Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Rare Diseases

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Childhood Acute Lymphoblastic Leukemia

Lymphosarcoma

Yung-Li Yang, MD

Dong-Tsamn Lin, MD

Chung-Yi Hu, PhD

Dong-Tsam Lin, MD

Shu-Wha Lin, PhD

Lan-Yang Chang, PhD

Emerging results suggest that a cure rate of nearly 90 percent will be attained in the near future. The advance was attributed to stringent application of prognostic factors for risk factor-directed therapy. Early response to treatment has greater prognostic strength than does any other biologic or clinical feature tested to dates. The measurement of minimal residual disease(MRD) affords a level of sensitivity and specificity that cannot be attained through traditional microscopic morphologic assessments. In Taiwan, detection for the most recurrent fusion genes and the MRD were not commonly available, the TPOG(Taiwan Pediatric Oncology Group) used clinical features, immunophenotypes, and cytogenetics to do risk group classifications and protocol assignment. A successful rate of 60-70% has been reached. In order to improve the cure rate of ALL in Taiwan, this project aims at establishing the methods for better risk classifications and establishing MRD detection for risk-directed therapy for childhood ALL in Taiwan.Intrinsic and acquired resistances to multiple anticancer agents represent major obstacles and accounts for 10-20% of treatment failure in the developed countries nowadays. Recent progress using DNA microarray identified differential expression level of the genes known to implicate in cell cycle control, DNA repair and apoptosis in different subsets of ALL patients, which were found to be related to drug response. Genetic polymorphisms in the genes of drug-metabolizing enzymes, drug transporters or drug targets, can influence the efficacy or toxicity of antileukemic agents. Specific genotype might be important in determining the pharmacokinetic effects of one population or disease subtype from that in others. Recently, the expression profiles of relatively few microRNAs (miRNAs) (\~200 genes), was noted to accurately classify human cancers. These informations hinted that expression of the genes in the leukemic cells might serve as additional risk factors for treatment stratification.

Specific aims and goals:

1. to establish better risk factors classification and use MRD to monitor early response to treatment.
2. to establish the expression profiles of 12 genes associated with drug resistance
3. to unravel the pharmacogenetic background of pediatric ALL in Taiwan, so that will help refine the therapy dose, achieve a better drug effect and avoid acute or chronic toxicity.
4. microRNA expression profiles in childhood ALL in Taiwan

In the 1990s, the five-year event-free survival rates for childhood ALL generally ranged from 70 to 83 percent in developed countries, with an overall cure rate of approximately 80 percent. Emerging results suggest that a cure rate of nearly 90 percent will be attained in the near future. Progress in the treatment of ALL, however, has been made largely by the optimization of the use of existing medicines rather than by the discovery of new agents. These factors predicting clinical outcomes include treatment regime, clinical features, global gene expression patterns and genetics of leukemia cells, host pharmacodynamics and pharmacogenetics, early response to treatment. In Taiwan, detection the most recurrent fusion gene occurred in ALL were not popular applied yet. Minimal residual disease (MRD) detection is not commonly available for the evaluation of initial response to chemotherapy protocol we have assigned. The TPOG (Taiwan Pediatric Oncology Group) use only clinical features (age, PB white blood counts, immunophenotypes, and cytogenetics) to assign the protocols. Only around 60-70% of patients were successful treated. The ultimate goal of this project is to establish the methods for better risk classifications for pediatric ALL patients in Taiwan in order increase cure rate.

Classification of childhood ALL by molecular methods Risk factors based on a patient's physical manifestations or hematologic and biochemical tests have been largely replaced by more specific tests of the biologic features of leukemic cells. The recently introduced World Health Organization (WHO) classification takes into consideration of morphologic and immunologic features plus well-studied, common nonrandom chromosomal abnormalities that clearly influence the laboratory and clinical features of ALL. Genetic makeup of the leukemic cells has been recognized as the most important prognostic factors in childhood ALL. The most frequent fusion gene TEL-AML1 (about 25% of the childhood B-ALL) which was caused by t(12;21) and hyperdiploidy (\>50 chromosomes)(accounts for about 25% of B-ALL) were noticed to be associated with favorable prognosis. The recurrent chromosome translocation changes/fusion genes t(4;11)/MLL-AF4, t(9:22)/BCR-ABL, t(1;19)/E2A-PBX1 were recognized as adverse prognostic factors. Recently, treatment of t(1;19) B-ALL with high dose chemotherapy gave successful results. Cytogenetic analysis has been the standard method for identifying chromosomal translocations in childhood ALL for many years. However, this approach is technically difficult and takes at least two weeks to obtain the results. Undetermined results were inevitable in a substantial proportion of cases. This is most prevalent in patients with t(12; 21), which is not visible by routine cytogenetics examinations. A multiplex RT-PCR assay for the detection of common chimeric transcripts TEL-AML1, MLL/AF4, BCR-ABL , and E2A-PBX1 has been designed to classify pediatric ALL patients. The application of this assay to routine clinical screening will significantly improve the clinical diagnosis of childhood ALL.

