Infections

All Conditions

Neoplasms

Blood and Lymph Conditions

Mycoses

Hematologic Neoplasms

Invasive Fungal Infections

Hematologic Diseases

Anti-Infective Agents

All Drugs and Chemicals

Isavuconazole

Clotrimazole

Miconazole

Antifungal Agents

Patients will receive an intravenous (IV) loading regimen of isavuconazonium sulfate, which consists of a dose every 8 hours (+/- 2 hours) on days 1 and 2, followed by once daily IV maintenance dosing for up to 26 additional days (for a maximum of 28 days of dosing).

Patients will receive an IV loading regimen of isavuconazonium sulfate, which consists of a dose every 8 hours (+/- 2 hours) on days 1 and 2, followed by once daily IV maintenance dosing for up to 26 additional days (for a maximum of 28 days of dosing).

Patients will receive a loading regimen of isavuconazonium sulfate by oral administration, comprising one dose every 8 hours (+/- 2 hours) on days 1 and 2 (a total of six doses), followed by once daily oral maintenance dosing for up to 26 additional days (for a maximum of 28 days of dosing).

isavuconazonium sulfate - intravenous

isavuconazonium sulfate - oral

Senior Medical Director

The purpose of the study is to evaluate the pharmacokinetics (PK), safety and tolerability of multiple doses of intravenous (IV) and oral isavuconazonium sulfate administered daily in pediatric patients. The PK data will be utilized to establish a pediatric population PK model of isavuconazole, the active moiety of isavuconazonium sulfate.

A Study of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients

A Phase 1, Open-label, Multicenter, Non-comparative Pharmacokinetics and Safety Study of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients

Access to anonymized individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas."

Maximum concentration at steady state (Cmax) will be derived from the PK plasma samples collected.

Area under the concentration time curve from the time of dosing to the start of next dosing interval at multiple dose conditions (AUCtau) will be derived from the PK plasma samples collected.

Time of maximum concentration (tmax) will be derived from the PK plasma samples collected.

Concentration - trough level (Ctrough) will be derived from the PK plasma samples collected.

Volume of distribution at steady state (Vss) will be model-derived.

Area under the concentration-time curve at steady state (AUCss) will be model-derived.

A TEAE is defined as an Adverse Event (AE) observed after starting administration of the study drug through follow-up. AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Number of patients with TEAE's will be summarized.

An abnormality identified during a medical test (e.g. vital signs) should be defined as an AE only if the abnormality meets 1 of the following criteria: induces clinical signs or symptoms; requires active intervention; requires interruption or discontinuation of study drug; or the abnormality or test value is clinically significant.

An abnormality identified during a medical test (e.g. laboratory parameter) should be defined as an AE only if the abnormality meets 1 of the following criteria: induces clinical signs or symptoms; requires active intervention; requires interruption or discontinuation of study drug; or the abnormality or test value is clinically significant.

Standard 12-lead ECG recordings will be used for the purposes of safety assessment. A 12-lead, resting ECG is to be recorded. Patients should remain supine for at least 5 minutes prior to all ECGs being performed. The results (normal, abnormal not clinically significant, abnormal clinically significant) are to be recorded.

Basilea Pharmaceutica International Ltd

Astellas Pharma Global Development, Inc.

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Antineoplastic Agents

Analgesics

Etoposide

Cytarabine

Mitoxantrone

Fludarabine

Fludarabine phosphate

Daunorubicin

Etoposide phosphate

Idarubicin

Midostaurin

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Enzyme Inhibitors

Antiviral Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Protein Kinase Inhibitors

In Part 1, midostaurin with standard induction (Block 1 induction according to local practice, Block 2 induction containing fludarabine, cytarabine, daunorubicin/idarubicin) and consolidation (Block 3: cytarabine + mitoxantrone, Block 4: cytarabine + etoposide, Block 5: cytarabine) followed by single agent midostaurin post-consolidation therapy.

