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Cytochrom p450 3A4 and 1A2 Phenotyping for the Individualization of Treatment With Sunitinib or Erlotinib in Cancer Patients

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Cantonal Hospital of St. Gallen
Sponsor:
Collaborator:
University of Basel
Information provided by (Responsible Party):
Markus Joerger, Cantonal Hospital of St. Gallen
ClinicalTrials.gov Identifier:
NCT01402089
First received: July 20, 2011
Last updated: August 31, 2014
Last verified: August 2014
  Purpose

It is well known that substantial interindividual variability of CYP3A4/1A2-phenotype activity is an important contributor to individual differences in the sensitivity to the frequently used tyrosine kinase inhibitors sunitinib and erlotinib. This study tests the potential for CYP-phenotyping to predict individual pharmacology and derive dosing algorithms for more tailored treatment of these drugs.


Condition Intervention Phase
Non Small-cell Lung Cancer
Renal-cell Cancer
Gastrointestinal Stroma Tumor
Drug: Sunitinib
Drug: Erlotinib
Drug: Midazolam
Drug: Caffeine
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Cytochrom p450 3A4 and 1A2 Phenotyping for the Individualization of Treatment With Sunitinib or Erlotinib in Cancer Patients

Resource links provided by NLM:


Further study details as provided by Cantonal Hospital of St. Gallen:

Primary Outcome Measures:
  • Steady-state partial area-under the plasma concentration-time curve over 24 hours (AUC24h) of sunitinib and erlotinib and CYP3A4/1A2-phenotype activity as defined in the protocol [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
    Sunitinib or erlotinib area under the concentration-time curve during 24 hours at steady-state conditions, compared with the CYP3A4 or CYP1A2 phenotype activity as assessed by the two probe drugs midazolam (CYP3A4) and/or caffeine (CYP1A2)


Secondary Outcome Measures:
  • Sunitinib and Erlotinib-associated toxicity according to the CTC criteria (v.3.0) [ Time Frame: 12 weeks (end of study) ] [ Designated as safety issue: Yes ]
  • Concentrations of Sunitinib, Erlotinib and probe drugs (Midazolam, Caffeine) in whole blood, sampled from patient's dried blood spots (DBS) [ Time Frame: 12 weeks (end of study) ] [ Designated as safety issue: No ]
    Dried blood spots are a potential alternative to venous blood samples to assess drug exposure in cancer patients.


Estimated Enrollment: 60
Study Start Date: January 2012
Estimated Study Completion Date: May 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Sunitinib
    Patients with renal-cell cancer or GIST are receiving conventional treatment with sunitinib (50mg/day for 4 out of 6 weeks)
    Other Name: Sutent
    Drug: Erlotinib
    Patients with non small-cell lung cancer receive conventional treatment with erlotinib 150mg/day.
    Other Name: Tarceva
    Drug: Midazolam
    For phenotyping of CYP3A4, all patients receive one-time midazolam 2mg as a drinking solution at the start of study treatment.
    Other Name: Midazolam drinking solution
    Drug: Caffeine
    For phenotyping of CYP1A2, patients with non small-cell lung cancer receive additionally one-time caffeine 100mg as a tablet.
    Other Name: Coffeinum N 0.2g
  Hide Detailed Description

Detailed Description:

Objectives:

The primary objective of this study is to show that the individual CYP3A4 and CYP1A2-phenotype as assessed by probe drugs predicts drug exposure to sunitinib and erlotinib. Secondary objectives of the study are to define the correlation between the individual CYP-phenotype and treatment-related toxicity, testing the feasibility of drug bioanalysis from patient's dry blood spots (DBS), build an integrated covariate model on sunitinib and erlotinib pharmacokinetics and define a dosing algorithm for both sunitinib and erlotinib based on the individual CYP-phenotype.

Study endpoints:

Primary endpoint:

• To show that individual drug clearance of sunitinib or erlotinib is significantly higher in patients with a high-activity CYP3A4/1A2-phenotype.

Secondary endpoints:

  • To specify the correlation between the CYP-phenotype and treatment-related toxicity.
  • To assess the feasibility of drug bioanalysis from patient's dry blood spots (DBS).
  • To build an integrated covariate model of sunitinib and erlotinib pharmacokinetics to define the quantitative relationship between the CYP-phenotype activity and drug exposure.
  • To define a dosing algorithm for both sunitinib and erlotinib based on the individual CYP-phenotype using data simulations on the previously defined population covariate model.

Trial Design:

Prospective, nonrandomized, pharmacological cohort study.

