Geneticky upravené buňky (CD83 CAR T buňky) pro léčbu relapsované nebo refrakterní akutní myeloidní leukémie
CD83 (RPCAR01) CAR T in Relapsed or Refractory Acute Myeloid Leukemia (AML): A Phase I Trial
This phase I trial tests the safety, side effects, and best dose of genetically engineered cells (CD83 chimeric antigen receptor [CAR] T cells) in treating patients with acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or has not responded to previous treatment (refractory). CD83 is a protein that is found on AML blasts. Blasts are abnormal immature white blood cells that can multiply uncontrollably: filling up the bone marrow and preventing the production of other cells important for survival. CD83 CAR T cells represent a new cell therapy to eliminate AML blasts, while avoiding the risk for graft versus host disease (GVHD) after stem cell transplant to replace bone marrow or, tumor toxicity like myeloid aplasia where the body's own immune system causes damage to the bone marrow stem cells. Therefore, human CD83 CAR T cells are a promising cell-based approach to preventing two critical complications of stem-cell transplant - GVHD and relapse. Giving CD83 CAR T cells may be safe, tolerable, and/or effective in treating patients with relapsed or refractory AML.
Přehled studie
Postavení
Intervence / Léčba
- Lék: Cyclophosphamide
- Lék: Fludarabine Phosphate
- Postup: Computed Tomography
- Jiný: Questionnaire Administration
- Postup: Positron Emission Tomography
- Postup: Lumbar Puncture
- Postup: Echocardiography
- Postup: Chest Radiography
- Postup: Leukapheresis
- Lék: Autologous Anti-CD83 CAR T-cells
- Postup: Biospecimen Collection
- Lék: Hydroxyurea
Detailní popis
PRIMARY OBJECTIVE:
I. To evaluate the safety and determine the maximal tolerated dose (MTD) of autologous anti-CD83 CAR T-cells (CD83 CAR T cells) administered as a single infusion to refractory/relapsed acute myeloid leukemia (AML) patients.
SECONDARY OBJECTIVES:
I. To observe and record activity against AML. II. To evaluate response for AML using 2022 European Leukemia Net (ELN) criteria.
III. To evaluate progression-free and overall survival after CAR T cell infusion.
IV. To evaluate the time to hematological recovery after CAR T cell infusion. V. To evaluate in vivo CAR T cell expansion and persistence. VI. To evaluate acute GVHD within 6 weeks after infusion of CAR T cells in patients who relapsed after allogeneic hematopoietic cell transplantation (HCT).
VII. To evaluate the incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).
EXPLORATORY OBJECTIVES:
I. To evaluate the relationship between cytokine expression and cytokine release syndrome (CRS).
II. To determine predictors of response and mechanisms or resistance to CAR-T cells.
III. To evaluate immune effects by CD83 CAR T cells on peripheral blood T cell subsets, B cells and dendritic cells.
IV. To evaluate the relationship between baseline levels of CD83 expression on AML blasts and response following CAR T cell infusion.
V. To evaluate the relationship between proportion of infused CAR T cell subsets (γδ T cells versus [vs.] αβ T cells) and disease response.
VI. To evaluate immunity after CAR T cell infusion. VII. To determine the rate of successful manufacturing and time required to complete.
VIII. To evaluate for CAR T phenotype, exhaustion, and CAR versus non-CAR subsets associated with response and relapse.
IX. Evaluate the effect of CAR T infusion on quality of life.
OUTLINE:
Patients undergo leukapheresis to obtain peripheral blood mononuclear cells (PBMCs) for CD83 CAR T cell product manufacturing on day -21 and may receive hydroxyurea at the discretion of the treating physician on study. Patients then receive fludarabine intravenously (IV) over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive CD83 CAR T cells IV over 15 minutes on day 0. Patients also undergo echocardiography (ECHO) and chest x-ray during screening, blood sample collection throughout the study, and computed tomography (CT) and/or positron emission tomography (PET), as well as lumbar puncture as clinically indicated. In addition, patients may undergo bone marrow aspiration throughout the study.
After completion of study treatment, patients are followed up every 2 weeks for 2 months then at 3, 6, and 12 months.
Typ studie
Zápis (Odhadovaný)
Fáze
- Fáze 1
Kontakty a umístění
Studijní místa
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New York
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Buffalo, New York, Spojené státy, 14263
- Nábor
- Roswell Park Cancer Institute
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Kontakt:
- Ask RPCI
- Telefonní číslo: 1-800-767-9355
- E-mail: askrpci@roswellpark.org
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Vrchní vyšetřovatel:
- Chelsea Peterson, DO
-
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Kritéria účasti
Kritéria způsobilosti
Věk způsobilý ke studiu
Přijímá zdravé dobrovolníky
Pohlaví způsobilá ke studiu
Popis
Inclusion Criteria:
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Age ≥ 18 years old.
