Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Adjuvants, Anesthesia

Central Nervous System Depressants

Psychotropic Drugs

All Drugs and Chemicals

Midazolam

Anesthetics

Hypnotics and Sedatives

Anti-Anxiety Agents

Anesthetics, Intravenous

Anesthetics, General

GABA Modulators

Neurotransmitter Agents

Patients will receive 2 mg midazolam orally on day 1 of the study and 1 mg midazolam intravenously on day 2 of the study.

F Opdam, MD, PhD

The hepatic enzyme, cytochrome P450 3A4 (CYP3A4) is important for the metabolism of many drugs including taxanes. Previous reported studies reported a decreases in docetaxel exposure in prostate cancer patients compared to patients with other solid tumours. The difference was 1.8-fold for intravenous administration and 2.8-fold for oral administration.

The underlying mechanism for these observations remains to be elucidated. The lower docetaxel exposure with IV and oral docetaxel treatment might be related to a higher CYP3A4 activity in prostate cancer patients. Therefore, it is important to directly compare the CYP3A4 activity with a phenotyping test in prostate cancer patients and patients with other types of solid tumours.

This is an in vivo phenotyping studying using midazolam as a probe for CYP3A4 activity in patients with prostate cancer and patients with other solid tumours. The primary objective is the comparison of CYP3A4 activity in prostate cancer patients versus male patients with other types of solid tumours by use of an oral midazolam phenotyping test. Secondary objectives are: (1) measurement of plasma concentrations of midazolam and it's two primary metabolites (1'-hydroxy midazolam and 4'-hydroxy midazolam), (2) determination of the metabolite pharmacokinetics of midazolam. (3) retrospective assessment of single nucleotide polymorphisms of CYP3A4. The exploratory objective is to differentiate between gastro-intestinal and hepatic CYP3A4 activity with oral and intravenous administration of midazolam.

The metabolizing enzyme cytochrome P450 (CYP) 3A4 is an important factor in the pharmacokinetics (PK) of many (anticancer) drugs, including taxanes \[1\]. Recently, it has been reported that the PK of intravenous docetaxel are different in patients with castration resistant prostate cancer, as compared to patients with other types of solid tumours \[2\]. Different phase I studies with the oral docetaxel formulation ModraDoc006 in combination with ritonavir (denoted as ModraDoc006/r), were conducted in our institute in patients with hormone-sensitive prostate cancer (HSPC), metastatic castration-resistant prostate cancer (mCRPC) and other types of solid tumours \[3-5\]. The exposure to docetaxel and ritonavir after administration of the same dose and schedule of ModraDoc006/r was substantial lower in prostate cancer patients as compared to the patients with other types of solid tumours. In contrast to the 1.8-fold difference reported with IV docetaxel, the difference in the area under the plasma concentration versus time curve (AUC) was 2.8-fold with oral ModraDoc006/r treatment \[2-5\]. The PK-curves of docetaxel and ritonavir are shown in figure 1A and 1B.

The underlying mechanism for these observations remains to be elucidated. The lower docetaxel exposure with IV and oral docetaxel treatment and the lower ritonavir exposure with ModraDoc006/r treatment might be related to a higher CYP3A4 activity in prostate cancer patients. Therefore, it is important to directly compare the CYP3A4 activity with a phenotyping test in prostate cancer patients and patients with other types of solid tumours.

As a potential cause for this, CYP3A4 activity might be altered by medical castration. Franke et al. showed that the clearance of docetaxel was higher in castrated versus non-castrated prostate cancer patients. However, comparison of the CYP3A4 activity in the castrated versus the prostate cancer patients with normal levels of testosterone showed no significant differences \[6\]. However, this was done in 6 CRPC patients, of which one patient had an extremely low CYP3A4 activity. The intravenous erythomycin breath test that was used in this study only reflects the hepatic CYP3A4 activity and not the gastro-intestinal CYP3A4 activity. The latter is important in treatment with oral docetaxel (ModraDoc006) in combination with ritonavir. Furthermore, erythomycin is also a substrate for P-glycoprotein (P-gp), indicating that the erythomycin breath test might reflect P-gp activity as well as CYP3A4 activity \[7,8\]. Therefore, it is necessary to evaluate prostate cancer patients with a phenotyping test that includes both the hepatic and gastro-intestinal CYP3A4-activity.