Main selection criteria

  • Histologically or cytologically confirmed renal-cell cancer (sunitinib), gastrointestinal stromal tumor (sunitinib) or non small-cell lung cancer (erlotinib)
  • Both early or advanced tumor stage
  • Indication for the therapeutic use of either sunitinib or erlotinib
  • Written informed consent and willing to undergo PK-sampling
  • Adequate organ function
  • No concurrent radiotherapy or systemic anticancer treatment with another drug

Trial Duration The present study is projected to start in June 2011, with the inclusion of a total of 60 patients (at least 25 patients for each sunitinib and erlotinib). The study is expected to finalize patient accrual in December 2013.

Statistical considerations The trial is designed to show a linear inverse relationship between the individual CYP-phenotype and total drug steady-state AUC (sunitinib plus SU12662 and erlotinib plus OSI-420, respectively), whereat CYP1A2 only accounts for the metabolism of erlotinib. With the inclusion of 60 patients, the study has a power of 90% to detect a relevant relationship between the CYP-phenotype activity and sunitinib/erlotinib steady-state AUC, with a regression coefficient of >0.4 for the H1-hypothesis (and accepting a regression coefficient of >0.1 for the H0-hypothesis) at the 5% significance level.

Trial Treatment Sunitinib: 50 mg p.o. daily for 4 out of 6 weeks, or 37.5 mg daily continuous until disease progression, unacceptable toxicity or withdrawal of informed consent.

Erlotinib: 150 mg p.o. daily until disease progression, unacceptable toxicity or withdrawal of informed consent.

Potential study outcome This study makes a significant contribution to global efforts for more individualized anticancer treatment. If successful, we will be able to make dosing recommendations for sunitinib and erlotinib based on a simple probe drug assay.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed renal-cell cancer or gastrointestinal stromal tumor (for sunitinib) or non small-cell lung cancer (for erlotinib)
  • Both early or advanced tumor stage
  • Indication for the therapeutic use of either sunitinib or erlotinib
  • Written informed consent and willing to undergo PK-sampling
  • Patients > 18 years of age
  • ECOG performance status or ≤2
  • Adequate laboratory parameters:

    i. Serum creatinine and serum bilirubin ≤ 1.5 X ULN ii. Serum ALT and AST ≤ 2.5 X ULN (or ≤ 5 in case of liver metastases) iii. Serum calcium ≤ 11,6 mg/dl (2.9 mmol/L)

Exclusion Criteria:

  • Previous treatment with sunitinib or erlotinib
  • Known hypersensitivity to trial drug or any compounds of the drug
  • Concurrent radiotherapy
  • Concurrent systemic anticancer treatment with the exception of bisphosphonates and bevacizumab in patients with non small-cell lung cancer
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01402089

Contacts
Contact: Gabriela Kramer, MsC 714941111 ext +41 gabriela.kramer@kssg.ch

Locations
Switzerland
Cantonal Hospital St.Gallen Recruiting
St.Gallen, Switzerland, 9007
Contact: Markus Joerger, MD-PhD-ClinPharm    +41-76-559-10-70 ext 0041    markus.joerger@kssg.ch   
Principal Investigator: Markus Joerger, MD-PhD ClinPharm         
Sponsors and Collaborators
Markus Joerger
University of Basel
Investigators
Study Chair: Markus Joerger, MD PhD Cantonal Hospital St.Gallen (Switzerland)
  More Information

Additional Information:
No publications provided

Responsible Party: Markus Joerger, MD-PhD-ClinPharm, Cantonal Hospital of St. Gallen
ClinicalTrials.gov Identifier: NCT01402089     History of Changes
Other Study ID Numbers: SG 327/10
Study First Received: July 20, 2011
Last Updated: August 31, 2014
Health Authority: Switzerland: Swissmedic

Keywords provided by Cantonal Hospital of St. Gallen:
phenotyping
cytochrome p450
erlotinib
sunitinib
lung cancer
renal-cell cancer
gastrointestinal stromal tumor

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Carcinoma, Renal Cell
Lung Neoplasms
Adenocarcinoma
Bronchial Neoplasms
Carcinoma
Carcinoma, Bronchogenic
Kidney Diseases
Kidney Neoplasms
Lung Diseases
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Urogenital Neoplasms
Urologic Diseases
Urologic Neoplasms
Erlotinib
Midazolam
Sunitinib
Adjuvants, Anesthesia
Anesthetics
Anesthetics, General
Anesthetics, Intravenous
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Anti-Anxiety Agents

ClinicalTrials.gov processed this record on November 24, 2014