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Congenital Bone Marrow Failure Syndromes

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Antineoplastic Agents

All Drugs and Chemicals

Fludarabine

Fludarabine phosphate

All patients enrolled in this study will be located on the inpatient pediatric bone marrow transplant unit at University of California, San Francisco Benioff Children's Hospital.

Janel R Long-Boyle, PharmD, PhD

Fludarabine is a chemotherapy drug used extensively in bone marrow transplantation. The goal of this study is to determine what causes some children to have different drug concentrations of fludarabine in their bodies and if drug levels are related to whether or not a child experiences severe side-effects during their bone marrow transplant. The hypothesis is that clinical and genetic factors cause changes in fludarabine drug levels in pediatric bone marrow transplant patients and that high levels may cause severe side-effects.

Fludarabine is a nucleoside analog with potent antitumor and immunosuppressive properties used in conditioning regimens of pediatric allogeneic hematopoietic cell transplantation (alloHCT) to promote stem cell engraftment.

This is a single-center, pharmacokinetic-pharmacodynamic (PK-PD) study investigating the clinical pharmacology of fludarabine in 45 children undergoing alloHCT at University of California, San Francisco Benioff Children's Hospital.

Patients would receive fludarabine regardless of whether or not they decide to consent to PK sampling.

Fludarabine doses will not be adjusted based on PK data.

We will apply the combination of a D-optimality-based limited sampling strategy and population PK methodologies to determine specific factors influencing fludarabine exposure in pediatric alloHCT recipients and identify exposure-response relationships.

Subjects will undergo PK sampling of plasma (f-ara-a) and intracellular (f-ara-ATP) drug concentrations over the duration of fludarabine therapy (3 to 5 days).

To evaluate sources of variability impacting fludarabine exposure clinical data will be obtained from the patient's medical chart on each day of PK sampling.

A single blood draw for the collection of DNA and genotyping of single nucleotide polymorphisms of genes involved in fludarabine activation, transport or elimination will occur in all patients.

To assess exposure-response relationships neutrophil engraftment, treatment-related toxicity, and survival data will be collected through day 100 post-transplant.

Study of Fludarabine Drug Exposure in Pediatric Bone Marrow Transplantation

Population Pharmacokinetics of Fludarabine in Pediatric Patients Undergoing Hematopoietic Cell Transplantation

Thrasher Research Fund

University of California, San Francisco

Thiotepa

Antineoplastic Agents, Alkylating

Alkylating Agents

Immunosuppressive Agents

Immunologic Factors

Children undergoing hematopoietic stem cell transplant (HCT) at University of California, San Francisco Benioff Children's Hospital

Janel Long-Boyle, PharmD, PhD

Thiotepa is a chemotherapy drug used extensively in bone marrow transplantation. Thiotepa is a prodrug that undergoes metabolic conversion in the liver by CYP2B6 and CYP3A4 to its primary active metabolite, triethylene phosphoramide (TEPA). The goal of this study is to determine what causes some children to have different drug concentrations of thiotepa and TEPA in their bodies and if drug levels are related to whether or not a child experiences severe side-effects during their bone marrow transplant. The hypothesis is that certain clinical and genetic factors cause changes in thiotepa and TEPA drug levels in pediatric bone marrow transplant patients and that high levels may cause severe side-effects.

Thiotepa is an alkylating agent with potent antitumor and immunosuppressive properties used in conditioning regimens of pediatric hematopoietic cell transplantation (HCT) to promote stem cell engraftment. Thiotepa is a prodrug that undergoes metabolic conversion in the liver by CYP2B6 and CYP3A4 to its primary active metabolite, TEPA.

This is a single-center, prospective, non-interventional pharmacokinetics (PK) study investigating the clinical pharmacology of thiotepa and TEPA in 60 children undergoing hematopoietic stem cell transplant (HCT) at University of California, San Francisco Benioff Children's Hospital. Patients would receive thiotepa regardless of whether or not they decide to consent to PK sampling.

Thiotepa doses will not be adjusted based on PK data. The investigators will apply the combination of a limited sampling strategy and population PK methodologies to determine specific factors influencing thiotepa and TEPA exposure in pediatric HCT recipients. Population PK methodologies support the use of sparse sampling and therefore allow the investigators to investigate drug levels in a pediatric population that would otherwise not be feasible using traditional intensive PK sampling.

Subjects will undergo PK sampling of plasma thiotepa and TEPA drug concentrations over the duration of thiotepa therapy (3 to 5 days).

To evaluate sources of variability impacting thiotepa and TEPA exposure clinical data will be obtained from the patient's medical chart on each day of PK sampling.

A single blood draw for the collection of DNA and genotyping of single nucleotide polymorphisms of genes involved in fludarabine activation, transport or elimination will occur in all patients.