Midazolam is one of the most frequently used test compounds used for evaluation of CYP3A4 activity \[9-11\]. Midazolam has several advantages over other CYP3A4 probes such as erythromycin, dapsone, quinine, and nifedipine \[11\]. First, midazolam is selectively metabolized by CYP3A4 \[9,10\]. Furthermore, midazolam clearance after both oral and intravenous administration is a widely accepted and validated metric of CYP3A4 activity \[9-11\]. Continuing, midazolam AUC and metabolite clearance to its major metabolite 1-hydroxy midazolam correlate well with hepatic CYP3A content \[11-13\]. Also, midazolam PK are highly sensitive to changes in CYP3A4 activity \[9-11\]. Therefore, oral midazolam will be used in this study to further evaluate the CYP3A4 activity in prostate cancer patients in comparison to patients with other types of solid tumours. To further differentiate between gastro-intestinal and hepatic CYP3A4 activity, evaluation with both oral and intravenous midazolam is included in this study.

1. Mathijssen RHJ, van Schaik RHN. Genotyping and phenotyping cytochrome P450: perspectives for cancer treatment. Eur J Cancer 2006; 42(2):141-8
2. De Vries Schultink AHM, Crombag MBS, van Werkhoven E, et al. Neutropenia and docetaxel exposure in metastatic castration-resistant prostate cancer patients: A meta-analysis and evaluation of a clinical cohort. Cancer Med 2019; 8(4): 1406-15.
3. De Weger VA, Stuurman FE, Hendrikx J, et al. A dose-escalation study of bi-daily once weekly oral docetaxel either as ModraDoc001 or ModraDoc006 combined with ritonavir. Eur J Cancer 2017; 86: 217-25.
4. Vermunt MAC, Janssen JM, Vrijenhoek GL, Van der Poel HG, Thijssen B, Beijnen JH et al. Addition of an oral docetaxel treatment (ModraDoc006/r) to androgen deprivation therapy (ADT) and intensity-modulated radiation therapy (IMRT) in patients with high risk N+M0 prostate cancer. Ann Oncol 2019; 30(suppl_5): v325-v355
5. Vermunt M, Robbrecht D, Devriese L, Janssen J, Keessen M, Eskens F et al. ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastasized castration-resistant prostate cancer (mCRPC): A multicenter phase I study. J Clin Oncol. 2020; 38(suppl 6;abstr 79)
6. Franke RM, Carducci MA, Rudek MA, Baker SD, Sparreboom A. Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer. J Clin Oncol. 2010 Oct;28(30):4562-7
7. Lan LB, Dalton JT, Schuetz EG. Mdr1 limits CYP3A metabolism in vivo. Mol Pharmacol 2000;58:863-9
8. Chiou WL, Chung SM, Wu TC. Potential role of P-glycoprotein in affecting hepatic metabolism of drugs. Pharm Res 2000;17:903-5.
9. Streetman DS, Bertino JS, Nafziger AN. Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics 2000; 10(3):187-216
10. Hohmann N, Haefeli WE, Mikus G. CYP3A activity: towards dose adaptation to the individual. Expert Opin Drug Metab Toxicol 2016; 12(5):479-97
11. Fuhr U, Jetter A, Kirchheiner J. Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the "cocktail" approach. Clin Pharmacol Ther 2007; 81(2): 270-83
12. Thummel KE, Shen DD, Podoll TD, Kunze KL, Trager WF, Hartwell PS et al. Use of midazolam as a human cytochrome P450 3A probe: I. In vitro-in vivo correlations in liver transplant patients. J Pharmacol Exp Ther 1994; 271(1):549-56
13. Thummel KE, Shen DD, Podoll TD, Kunze KL, Trager WF, Bacchi CE et al. Use of midazolam as a human cytochrome P450 3A probe: II. Characterization of inter- and intraindividual hepatic CYP3A variability after liver transplantation. J Pharmacol Exp Ther 1994; 271(1):557-66

