| 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 estimate the objective response rate (ORR, defined as CR + PR) of pazopanib and lapatinib combination therapy and lapatinib alone, in patients with relapsed or refractory IBC whose tumors overexpress ErbB2.. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess overall survival (OS) between patients treated with lapatinib and
pazopanib combination therapy versus patients treated with lapatinib alone.
• To assess overall survival (OS) between patients treated with lapatinib and
pazopanib combination therapy versus patients treated with pazopanib alone.
• To estimate the objective response rate (ORR) of pazopanib alone.
• To assess progression-free survival (PFS) in the three treatment arms
• To assess response duration after treatment in the three treatment regimens.
• To compare the safety and tolerability of the regimens. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For Cohort 1 of this study, eligible patients met inclusion criteria outlined in the original version of the protocol and protocol amendment 1.
For Cohort 2 of this study, eligible patients must meet all of the following criteria:
1. Patients must have evaluable Inflammatory Breast Cancer (IBC) substantiated by all of the following prior to randomization:
• History of invasive breast cancer documented by a biopsy and accompanying pathology report
• Current photographs* (global view and close-up views of all skin lesions) submitted at screening demonstrating unequivocal evidence of IBC as determined by either the medical monitor alone or in consultation with one or more of the study Principal Investigators.
*All patients must have photography at screening. Canfield Scientific Inc. will provide centralized monitoring, tracking, and collection of patients' photographs throughout the study. Screening photographs must be uploaded to the Canfield Scientific Inc website and approved by Canfield Scientific Inc, as the central photography vendor or by GSK. The photographs, along with the completed Inflammatory Breast Cancer Skin Assessment Tool (IBSAT), must be reviewed and approved by GSK before a patient can be randomized. Sites should allow a minimum of 3 business days for this process. Sites submitting quality photographs and IBSATs on a regular basis will receive an exemption from this requirement for future patients.
2. Patients with secondary IBC are eligible.
3. Measurable lesions (cutaneous or radiographic) may be in the field of prior standard or palliative radiation therapy; however, there must be at least a 4 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.
4. Disease progression or relapse following treatment for invasive breast cancer, 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.
*(Barriers to access may include financial considerations)
5. Unequivocal ErbB2 overexpressing breast cancer, defined as 3+ staining by immunohistochemistry (IHC), or 2+ staining by IHC in conjunction with ErbB2 gene amplification by FISH/CISH, or ErbB2 gene amplification by FISH/CISH alone (in subjects whose tumor blocks were not assessed by IHC). ErbB2 gene amplification is defined by: > six (6) ErbB2 gene copies/nucleus for test systems without an internal control probe or an ErbB2/CEP 17 ratio of more than 2.2.
Sites must submit a copy of the laboratory report demonstrating unequivocal ErbB2 overexpression with the screening worksheet.
6. 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.
7. Females age ≥ 18 years, except in Tunisia. In Tunisia, patients must be ≥ 20 years to be eligible for this study.
8. Adequate organ function as defined in Table 1 of the protocol
9. 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.
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
|
|
| E.4 | Principal exclusion criteria |
1. Treatment in the 14 days prior to randomization with any cancer therapy (tumor embolization, chemotherapy, 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. Biophosphonates are permitted if started prior to Day 1.
2. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity.
3. Prior lapatinib therapy or other Her2/ErbB2 targeted therapy (except trastuzumab).
4. Prior therapy with an anti-VEGF antibody or VEGF-R targeted therapy.
5. 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.
6. Use of any prohibited medication within the timeframes listed in Section 8.2.
7. History of another malignancy. Note: Subjects who have had another malignancy and have been disease-free for 5 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible. If subject previously had breast cancer, it must have been HER2+ with either 3+ overexpression by IHC or unequivocal HER2 gene amplification by FISH or CISH.
8. 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.
9. Clinically significant gastrointestinal abnormalities that may increase the risk for GI bleeding including, but not limited to:
• Active peptic ulcer disease
• Known intraluminal metastatic lesion/s with suspected bleeding
• 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.
10. 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.
11. Presence of uncontrolled infection.
12. Prolongation of corrected QT interval (QTc) > 480 msecs.
13. History of any one or more of the following cardiovascular conditions within the past 6 months:
• Cardiac angioplasty or stenting
• Myocardial infarction
• Unstable angina
• Arterial thrombosis
• Symptomatic peripheral vascular disease
• Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) (See Section 15.7 Appendix 7 for description).
14. 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 1 hour. 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.
15. History of cerebrovascular accident, including TIA, 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.
16. 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 (other than ulcers due to inflammatory breast cancer.
17. Evidence of active bleeding or bleeding diathesis.
18. Hemoptysis within 6 weeks prior to first dose of investigational product.
19. Known endobronchial lesions or involvement of large pulmonary vessels by tumor.
20. 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.
21. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or lapatinib.
22. Have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR (defined as CR + PR). |
|
| 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 | 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 | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 71 |
| 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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