Prediction of the therapy-resistant leukemia clones---global gene expression pattern of the leukemic cells Recent work indicates that global gene expression profiling using DNA microarrays can identify genes with levels of expression that are related to drug response. Significant differences in the expression of genes involved in cell-cycle regulation, DNA repair, and apoptosis were noticed between diagnostic and early relapse samples or between therapy-sensitive and therapy-resistant samples. These discoveries provide means to enhance classification systems based on relapse hazard and to identify signaling pathways that wound be potentially targeted with novel therapies. Holleman A et al used microarrays to investigate the expression of 70 apoptosis genes and revealed that BCL2L13 expression was an independent prognostic factor. Flotho C et al analyzed gene expression of diagnostic lymphoblasts and compared the findings with MRD levels on days 19 and 46 of remission induction therapy. Seventeen genes were identified to be significantly associated with MRD. Caspase 8-associated protein 2 gene(CASP8AP2) was studied further and showed a strong relationship with prognosis. The study of Cario et al demonstrated that low expression of TTK was associated with poorer treatment response and the presence of MRD on both days 19 and 46 after chemotherapy. These studies demonstrated the association of apoptosis pathways with treatment prognosis and treatment failure. These genes may serve as functionally-defined risk factor for treatment stratification in addition to the currently used risk factors.Recent evidence indicates that small non-protein-coding RNA molecules, microRNAs (miRNAs), might function as tumor suppressors and oncogenes. A recent report by Cimmino et al showed that miR-15a and miR-16-1 negatively regulate anti-apoptotic gene BCL2. Therefore, it is thought that the deletion or down-regulation of mir-15a and mir-16-1 promotes leukaemogenesis and lymphomagenesis in haematopoietic cells. These studies hint the oncogenesis roles the miRNA might play. A report by Sonoki et a. also linked mir-125b-1 with leukemia. A recent report from Lu J et al. found that the expression profiles of relatively few miRNAs (\~200 genes), accurately classify human cancers. They examined the miRNA profiles of 73 bone marrow samples obtained from children with acute lymphoblastic leukemia. Hierarchical clustering revealed non-random partitioning of the samples into three major branches. This patter is similar to the classification drawn by microarray analysis. Therefore, we expect that different microRNA profile could be associated with drug resistancein childhood ALL.

Host pharmacogenetics and genetic polymorphisms associated with drug metabolism, disposition, chemotherapy cross-resistance, and complications Genetic polymorphisms of the drug-metabolizing enzymes (drug transporters) or drug targets in ALL patients can influence the efficacy or toxicity of antileukemic agents. The most intriguing example of pharmacogenomic application was thiopurine S-methyltransferase (TPMT). The purine analogs antimetabolites, Azathioprine and 6-mercaptopurine (6MP), interfere with nucleic acid metabolism and cell proliferation and used to treat leukemia. Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that preferentially catalyzes the S-methylation and inactivation of the purine analogs. About 90% of white and black persons have high TPM activity, and 10% have intermediate activity caused by heterozygosity at the TPMT locus. About 1 out of 300 persons inherits TPMT deficiency. Clinical studies have established an inverse correlation between TPMT activity and accumulation of the active thioguanine nucleotide metabolites of mercaptopurine and azathioprine in erythrocytes. Accumulation of nucleotides usually leads to severe hematopoietic toxicity and possibly death, but this outcome can be averted if the thiopurine dose is decreased substantially (an 8- to 15-fold reduction). Patients who have intermediate TPMT activity were at an intermediate risk for toxicity. To avoid bone marrow toxicity in TPMT deficiency patients, a prospective measurement of erythrocyte TPMT activity prior to therapy was advocated. However, TPMT assays are not easily available. The genetic basis for TPMT deficiency can be defined and polymerase chain reaction (PCR)-based methods, and has been well established to diagnose TPMT deficiency and heterozygosity in Western countries to the adjustment thiopurine dose. Recently, the TPMT genotype was linked to early ALL treatment response (MRD on day 78 after remission-induction therapy including mercaptopurine for 4 weeks).