CYP3A4 Activity in Patients With Prostate Cancer Versus Male Patients With Other Solid Tumours

Phenotyping Study of CYP3A4 Activity in Patients With Prostate Cancer Versus Male Patients With Other Types of Solid Tumours With Midazolam

Non-linear mixed effects modelling (NONMEM) will be performed to determine the contribution of hepatic CYP3A4 content and gastro-intestinal CYP3A4 concent on midazolam clearance.

Midazolam clearance is a generally accepted biomarker for CYP3A4 actiivty

Plasma concentrations will be determined with LC-MS/MS. The unit will be microgram/L.

Non-lineair mixed effects modelling (NONMEM) will be performed to determine the pharmacokinetic profile

polymerase chain reaction to identify single nucleotide polymorphisms in the genes encoding for CYP3A4

The Netherlands Cancer Institute

Digestive System Diseases

Rare Diseases

Cholangiocarcinoma

Liver Neoplasms

Adenocarcinoma

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Bile Duct Cancer

Hematinics

Liver Extracts

phenotyping

Julien Calderaro

Our project is a large-scale characterisation of cHCC-CCA will allow us to determine which subsets harbor actionable gene alterations. We will also aim to improve diagnosis of this tumor type by the use of immunohistochemical biomarkers and the development of deep-learning based models able to help cHCC-CCA diagnosis. This will represent an important step towards precision medicine for the patients with this highly aggressive malignancy.

* Scientific background Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare liver cancer characterized by a dual hepatocytic and biliary differentiation. It is resistant to conventional anti-cancer treatments and there is currently no effective systemic therapy available. Inter-observer agreement for diagnosis of cHCC-CCA is low, even among expert pathologists, and the development of clinical trials remain thus challenging. The molecular mechanisms that drive its progression also remain under-investigated.
* Project objectives and brief description of the methods which will be used to achieve them We aim to perform an integrative molecular, immune and phenotypical study of cHCC-CCA that will allow the distinction of different tumor subgroups linked to particular actionable genetic/immune alterations. The development of immunohistochemical markers and artificial intelligence-based approaches is also likely to improve the diagnosis of cHCC-CCA.

A overall multicentric series of 357 cHCC-CCA samples, already available in our biobanks, will be investigated by means of gene and RNA sequencing, digital pathology and immunohistochemistry in order to build a morphomolecular classification of this tumor. Spatial transcriptomics and in situ proteomics will be performed to decipher the intra-tumor heterogeneity and identify biomarkers of the different subclasses. Finally, deep-learning based models will be developed in order to 1) improve the diagnosis of cHCC-CCA and 2) identify the morphological features linked to prognosis.

• Expected results This large-scale characterisation of cHCC-CCA will allow us to determine which subsets harbor actionable gene alterations. We will also aim to improve diagnosis of this tumor type by the use of immunohistochemical biomarkers and the development of deep-learning based models able to help cHCC-CCA diagnosis. This will represent an important step towards precision medicine for the patients with this highly aggressive malignancy.

Precision Medicine for Combined Hepatocellular-Cholangiocarcinoma

Inserm U955

Full Professor

Respiratory Tract (Lung and Bronchial) Diseases

Skin and Connective Tissue Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma, Renal Cell

Gastrointestinal Stromal Tumors

Kidney Neoplasms

Urologic Neoplasms

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic 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

Antineoplastic Agents

Other Dietary Supplements

Amino Acids

Caffeine

Sunitinib

Erlotinib Hydrochloride

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

Clear Cell Renal Cell Carcinoma

Herbal and Botanical

Imatinib Mesylate

Orange

Grapefruit Seed Extract

The grapefruit juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment

The orange juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment.