In Part 2, midostaurin with standard induction (Block 1 induction according to local practice, Block 2 induction containing cytarabine + mitoxantrone) and consolidation (Block 3: cytarabine + etoposide, Block 4: cytarabine + mitoxantrone, Block 5: cytarabine) followed by single agent midostaurin post-consolidation therapy.

Part 1:

2000mg/m2/day D1 to D5 of Block 2 FLADx 1000mg/m2 every 12 hours D1 to D3 Block 3 HAM 3000mg/m2 every 12 hours D1 to D3 Block 4 HA3E 3000mg/m2 every 12 hours D1 to D3 Block 5 HIDAC

Part 2:

1000mg/m2 every 12 hours D1 to D3 Block 2 HAM 3000mg/m2 every 12 hours D1 to D3 Block 3 HA3E 1000mg/m2 every 12 hours D1 to D3 Block 4 HAM 3000mg/m2 every 12 hours D1 to D3 Block 5 HIDAC

daunorubicin 60 mg/m2/day OR idarubicin 12mg/m2/day On D2, D4, D6 of Block 2 FLADx

Daunorubicin or idarubicin

Novartis Pharmaceuticals

This study will evaluate the safety, efficacy and pharmacokinetics of midostaurin in combination with standard chemotherapy in pediatrics patients with newly diagnosed FLT3-mutated Acute Myeloid Leukemia. The study has two parts: Part 1 to define the Recommended Phase 2 Dose, and Part 2 to evaluate safety and tolerability and efficacy of midostaurin. Both parts will consist of 2 induction blocks, 3 consolidation blocks, 12 cycles of post-consolidation consisting of continuous therapy with midostaurin, and a follow-up phase.

This trial is an open label, multi center single arm study to evaluate twice daily oral midostaurin with standard induction, consolidation chemotherapy with sequential midostaurin therapy for 5 treatment blocks (2 induction blocks, 3 consolidation blocks, followed by single agent midostaurin post consolidation therapy for 12 cycles).

The total maximum planned duration on treatment is 17 cycles (5 blocks and 12 cycles). A block is defined as the time from start of study treatment to the time of hematopoietic recovery, at the latest at Day (D) 42, or determination of persistent disease, whichever occur first.

In both Part 1 and Part 2, patients will receive the first course of induction chemotherapy according to local standard and duration is from 8 to 12 days. Upon FLT3 mutation confirmation, patients will receive midostaurin for 14 days. After determination of remission and hematopoietic recovery, patients will receive Block 2.

In Part 1:

* Block 2 FLADx treatment duration is D1 to D6, and midostaurin from D8 to D21. Patients who achieve documented CR (and hematopoietic recovery at the latest at D42 from the first day of Block 2) will receive Block 3.
* Block 3 consolidation HAM treatment duration is D1 to D4, followed by midostaurin D8 to D21. Patients who achieve hematopoietic recovery at the latest at D42 from the first day of Block 3 will receive Block 4. Patients who relapse will discontinue further study treatment.
* Block 4 HA3E treatment duration is D1 to D5 followed by midostaurin D8 to D21. Patients who achieve hematopoietic recovery at the latest at D42 from the first day of Block 4 will receive Block 5.
* Block 5 HiDAC treatment duration is D1 to D3 followed by midostaurin D8 to D21. Patients who relapse will discontinue further study treatment.

Patients in continuous remission with hematopoietic recovery will receive continuous post consolidation therapy of midostaurin, during 12 cycles (28 days per cycle).

In Part 1 of the study, patients in cohorts of 3 will receive sequential midostaurin administered at 30mg/m2bid. If the 30mg/m2 bid is well tolerated as measured by the Dose Limited Toxicity (DLT) rate during Bock 1, additional patients in cohort of 3 will be treated with sequential midostaurin at 60mg/m2 bid. When the recommended phase 2 dose (RP2D) is confirmed, subsequent patients will be treated in Part 2 of the study at the RP2D.