Other germ line polymorphisms in the MTX associated genes are plausibly linked to drug resistance or prognosis of childhood ALL under current regimes. It may also affect the development of de novo or therapy-related leukemias. The polymorphisms in the folate-related genes MTHFR, MTRR, and SHMT1 are reported to relate to resistance to methotrexate in childhood ALL. Rocha JC et al. found that the GSTM1 non-null and TYMS 3/3 genotype are linked to drug resistance. It is important to investigate these common polymorphisms of patients in Taiwan. We will detect these polymorphisms in Taiwan pediatric patients and revealed their relationship with outcome and complications.

Methods to monitor the early response to chemotherapy Response to therapy reflects the genetics of leukemia cells and the pharmacodynamics and pharmacogenetics of the host, has greater prognostic strength than does any other biologic or clinical feature tested to date. The measurement of minimal residual disease, with the use of either flow cytometry or quantitative reverse transcription polymerase-chain-reaction (Q-RT-PCR) analysis, affords a level of sensitivity and specificity that cannot be attained through traditional morphologic assessments.

A simplified flow cytometric assay of CD19, CD10, and CD34 antigens on bone marrow mononuclear cells on day 14 or 21 of remission induction therapy would provide the means to achieve the goal of MRD detection and could be readily applied in centers with only minimal laboratory resources (Coustan-Smith E et al).

RESEARCH DESIGN AND METHODS Experimental Design A total of 160 ALL patients will be recruited to this study as well as age-matched controls. Patients with newly diagnosed ALL and enrolled on the TPOG ALL 2002 protocols and those previously diagnosed patients in the past 3 years will be recruited under theirs or their parents' informed consent. For each patient, we will prepare their total RNA and genomic DNA samples form the blast cells in the initial diagnostic samples (leukemic cells from bone marrow aspirations and peripheral blood).

Multiplex RT-PCR for recurrent BCR-ABL, MLL-AF4, E2A-PBX1, and TEL-AML1 fusion genes will be setup for the more specific initial prognostic factors assignment ALL patients. We will also analyze the relationships between the presence of the 16 genetic polymorphisms on the 6 important drug-metabolizing genes (CYP3A4\*1B (A\>G at position -392) and CYP3A5\*3 (G\>A at position 22893); GSTP1 313A\>G, GSTM1 deletion and GSTT1 deletion; MDR1 exon 21 (2677G\>T/A) and MDR1 exon 26 (3435C\>T); MTHFR 677C\>T and MTHFR 1298A\>C; NR3C1 1088A\>G; RFC 80G\>A; TPMT 238G\>C, TPMT 460G\>A, and TPMT 719A\>G; TYMS enhancer repeat; UGT1A1 promoter repeat polymorphism; VDR intron 8 G\>A, and VDR FokI (start-site) T\>C) and their influences in the pharmacodynamics of anti-leukemic agents received by the ALL eill be investigated.After induction chemotherapy, flow cytometric assay to detect the MRD levels will be applied to reflect the early response to initial chemotherapy protocols. A residual disease level of less than 0.01 percent during or on completion of initial remission-induction therapy reliably identifies patients with an exceptionally good treatment outcome. By contrast, patients with a level of 1 percent or more at the end of remission-induction therapy or those with a level of 0.1 percent or more at later times have a very high risk of relapse. Patients who have a residual leukemia level of 0.01 percent or more after six weeks of remission-induction therapy will be managed with intensified therapy protocols or seek hematopoietic stem cell transplantation donors.The expression profile of 12 genes associated with prognosis will be assayed (CASP8AP2, PTTG1, BCL2L13 BIRC5 (survivin), HRK TOP2A, TTK, CCNB1, TNF, RAB5C, BCL7A GRP58). MicroRNA array profiles will be applied also.

Clinical courses such as acute or chronic complicationswill be followed and recorded to assess the relationships between these polymorphisms and clinical courses.

