E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced and/or metastatic liposarcoma |
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E.1.1.1 | Medical condition in easily understood language |
Advanced and/or metastatic liposarcoma |
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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 | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10024629 |
E.1.2 | Term | Liposarcoma metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10024627 |
E.1.2 | Term | Liposarcoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the activity of Pazopanib in patients with advanced and/or metastatic liposarcoma by means of progression-free survival (PFS) assessed 12 weeks after start of treatment. (According the RECIST criteria 1.1 and central radiology review). |
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E.2.2 | Secondary objectives of the trial |
Median progression-free survival (median PFS) Objective tumor response (confirmed complete response [CR] and partial response [PR] using modified Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) Time to onset of response Duration of response Overall survival (OS) Clinical benefit rate (CBR) Growth Modulation Index (GMI). Safety profile (according CTCAE, version 4.0) |
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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 |
PRIMARY OBJECTIVES: To evaluate the influence of the angiogenic status of the tumor on the response to Pazopanib. To evaluate the serum profile of serum cytokine markers as indicator of response to Pazopanib.
SECONDARY OBJECTIVES: To evaluate microvessel density (MVD) and p53, MDM2, PTEN and VEGF/PDGF pathways by IHQ expression and their correlation with prognosis as well as their role as predictive factors to treatment with Pazopanib (Response, PFS and OS). To evaluate serum levels of several angiogenic factors/cytoquines using Luminex XMAP Technology at baseline, after the first 3 weeks of treatment, at maximum response and at progression and their predictive value for survival and response to treatment: VEGF-A, PlGF-1, SDF-1 alpha (CXCL12), TNF alpha, IL-8, IL-6, PDGF ?beta, HGF, E- Selectine, ICAM1, MMP-9 and FGFb. To analyse PIK3CA mutations in order to demonstrate if those liposarcomas with PIK3CA mutations defines a subgroup of patients with differential response to Pazopanib. |
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E.3 | Principal inclusion criteria |
1.Subjects 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. 2.Age ? 18 years or legal age of consent if greater than 18 years 3.Histological confirmed diagnosis of high or intermediate grade malignant liposarcoma with metastatic or locally advanced disease. Formaline fixed paraffin embedded tumour block and/or representative H/E (haematoxylin/eosin) slides must be available for central pathologic review. 4.Patient must have documentation of disease progression within 6 months prior to study entry. 5.Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 6.Measurable disease by RECIST v1.1 criteria. At least one measurable lesion located outside of a previously irradiated area. If the only measurable lesion is in a previously irradiated area, RECIST progression should be documented after radiotherapy, in the previous 6 months before study entry. 7.The patient should not be considered eligible for surgery or radical radiotherapy. e.g. Patients to whom surgery/radiotherapy can not be performed with a curative intent due to the extension of the disease. In the case of radiotherapy, it may also be limited due to a previous treatment with radiotherapy in the same area. 8.The patient must have either been considered ineligible for systemic chemotherapy or received at least one previous regimen for relapsed, refractory or metastatic disease. A maximum of three previous lines for advanced/metastatic disease are allowed. 9.The patient should be able to swallow and retain study drug 10.Adequate organ system function as defined in Table 1 of protocol. 11.A subject is eligible to enter and participate in this study if she/he is following the contraceptive indication detailed in protocol. 12.LVEF above the lower limit of normal for the institution, based on ECHO or MUGA. |
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E.4 | Principal exclusion criteria |
1.Prior history of malignancies other than liposarcoma. Subjects who have had another malignancy and have been disease-free for 3 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible. 2.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 6 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. 3.Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding. 4.Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product. 5.Corrected QT interval (QTc) > 480 msecs 6.History of any one or more of cardiovascular conditions within the past 6 months. 7.Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ?140 mmHg or diastolic blood pressure (DBP) of ? 90mmHg]. 8.History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible 9.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 (procedures such as catheter placement not considered to be major surgery). 10.Evidence of active bleeding or bleeding diathesis. 11.Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage. Lesions infiltrating major pulmonary vessels (contiguous tumour and vessels) are excluded; however, the presence of a tumor that is touching, but not infiltrating (abutting) the vessels is acceptable (CT with contrast is strongly recommended to evaluate such lesions). 12.Recent hemoptysis (? ½ teaspoon of red blood within 8 weeks before first dose of study drug). 13.Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject?s safety, provision of informed consent, or compliance to study procedures. 14.Unable or unwilling to discontinue use of prohibited medications listed in section 7.4 of this protocol or at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study. 15.Treatment with any of the following anti-cancer therapies: radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of Pazopanib chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of Pazopanib 16.Administration of any non-oncologic investigational drug within 30 days or 5 half lives whichever is longer prior to receiving the first dose of study treatment 17.Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity, except alopecia. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary end-point of the study is progression free survival 12 weeks after start of therapy, measured as a binary variable. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
This will be based on the disease evaluation performed 12 weeks after start of treatment with central radiology review. Patients who are alive and progression free at this time will be considered as successes. Patients who have progressed or are dead at this time will be considered as failure. Patients with an unknown progression status will be considered as failure. The diagnosis of progression should be based on tumor measurements, according to the RECIST 1.1 criteria. |
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E.5.2 | Secondary end point(s) |
Overall progression free survival (median PFS) Objective tumor response Time to onset of response Duration of response Overall survival (OS) Clinical benefit rate Growth Modulation Index (GMI) Safety profile (according CTCAE, version 4.0) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Disease should be captured and target/non-target identified at baseline by CT or MRI as appropriate. Subsequently, imaging studies required to investigate known disease should be repeated every 6 weeks for the first 12 weeks and every 8 weeks thereafter until disease progression or new anticancer therapy among others. Assessment of adverse events will include type, incidence, severity, timing, seriousness, and relatedness; and laboratory abnormalities. In each study visit all adverse events will be registered according to NCI-CTC version 4.0 |
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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 | No |
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 | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 | No |
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
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LPLV. The study will be considered closed from a normative point of view after data on primary and secondary variables are sufficiently prepared for its initial publication. |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 36 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 36 |
E.8.9.2 | In all countries concerned by the trial days | 0 |