| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or unresectable renal cell carcinoma |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067946 |
| E.1.2 | Term | Renal cell carcinoma |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this trial is to assess the progression free rate at 4 months (i.e. completion of 4 months of treatment, with no disease progression at 8 weeks, and no evidence to suggest disease progression before the 4 month time-point). |
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| E.2.2 | Secondary objectives of the trial |
• To determine the median Progression Free Survival of patients enrolled in the study. Progression Free Survival is defined as the length of time between the date of starting treatment and the earliest date of disease progression or death due to any cause.
• To determine the Overall Response Rate of patients enrolled in this study based on RECIST criteria version 1.1 [28]
• To determine the median Overall Survival of patients enrolled in the study
• To evaluate the Safety and Tolerability of pazopanib when given post sunitinib to patients with metastatic RCC.
The Exploratory objectives are
• To determine peak and trough levels of pazopanib in the blood at specific time points in the study and evaluate if this is correlated with response (Pharmokinetic studies).
• To identify protein markers that may correlate with or are predictive of clinical response/benefit to pazopanib
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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.
Procedures conducted as part of the subject’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.
2. Age ≥ 18 years
3. Diagnosis of metastatic/unresectable renal cell carcinoma of the clear cell type or with a component of clear cell histology
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
5. Measurable disease by RECIST criteria (Version 1.1) [28].
6. Eligible patients must have been treated with sunitinib for a minimum of 12 weeks. Patients must have evidence of progressive disease following treatment with sunitinib as assessed by the site investigator on the basis of CT scans and other appropriate clinical documentation.
Patients who received sunitinib for a minimum of 12 weeks (2 cycles) but stopped the drug due to toxicity rather than disease progression are also eligible for this study.
The Investigator should be aware of the patient’s intolerance/toxicity with prior sunitinib treatment and take this in to account when assessing eligibility for the pazopanib study.
Patients who have had prior treatment with either temsirolimus or everolimus are also eligible for the trial.
No prior treatment with bevacizumab or sorafenib or immunotherapies are allowed.
Previous radiotherapy (RT) is permissible provided the measurable disease is outside the RT port. RT must be completed > 2 weeks prior to randomisation.
7. Adequate organ system function as defined belowin the protocol.
8. 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:
• Oral contraceptive, either combined or progestogen alone
• Injectable progestogen
• Implants of levonorgestre
• Estrogenic vaginal ring
• Percutaneous contraceptive patches
• Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year
• Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject
• Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)
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.
9. Left Ventricular Ejection Fraction > Lower Limit of Institutional Normal as assessed by Echocardiograph or MUGA
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| E.4 | Principal exclusion criteria |
Exclusion Criteria
1. Prior malignancy.
Note: 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 (surgery radiotherapy, radiosurgery, or gamma knife) and meet all 3 of the following criteria are eligible: a) are asymptomatic, b) have had no evidence of active CNS metastases for 6 months prior to enrolment, and c) have no requirement for steroids or Enzyme -inducing anticonvulsants EIACs
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 GI bleeding including, but not limited to:
• Active peptic ulcer disease
• Known intraluminal metastatic lesion/s with suspected bleeding
• Inflammatory bowel disease (e.g. ulcerative colitis, Chrohn’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.
4. 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. Prolongation of corrected QT interval (QTc) > 480 msecs using Bazett’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) [http://www.abouthf.org/questions_stages.htm, accessed 8th December 2009]
o Class III (Moderate): marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea.
o Class IV (Severe): unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased.
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) SBP / DBP values from each BP assessment must be <140/90 mmHg in order for a subject to be eligible for the study. (see Appendix H for details on BP control and re-assessment prior to study enrollment)
9. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible
10. 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).
11. Evidence of active bleeding or bleeding diathesis.
12. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
13. Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of study drug.
14. 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.
15. Unable or unwilling to discontinue use of prohibited medications list in Section 6.2.4 for at least 14 days prior to the first dose of study drug and for the duration of the study.
16. Treatment with any of the following anti-cancer therapies:
• Minor surgical procedure or tumor embolization within 14 days prior to the first dose of pazoapnib
• Previous radiotherapy (RT) is permissible provided the measurable disease is outside the RT port. RT must be completed > 2 weeks prior to registration.
• sunitinib, everolimus or temsirolimus within 14 days prior to the first dose of pazopanib
Note: No other prior treatment with bevacizumab, sorafenib, immunotherapies, chemotherapy, biologic therapy or investigational therapy is allowed.
See Protocol for Exclusion 17 and 18
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free rate at 4 months (i.e. completion of 4 months of treatment, with no disease progression at 8 weeks, and no evidence to suggest disease progression before the 4 month time-point) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At 16 weeks of pazopanib treatment |
|
| E.5.2 | Secondary end point(s) |
1. To determine Progression Free Survival of patients enrolled in the study. Progression Free Survival is defined as the length of time between the date of starting treatment and the earliest date of disease progression or death due to any cause.
2. To determine the Overall Response Rate of patients enrolled in this study based on RECIST criteria version 1.1 [28]
3. To determine the median Overall Survival of patients enrolled in the study
4. To evaluate the Safety and Tolerability of pazopanib when given post sunitinib to patients with metastatic RCC
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Disease Progression or Treatment Discontinuation
2. Disease Progression or Treatment Discontinuation
3. Patients are followed for 5 years for survival until notoification of death
4. Treatment Discontinuation |
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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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| To identify protein markers that may correlate with or are predictive of clinical response/benefit |
|
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 10 |
| 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 | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 |
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| 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
|
Patients may be withdrawn from the study prematurely if:
•it is in the best interest of their health
•adverse event(s)
•becoming pregnant
•disease progression
•protocol violation
•subject withdrew consent
•the study is stopped by the sponsor or regulatory authority
•death
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| 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 | 5 |
| 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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