In Part 2:

* Block 2 HAM treatment duration is D1 to D4 and midostaurin from D8 to D21. Patients who achieve documented CR (and hematopoietic recovery at the latest at D42 from the first day of Block 2) will receive Block 3.
* Block 3 consolidation HA3E treatment duration is D1 to D5, followed by midostaurin D8 to D21. Patients who achieve hematopoietic recovery at the latest at D42 from the first day of Block 3 will receive Block 4. Patients who relapse will discontinue further study treatment.
* Block 4 HAM treatment duration is D1 to D4 followed by midostaurin D8 to D21. Patients who achieve hematopoietic recovery at the latest at D42 from the first day of Block 4 will receive Block 5.
* Block 5 HiDAC treatment duration is D1 to D3 followed by midostaurin D8 to D21. Patients who relapse will discontinue further study treatment.

Patients in continuous remission with hematopoietic recovery will receive continuous post consolidation therapy of midostaurin, during 12 cycles (28 days per cycle). Patients who relapse will discontinue further study treatment.

A Global Study of Midostaurin in Combination With Chemotherapy to Evaluate Safety, Efficacy and Pharmacokinetics in Newly Diagnosed Pediatric Patients With FLT3 Mutated AML

A Phase II, Open-label, Single Arm Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Twice Daily Midostaurin (PKC412) Combined With Standard Chemotherapy and as a Single Agent Post-consolidation Therapy in Children With Untreated FLT3-mutated AML

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

Dose-limiting toxicity (DLT) is defined as any death due to toxicity related to study treatment (chemotherapy + midostaurin) and/or any CTCAE grade 4 non-hematological adverse event or abnormal laboratory value grade 4 related to study treatment unless the event improves sufficiently by day 42 and therefore does not further delay the next cycle of study treatment.

Safety profile includes type, frequency and severity of adverse events during the induction, consolidation and post consolidation phase. AEs are also collected during post treatment follow-up phase

Number of dose interruptions/reductions and discontinuations due to study drug

Percentage of participants with a response of CR, CRi or modified CRi at the end of Block 2

TTR is defined as the time between start of treatment to the date of first onset of response (CR, CRi or modified CRi).

Response duration is defined as the time from CR, CRi or modified CRi to relapse or death due to any cause.

EFS is defined as the time from Day 1 of chemotherapy until an EFS event is observed.

An EFS event is defined as a failure to obtain CR/Modified CRi within induction, relapse after CR/modified CRi, or death due to any cause, whichever occurs first. EFS will be measured after all participants completed at least 18 months of follow-up.

OS is defined as the time from Day 1 of chemotherapy to the date of death due to any cause.

DFS is defined as the time from CR/modified CRi in induction to relapse or death due to any cause

Percentage of patient with MRD negative status by multiparameter flow cytometry

Palatability is assessed through questionnaires- Palatability PRO and obsPRO

Bone marrow and peripheral blood parameters and extramedullar involvement at the end of induction Block 1 and Block 2

Plasma concentration of midostaurin and its 2 metabolites

Substance Related Disorders

Drug-Related Side Effects and Adverse Reactions

Aspergillosis

Chemically-Induced Disorders

Voriconazole

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 CYP3A Inhibitors

All eligible patients will be followed up for voriconazole related adverse drug events and efficacy

This is an observational study and only the patients already on voriconazole treatment will be included in the study.

Mukaddes Gumustekin, Professor, MD, PhD

Ozge Akcay, MD

Hale Oren, Professor, MD

Sebnem Yilmaz, Professor, MD

Nursen Belet, Professor, MD

Deniz Yilmaz Karapinar, Professor, MD

Bucak Tatli Gunes, MD

Ayfer Ulgenalp, Professor, PhD

Altug Koc, MD, PhD

Muharrem Anil Gurkan, MD

Mert Sarilar, MD

Richard Myles Turner, MD, PhD

Munir Pirmohamed, Professor, MD, PhD

Voriconazole is a drug used to treat invasive fungal infections. The amount of voriconazole in a person's blood helps to determine how effectively it treats an infection, and how safe it is. Patients respond differently when receiving the same dose - some clearly benefit, other patients experience side effects, and others see limited improvement in their infection.

