| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Brain metastases from ErbB2-positive breast cancer |
|
| 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 |
|
| 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 is to determine the CNS objective response rate to the combination of lapatinib plus capecitabine 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. |
|
| E.2.2 | Secondary objectives of the trial |
For subjects who received lapatinib plus capecitabine as initially assigned study therapy, the secondary objectives are:
•Percentage of subjects with disease stabilization ≥6 months
•Percentage of subjects with clinical benefit (complete or partial CNS composite response or disease stabilization ≥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)
•Percentage of subjects with ≥20% volumetric reduction in CNS lesions, as an exploratory analysis
•Time to CNS objective response
•Site of first disease progression (CNS or non-CNS, whichever occurs first)
•Overall progression free survival
•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. |
|
| 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 age ≥ 18 years old;
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 in conjunction with ErbB2 gene
amplification by FISH, or ErbB2 gene amplification by FISH alone.
7. At least one measurable lesion in the brain, defined as any lesion ≥10 mm in longest dimension. Measurable brain lesions should not have been treated with prior stereotactic radiosurgery (SRS); an exception being a brain lesion whose longest linear dimension increased ≥ 50% following SRS and whose absolute longest dimension now measures ≥ 15mm;
8. Prior treatment of brain metastases with WBRT and/or SRS;
9. Unequivocal evidence of new and / or progressive lesions in the brain on an imaging study; (view protocol).
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. MUGA
scans will be accepted in cases where an echocardiogram cannot be performed or is
inconclusive;
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, if appropriate (for
example, intrauterine device [IUD], birth control pills, or barrier device) 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 (please view protocol).
|
|
| 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 1 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 Section 7.2 and Section 13.6,
Prohibited Medications;
13. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with active, uncontrolled
ulcerative colitis are also excluded;
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 at study entry (other than coumadin or aspirin as catheter
prophylaxis, or a low dose heparin [i.e. 50 unit unfractionated] flush of a central
venous device);
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;
24. Have current active hepatic or biliary disease (with exception of subjects with
Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver
disease per investigator assessment). |
|
| 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) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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
| Yes |
| 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 | 1 |
| 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 | No |
| 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 | 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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