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

NCT05476770 | Recruiting Phase 1 FDA Drug

• 1 other identifier: T2020-006
• Study Type: interventional
• Target: 54
• Locations: 2 countries
• Sites: 31

Brief Summary

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.

Conditions

Hematologic Malignancy; AML; ALL; BPDCN; MDS; Lymphoblastic Lymphoma; Lymphoma, B-Cell; Lymphoma, T-Cell; Hodgkin Lymphoma; Mixed Phenotype Acute Leukemia; Acute Undifferentiated Leukemia

Outcome Measures

Primary Outcomes (1)

• Occurrence of dose limiting toxicity (DLT) during cycle 1 of therapy

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

  At the end of Cycle 1 (21 days for Part 1, and 28 days for Part 2)

Study Arms (4)

Part 1

EXPERIMENTAL

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

Drug: Tagraxofusp; Drug: Methotrexate; Drug: Cytarabine IT; Drug: Hydrocortisone

Part 2 - Cohort A

EXPERIMENTAL

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

Drug: Tagraxofusp; Drug: Fludarabine; Drug: Cytarabine; Drug: Methotrexate; Drug: Cytarabine IT; Drug: Hydrocortisone

Part 2 - Cohort B

EXPERIMENTAL

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

Drug: Tagraxofusp; Drug: Dexamethasone; Drug: Vincristine; Drug: Methotrexate; Drug: Cytarabine IT; Drug: Hydrocortisone

Part 2 - Cohort C

EXPERIMENTAL

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

Drug: Tagraxofusp; Drug: Azacitidine; Drug: Methotrexate; Drug: Cytarabine IT; Drug: Hydrocortisone

Interventions

Tagraxofusp DRUG

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

Also known as: Elzonris

Part 1; Part 2 - Cohort A; Part 2 - Cohort B; Part 2 - Cohort C

Fludarabine DRUG

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.

Part 2 - Cohort A

Cytarabine DRUG

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.

Also known as: Cytosar

Part 2 - Cohort A

Dexamethasone DRUG

* 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

Also known as: Decadron

Part 2 - Cohort B

Vincristine DRUG

* 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.

Also known as: Oncovin

Part 2 - Cohort B

Azacitidine DRUG

* 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.

Also known as: AZA, Vidaza

Part 2 - Cohort C

Methotrexate DRUG

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

Also known as: MTX, Amethopterin

Part 1; Part 2 - Cohort A; Part 2 - Cohort B; Part 2 - Cohort C

Cytarabine IT DRUG

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

Also known as: Cytosar

Part 1; Part 2 - Cohort A; Part 2 - Cohort B; Part 2 - Cohort C

Hydrocortisone DRUG

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

Part 1; Part 2 - Cohort A; Part 2 - Cohort B; Part 2 - Cohort C

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age
• Patients must be ≥ 1 and ≤21 years of age at the time of study enrollment.
• Diagnosis
• Relapsed and/or refractory hematologic malignancy (including, but not limited to, acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, mixed phenotype acute leukemia, acute undifferentiated leukemia, blastic plasmacytoid dendritic cell neoplasm, Hodgkin lymphoma, and non-Hodgkin lymphoma).
• Tumor cells must demonstrate surface expression of CD123 at the time of enrollment by flow cytometry or immunohistochemistry, as defined by the local institution.
• Disease Status:
• Monotherapy, Part 1
• Second or greater relapse; or
• Refractory after 2 or more chemotherapy cycles; or
• First relapse after primary chemotherapy-refractory disease; or
• BPDCN in first relapse or refractory after 1 or more chemotherapy cycles
• Combination therapy, Part 2
• First or greater relapse; or
• Refractory after 2 or more chemotherapy cycles; or
• BPDCN in first relapse or refractory after 1 or more chemotherapy cycles

You may not qualify if:

• Myelosuppressive chemotherapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. At least 14 day must have elapsed since the completion of myelosuppressive therapy. However, individuals may receive any of the following medications within 14 days without a "wash-out period":
• Hydroxyurea: Hydroxyurea can be initiated and/or continued for up to 24 hours prior to the start of protocol therapy.
• "Maintenance-style" therapy: therapy including vincristine (dosed a maximum of one-time weekly), oral 6-mercaptopurine, oral methotrexate (dosed a maximum of one-time weekly), intrathecal therapy (dosed a maximum of one-time weekly) and/or dexamethasone (dosed at ≤3 mg/m2/dose twice daily) or prednisone (dosed at ≤20 mg/m2/dose twice daily) can be continued for up to 24 hours prior to entering the study.
• Hematopoietic stem cell transplant: Patients who have experienced their relapse after a HSCT are eligible, provided they have no evidence of acute or chronic Graft-versus-Host Disease (GVHD) and are at least 100 days post-transplant at the time of enrollment.
• Hematopoietic growth factors: It must have been at least 7 days since the completion of therapy with granulocyte colony stimulating factor (GCSF) or other growth factors at the time of enrollment. It must have been at least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).
• Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
• Monoclonal antibodies: Maximum of 3 half-lives of the antibody or 21 days (whichever is shorter) must have elapsed after the last dose of monoclonal antibody.
• Immunotherapy: At least 30 days from last infusion of chimeric antigen receptor T cell (CART) therapy or tumor vaccine.
• Radiation Therapy (XRT):
• ≥ 84 days must have passed, from the end of therapy, if patient received prior total body irradiation (TBI).
• ≥ 42 days must have passed, from the end of therapy, if patient received craniospinal irradiation (CSI).
• ≥ 14 days must have passed after whole brain radiotherapy or stereotactic radiation therapy.
• No washout period is required for:
• i. Extramedullary site other than CNS that is a maximum 10 x 10 cm total radiation non-CNS field. If the field is \> 10 x 10 cm, a 14-day washout period is required. ii. Local ocular radiotherapy as long as subject has measurable/evaluable disease outside the radiation port.
• Patients that have received other non-tagraxofusp CD123 targeting agents are eligible. Patients that have previously received tagraxofusp are not eligible.

Sponsors & Collaborators

• Therapeutic Advances in Childhood Leukemia Consortium: lead

Study Sites (31)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

RECRUITING

Children's Hospital Orange County

Orange, California, 92868, United States

NOT YET RECRUITING

UCSF School of Medicine

San Francisco, California, 94143-0106, United States

RECRUITING

Children's Hospital Colorado

Denver, Colorado, 80045, United States

RECRUITING

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

RECRUITING

University of Miami

Miami, Florida, 33136, United States

NOT YET RECRUITING

Children's Healthcare of Atlanta, Emory University

Atlanta, Georgia, 30322, United States

NOT YET RECRUITING

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

RECRUITING

Riley Hospital for Children

Indianapolis, Indiana, 46202, United States

RECRUITING

Johns Hopkins University

Baltimore, Maryland, 21231, United States

NOT YET RECRUITING

National Cancer Institute, Pediatric Oncology Branch

Bethesda, Maryland, 20892, United States

NOT YET RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

NOT YET RECRUITING

C.S. Mott Children's Hospital

Ann Arbor, Michigan, 48109-0914, United States

RECRUITING

Children's Hospital and Clinics of Minnesota

Minneapolis, Minnesota, 55404, United States

NOT YET RECRUITING

Children's Hospital New York-Presbyterian

New York, New York, 10032, United States

NOT YET RECRUITING

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

RECRUITING

Carolina-Levine Children's Hospital

Charlotte, North Carolina, 28204, United States

NOT YET RECRUITING

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

RECRUITING

Rainbow Babies

Cleveland, Ohio, 44106, United States

NOT YET RECRUITING

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

NOT YET RECRUITING

Oregon Health & Science University

Portland, Oregon, 97239, United States

NOT YET RECRUITING

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

NOT YET RECRUITING

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

NOT YET RECRUITING

University of Texas, Southwestern

Dallas, Texas, 75235, United States

RECRUITING

Cook Children's Hospital

Fort Worth, Texas, 76104, United States

RECRUITING

Texas Children's Hospital/Baylor College of Medicine

Houston, Texas, 77030, United States

RECRUITING

Primary Children's Hospital

Salt Lake City, Utah, 84113, United States

RECRUITING

Seattle Children's Hospital

Seattle, Washington, 98105, United States

NOT YET RECRUITING

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53226, United States

RECRUITING

Children's Hospital at Westmead

Westmead, New South Wales, Australia

RECRUITING

Sydney Children's Hospital

Sydney, Australia

NOT YET RECRUITING

MeSH Terms

Conditions

Hematologic Neoplasms; Blastic Plasmacytoid Dendritic Cell Neoplasm; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, B-Cell; Lymphoma, T-Cell; Hodgkin Disease; Leukemia, Biphenotypic, Acute

Interventions

tagraxofusp; fludarabine; Cytarabine; Dexamethasone; Calcium Dobesilate; Vincristine; Azacitidine; Methotrexate; Hydrocortisone

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Histiocytic Disorders, Malignant; Neoplasms by Histologic Type; Leukemia; Lymphoma; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Aza Compounds; Ribonucleosides; Aminopterin; Pterins; Pteridines; Pregnenediones; Pregnenes; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids

Study Officials

• Adam Lamble, MD

  Seattle Children's Hospital

  STUDY CHAIR

Central Study Contacts

Benjamin N Brookhart

CONTACT

323-361-5429; bbrookhart@chla.usc.edu

Ellynore Florendo

CONTACT

323-361-3022; eflorendo@chla.usc.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 25, 2022
• First Posted: July 27, 2022
• Study Start: November 11, 2022
• Primary Completion: November 11, 2025
• Study Completion (Estimated): November 11, 2027
• Last Updated: December 6, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (29); AU (2)