NCT07347418招募中1 期
Phase 1, Open Label, Dose Escalation Study to Evaluate the Safety, Expansion, Persistence, and Preliminary Clinical Activity of Autologous CD64 CAR T Cells in Patients With Relapsed and/or Refractory Acute Myeloid Leukemia (AML)
适应症
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 23
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD)
研究概览
简要总结
This is a Phase 1, open label, dose-escalation study to evaluate the safety, expansion, persistence, and preliminary clinical activity of lentivirally transduced autologous T cells expressing anti-CD64 chimeric antigen receptors (CAR) expressing tandem CD3ζ and 4-1BB (CD3ζ/4-1BB) costimulatory domains in subjects with refractory or relapsed (R/R) acute myeloid leukemia (AML). This CAR T cell product will be referred to as "CD64 CAR T" which is CD64 directed, autologous, genetically modified CAR T cells. The primary objective of the study is to identify the safety profile and maximum tolerated dose (MTD) of CD64 CAR T in subjects with R/R AML as determined by the defined DLTs using a standard Bayesian Optimal Interval (BOIN) design.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •≥ 18 years of age.
- •Subjects must have one of the following diagnoses per the International Consensus Classification (ICC) 2022 criteria:
- •a. Acute Myeloid Leukemia (AML).
- •Refractory OR relapsed AML:
- •a. Refractory disease i. ≥5% blasts in the bone marrow or peripheral blood by morphology, flow cytometry, or immunohistochemistry after a minimum of 1 cycle of a hypomethylating agent (HMA) and venetoclax (Ven) combination (Ven/HMA) b. Relapsed disease i. Recurrence of ≥ 5% blasts in the bone marrow or peripheral blood by morphology, flow cytometry or immunohistochemistry.
- •Subjects must have received at least one prior line of therapy, including at least one line of therapy containing Ven.
- •Documentation of CD64 expression on ≥70% of myeloid blasts by flow cytometry after the most recent relapse, as determined by standardized and validated multiparameter flow cytometry assay (Hematologics, Inc., Seattle, WA).
- •Total white blood cell (WBC) count ≤ 25 x 10(to the 9th)/L prior to apheresis. Hydroxyurea is permitted to achieve this
- •Absolute lymphocyte count (ALC) ≥ 200/µL prior to apheresis OR ALC < 200 µL with concurrent lymphocyte subset analysis (CD3, CD4, and CD8 counts) confirming an absolute CD3 count ≥ 150/µL.
- •Confirmed availability of cells for a rescue stem cell transplant AND subject must be deemed an appropriate candidate for such therapy per institutional standards.
- •Subjects who have undergone prior allogeneic stem cell transplant must be ≥ 6 months out from transplant and be off systemic immunosuppression for at least 1 month at the time of enrollment with no evidence of active graft versus host disease.
- •Adequate organ function, defined as:
- •Creatinine clearance ≥ 30 mL/min, based on the CKD-EPI Creatinine Equation (2021).
- •AST/ALT ≤ 5x upper limit of the normal range, unless considered to be due to leukemic involvement.
- •Bilirubin ≤ 3x upper limit of the normal range, unless the subject has Gilbert's Syndrome or considered to be due to leukemic involvement.
- •Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air, unless considered to be due to leukemic involvement.
- •Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA.
- •ECOG performance status 0, 1, or
- •Signed informed consent form.
- •Subjects of reproductive potential must agree to use acceptable birth control methods, as described in the protocol main text.
- •Willing to participate in the long-term follow-up protocol that is required if CAR T cell therapy is administered.
排除标准
- •Subjects with Acute Promyelocytic Leukemia (APL) with t(15;17)
- •Receipt of previous chemotherapy for AML, as follows:
- •a. Prior to apheresis, the following washout periods apply: i. Hydroxyurea: 1 day ii. Hypomethylating agent and/or venetoclax: 7 days iii. Small molecule targeted therapy (including tyrosine kinase inhibitors): 3 half-lives or 7 days, whichever is shorter.
- •iv. Immune checkpoint inhibitors or other immunological agents: 5 half-lives or 28 days, whichever is shorter.