Functional Pharmacogenomics of Childhood Acute Lymphoblastic Leukemia in Taiwan

National Taiwan University Hospital

Oral administration after fasting/high-fat meal

VC004 Capsules

Oral administration after high-fat/fasting meal

This study will adopt a randomized, open-label, two-period, 2-way crossover design to evaluate pharmacokinetics of a single oral dose of VC004 capsules under fasting and fed conditions in healthy subjects.

Food Effect Study on the Pharmacokinetics of VC004 Capsules in Healthy Adult Subjects

Jiangsu vcare pharmaceutical technology co., LTD

2 cycles of 3-day fasting mimicking spaced by a 2 week interval

Low-caloric, low-protein, plant-based diet regiment for 3 days

Fasting Mimicking Diet

Judith R Kroep

Fasting or a Fasting Mimicking diet (FMD) can lower blood concentration of glucose and IGF1. Since cancer cells rely mostly on a glucose-based metabolism, FMD renders cancer cells more vulnerable to chemotherapy, thereby enhancing therapeutic efficacy. This process is known as differential stress sensitization (DSS). Another response to nutritional stress by fasting is known as differential stress resistance (DSR). DSR is a state in which healthy cells rather focus resources on protection and internal repair, which can result in reduced chemotherapeutic toxicity. Recent preclinical studies found that fasting or FMD not only aids healthy cell protection, but also has the potential to benefit effector T-cells and could thereby improve antitumor immunity. However in most oncotherapeutic clinical trials investigating the addition of a fasting regimen, other factors such as chemotherapy, surgery and additional medication affect the immune system as well. That is why this explorative study, conducted in healthy subjects, might be more suitable to investigate the immunological alterations upon FMD more specifically. This exploratory study aims to identify immunological alterations by using extensive immunoprofiling before and after three days of FMD in healthy subjects, as well as investigate possible side effects of FMD.

The Effect of a Fasting MimickINg Diet on the Immune System

The Effect of a Fasting MimickINg Diet on the Immune System: an Exploratory Study

PBMCs are retrieved from whole blood samples. Gene expression signature is retrieved from PBMCs using RNA-Nanostring technique with the Pancancer IO 360 panel. The Nanostring will report RNA counts for a panel of 770 genes, including 40 housekeeping genes. The data will be normalized on the 40 housekeeping genes for internal control using Nanostring nSolver software. The fold change from baseline to overnight fast and after completion of second fasting mimicking diet will provide insight in affected pathways as well as metabolic and immune signatures.

PBMCs retrieved from whole blood samples will be analysed with a 40-plex Aurora flowcytometry panel with markers for T cells and myeloid cells. The flow cytometry will generate frequencies of the different immune cell markers,. A comparison of the frequency data between blood samples will determine change in immune cell properties.

This analysis will be used to confirm and complement gene expression signature findings on a protein level.

Measured in blood plasma taken at 3 time points.

Descriptive analysis of adverse events by type and grade according to NCI CTCAE v5.0 experienced by participants during fasting mimicking diet assessed after second cycle on day 22.

Leiden University Medical Center

medical oncologist, associate professor

All Drugs and Chemicals

Linrodostat

Enzyme Inhibitors

Single, 100 mg dose of BMS-986205 under fasted conditions (Day 1) followed by single, 100 mg dose of BMS-986205 with a high-fat meal (Day 15).

Single, 100 mg dose of BMS-986205 with a high-fat meal (Day 1) followed by single, 100 mg dose of BMS-986205 under fasted conditions (Day 15).

Single, 100 mg dose of BMS-986205 under fasted conditions (Day 1) followed by single, 100 mg dose of BMS-986205 with a light meal (Day 15).

Single, 100 mg dose of BMS-986205 with a light meal (Day 1) followed by single, 100 mg dose of BMS-986205 under fasted conditions (Day 15).

Single dose, 100 mg administered at Day 1 and at Day 15.

BMS-986205

Bristol-Myers Squibb

The purpose of this study is to investigate the effect of a light meal and a high-fat meal on the bioavailability (absorption) of of BMS-986205 commercial tablet in healthy participants. Eligible participants will receive a single dose of BMS-986205 under fasted or fed (high-fat meal or light meal) conditions on Day 1 and Day 15. The safety, tolerability and movement of the BMS-986205 into, through and out of the body (pharmacokinetics/PK) under these conditions will be assessed.

