinib
                ditosylate in combination with FEC chemotherapy until the MTD is determined. The
                MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients
                experience DLT.

        -  Phase II: Patients are randomized to 1 of 3 treatment arms.

             -  Arm I: Patients receive docetaxel and lapatinib ditosylate at the MTD as in the
                bridge step of phase I followed by FEC chemotherapy.

             -  Arm II: Patients receive docetaxel IV over 60 minutes and trastuzumab (Herceptin®)
                IV over 30-90 minutes on days 1, 8, and 15. Patients then receive FEC chemotherapy
                as in the bridge step of phase I. Treatment with docetaxel and trastuzumab repeats
                every 3 weeks for 3 courses in the absence of disease progression or unacceptable
                toxicity.

             -  Arm III: Patients receive docetaxel IV over 60 minutes, lapatinib ditosylate at the
                MTD as in the bridge step of phase I, and trastuzumab (Herceptin®) IV over 30-90
                minutes on days 1, 8, and 15. Patients then receive FEC chemotherapy as in the
                bridge step of phase I. Treatment with docetaxel, lapatinib ditosylate, and
                trastuzumab repeats every 3 weeks for 3 courses in the absence of disease
                progression or unacceptable toxicity.

      All patients then undergo surgery to remove the tumor. Patients may then receive trastuzumab
      every 3 weeks for 1 year.

      Blood samples are collected at baseline and periodically during study for pharmacokinetic
      studies. Patients also undergo tumor biopsies at baseline and periodically during study for
      laboratory studies. Blood and tissue samples are analyzed by quantitative reverse
      transcriptase polymerase chain reaction for biomarker profiling (HER1-3, Akt 1-3, mTOR,
      RICTOR, RAPTOR, CCND1, p21, survivin, PTEN), immunohistochemistry, fluorescent in situ
      hybridization (TopoII, HER2), and proteomics.

      After completion of study treatment, patients are followed periodically.

      PROJECTED ACCRUAL: A total of 150 patients will be accrued for the phase II.
    

Intervention name(s): docetaxel+lapatinib; docetaxel + trastuzumab; docetaxel + trastuzumab + lapatinib
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 3 cycles of docetaxel (100 mg/m²) + lapatinib (1000 mg/d) followed by 3 cycles of FEC; 3 cycles of docetaxel (100 mg/m²) + trastuzumab weekly schedule followed by 3 cycles of FEC 100; 3 cycles of docetaxel (100 mg/m²) + trastuzumab weekly schedule
+lapatinib (1000 mg/d) followed by 3 cycles of FEC 100
Intervention MeSH terms: Docetaxel; Trastuzumab; Lapatinib
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: inflammatory breast cancer; stage II breast cancer; stage IIIA breast cancer; stage IIIB breast cancer; stage IIIC breast cancer