| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or progressive Transitional Cell Carcinoma (TCC) of the urothelium |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed or progressive Transitional Cell Carcinoma (TCC) of the urothelium |
|
| 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 | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10044426 |
| E.1.2 | Term | Transitional cell carcinoma urethra |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10044420 |
| E.1.2 | Term | Transitional cell carcinoma of the bladder stage unspecified |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10044407 |
| E.1.2 | Term | Transitional cell cancer of the renal pelvis and ureter |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 the study is to investigate whether pazopanib increases the overall survival time for patients with relapsed or progressive disease; in comparison to the current standard treatment, paclitaxel. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study are to measure the following for pazopanib in comparison to the current standard treatment, paclitaxel: -Toxicity -Clinical benefit at 12 weeks -Progression free survival time -Clinical benefit at 24 weeks -Quality of Life |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1.Histologically or cytologically confirmed TCC (bladder, renal pelvis, ureter, urethra), which is locally advanced or metastatic (T4b and/or N1-3 and/or M1). Patients with mixed or differentiation pattern pathology will be permitted entry providing that TCC is a component pathology. 2.Progressive disease during or after one prior platinum-based chemotherapy regimen for advanced disease or as peri-operative therapy for muscle-invasive / node positive disease (if completed < 12 months prior to documented disease progression). The regimen must have included either cisplatin or carboplatin. Patients who have had two platinum containing regimens are eligible if one of these was given peri-operatively, and provided that there was a chemotherapy-free interval of at least 12 months between completing the 1st course and commencing the second course of chemotherapy. Chemotherapy given during radical radiotherapy as a radiosensitizer will not be considered as a chemotherapy treatment for the purposes of study eligibility. 3.Age ≥ 18 years. 4.Measurable disease by RECIST 1.1. 5.Adequate organ function as defined by the following criteria: •Total serum bilirubin ≤1.5 x upper level of normal (ULN). •Serum transaminases <2.5 x ULN. Concomitant elevations of transaminases and bilirubin are not permitted. •Creatinine clearance >30ml/min (calculated by Cockcroft Gault equation) or Creatinine ≤1.5 x ULN. •Absolute neutrophil count (ANC) ≥1500/mm3 without growth factor support •Platelets ≥ 100,000/mm3 •Urine protein to creatinine ratio (UPC) < 110 mg/mmol (1g/g) (or total urinary protein < 1g/24hrs) •Activated partial thromboplastin time (APTT) ≤1.2 x ULN •International normalised ratio (INR)≤ 1.2 6.Signed and dated informed consent indicating that the patient has been informed of all the pertinent aspects of the trial prior to enrolment. 7.A negative pregnancy test for women of childbearing potential. 8.Life expectancy of 3 months or more. 9.Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures. 10.ECOG performance status of 0 or 1. |
|
| E.4 | Principal exclusion criteria |
| 1.Congestive heart failure, myocardial infarction, coronary artery bypass graft or thrombotic cerebrovascular event in the previous six months, or ongoing severe or unstable arrhythmia requiring medication. Patients with rate controlled atrial fibrillation are permitted to enter the study. 2.History of clinically significant bleeding in the 6 months prior to study initiation (including haemoptysis, cerebrovascular bleed or haematemesis; patients with haematuria are permitted entry as long as there is no indication for intervention). 3.Major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any unhealed wound, fracture, or ulcer (procedures such as catheter placement not considered to be major surgery). 4.Cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been therapeutically anti-coagulated for at least 6 weeks are eligible. 5.History of another malignancy in the last 5 years (other than treated squamous/basal cell skin cancer, treated early stage cervical cancer or treated / biochemically stable, organ confined prostate cancer). 6.Ongoing major gastrointestinal disease including unstable inflammatory bowel disease or bleeding peptic ulcer disease. 7.Known endobronchial lesions which have a high risk of pulmonary haemorrhage . 8.Previously identified brain, or central nervous system (CNS) metastases at baseline, with the exception of those subjects who have previously-treated CNS metastases (surgery ± radiotherapy, radiosurgery, or gamma knife) and who meet both of the following criteria: a) are asymptomatic and b) have no requirement for steroids or enzyme-inducing anticonvulsants in prior 28 days. 9.Pregnant or breastfeeding. Patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy. Male patients must be surgically sterile or agree to use effective contraception. 10.Administration of any investigational drug within 28 days or 5 half lives, whichever is longer, prior to receiving the first dose of study treatment 11.Treatment with any of the following anti-cancer therapies: Radiation therapy, surgery or tumour embolisation within 14 days prior to the first dose of study medication Chemotherapy, immunotherapy, biologic therapy, investigational therapy within 28 days or 5 half-lives of a drug (whichever is longer) prior to the first dose of study medication. 12.Peripheral neuropathy of grade 2 or more. 13.Any on-going toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity, except alopecia. 14.Other severe or uncontrolled systemic disease or evidence of any other significant clinical disorder or lab finding that makes it undesirable for the patient to participate in the study. 15.Any psychological, familial, sociological or geographical consideration potentially hampering compliance with the study protocol and follow up schedule; those considerations should be discussed with the patient before registration in the trial. 16.Known HIV or other chronic immunosuppressive disease. 17. QTc that is immeasurable or >480 msec on screening ECG. (Note: If a subject has a QTc interval >480 msec on screening ECG, the screening ECG may be repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs must be <480 msec in order for the subject to be eligible for the study.) Patients who are receiving a drug that has a risk of Torsades de Pointes are excluded if QTc is ≥ 460 msec. Note: the method for estimating QTc must be consistent between all time points for any individual patient. 18.History of symptomatic peripheral vascular disease within 6 months prior to trial entry. 19.Uncontrolled hypertension (blood pressure (BP) >150/90 at screening visit – if screening value is higher than this, then study entry will be permitted if there is evidence documented by a trained healthcare professional of controlled blood pressure during the 4 weeks prior to study entry). 20.Evidence of active bleeding or bleeding diathesis. 21.Recent haemoptysis (greater than or equal to ½ teaspoon of red blood within 8 weeks before first dose of study drug). 22.Patients who are unable or unwilling to withdraw potent CYP3A4 inhibitors, inhibitors of P-glycoprotein or BCRP (see Appendix VI). 23.Prior hypersensitivity to cremophor or known sensitivity to any component of pazopanib. 24.Prior treatment with paclitaxel or pazopanib |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint is overall survival. Data relating to any patient death that occurs throughout the study period will be captured via the Case Report Form (CRFs), both during the treatment period and active follow up. |
|
| E.5.2 | Secondary end point(s) |
| The secondary end points of the study are to measure the following for pazopanib in comparison to the current standard treatment, paclitaxel: -Toxicity -Clinical benefit at 12 weeks -Progression free survival time -Clinical benefit at 24 weeks -Quality of Life |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| -Toxicity will be assessed at all study visits while the patient is receiving treatment and until any ongoing toxicity is resolved. -Clinical benefit will be assessed after 12 and 24 weeks on treatment. Assessment will be by CT scans/MRI as appropriate and the tumour response (stable disease (SD), partial response (PR) or complete response (CR) will be reported in accordance with RECIST 1.1. -Progression free survival will be assessed on an ongoing basis, by radiology and/or any other means of idenitification, or the opinion of the investigator. -Quality of Life (QoL)will be assessed continuously throughout the trial. QoL questionnaires will be collected at baseline (Week 1), and at Weeks 9, 17, 25, 37, 49, 61, 73, 85 and 97. |
|
| 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 | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 30 |
| 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 | No |
| 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
|
| For the purpose of the Clinical Trial Authorisation the trial is deemed to have ended 30 days after the last patient remaining on treatment receives the last dose of pazopanib. For the purposes of the main REC approval, the study end date is deemed to be the date of the last data capture. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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