An Investigational Study to Assess the Effect of a Light Meal and a High-Fat Meal on the Absorption of BMS-986205 in Healthy Participants

Randomized, Open-Label Study to Assess the Effect of a Light Meal and a High-Fat Meal on the Bioavailability of a Single 100-mg Dose of BMS-986205 Commercial Tablet in Healthy Participants

Safety and tolerability of BMS-986205 measured by investigator assessment.

Skin and Connective Tissue Diseases

Breast Neoplasms

Oculocerebral Syndrome With Hypopigmentation

Micronutrients

Vitamins

Tocopherols

Vitamin E

Tocotrienols

alpha-Tocopherol

Antioxidants

Protective Agents

Trace Elements

Tocopherol

Tocotrienol

Single oral TRF or Gamma-Delta Tocotrienol dosage

Gamma-Delta Tocotrienol and Tocotrienol Rich Fraction

Nur Aishah Mohd Taib

Twelve healthy volunteers who fit the inclusion and exclusion criteria and provide written informed consent to participate in the trial will be recruited to compare the rate and extent of absorption and pharmacokinetics of the newly formulated Gamma-Delta formulation with TRF.

Twelve healthy subjects will be admitted to a clinical study ward on the Day 0. Physical check up and the health status will be confirmed during check in. After fasting for a minimum of 10 hours overnight, each subject will be administered a single dose of TRF or Gamma-Delta after taking a standardized high-fat meal breakfast on Day 1. Thereafter, standard meals will be provided at 4 and 12 hours after dosing. Blood samples (5mL will be taken using an in-dwelling canula placed in the antecubital vein immediately before and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 14, and 24 hours after dosing. Subjects will be admitted for 24 hours and discharged after the last blood sampling. During the study, blood pressure and the heart rate will be monitored regularly for safety profile.

After a one week wash out period, subject will return to the ward and be given the other formulation (TRF or GDT) and the same procedures will be repeated. Any adverse events that arise during the treatment will be recorded and followed up till resolution.

Gamma-delta Tocotrienol as Potential Maintenance Treatment in Women With Metastatic Breast Cancer

Phase 1a: A Randomized, 2-period Cross-over Study to Compare the Bioavailability of Gamma-Delta Tocotrienol (GDT) With That of Tocotrienol Rich Fraction (TRF) in Twelve Healthy Subjects

University of Malaya

Malaysia Palm Oil Board

Amino Acids

Neratinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

neratinib

Puma

Safety and tolerability of HKI-272 in healthy subjects; the influence of food intake on the same.

Study Evaluating HKI-272 Administered to Healthy Subjects

Ascending Single Dose Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of HKI-272 Administered Orally to Healthy Subjects.

Puma Biotechnology, Inc.

Menopause

Anti-Infective Agents

Estrogens

Itraconazole

Hydroxyitraconazole

Clotrimazole

Miconazole

Antifungal Agents

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 CYP3A Inhibitors

Subjects will receive a single oral dose of Camizestrant on Day 1 of treatment period 1. Following washout period of 7 to 10 days, subjects will receive Itraconazole on Days 1, 2, and 3 of treatment period 2, and single oral dose of Camizestrant plus a dose of Itraconazole on Day 1, followed by Itraconazole alone on Day 2 and Day 3 of treatment period 3.

Subjects will be administered a single oral dose of Camizestrant on Day 1 of treatment period 1 and treatment period 3.

Camizestrant

Subjects will be administered Itraconazole twice a day on Day 1 and once daily on Day 2 and Day 3 of treatment period 2, and once daily on Day 1, 2 and 3 of treatment period 3.

This study will be conducted in healthy post-menopausal female subjects to assess the pharmacokinetics (PK) of Camizestrant (AZD9833) when administered alone and in combination with Itraconazole.

This open-label, fixed sequence study will comprise of:

* A screening period of 28 days;
* A fixed sequence of three treatment period:

Treatment Period 1: Camizestrant only, Treatment Period 2: Itraconazole only, Treatment Period 3: Camizestrant and Itraconazole in combination.

• A Follow-up Visit at 7 to 14 days after the last Camizestrant PK sample in Period 3.

There will be a washout period of 7 to 10 days between Period 1 and Period 2. Each subject will be involved in the study for approximately 8 or 9 weeks.

