| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patient with non penetrated brain metastasis from HER2 positive breast cancer. |
|
| 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 | 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 |
To assess the objective response rate by volumetric analysis of the combination lapatinib and
capecitabine on brain metastasis as assessed by MRI, in metastatic HER2 positive breast cancer
patients, prior to any brain radiotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
- To document any toxicity evaluated by NCI-CTC-V3.0.
- To assess the time to radiotherapy
- To document the time to disease progression in the central nervous system (CNS).
- To evaluate the overall response rate for extra-CNS disease.
- To assess the clinical benefit (complete response [CR], partial response [PR], and stable disease [SD] for at least 6 months) for both CNS and extra-CNS disease. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
- To evaluate serum proteomic and metabonomic markers as predictors of responses.
- To evaluate the predictive value of Circulating Tumor Cells (CTC) on response. |
|
| E.3 | Principal inclusion criteria |
1. Histologically confirmed invasive breast cancer with stage IV disease.
2. HER-2 positive primary tumor, defined as : IHC3+, or IHC2+ and FISH positive.
3. At least one measurable CNS lesion ≥ 10 mm on T1-weighted gadolinium-enhanced MRI.
4. At least two weeks from any specific breast cancer treatment (such as Trastuzumab,
chemotherapy, immunotherapy/biological response modifiers, endocrine therapy and
radiotherapy).
5. Adequate hematologic function (ANC ≥ 1.0x109/L, platelets ≥ 100 000 ; Hb ≥ 10g/l), renal
function (creatinine ≥ 1.5 UNL) and hepatic function (albumin ≥ 2.5 g/dL ;
serum bilirubin ≤ 1.5x ULN unless due to Gilbert’s syndrome ; ASAT and ALAT ≤ 5x ULN if
documented liver metastases or ≤ 3x ULN without liver metastases)
6. Patients able to swallow and retain oral medication.
7. At least 18 years old.
8. ECOG Performance Status of 0 to 2.
9. Life expectancy ≥ 3 months.
10. Potentially reproductive patients must agree to use an effective contraceptive method while
on treatment, beginning 2 weeks before the first dose of investigational product and for 28
days after the final dose of investigational product for women. 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.
11. Women of childbearing potential must have a negative serum pregnancy test within 14
days of enrollment and/or urine pregnancy test 48 hours prior to the administration of the
first study treatment.
12. Patients must be affiliated to a Social Security System.
13. Patient information and written informed consent form signed. |
|
| E.4 | Principal exclusion criteria |
1) Previous whole brain radiotherapy (WBRT) or brain stereotactic radiotherapy.
2) Planned or concurrent systemic treatment or radiation therapy for breast cancer (other that
corticosteroid, biphosphonates or mannitol).
3) Single brain metastasis which could be treated by surgery.
4) Known contra-indication to MRI.
5) Active concurrent malignancy. If there is a history of prior malignancy, the patient must be
disease free for at least 10 years.
6) Previous treatment with capecitabine, and/or lapatinib.
7) Patients with other concurrent severe and/or uncontrolled medical disease which could
compromise participation in the study, such as :
a) infection,
b) cardiac disease such as uncontrolled hypertension, congestive cardiac failure,
ventricular arrhythmias, active ischemic heart disease, myocardial infarction within one
year, LVEF > grade 2,
c) 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),
d) renal disease,
e) active GI tract ulceration, malabsorption syndrome, disease significantly affecting
gastrointestinal function, or resection of the stomach or small bowel. Subjects with
active, uncontrolled ulcerative colitis are also excluded,
f) severely impaired lung function (spirometry and DLCO 50% or less of normal and O2
saturation of 88% or less at rest on room air).
8) Known dihydropyrimidine dehydrogenase (DPD) deficiency.
9) Patients being treated with drugs recognized as being strong inhibitors or inducers of the
isoenzyme CYP3A (Clarithromycin, Ketoconazole, Itroconazole, Voriconazole, Ritonavir, etc.)within the last 7 to 14 days prior to inclusion and/or during the study.
10) Pregnant women, women who are likely to become pregnant or are breast-feeding.
11) Patients with significantly altered mental status prohibiting the understanding of the study or
with psychological, familial, sociological or geographical condition potentially hampering
compliance with the study protocol and follow-up schedule; those conditions should be
discussed with the patient before registration in the trial.
12) Patients who received any other investigational drugs within the 30 days prior to the
screening visit.
13) Individual deprived of liberty or placed under the authority of a tutor. |
|
| 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 centralized 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).
MRI for volumetric assessments will be performed every 6 weeks according to protocol specific acquisition guidelines (appendix 12). If a CNS PR or CR is assigned following an MRI scan of the brain, a follow-on disease assessment by MRI should be performed approximately 4 weeks after the criteria for response are first met, and then repeated once more, 4 weeks later.
|
|
| 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 | No |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 15 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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