All patients receive once daily 50 mg sunitinib for 6 weeks in the registered schedule of 4 weeks on two weeks off treatment.

All patients receive three times midazolam 7,5 mg on PK day 1,2, and 3 e.g. between day 14-21 of treatment, on day 28 of treatment and on day 42 of treatment.

The orange juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment with sunitinib, just before PK day 2 on day 28 of treatment

Orange juice

The grapefruit juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment with sunitinib, just before PK day 2 on day 28 of treatment

Grapefruit juice

Hans Gelderblom

In this prospective pharmacokinetic we investigate the following topics:

* The influence of grapefruit juice and orange juice on the steady-state pharmacokinetics of sunitinib in cancer patients
* The influence of sunitinib on the pharmacokinetics of midazolam in cancer patients
* The relationship between Cytochrome-P450-3A4 (CYP3A4) phenotype, as assessed using the midazolam clearance test, and the steady-state pharmacokinetics of sunitinib in cancer patients
* The effect of grapefruit juice and orange juice on CYP3A4 metabolism

This is a prospective pharmacokinetic study in two groups of 10 adult patients with imatinib-resistant gastro-intestinal stromal cell tumor or metastatic renal cell carcinoma treated with sunitinib for at least one month.

Patients are treated at the recommended United States Food and Drug Administration approved schedule of oral sunitinib administered at 25-50 mg per day for 4 weeks, in cycles of six weeks. Four weeks of treatment with sunitinib, 25-50 mg per day followed by a 2 weeks off period. In the absence of disease progression, administration of sunitinib will continue.

Within one month of the start of the study, patients will be requested to refrain from drinking grapefruit and orange juice. The study will take place in 1 sunitinib treatment cycle of 6 weeks (4 weeks of treatment with sunitinib (week 1-4) and 2 weeks off period (week 5 and 6). The grapefruit juice or orange juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment with sunitinib.

The first sunitinib (total drug) pharmacokinetics day will be performed after steady-state sunitinib levels are reached, meaning at least 14 days after starting sunitinib 25 - 50 mg per day treatment (week 3 in the treatment cycle of sunitinib). On this first pharmacokinetic day a dose of midazolam 7.5 mg will be given at the same time as the sunitinib dose, to observe the effect of sunitinib on CYP3A4 capacity. Before the second pharmacokinetic day (day 28 of sunitinib treatment) the patient will drink 3 times a day a glass of grapefruit juice or orange juice for three consecutive day.Patients will be assigned either to a grapefruit juice or orange juice arm. On this second pharmacokinetic day the patient again will use a dose of midazolam at the sam time as the sunitinib dose, to observe the effect of grapefruit juice or orange juice on the metabolic capacity pf CYP3A4. The third pharmacokinetic day will take place at the end of week 6 of the treatment cycle, the second week of the 2 week off period. The patient will receive a single oral dose of midazolam 7.5mg, followed by midazolam pharmacokinetics to determine the base-line CYP3A phenotypic expression. Pharmacokinetic parameters based on measurement in plasma samples will be compared between the treatment periods.

The Influence of Phenotype, Grapefruit Juice and Orange Juice on the Pharmacokinetics of Sunitinib in Cancer Patients

The Influence of Genotype/Phenotype, Grapefruit Juice and Orange Juice on the Pharmacokinetics of Sunitinib (Sutent, SU011248) in Patient With Imatinib Resistant Gastrointestinal Stromal Cell Tumor (GIST) or Metastatic Renal Cell Carcinoma

Subjects will receive sunitinib in the registered schedule of 4 weeks "on" (28 days) 2 weeks "off" (14 days).Sunitinib steady state is reached after 14 days. Additionally patients receive grapefruit juice on day 25-27 of treatment. To determine the influence of grapefruit juice, sunitinib pharmacokinetics (PK) will be assessed on PK day 1, which will be between treatment day 14-20 (without grapefruit juice) and on PK day 2 on day 28 of treatment (after taking grapefruit juice for 3 days).

