90Yttrium-labelled Anti-CD66 Monoclonal Antibody as Part of a Reduced Toxicity Conditioning Regimen Prior to Allogeneic Haematopoietic Stem Cell Transplantation: an Open Label, Phase II Study in Children and Adolescents With High Risk Leukaemia
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 25
- 试验地点
- 2
- 主要终点
- Disease response after [90Y]-labelled anti-CD66 monoclonal antibody
研究概览
简要总结
Children affected by high risk or relapsed/refractory leukaemia have a poor prognosis, with an increased risk of relapse. These patients generally need treatment intensification and a bone marrow transplantation (BMT).
Nevertheless, with conventional treatent the risk of relapse after transplant remains high.
Radioimmunotherapy provides a way to deliver high dose irradiation to the bone marrow (where leukaemia resides), while sparing normal organs and tissues from its toxicity.This can be achieved by linking a radioactive molecule (Yttrium90) to an antibody that, once infused in the blood, targets marrow/leukemic cells.
详细描述
In our Phase 1 trial which concluded in 2019, 9 children affected by refractory or relapsed leukaemia were enrolled at Great Ormond Street Hospital or UCLH. Participants received infusion of a tumour cell targeting antibody to deliver irradiation to the bone marrow and sites containing leukemic blasts prior to BMT. The aim of the Phase 1 study was to identify the dose limiting toxicity and maximum tolerated dose of targeted radiotherapy, and it was found that this treatment was well tolerated with minimal infusion-related side effects.
The current study will enrol a larger cohort of children (aged 0.5 - 18 years) who will receive 90Yttrium administered at an infused activity to target the optimal absorbed dose to the bone marrow. Patients will be treated at GOSH and UCLH and followed up for 12 months post-BMT to evaluate safety and efficacy of targeted radiotherapy with a reduced toxicity conditioning regimen prior to BMT.
PURPOSE AND DESIGN OF THE STUDY Children with high risk or relapsed leukaemia have a poor prognosis with an increased risk of relapse after standard bone marrow transplant. There is an urgent need to offer a different therapeutic strategy for children with such poor risk diseases.
There is evidence that targeted radioimmunotherapy prior to a stem cell transplantation is a feasible and effective treatment that delivers high dose radiation to the bone marrow and spleen (where leukaemia resides),while sparing other tissues and organs from its toxicity. Since leukaemic cells are generally radiosensitive, this approach might increase leukaemia-free survival, while reducing transplant-related morbidity and mortality.
Our previous phase 1 radio-immunotherapy study demonstrated that radio-immunotherapy is non-toxic, but can elicit myelosuppression, with potential for better disease eradication.
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
- 6 Months 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •An underlying hematological malignancy including:
- •a) relapse of AML after allogeneic hematopoietic stem cell transplantation; b) relapse of ALL after allogeneic hematopoietic stem cell transplantation; c) relapse of JMML after allogeneic hematopoietic stem cell transplantation; e) refractory ALL; f) refractory AML; g) high risk infant ALL;
- •be ≥ 0.5 year old and ≤ 18 years old;
- •must not be eligible for therapy of higher curative potential. Where an alternative therapy has been shown to prolong survival in an analogous population, this should be offered to the patient prior to discussing this study;
- •have a Karnofsky Performance Status ≥ 50 or Lansky Performance Status ≥ 30;
- •provide signed, written informed consent from parent or guardian;
- •be able to comply with study procedures and follow-up examinations;
- •have adequate cardiac function (irrespective of concomitant cardio-vascular treatment) at PI/CI discretion;
- •have adequate organ function (as indicated by Table 5) within 30 days prior to 111In infusion;
- •patients who have received any other chemotherapy within the previous 2 weeks and must have recovered from acute toxicity of all previous therapy prior to enrolment;
- •be negative for human-anti-murine antibodies (HAMA).
排除标准
- •patients who are positive for human anti-murine antibodies (HAMA);
- •patients with compromised organ function within 30 days prior to 111In infusion;
- •patients with isolated CNS disease relapse*;
- •patients with an active, uncontrolled systemic infection considered opportunistic, life threatening, or clinically significant at the time of treatment;
- •Pregnant or breast-feeding females are excluded due to potential risks of foetal adverse events of an investigational agent. Pregnancy tests must be obtained prior to enrolment on this study for girls of reproductive potential. The need to commence pregnancy testing will be at the discretion of the treating physician to facilitate taking in to account factors such as precocious puberty, endocrine status and medications which can affect pubertal status. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Sexual Abstinence is an acceptable method of birth control**.
- •patients with any other severe concurrent disease, which, in the judgment of the Investigator, would make the patient inappropriate for entry into this study;
- •patients with extensive chronic graft versus host disease (GVHD);
- •patients with unstable cardio-vascular disease. -
研究组 & 干预措施
90-Yttrium-labelled anti-CD66 monoclonal antibody
The medicinal product consists of the murine IgG1 anti-CD66 monoclonal antibody radio-labelled with 111In for imaging and dosimetry and with 90Y for therapy.
Dosage indications The [111In]-labeled anti-CD66 monoclonal antibody (MAb) will be given at an infused activity of 100MBq/sqm between 1-4 weeks before the therapeutic dose of radiolabelled antibody.
[90Y]-yttrium-labeled anti-CD66 MAb will be given as a single infusion on day - 14 prior to transplant. [90Y]-yttrium labelled anti-CD66 MAb will be given to target an absorbed dose to the bone marrow of 45 Gy +/- 10%. The maximum dose to be delivered to the liver and the kidneys is 15 Gy and 10 Gy, respectively.
干预措施: 90-Yttrium-labelled anti-CD66 monoclonal antibody (Drug)
结局指标
主要结局
Disease response after [90Y]-labelled anti-CD66 monoclonal antibody
时间窗: through study completion, upto 2 years post study
recovery of normal hematopoiesis in the bone marrow, with blasts \< 5% of lymphoid/myeloid cells and lack of evidence for residual leukemia using any informative cytogenetic/molecular marker. The number and proportion of patients who have a response will be provided in each cohort.
次要结局
- Assessment of timing of myeloid and platelet engraftment after allogeneic hematopoietic stem cell transplantation.(through study completion, upto 2 years post study)
- Assessment of chimerism on bone marrow and peripheral blood to confirm engraftment of donor origin.(through study completion, upto 2 years post study)
- Safety Outcome(through study completion, upto 2 years post study)