| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER 2 positive advanced or metastatic breast cancer |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this trial is to recommend a dose of Lapatinib and Docetaxel to be given in HER-2 positive metastatic breast cancer patients. In order to achieve this, the study will first determine the optimal tolerated regimen (OTR) based on the documentation of the acute dose limiting toxicity (DLT). |
|
| E.2.2 | Secondary objectives of the trial |
• to evaluate anti-tumor activity, in terms of response (Best Overall objective response rate), time to response, the response duration, time to progression (TTP), time to treatment failure (TTF) and overall survival (OS).
• to evaluate the dose-limiting toxicity.
• to further evaluate safety and tolerability profile of lapatinib when given in combination with docetaxel.
• to further characterize, where possible, the patient population by determination of relevant biomarkers from tumor tissues such as ErbB1, ErbB2, ErbB3, and ErbB4, AKT, and potentially other biomarkers that are downstream of ErbB1 or ErbB2 receptors.
• to prospectively correlate tumor response rates in both cohorts following therapy with serum concentrations of ErbB1 and ErbB2.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Subjects must have histological or cytological confirmed breast cancer, HER positif (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 metastastic 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 trastuzumanb within the six weeks
• 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
• Patients must have measurable disease, 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.
• Age 18 years. Because no dosing or adverse event data are currently available on the use of lapatinib in patients <18 years of age, children are excluded from this study.
• Life expectancy of greater than 12 weeks.
• ECOG performance status 2 (Karnofsky 60%)
• Patients must have normal organ and bone marrow function as defined below:
Hemoglobin 9 g/dl
leukocytes 3,000/L
absolute neutrophil count 1,500/L
platelets 100,000/L
total bilirubin within normal institutional limits
AST (SGOT)/ALT(SGPT) 2.5 X institutional upper limit of normal
creatinine within normal institutional limits
OR
creatinine clearance 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
• Cardiac ejection fraction within the institutional range of normal as measured by echocardiogram or MUGA scan. Note that baseline and on treatment scans should be performed using the same modality and preferably at the same institution.
• The effects of lapatinib on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document.
• Able to swallow and retain oral medication
|
|
| E.4 | Principal exclusion criteria |
• 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.
• Patients may not be receiving any other investigational agents within the past 30 days or receiving concurrent anticancer therapy. In addition, all herbal (alternative) medicines are excluded
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• 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. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with lapatinib, breastfeeding should be discontinued if the mother is treated with lapatinib
• HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with lapatinib. Appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated
• 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).
• 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
• Any other cardiac condition, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
In order to determine the recommended dose, the study will determine the optimal tolerated regimen (OTR) based on the documentation of the acute dose limiting toxicity (DLT) in the phase I dose escalation step.
The DLT for this study is defined during cycle 1 for the dose escalation step and during cycle 4 for the bridge 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, infusion related reaction that can be rapidly controlled with appropriate measures), clinical heart failure.
- An absolute neutrophil count (ANC) < 0.5x109/L lasting for ≥ 7 days (grade 4 as defined by
the Common Toxicity Criteria, version 3.
- Febrile neutropenia defined as ANC < 1.0x109/L and fever at least 38.5°C (grade 4 as defined by the Common Toxicity Criteria, version 3)
- Thrombocytopenia ≤ 25, 000/µl or thrombocytopenic bleeding requiring transfusion (grade 4 as defined by the Common Toxicity Criteria, version 3)
- 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
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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