| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Brain metastases from ErbB2-positive breast cancer |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006128 |
| E.1.2 | Term | Brain metastases |
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| 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 |
| In each of the two study arms (lapatinib plus topotecan or lapatinib plus capecitabine), the primary objective is to determine the CNS objective response rates in subjects with progressive brain metastases from ErbB2-overexpressing breast cancer. A CNS objective response is defined as either a Complete Response (CR) or Partial Response (PR), as assessed by volumetric analysis of brain magnetic resonance imaging (MRI), provided there is no progression of systemic disease outside of the CNS or increasing steroid requirements. |
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| E.2.2 | Secondary objectives of the trial |
In each of the two study arms (lapatinib plus topotecan or lapatinib plus capecitabine), the secondary objectives are to determine:
• Percentage of subjects with disease stabilization ≥ 6 months;
• Percentage of subjects with clinical benefit (complete response, partial response or stable disease for at least 6 months);
• Duration of CNS objective response;
• Percentage of subjects with objective response by RECIST in non-CNS disease (of those subjects with measurable non-CNS disease at baseline);
• Time to CNS objective response;
• Initial site of disease progression;
• Time to disease progression at any site;
• Overall survival;
• Percentage of subjects with baseline tumour-related neurological signs and symptoms (NSS), who experience improvement in NSS;
• Qualitative and quantitative toxicities associated with the study regimens.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Signed written informed consent;
2. Females or males of 18 years of age or older;
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1;
4. Life expectancy of at least 12 weeks;
5. Subjects must have histologically or cytologically confirmed invasive breast cancer, with Stage IV disease;
6. ErbB2 overexpressing breast cancer, defined as 3+ staining by immunohistochemistry (IHC), or 2+ staining by IHC with ErbB 2 gene amplification by FISH, or ErbB 2 gene amplification by FISH alone;
7. At least one measurable lesion in the brain, defined as any lesion of 10mm or greater in longest dimension. Measurable brain lesions should not have been treated with prior stereotactic radiosurgery (SRS);
8. Prior treatment of brain metastases with whole-brain radiotherapy and/or SRS;
9. Evidence of new and / or progressive lesions in the brain;
Note: Subjects with progressive brain lesions are not required to meet RECIST criteria for CNS progression in order to be eligible for this study.
10. Prior treatment with trastuzumab, either alone or in combination with chemotherapy is required. Trastuzumab will be discontinued at least 2 weeks prior to enrollment on study;
11. Cardiac ejection fraction within institutional range of normal as measured by echocardiogram. Subjects who require cardiac medications (e.g. positive inotropic agents or afterload reducers) for normal ejection fraction are ineligible;
12. At least 2 weeks since prior radiotherapy, last chemotherapy, immunotherapy, biologic therapy, or hormonal therapy for cancer, and sufficiently recovered or stabilized from side effects associated with prior therapy. Concurrent treatment with bisphosphonates is permitted;
13. At least 3 weeks since major surgical procedures;
14. Able to swallow and retain oral medications;
15. Women of childbearing potential must have a negative serum pregnancy test at screening and must use an approved contraceptive method, beginning 2 weeks before the first dose of investigational product and for 28 days after the final dose of investigational product. Males able to father a child must practice adequate methods of birth control or practice complete abstinence from intercourse from the first dose of investigational treatment until one week after the final dose of investigational treatment.
16. Subjects must complete all screening assessments as outlined in the protocol;
17. Subjects must have normal organ and marrow function (as defined in the protocol).
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|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Subjects who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or who have unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment;
2. Concurrent treatment with an investigational agent or participation in another treatment clinical trial;
3. Prior therapy with a topoisomerase inhibitor;
4. Prior lapatinib therapy;
5. Prior therapy with capecitabine;
6. Known dihydropyrimidine dehydrogenase (DPD) deficiency;
7. ECOG Performance Status 2 or greater;
8. Subjects receiving concurrent chemotherapy, radiation therapy, immunotherapy, biologic therapy (including an ErbB1 and/or ErbB2 inhibitor), or hormonal therapy for treatment of their cancer. Hormone therapy for ovarian suppression which has been used for > 6 months, during which time there has been disease progression in the brain, is allowed. Concurrent treatment with bisphosphonates is allowed;
9. Subjects with evidence of leptomeningeal carcinomatosis at screening;
10. History of allergic reactions attributed to compounds of similar chemical composition (quinazolines) to lapatinib;
11. History of allergic reactions attributed to compounds chemically related to capecitabine, fluorouracil or any excipients;
12. Concurrent treatment with medications listed in the protocol;
13. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or active, uncontrolled ulcerative colitis;
14. History of immediate or delayed hypersensitivity reaction to gadolinium contrast agents, or other contraindication to gadolinium contrast;
15. Other known contraindication to MRI, such as a cardiac pacemaker, implanted cardiac defibrillator, brain aneurysm clips, cochlear implant, ocular foreign body, or shrapnel;
16. Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical or psychiatric disorder that would interfere with the subject's safety;
17. Anticoagulant therapy (other than coumadin or aspirin as catheter prophylaxis) at study entry;
18. Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent, unless a legally acceptable representative could provide informed consent (if in accord with the policies of the local Ethics Committee);
19. Pre-existing severe cerebral vascular disease, such as stroke involving a major vessel, CNS vasculitis, or malignant hypertension;
20. Active cardiac disease, defined as one or more of the following:
• History of uncontrolled or symptomatic angina
• History of arrhythmias requiring medications, or clinically significant
• 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;
21. Uncontrolled infection;
22. Pregnant or lactating females;
23. History of other malignancy, except for curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix. Subjects with other malignancies who have been disease-free for at least 5 years are eligible.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary indicator of drug efficacy is CNS response rate, defined as the percentage of subjects achieving either a complete or partial CNS tumor response. |
|
| 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 | Yes |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | 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) | No |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| 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 | 1 |
| 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 | 1 |
| 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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