Subjects will receive sunitinib in the registered schedule of 4 weeks "on" (28 days) 2 weeks "off" (14 days).Sunitinib steady state is reached after 14 days. To determine the feasibility of midazolam as a phenotyping probe, sunitinib PK from PK day 1, which is between treatment day 14-20 and the PK of midazolam from PK day 3 on day 42 of treatment (the end of the wash out period of sunitinib) will be determined.

Subjects will receive sunitinib in the registered schedule of 4 weeks "on" (28 days) 2 weeks "off" (14 days).Sunitinib steady state is reached after 14 days. Additionally patients receive grapefruit juice on day 25-27 of treatment and midazolam on PK days. To determine the influence of grapefruit juice on CYP 3A4 metabolism, midazolam PK will be assessed on PK day 1, which will be between treatment day 14-20 (without grapefruit juice) and on PK day 2 on day 28 of treatment (after taking grapefruit juice for 3 days).

Subjects will receive sunitinib in the registered schedule of 4 weeks "on" (28 days) 2 weeks "off" (14 days).Sunitinib steady state is reached after 14 days. Additionally, patients receive midazolam on PK day 1 (between treatment day 14-20)and PK day 3 (day 42 of treatment,the end of the wash out period of sunitinib). To determine the influence of sunitinib on CYP3A4 activity, midazolam PK of PK day 1 (sunitinib AND midazolam) will be compared to midazolam PK of PK day 3 (midazolam alone)

Leiden University Medical Center

Prof.

Capecitabine

Fluorouracil

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Patients screened for four single nucleotide polymorphisms (SNPs) in DPYD (DPYD\*2A, c.2846A\>T, c.1236G\>A/HapB3 and DPYD\*13) that are found to be wild type for these SNPs

Patients screened for four single nucleotide polymorphisms (SNPs) in DPYD (DPYD\*2A, c.2846A\>T, c.1236G\>A/HapB3 and DPYD\*13) that are found to be heterozygous for c.1236G\>A or c.2846A\>T of these SNPs

Patients screened for four single nucleotide polymorphisms (SNPs) in DPYD (DPYD\*2A, c.2846A\>T, c.1236G\>A/HapB3 and DPYD\*13) that are found to be homozygous or compound heterozygous for these SNPs

Patients that are found to be wild type and have a pre-treatment uracil concentration above 16 ng/mL will receive a reduced dosage of capecitabine or 5-fluorouracil (50% reduction). The dose will be titrated after 2 cycles , to achieve maximal safe exposure. Patients that are wildtype with a uracil concentration below 16 ng/mL will receive a normal (full) dose.

Fluoropyrimidine (capecitabine or 5-fluorouracil)

Patients that are heterozygous carriers of c.1236G\>A or c.2846A\>T DPYD variant will receive a reduced dosage of capecitabine or 5-FU (50 % reduction). The dose will be titrated after 2 cycles, to achieve maximal safe exposure.

Patients with homozygous or compound heterozygous DPYD variants will be treated with a reduced dose of capecitabine or 5-FU based on the DPD enzyme activity measured in peripheral blood mononuclear cells.

Jonathan Knikman, PharmD

Annemieke Cats, MD, PhD

In this study it will be determined whether the rate of severe toxicity associated with fluoropyrimidine treatment (capecitabine or 5-fluorouracil) can be significantly diminished by individualized dosing of fluoropyrimidines based on upfront phenotypic assessment of dihydropyrimidine dehydrogenase (DPD) deficiency.

