| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or refractory inflammatory breast cancer with ErbB2 tumours. |
|
| 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 | 10021974 |
| E.1.2 | Term | Inflammatory breast cancer |
|
| 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 this study is to compare the progression-free survival between pazopanib in combination with lapatinib versus lapatinib alone in patients with relapsed or refractory IBC whose tumors overexpress ErbB2. |
|
| E.2.2 | Secondary objectives of the trial |
The main secondary objective is to compare overall survival (OS) between patients treated with lapatinib and pazopanib combination therapy versus patients treated with lapatinib alone.
Other secondary objectives will:
(i) compare objective response rate (ORR, defined as CR + PR) and response duration after treatment with the combination of lapatinib and pazopanib versus lapatinib alone.
(ii) compare the safety and tolerability of the two regimens.
(iii) compare health status assessments between the two regimens.
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histological confirmation of breast carcinoma with a clinical diagnosis of IBC at original diagnosis based on the presence of inflammatory changes in the involved breast, including diffuse erythema and edema (peau d’orange), with or without an underlying palpable mass. Pathologic evidence of dermal lymphatic invasion should be noted but is not required for diagnosis. Documentation of initial diagnosis of IBC must be included in source documentation.
2. Disease progression or relapse following treatment for IBC, which must have included a chemotherapy regimen. In regions where trastuzumab is available with no barriers to access, patients must have received prior trastuzumab in addition to chemotherapy in order to be eligible.
3. Tumor that overexpresses ErbB2 as defined by at least one of the following based on local results: 1.) 3+ overexpression by IHC or 2.) HER2 gene amplification by FISH or CISH. Archived tumor tissue must be provided for all patients for ErbB2 FISH testing by the central laboratory. Central testing is for analysis only. Patients will remain on study based on local ErbB2 expression results.
4. Patients will have radiographically measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) [Therasse, 2000] or evaluable IBC cutaneous disease. If the only evidence of recurrent IBC is cutaneous disease, the cutaneous disease must have been biopsied at some time.
Radiographically measurable lesions may be in the field of prior adjuvant irradiation; however, there must be at least an 8 week period between the last radiation treatment and the baseline scan documenting disease status for the lesion to be measurable. If the irradiated lesion is the only site of disease, documented progression of the irradiated lesion is required.
5. Patients must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow up. Procedures conducted as part of the patient’s routine clinical management (e.g., blood count, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol.
Note: It is not necessary that informed consent be obtained within the protocol-specified screening window.
6. Age ≥ 18 years.
7. Adequate organ function as defined in Table 1 of the protocol
8. Cardiac ejection fraction within the institutional range of normal as measured by echocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive or where MUGA scans are the accepted standard. Patients with known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure are not eligible.
9. Archived tumor tissue must be provided for all patients.
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
11. A female is eligible to enter and participate in this study if she is of:
Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had:
• A hysterectomy
• A bilateral oophorectomy (ovariectomy)
• A bilateral tubal ligation
• Is post-menopausal
Patients not using hormone replacement therapy (HRT) must have experienced total cessation of menses for ≥ 1 year and be greater than 45 years in age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).
Patients must discontinue HRT prior to study enrollment due to the potential for inhibition of CYP enzymes that metabolize estrogens and progestins (See Section 8). For most forms of HRT, at least 2-4 weeks must elapse between the cessation of HRT and determination of menopausal status; length of this interval depends on the type and dosage of HRT. If a female patient is determined not to be post-menopausal, they must use adequate contraception, as defined in the protocol.
12. French patients: In France, a patient will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
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|
| E.4 | Principal exclusion criteria |
1. Treatment in the 14 days prior to randomization with any cancer therapy (surgery, tumor embolization, chemotherapy, radiation therapy, immunotherapy, biological therapy, or hormonal therapy) or treatment with mitomycin within 6 weeks prior to randomization. Such treatment may not be resumed or begun after study entry. Note: Patients receiving LH-RH analogue therapy prior to the study may continue to receive LH-RH analogues for the duration of study participation.
2. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity.
3. Prior lapatinib therapy.
4. Use of an investigational agent, including an investigational anti-cancer agent, within 28 days or 5 half-lives, whichever is longer, prior to the first dose of investigational product.
5. Use of any prohibited medication within the timeframes listed in Section 8.2.
6. Evidence of recurrence or active disease from prior malignancy.
7. History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for 2 months prior to first dose of study drug. Screening with CNS imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the subject has a history of CNS metastases.
8. Clinically significant gastrointestinal abnormalities that may increase the risk for GI bleeding including, but not limited to:
• Active peptic ulcer disease
• Inflammatory bowel disease
• Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation
• History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.
9. Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but limited to:
• Malabsorption syndrome
• Major resection of the stomach or small bowel.
10. Presence of uncontrolled infection.
11. Prolongation of corrected QT interval (QTc) > 480 msecs.
12. History of any one or more of the following cardiovascular conditions within the past 6 months:
• Cardiac angioplasty or stenting
• Myocardial infarction
• Unstable angina
• Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) (See Section 15.7 Appendix 7 for description).
13. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg].
Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Blood pressure must be re-assessed on two occasions that are separated by a minimum of 24 hours. The mean SBP / DBP values from each blood pressure assessment must be < 140/90mmHg in order for a patient to be eligible for the study. See Sections 6.2 and 6.4.2 for details on blood pressure control and reassessment prior to study enrollment.
14. History of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
Note: Patients with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.
15. Prior major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any non-healing wound, fracture, or ulcer
16. Evidence of active bleeding or bleeding diathesis.
17. Hemoptysis within 6 weeks prior to first dose of investigational product.
18. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with patient’s safety, provision of informed consent, or compliance to study procedures.
19. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or lapatinib.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS defined as the interval between the date of randomization and the earliest date of disease progression or death due to any cause. |
|
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of Life, Translational research (Biomarkers) |
|
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 67 |
| 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
|
| Subjects will be followed for survival until death at 3 month intervals as outlined in Section 9.2 of the protocol. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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 |
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