Symptoms and General Pathology

All Conditions

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Rare Diseases

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Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Antineoplastic Agents

All Drugs and Chemicals

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Amino Acids

Etoposide

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Cytarabine

Fludarabine

Fludarabine phosphate

Methotrexate

Prednisolone

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Methylprednisolone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

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Prednisolone phosphate

Quizartinib

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Enzyme Inhibitors

Antiviral Agents

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

All participants will receive re-induction therapy that includes fludarabine and cytarabine in combination with experimental drug quizartinib. For prophylaxis, IT chemotherapy with cytarabine, methotrexate and prednisolone/hydrocortisone will be given prior to or between re-induction cycles. After completing re-induction therapy, eligible participants may also receive optional consolidation chemotherapy which includes cytarabine, etoposide and quizartinib, if HSCT is not available immediately. After completing re-induction or HSCT successfully, eligible participants can go on to receive continuation therapy with quizartinib.

Administered orally once daily starting on Day 6 and continuing through Day 28;

Optional low intensity consolidation with chemotherapy:

Administered orally once daily starting on Day 1 and continuing through Day 28

30 mg/m\^2/day IV infusion given over 30 minutes on Days 1 through 5 (administered based on body weight)

2000 mg/m\^2/day IV infusion given over 3 hours on Days 1 through 5 (begin 4 hours after the start of fludarabine) (administered in accordance with standard of care);

Optional high intensity consolidation with chemotherapy and quizartinib:

500 mg/m\^2/day as a continuous 96-hour IV infusion on Days 1 through 4;

Optional low intensity consolidation with chemotherapy:

75 mg/m\^2/day as once daily subcutaneous or IV on Days 1 through 4 and Days 15 through 18

IT cytarabine, methotrexate, and either prednisolone or hydrocortisone; doses are based on the participant's age and standard practice at each site

Intrathecal (IT) triple chemotherapy prophylaxis

Optional high intensity consolidation with chemotherapy and quizartinib:

100 mg/m\^2/dose once daily as an IV infusion over 3 hours on Days 1 through 5

Daiichi Sankyo Contact for Clinical Information

Study Coordinator

Site Coordinator

Principal Investigator

Global Clinical Leader

Quizartinib is an experimental drug. It is not approved for regular use. It can only be used in medical research.

Children or young adults with a certain kind of blood cancer (FLT3-ITD AML) might be able to join this study if it has come back after remission or is not responding to treatment.

The medical condition being investigated is relapsed or refractory AML in participants aged ≥1 month to ≤21 years with Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutations (FLT3-ITD AML), following failure of front-line intensive chemotherapy.

The trial will be conducted in multiple phases. An independent data monitoring committee (DMC) will protect the rights, safety, and well-being of participants by monitoring the progress and results. The DMC will comprise qualified physicians and scientists who are not Investigators in the study and not otherwise directly associated with the Sponsor and will be convened at the end of Phase 1.

A. Dose Escalation/De-escalation Phase:

Number of participants is determined by age group. Participants will be enrolled by dose-level to determine the recommended Phase 2 dose (RP2D) of quizartinib for pediatric participants that provides similar exposure to adult patients treated at the target adult dose of 60 mg orally once daily.

B. Dose-Expansion Phase:

Participants will receive the RP2D of quizartinib for their respective age group.

During both dose escalation and dose expansion phases, participants will receive:

Re-Induction Therapy

* Intrathecal (IT) triple chemotherapy prophylaxis prior to and between cycles
* In re-induction Cycles 1 and 2, fludarabine/cytarabine (FLA) followed by quizartinib as a single agent

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Period:

After re-induction therapy, participants will be evaluated for eligibility to undergo allogeneic hematopoietic stem cell transplant (HSCT). Eligible participants may receive a single 28-day cycle of consolidation therapy (standard of care chemotherapy with or without quizartinib) if an allogeneic HSCT is not available immediately. The options for consolidation therapy are as follows:

* High intensity chemotherapy with quizartinib, or
* Low intensity chemotherapy alone, or
* Low intensity therapy with quizartinib as a single agent

Continuation Therapy:

Participants in remission after HSCT, or who are not eligible for HSCT but achieve at least a partial remission (PR) after re-induction, will receive up to 12 continuous 28-day cycles of quizartinib continuation therapy at the same dose received during re-induction in the dose expansion phase.

Long-term Follow-up:

The long-term follow-up phase begins upon completion of 12 cycles of quizartinib Continuation Therapy or permanent discontinuation of quizartinib at any time. After completion of the 30-day safety follow-up visit, subsequent visits will occur at the following frequencies to assess survival and anti-leukemic treatments:

* every 3 months for the first 2 years, and then
* once a year thereafter until the last participant enrolled has been followed for three years from the date of enrollment

A single group will progress through a multiple phase study design as described in the detailed description.

Safety and Efficacy of Quizartinib in Children and Young Adults With Acute Myeloid Leukemia (AML), a Cancer of the Blood

A Phase 1/2, Multicenter, Dose-Escalating Study To Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy Of Quizartinib Administered in Combination With Re-Induction Chemotherapy, and as a Single-Agent Continuation Therapy, in Pediatric Relapsed/Refractory AML Subjects Aged 1 Month to <18 Years (and Young Adults Aged up to 21 Years) With FLT3-ITD Mutations

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/

CRc rate is defined as percentage of participants with best response of complete remission (CR) or CR with incomplete hematological recovery (CRi) after completion of up to 2 re-induction cycles

CR rate is defined as the percentage of participants achieving CR after completion of up to 2 re-induction cycles

CRi rate is defined as the percentage of participants achieving CRi after completion of up to 2 re-induction cycles

Duration of CR is defined as the time from the first documented CR until documented relapse

Duration of CRi is defined as the time from the first documented CRi until documented relapse

Duration of CRc is defined as the time from the first documented CR or CRi until documented relapse

CR rate after completion of re-induction Cycle 1 is defined as the percentage of participants achieving a CR after completion of re-induction Cycle 1

CRi rate after completion of re-induction Cycle 1 is defined as the percentage of participants achieving a CRi after completion of re-induction Cycle 1

CRc rate after completion of re-induction Cycle 1 is defined as the percentage of participants achieving CRc after completion of re-induction Cycle 1

Time to relapse is defined as the time from the first documented response (CR, CRi) until documented relapse

Rate of relapse is defined as the percentage of participants who achieved CRc at the end of re-induction and had relapsed at 3 categorical time points Categories: 1 year, 2 years, 3 years

Cumulative incidence of relapse at the end of the study is defined as the percentage of participants who achieved CRc at the end of re-induction and relapsed by the end of the study

Overall survival is defined as the time from the start of re-induction therapy until death from any cause

Event-free survival is defined as the time from the start of re-induction therapy until the earliest date of the following:

* Refractory disease at the end of re-induction
* Relapse after CR or CRi
* Death from any cause at any time during the study

MRD is defined as the presence of leukemic cells in the bone marrow detected above a predefined cut-off level by a validated assay in participants who achieved a CR or CRi

Categories: at screening, at re-induction cycle 1, at re-induction cycle 2, at time of relapse

Acceptability is assessed by palatability using a 5-point hedonic scale (from "Super bad" to "Super good") for participants who are developmentally able to answer. If unable, the caregiver provides information in a free text field stating whether the participant spit it out, may not have liked the flavor, etc.

Innovative Therapies For Children with Cancer Consortium

Children's Oncology Group

Daiichi Sankyo

Infections

Musculoskeletal Diseases

Mycoses

Hematologic Neoplasms

Communicable Diseases

Invasive Fungal Infections

Bone Neoplasms

Bacterial Infections

Bacterial Infections and Mycoses

Voriconazole

Clotrimazole

Miconazole

Antifungal Agents

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 CYP3A Inhibitors

Voriconazole Starting oral dose of 400 mg pills twice a day for first day, followed by 200 mg by mouth twice a day thereafter.

Voriconazole 6 mg/kg by vein (IV) first dose then 200 mg pills two times a day thereafter.

Starting dose of 400 mg by mouth twice a day for first day, followed by 200 mg by mouth twice a day thereafter.

6 mg/kg by vein for first dose, followed by 200 mg by mouth twice a day thereafter.

Jorge Cortes, MD

Objectives:

To investigate the relationship between the administration of intravenous (IV) and oral voriconazole (vori) and the occurrence of false positive (1,3) beta-d- glucan (BG) relative to the standard assessment criteria used to diagnose invasive fungal infection in patients with hematologic malignancies.

Chemotherapy can lower immune system function, which can cause fungal infections to occur more easily. These fungal infections are found by certain blood tests. One of these blood tests looks for a part of the fungal cell floating freely in the human blood.

When certain drugs are given to patients to prevent fungal infections, these blood tests may show that there is an infection when there actually is not one present. Some of these drugs are similar to the study drug voriconazole.

The Study Drug:

Voriconazole is designed to slow the growth of fungal cells, which may cause the fungal cells to die.

