E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Women with early-stage ErbB2-overexpressing breast cancer. Eligible women must have had an initial diagnosis of histologically or cytologically confirmed invasive breast cancer (Stage I through Stage IIIc) with ErbB2 overexpression defined as 3+ by immunohistochemisty (IHC) OR c-erbB2 gene amplification by fluorescence in-situ hybridization (FISH) OR 0, 1+, 2+ by IHC and c-erbB2 geneamplification by FISH. |
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E.1.1.1 | Medical condition in easily understood language |
Women with early-stage ErbB2-overexpressing breast cancer. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER-2 positive breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 |
The primary objective of the study is to determine whether adjuvant therapy with
lapatinib will improve disease-free survival in women with early-stage ErbB2-
overexpressing breast cancer. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to
- evaluate and compare between treatment arms the following: overall survival, recurrence-free intervals [local, regional, distant, and central nervous system (CNS)], rate of CNS recurrence, toxicity, and quality of life.
- to determine the qualitative and quantitative toxicities and the incidence of cardiac dysfunction associated with oral lapatinib administered daily versus placebo.
- to identify biomarkers (encoded in protein or RNA) derived from the tumor tissue obtained at the time of initial diagnosis (archived tumor tissue sample) and compare these to those derived from a tumor biopsy sample obtained at the time of disease recurrence
- to investigate the relationship between genetic variations in select candidate genes in the host DNA and response (safety, efficacy and tolerability) following treatment with lapatinib |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have histologically or cytologically confirmed ErbB2-overexpressing invasive carcinoma (Tx or T1-4) of the breast at the time of the initial diagnosis and have
undergone adequate excision of tumor;
2. Had tumors that overexpress ErbB2 defined as either 3+ by IHC OR c-erbB2 gene amplification by FISH OR 0, 1+, 2+ by IHC and c-erbB2 gene amplification by FISH.
3. Using the American Joint Committee on Cancer (6th edition) staging criteria for
breast cancer, a woman must have Stage I through Stage IIIc disease.
4. Women with synchronous bilateral invasive breast cancer or synchronous DCIS of
either the contralateral or ipsilateral breast at the time of the initial diagnosis are also
eligible; prior endocrine therapy as treatment for or as primary prevention of DCIS is
allowed.
5. Have completed all primary neoadjuvant or adjuvant chemotherapy regimens prior to study enrolment. However, adjuvant endocrine therapy and radiotherapy may continue as described in Inclusion Criteria #11 and #13, respectively. For women who received an anthracycline-based adjuvant regimen, the interval between the completion of this therapy and study entry must be at least 4 weeks and all therapy-related toxicity must be resolved.
6. All women eligible for adjuvant treatment with trastuzumab, including those diagnosed and treated within the last six months, must be considered for such treatment prior to being offered participation in this study. Participation in this study will be allowed only if the physician and patient have considered and discussed at length the advantages of trastuzumab, but have mutually decided against initiating trastuzumab therapy. Clear documentation of such a decision must appear in the Electronic Case Report Form (eCRF).
7. Have clinical and radiologic assessments that are negative for local or regional recurrence of disease or metastatic disease at the time of study entry.
8. Must have had an analysis of both ER and progesterone receptor (PgR) on the primary tumour prior to study entry;
9. Have undergone either mastectomy or lumpectomy;
10. Must have received a prior neoadjuvant or adjuvant chemotherapy regimen containing either an anthracycline or a taxane; or any cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen;
11. May continue to receive endocrine therapy, including tamoxifen or an aromatase inhibitor, while taking study medication, if endocrine therapy was initiated as either adjuvant therapy for treatment of the initial diagnosis of invasive breast cancer or for ovarian function suppression; however, endocrine therapy may not be initiated while taking study medication. Endocrine therapy agents may be switched while participating in this study (e.g., stop tamoxifen and start letrozole);
12. May have received prior radiotherapy as treatment for primary tumour; however, is not required for study entry;
13. May continue to receive radiotherapy while taking study medication, if radiotherapy was initiated as adjuvant therapy for treatment of the initial diagnosis of invasive breast cancer;
14. May continue to receive bisphosphonates only for treatment of documented osteoporosis, but not as treatment or prophylaxis of bone metastases;
15. Have not received prior therapy with an ErbB1 and/or ErbB2 inhibitor;
16. Have a cardiac ejection fraction within institutional range of normal as measured by either echocardiogram or multigated acquisition (MUGA) scans.
17. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1
18. Women with a history of non-breast malignancies are eligible if they have been
disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence. Women with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical carcinoma in situ, melanoma in situ, and basal cell or squamous cell carcinoma of the skin;
19. Are able to swallow and retain oral medication;
20. Have an archived tumour tissue sample available for biomarker analysis.
21. Are able to complete all screening assessments as outlined in the protocol;
22. Have adequate organ function
23. Have signed the informed consent form (ICF);
24. Are aged 18 years or over with any menopausal status;
• Non-child-bearing potential (i.e., women with functioning ovaries who have a
current documented tubal ligation or hysterectomy, or women who are post-menopausal);
• Child-bearing potential. These subjects must have a negative serum pregnancy test at screening and agree to a suitable form of contraception as outlined in the protocol. |
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E.4 | Principal exclusion criteria |
1. Have clinical and radiologic evidence of local or regional recurrence of disease or
metastatic disease at the time of study entry;
2. Had metachronous invasive breast cancer (breast cancers diagnosed at different times);
3. Have a prior history of other breast cancer malignancies, including DCIS;
4. Are unable to provide archived tumour tissue samples for assay;
5. Had prior therapy with an ErbB1 and/or ErbB2 inhibitor; women who experienced a
hypersensitivity or allergic reaction to trastuzumab during the first infusion and were unable to complete this infusion are eligible;
6. Receive concurrent anti-cancer therapy (chemotherapy, immunotherapy, and biologic therapy) while taking study medication;
7. Have unresolved or unstable, serious toxicity from prior administration of another
investigational drug and/or of prior cancer treatment;
8. Have malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Women with ulcerative colitis are also excluded;
9. Have a concurrent disease or condition that would make the woman inappropriate for
study participation, or any serious medical disorder that would interfere with the woman's safety;
10. Have an active or uncontrolled infection;
11. Have dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent;
12. Have a known history of uncontrolled or symptomatic angina, arrhythmias, or CHF;
13. Are pregnant or breastfeeding;
14. Receive concurrent treatment with an investigational agent; women, who are in follow-up in another clinical trial where the primary endpoint has been met and the interval between assessments is 12 months and radiological imaging is not required at these assessments, are eligible;
15. Receive concurrent treatment with prohibited medications.
16. Used an investigational drug within 30 days or 5 half-lives, whichever is longer,
preceding the first dose of study medication;
17. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to lapatinib or excipients;
18. In France, subjects are neither affiliated with nor a beneficiary of a social security
category. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint for analysis is disease-free survival (DFS) which includes the following events:
•local recurrence following mastectomy
•local recurrence in ipsilateral breast following lumpectomy
•regional recurrence
•distant recurrence
•contralateral breast cancer, including ductal carcinoma in situ (DCIS)
•other second primary cancer (excluding squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, or lobular carcinoma in situ of the breast)
•death from any cause without prior event (recurrence of breast cancer or second primary cancer)
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
E.6.2 | Prophylaxis | Information not present in EudraCT |
E.6.3 | Therapy | Information not present in EudraCT |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Information not present in EudraCT |
E.6.7 | Pharmacodynamic | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
E.6.13 | Others | Information not present in EudraCT |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
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 | 206 |
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 |
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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
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A subject will be considered as completing the study for data collection purposes to ensure adequate collection of survival information if:
•the subject is no longer receiving treatment with investigational product and has completed 5 years of follow-up;
OR
•the subject has died.
Note: When the follow-up period reaches a median of 5 years, the study objectives will have been met and the study will be closed. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 13 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 13 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |