| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic breast cancer overexpressing ErbB2 |
|
| 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 | 10006202 |
| E.1.2 | Term | Breast cancer stage IV |
|
| 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 evaluate the effect of lapatinib plus capecitabine on incidence of CNS as site of first relapse as compared with trastuzumab plus capecitabine |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate and compare the two treatment arms for the following:
• Progression free survival
• Time to first CNS progression
• Overall survival
• Overall response rate (CR or PR)
• Clinical benefit response rate (confirmed CR or PR at any time or SD for ≥ 24
weeks )
• Duration of response
• Incidence of CNS progression at any time (brain scans will not be required following
non-CNS progression; therefore incidence of CNS progression at any time will
include progression documented by brain scan on study as well as CNS progression
as indicated by the investigator on follow-up eCRF page).
• The qualitative and quantitative toxicities. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Signed written informed consent;
2. Females age ≥ 18 years old;
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2;
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 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,CISH or SISH;
• ErbB2 gene amplification by FISH, CISH or SISH HER2/neu gene amplification by fluorescence, chromogenic or silver in situ hybridization [FISH, CISH or SISH; >6 HER2/neu gene copies per nucleus or a FISH, CISH or SISH test ratio (HER2 gene copies to chromosome 17 signals) of ≥2.0]
• subjects with a negative or equivocal overall result are not eligible for participation in the trial.
7. Subjects must have evidence of metastatic disease, but measurable disease is not
mandatory.
NOTE: Pleural effusion or ascites (without cytologic verification) as the only
evidence of metastatic disease do not meet the eligibility criteria.
8. Prior treatment with taxanes or anthracyclines is required. All treatment related
adverse events must be ≤ Grade 1 at the time of randomization;
9. Prior treatment with other chemotherapeutic agents is permitted provided that all
treatment related adverse events are ≤ Grade 1 at the time of randomization;
10. Prior treatment with trastuzumab is permitted provided that all treatment related
adverse events are
≤ Grade 1 at the time of randomization;
11. Prior treatment with endocrine therapy is permitted provided that therapy has been discontinued and all treatment related adverse events are ≤ Grade 1 at the time of randomization;
12. Prior treatment with radiation therapy is permitted provided that at least 2 weeks have elapsed since the last fraction of radiation therapy and all treatment related adverse events are ≤ Grade 1 at the time of randomization;
13. Baseline LVEF ≥ 50% and not lower than the institutional lower limit of normal
measured by echocardiography or MUGA scan;
NOTE: The same modality used at baseline must be used for repeat assessment
throughout study.
14. Concurrent treatment with bisphosphonates is permitted; however treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in subjects without bone disease is not permitted, except for the treatment of osteoporosis;
15. Able to swallow and retain oral medications;
16. A female who is of:
• non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
including any female who has had hysterectomy, a bilateral oopheroctemy,
bilateral tubular ligation or is post-menopausal (total cessation of menses for ≥ 1
year;
• childbearing potential who must have a negative serum pregnancy test within 2
weeks prior to the first dose of study treatment, preferably as close to the first
dose as possible, and agrees to use adequate contraception (for example,
intrauterine device [IUD], birth control pills unless clinically contraindicated, or
barrier device) beginning 2 weeks before the first dose of investigational product
and for 28 days after the final dose of investigational product.
17. Subjects must complete all screening assessments as outlined in the protocol;
18. Subjects must have normal organ and marrow function as defined in the protocol on page 34. |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. History and/or current evidence of CNS metastases (including leptomeningeal
involvement). or evidence of benign or malignant brain tumors and/or evidence of
spinal cord metastases at Baseline. Any evidence of brain metastases on Baseline
MRI scan (performed within 4 weeks prior to randomization) as determined by
Independent Reviewer;
2. Concurrent treatment with an investigational agent or participation in another
treatment clinical trial;
3. Prior therapy with lapatinib or an ErbB2 inhibitor other than trastuzumab(including
but not limited to trastuzumab-DM1 and neratinib);
4. Prior treatment with capecitabine;
5. Known dihydropyrimidine dehydrogenase (DPD) deficiency;
6. ECOG Performance Status >2;
7. Concurrent chemotherapy, radiation therapy, immunotherapy, biologic therapy
(including an ErbB1 and/or ErbB2 inhibitor), or hormonal therapy for treatment of
cancer;
8. History of allergic reactions attributed to compounds of similar chemical composition to lapatinib (quinazolines);
9. History of allergic reactions attributed to compounds chemically related to capecitabine, fluorouracil or any excipients;
10. Concurrent treatment with medications listed in Section 4.11.2, Prohibited
Medications and Non-Drug Therapies;
11. Concomitant use of CYP3A4 inhibitors or inducers (also refer to Table 7 in protocol);
12. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel;
13. History of immediate or delayed hypersensitivity reaction to gadolinium contrast
agents, or other contraindication to gadolinium contrast;
14. Compromised renal function that would exclude subjects from receiving gadolinium based contrast agents as guided by local institutional policy;
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 or compliance to study procedures;
17. Have acute or currently active/requiring anti-viral therapy hepatic or biliary disease (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment);
18. Any on-going toxicity from prior anti cancer therapy that is > Grade 1 and/or is
progressing in severity except alopecia;
19. 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);
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;
• Cardiac angioplasty or stenting;
• Ejection fraction below the institutional normal limit;
• History of documented congestive heart failure (CHF) or systolic dysfunction;
• Clinically significant valvular heart disease;
• 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. History of other malignancy unless curatively treated with no evidence of disease for at east 5 years; subjects with adequately treated DCIS or LCIS, adequately treated nonmelanoma skin cancer or curatively treated in-situ cancer of the cervix are eligible;
23. Used an investigational drug within 30 days or 5 half-lives, whichever is longer,
preceding the first dose of protocol treatment;
24. Pregnant or lactating females.
French subjects: the French subject has participated in any study using an
investigational drug during the previous 30 days or 5 half-lives, whichever is longer,
preceding the first dose of protocol treatment |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Incidence of CNS as site of first relapse will be the primary endpoint of this study. CNS disease progression will be assigned using protocol-defined criteria as specified in Section 5.2.3.2. |
|
| 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 | No |
| 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 | 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 96 |
| 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
|
| last visit of last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
| 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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