Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Digestive System Diseases

Rare Diseases

Melanoma

Gastrointestinal Stromal Tumors

Fibromatosis, Aggressive

Carcinoma, Adenoid Cystic

Chordoma

Dermatofibrosarcoma

Ocular Melanoma

Desmoid Tumor

Adenoid Cystic Carcinoma

Conjunctival Melanoma

Dermatofibrosarcoma Protuberans

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Amino Acids

Cyclophosphamide

Imatinib Mesylate

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

CYCLE 1 (42 days):

* Day 1 to 14 Imatinib mesylate : 400 mg/day, per os
* Day 15 to 42 Cyclophosphamide : 50 mg x 2/day, per os Imatinib mesylate : 400 mg/day, per os

NEXT CYCLE (28 days):

Cyclophosphamide : 50 mg x 2/day, per os Imatinib mesylate : 400 mg/day, per os

Imatinib mesylate, Cyclophosphamide (Dosing level 1 )

CYCLE 1 (42 days):

* Day 1 to 14 Imatinib mesylate : 600 mg/day,(300 mg in the morning and 300 mg in the evening) per os
* Day 15 to 42 Cyclophosphamide : 50 mg x 2/day, per os Imatinib mesylate : 600 mg/day,(300 mg in the morning and 300 mg in the evening) per os

NEXT CYCLE (28 days):

Cyclophosphamide : 50 mg x 2/day, per os Imatinib mesylate : 600 mg/day,(300 mg in the morning and 300 mg in the evening)per os

Imatinib mesylate, Cyclophosphamide (Dosing level 2)

CYCLE 1 (42 days):

* Day 1 to 14 Imatinib mesylate : 800 mg/day,(400 mg in the morning and 400 mg in the evening) per os
* Day 15 to 42 Cyclophosphamide : 50 mg x 2/day, per os Imatinib mesylate : 800 mg/day,(400 mg in the morning and 400 mg in the evening) per os

NEXT CYCLE (28 days):

Cyclophosphamide : 50 mg x 2/day, per os Imatinib mesylate : 800 mg/day,(400 mg in the morning and 400 mg in the evening)per os

Imatinib mesylate, Cyclophosphamide (Dosing level 3)

ONLY FOR CYCLE 1, at day 15 and day 28 :

11 sampling for dosing level 1 (pre-dose, imatinib mesylate + 30 min, +1, +2, +3, +4, +6, +10, +12 , +24 hours, cyclophosphamide + 12 hours) 10 sampling for the next dosing level (pre-dose, imatinib mesylate + 30 min, +1, +2, +3, +4, +6, +10, +12,cyclophosphamide + 12 hours)

Blood sampling

Antoine ADENIS, MD, PhD

The purpose of this study is to determine the maximum tolerated dose of imatinib mesylate, given in association with a fixed dose of cyclophosphamide (50 mg bid).

Imatinib Mesylate And Cyclophosphamide In Metronomic Administration: Dose Escalation Study Of Imatinib Mesylate

Imatinib Mesylate And Cyclophosphamide In Metronomic Administration: Dose Escalation Study Of Imatinib Mesylate in Patient With Rare Tumor (Phase I Study)

Centre Oscar Lambret

Respiratory Tract (Lung and Bronchial) Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma, Renal Cell

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

Pharmaceutical Solutions

Adjuvants, Anesthesia

Central Nervous System Depressants

Psychotropic Drugs

Other Dietary Supplements

Caffeine

Midazolam

Sunitinib

Erlotinib Hydrochloride

Anesthetics

Hypnotics and Sedatives

Anti-Anxiety Agents

Anesthetics, Intravenous

Anesthetics, General

GABA Modulators

Neurotransmitter Agents

Angiogenesis Inhibitors

Growth Inhibitors

Phosphodiesterase Inhibitors

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Imatinib Mesylate And Cyclophosphamide In Metronomic Administration: Dose Escalation Study Of Imatinib Mesylate	NCT01046487	Cancer	Imatinib mesyla... Imatinib mesyla... Imatinib mesyla... Blood sampling	18 Years -	Centre Oscar Lambret
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
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 gastrointestinal stroma tumor