| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or metastatic clear cell renal cancer. |
|
| 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 | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038416 |
| E.1.2 | Term | Renal clear cell carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009251 |
| E.1.2 | Term | Clear cell carcinoma of the kidney |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10023400 |
| E.1.2 | Term | Kidney cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 is to assess the progression-free survival of patients who receive bi-monthly rotations of Pazopanib and Everolimus versus patients who receive Pazopanib as a first line treatment. |
|
| E.2.2 | Secondary objectives of the trial |
| Time to second progression or death: defined as time to progressive disease per RECIST 1.1 on Everolimus monotherapy (when PD after 8 weeks Pazopanib) or on Pazopanib monotherapy (when PD after 8 weeks Everolimus) as second line treatment in arm A and time to progressive disease on Everolimus in arm B. Comparing time to 2nd PD with time to 2nd PD. Quality of life and toxicity. Quality of life assessments and Common Toxicity Criteria will be used. Overall survival Pharmacodynamic measurements and pharmacokinetic assessments at the switch of Pazopanib and Everolimus and vice versa. Genetic analysis of tumorbiopsies (optional). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- 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.
- Age ≥ 18 years.
- Histologically confirmed diagnosis of progressive metastatic clear cell renal cell cancer defined as >10% of the tumor cells having the clear cell phenotype.
- Locally advanced (defined as disease not amenable to curative surgery or
radiation therapy) or metastatic RCC (equivalent to Stage IV RCC according to
AJCC staging
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
- Measurable disease.
- No prior systemic anti-cancer treatment against clear cell renal cell cancer.
- Adequate organ system function.
- Non-childbearing potential.
|
|
| E.4 | Principal exclusion criteria |
- Prior malignancy.
- History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis.
- Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:
1)Active peptic ulcer disease.
2)Known intraluminal metastatic lesions with risk of bleeding.
3) Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease), or other gastrointestinal conditions with increased risk of perforation.
4)History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment.
-Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:
1)Malabsorption syndrome.
2)Major resection of the stomach or small bowel.
-Presence of uncontrolled infection.
-Known past or present infection with Hepatitis B virus (HBV), Hepatitis C virus (HCV) or Human Immunodeficiency Virus (HIV).
-Corrected QT interval (QTc) > 480 msecs using Bazett’s formula.
-History of one or more of the following cardiovascular conditions within the past 6 months:
1)Cardiac angioplasty or stenting
2)Myocardial infarction
3)Stable or unstable angina pectoris.
4)Coronary artery bypass graft surgery.
5)Symptomatic peripheral vascular disease
6)Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA).
- Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥160 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg].
- History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
- 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).
- Evidence of active bleeding or bleeding diathesis.
- Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
- Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of study drug.
- 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.
- Unable or unwilling to discontinue use of prohibited medications or modify the dosing of interacting drugs as listed in Section 6.8.1. and 6.8.2 of the protocol 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.
- Pregnant or lactating female.
- 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 OR
Chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| one year after randomization of the last subject |
|
| E.5.2 | Secondary end point(s) |
Time to second progression
Quality of life
Toxicity
Overall survival
Pharmacodynamic and pharmacokinetic assessments
(optional) tumor biopsies for genetic profiling |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time to second progression, Quality of life, Toxicity, Overall survival: one year after randomization of the last subject
Biomarkers: aim is within one year after randomization of last subject |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 17 |
| 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
|
The trial ends 1 years after randomization of the last subject.
The last visit will be the end-of-treatment visit one month after the subject ceased treatment for any reason.
Justification for the last visit not being the end of trial consists of the following reasons: Survival information will enable correlation of biomarkers with overall survivall. To collect information on initiation of other anti-cancer therapies. To signal late adverse events.
|
|
| 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 | 0 |
| 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 | 0 |
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