A Study to Assess the Pharmacokinetics of Camizestrant (AZD9833) When Administered Alone and in Combination With Itraconazole

An Open-Label, Fixed Sequence Study in Healthy Post Menopausal Female Subjects to Assess the Pharmacokinetics of Camizestrant (AZD9833) When Administered Alone and in Combination With Itraconazole

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

To assess the effect of Itraconazole on AUCinf of Camizestrant.

To assess the effect of Itraconazole on AUClast of Camizestrant.

To assess the effect of Itraconazole on Cmax of Camizestrant.

Safety and tolerability of Camizestrant alone and in combination with Itraconazole will be assessed.

Number of subjects who discontinue the study drug due to adverse events will be assessed.

Parexel

AstraZeneca

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Carcinoma

Carcinoma, Non-Small-Cell Lung

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

NSCLC patients,including stage I to stage IV.

Without intervention,this study is just an observational study.

without intervention type

dong xiaorong, Dr

Relationship between human microbiota and epidemiology of lung cancer

In this study,We aim to find some kinds of human microbiota , which were associated with development of non-small cell lung cancer.

We intend to collect the following samples：

1. Blood samples
2. Stool samples
3. Sputum samples
4. Tumor tissue samples

The Role of Microbiota on the Development of Lung Cancer

Find some human microbes that are associated with the development of lung cancer, we can detect these human microbiological content as a biomarker of lung cancer.

Xiaorong Dong

Professor

Musculoskeletal Diseases

Digestive System Diseases

Giant Cell Tumors

Giant Cell Tumor of Tendon Sheath

Liver Diseases

Gastrointestinal Diseases

Pigmented Villonodular Synovitis

Participants with moderate hepatic impairment who will receive a single oral dose of pexidartinib.

Sex-, age-, and weight-matched healthy participants who will receive a single oral dose of pexidartinib.

Single, 200-mg capsule will be administered orally on Day 1 with 240 mL of water, following an overnight fast of at least 10 hours.

Pexidartinib

Clinical Study Leader

The pharmacokinetics of a single dose of pexidartinib was investigated in participants with impaired hepatic function and compared with healthy control participants with normal hepatic function.

Pexidartinib is an orally administered tyrosine kinase inhibitor, currently approved in the US for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery.

The primary objective of this study is to determine the plasma pharmacokinetics (PK) of pexidartinib after a single oral dose of 200 mg in participants with moderate hepatic impairment (HI) as defined by National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria compared to the healthy controls participants with normal hepatic function.

Study of Pexidartinib in Participants With Moderate Hepatic Impairment Compared With Healthy Participants

An Open-label, Single-dose Study to Assess the Pharmacokinetics of Pexidartinib in Subjects With Moderate Hepatic Impairment Compared to Healthy Subjects

De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis.

Time of Maximum Plasma Concentration (Tmax) is defined as the time of maximum observed plasma concentration and was calculated using non-compartmental analysis.

Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method and was calculated using non-compartmental analysis.

Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf ) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and was calculated using non-compartmental analysis.

Elimination Rate Constant (Kel) is defined as elimination rate constant and was calculated using non-compartmental analysis.

Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis.

Total Apparent Clearance (CL/F) is defined as total apparent clearance and was calculated using non-compartmental analysis.

Volume of Distribution in the Terminal Phase (Vz/F) is defined as volume of distribution in the terminal phase and was calculated using non-compartmental analysis.

Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was calculated using non-compartmental analysis.

Area Under the Concentration-Time Curve (AUCinf) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and AUClast is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. AUCinf and AUClast are reported and were calculated using non-compartmental analysis.

AUCinf is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and AUClast is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. MPR is defined as a metabolite to parent ratio with metabolite as the numerator and the parent as the denominator. MPR corrected for molecular weight of ZAAD-1006a of AUCinf and AUClast are reported and were calculated using non-compartmental analysis.

Protein binding (percentage bound) was determined in all participants at 2.5h and 24h post-dose. Plasma was harvested and analyzed for the quantification of pexidartinib using a validated liquid chromatography-tandem mass spectrometry method and the ZAAD-1006a metabolite was analyzed using a qualified liquid chromatography-tandem mass spectrometry assay.

A Treatment-Emergent Adverse Event (TEAE) is defined as any event not present prior to the initiation of the drug treatment or any event already present that worsens in either intensity or frequency following exposure to the drug treatment.