Voriconazole is broken down in the liver mainly by an enzyme called CYP2C19, before being excreted from the body. The activity of CY2C19 differs between people because of variation in the DNA that encodes the body's instructions to make CYP2C19.

If CYP2C19 activity is very high, voriconazole blood levels may remain below the target range when a patient receives a standard dose of voriconazole, which may be insufficient to treat their infection. Besides, children tend to have faster voriconazole metabolism regardless of the genetic makeup, mainly because of higher liver mass/body proportion. That's why, younger patients needs higher doses and it is harder for them to reach target range. Having a high CYP2C19 activity and being young combined may cause to consider choosing an alternative drug. By contrast, decreased CYP2C19 activity due to genetic variation may result in excessively high voriconazole blood levels, predisposing to serious side effects.

Therefore, knowing a patient's CYP2C19 genetic makeup is very important for predicting their response to voriconazole.

Thus, we aim to determine the influence of genetic variation in CYP2C19 on the frequency and severity of side effects related to voriconazole, and on the effectiveness of voriconazole for treating serious fungal infections. The findings from this study will contribute to determining the optimal dose of voriconazole that patients with different genetic variants in CYP2C19 should be started on, and will take us one step closer to both understanding the genetic structure of CYP2C19 in the Turkish population, and to 'personalised medicine'.

Invasive fungal infections are the leading cause of mortality and morbidity in immune compromised children. Aspergillus species are reported to be the most common molds that cause invasive infections among pediatric patients both in the United States and in Europe.

Voriconazole is recommended as the first line therapy for invasive Aspergillosis. The major proportion of the drug undergoes hepatic metabolism via cytochrome enzymes. The hepatic cytochrome enzyme that mainly involves in the metabolism of voriconazole is CYP2C19, which is known to be highly polymorphic. So far, more than 30 variant alleles have been defined in the gene that codes CYP2C19 enzyme.

Polymorphisms in CYP2C19 gene are associated with alterations in voriconazole metabolism. It is postulated that only 35-50% of the populations has normal metabolic activity for this drug. The carriers of defective alleles (\*2/\*2, \*2/\*3, \*3/\*3) in CYP2C19 gene have slower metabolic activity for voriconazole, while the carriers of \*17 allele have increased enzyme activity and higher metabolic capacity for the drug.

Voriconazole has a narrow therapeutic window. When the therapy is initiated with standard doses, interpersonal differences in CYP2C19 activity make it difficult to remain in the optimal therapeutic range. Furthermore, it is reported that voriconazole concentrations in pediatric patients can exhibit up to 3-fold variation among individuals and it is extremely hard to reach and remain therapeutic concentration in younger children. As low serum concentrations cause decreased efficacy, supratherapeutic concentrations may cause voriconazole toxicity which also leads to significant morbidity, mortality and high treatment costs.

To ensure desired efficacy and safety of voriconazole treatment, therapeutic drug monitoring (TDM) is recommended, but unfortunately, it is not a part of routine clinical care in many hospitals, due to frequent blood sampling and analysis requirements and the high analysis costs. On the other hand, starting the therapy with standard doses and adjusting it with subsequent TDMs may cause delay in selecting optimal voriconazole dose and providing effective treatment.

It is reported that, pediatric patients those are initiated voriconazole therapy with pharmacogenetic-guided dose selection reaches targeted serum voriconazole concentration 4-fold faster than the patients those are given standard doses and undergoes subsequent dose adjustments according to TDM results. Thus, CYP2C19 genotyping is essential in reaching the optimal voriconazole concentration in shorter times. Genotype-guided first dose selection would make it easier to reach the targeted serum voriconazole concentration, minimize frequent TDM requirement, prevent the treatment failure and lead to better clinical outcomes. On the other hand, pharmacogenetic analysis results can also be used for adjusting dose of other drugs that is metabolized by the same enzyme.

