A Multicenter Open-label, Phase I/II Dose Escalation Study of Oral Lapatinib in Combination With Docetaxel in Patients With HER-2 Positive Advanced or Metastatic Breast Cancer
Docetaxel is a major drug in the treatment of metastatic breast cancer. In HER2 negative
tumor, the first line treatment is based on docetaxel containing regimen: docetaxel alone,
docetaxel + anthracycline or docetaxel + capecitabine. The efficacy of docetaxel in
combination with trastuzumab has been demonstrated in first line metastatic breast cancer
overexpressing erbB2 receptor. The response rate (RR) and the time to progression (TTP)
observed were even higher than those obtained with paclitaxel +trastuzumab. Docetaxel is
more and more used in first line metastatic setting, becoming the first Taxane used in this
setting.As trastuzumab may raise safety/tolerability concerns, and as its interest in
trastuzumab refractory patients may be limited, there is a need to find new drugs to combine
with docetaxel in breast cancer, and to address the specific interaction/safety profile of
this combination.The association of lapatinib and docetaxel will be the key combination in
metastatic breast cancer development for GSK.The conclusion of a phase I trial EGF 10021
trial conducted in the US which assessed the combination of lapatinib and docetaxel showed
that the acceptable optimal tolerated regimen (OTR) of docetaxel (75 mg/m²) was obtained in
combination with lapatinib 1250 mg with systematic growth factor support.Data from an
ongoing EGF100161 phase I study evaluating the OTR of lapatinib + docetaxel + trastuzumab
shows that the association of lapatinib 1250 mg with docetaxel 75mg/m² is haematological
toxic and has recently been amended to evaluate lapatinib 1250 mg with docetaxel 75 mg/m²
with systematic growth factor support.A phase I/II EORTC study evaluating docetaxel plus
lapatinib in neoadjuvant breast cancer patients has just started. The phase I part of this
study will evaluate several lapatinib and docetaxel dose levels before conducting phase II.
The phase I part will enrol patients (in cohorts of 3 or 6) to determine in a step-wise
approach, the OTR of lapatinib and docetaxel. Patients should not be entered at a higher
dose level until all patients in the previous cohort complete the first cycle of treatment,
this first cycle is used to determine OTR. Dose modification of lapatinib will be based on
any observed toxicity in the treatment period. The OTR will be defined as the dose level at
which £ 1 of 6 patients experiences the DLT (dose limiting toxicity).If no DLT is observed
in the first 3 patients at a particular dose level during the first cycle (3 week treatment
period), recruitment will start at the next dose levelIf 1/3 patients experiences a DLT at a
particular dose level, additional 3 patients will be enrolled at that dose level to a total
of 6 patients if no DLT occurred againIf 1/6 patients experiences a DLT at a particular dose
level, recruitment will start at the next dose levelIf ³ 2/6 patients experiences the same
DLT at a particular dose level, the dose level is not considered to be tolerableIf ³ 2/6
patients experiences two distinct DLT at a particular dose level, additional 3 patients will
be enrolled at that dose level to a total of 9 patients. If one of the previously described
DLT occurred again among the new enrolled patients, the dose level is not considered to be
tolerableA total of 12 patients will be treated at the OTR.The OTR is defined as the dose
level at which no more than 1 of 6 patients experiences a DLT.The DLT for this study is
defined during cycle 1 for the dose escalation step as:· any grade 3-4 non hematological
toxicity as defined by the Common Toxicity Criteria, version 3 (with the exclusion of
alopecia, nausea, vomiting, diarrhea, infusion related that can be rapidly controlled with
appropriate measures)· an absolute neutrophil count (ANC) < 0.5x109 /L lasting for > = 7
day· febrile neutropenia defined as ANC < 1.0 x109 /L and fever at least 38.5°C·
thrombocytopenia < 25, 000/µl or thrombocytopenic bleeding requiring transfusion· grade 3 or
higher left ventricular cardiac dysfunction or a ≥ 20% decrease from baseline in left
ventricular ejection fraction (LVEF) that is also below the institution's lower limit of
normal (LLN), and confirmed by a repeat evaluation 1 to 2 weeks following the first
evaluation.
Interventional
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the optimal tolerated regimen of lapatinib administered in combination with docetaxel as first-line therapy in patients with metastatic breast cancer
during first cycle ( each cycle last 3 weeks)
Yes
Nicolas Isambert, MD
Principal Investigator
Centre Georges François Leclerc
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
0205-1isni 07 / 001.112
NCT01044485
November 2008
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