Haploidentical stem cell transplantation with iCasp9 T cell addback in patients with poor risk haematological malignancies

Phase 1

• Conditions: Patients with high risk acute leukaemia, myelodysplastic syndrome or chronic myeloid leukaemia, who lack a suitable fully human leukocyte antigen (HLA)-matched or single-antigen mismatched donor.; Cancer - Leukaemia - Acute leukaemia; Cancer - Leukaemia - Chronic leukaemia; Blood - Haematological diseases

• Registration Number: ACTRN12614000290695
• Lead Sponsor: Metro North Hospital and Health Service - Royal Brisbane and Womens’ Hospital

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2014-03-19
• Last Update Posted: 29 August 2022

Recruitment & Eligibility

• Status: Stopped early
• Sex: All
• Target Recruitment: 3

Inclusion Criteria

RECIPIENT INCLUSION:
*Lack of a fully HLA-matched or single-antigen mismatched (9/10 matched) related or unrelated donor
*Poor risk haematological malignancy defined as follows:
a.Acute myeloid leukaemia (AML)

i.High risk disease in first complete remission (CR1 )
-high risk features include poor risk cytogenetics, normal cytogenetics with Flt3-ITD mutation, and secondary AML
ii.Primary refractory after 2 induction cycles
iii.Relapsed disease in morphological remission

b.Acute lymphoblastic leukaemia (ALL)
i.CR1 with high risk cytogenetics (includes t(9;22), MLL/11q23 translocation)
ii.Second or greater CR

c.Chronic myeloid leukaemia (CML) beyond first chronic phase (>CP1)

d.Myelodysplastic syndrome (MDS) that is intermediate-2 or high risk according to International Prognostic Scoring system

*Life expectancy greater than 3 months
*Eastern Cooperative Oncology Group (ECOG) performance status less than 2 (Karnofsky more than 50%)
*Adequate organ function for allogeneic stem cell transplantation: bilirubin less than or equal to 30 micrometre, creatinine clearance more than or equal to 50ml/min/1.73m2, DLCOc more than or equal to 50% predicted, or left ventricular ejection fraction ( LVEF) more than or equal to 50%

*Able and willing to provide written informed consent
DONOR ELIGIBILITY:
*5/10 to 8/10 HLA-matched family member (first, second or third degree relative) aged 18-65 years old
*Seronegativity for Hepatitis B surface Ag, Hepatitis C antibody, and HIV antibody
*Able and willing to undergo venesection and/or additional apheresis procedure to donate T cells for post-transplant add-back

Exclusion Criteria

RECIPIENT EXCLUSION:
*Active, uncontrolled infection
*Inadequate organ function for allogeneic stem cell transplantation: bilirubin more than 30 micrometre, creatinine clearance less than 50ml/min/1.73m2, DLCOc less than 50% predicted, or LVEF less than 50%
*Seropositivity for Hepatitis B surface Ag, Hepatitis C antibody, or HIV antibody
*Pregnant or breastfeeding, or patient with reproductive potential who is not willing to use adequate contraceptive precautions in the judgement of the investigator.
*Psychiatric illness or social circumstances that would limit compliance with study requirements

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Overall survival (OS)<br>[1 year];The maximum tolerated dose (MTD) for iCasp9-transduced T cell addback that will result in no more than 25% acute GVHD grade III or IV. Acute GVHD will be assessed clinically and graded using the Seattle (Glucksberg) criteria. The MTD is determined by a modified continual reassessment method (mCRM) using a cohort size of 2 patients per dose.[Acute GVHD is assessed up to 100 days post T cell addback. Only patients who survive at least 28 days post T cell addback are evaluable unless acute GVHD grade III or IV occurred prior to day 28. ]

Secondary Outcome Measures

Name	Time	Method
Progression free survival (PFS)[1 year];Transplant related mortality (TRM)[1 year];Incidence of and time to engraftment. This is assessed by daily full blood counts (laboratory test) until such time when the neutrophil count has reached >0.5x10e9/L on 3 consecutive days and platelet >20x10e9/L (unsupported) for 5 consecutive days.[1 year];Incidence of infection. This is assessed clinically and by laboratory test (culture from blood, urine, faeces, other sample sites, if indicated). [1 year];Incidence of acute GVHD. This is assessed by clinical examination and laboratory tests (blood test and, if indicated, biopsy) and graded according to the Seattle (Glucksberg) acute GVHD criteria.[100 days after iCasp9 T cell addback];Incidence of chronic GVHD. This is assessed by clinical examination and laboratory tests (blood test and, if indicated, biopsy) and graded according to the Seattle chronic GVHD criteria.[1 year];Time to immune reconstitution. This is assessed by laboratory analysis of blood samples. [1 year]