We could only located one conference proceeding reporting the effect of CYP2C19 polymorphisms on safety of voriconazole use in 6 patients in Turkish population. Current literature is limited and the guidelines does not make a clear recommendation about the pharmacogenetic-guided dose selections. Thus, to build safe pharmacogenetic- guided dose selection algorithms, more data in that field is required.

This study is designed to prospectively determine the influence of CYP2C19 polymorphisms on frequency and severity of voriconazole related adverse event reactions during the study follow up period and on the efficacy of voriconazole treatment/ prophylaxis. Samples for pharmacogenetic analysis will be stored for further studies depending on participant's and the parents' discreation.

METHOD This is a multi centre, observational cohort study.

Study population:

Patients aged between ≥2 years and \<18 years hospitalized in pediatric hematology clinics in research centers (Dokuz Eylul University Hospital, Ege University Hospital, Izmir University of Health Sciences Tepecik Training and Research Hospital) due to a hematological malignancy (acute lymphoblastic leukemia, acute myeloid leukemia) and receiving voriconazole as part of invasive fungal infection prophylaxis or treatment.

Data and sample collection 1.1.1.Data collection: At baseline, demographics and clinical information will be recorded from all patients directly and complemented from their medical records. All patients will be followed up by the research team daily for the first 7 days following voriconazole initiation, and then on days 14, 30 and 60. All follow up will be initially via assessment of medical records, with additional data input from the patient directly. The medical records include: the electronic hospital record system (PROBEL), paper-based patient records and other patient follow-up- documents.

During routine clinical care, ADRs are monitored daily by a pediatric hematology fellow and/or pediatrician. On days one to seven following voriconazole initiation, the investigators will record these clinical evaluations daily; they will also capture these data on days 14 and 30.

For participants that had either started voriconazole active treatment before they were recruited, or were recruited during the maintenance phase of their voriconazole regimen, the research team will assess their medicals records retrospectively between the point of recruitment and day one of their active voriconazole treatment to detect ADRs.

On days 30 and 60, patient survival will be recorded by review of patient records only.

Treatment response (efficacy) will be determined based on the EORTC/MSG consensus criteria. These data will be obtained at all follow up points (from day one to seven, and days 14, 30 and 60).

1.1.2.Sample collection: 1.1.2.1.Samples fo PGx analysis: All pediatric patients with a hematologic malignancy (acute lymphoblastic leukemia, acute myeloid leukemia) hospitalized aforementioned study centers and their parents will be informed of the study. Those agree to participate in will donate 2 mL blood sample collected into an EDTA (Ethylenediaminetetraacetic Acid) tube on day one whilst blood samples are being taken from the patient for daily routine clinical purposes (without requiring any other needle insertion). Samples for PGx analysis will be coded and stored securely in Dokuz Eylul University Hospital, Department of Medical Pharmacology. The samples will be stored -80 celcius degree until used up. PGx analysis will be performed in the Department of Medical Genetics at Dokuz Eylul University Hospital at the end of the study. Participants and physicians will not be informed of the participant's genotype during the study period. The participant's clinical care will not be affected in any way by taking part in the study.

1.1.2.2.Samples for voriconazole concentration determination: The patients those start using voriconazole as part of invasive fungal infection prophylaxis or treatment will The second 2 mL blood sample will be collected into a red cap tube on the fifth day (9th dose) of treatment before the morning voriconazole dose, again whilst blood is being collected as part of routine clinical care (without requiring any other needle insertion) to determine the trough voriconazole concentration at steady state. This blood sample will be centrifuged and the serum stored in the Department of Medical Pharmacology at the Dokuz Eylul University Faculty of Medicine. When follow up is completed for a given patient, this serum sample will be transferred to an accredited laboratory in Istanbul, Turkey, with maintenance and assurance of the cold chain during sample transportation to guarantee sample integrity.