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Karnofsky performance status score ≥ 70%.
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Relapsed or refractory AML.This can include detection of AML by morphologic, flow cytometric, or molecular means.(20).
- Relapsed AML is defined as the reappearance of malignant blasts in the bone marrow, reappearance of malignant blasts in the peripheral blood, or development of extramedullary disease after a documented complete remission.
- Refractory AML is defined as failure to achieve complete remission after at least one cycle of induction chemotherapy.
- At least 15% of AML blasts must be positive for CD83 expression by flow cytometry.
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Creatinine clearance: ≥ 40 mL/min (Cockroft-Gault).
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Total bilirubin: ≤ 2mg/dL except for patients with Gilbert's syndrome, hemolysis, or related to disease.
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Aspartate aminotransferase (AST) and alanine transaminase (ALT) < 3.0 x upper limit of normal (ULN).
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Left ventricular (LV) ejection fraction: > 45% and be free of symptomatic congestive heart failure or uncontrolled arrhythmia.
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Oxygen (O2) saturation: ≥ 92% on room air without needs for supplemental O2.
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Absolute lymphocyte count: ≥ 0.2 x 10^9/L
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Life expectancy ≥12 weeks from the time of enrollment, per clinical judgment.
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Negative serum pregnancy test in females of child-bearing potential (FOCBP). FOCBP is defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal.
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If history of allogeneic HCT, must have completed transplant at least 3 months prior, be off immunosuppression, including ruxolitinib, at least 2 weeks prior to apheresis, and have no evidence of GVHD requiring treatment at enrollment.
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Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry and for 12 months following duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
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Participants must be considered preliminarily eligible for an allogeneic hematopoietic cell transplantation, with potential donors identified per a transplant and cellular therapy consult at Roswell Park Comprehensive Cancer Center.
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Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure.
Exclusion Criteria:
- Concomitant systemic glucocorticoid use at a dose equivalent to > 10 mg daily prednisone at the time of apheresis and/or within 4 weeks of CD83 CAR T infusion for any reasons other than GVHD.
- Diagnosis of acute promyelocytic leukemia (APL; AML M3 by French-American-British [FAB] classification).
- Active central nervous system (CNS) leukemia; patients with history of CNS leukemia in complete response (CR) are eligible.
- Patients enrolled in another investigational therapy protocol for their disease within 14 days or 5 half-lives prior to leukapheresis, whichever is shorter.
- Patients requiring agents or any treatments other than hydroxyurea, single agent cytarbine,hypomethylating agents with or without ventoclax and/or targeted agents (i.e., FLT3, IDH2 or IDH1 inhibitors) to control blast counts within 14 days or 5 half-lives (whichever is shorter) prior to lymphodepletion.
- Ongoing uncontrolled serious infection, pulmonary disease or psycho/social concerns.
- HIV seropositivity or active hepatitis B or C infection within (defined by positive polymerase chain reaction [PCR]) 4 weeks of enrollment.
- Other active malignancy within 2 years of study entry, except for basal cell cancer of skin, cervical cancer treated surgically with curative intent or localized prostate cancer managed with observational approach.
- Active grade II-IV acute GVHD in patients with relapsed AML after HCT requiring treatment.
- Prior solid organ transplant.
- Active autoimmune disease requiring immunosuppressive therapy.
- Pregnant or nursing female participants.
- Unwilling or unable to follow protocol requirements.
- Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug.
Studijní plán
Jak je studie koncipována?
Detaily designu
- Primární účel: Léčba
- Přidělení: N/A
- Intervenční model: Přiřazení jedné skupiny
- Maskování: Žádné (otevřený štítek)
Zbraně a zásahy
Skupina účastníků / Arm |
Intervence / Léčba |
|---|---|
|
Experimentální: Treatment (fludarabine, cyclophosphamide, CD83 CAR T-cells)
Patients undergo leukapheresis to obtain PBMCs for CD83 CAR T-cell product manufacturing on day -21 and may receive hydroxyurea at the discretion of the treating physician on study. Patients then receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive CD83 CAR T-cells IV over 15 minutes on day 0. Patients also undergo ECHO and chest x-ray during screening, blood sample collection throughout the study, and CT and/or PET, as well as lumbar puncture as clinically indicated. In addition, patients may undergo bone marrow aspiration throughout the study. |
Given IV
Ostatní jména:
Given IV
Ostatní jména:
Undergo CT
Ostatní jména:
Ancillary studies Undergo PET
Ostatní jména:
Undergo lumbar puncture
Ostatní jména:
Undergo ECHO
Ostatní jména:
Undergo chest x-ray
Ostatní jména:
Undergo leukapheresis
Ostatní jména:
Given IV
Ostatní jména:
Undergo bone marrow aspiration blood sample collection
Ostatní jména:
Given hydroxyurea
Ostatní jména:
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Co je měření studie?
