Locally advanced/inflammatory or large operable brest cancer. MedDRA version: 12.1 Level: LLT Classification code 10006187 Term: Breast cancer
Conditions
Interventions
Trade Name: Tyverb
Product Name: Lapatanib
Product Code: GW572016
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Lapatinib
CAS Number: 388082-78-8
Other descriptive name: LAPATINIB TOSIL
Sponsors
European Organisation for Research and Treatment of Cancer (EORTC)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Breast cancer population for Phase I part * Female patients with locally advanced or inflammatory, or specified subgroup of large operable (see below) breast cancer for whom neo-adjuvant chemotherapy is appropriate defined as: - Clinical T4 a,b,c,d, any N (inflammatory breast carcinoma: tumor mass, breast enlargement, oedema and warmth of the skin are often present but not mandatory for the diagnosis) - Or any clinical T, N2 or N3 (ipsilateral supraclavicular nodes) - Or cT3cN0,1 any ER - Or cT2cN1 any ER - Or cT2cN0 ER neg * Presence of bilateral breast cancer is allowed * Patients with minimal lung, skin, or nodal metastatic disease shall be discussed case-by-case with the study co-ordinators. Patients with bone, liver or other extensive metastases are non eligible Breast cancer population for Phase II part * Female patients with any large operable T2 or T3 breast cancers, M0 * Or female patients with locally advanced or inflammatory breast cancer defined as: - Clinical T4 a,b,c,d, any N (inflammatory breast carcinoma: tumor mass, breast enlargement, oedema and warmth of the skin are often present but not mandatory for the diagnosis) - any clinical T, N2 or N3 (ipsilateral supraclavicular nodes) - And M0 * Presence of bilateral breast cancer, provided only 1 side is HER2 positive Eligibility criteria for both phase I and II * Histologically confirmed diagnosis of invasive breast cancer * Known hormone receptor status: ER/PR positive or negative. * HER-2 positive (IHC 3+, or IHC 2+ and FISH/CISH +, or FISH, or CISH+ only) * Two frozen trucuts with a 14 G needle are mandatory for every core biopsy indicated by the translational research study * Age 18 to 70 years * WHO performance status 0-2 * Adequate bone marrow function: hemoglobin > 10.0 g/dl or 6.2 mmol/L, neutrophils > 1.5 x 10exp9/L and platelets > 100 x 10exp9/L * Adequate hepatic and renal function, defined as follows: - Bilirubin 180mm Hg or diastolic greater than 100mm Hg) * Drugs and several HERBAL CONSTITUENTS (e.g. bergamottin and glabridin), which are inducers or inhibitors of CYP3A4 must not be taken within 10 days prior to initiation of treatment and are prohibited while the patient is being treated with lapatinib (a detailed list is provided in chapter 5 of the protocol) * Women should either not be of childbearing potential (having had a hysterectomy, a bilateral oophorectomy or bilateral tubal ligation, or be post-menopausal with a total cessation of menses of > 1 year), or not be pregnant (negative serum pregnancy test at entry); should not be lactating; should agree to use contraceptive methods (with a documented failure rate < 1%, vasectomized partner sterile prior to trial entry and sole sexual partner or double-barrier contraception) from 2 weeks before your first study treatment until 4 weeks after
Exclusion criteria
Exclusion criteria: Exclusion criteria for Phase I part: * Prior therapy for any cancer, including chemotherapy, radiotherapy, hormonal therapy for breast cancer, EGFR or HER-2 or antibody therapy Exclusion criteria for Phase II part: * Prior history of malignancies except: - basal cell or squamous cell carcinoma of the skin - carcinoma in situ of the cervix - the patient has been free of any other malignancies for > 3 years. Exclusion criteria for both phase I and II: * Current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones or stable chronic liver disease not requiring therapy as per investigator assessment) * Clinical signs of CNS involvement * Patients with active or uncontrolled infections or with serious illnesses, malabsorption syndrome or medical conditions, including patients with a history of chronic alcohol abuse, hepatitis, HIV and/or cirrhosis
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the Phase I stage of the trial is to recommend a dose of lapatinib and docetaxel to be given pre-operatively over 3 cycles to HER-2 positive breast cancer patients, following 3 cycles of FEC. In order to achieve this, the study will determine the maximum tolerated dose (MTD) based on the documentation of the acute dose limiting toxicity (DLT). The primary objective of the phase II is to assess the activity of the combination docetaxel + anti-HER2 treatment (lapatinib or lapatinib+trastuzumab) followed by FEC. The pathological response rate will be used as a surrogate for activity. The reference arm will be docetaxel+trastuzumab (3 cycles) followed by FEC 100 (3 cycles).;Secondary Objective: Secondary objectives of the Phase I stage are: To explore the biological activity of the treatment through a translational research program investigating changes in apoptosis and proliferation markers. Several downstream effectors (pTEN mutation and function, pAKT, mTOR and associated proteins) known to be down regulated and/or to influence the activity of the standard combination of trastuzumab/docetaxel will be looked at. To determine any relationship between the drug exposure and adverse events or biological modifications. Secondary objectives of the Phase II stage are: * To assess tolerability * To assess clinical activity. * To identify genes that may predict response to lapatinib + docetaxel combination;Primary end point(s): Phase I Primary endpoint: To document the acute dose limiting toxicity (DLT) in cycle 1 to identify the maximum tolerated dose (MTD). Phase II Primary endpoint: Pathological complete response rate defined as: “complete disappearance of invasive cancer with the exception of very few scattered tumour cells”. | — |
Countries
Belgium, France, Slovenia, United Kingdom
Outcome results
None listed