| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or unresectable renal cell carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 16.0 |
| 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) |
|
| 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) |
|
| 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.
|
|
| E.2.3 | Trial contains a sub-study | No |
| 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
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 (2 cycles). 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 (2cycles) but stopped the drug due to toxicity rather than disease progression are also eligible for this study.
Patients who have had prior treatment with either temsirolimus or everolimus are also eligible for the trial.
No other prior treatment with bevacizumab, sorafenib, immunotherapies, chemotherapy, biologic therapy or investigational therapy is allowed.
Previous radiotherapy (RT) is permissible provided the measurable disease is outside the RT port. RT must be completed > 2 weeks prior to registration.
7) Adequate organ system function as defined below
Absolute neutrophil count (ANC) 1.5 X 109/L
Hemoglobin 9 g/dL (5.6 mmol/L)
Platelets 100 X 109/L
Prothrombin time (PT) or international normalized ratio (INR) 1.2 X ULN
Activated partial thromboplastin time (aPTT) 1.2 X ULN
Total bilirubin 1.5 X ULN
ALT and AST 2.5 X ULN
Serum creatinine 1.5 mg/dL (133 μmol/L) Or, if >1.5 mg/dL: Calculated creatinine clearance 50 mL/min
Urine Protein to Creatinine Ratio <1
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 or urine 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 |
|
| E.4 | Principal exclusion criteria |
1) Prior malignancy.
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
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 or 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, MI, Unstable angina, Coronary artery bypass graft surgery, Symptomatic peripheral vascular disease, NYHA Class III or IV congestive heart failure
8) Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥150 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg].
9) History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
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 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
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
17) Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity, except alopecia. Note: Except where the toxicity is defined according to CTCAE v4.0 criteria as >Grade 1 due to the fact that the patient is taking medication for the toxicity (and the toxicity is being controlled by this medication)
18) Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib. |
|
| 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. Progression-free survival (PFS), 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. Objective response rate
3. Overall Survival (OS)
4. Safety and tolerability
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Disease Progression or Treatment Discontinuaton
Disease Progression or Treatment Discontinuaton
Patients are followed for 5 years for survival or until notification of death
Treatment discontinuation |
|
| 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) | 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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
|
Patients may be withdrawn from the study prematurely if:
-it is in the best interest of their health
-Due to AE(S)
-patient does not follow their responsibilities for taking part in the study,
-it is discovered at a later time that the patient does not meet the study participation requirements
-patient needs treatment not allowed in the study
-becoming pregnant
-DP
-subject withdrew consent
-lost to follow-up
-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 | 4 |
| 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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