Primární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
|
Incidence of dose-limiting toxicity (DLT)
Časové okno: Up to 28 days
|
Will be defined as any adverse events based on Common Terminology Criteria for Adverse Events (CTCAE) version (v)5. Cytokine release syndrome(CRS)/immune effector cell-associated neurotoxicity syndrome will be graded according to American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Guidelines. The DLTs will be summarized by dose level using frequencies and relative frequencies. Will employ the Bayesian optimal interval design to find the maximal tolerated dose (MTD). The target DLT rate for the MTD is = 0.33. |
Up to 28 days
|
Sekundární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
|
Objective response
Časové okno: At 28 days and 1 year
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Will be determine as the number of patients achieving complete remission, partial remission, and/or morphologic leukemia free state by 2022 European Leukemia Net Response Criteria. Will be summarized by dose level using frequencies and relative frequencies. Rates will be estimated using 95% credible regions obtained by Jeffrey's prior method. As exploratory analyses, comparisons between dose levels may be made using Fisher's exact test. |
At 28 days and 1 year
|
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Overall survival
Časové okno: From treatment initiation until death due to any cause or last follow-up, assessed up to 1 year
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Will be summarized by dose level using cumulative incidence or Kaplan-Meier curves, as appropriate. Estimates of the median times will be obtained with 95% confidence intervals calculated using the log-log transformation. As exploratory analyses, comparisons between dose levels may be made using Gray's or the log-rank test, as appropriate. |
From treatment initiation until death due to any cause or last follow-up, assessed up to 1 year
|
|
Progression-free survival
Časové okno: From treatment initiation until disease progression/relapse, death due to any cause, subsequent treatment (censored), or last follow-up, assessed up to 1 year
|
Will be summarized by dose level using cumulative incidence or Kaplan-Meier curves, as appropriate. Estimates of the median times will be obtained with 95% confidence intervals calculated using the log-log transformation. As exploratory analyses, comparisons between dose levels may be made using Gray's or the log-rank test, as appropriate. |
From treatment initiation until disease progression/relapse, death due to any cause, subsequent treatment (censored), or last follow-up, assessed up to 1 year
|
|
Hematologic recovery
Časové okno: At 28 days
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Will be assessed by achieving an absolute neutrophil count recovery (> 0.5 x 10^9/L). Will be summarized by dose level using frequencies and relative frequencies. Rates will be estimated using 95% credible regions obtained by Jeffrey's prior method. As exploratory analyses, comparisons between dose levels may be made using Fisher's exact test. |
At 28 days
|
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Time to hematologic recovery
Časové okno: From treatment initiation until hematologic recovery or last follow-up, assessed up to 1 year
|
Relapse or death will be considered the competing risk. Will be summarized by dose level using cumulative incidence or Kaplan-Meier curves, as appropriate. Estimates of the median times will be obtained with 95% confidence intervals calculated using the log-log transformation. As exploratory analyses, comparisons between dose levels may be made using Gray's or the log-rank test, as appropriate. |
From treatment initiation until hematologic recovery or last follow-up, assessed up to 1 year
|
|
Acute graft-versus-host disease (GVHD)
Časové okno: Up to 6 weeks
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Will be defined as a grade II-IV acute GVHD. Will be summarized by dose level using cumulative incidence or Kaplan-Meier curves, as appropriate. Estimates of the median times will be obtained with 95% confidence intervals calculated using the log-log transformation. As exploratory analyses, comparisons between dose levels may be made using Gray's or the log-rank test, as appropriate. |
Up to 6 weeks
|
|
Time to GVHD
Časové okno: From treatment initiation until grade II-IV GVHD, 6 weeks post infusion, or last follow-up, assessed up to 1 year
|