2 mL of blood sample collected into an EDTA (Ethylenediaminetetraacetic Acid) tube for PGx analysis and another 2 mL of blood sample collected into an EDTA (Ethylenediaminetetraacetic Acid) tube for voriconazole TDM

Influence of CYP2C19 Genotype on Safety and Efficacy of Voriconazole in Pediatric Patients With Hematologic Malignancy

Voriconazole related adverse drug reactions of grade 3-5 systematically evaluated using Liverpool Causality Assessment Tool identified during study follow up.

Severity of all adverse events will be graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.

The efficacy of voriconazole treatment will be assessed based on reviews of clinical, mycological and radiological data according to the Mycoses Study Group and European Organization for Research and Treatment of Cancer Consensus Criteria (EORTC/MSG criteria).

Voriconazole trough concentration will be measured once for each participant from plasma samples collected 30 minutes before the 9th dose of voriconazole

Patient survival will be evaluated on days 30 and 60 by reference to the Dokuz Eylul University Hospital Hematology Service; date of death will be captured to permit survival analysis.

University of Liverpool

Dokuz Eylul University

Full Professor

Palliative care has received considerable attention in Taiwan in recent years. The relevant research has been widely conducted for palliative care in adult population. However, the research in children population is relatively insufficient. In the limited studies, most of them are the experiences generated from individual institutions. This study is going to retrieve the data from 2008-2017 National Health Insurance Research Database, Cancer Registry Database, Death Registry Database and other relevant materials in order to analyze the trends of using pediatric palliative care service, the types of services, the timing of initiating palliative care, and the preference of using palliative care service among different life span in the past decade. In addition, the study will examine the differences of the timing of initiating of pediatric palliative care service and the types of diseases among different characteristics of children and healthcare providers. And the study will discuss how pediatric palliative care services affect medical costs.

Trend Analysis of the Service of Pediatric Palliative Care

The Trend Analysis and Associated Factors of Initiating the Service of Pediatric Palliative Care

The study will use the National Health Insurance Database, Cancer Registry Database and other relevant materials from Ministry of Health and Welfare in Taiwan to conduct research.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients	NCT03241550	Hematological M...	isavuconazonium... isavuconazonium...	1 Year - 17 Years	Astellas Pharma Inc
A Global Study of Midostaurin in Combination With Chemotherapy to Evaluate Safety, Efficacy and Pharmacokinetics in Newly Diagnosed Pediatric Patients With FLT3 Mutated AML	NCT03591510	FLT3-mutated Ac...	Midostaurin Fludarabine Cytarabine Daunorubicin or... Mitoxantrone Etoposide	3 Months - 17 Years	Novartis
Influence of CYP2C19 Genotype on Safety and Efficacy of Voriconazole in Pediatric Patients With Hematologic Malignancy	NCT04743544	Adverse Drug Re...	Voriconazole	2 Years - 18 Years	Dokuz Eylul University
A Study of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients	NCT03241550	Hematological M...	isavuconazonium... isavuconazonium...	1 Year - 17 Years	Astellas Pharma Inc
A Study of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients	NCT03241550	Hematological M...	isavuconazonium... isavuconazonium...	1 Year - 17 Years	Astellas Pharma Inc
Influence of CYP2C19 Genotype on Safety and Efficacy of Voriconazole in Pediatric Patients With Hematologic Malignancy	NCT04743544	Adverse Drug Re...	Voriconazole	2 Years - 18 Years	Dokuz Eylul University
A Global Study of Midostaurin in Combination With Chemotherapy to Evaluate Safety, Efficacy and Pharmacokinetics in Newly Diagnosed Pediatric Patients With FLT3 Mutated AML	NCT03591510	FLT3-mutated Ac...	Midostaurin Fludarabine Cytarabine Daunorubicin or... Mitoxantrone Etoposide	3 Months - 17 Years	Novartis
Trend Analysis of the Service of Pediatric Palliative Care	NCT03925831	Nursing Caries Palliative Care Pediatric Popul... Pediatric Cance... Oncology		-	National Taiwan University Hospital

Spots Global Cancer Trial Database for pediatric population