CART123 Cells With or Without Ruxolitinib in Relapsed/Refractory Acute Myeloid Leukemia

Официальное название

Phase 1 Trial of Autologous CD123-Directed CAR T-Cells (CART123) as Monotherapy or in Combination With Ruxolitinib in Relapsed/Refractory Acute Myeloid Leukemia

Обзор

This study is designed to evaluate the safety and effectiveness of CART123 cells either alone or when combined with ruxolitinib in pediatric and young adult subjects with relapsed or refractory AML. Subjects will be enrolled into one of two treatment cohorts: subjects who will receive CART123 alone (Cohort A) or subjects who will receive CART123 in combination with ruxolitinib (Cohort B).

Подробное описание

This trial will be conducted at the Children's Hospital of Philadelphia with CART123 infusions occurring in an outpatient setting with close follow-up. Approximately 18 subjects will be treated on Cohort A and 12 patients treated on Cohort B.

Cohort A will consist of a dose escalation of CART123 cells administered intravenously on Day 0 after lymphodepleting chemotherapy. Subjects enrolled on Cohort A will receive a standard regimen of fludarabine (30 mg/m2/day x 4 days) and cyclophosphamide (500 mg/m2/day x 2 days). There is the most experience with the use of this regimen in facilitating adoptive immunotherapy in completed and ongoing pediatric CART trials.

Cohort B will consist of a fixed dose of CART123 cells (2x10\^6 CART123 cells/kg) to be administered intravenously on Day 0 in combination with age and BSA-based dosing of ruxolitinib given orally from the start of lymphodepleting chemotherapy until Day -2 and again from Day+7 to Day+13. Subjects enrolled on Cohort B will receive the regimen fludarabine (30 mg/m2/day x 4 days) and cyclophosphamide (1000 mg/m2/day x 3 days). This regimen of enhanced lymphodepletion has been employed with other investigational CAR T-cell therapies with the goal of improving CAR T-cell expansion. There is no dose escalation of CART123 cells or ruxolitinib on this cohort, but a dose de-escalation of ruxolitinib is planned in the event of unacceptable toxicity defined by dose de-escalation rules.

Вмешательства

• Биопрепарат Anti-CD123 LV redirected T cells (CART123)
  CART123 cells: lentivirally transduced T cells expressing anti-CD123 chimeric antigen receptors expressing tandem TCRζ and 4-1BB (TCRζ /4-1BB) costimulatory domains.
• Препарат Ruxolitinib (JAKAVI®)
  Ruxolitinib: an orally administered janus-activated kinase (JAK) inhibitor that selectively inhibits JAK1 and JAK2.

Первичные конечные точки

• Evaluate the Safety of CART123 [Срок оценки: 5 years]
• Safety of CART123 in combination with Ruxolitinib [Срок оценки: 5 Years]
• Determine Maximum Tolerated Dose of CART123 [Срок оценки: 5 years]

Вторичные конечные точки (5)

• Determine Feasibility of CART123 Treatment [Срок оценки: 5 years]
• Determine feasibility of combination treatment with CART123 and ruxolitinib [Срок оценки: 5 years]
• Determine the Preliminary Efficacy of CART123 [Срок оценки: 5 years]
• Determine the Preliminary Efficacy of CART123 + Ruxolitinib [Срок оценки: 5 years]
• Evaluate the need for rescue stem cell transplant following treatment with CART123 or CART123 with Ruxolitinib [Срок оценки: 5 years]

Критерии участия

Критерии включения

• 1\. Age at time of consent: Cohort A: 0-29 years. Cohort B: 1-29 years (Note: the first subject at each dose level of Cohort B must be ≥12 years old)
• 2\. Subjects with AML in second or greater relapse, post-transplant relapse, or with chemotherapy-refractory disease. Specifically:

• Second or greater relapse defined as bone marrow flow cytometric confirmation of myeloid leukemia of at least 0.1% or development of extramedullary disease by imaging or biopsy after second documented complete remission; OR
• Any detectable disease post-allogeneic transplant with bone marrow flow cytometric confirmation of myeloid leukemia of at least 0.1% or development of extramedullary disease by imaging or biopsy; OR
• Refractory disease, defined as: Persistent bone marrow involvement with ≥0.1% disease by flow cytometry or persistent extramedullary disease by imaging or biopsy after two courses of induction chemotherapy for patients at initial presentation, ≥ 0.1% bone marrow disease by flow cytometry or persistent extramedullary disease by imaging or biopsy after one course of induction chemotherapy for patients who have relapsed after previously achieving a CR , and ≥ 0.1% bone marrow disease by flow cytometry or persistent extramedullary disease by imaging or biopsy after one course of AML-directed chemotherapy for those with myeloid lineage switch.
• 3\. Subjects must have an identified stem cell donor with the ability to proceed rapidly to transplant following CART123 treatment if indicated.
• 4\. Adequate organ function defined as:

• Serum creatinine based on age/gender.
• Adequate liver function: ALT ≤ 500 U/L, Bilirubin ≤3x the upper limit of normal, and ALT and/or bilirubin results that exceed this range are acceptable if, in the opinion of the physician-investigator (or as confirmed by liver biopsy), the abnormalities are directly related to AML infiltration of the liver.
• Must have a minimum level of pulmonary reserve defined as ≤Grade 1 dyspnea and <Grade 3 hypoxia; DLCO ≥ 40% (corrected for anemia if necessary) if PFTs are clinically appropriate as determined by the treating investigator.
• Left Ventricular Shortening Fraction (LVSF) ≥ 28% or Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or another scan.
• 5\. Adequate performance status defined as Lansky or Karnofsky performance score ≥ 50.
• 6\. Subjects of reproductive potential must agree to use acceptable birth control methods.

Критерии исключения

• 1\. Active hepatitis B or active hepatitis C
• 2\. HIV infection
• 3\. Active acute or chronic GVHD requiring systemic therapy
• 4\. Concurrent use of systemic steroids or immunosuppression at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy or immunosuppression during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of physiologic replacement hydrocortisone or inhaled steroids is permitted as well.
• 5\. CNS disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity.
• 6\. Pregnant or nursing (lactating) subjects.
• 7\. Uncontrolled active infection

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Children's Hospital of Philadelphia — Philadelphia

Идентификаторы

NCT: NCT07464951 · 25CT017, 25-024116

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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