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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

Phase 1/Phase 2
18 Years
Not Enrolling
Metastatic Breast Cancer

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Trial Information

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

Inclusion Criteria:

- Age over or equal 18 years·

- ECOG Performance Status of 0 to 2·

- Patients with histological or cytological confirmed breast cancer, HER positive (IHC
3+, or IHC 2+ and FISH/CISH +, or FISH+ or CISH+ only), not amenable for an
alternative curative strategy in first line metastatic setting·

- Patients who receive hormonotherapy for metastatic disease or who received
chemotherapy in adjuvant setting if recurrence occur after 6 months are eligible·

- Patient must have not received the last injection of trastuzumab within the six

- Subjects must have completed prior radiotherapy treatment at least 4 weeks from
enrolment and recovered from all treatment-related toxicities· Subjects must have
tissue available to prospectively determine treatment assignment and to compare tumor
response with intra-tumor expression levels of relevant biomarkers·

- No prior systemic investigational agent within the past 30 days or topical
investigational drugs within the past 7 days·

- Subjects must have a cardiac ejection fraction within the institutional range of
normal as measured by ECHO (echocardiogram) or MUGA (Multigated Acquisition) scan·

- Subjects must have adequate haematological, hepatic, and renal function·

- Affiliation to a social insurance program is required

Exclusion Criteria:

- Subjects with elevations of transaminase (ALT and/or AST) greater than 2.5 times the
upper limit of the normal range (ULN) are NOT eligible for the study·

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or patients who have not
recovered from adverse events due to agents administered more than 4 weeks earlier·

- Patients who have had prior treatment with EGFR targeting therapies· All herbal
(alternative) medicines are excluded·

- Patients with known brain metastases·

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to lapatinib.·

- Uncontrolled inter-current illness including, but not limited to, ongoing or active
infection, peripheral neuropathy of grade 2 or greater, or psychiatric illness/social
situations that would limit compliance with study requirements·

- Pregnant women are excluded from this study because lapatinib is member of the
4-anilinoquinazoline class of kinase inhibitors with the potential for teratogenic or
abortifacient effects·

- HIV-positive patients receiving combination anti-retroviral therapy are excluded from
the study because of possible pharmacokinetic interactions with lapatinib·

- Patients with gastro intestinal (GI) tract disease resulting in an inability to take
oral medication, malabsorption syndrome, a requirement for IV alimentation, prior
surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g.,
Crohn's, ulcerative colitis)· Current active hepatic or biliary disease (with
exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver
metastases or stable chronic liver disease per investigator assessment)· Previous
allergic reaction to docetaxel and/or polyascorbate· Concomitant requirement for
medication classified as CYP3A4 inducers or inhibitors·

- Active cardiac disease, defined as: history of uncontrolled or symptomatic angina
pectoris, history of cardiac arrhythmias requiring medications, or clinically
significant, with the exception of asymptomatic atrial fibrillation requiring
anticoagulation, myocardial infarction < 6 months from study entry, uncontrolled or
symptomatic congestive heart failure, ejection fraction below the institutional
normal limit

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the optimal tolerated regimen of lapatinib administered in combination with docetaxel as first-line therapy in patients with metastatic breast cancer

Outcome Time Frame:

during first cycle ( each cycle last 3 weeks)

Safety Issue:


Principal Investigator

Nicolas Isambert, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Centre Georges François Leclerc


France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Study ID:

0205-1isni 07 / 001.112



Start Date:

November 2008

Completion Date:

Related Keywords:

  • Metastatic Breast Cancer
  • HER-2 positive advanced or metastatic breast cancer
  • dose escalation study
  • lapatinib
  • docetaxel
  • Breast Neoplasms