E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Progressive symptomatic or asymptomatic ErbB2 overexpressing breast cancer brain metastases. |
|
MedDRA Classification |
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 determine the CNS objective response rate to monotherapy lapatinib 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, increasing steroid
requirements, or worsening of tumor-related neurological signs and symptoms (NSS). |
|
E.2.2 | Secondary objectives of the trial |
To determine improvement in neurological signs and symptoms (NSS),
measured using the Neurological Examination Worksheet
To determine the percentage of subjects who obtain a CNS objective response or
improvement in baseline NSS
To determine duration of CNS objective response
To determine percentage of subjects with CNS disease control (complete
response, partial response or stable disease) at 6 months of lapatinib therapy
To determine time to progression at any site
To determine overall survival (OS)
To describe and summarize site of first progression and cause of death
To determine the qualitative and quantitative toxicities associated with oral
lapatinib, given at a dose of 750 mg BID.
To explore the relationship of PET uptake at Baseline and Week 1, as predictors of
response.
To investigate the relationship between genetic variants in select candidate genes in the
host and the efficacy and safety of lapatinib. |
|
E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1. Signed written informed consent;
2. 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 overexpressing breast cancer, defined as 3+ staining by
immunohistochemistry (IHC), or 2+ staining by IHC in conjunction with ErbB 2
gene amplification by FISH, or ErbB 2 gene amplification by FISH alone (in subjects whose tumor blocks were not assessed by IHC). Subjects with tumors that
are 2+ by IHC but negative by FISH assay are ineligible;
7. At least one measurable lesion in the brain, defined as any lesion ≥ 10mm in longest dimension on T1-weighted, gadolinium-enhanced MRI;
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;
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. 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. Female subjects with child bearing potential or male subjects able to father a child must be completely abstinent from intercourse or use acceptable methods for birth control during the course of the study;
16. Subjects must complete all screening assessments as outlined in the protocol;
17. Subjects must have normal organ and marrow function as defined below:
ANC (absolute neutrophil count)- 1.0 x 10*9/L
Hemoglobin - ≥ 9 g/dL (after transfusion if needed)
Platelets - ≥ 50 x 10*9/L
Albumin - ≥ 2.5 g/dL
Serum bilirubin - ≤ 1.5x ULN unless due to Gilbert’s syndrome
AST and ALT - ≤ 5x ULN if documented liver metastases
≤ 3x ULN without liver metastases
Serum Creatinine - ≤ 2.0 mg/dL
or
Calculated Creatinine Clearance* ≥ 25 mL/min
*Calculated by the Cockcroft and Gault Method |
|
E.4 | Principal exclusion criteria |
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. 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;
4. Subjects with leptomeningeal carcinomatosis as the only site of CNS involvement;
5. History of allergic reactions attributed to compounds of similar chemical
composition (quinazolines) to lapatinib;
6. Concurrent treatment with medications that are either inducers or inhibitors of
CYP3A4 is prohibited. (For important exceptions, refer to Section 8.2, Prohibited
Medications);
7. Malabsorption Syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel. Subjects with active, uncontrolled
ulcerative colitis are also excluded;
8. History of immediate or delayed hypersensitivity reaction to gadolinium contrast
agents, or other contraindication to gadolinium contrast;
9. Other known contraindication to MRI, such as a cardiac pacemaker, implanted
cardiac defibrillator, brain aneurysm clips, cochlear implant, ocular foreign body, or
shrapnel;
10. 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;
11. Dementia, altered mental status, or any psychiatric condition that would prohibit the
understanding or rendering of informed consent;
12. Pre-existing severe cerebral vascular disease, such as stroke involving a major
vessel, CNS vasculitis, or malignant hypertension;
13. 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, with the
exception of asymptomatic atrial fibrillation requiring anticoagulation
• 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
14. Uncontrolled infection;
15. 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;
16. Pregnant or lactating females. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
CNS objective response rate is the primary study endpoint, where CNS objective
response is defined as either a CR or PR, assessed by volumetric analyses of magnetic resonance imaging (MRI), provided there is no progression of systemic disease outside of the CNS, increasing steroid requirements, or worsening of neurological signs and symptoms (NSS). |
|
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 | Information not present in EudraCT |
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) | 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 | Yes |
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
| 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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
|
Study will be considered complete for the purpose of analysing and reporting the data when:
(i) patients have completed 1 year of study treatment;
or
(ii) patients have stopped study treatment and been followed-up for 1 year;
or
(iii) the patients have died. All patients in the study will be monitored until death. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
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 |