A Phase I-II Study of Lapatinib and Docetaxel as Neoadjuvant Treatment for HER-2 Positive Locally Advanced/Inflammatory or Large Operable Breast Cancer
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.
Interventional
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Phase I part: Dose limiting toxicity during cycle 1
during study
Yes
David Cameron, MD
Study Chair
Edinburgh Cancer Centre at Western General Hospital
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
EORTC-10054
NCT00450892
February 2007
June 2013
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