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Tagraxofusp

-Days 1-5

IT Therapy (may include methotrexate, cytarabine, or triple IT)

* Day 1
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

Tagraxofsup

-Days 4-8

Fludarabine -Days 1-5

Cytarabine

-Days 1-5

IT Therapy (may include methotrexate, cytarabine, or triple IT) CNS1 IT Therapy

* Day 1
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

CNS2/3 IT Therapy

* Days 1, 8, 15, and 22
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

Tagraxofsup

-Days 8-12

Dexamethasone -Days 1-5

Vincristine

-Days 1, 8, 15, and 22

IT Therapy (may include methotrexate, cytarabine, or triple IT) CNS1 IT Therapy

* Day 1
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

CNS2/3 IT Therapy

* Days 1, 8, 15, and 22
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

Tagraxofsup -Days 1-5

Azacitidine

-Days 1-5

IT Therapy (may include methotrexate, cytarabine, or triple IT) CNS1 IT Therapy

* Day 1
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

CNS2/3 IT Therapy

* Days 1, 8, 15, and 22
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

Dose will be assigned at study entry. Give IV over 15 minutes.

Tagraxofusp

30 mg/m\^2 will be given IV over 30 minutes on days 1-5.

Infusion will start 30 minutes after start of tagraxofusp on days 4 and 5.

2000 mg/m2 intravenously will be given daily over 1-3 hours for 5 days on days 1 through 5. Infusion will begin 4 hours after start of fludarabine. Because of an increased risk of neurotoxicity, it is recommended that IT cytarabine be separated from high dose IV cytarabine administration by at least 24 hours on C1D1.

* 20 mg/m2/day divided BID (max 40 mg/day) given orally on days 1 through 5 and 15 through 19. The two doses should be separated by at least 8 hours.
* Any oral formulation of dexamethasone is acceptable.
* IV may be given if oral formulation is not tolerated

* 1.5 mg/m2 (maximum dose 2 mg) given intravenously as an IV push over 1-5 minutes or infusion via minibag as per institutional policy on days 1, 8, 15, and 22.
* Infusion will start 30 minutes after start of tagraxofusp on day 8.

* 75 mg/m2 subcutaneously or intravenously will be given daily over 15 minutes for 5 days on days 1 through 5.
* Azacitidine will be given 30-60 minutes before beginning the tagraxofusp infusion.

Give intrathecally:

* 8 mg for patients age 1-1.99
* 10 mg for patients age 2-2.99
* 12 mg for patients 3-8.99 years of age
* 15 mg for patients ≥9 years of age

Give intrathecally:

* 30 mg for patients age 1-1.99
* 50 mg for patients age 2-2.99
* 70 mg for patients ≥3 years of age

If given as part of Triple IT Therapy:

AML Patients:

Age 1-1.99 - 24 mg Age 2-2.99 - 30 mg Age ≥3 years of age - 36 mg

AML Patients:

Age 1-1.99 - 16 mg Age 2-2.99 - 20 mg Age 3-8.99 - 24 mg Age ≥9 years of age - 30 mg

Cytarabine IT

Given intrathecally.

AML Patients:

Age 1-1.99 - 16 mg Age 2-2.99 - 20 mg Age ≥3 years of age - 24 mg

AML Patients:

Age 1-1.99 - 8 mg Age 2-2.99 - 10 mg Age 3-8.99 - 12 mg Age ≥9 years of age - 15 mg

Benjamin N Brookhart

Ellynore Florendo

Alan Wayne, MD

Van Thu Huynh, MD

Michelle Hermiston, MD

Margaret Macy, MD

Reuven Schore, MD

Julio Barredo, MD

Melinda Pauly, MD

Jenna Rossoff, MD

Sandeep Batra, MD

Pat Brown, MD

Nirali Shah, MD

Andrew Place, MD

Rajen Mody, MD

Nathan Gossai, MD

Nobuko Hijiya, MD

Maria Sulis, MD, MS

Joel Kaplan, MD

Robin Norris, MD

Rachel Egler, MD

Susan Vear-Colace, MD

Bill Chang, MD

Sue Rheingold, MD

Jeffrey Rubnitz, MD

Tamra Slone, MD

Kenneth Heym, MD

Eric Schafer, MD

Anupam Verma, MD

Adam Lamble, MD

Michael Burke, MD

Luciano Dalla-Pozza, MD

Tracey O'Brien, MD

Tagraxofusp is a protein-drug conjugate consisting of a diphtheria toxin redirected to target CD123 has been approved for treatment in pediatric and adult patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). This trial aims to examine the safety of this novel agent in pediatric patients with relapsed/refractory hematologic malignancies.