In this study a phenotypic approach will be studied to determine the additional value of pretreatment uracil level-guided dose individualization in wildtype patients. Patients with a pretreatment serum uracil concentration above 16 ng/ml will be treated with a 50% reduced fluoropyrimidine starting dose. The pretreatment serum uracil levels in DPYD variant carriers will be assessed retrospectively and non-interventional. Additionally, the effect of a higher dose reduction in c.1236G\>A and c.2846A\>T DPYD variants carriers (50% instead of 25%) will be studied.

Improving the Safety of Fluoropyrimidine-based Chemotherapy

Improving the Safety of Fluoropyrimidine-based Chemotherapy by Combined DPYD Genotype-guided and DPD Phenotype-guided Dose Individualization: The ALPE2U Study

Immune System Diseases

Breast Neoplasms

Hypersensitivity

Breast Diseases

Skin Diseases

Bone Density Conservation Agents

Anticoagulants

Tamoxifen

Citric Acid

Sodium Citrate

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Selective Estrogen Receptor Modulators

Estrogen Receptor Modulators

Citrate

tamoxifen citrate

laboratory biomarker analysis

pharmacological study

Alexandre Bodmer, MD

Khalil Zaman, MD

RATIONALE: Estrogen can promote growth of endocrine sensitive breast cancer cells. Endocrine therapy with tamoxifen citrate may fight breast cancer by blocking the use of estrogen by the tumor cells. Pharmacokinetics and -genomics can have an impact on the efficacy of the treatment.

PURPOSE: This phase III trial is studying blood samples to see if the level of active metabolites of tamoxifen can be improved in patients with breast cancer.

OBJECTIVES:

Primary

* To determine how the increase of tamoxifen citrate dose influences the level of its major metabolites in patients with hormone-sensitive breast cancer.

Secondary

* To characterize the population pharmacokinetic profile
* To investigate the role of the other CYPs
* To assess the relation between clinical symptoms and CYP2D6 genotypes and/or active metabolites levels
* To explore the correlation between genotypes/metabolites levels and clinical outcomes in terms of tumor relapse.
* To assess the feasibility, efficacy, and safety of concentration-guided adjustment of tamoxifen citrate dosage.
* To conduct other exploratory analysis based on the eventual new data coming up in the future.

OUTLINE: Patients receive oral tamoxifen citrate (at a dose of 40 mg/day) daily for 4 months in the absence of disease progression or unacceptable toxicity.

Blood samples are collected for PK, genotyping, phenotyping, and further analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
CYP3A4 Activity in Patients With Prostate Cancer Versus Male Patients With Other Solid Tumours	NCT05518799	Prostate Cancer Solid Tumor, Ad...	Midazolam	-	The Netherlands Cancer Institute
Precision Medicine for Combined Hepatocellular-Cholangiocarcinoma	NCT06146127	Liver Cancer	phenotyping	18 Years -	Inserm U955
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 Influence of Phenotype, Grapefruit Juice and Orange Juice on the Pharmacokinetics of Sunitinib in Cancer Patients	NCT01743300	Healthy	Sunitinib Midazolam Orange juice Grapefruit juic...	18 Years -	Leiden University Medical Center
Improving the Safety of Fluoropyrimidine-based Chemotherapy	NCT04194957	Neoplasms	Fluoropyrimidin... Fluoropyrimidin... Fluoropyrimidin...	18 Years -	The Netherlands Cancer Institute
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
Improving the Safety of Fluoropyrimidine-based Chemotherapy	NCT04194957	Neoplasms	Fluoropyrimidin... Fluoropyrimidin... Fluoropyrimidin...	18 Years -	The Netherlands Cancer Institute
Tamoxifen Citrate in Patients With Breast Cancer	NCT00963209	Breast Cancer	tamoxifen citra... laboratory biom... pharmacological...	18 Years -	Centre Hospitalier Universitaire Vaudois

Spots Global Cancer Trial Database for phenotyping

Every month we try and update this database with for phenotyping cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for phenotyping

Every month we try and update this database with for phenotyping cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for phenotyping cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.