Relapse or death will be considered the competing risk. Will be summarized by dose level using cumulative incidence or Kaplan-Meier curves, as appropriate. Estimates of the median times will be obtained with 95% confidence intervals calculated using the log-log transformation. As exploratory analyses, comparisons between dose levels may be made using Gray's or the log-rank test, as appropriate. |
From treatment initiation until grade II-IV GVHD, 6 weeks post infusion, or last follow-up, assessed up to 1 year
|
|
Treatment-related adverse events
Časové okno: Up to 12 months
|
Will be defined as by CTCAE v5 and CRS by ASTCT Consensus Grading for CRS and Neurological Toxicity Associated with Immune Effector Cells. Will be summarized by dose level using frequencies and relative frequencies. Rates will be estimated using 95% credible regions obtained by Jeffrey's prior method. As exploratory analyses, comparisons between dose levels may be made using Fisher's exact test. |
Up to 12 months
|
|
Time to treatment related adverse event
Časové okno: From treatment initiation until a treatment related adverse event, 12 months post infusion, or last follow-up, assessed up to 1 year
|
Relapse or death will be considered the competing risk. Will be summarized by dose level using cumulative incidence or Kaplan-Meier curves, as appropriate. Estimates of the median times will be obtained with 95% confidence intervals calculated using the log-log transformation. As exploratory analyses, comparisons between dose levels may be made using Gray's or the log-rank test, as appropriate |
From treatment initiation until a treatment related adverse event, 12 months post infusion, or last follow-up, assessed up to 1 year
|
|
Number of peripheral blood chimeric antigen receptor (CAR) T cells
Časové okno: Up to 1 year
|
Will be summarized by dose level and timepoint (pre- and post-therapy) using the mean, median, and standard deviation; and graphically using dot plots. The log absolute number of CD83 CAR T cells per peripheral blood volume will be modeled as a function of dose level, time, their two-way interaction, and a random subject effect using a linear mixed model. Tests about the appropriate contrasts on model estimates will be sued to compare: 1) changes relative to pre-therapy within each dose level, and 2) changes at a given timepoint between dose levels. All model assumptions will be verified graphically, and transformations applied as appropriate. |
Up to 1 year
|
Spolupracovníci a vyšetřovatelé
Sponzor
Spolupracovníci
Vyšetřovatelé
- Vrchní vyšetřovatel: Chelsea Peterson, DO, Roswell Park Cancer Institute
Termíny studijních záznamů
Hlavní termíny studia
Začátek studia (Aktuální)
Primární dokončení (Odhadovaný)
Dokončení studie (Odhadovaný)
Termíny zápisu do studia
První předloženo
První předloženo, které splnilo kritéria kontroly kvality
První zveřejněno (Aktuální)
Aktualizace studijních záznamů
Poslední zveřejněná aktualizace (Aktuální)
Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality
Naposledy ověřeno
Více informací
Termíny související s touto studií
Další relevantní podmínky MeSH
- Novotvary
- Novotvary podle histologického typu
- Hematologická onemocnění
- Leukémie, myeloidní
- Leukémie
- Hemická a lymfatická onemocnění
- Leukémie, myeloidní, akutní
- Organické chemikálie
- Vyšetřovací techniky
- Terapeutika
- Klinické laboratorní techniky
- Diagnostické techniky a postupy
- Diagnóza
- Vpichy
- Chirurgické postupy, operativní
- Cytologické techniky
- Biopsie
- Uhlovodíky
- Fyzické jevy
- Amidy
- Techniky chemie, analytické
- Analýza spektra
- Fosforamidové hořčice
- Sloučeniny hořčice dusíku
- Hořčičné sloučeniny
- Uhlovodíky, halogenované
- Fosforamidy
- Organofosforové sloučeniny
- Elektromagnetické jevy
- Magnetické jevy
- Biologická terapie
- Cytaferéze
- Odstraňování složek krve
- Postupy redukce leukocytů
- Separace buněk
- Diagnostické techniky, neurologické
- Elektromagnetické záření
- Záření
- Záření, ionizující
- Močovina
- Cyklofosfamid
- Hydroxymočovina
- Manipulace se vzorkem
- Magnetická rezonanční spektroskopie
- Fludarabin fosfát
- Leukapheresis
- Spinální punkci
- Rentgenové paprsky
Další identifikační čísla studie
- I-3916824
- NCI-2025-01523 (Identifikátor registru: CTRP (Clinical Trial Reporting Program))
- CDMRP-CA250315 (Jiné číslo grantu/financování: DoD)
Informace o lécích a zařízeních, studijní dokumenty
Studuje lékový produkt regulovaný americkým FDA
Studuje produkt zařízení regulovaný americkým úřadem FDA
produkt vyrobený a vyvážený z USA
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