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

Recruiting now · Phase 1

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

In brief

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.

Key facts

Study ID

NCT05476770

Run by

Therapeutic Advances in Childhood Leukemia Consortium

People needed

54

Starts

2022-11-11

Expected to finish

2027-11-11

Last updated by the study team

2024-12-06

Who can join

Age: 1 and older, up to 21. Sex: any. Healthy volunteers: not accepted.

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
• For relapsed/refractory leukemia, patients must have:
• >5% blasts in the bone marrow aspirate or biopsy by morphology or flow cytometry
• Patients with 1% - 5% blasts are eligible for Part 2, Cohort C (only), if A single bone marrow sample with flow cytometry and at least one other test (e.g. karyotype, FISH, PCR, or NGS) shows ≥ 1% leukemic blasts and/or flow cytometry demonstrates a stable or rising level of disease on two serial bone marrows.
• For relapsed/refractory non-Hodgkin or Hodgkin lymphoma, patients must have:
• Histologic verification of relapse
• Measurable disease documented by radiographic criteria or bone marrow
• Patients in Part 1 may have sites of non-CNS extramedullary disease, but no CNS disease. Patients in Part 2 may have CNS disease and/or other non-CNS extramedullary disease. No cranial irradiation is allowed during the protocol therapy.
• Patients with Down syndrome are eligible to participate in Part 1 only.
• Performance Level
• Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of age (See Appendix I for Performance Scales). Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

You may not qualify if…

• Disease Status:
• Patients with CNS disease are not eligible for Part 1.
• Patients with isolated CNS disease are not eligible for Part 1 or Part 2.
• Patients with isolated non-CNS disease are eligible for Part 1 and Part 2.
• Concomitant Medications
• Corticosteroids - Patients receiving corticosteroids for disease control who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible.
• Investigational Drugs - Patients who are currently receiving another investigational drug are not eligible. The definition of "investigational" for use in this protocol means any drug that is not licensed by the FDA, Health Canada or the Therapeutic Goods Administration to be sold in the countries they govern. (United States, Canada and Australia)
• Anti-cancer Agents - Patients who are currently receiving or may receive while on therapy, other anti-cancer agents, radiation therapy or immunotherapy are not eligible [with the exceptions being laid out in the inclusion criteria under 'Prior Therapy']. Intrathecal chemotherapy (at the discretion of the primary oncologist) may be given up to one week prior to the initiation of study treatment (day 1 therapy).
• Anti-GVHD or agents to prevent organ rejection post-transplant - Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial. At least 4 weeks must have elapsed after the last dose of GVHD meds.
• Infection Criteria - Patients are excluded if they have:
• Positive blood culture within 48 hours of study enrollment;
• Fever above 38.2 within 48 hours of study enrollment with clinical signs of infection. Fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability.
• A positive fungal culture within 30 days of study enrollment.
• Active fungal, viral, bacterial, or protozoal infection requiring IV treatment. Chronic prophylaxis therapy to prevent infections is allowed.
• Patients will be excluded if they have a known allergy to any of the drugs used in the study.
• Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results.
• Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are excluded.

Where it is running

• Children's Hospital Los Angeles — Los Angeles, California, United States (enrolling)
• UCSF School of Medicine — San Francisco, California, United States (enrolling)
• Children's Hospital Colorado — Denver, Colorado, United States (enrolling)
• Children's National Medical Center — Washington D.C., District of Columbia, United States (enrolling)
• Ann & Robert H. Lurie Children's Hospital of Chicago — Chicago, Illinois, United States (enrolling)
• Riley Hospital for Children — Indianapolis, Indiana, United States (enrolling)
• C.S. Mott Children's Hospital — Ann Arbor, Michigan, United States (enrolling)
• Memorial Sloan Kettering Cancer Center — New York, New York, United States (enrolling)
• Cincinnati Children's Hospital Medical Center — Cincinnati, Ohio, United States (enrolling)
• University of Texas, Southwestern — Dallas, Texas, United States (enrolling)
• Cook Children's Hospital — Fort Worth, Texas, United States (enrolling)
• Texas Children's Hospital/Baylor College of Medicine — Houston, Texas, United States (enrolling)
• Primary Children's Hospital — Salt Lake City, Utah, United States (enrolling)
• Children's Hospital of Wisconsin — Milwaukee, Wisconsin, United States (enrolling)
• Children's Hospital at Westmead — Westmead, New South Wales, Australia (enrolling)
• Seattle Children's Hospital — Seattle, Washington, United States
• Carolina-Levine Children's Hospital — Charlotte, North Carolina, United States
• Children's Hospital Orange County — Orange, California, United States
• Sydney Children's Hospital — Sydney, Australia
• Rainbow Babies — Cleveland, Ohio, United States
• Nationwide Children's Hospital — Columbus, Ohio, United States
• University of Miami — Miami, Florida, United States
• Children's Healthcare of Atlanta, Emory University — Atlanta, Georgia, United States
• Oregon Health & Science University — Portland, Oregon, United States
• Children's Hospital of Philadelphia — Philadelphia, Pennsylvania, United States

Full record on ClinicalTrials.gov

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