Daiichi Sankyo

Adverse events were defined as any untoward, unfavorable, unintended medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. All-cause mortality includes all deaths that occurred during the study and within the 30 days after the last dose of the study drug.

Healthy matched participants with normal HF who received 200mg pexidartinib on Day 1 with 240 mL water. Participants fasted for at least 10h before pexidartinib dosing and continued to fast for at least 4h after pexidartinib administration.

Normal HF

Participants with moderate HI who received 200mg pexidartinib on Day 1 with 240 mL water. Participants fasted for at least 10h before pexidartinib dosing and continued to fast for at least 4h after pexidartinib administration. Moderate hepatic impairment (HI) was assessed by National Cancer Institute - Organ Dysfunction Working Group (NCI-ODWG).

Moderate HI

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Weight

Baseline characteristics were assessed using the Safety Analysis Set.

Contact for Clinical Trial Information

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.

Maximum Plasma Concentration (Cmax) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

Time of Maximum Plasma Concentration (Tmax) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

The pharmacokinetic parameter of Area Under the Plasma Concentration-Time Curve up to Infinity was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis.

Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf ) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

The pharmacokinetic parameter of Elimination Rate Constant was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis..

Elimination Rate Constant (Kel) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

The pharmacokinetic parameter of Terminal Elimination Half-Life was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis.

Terminal Elimination Half-Life (t1/2) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

The pharmacokinetic parameter of Total Apparent Clearance was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis.

Total Apparent Clearance (CL/F) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Functional Pharmacogenomics of Childhood Acute Lymphoblastic Leukemia in Taiwan	NCT00526084	Leukemia, Lymph...		1 Year - 18 Years	National Taiwan University Hospital
Food Effect Study on the Pharmacokinetics of VC004 Capsules in Healthy Adult Subjects	NCT05528120	Locally Advance...	VC004 Capsules VC004 Capsules	18 Years - 45 Years	Jiangsu vcare pharmaceutical technology co., LTD
Functional Pharmacogenomics of Childhood Acute Lymphoblastic Leukemia in Taiwan	NCT00526084	Leukemia, Lymph...		1 Year - 18 Years	National Taiwan University Hospital
The Effect of a Fasting MimickINg Diet on the Immune System	NCT04833439	Healthy Subject... Cancer Neoplasms	Fasting Mimicki...	18 Years -	Leiden University Medical Center
An Investigational Study to Assess the Effect of a Light Meal and a High-Fat Meal on the Absorption of BMS-986205 in Healthy Participants	NCT03312426	Healthy Volunte...	BMS-986205	18 Years - 50 Years	Bristol-Myers Squibb
The Effect of a Fasting MimickINg Diet on the Immune System	NCT04833439	Healthy Subject... Cancer Neoplasms	Fasting Mimicki...	18 Years -	Leiden University Medical Center
Gamma-delta Tocotrienol as Potential Maintenance Treatment in Women With Metastatic Breast Cancer	NCT01571921	Healthy Subject...	Gamma-Delta Toc...	21 Years - 55 Years	Malaysia Palm Oil Board
The Effect of a Fasting MimickINg Diet on the Immune System	NCT04833439	Healthy Subject... Cancer Neoplasms	Fasting Mimicki...	18 Years -	Leiden University Medical Center
Study Evaluating HKI-272 Administered to Healthy Subjects	NCT00366600	Healthy	neratinib	18 Years - 50 Years	Puma Biotechnology, Inc.
A Study to Assess the Pharmacokinetics of Camizestrant (AZD9833) When Administered Alone and in Combination With Itraconazole	NCT05551897	Healthy Subject...	Camizestrant Itraconazole	50 Years - 70 Years	AstraZeneca
The Role of Microbiota on the Development of Lung Cancer	NCT03454685	NSCLC, Stage I NSCLC, Stage II NSCLC, Stage II... NSCLC Stage IV Healthy Subject...	without interve...	18 Years - 70 Years	Wuhan Union Hospital, China
Study of Pexidartinib in Participants With Moderate Hepatic Impairment Compared With Healthy Participants	NCT04223635	Moderate Hepati...	Pexidartinib	18 Years - 75 Years	Daiichi Sankyo
An Investigational Study to Assess the Effect of a Light Meal and a High-Fat Meal on the Absorption of BMS-986205 in Healthy Participants	NCT03312426	Healthy Volunte...	BMS-986205	18 Years - 50 Years	Bristol-Myers Squibb

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