Metastatic breast cancer in patients who are HER-2-positive and Topoisomerase II alpha positive. MedDRA version: 14.0 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Tyverb
Product Name: Tyverb
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: LAPATINIB
CAS Number: 231277-92-2
Concentration unit: mg milligram(s)
Concentration type: equal
Con
Sponsors
ICORG-the All Ireland co-operative Oncology Research group
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Ability to understand and has signed a written informed consent document prior to any study related procedures. 2. Female patients age= 18 years 3. ECOG Performance Status of = 2 4. Histologically or cytologically-confirmed invasive breast cancer with Stage IV disease (metastatic breast cancer) 5. Patients must have measurable disease according to RECIST 1.1 criteria, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan. 6. HER2-positivity defined as IHC score of 3+ or ratio of HER2 gene signals to centromere 17 (Cep17) signals =2.0 by fluorescent in situ hybridization (FISH). 7. TopoII alpha amplification defined as a ratio of TopoIIa gene signals to centromere 17 signals =1.5 by in situ hybridisation. 8. Cardiac ejection fraction within the institutional range of normal as measured by MUGA or ECHO. 9. Adequate haematological, hepatic, and renal function. • Haemoglobin = 9g/dL. • Absolute granulocyte count =1.5 x 10^9/L. • Platelets = 100 x 10^9/L. • Total bilirubin =ULN of the treating institution, unless the patient has a documented history of congenital hyperbilirubinemia (Gilbert's syndrome). • Both ALT and AST = 3 x ULN with or without liver metastases. • Alkaline phosphatase = 2.5 x ULN. • Calculated creatinine clearance (CrCl) = 40mL/min according to the formula of Cockcroft and Gault 10. women of child-bearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation. Acceptable methods of birth control: • Complete abstinence from intercourse from the time of the screening pregnancy test until 28 days after the final dose of lapatinib; or • Consistent and correct use of one of the following acceptable methods of birth control: • Male partner who is sterile prior to the female patient’s entry into the study and is the sole sexual partner for that female patient; or • Any intrauterine device (IUD) with a documented failure rate of less than 1% per year; or • Barrier methods (e.g. condoms, diaphragms, caps) only if used in combination with one of the above acceptable methods. 11. Life expectancy greater than 12 weeks 12. Patients may receive bisphosphonates where they are clinically indicated if started prior to first study treatment administration. 13. Patients with a history of any of the following cancers are eligible if diagnosed and treated longer than 5 years: cervical carcinoma in situ, melanoma in situ, and basal cell or squamous cell carcinoma of the skin; 14. Are able to swallow and retain oral medication. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Untreated and uncontrolled central nervous system (CNS) metastases. Patients with known CNS metastases are eligible if metastases are treated and proven stable for at least 3 months (asymptomatic and not receiving steroids). CNS metastases cannot be used as target lesions to assess objective response 2. Prior anthracycline or anthracenedione therapy (Prior- non-anthracycline adjuvant therapy is NOT an exclusion criterion) 3. No prior chemotherapy and/or trastuzumab for metastatic breast cancer. Prior adjuvant trastuzumab is allowed (provided at least 3 months has elapsed from the most recent trastuzumab infusion). No prior other therapy with ErbB inhibitors is allowed. Subjects who have acute or currently active /requiring anti-viral therapy hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment) 4. Uncontrolled or symptomatic angina, arrhythmias, congestive heart failure or other cardiac disorders. 5. Evidence of or history of QT (QTc) interval above 470msec 6. Patients with elevated troponin I (TNI) 7. Immediate or delayed hypersensitivity or untoward reaction to lapatinib, epirubicin or other related compounds, or to drugs chemically related to lapatinib (including other anilinoquinazolines, e.g. gefitinib (Iressa) and erlotinib (Tarceva), or other chemically-related compounds). 8. Pregnant women are excluded from this study. (breastfeeding should be discontinued if the mother is treated with lapatinib). 9. Have unresolved or unstable grade = 2 toxicity from administration of prior cancer treatment 10. Prior lapatinib treatment. Patients who received lapatinib in the adjuvant or neo-adjuvant setting as part of a clinical trial are NOT eligible, 11. Prior investigational drugs within the past 30 days 12. Concurrent treatment with prohibited medications (refer to Section 7.5 for details on prohibited medications) 13. Patients with 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). 14. Have a concurrent disease or condition that would make the patient inappropriate for study participation, or any serious medical disorder that would interfere with the patient safety; 15. Have an active or uncontrolled infection; 16. Have dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent; 17. HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with lapatinib.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the clinical efficacy (Overall Response Rate) of the combination of epirubicin and lapatinib in HER2+, TopoII alpha positive metastatic breast cancer. ;Secondary Objective: • Provide further toxicological data on the combination of epirubicin with lapatinib. • To evaluate the study population with respect to the following: overall survival (from treatment start until death from any cause), progression free survival (from treatment start until progression or death from any cause), clinical benefit (CR, PR and stable disease for at least 6 months). • To carry out translational research in order to determine biomarkers that correlate with clinical benefit/response to epirubicin-lapatinib therapy. • To carry out translational research to examine trough levels of lapatinib prior to anthracycline therapy and monitor patient compliance on lapatinib therapy. ;Primary end point(s): Overall Response Rate (ORR) (defined as the percentage of patients with a confirmed CR or PR as per RECIST 1.1 criteria). ;Timepoint(s) of evaluation of this end point: The number of patients deemed to have shown a response will be expressed as a proportion of those taking part in the study (15 if only one stage, 46 if both stages are completed). Response will be assessed six months after the last patient is enrolled. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Progression Free Survival (PFS). • Overall survival (OS). • Clinical benefit Rate . • Provide further toxicological data on the combination of an anthracycline with lapatinib. • Determine biomarkers that correlate with clinical benefit/response to epirubicin-lapatinib therapy. ;Timepoint(s) of evaluation of this end point: Progression free survival will be analysed 12 months after the last patient is enrolled on the study. Overall survival will be analysed 24 months after the last patient is enrolled on the study. Progression-free and overall survival probabilities over time will be estimated at 12 months and 24 months for PFS and overall survival respectively. The number of patients deemed to have shown clinical benefit will be expressed as a proportion of those taking part in the study (15 if only one stage, 46 if both stages are completed). Clinical benefit will be assessed six months after the last patient is enrolled. | — |
Countries
Ireland
Contacts
Public ContactTanya O' Shea
ICORG-the All Ireland co-operative Oncology Research group
Outcome results
None listed