The mechanism by which tagraxofusp kills cells is distinct from that of conventional chemotherapy. Tagraxofusp directly targets CD123 that is present on tumor cells, but is expressed at lower or levels or absent on normal hematopoietic stem cells. Tagraxofusp also utilizes a payload that is not cell cycle dependent, making it effective against both highly proliferative tumor cells and also quiescent tumor cells.

The rationale for clinical development of tagraxofusp for pediatric patients with hematologic malignancies is based on the ubiquitous and high expression of CD123 on many of these diseases, as well as the highly potent preclinical activity and robust clinical responsiveness in adults observed to date.

This trial includes two parts: a monotherapy phase and a combination chemotherapy phase. This design will provide further monotherapy safety data and confirm the FDA approved pediatric dose, as well as provide safety data when combined with chemotherapy.

The goal of this study is to improve survival rates in children and young adults with relapsed hematological malignancies, determine the recommended phase 2 dose (RP2D) of tagraxofusp given alone and in combination with chemotherapy, as well as to describe the toxicities, pharmacokinetics, and pharmacodynamic properties of tagraxofusp in pediatric patients.

About 54 children and young adults will participate in this study. Patients with Down syndrome will be included in part 1 of the study.

Tagraxofusp in Pediatric Patients With Relapsed or Refractory CD123 Expressing Hematologic Malignancies

A Phase I Study of Tagraxofusp With or Without Chemotherapy in Pediatric Patients With Relapsed or Refractory CD123 Expressing Hematologic Malignancies

The incidence of dose limiting toxicity (DLT) will be measured at different dose levels.

Therapeutic Advances in Childhood Leukemia Consortium

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Tagraxofusp in Pediatric Patients With Relapsed or Refractory CD123 Expressing Hematologic Malignancies	NCT05476770	Hematologic Mal... AML ALL BPDCN MDS Lymphoblastic L... Lymphoma, B-Cel... Lymphoma, T-Cel... Hodgkin Lymphom... Mixed Phenotype... Acute Undiffere...	Tagraxofusp Fludarabine Cytarabine Dexamethasone Vincristine Azacitidine Methotrexate Cytarabine IT Hydrocortisone	1 Year - 21 Years	Therapeutic Advances in Childhood Leukemia Consortium
Tagraxofusp in Pediatric Patients With Relapsed or Refractory CD123 Expressing Hematologic Malignancies	NCT05476770	Hematologic Mal... AML ALL BPDCN MDS Lymphoblastic L... Lymphoma, B-Cel... Lymphoma, T-Cel... Hodgkin Lymphom... Mixed Phenotype... Acute Undiffere...	Tagraxofusp Fludarabine Cytarabine Dexamethasone Vincristine Azacitidine Methotrexate Cytarabine IT Hydrocortisone	1 Year - 21 Years	Therapeutic Advances in Childhood Leukemia Consortium
Tagraxofusp in Pediatric Patients With Relapsed or Refractory CD123 Expressing Hematologic Malignancies	NCT05476770	Hematologic Mal... AML ALL BPDCN MDS Lymphoblastic L... Lymphoma, B-Cel... Lymphoma, T-Cel... Hodgkin Lymphom... Mixed Phenotype... Acute Undiffere...	Tagraxofusp Fludarabine Cytarabine Dexamethasone Vincristine Azacitidine Methotrexate Cytarabine IT Hydrocortisone	1 Year - 21 Years	Therapeutic Advances in Childhood Leukemia Consortium

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