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 | 19.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006202 |
E.1.2 | Term | Breast cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 |
As the study was stopped on 11th June 2012, no further subjects will be enrolled.
However, current ongoing subjects eligible for enrolment in the study must meet all of the following criteria:
1. Able to give 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
• If the metastatic disease is restricted to a solitary lesion, its neoplastic nature
should be confirmed by cytology or histology.
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;
• 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.
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 at least 6 weeks has
elapsed since the last dose of therapy and 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 above the institutional lower limit of normal measured by echocardiography or MUGA scan
14. Concurrent treatment with bisphosphonates is permitted; however treatment must be initiated prior to the first dose of study therapy
15. Able to swallow and retain oral medications;
16. A female who is of:
• non-childbearing potential, 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. |
|
E.4 | Principal exclusion criteria |
As the study was stopped on 11th June 2012, no further subjects will be enrolled.
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 tumours and/or spinal cord metastases at baseline. Any evidence of brain metastases on Baseline MRI scan (performed within 4 weeks prior to randomisation) as determined by the independent reviewer. Concurrent treatment with an investigational agent
2. Concurrent treatment with an investigational agent or participation in another
treatment clinical trial 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/TDMI or 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 the protocol (Section 4.11.2 Prohibited Medications and Non-Drug Therapies)
11. Concomitant use of CYP3A4 inhibitors or inducers (also refer to Table 7)
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 current active/requiring anti-viral therapy hepatic or biliary disease (with 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
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 least five years, subjects with adequately treated DCIS or LCIS, adequately treated non-melanoma 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. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
As the study was stopped on 11th June 2012, No further subjects will be enrolled 2012 after IDMC review of the Interim Analysis.
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 and analysis will be done on M-ITT (modified intent-to-treat) population as defined in Section 7.3.1.
|
|
E.5.2 | Secondary end point(s) |
•Progression Free Survival (PFS) which is defined as time from
randomization to the time of first documented disease progression at any site or death due to any cause.
• Overall Survival (OS), which is defined as the time from randomization until death due to any cause.
• Time to first CNS progression, which is defined as the time from
randomization until documented CNS progression.
• Overall Response Rate, which is defined as percent of subjects
experiencing confirmed Complete Response (CR) and Partial Response (PR)
• Clinical Benefit Response Rate, which is defined as percentage of
subjects experiencing confirmed CR or PR at any time or Stable Disease (SD) for ≥24 weeks.
• Duration of Response, which is defined as the time from first objective response (CR or PR) until tumor progression at any site or death due to breast cancer.
• Incidence of CNS progression at any time, defined as the proportion of subjects who have relapsed with brain metastases at any time regardless of whether or not progression has been documented via radiological scan. Subjects who have not relapsed at the time of analysis will be included in the denominator.
|
|
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.8.5 | 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 | 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 | 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 |