| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Resectable Soft Tisue Sarcomas (cancer of conective soft tissues) |
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| 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 asses the response to preoperative pazopanib in terms of tumour vascularity and blood flow (vascular responses) using functional (Dynamic Contrast Enhanced - DCE) magnetic resonance imaging (MRI). |
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| E.2.2 | Secondary objectives of the trial |
| SECONDARY OBJECTIVES To assess vascular and cellular responses to preoperative pazopanib using other modalities of functional MRI (diffusion-weighted [DW-MRI] and blood oxygenation level-dependent [BOLD-MRI]. To assess the tolerability and toxicity profile of pazopanib given in the preoperative and postoperative settings in this population. To describe any radiological evidence of antitumour activity with neoadjuvant pazopanib by assessment of objective response using RECIST. To describe any histopathological evidence of antiangiogenic (loss of blood vessels) and antitumour activity with neoadjuvant pazopanib by examining the resected tumor specimens. To examine changes in angiogenesis (blood vessels growth) markers in tumor tissue after pre-operative treatment with pazopanib. EXPLORATORY OBJECTIVES To explore the value of monitoring early changes in circulating angiogenesis-related proteins during preoperative treatment with pazopanib. To explore the value of |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Provision of written informed consent. 2. Age ≥ 18 years. 3. Confirmed histological diagnosis of intermediate-high grade STS: synovial sarcoma, leiomyosarcoma, myxofibrosarcoma, and others subtypes including angiosarcoma. 4. Stage I-III deemed suitable for surgical treatment, and naïve for either preoperative chemotherapy, radiotherapy, or any other molecularly targeted or experimental therapy. 5. Measurable tumor at least 3 cm in the longest diameter and suitable for magnetic resonance imaging (MRI) scanning and functional (DCE-, DW-, and BOLD) MRI studies. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 7. Tumor tissue must be provided for all subjects for correlative biomarker studies before and at surgery (or progression if a patient is not finally deemed suitable for surgery). Pre-treatment samples could include tumor tissue obtained for other purposes, if the patient has not had any anticancer treatment between the biopsy and the start day on pazopanib. 8. Adequate bone marrow function as defined by: - Absolute neutrophil count (ANC) > 1.5 x10^9/L - Haemoglobin = or > 10 g/dL (without a transfusion within 7 days of screening assessment). - Platelets = or > 100 X 10^9/L 10. Adequate organs function as defined by: - Liver function: Total bilirubin <1.5 X UNL, ALT and AST 2.5 X UNL. - Renal function: Serum creatinine <1.5 mg/dL (133 µmol/L) (or if greater calculated creatinine clearance [Cockcroft-Gault formula] >50 mL/min, and normal urine protein to creatinine ratio (UPC) or if >1, then urinary protein excretion must be <1.5g in a 24 hr period. - Coagulation: Partial thromboplastin time (PTT), and prothrombin time (PT) or international normalized ratio (INR) < 1.2 X UNL. 10. 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 Subjects 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). Subjects using HRT must have experienced total cessation of menses for > 1 year and be greater than 45 years of age OR have had documented evidence of menopause based on FSH and estradiol concentrations prior to initiation of HRT Childbearing potential, including any female who has had a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception. Acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follow: • An intrauterine device with a documented failure rate of < 1% per year. • Vasectomized partner who is sterile prior to the female subject’s entry and is the sole sexual partner for that female. • Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product. • Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide). • Oral contraceptives • Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug 11. Patient must be able and willing to comply with treatment evaluations and follow up. |
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| E.4 | Principal exclusion criteria |
| 1. No prior diagnosis of other malignancies, except subjects who have had another malignancy and have been disease-free for 10 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 metastases, including central nervous system (CNS) metastases whether they have been treated or not. 3. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to: • Active peptic ulcer disease • Known intraluminal metastatic lesion/s with risk of bleeding • Inflammatory bowel disease (e.g. ulcerative colitis, crohn's disease), 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. 6. Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to: • Malabsorption syndrome • Major resection of the stomach or small bowel. 5. Presence of uncontrolled infection. 6. Corrected QT interval (QTc) < 480 msecs using Fridericia’s formula 7. History of any one or more of the following cardiovascular conditions within the past 6 months: • Cardiac angioplasty or stenting • Myocardial infarction • Unstable angina • Coronary artery bypass graft surgery • Symptomatic peripheral vascular disease • Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) 8. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg]. Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. BP must be re-assessed on two occasions that are separated by A minimum of 1 hour; on each of these occasions, the mean (of 3 readings) systolic blood pressure (SBP) / DBP values from each BP assessment must be <140/90 mmHg in order for a subject to be eligible for the study. 9. History of cerebrovascular accident including transient ischemic attack (TIA). 10. Patients who require anticoagulants are not eligible for this study. 11. History of pulmonary embolism or deep venous thrombosis (DVT) only if requiring anticoagulant treatment at the present. 12. Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major). 13. Evidence of active bleeding or bleeding diathesis, and including hemoptysis of any cause within 6 weeks of first dose of study drug. 15. 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. 16. Patients known to be allergic to gadolinium based MRI contrast agents or ineligibility for MRI scanning (for example metal implants such as cochlear implants, cardiac pacemakers, heart valves, aneurysm clips and metal fragments in eyes). 17. Unable or unwilling to discontinue use of prohibited medications for 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. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective of TOPPS is to assess vascular tumor responses to short-term preoperative pazopanib by functional DCE-MRI parameters of tumor vasculature and blood flow such as Ktrans. |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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
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| 4-12 weeks after the last trial participant receives the last dose of the investigational medicinal product (It will represent the end of study visit of the last patient on trial). |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 15 |
| 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 | 15 |
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