Screening Tests:

Signing this consent form does not mean that you will be able to take part in this study. You will have "screening tests" to help the doctor decide if you are eligible to take part in this study. The following tests and procedures will be performed:

* Your medical history will be recorded.
* You will have a complete physical exam.
* Blood (about 1 teaspoon) will be drawn for routine tests.
* If your doctor thinks it is needed, you will have a chest x-ray or computed tomography (CT) scan of the chest to check for pneumonia.

The study doctor will discuss the screening test results with you. If the screening tests show that you are not eligible to take part in the study, you will not be enrolled. Other treatment options will be discussed with you.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to 1 of 2 study groups. Group 1 will consist of the first 10 patients enrolled on the study. Group 2 will consist of the next 10 patients enrolled on the study. If you are in Group 1, you will take only pills of study drug 2 times every day while you are on study. If you are in Group 2, you will receive the study drug through a needle in your vein 1 time when you begin the study and then take pills of study drug 2 times every day for the rest of the time you are on study.

Blood Draws for Fungal Infection Tests:

If you are in Group 1, blood (about 1 teaspoon each time) will be drawn for fungal infection tests at the following times:

* Before the first dose of study drug.
* 1, 2, 4, and 8 hours after the first dose of study drug.
* Before the third dose of study drug.
* 1, 2, 4, and 8 hours after the third dose of study drug.

If you are in Group 2, blood (about 1 teaspoon each time) will be drawn for fungal infection tests at the following times:

* Before the first dose of study drug.
* 1, 2, 4, and 8 hours after the first dose of study drug.
* 1, 2, and 4 hours after the second dose of study drug.

Length of Study:

You may continue taking the study drug for up to 35 days if you are receiving chemotherapy for the first time and up to 42 days if you have had chemotherapy before. Your doctor may decide that you should take the study drug for an even longer period of time or that you need to have another drug to prevent fungal infections. You will be taken off study if intolerable side effects occur or if you get a fungal infection.

Additional Information:

There are several drugs that should not be taken in combination with voriconazole. You should talk to the study doctor about any drugs you may be taking and about any drugs you may plan to start taking while on study. You should also avoid eating/drinking grapefruit/grapefruit products while you are on study, as they may interfere with the effects of the study drug.

This is an investigational study. Voriconazole is FDA approved and commercially available for the treatment of fungal infections.

Up to 20 patients who are found to be eligible after screening will take part in this study. All will be enrolled at M. D. Anderson.

Beta Glucan Assay in Patients Receiving Voriconazole Prophylaxis

Kinetics of 1, 3 Beta-d- Glucan Assay in Patients With Hematologic Malignancies Receiving Voriconazole Prophylaxis

Rate calculated as number of participants with positive levels divided by total number of participants. beta-d-glucan (BG), a cell wall constituent of fungi, can be detected in serum as a marker of Invasive fungal infections (IFI).

Blood samples were drawn on first 2 days of treatment at baseline (before the drug) and at 1, 2, 4, 8 hours after the first dose of the day. BG serum levels were measured using the Fungitell assay, using a cut off value of 60 pg/ml for positivity.

Pfizer

M.D. Anderson Cancer Center

Voriconazole starting oral dose of 400 mg pills twice a day for first day, followed by 200 mg by mouth twice a day thereafter.

Group 1 - Oral

Group 2 - IV + Oral

Total

Age Continuous

Sex: Female, Male

United States

Region of Enrollment

Jorge Cortes, MD / Professor

Samples BG levels > 60pg/ml, First Test

Samples BG levels > 60pg/ml, Following Re-Test

Analysis was intent to treat with a total of 182 samples (mean 8.6 samples/participant) drawn from participants.

Percentage of Samples With BG Levels > 60pg/ml

Overall Study

Posaconazole

Antiprotozoal Agents

Antiparasitic Agents

Posaconazole 200 mg (liquid) by mouth 3 times per day.

200 mg (liquid) by mouth 3 times per day.

The goal of this clinical research study is to learn the amount of posaconazole that is in the body at different time points when given to patients with leukemia. The safety of this drug will also be studied.

Objectives:

Primary:

To study the plasma pharmacokinetics of posaconazole in patients with newly diagnosed acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS) undergoing induction chemotherapy or relapsed or refractory patients who will receive salvage chemotherapy.

Secondary:

To evaluate the safety of posaconazole given as prophylaxis.

Chemotherapy can lower immune system function, which can cause fungal infections to occur more easily. The standard treatment for prevention of such infections includes drugs such as voriconazole and liposomal amphotericin B that help prevent fungus from growing.

