Haploidentical stem cell transplantation with iCasp9 T cell addback in patients with poor risk haematological malignancies
A phase I study of haploidentical haematopoietic stem cell transplantation with add-back of donor T cells transduced with inducible caspase 9 suicide gene in patients with poor risk haematological malignancies
Metro North Hospital and Health Service - Royal Brisbane and Womens’ Hospital
12 participants
Dec 5, 2014
Interventional
Conditions
Summary
Purpose This study is evaluating the safety of haploidentical stem cell transplantation using high dose chemotherapy and radiotherapy, with the infusion of donor stem cells followed by the infusion of genetically modified donor T cells. The genetic modification involves the insertion of a safety switch, called iCasp9, into the donor T cells, which allows the cells to be removed with a drug, AP1903, if the patient develops graft-versus-host disease, which is a life-threatening complication of stem cell transplantation. Who is it for? You may be eligible to join this study if you have a poor risk haematological malignancy (leukaemia or myelodysplastic syndrome) that requires treatment with an allogeneic stem cell transplant but do not have a suitable conventional donor, meaning you do not have a fully-matched or single-antigen mismatched (9/10 matched) related or unrelated donor. You should be aged 18 to 59years old and have adequate organ function to undergo an allogeneic stem cell transplant. You should have a suitable first, second or third degree relative who can be your donor. Trial details Participants in this study will undergo myeloablative conditioning which involves high dose chemotherapy and radiotherapy. This consists of total body irradiation, thiotepa, fludarabine and rabbit antithymocyte globulin (Thymoglobuline). Donor mobilised peripheral blood stem cells are CD34+-selected and infused fresh on day 0 without post-transplant immunosuppression. On day +21 or later, patients are given a single infusion of iCasp9-transduced T cells, which are generated from unmobilised donor peripheral blood using a clinical grade retroviral vector. The iCasp9 T cell dose is increased in cohort size of two: 5x10e5/kg, 1x10e6/kg, 5x10e6/kg and 1x10e7/kg. Each patient will receive only a single dose. Patients who develop grade II or above acute Graft Versus Host Disease (GVHD) are treated with an infusion of AP1903. AP1903 is a chemical dimeriser that triggers the apoptotic death of iCasp9-transduced T cells. Participants will be required to undergo regular assessment to evaluate the safety of this study treatment.
Eligibility
Inclusion Criteria20
- 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:
- /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 Criteria5
- 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
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Interventions
The patients will undergo myeloablative conditioning consisting of total body irradiation 8 Gy (lung shielded to 4 Gy) on day -9, intravenous thiotepa (5 mg/kg/day) on days -8 and -7; intravenous fludarabine (40 mg/m2/day) from day -7 to day -3; and intravenous rabbit antithymocyte globulin (Thymoglobuline; 1.5mg/kg/day) on days -5 to -2. Donor mobilised peripheral blood stem cells are CD34+-selected and infused fresh on day 0 without post transplant immunosuppression. On day +21 or later, patients are given a single intravenous infusion of iCasp9-transduced T cells, which are generated from unmobilised donor peripheral blood using a clinical grade retroviral vector. The iCasp9 T cell dose is increased in cohort size of two: 5x10e5/kg, 1x10e6/kg, 5x10e6/kg and 1x10e7/kg. Patients who develop grade II or above acute Graft Versus Host Disease (GVHD)are treated with an intravenous infusion of AP1903. AP1903 is a chemical dimeriser that triggers the apoptotic death of iCasp9-transduced T cells. Up to four doses of AP1903 can be given if necessary.
Locations(1)
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ACTRN12614000290695