To Assess the Interaction Between Sunitinib and Ketoconazole to Reduce the Dose and Cost of Sunitinib

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
ClinicalTrials.gov Identifier:
NCT01548170
First received: December 23, 2011
Last updated: March 5, 2012
Last verified: March 2012
  Purpose

Sunitinib is an ATP competitive tyrosine kinase inhibitor of several membrane receptors including VEGFR-1, -2, and -3, PDGFR-α and -β, c-KIT, CSF-1R, FLT-3, and RET. Through this molecular mode of action, sunitinib is able to avoid tumoral angiogenesis and proliferation. Sunitinib is already approved by the FDA, EMEA and AEMPS for the treatment of patients with metastatic renal cell carcinomas and those with metastatic gastrointestinal stromal tumors (GIST) with progression or intolerance to imatinib.

Suntinib has recently reported to be superior than placebo in terms of response rate (9.3% vs. 0%; p<0.05), progression free survival (11.4 vs. 5,5 months; HR 0.41;p<0.05), and overall survival (HR 0.40;p<0.05) when administered in a phase 3 trial to patients with advanced pancreatic neuroendocrine tumors (NETs).

Sunitinib is an expensive drug that drains the budget of health public system therefore it demands a rational drug use.

Sunitinib is metabolized by CYP3A4, that belongs to the P450 cytochrome system in the liver. Most of the drug is eliminated in faeces and only 16% by urine. Sunitinib has no food-effect when taken with meals. Pharmacokinetics parameters did not differ between cancer patients and healthy volunteers.

Houk et al. Showed that the area under the curve of plasmatic concentration of sunitinib and its active metabolite did correlate with clinical outcome. In other words, the higher plasma concentration area under the curve the highest rates of radiological response, progression free and overall survival rates.

Ketoconazol is an antifungal drug that inhibits the CY3A4 inducing an elevation of peak plasma levels of other drugs administered simultaneously and that are metabolized by the same system. In the labeling sheet of sunitinib it is said that ketoconazol induced a 49% and 51% of increase of plasmatic sunitinib Cmax y AUC0-∞ when both drugs were administered together. This fact makes that the investigatorspropose that by administering both drugs simultaneously the investigators could reduce sunitinib dose by a lower metabolization with similar plasma concentration. The dose reduction would impact in drug cost.

Here the investigators propose to determine the most optimal combination dose of sunitinib (25 mg or 37.5 mg) and ketoconazol (200mg o 400mg) by which the investigators could have plasmatic bioequivalent concentrations compared with single dose of sunitinib 50mg.

Each volunteer will be assigned to a treatment arm (Arm A and Arm B). Volunteers included in Arm A will take: sunitinib 50 mg, sunitinib 37.5 mg + ketoconazole 200 mg and sunitinib 37.5 mg + 400 mg ketoconazole. Volunteers included in Arm B will take: sunitinib 50 mg, sunitinib 25 mg + ketoconazole 200 mg and sunitinib 25 mg + 400 mg ketoconazole


Condition Intervention Phase
Cancer
Drug: Sunitinib
Drug: Sunitinib and Ketoconazol
Drug: Sunitiinb and Ketoconazol
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I, Pilot, Dose Finding Clinical Trial to Assess the Interaction Between Sunitinib and Ketoconazole to Reduce the Dose and Cost of Sunitinib for National Health System

Resource links provided by NLM:


Further study details as provided by Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal:

Primary Outcome Measures:
  • Sunitinib pharmacokinetic parameters (Maximum plasma concentration (Cmax) and Area under the plasma concentration curve (AUC0-72) obtained in the different treatment groups. [ Time Frame: Up to 72 hours postdose for each period ] [ Designated as safety issue: No ]
    On the fourth day of each period patient will be hospitalized in the clinical trial unit in order to obtain plasma concentrations previous to the administration of the corresponding dose and at the following times port-administration: 2h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 14h, 16h, 24h, 36h, 48h amd 72h. These measures will be calculated in order to describe the pharmacokinetic profile of each treatment arm.


Secondary Outcome Measures:
  • Other Sunitinib pharmacokinetic parameters (first time to reach Cmax (tmax) and Area under the plasma concentration curve (AUC0-Inf) obtained in the different treatment groups. [ Time Frame: Up to 72 hours postdose for each period ] [ Designated as safety issue: No ]
    On the fourth day of each period patient will be hospitalized in the clinical trial unit in order to obtain plasma concentrations previous to the administration of the corresponding dose and at the following times port-administration: 2h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 14h, 16h, 24h, 36h, 48h amd 72h. These measures will be calculated in order to describe the pharmacokinetic profile of each treatment arm.

  • Coefficient of variation of AUC and Cmax [ Time Frame: 9 months ] [ Designated as safety issue: No ]
    To estimate the actual coefficient of variation of AUC and Cmax of sunitinib in our environment when given alone and in combination with ketoconazole.

