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Ibrutinib

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Tyrosine

All participants will receive a single oral solution dose of 50 mg to 140 mg -ibrutinib containing 1480 kBq (40 µCi) of 14C-labeled ibrutinib, with a total radiation burden of approximately 0.916 mSv.

Type=exact number, unit=mg, number=50-140, form=solution, route=oral. Participants will receive a single oral solution dose of 50 mg to 140 mg -ibrutinib containing 1480 kBq (40 µCi) of 14C-labeled ibrutinib, with a total radiation burden of approximately 0.916 mSv.

Janssen Research & Development, LLC Clinical Trial

The purpose of this study is to investigate the absorption, the metabolic pathways and the excretion of ibrutinib in healthy male adult participants after administration of a single oral dose of 50 mg to 140 mg (5 mg/mL solution) of unlabeled ibrutinib admixed with 14C ibrutinib.

This is an open-label (all people know the identity of the intervention), single-center, single-dose study in healthy male participants. Six men will be enrolled to allow a minimum of 4 participants to complete the study. All participants will receive a single oral solution dose of 50 to 140 mg ibrutinib containing 1480 kBq (40 µCi) of 14C labeled ibrutinib, constituting a total radiation burden of approximately 0.916 mSv (ICRP risk category IIa). The duration of the study is approximately 73 days including screening period of 28 days, treatment period of 15 days, and follow-up period of 30 days. Safety will include adverse events, laboratory safety, 12 lead electrocardiogram, physical examination, and vital signs.

A Study to Determine the Absorption, Metabolism, and Routes of Excretion of (14C) Radiolabeled Ibrutinib in Healthy Male Participants

An Open-Label Phase 1 Study to Determine the Pharmacokinetics, Metabolism, and Routes of Excretion of (14C) Radiolabeled PCI-32765 in Healthy Male Subjects

Pharmacokinetic parameter Cmax of ibrutinib will be determined.

Pharmacokinetic parameter tmax of ibrutinib will be determined.

Pharmacokinetic parameter AUC of ibrutinib will be determined.

Pharmacokinetic parameter Ae of ibrutinib will be determined by multiplying the urinary volume with the urinary concentration.

Janssen Research & Development, LLC

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

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

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Rare Diseases

Melanoma

Disease Progression

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

Nilotinib

Trametinib

Dabrafenib

Patients in this group will receive 100mg Nilotinib PO BID.

Patients in this group will receive 200mg Nilotinib PO BID.

Patients in this group will receive 300mg Nilotinib PO BID.

Patients in this group will receive 400mg Nilotinib PO BID.

Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) on day one and will continue for 28 days. After 7 days, nilotinib will be added at 100mg PO BID and will continue for 21 days. For each subsequent cycle, nilotinib will be given for 28 days.

Nilotinib 100mg

Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) on day one and will continue for 28 days. After 7 days, nilotinib will be added at 200mg PO BID and will continue for 21 days. For each subsequent cycle, nilotinib will be given for 28 days.

Nilotinib 200mg

Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) on day one and will continue for 28 days. After 7 days, nilotinib will be added at 300mg PO BID and will continue for 21 days. For each subsequent cycle, nilotinib will be given for 28 days.

Nilotinib 300mg

Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) on day one and will continue for 28 days. After 7 days, nilotinib will be added at 400mg PO BID and will continue for 21 days. For each subsequent cycle, nilotinib will be given for 28 days.

Nilotinib 400mg

All patients will begin dabrafenib (150mg PO BID) on day one and will continue for 28 days.

All patients will begin trametinib (2mg PO once daily) on day one and will continue for 28 days.

Yvonne Taul, RN

Amy Grossman

Douglas B Johnson

Mark Evers, MD

This is a phase 1 dose-escalation study of nilotinib in combination with fixed-dose dabrafenib and trametinib regimen for patients with metastatic or unresectable melanoma carrying a BRAF V600 mutation and have relapsed on a BRAF/MEK inhibitor therapy. The goal is to assess the toxicity and tolerability and determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of the combination of nilotinib with dabrafenib and trametinib. Additionally, this study will assess pharmacokinetic parameters of dabrafenib and nilotinib when used in combination.

This is a phase 1 dose-escalation study of nilotinib in combination with a fixed-dose of dabrafenib and trametinib. The first week, patients will be treated with dabrafenib (150mg, twice daily) and trametinib (2mg, once daily). After 7 days, when both drugs have achieved steady-state levels and there is maximal induction of CYP3A4, nilotinib will be added, and all three drugs dosed concurrently for the rest of the study. Plasma pharmacokinetic (PKs) samples for dabrafenib and nilotinib will be obtained at baseline, weekly for the first four weeks, and at regular study visits for the duration of the trial. Tissue core biopsies and correlative plasma samples will be obtained at baseline, and 2 weeks after the start of nilotinib.

Nilotinib Plus Dabrafenib/Trametinib in Metastatic Melanoma

A Phase 1 Study of Nilotinib in Combination With Dabrafenib and Trametinib in BRAF V600 Mutant Metastatic Melanoma After Progression on BRAF/MEK Inhibition

Percentage of patients who experienced dose-limiting toxicities associated with Nilotinib as defined by the study protocol.

The dose-adjusted steady state concentrations (Css) of dabrafenib will be calculated on day 8 (dabrafenib alone) compared to day 15 (dabrafenib + nilotinib).

Plasma concentrations of Nilotinib will be measured on day 8 (pre-Nilotinib) and day 29.

Duration of overall response will be determined by the time measurement criteria are met for complete response (CR) or partial response (PR) - whichever is first recorded - until the first date that recurrent or progressive disease is objectively documented.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study to Determine the Absorption, Metabolism, and Routes of Excretion of (14C) Radiolabeled Ibrutinib in Healthy Male Participants	NCT01674322	Healthy Partici...	Ibrutinib	30 Years - 55 Years	Janssen Research & Development, LLC
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
A Study to Determine the Absorption, Metabolism, and Routes of Excretion of (14C) Radiolabeled Ibrutinib in Healthy Male Participants	NCT01674322	Healthy Partici...	Ibrutinib	30 Years - 55 Years	Janssen Research & Development, LLC
Nilotinib Plus Dabrafenib/Trametinib in Metastatic Melanoma	NCT04903119	Metastatic Mela... BRAF Gene Mutat...	Nilotinib 100mg Nilotinib 200mg Nilotinib 300mg Nilotinib 400mg Dabrafenib Trametinib	18 Years -	University of Kentucky
Nilotinib Plus Dabrafenib/Trametinib in Metastatic Melanoma	NCT04903119	Metastatic Mela... BRAF Gene Mutat...	Nilotinib 100mg Nilotinib 200mg Nilotinib 300mg Nilotinib 400mg Dabrafenib Trametinib	18 Years -	University of Kentucky
A Study to Determine the Absorption, Metabolism, and Routes of Excretion of (14C) Radiolabeled Ibrutinib in Healthy Male Participants	NCT01674322	Healthy Partici...	Ibrutinib	30 Years - 55 Years	Janssen Research & Development, LLC

Spots Global Cancer Trial Database for cyp3a4

Every month we try and update this database with for cyp3a4 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 cyp3a4

Every month we try and update this database with for cyp3a4 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 cyp3a4 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.