ACHIEVE - Efficacy and Effectiveness of Adoptive Cellular tHerapy wIth Ex-Vivo Expanded Allogeneic γδ T-lymphocytes (TCB-008) for Patients With Refractory or Relapsed Acute Myeloid Leukaemia (AML)

Study Overview
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Brief Summary
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This is an open label, adaptive, efficacy and effectiveness, phase II clinical trial in adult patients with AML with refractory and relapsed disease. An adaptive trial approach with a two-stage Simon design will be utilised for a total of up to 74 adult patients per dose level of TCB008 cells

Detailed Description
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Patients with AML who have completed the induction phase of treatment and have failed to attain a morphological CR will be considered refractory. Patients who have relapsed after previously achieving a morphological CR will also be included. Similarly, patients who have achieved a morphological CR but have detectable measurable residual disease (MRD) by any method will be included, representing low disease burden chemotherapy resistant AML. These patients will be screened according to inclusion and exclusion criteria at the screening visit and enrolled into one of two cohorts: High disease burden cohort (A): relapsed or refractory AML, or Low disease burden cohort (B): MRD persistent AML. All patients will receive lymphodepleting chemotherapy prior to dosing of TCB008 as an in-patient. Patients will be followed up for up to 52 weeks. Patients may also receive additional dosing based on response assessment.

Official Title
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ACHIEVE - An Adaptive Trial of the Efficacy and Effectiveness of Adoptive Cellular tHerapy wIth Ex-Vivo Expanded Allogeneic γδ T-lymphocytes (TCB-008) for Patients With Refractory or Relapsed Acute Myeloid Leukaemia (AML)

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: TCB008


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 to ≤ 75 years Karnofsky performance status ≥ 70% and WHO/ECOG performance status 0 -1 at enrolment and up to 2 at the time of infusion. Must be able to remain free of systemic corticosteroid (e.g., prednisolone) and other immunosuppressive therapy at screening and for at least 5 days prior to the infusion of γδ T cells. Maintenance replacement steroid after assessment of the primary endpoint is permitted. Must be able to understand and sign written informed consent and willing to participate in a clinical trial for an advanced therapy investigational medicinal product (AT(I)MP). Women of childbearing potential must receive a pregnancy test within 7 days prior to initiation of treatment with the lymphodepleting regimen for either the first or subsequent administration of TCB008, and the result must be negative; subjects should be placed on contraception as per local practice throughout the duration of the study and must use an effective contraceptive to ensure 3 months after discontinuation of treatment. Pathologically confirmed diagnosis of AML or MDS/AML confirmed according to WHO 2016 criteria. For Cohort A1, patients must have AML or MDS/AML that is primary refractory defined as not achieving a morphological CR after 2 cycles of intensive or non-intensive induction chemotherapy. For Cohort A2, patients with AML or MDS/AML must have previously achieved a morphological CR to previous intensive or non-intensive therapy, then have experienced relapsed AML. For Cohort B, patients with AML who have achieved morphological CR but have persistent MRD. Included patients will not be deprived of standard of care by participating in this trial. Exclusion criteria Suspected or proven active CNS disease Previous reactions to Fludarabine or Cyclophosphamide or patients at risk of Fludarabine related neurotoxicity Acute promyelocytic leukaemia Bisphosphonates (≤2 months before study entry) Corticosteroids (cumulative dose of systemic steroids >20mg of prednisolone per day or equivalent) that cannot be discontinued 5 days prior to TCB008 infusion. Antihyperlipidemic medications (e.g., statins) that cannot be discontinued prior to enrolment. Cardiac failure: EF < 40%. Kidney function: creatinine clearance ≤ 60 mL/min Liver function: total bilirubin > 3 × ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 5 × ULN, Neurological condition(s) which might be exacerbated by therapy or prevent assessments for neurotoxicity/ICANS GVHD of any grade or anti-GVHD treatment. Lung function: symptoms of respiratory failure or < 92% oxygen saturation on air. Active infections that are difficult to control, including positive COVID-19 diagnosis at screening. Received autologous or allogeneic cell therapy within 4 weeks, such as donor lymphocyte infusion. Received autologous or allogeneic gene modified adoptive cell therapy (e.g CAR-T, TCR-T, CAR-NK cell therapy, etc). Subject received anti-tumour treatment (chemotherapy, monoclonal antibody, or hormone) within one week of screening (hydroxycarbamide is permitted until lymphodepletion). Pregnant or lactating women. hypersensitivity to iron-dextran or murine antibodies. Patients who are active participants in other interventional clinical trials at the same time. Co-enrolment is permitted for non-interventional studies if approved by the CI. The principal investigator believes that there are other factors that are not suitable for inclusion or influence the patient's participation or completion of the study. Considered unsuitable for further intensive therapy or expected to survive less than 3 months with conventional available treatments

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: γδ T cells (IMP, TCB008)<br>After inclusion, all patients will receive lymphodepleting chemotherapy with fludarabine 30mg/m2 Day -6 to Day -3 [total 120 mg/m2] and cyclophosphamide 0.5g/m2 [total 1.5 g/m2) Day -5 to Day -3,]. This will be followed by a rest day (Day -2). TCB008 treatment (consisting initially of one dose of 7 X 10^7 or 7 X 10^8 cells ) is administered on Day 0 | Drug: TCB008<br>* administration of TCB008<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the efficacy of TCB008 in patients with AML | Overall response rate (ORR) defined as number of patients reaching CR | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the safety of TCB008 in the treatment of AML | Safety assessment of adverse events (AEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ATMP