- •v. Investigational products: 5 half-lives or 28 days, whichever is shorter. vi. Any other systemic chemotherapy: 14 days vii. Allogeneic stem cell transplantation: 180 days viii. Donor lymphocyte infusion (DLI): 60 days ix. Craniospinal or total body radiation: 42 days b. After apheresis and prior to lymphodepletion, no treatment for AML is permitted, with the exception of bridging hydroxyurea with a washout period of 1 day prior to the start of the lymphodepletion regimen.
- •Concurrent use of systemic steroids or immunosuppressant medications. Recent or current use of inhaled steroids or physiologic replacement with hydrocortisone is not exclusionary.
- •Previous treatment with investigational gene or cell therapy (including CAR therapy).
- •Signs or symptoms indicative of CNS leukemia involvement. A CNS evaluation should be performed if CNS involvement is suspected to rule out CNS leukemia involvement.
- •Pregnant or lactating (nursing) women.
- •Known HIV infection or active Hepatitis B or Hepatitis C infection.
- •Known history of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
- •Class III/IV cardiovascular disability according to the New York Heart Association Classification.
- •Subjects with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system, and unrelated to leukemia or previous leukemia treatment.
- •Subjects with cardiac arrhythmia, or arrhythmias that are not stable with medical management, within 2 weeks of the Screening/Enrollment visit.
- •Any uncontrolled active medical disorder that would preclude participation as outlined.
- •Evidence of another uncontrolled malignancy.
- •Apheresis Eligibility To proceed with apheresis, enrolled participants must continue to meet all inclusion criteria within no more than 21 days prior to apheresis, unless otherwise specified.
- •Note: Disease evaluation (bone marrow aspirate and biopsy) to meet inclusion criteria must be completed within 30 days prior to enrollment.
- •Lymphodepleting Chemotherapy Eligibility To proceed with lymphodepleting chemotherapy, enrolled participants must have specific assessments completed and continue to meet all inclusion criteria within 72 hours of initiation of lymphodepletion
- •CD64 CAR T Infusion Eligibility
- •Participants must meet the following criteria in order for cells to be infused (based on labs obtained within 24 hours of cell infusion):
- •CD64 CAR T must have met manufacturing criteria (unless prospectively approved by IND Sponsor, Gates Institute Medical Lead, and FDA)
- •Confirmation that the site has Anakinra and Ruxolitinib in stock and available (should IEC-HS treatment be required).
- •Performance status determination (ECOG must be 0, 1 or 2).
- •Participant remains clinically stable without evidence of vital sign instability including the lack of supportive vasoactive drugs or intensive care support.
- •Must not have ALT/SGPT and AST/SGOT > 10x the ULN or total bilirubin > 3x the ULN, (unless the subject has Gilbert's Syndrome or considered to be due to leukemic involvement)
- •Adequate renal function, as defined in the Inclusion Criteria.
- •No evidence of uncontrolled infection within 48 hours prior to cell infusion as determined by the PI or sub-investigator.
研究组 & 干预措施
CD64 CAR T Infusion
Experimental
Patients with relapsed and/or refractory acute myeloid leukemia (AML) will receive lymphodepleting chemotherapy followed by infusion of CD64 CAR T-cells.
干预措施: CD64 CAR T Cells (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD)
时间窗: Day 0 through Day 42
MTD will be established from the DLTs, which will be considered from the time of CD64 CAR T infusion (Day 0) through Day 42 after the subject's last infusion. A DLT is a treatment-emergent adverse event, or a clinically significant abnormal laboratory value, observed during the DLT observation period.
次要结局
- Manufacturability - Product Release Failure(Day 0 (Infusion))
- Manufacturability - Dose Failures(Day 0 (Infusion))
- Efficacy - Overall Response Rate (ORR)(Day 28, Month 3, and Month 6)
- Efficacy - Overall Survival(Up to 12 months post infusion)
- Efficacy - Progression Free Survival (PFS)(From treatment to end of study)
- Efficacy - Duration of Response (DOR)(From treatment to end of study)
- Efficacy - Need for Rescue Allogenic Stem Cell Transplant(From treatment to early termination for transplant)
研究者
研究点 (1)
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