This is an open-label, phase II study designed to evaluate the efficacy and effectiveness of TCB008 in patients with Acute Myeloid Leukemia (AML), or Myelodysplastic Syndromes (MDS)/AML, with either refractory or relapsed disease. Five patients will be recruited for an initial safety cohort. The safety cohort will be followed by a two-stage Simon's Design, where a further 48 patients will be recruited into one of two cohorts and dosed with TCB008.
TCB008-001 (ACHIEVE) is an open-label, phase II study designed to evaluate the efficacy and effectiveness of TCB008 in patients with Acute Myeloid Leukemia (AML), or Myelodysplastic Syndromes (MDS)/AML, with either refractory or relapsed disease. TCB008 is derived from the peripheral blood mononuclear cells (PBMCs) of unrelated, healthy donors and consists of expanded cluster designation (CD)3+ T cells expressing the γ-chain variable region 9 δ-chain variable region 2 (Vγ9Vδ2) T cell receptor (TCR); it is infused into patients to boost their immune system. It is currently developed for treatment of cancers and infectious diseases. 53 patients will take part in this study; five patients in an initial safety cohort followed by a two-stage Simon's Design that will recruit a further 48 patients into one of two patient cohorts. Patients will be screened to assess their eligibility to enter the study 35 days prior to the first dose of the investigational medicinal product (IMP). Once enrolled in the study, patients will undergo lymphodepletion chemotherapy prior to administration of the IMP using the following regimen: fludarabine (30mg/m2/day) will be administered from days -6 to -3 (total 120mg/m2), and cyclophosphamide (0.5g/m2/day) from days -5 to -3 (total 1.5g/m2). No chemotherapy will be administered on days -2 and -1. Cohort A will recruit patients with relapsed or refractory AML or MDS/AML. These patients will be split between one of two sub-cohorts; * Cohort A1 will include patients with primary refractory AML or MDS/AML who have not achieved a CR, CRi, or CRh after two cycles of induction chemotherapy. * Cohort A2 will include patients with AML or MDS/AML who have relapsed after initially achieving a CR, CRi, or CRh to previous chemotherapy. This cohort would include MDS/AML patients with 10 to 19% blast levels in the bone marrow or peripheral blood as defined in the European Leukemia Net 2022 Criteria (as per international consensus classification of AML). Cohort B will recruit patients with AML or MDS/AML who have achieved CR, CRi, or CRh but have a detectable measurable residual disease by MFC-MFD or Mol-RD by qPCR. Patients may receive repeat infusions of TCB008, on up to three occasions, 14 days after the previous infusion. Re-infusions will not be preceded by lymphodepleting chemotherapy. Patients will be followed for up to 52 weeks following the first infusion of TCB008, or until either; they are lost to follow-up, or early termination. Blood and bone marrow samples will be taken pre- and post-infusion to evaluate the study objectives and endpoints. The total duration of study participation for each patient, from screening through to the end of study visit, is anticipated to be approximately 15 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
16
TCB008 is derived from the peripheral blood mononuclear cells (PBMCs) of unrelated, healthy donors and consists of expanded cluster designation (CD)3+ T cells expressing the γ chain variable region 9 δ-chain variable region 2 (Vγ9Vδ2) T cell receptor (TCR); it is infused into patients to boost their immune system. It is currently developed for treatment of cancers and infectious diseases.
Bristol and Weston NHS foundation trust
Bristol, United Kingdom
Cardiff and Vale University LHB
Cardiff, United Kingdom
Queen Elizabeth University Hospital
Glasgow, United Kingdom
Guys&St Thomas NHS foundation Trust
London, United Kingdom
Kings College Hospital
London, United Kingdom
Royal Marsden Hospital
London, United Kingdom
Reduction in myeloblast levels in response to TCB008 dosing
Reduction in myeloblast levels compared to baseline, measured according to the ELN AML 2022 Response Criteria.
Time frame: The total duration of study participation for each patient (from screening through end of study visit) is anticipated to be approximately 15 months).
Patient relapse and subsequent response to repeat TCB008 dosing
Measured by the numbers of patients who, after initial response, subsequently relapse and then respond to an additional infusion.
Time frame: The total duration of study participation for each patient (from screening through end of study visit) is anticipated to be approximately 15 months).
Overall response rate to TCB008 dosing
Overall response rate, defined as morphological CR, CRi, Rh, PR, and MLFS at 28-days post-infusion, measured according to the ELN AML 2022 Response Criteria.
Time frame: The total duration of study participation for each patient (from screening through end of study visit) is anticipated to be approximately 15 months).
Measurable Residual Disease in response to TCB008 dosing
MRD-negative remission (CR without MRD or CR MRD-) by multiparameter flow cytometry-based MRD (MFC-MRD) or molecular MRD (Mol-MRD) assessed by qPCR, according to the ELN AML 2022 Response Criteria.
Time frame: The total duration of study participation for each patient (from screening through end of study visit) is anticipated to be approximately 15 months).
Severity of adverse events in response to TCB008 dosing
Safety assessment of AEs graded by Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Time frame: The total duration of study participation for each patient (from screening through end of study visit) is anticipated to be approximately 15 months).
Incidence and severity of CRS and neurotoxicity in response to TCB008 dosing
Incidence and severity of cytokine release syndrome (CRS) and neurotoxicity, using the ASTCT consensus grading system.
Time frame: The total duration of study participation for each patient (from screening through end of study visit) is anticipated to be approximately 15 months).
Overall survival rates following TCB008 dosing
Overall survival assessed at 52 weeks according to the ELN AML 2022 Response Criteria.
Time frame: The total duration of study participation for each patient (from screening through end of study visit) is anticipated to be approximately 15 months).
Relapse-free survival following TCB008 dosing
Relapse-free survival assessed at 52 weeks according to the ELN AML 2022 Response Criteria.
Time frame: The total duration of study participation for each patient (from screening through end of study visit) is anticipated to be approximately 15 months).
Event-free survival following TCB008 dosing
Event-free survival assessed at 52 weeks according to the ELN AML 2022 Response Criteria.
Time frame: The total duration of study participation for each patient (from screening through end of study visit) is anticipated to be approximately 15 months).
Cumulative incidence of relapse following TCB008 dosing
Cumulative incidence of relapse assessed at 52 weeks according to the ELN AML 2022 Response Criteria.
Time frame: The total duration of study participation for each patient (from screening through end of study visit) is anticipated to be approximately 15 months).
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