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Official Title

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

Phase
Phase 1
Sponsor
Therapeutic Advances in Childhood Leukemia Consortium
Enrollment
54
Timeline
Nov 2022 → Nov 2027
About This Study

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.

Eligibility Criteria

Inclusion Criteria

  • 1Age
  • 2Patients must be ≥ 1 and ≤21 years of age at the time of study enrollment.
  • 3Diagnosis
  • 4Relapsed 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).
  • 5Tumor cells must demonstrate surface expression of CD123 at the time of enrollment by flow cytometry or immunohistochemistry, as defined by the local institution.
  • 6Disease Status:
  • 7Monotherapy, Part 1
  • 8Second or greater relapse; or
  • 9Refractory after 2 or more chemotherapy cycles; or
  • 10First relapse after primary chemotherapy-refractory disease; or
  • 11BPDCN in first relapse or refractory after 1 or more chemotherapy cycles
  • 12Combination therapy, Part 2
  • 13First or greater relapse; or
  • 14Refractory after 2 or more chemotherapy cycles; or
  • 15BPDCN in first relapse or refractory after 1 or more chemotherapy cycles
  • 16For relapsed/refractory leukemia, patients must have:
  • 17\>5% blasts in the bone marrow aspirate or biopsy by morphology or flow cytometry
  • 18Patients 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.
  • 19For relapsed/refractory non-Hodgkin or Hodgkin lymphoma, patients must have:
  • 20Histologic verification of relapse
  • 21Measurable disease documented by radiographic criteria or bone marrow
  • 22Patients 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.
  • 23Patients with Down syndrome are eligible to participate in Part 1 only.
  • 24Performance Level
  • 25Karnofsky \> 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.
  • 26Prior Therapy
  • 27Anti-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.
  • 28Infection Criteria - Patients are excluded if they have:
  • 29Positive blood culture within 48 hours of study enrollment;
  • 30Fever 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.
  • 31A positive fungal culture within 30 days of study enrollment.
  • 32Active fungal, viral, bacterial, or protozoal infection requiring IV treatment. Chronic prophylaxis therapy to prevent infections is allowed.
  • 33Patients will be excluded if they have a known allergy to any of the drugs used in the study.
  • 34Patients 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.
  • 35Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are excluded.

Exclusion Criteria

  • 1Myelosuppressive 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":
  • 2Hydroxyurea: Hydroxyurea can be initiated and/or continued for up to 24 hours prior to the start of protocol therapy.
  • 3"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.
  • 4Hematopoietic 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.
  • 5Hematopoietic 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®).
  • 6Biologic (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.
  • 7Monoclonal 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.
  • 8Immunotherapy: At least 30 days from last infusion of chimeric antigen receptor T cell (CART) therapy or tumor vaccine.
  • 9Radiation Therapy (XRT):
  • 10≥ 84 days must have passed, from the end of therapy, if patient received prior total body irradiation (TBI).
  • 11≥ 42 days must have passed, from the end of therapy, if patient received craniospinal irradiation (CSI).
  • 12≥ 14 days must have passed after whole brain radiotherapy or stereotactic radiation therapy.
  • 13No washout period is required for:
  • 14i. 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.
  • 15Patients that have received other non-tagraxofusp CD123 targeting agents are eligible. Patients that have previously received tagraxofusp are not eligible.
  • 16Organ Function Requirements
  • 17Adequate Bone Marrow Function Defined as:
  • 18Patients should not be known to be refractory to red blood cell or platelet transfusions.
  • 19Blood counts are not required to be normal prior to enrollment on trial. However, platelet count must be ≥20,000/mm3 to initiate therapy (may receive platelet transfusions).
  • 20Adequate Renal Function Defined as:
  • 21Patient must have a calculated creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender in the chart below:
  • 22Maximum Serum Creatinine (mg/dL):
  • 231 to \< 2 years old - Male: 0.6, Female: 0.6
  • 242 to \< 6 years old - Male:0.8, Female: 0.8
  • 256 to \< 10 years old - Male: 1, Female: 1
  • 2610 to \< 13 years old - Male: 1.2, Female: 1.2
  • 2713 to \< 16 years old - Male: 1.5, Female: 1.4
  • 28≥ 16 years old - Male: 1.7, Female: 1.4
  • 29The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.
  • 30Adequate Liver Function Defined as:
  • 31Total bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x institutional upper limit of normal for age
  • 32SGPT (ALT) and SGOT (AST) must be less than 3x institutional upper limit of normal.
  • 33Serum albumin ≥3.2 g/dL (albumin infusion independent).
  • 34Adequate Cardiac Function Defined as:
  • 35Shortening fraction of ≥27% by echocardiogram, or
  • 36Ejection fraction of ≥ 50% by gated radionuclide study/echocardiogram.
  • 37Adequate Pulmonary Function Defined as:
  • 38Pulse oximetry \> 94% on room air (\> 90% if at high altitude)
  • 39No evidence of dyspnea at rest and no exercise intolerance.
  • 40Reproductive Function
  • 41Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.
  • 42Female patients with infants must agree not to breastfeed their infants while on this study.
  • 43Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for 12 weeks after the last dose of tagraxofusp.
  • 44Disease Status:
  • 45Patients with CNS disease are not eligible for Part 1.
  • 46Patients with isolated CNS disease are not eligible for Part 1 or Part 2.
  • 47Patients with isolated non-CNS disease are eligible for Part 1 and Part 2.
  • 48Concomitant Medications
  • 49Corticosteroids - 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.
  • 50Investigational 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)

Locations

31 sites participating in this study

Children's Healthcare of Atlanta, Emory University

Atlanta, Georgia 30322

Recruiting

Melinda Pauly, MD

Children's Hospital Los Angeles

Los Angeles, California 90027

Recruiting

Alan Wayne, MD

Children's Hospital Orange County

Orange, California 92868

Recruiting

Van Thu Huynh, MD

Data sourced from ClinicalTrials.govView on ClinicalTrials.gov →