To assess exposure-response relationships neutrophil engraftment, treatment-related toxicity, and survival data will be collected through day 100 post-transplant.

Study of Thiotepa and TEPA Drug Exposure in Pediatric Hematopoietic Stem Cell Transplant Patients

Population Pharmacokinetics and Pharmacodynamics of Thiotepa and TEPA in Pediatric Patients Undergoing Hematopoietic Cell Transplantation (HCT).

Area-under-the-curve (AUC) will be derived from the empirical Bayes estimates of individual clearance

Death due to any cause within 1 month post-transplant will be considered an event.

Death due to any cause within day 3 months post-transplant will be considered an event.

Death due to any cause within day 1 year post-transplant will be considered an event.

Melphalan

Children undergoing allogeneic hematopoietic stem cell transplant (alloHCT) at University of California, San Francisco Benioff Children's Hospital.

Melphalan is a chemotherapy drug used extensively in bone marrow transplantation. The goal of this study is to determine what causes some children to have different drug concentrations of melphalan in their bodies and if drug levels are related to whether or not a child experiences severe side-effects during their bone marrow transplant. The hypothesis is that certain clinical and individual factors cause changes in melphalan drug levels in pediatric bone marrow transplant patients and that high levels may cause severe side-effects.

Melphalan is an alkylating agent with potent antitumor and immunosuppressive properties used in conditioning regimens of pediatric allogeneic hematopoietic cell transplantation (alloHCT) to promote stem cell engraftment.

This is a single-center, prospective, non-interventional pharmacokinetics (PK) study investigating the clinical pharmacology of melphalan in 24 children undergoing allogeneic hematopoietic stem cell transplant (alloHCT) at University of California, San Francisco Benioff Children's Hospital.

Patients would receive melphalan regardless of whether or not they decide to consent to PK sampling.

Melphalan doses will not be adjusted based on PK data.

The investigators will apply the combination of a limited sampling strategy and population PK methodologies to determine specific factors influencing melphalan exposure in pediatric alloHCT recipients. Population PK methodologies support the use of sparse sampling and therefore allow us to investigate drug levels in a pediatric population that would otherwise not be feasible using traditional intensive PK sampling.

Subjects will undergo PK sampling of plasma melphalan drug concentrations over the duration of melphalan therapy (3 to 5 days).

To evaluate sources of variability impacting melphalan exposure clinical data will be obtained from the patient's medical chart on each day of PK sampling.

To assess exposure-response relationships neutrophil engraftment, treatment-related toxicity, and survival data will be collected through day 100 post-transplant.

Study of Melphalan Drug Exposure in Pediatric Hematopoietic Stem Cell Transplant Patients

Population Pharmacokinetics (PK) of Melphalan in Pediatric Patients Undergoing Allogeneic Hematopoietic Cell Transplantation (HCT)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Fludarabine Drug Exposure in Pediatric Bone Marrow Transplantation	NCT01316549	Hematologic Mal... Nonmalignant Di... Immunodeficienc... Hemoglobinopath... Genetic Inborn ... Fanconi Anemia Thalassemia Sickle Cell Dis...	Fludarabine	- 17 Years	University of California, San Francisco
Study of Thiotepa and TEPA Drug Exposure in Pediatric Hematopoietic Stem Cell Transplant Patients	NCT03609840	Hematologic Mal... Nonmalignant Di... Immune Deficien... Hemoglobinopath... Genetic Inborn ... Fanconi Anemia Thalassemia Sickle Cell Dis...	Thiotepa	- 17 Years	University of California, San Francisco
Study of Thiotepa and TEPA Drug Exposure in Pediatric Hematopoietic Stem Cell Transplant Patients	NCT03609840	Hematologic Mal... Nonmalignant Di... Immune Deficien... Hemoglobinopath... Genetic Inborn ... Fanconi Anemia Thalassemia Sickle Cell Dis...	Thiotepa	- 17 Years	University of California, San Francisco
Study of Fludarabine Drug Exposure in Pediatric Bone Marrow Transplantation	NCT01316549	Hematologic Mal... Nonmalignant Di... Immunodeficienc... Hemoglobinopath... Genetic Inborn ... Fanconi Anemia Thalassemia Sickle Cell Dis...	Fludarabine	- 17 Years	University of California, San Francisco
Study of Melphalan Drug Exposure in Pediatric Hematopoietic Stem Cell Transplant Patients	NCT03609827	Hematologic Mal... Nonmalignant Di... Immunodeficienc... Hemoglobinopath... Genetic Inborn ... Fanconi's Anemi... Thalassemia Sickle Cell Dis...	Melphalan	- 17 Years	University of California, San Francisco

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