Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Digestive System Diseases

Skin and Connective Tissue Diseases

Rare Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma, Renal Cell

Gastrointestinal Stromal Tumors

Carcinoma

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Kidney Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Renal Cell Carcinoma

Central Nervous System Stimulants

All Drugs and Chemicals

Pharmaceutical Solutions

Adjuvants, Anesthesia

Central Nervous System Depressants

Psychotropic Drugs

Antineoplastic Agents

Other Dietary Supplements

Amino Acids

Caffeine

Midazolam

Sunitinib

Erlotinib Hydrochloride

Anesthetics

Hypnotics and Sedatives

Anti-Anxiety Agents

Anesthetics, Intravenous

Anesthetics, General

GABA Modulators

Neurotransmitter Agents

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Angiogenesis Inhibitors

Growth Inhibitors

Phosphodiesterase Inhibitors

Tyrosine

Patients with renal-cell cancer or GIST are receiving conventional treatment with sunitinib (50mg/day for 4 out of 6 weeks)

Patients with non small-cell lung cancer receive conventional treatment with erlotinib 150mg/day.

Erlotinib

For phenotyping of CYP3A4, all patients receive one-time midazolam 2mg as a drinking solution at the start of study treatment.

For phenotyping of CYP1A2, patients with non small-cell lung cancer receive additionally one-time caffeine 100mg as a tablet.

Markus Joerger, MD PhD

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.

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.

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

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)

Dried blood spots are a potential alternative to venous blood samples to assess drug exposure in cancer patients.

University of Basel

Markus Joerger

MD-PhD-ClinPharm

Gland and Hormone Related Diseases

Thyroid Neoplasms

Thyroid Diseases

Hyperthyroidism

Hypothyroidism

Endocrine System Diseases

Endocrine Gland Neoplasms

Head and Neck Neoplasms

Anti-Infective Agents

Hormones

polysaccharide-K

Skin Biopsy

This study will examine whether and how levothyroxine (Synthroid, a synthetic thyroid hormone) affects the way the body handles other drugs. If levothyroxine does affect the metabolism of other drugs, the dose of those medications may need to be increased to enhance their action or decreased to avoid adverse reactions.

Patients 18 years of age and older with thyroid cancer who are participating in NIH protocol #77-DK-0096 and are receiving long-term suppression therapy with levothyroxine may be eligible for this study. This is not a study of thyroid cancer or of potential new drugs to treat it. Thyroid cancer patients are being studied because their treatment regimen provides an opportunity to study drug metabolism while patients are both on and off levothyroxine therapy.

Participants come to the NIH Clinical Center on two occasions: once while they are regularly taking their levothyroxine, and once while they are off the medication in preparation for their radioactive iodide diagnostic scan for the procedures outlined below. The time interval between the two clinic visits depends on whether the first visit is while the patient is on or off medication. Participants are asked to fast overnight before each visit and to abstain from certain foods and beverages for 48 to 72 hours before the visit. At each visit, patients undergo the following procedures:

* Medication history, limited physical examination, and blood draw for laboratory tests, including a test to look for genes important in eliminating medications from the body.
* Insertion of a catheter (thin plastic tube) into an arm vein for collecting blood samples.
* Shave skin biopsy (optional) to explore how proteins in the skin that metabolize and transport drugs are affected by thyroid hormone. For this procedure, the skin is cleaned, numbed with medicine, and a small sample of the top layer is removed with a razor blade. The wound heals in 2 to 3 days.
* Medication dosing. Participants take all of the following substances by mouth at the same time: 1) 200 mg of caffeine, a compound commonly found in chocolate, soda/pop, coffee, tea and non-prescription products to prevent sleep; 2) 30 mg of dextromethorphan, a non-prescription cough suppressant; 3) 40 mg of omeprazole, a prescription drug for heartburn and stomach ulcers; 4) 8 mg of midazolam, a prescription drug used to cause relaxation and drowsiness; and 5) 120 mg of fexofenadine, a non-sedating prescription antihistamine used to treat allergies.
* Blood and urine sampling. Fifteen blood samples of about 5 mL (1 teaspoon) each are collected through the catheter and urine is collected over the next 24 hours to determine what happens to the test drugs in the body.

Participants may resume their normal diet 4 hours after taking the study medications.

Interaction between thyroid hormones and commonly prescribed drugs has been well documented, resulting in augmentation or attenuation of the action of either compound. Phase I drug metabolism is mediated mostly by enzymes belonging to the cytochrome p450 superfamily. Studies in animals and cell cultures have shown that thyroid hormones play an important role in the constitutive expression of the p450 enzymes, thus potentially altering the metabolism and the effects of a variety of drugs. P-glycoprotein is expressed in the major organs associated with drug absorption, distribution, and elimination from the body (e.g. intestine, kidney, liver, skin, and the blood-brain barrier). Expression of intestinal P-glycoprotein in humans also appears to be influenced by thyroid hormones. We intend to study the effect of thyroid hormones on the activity of CYP1A2, CYP2C19, CYP2D6, CYP3A4 and P-glycoprotein by using a five-drug cocktail (caffeine, omeprazole, dextromethorphan, midazolam, and fexofenadine) administered in patients with thyroid cancer, both on thyroid hormone suppression therapy (in conditions of subclinical hyperthyroidism) and off this treatment (in conditions of hypothyroidism) at the time of their routine radioactive iodine scan. Additionally we will perform two skin biopsies in order to assess the pattern of expression of metabolic enzymes and drug transport proteins on and off thyroid hormone suppression therapy.

The Effect of Thyroid Hormone on Drug Elimination in Cancer Patients

The Effects of Thyroid Hormone on Cytochrome P450 and P-Glycoprotein Activity in Thyroid Cancer Patients

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cytochrom p450 3A4 and 1A2 Phenotyping for the Individualization of Treatment With Sunitinib or Erlotinib in Cancer Patients	NCT01402089	Non Small-cell ... Renal-cell Canc... Gastrointestina...	Sunitinib Erlotinib Midazolam Caffeine	18 Years -	Cantonal Hospital of St. Gallen
The Effect of Thyroid Hormone on Drug Elimination in Cancer Patients	NCT00080574	Thyroid Cancer	Skin Biopsy	-	National Institutes of Health Clinical Center (CC)
Cytochrom p450 3A4 and 1A2 Phenotyping for the Individualization of Treatment With Sunitinib or Erlotinib in Cancer Patients	NCT01402089	Non Small-cell ... Renal-cell Canc... Gastrointestina...	Sunitinib Erlotinib Midazolam Caffeine	18 Years -	Cantonal Hospital of St. Gallen

Spots Global Cancer Trial Database for cytochrome p450