  • Change in QT interval [ Time Frame: On day 4 of each period ] [ Designated as safety issue: No ]
    An ECG to measure the QT interval will be performed coinciding with blood samples taken basal and at 6h, 8h, 10h, 12h and 72 h after drug administration in each period.

  • Adverse events reported [ Time Frame: 9 months ] [ Designated as safety issue: No ]

Enrollment: 12
Study Start Date: April 2011
Study Completion Date: July 2011
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Sunitinib 50mg
Sunitinib 50 mg administered as a single dose.
Drug: Sunitinib
One capsule of sunitinib 50 mg orally. Single dose
Experimental: Sunitinib 37.5mg + Ketoconazol 200mg

The drugs will be administered as follows:

  • Sunitinib 37.5mg oral single dose.
  • Ketoconazole 200 mg orally, once daily for 6 days. (Combination with sunitinib will be performed on day 4)
Drug: Sunitiinb and Ketoconazol
Sunitinib capsule 37.5mg. Single dose Ketoconazol 1 tablet of 200mg administered daily during 6 days.
Experimental: Sunitinib 37.5 mg + Ketoconazol 400 mg

The drugs will be administered as follows:

  • Sunitinib 37.5mg oral single dose.
  • Ketoconazole 400 mg orally, once daily for 6 days. (Combination with sunitinib will be performed on day 4)
Drug: Sunitinib and Ketoconazol
Sunitinib capsule 37.5mg. Single dose Ketoconazol 2 tablets of 200mg administered daily during 6 days.
Experimental: Sunitinib 25mg + Ketoconazol 200mg

The drugs will be administered as follows:

  • Sunitinib 25mg oral single dose.
  • Ketoconazole 200 mg orally, once daily for 6 days. (Combination with sunitinib will be performed on day 4)
Drug: Sunitinib and Ketoconazol
Sunitinib capsule 25mg. Single dose Ketoconazol 1 tablet of 200mg administered daily during 6 days.
Experimental: Sunitinib 25mg + Ketoconazol 400mg

The drugs will be administered as follows:

  • Sunitinib 25mg oral single dose.
  • Ketoconazole 400 mg orally, once daily for 6 days. (Combination with sunitinib will be performed on day 4)
Drug: Sunitinib and Ketoconazol
Sunitinib capsule 25mg. Single dose Ketoconazol 2 tablets of 200mg administered daily during 6 days.

Detailed Description:

This is a phase I, pilot, open, randomized, parallel, and cross-over trial to assess the interaction between three different dose levels of sunitinib (50 mg, 37.5 mg, and 25 mg) and two dose levels of ketoconazole (200 mg and 400 mg) in 12 healthy volunteers (6 voluunteers in each group of treatment) Each volunteer will be assigned to a treatment arm (Arm A and Arm B. Volunteers included in Arm A will take: sunitinib 50 mg, sunitinib 37.5 mg + ketoconazole 200 mg and sunitinib 37.5 mg + 400 mg ketoconazole. Volunteers included in Arm B will take: sunitinib 50 mg, sunitinib 25 mg + ketoconazole 200 mg and sunitinib 25 mg + 400 mg ketoconazole

  Eligibility

Ages Eligible for Study:   18 Years to 35 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy individuals men who give their written consent to participate in the study, after having received information about the design, the project objectives, the risks and that at any moment they can refuse their cooperation.
  • Age between 18 and 35 years.
  • Subjects with a BMI that is between 19 and 28.
  • Healthy subjects, without any organic or psychological pathology.
  • Clinical history and physical examination within normal limits.
  • Lack of clinically relevant abnormalities in blood test (hematology, biochemistry, virology) and urine test
  • Vital signs and electrocardiographic recording in the normal range.

Exclusion Criteria:

  • Subjects suffering from organic or psychological pathology. Prior to the inclusion of any volunteer it should be considered all security parameters mentioned in the protocol (biochemical markers of kidney damage and / or liver out of the normal range set by the laboratory).
  • Subjects who have received prescription drug treatment in the last 15 days or any medication within 48 hours before receiving study medication.
  • Known hypersensitivity to any drug
  • Suspected of drug abuse
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01548170

Locations
Spain
Hospital Universitario Ramón y Cajal
Madrid, Spain, 28034
Sponsors and Collaborators
Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
Investigators
Principal Investigator: Enrique Grande Pulido Hospital Universitario Ramón y Cajal
  More Information

No publications provided

Responsible Party: Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
ClinicalTrials.gov Identifier: NCT01548170     History of Changes
Other Study ID Numbers: KS-ONCOFARMA-01, 2010-023739-41
Study First Received: December 23, 2011
Last Updated: March 5, 2012
Health Authority: Spain: Spanish Agency of Medicines

Keywords provided by Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal:
Pharmacokinetic
Sunitinib
Ketoconazol
interaction, Phase I

Additional relevant MeSH terms:
Ketoconazole
Sunitinib
14-alpha Demethylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors

ClinicalTrials.gov processed this record on April 15, 2014