The Study Drug:

Posaconazole is designed to block the ergosterol synthesis (a part of the fungal membrane). This may help to prevent fungal infections.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will take posaconazole by mouth 3 times per day. Posaconazole is a liquid. You should take the study drug after a full meal or with a liquid nutritional supplement (such as a protein shake). If you are not able to eat food, you should take it with a carbonated beverage (such as soda).

Food and Drug Diary:

You will be also be given a food and drug diary where you will write down the time you took each dose. You should also record the time eaten and describe what you ate or drank at each meal. This information will be used to find out the number of calories and amount of protein, carbohydrates, and fat you have consumed. You will be given a small bag where you can keep the drug and diary. You should return this diary after the last blood draw.

Blood Draws for Pharmacokinetics (PK) Testing:

While you are on study, blood (about 1 teaspoon each time) will be drawn for PK testing. PK testing measures the amount of study drug in the body at different time points.

* Days 1, 3, and 10, before your first dose of study drug and 3, 5, and 10 hours after the first dose of the day
* Days 2 and 4, about 24 hours after the first dose the day before

Blood (about 1 teaspoon) will also be drawn for PK testing 1 time at any of the following time points:

* Before you start a new dose of study drug, if the dose needs to be raised
* If you stop taking the study drug due to intolerable side effects or a fungal infection

Note that if you are not already in the hospital on the days of the PK blood draws, you will need to stay at the hospital for about 10 hours on these days.

Length of the Study:

You will take the study drug for up to 42 days. You will be taken off study if you experience intolerable side effects, if you develop an invasive fungal infection, or if the doctor thinks it is in your best interest.

This is an investigational study. Posaconazole is FDA approved and commercially available for the prevention of fungal infections.

Up to 25 patients will take part in the study. All will be enrolled at MD Anderson.

Pharmacokinetics of Posaconazole Prophylaxis in Acute Leukemia

Phase II Study of the Pharmacokinetics of Posaconazole Prophylaxis in Relapsed or Refractory Patients With Acute Leukemia

Pharmacokinetic samples were obtained on day 1, day 3 and day 10 of prophylaxis. A total of 15 samples (3 ml each sample) per participant were obtained, with thrice daily dosing planned around standard meal times. On day 1 and day 3 of prophylaxis sampling was done pre dose (0), and at 3, 5, 10 and 24 hours (±10 minutes) post dose from the time of the first dose of the day. On day 10 of prophylaxis sampling was done pre dose (0), and at 3, 5, and 10 hours (±10 minutes) post dose from the time of the first dose of the day.

Posaconazole levels were assayed by high performance liquid chromatography (HPLC). The testing range for posaconazole is from 125 - 5000 ng/ml. There are no established therapeutic ranges for posaconazole.

Schering-Plough

The adverse events presented below reflect all SAEs and AEs reported by participants, regardless of whether events were treatment-related or non-treatment-related.

Age, Continuous

AML, Induction

AML, Relapse

Participant Diagnosis

Cytarabine-containing regimen

Clofarabine-containing regimen

Miscellaneous*

Participant's first induction chemotherapy, either with a clofarabine-based regimen or a cytarabine-based regimen. Exception listed as miscellaneous chemotherapy treatment, and include AZD1152 (an experimental aurora kinase inhibitor) alone (1 participant) or in combination with low-dose cytarabine (2 participants).

Chemotherapy Received

Jorge Cortes, MD/Professor, Leukemia Department

Day 2, Hour 24

Day 4, Hour 24

Day 9, Hour 24

Posaconazole (Females)

Posaconazole (Males)

Of the 11 females enrolled, one was not evaluable for the outcome thus excluded from analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety and Efficacy of Quizartinib in Children and Young Adults With Acute Myeloid Leukemia (AML), a Cancer of the Blood	NCT03793478	Acute Myeloid L...	Quizartinib Fludarabine Cytarabine Intrathecal (IT... Etoposide	1 Month - 21 Years	Daiichi Sankyo
Beta Glucan Assay in Patients Receiving Voriconazole Prophylaxis	NCT00904995	Leukemia Fungal Infectio...	Voriconazole Voriconazole	18 Years -	M.D. Anderson Cancer Center
Beta Glucan Assay in Patients Receiving Voriconazole Prophylaxis	NCT00904995	Leukemia Fungal Infectio...	Voriconazole Voriconazole	18 Years -	M.D. Anderson Cancer Center
Pharmacokinetics of Posaconazole Prophylaxis in Acute Leukemia	NCT00936117	Leukemia Fungal Infectio...	Posaconazole	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for cancer of the blood