E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
patients with unresectable hepatocellular cancer, advanced clear-cell renal cell carcinoma, locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment. |
Patienten met niet resectabel HCC, gevorderd RCC, lokaal gerecidiveerd, gemetastaseerd, progressief of gedifferentieerd schildkliercarcinoom refractair na behandeling met radioactief jodium. |
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E.1.1.1 | Medical condition in easily understood language |
Liver cancer, Renal cancer or a certain type of thyroid cancer |
leverkanker, nierkanker of een bepaald type schildklierkanker |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
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 demonstrate the bioequivalence of sorafenib with probenecid relative to sorafenib without probenecid based on the AUC in patients with unresectable hepatocellular cancer, advanced clear-cell renal cell carcinoma, locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment. |
Bioequivalentie aantonen van sorafenib met probenecid tov sorafenib zonder probenecid gebaseerd op de AUC. |
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E.2.2 | Secondary objectives of the trial |
1. Other pharmacokinetic outcomes (i.e. clearance, maximum concentration (Cmax), Minimal concentration (Cmin), steady-state volume of distribution (Vss) and half-life (t½)). 2. To evaluate the incidence and severity of side-effects of treatment with sorafenib in absence and presence of probenecid (in particular HFSR) . 3. To evaluate the intracellular concentration of sorafenib in skin in patients treated with sorafenib in absence and presence of probenecid.
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1. Andere farmacokinetische uitkomsten (klaring, maximale concentratie (Cmax), minimale concentratie (Cmin), steady-state volume van verdeling (Vss) en halfwaardetijd (t1/2) 2. incidentie en ernst van bijwerkingen van de behandeling met sorafenib in aan- en afwezigheid van probenecid onderzoeken (mn hand-voetsyndroom) 3. Intracellulaire concentratie van sorafenib in de huid van patienten bepalen, die met sorafenib in aan- of afwezigheid van probenecid worden behandeld. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥ 18 years 2. Histological or cytological confirmed diagnosis of mRCC, HCC or differentiated thyroid carcinoma 3. Start of sorafenib therapy, at least 7 days prior to start of the study NB. Patients are allowed to have had previous sorafenib therapy or have started with sorafenib. 4. WHO Performance Status ≤ 2 (appendix D) 5. Able and willing to sign the Informed Consent Form prior to screening evaluations 6. Adequate organ function as defined by: a. Total bilirubin ≤ 1.5 x ULN (except in case of documented Gilbert’s disease) b. ASAT ≤ 3.0 x ULN (or ≤ 5 x ULN if liver metastases are present) c. ALAT ≤ 3.0 x ULN (or ≤ 5 x ULN if liver metastases are present) d. Serum creatinin ≤ 1.5 x ULN 7. Adequate baseline patient characteristics (complete blood count, and serum biochemistry which involves sodium, potassium, creatinin, calculation of creatinin clearance (MDRD), amylase, lipase, calcium, phosphate, AST, ALT, gamma glutamyltranspeptidase (-GT), lactate dehydrogenase (LDH), ALP, total bilirubin, albumin).
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1. Leeftijd >18 jaar 2. Histologisch of cytologisch bevestigde diagnose van gemetastaseerd RCC, gedifferentieerd schildkliercarcinoom of HCC 3. start van sorafenib therapie, tenminste 7 dagen voorafgaand aan de start van de studie NB. patienten mogen vooraf sorafenib hebben gehad of zijn gestart met sorafenib. 4. WHO performance status <2 5. Patient moet het toestemmingsformulier willen tekenen 6. adequate orgaanfunctie gedefinieerd door a. totaal billirubine ≤ 1.5 x ULN (behalve als iemand bekend is met de ziekte van Gilbert) b. ASAT ≤ 3.0 x ULN (of ≤ 5 x ULN of als er sprake is van levermetastasen) c. ALAT ≤ 3.0 x ULN (of ≤ 5 x ULN of als er sprake is van levermetastasen) d. serum kreatinine ≤ 1.5 x ULN 7. adequate baseline patientkarakteristieken (volledige bloedbeeld en plasma biochemie waaronder Natrium, Kalium, kreatinine, GFR, Amylase, lipase, calcium, fosfaat, ASAT, ALAT, GGT, LDH, AF, Totaal billirubine, albumine |
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E.4 | Principal exclusion criteria |
1. Use of drugs which may show an increased systemic exposure when taken concomitantly with probenecid. (see appendix C) 2. Patients with known blood dyscrasias, uric acid kidney stones or until an acute gouty attack has subsided. 3. Use of (over the counter) medication or (herbal) supplements which can interact with either sorafenib or probenecid, e.g. by induction or inhibition of CYP3A4, UGT1A9 (see appendix B and C) 4. Unable or unwilling to abstain from grapefruit, grapefruit juice, herbal dietary supplements, and herbal tea during the study 5. Previous use of probenecid during the last 2 weeks prior to sorafenib treatment 6. Contraindications for use of probenecid such as acute gouty attack or porphyria. 7. Unwilling to undergo a skin biopsy
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1. gebruik van medicatie die kan zorgen voor een toegenomen systemische blootstelling wanneer ze samen ingenomen worden met probenecid 2. patienten met hematologische problematiek, nierstenen obv urinezuur of patienten met een jichtaanval 3. gebruik van (OTC) medicatie of (kruiden) supplementen die een interactie hebben met sorafenib of probenecid obv inductie of inhibitie van CYP3A4 of UGT1A9 4. niet in staat of niet willend te stoppen met grapefruit, grapefruit sap, kruiden preparaten of kruidenthee tijdens de studie 5. probenecid gebruikt in de 2 weken voorafgaand aan de studie 6. contraindicaties voor het gebruik van probenecid zoals een acute jichtaanval of porfyrie 7. Niet willen ondergaan van een huidbiopt
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E.5 End points |
E.5.1 | Primary end point(s) |
To demonstrate the bioequivalence of sorafenib with probenecid relative to sorafenib without probenecid based on the AUC in patients with unresectable hepatocellular cancer, advanced clear-cell renal cell carcinoma, locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment. |
Bioequivalentie aantonen van sorafenib met probenecid tov sorafenib zonder probenecid gebaseerd op de AUC. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
End of study |
Einde van de studie |
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E.5.2 | Secondary end point(s) |
1. Other pharmacokinetic outcomes (i.e. clearance, maximum concentration (Cmax), Minimal concentration (Cmin), steady-state volume of distribution (Vss) and half-life (t½)). 2. To evaluate the incidence and severity of side-effects of treatment with sorafenib in absence and presence of probenecid (in particular HFSR) . 3. To evaluate the intracellular concentration of sorafenib in skin in patients treated with sorafenib in absence and presence of probenecid.
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1. Andere farmacokinetische uitkomsten (klaring, maximale concentratie (Cmax), minimale concentratie (Cmin), steady-state volume van verdeling (Vss) en halfwaardetijd (t1/2) 2. incidentie en ernst van bijwerkingen van de behandeling met sorafenib in aan- en afwezigheid van probenecid onderzoeken (mn hand-voetsyndroom) 3. Intracellulaire concentratie van sorafenib in de huid van patienten bepalen, die met sorafenib in aan- of afwezigheid van probenecid worden behandeld. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of study |
Einde van de studie |
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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 | No |
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 | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | Yes |
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 |
The comparator is probenecid |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 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
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LVLS |
Laatste visite van de laatste patient |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |