| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with ERB B2 positive metastatic breast cancer developing brain metastasis/es |
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| MedDRA Classification |
| 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 |
| To investigate the effect of lapatinib plus capecitabine compared with trastuzumab plus capecitabine on time to progression of central nervous system (CNS) metastases as measured by RECIST. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate and compare the two treatment arms for the following: • Progression-free survival (CNS or non-CNS) • Overall survival (deaths from any cause) • CNS overall response rate (CR or PR) • CNS clinical benefit response rate (confirmed CR or PR at any time or SD at the 24-week time-point) • Total days of steroid use for palliation of CNS symptoms • General and neurological quality of life (QoL) (as measured by the patient self-reported EORTC QLQ-C30 and BN20 questionnaires and patient self-reported toxicity assessments) • Delay/stabilisation of CNS symptoms • Qualitative and quantitative toxicities We also aim to assess the feasibility of recruitment into and patient follow-up in a phase III trial. Although not providing formal outcome measures, the functional imaging sub-study will provide data for further investigation. For patients included in this sub-study, perfusion and blood brain barrier (BBB) permeability of selected brain metastases will be measured at base |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| FUNCTIONAL IMAGING SUB-STUDY: DYNAMIC CONTRAST ENHANCED-MRI (DCE-MRI) EVALUATION. Date 18/10/2010 version 1.0. The primary objective is to compare the BBB permeability of identified brain metastases in the two treatment arms at baseline and then to assess changes in BBB permeability in those two arms between baseline, 6, 12 and 24 weeks post-randomisation. The secondary objectives are to evaluate and compare the two treatment arms for the following: measure perfusion of identified brain metastases at baseline, 6, 12 and 24 weeks post-randomisation measure blood volume of identified brain metastases at baseline, 6, 12 and 24 weeks post-randomisation This is an optional part of the LANTERN study and will involve a sub-set of approximately 30 patients from the main trial. PATIENT-REPORTED SYMPTOMS AND SIDE-EFFECTS ASSESSMENT SUB-STUDY. Date 18/10/2010 v1.0. The patient self-reported symptoms and side-effects assessment aims to capture participant perspective on key treatment-specific adverse events, as well as troublesome symptoms of disease, not included in the QoL questionnaires. This will assess the method and outcome of patient-reported toxicity and will involve all patients. |
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| E.3 | Principal inclusion criteria |
| 1. Male or female aged ≥ 18 years 2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 3. Given written informed consent prior to any trial specific procedures 4. Expected survival ≥ 12 weeks 5. Histologically or cytologically confirmed invasive breast cancer, with Stage IV disease including newly diagnosed CNS metastasis/es 6. ErbB2 overexpression in the invasive component of the primary or metastatic lesion as locally defined by: • 3+ staining by immunohistochemistry (IHC); • or 2+ staining by IHC in conjunction with ErbB2 gene amplification by FISH; • or ErbB2 gene amplification by FISH; Participants with a negative or equivocal overall result are not eligible for inclusion in the trial. 7. Evidence of metastatic brain disease. To be considered evaluable for the primary endpoint and the CNS response rates endpoints, participants must have at least one measurable brain lesion that can be accurately measured in at least one dimension (shortest dimension to be recorded) as >20mm with conventional techniques or as >10mm with spiral CT scan (see appendix X for the evaluation of measureable disease). Participants with leptomeningeal disease are not eligible for participation in the trial due to the lack of measurable disease. 8. Treated previously with taxanes or anthracyclines in the adjuvant or metastatic setting. All treatment related adverse events must be ≤ Grade 1 at the time of randomisation. 9. Prior treatment with trastuzumab is required and all treatment related adverse events must be ≤ Grade 1 at the time of randomisation 10. Completed local cranial therapy (Stereotactic Radio Surgery or Whole Brain Radiotherapy) 11. Able to swallow and retain oral medication 12. Normal organ and bone marrow function as defined below: • Leukocytes >3,000/µL • Absolute neutrophil count >1,500/µL • Platelets >100,000/µL • Total bilirubin within normal institutional limits • AST (SGOT)/ ALT (SGPT) ≤2.5 X institutional upper limits of normal • Creatinine within normal institutional limits or creatinine clearance ≥60ml/min/ 1.73m2 for participants with creatinine levels above institutional normal. 13. Cardiac ejection fraction ≥50% or within the institutional limit as measured by echocardiogram or MUGA scan. Note that the baseline and on treatment scan should be performed using the same modality and preferably the same institution. |
|
| E.4 | Principal exclusion criteria |
| 1. Prior therapy with lapatinib or an ErbB2 inhibitor other than trastuzumab 2. Prior treatment with capecitabine 3. Concurrent chemotherapy, radiation therapy, immunotherapy, biologic therapy (including an ErbB1 and/or ErbB2 inhibitor), or hormonal therapy for treatment of cancer 4. Known dihydropyrimidine dehydrogenase (DPD) deficiency 5. Current active hepatic or biliary disease (with exception of participants with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment) 6. Pregnant or lactating females. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to trial entry and for the duration of the trial participation. 7. History of significant non-breast malignancy (aside from non-melanomatous skin cancer, carcinoma in situ of the uterine cervix, superficial bladder cancer treated with curative intent) 8. History of allergic reactions attributed to compounds of a similar chemical or biological composition as to lapatinib 9. Uncontrolled inter-current illness including, but not limited to: • ongoing or active infection • symptomatic congestive heart failure • unstable angina pectoris • cardiac arrhythmia • psychiatric illness/social situations that would limit compliance with trial requirements 10. 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). 11. Renal function as measured by creatinine clearance <30ml/min (ratio to norm <0.1) 12. Not recovered from adverse events due to agents administered more than 4 weeks earlier with the exception of adverse events ≤grade 1 after previous chemotherapy 13. Prior treatment with EGFR targeting therapies 14. Active cardiac disease, defined as: • History of uncontrolled angina • History of arrhythmias requiring medications, or clinically significant, with the exception of asymptomatic atrial fibrillation requiring anticoagulation • Myocardial infarction < 6 months from trial entry • Uncontrolled or symptomatic congestive heart failure • Ejection fraction below 50% or the institutional lower normal limit • Any other cardiac condition, which in the opinion of the treating investigator, would make this protocol unreasonably hazardous for the participant 15. Any concomitant medications or substances forming part of normal ongoing care locally known to affect, or have the potential to affect, the activity or pharmacokinetics of lapatinib. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Time to progression of central nervous system (CNS) metastases defined as time from randomisation to the date of CNS disease progression as measured by RECIST and based on locally or centrally reviewed MRI scans. |
|
| 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 | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| 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 | No |
| 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
|
| The end of the trial is defined as the date all 24-week follow-up assessments are completed for all trial participants evaluable at this timepoint. Any participants still responding to treatment after their 24-week follow-up assessment point will continue to receive trial treatment and will be followed up only for serious adverse events until 30 days after their last dose of trial treatment. |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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