Genetic Ablation of CD33 in Hematopoietic Stem Cells to Broaden the Therapeutic Index of CD33-directed Immunotherapy in Patients with Acute Myeloid Leukemia (AML)
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 12
- 试验地点
- 2
- 主要终点
- dose-limiting toxicity
研究概览
简要总结
The study "GALAXY33" is an open-label, prospective, nonrandomized, one arm phase I clinical trial in which patients with relapsed AML after allogeneic hematopoietic stem cell transplantation will be transplanted with CD33-deleted CD34+ HSC derived from the initially matched family donor.
详细描述
CRISPR/Cas9-mediated inactivation of CD33 in hematopoietic stem cells (HSC) may broaden the therapeutic index of CD33-directed immunotherapy for patients with AML by rendering healthy hematopoietic stem and progenitor cells (HSPC) resistant to escalating doses and/or shorter dosing intervals of the CD33-specific antibody-drug conjugate (ADC) Gemtuzumab-ozogamicin (GO).
In this proof of concept trial, we will develop a platform for genome editing of CD34+ HSC and demonstrate the feasibility, safety and efficacy of this approach for targeted therapy of AML.
Upon implementation, the platform shall be used for innovative clinical trials in diverse types of cancer. Outside of leukemias, autologous HSC could be used to ease the procedure.
Patients with relapsed AML after allogeneic hematopoietic stem cell transplantation will be transplanted with CD33-deleted CD34+ HSC derived from the initially matched family donor.
Upon HSC engraftment, patients will be treated with escalating doses of the anti-CD33 antibodydrug conjugate Gemtuzumab-Ozogamicin (GO). A conditioning regimen containing GO (d-14, d-11, d-8),Fludarabine 30 mg/m2 (d-6 to d-3) and Melphalan 140mg/m2 (d-2) is used prior to transplantation.
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
- •confirmed AML according to the WHO classification
- •relapsed disease after allo-SCT from an HLA-identical family donor (≥ 2 months after allo-SCT at time of inclusion)
- •≤ 29% of bone marrow blasts as detected by cytomorphology or immunohistochemistry
- •age ≥ 18 years
- •confirmed CD33 expression on leukemic blasts at current relapse (as detected by flow cytometry)
- •adequate organ function:
- •Renal function defined as: serum creatinine of ≤ 2x ULN or eGFR ≥ 30 mL/min/1.73 m2
- •Liver function defined as:
- •ALT ≤ 3 times the ULN for the respective age
- •Bilirubin ≤ 2.0 mg/dl with the exception of patients with hyperbilirubinemia explained by Gilbert-Meulengracht syndrome (may be included if total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN) or extrahepatic disease (e.g. chronic hemolytic anemia)
- •Minimum level of pulmonary reserve defined as ≤ grade 1 dyspnea and pulse oxygenation > 90% on room air
- •Hemodynamic stability and LVEF ≥ 40% as confirmed by echocardiogram
- •Absolute lymphocyte count (ALC) ≥ 100/mm3
排除标准
- •ECOG performance status >2
- •Confirmed CNS involvement
- •Acute or chronic Graft versus Host disease (GvHD)
- •Availability of other curative standard treatment options
- •Prior treatment with GO
- •Prior hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS)
- •Uncontrolled active hepatitis B or C
- •HIV-positivity
- •Uncontrolled bacterial, viral or fungal infection
- •Participation in another clinical trial at the time of screening
- •Organ dysfunction (liver, kidney, lung, heart) that is a contraindication for conditioning therapy
- •Severe concomitant disease (e.g. uncontrolled arterial hypertension, heart failure NYHA III-IV, uncontrolled diabetes mellitus, uncontrolled hyperlipidemia)
- •Unstable angina and/or myocardial infarction within 3 months prior to screening
- •Pregnant or nursing (lactating) women
研究组 & 干预措施
Donor-derived CD33-deleted CD34+ HSC combined with Gemtuzumab-Ozogamicin (GO)
Patients will be transplanted with CD33-deleted CD34+ HSC derived from the initially matched family donor. Upon HSC engraftment, patients will be treated with escalating doses of the anti-CD33 antibodydrugconjugate Gemtuzumab-Ozogamicin (GO). A conditioning regimen containing GO (d-14, d-11, d-8), Fludarabine 30 mg/m2 (d-6 to d-3) and Melphalan 140mg/m2 (d-2) is used prior to transplantation.
干预措施: Donor-derived CD34+ HSC with CRISPR/Cas9-mediated CD33 deletion (Biological)
Donor-derived CD33-deleted CD34+ HSC combined with Gemtuzumab-Ozogamicin (GO)
Patients will be transplanted with CD33-deleted CD34+ HSC derived from the initially matched family donor. Upon HSC engraftment, patients will be treated with escalating doses of the anti-CD33 antibodydrugconjugate Gemtuzumab-Ozogamicin (GO). A conditioning regimen containing GO (d-14, d-11, d-8), Fludarabine 30 mg/m2 (d-6 to d-3) and Melphalan 140mg/m2 (d-2) is used prior to transplantation.
干预措施: Gemtuzumab Ozogamicin (Drug)
结局指标
主要结局
dose-limiting toxicity
时间窗: until EOS (day 90)
dose-limiting toxicity (DLT) of Gemtuzumab-Ozogamicin
toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
时间窗: until EOS (day 90)
frequency and grade of AEs with gene-edited HSC transplantation
engraftement of gene edited CD34+HSC
时间窗: on day 28
successful engraftement of gene edited CD34+HSC in the bone marrow
次要结局
- Time to response(until EOS (day 90))
- Overall response(until EOS (day 90))
- Overall survival(until EOS (day 90))
- Progression-free survival(until EOS (day 90))
- Anti-tumor efficacy of study treatment in patients with dCD33+ relapsed AML after allo-SCT(until EOS (day 90))
- Number of circulating gene edited cells(at screening and days 14, 28, 56, 90)