Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Myelodysplastic Syndrome
Conditions
Keywords
Haploidentical stem cell transplantation, Graft versus host disease, Immune reconstitution, Alloreactive T-cells, Photodynamic treatment, Hematologic malignancy, Transplant-related mortality
Brief summary
The purpose of this study is to determine whether a repeat dose administration of ATIR101 is safe and effective when infused in patients with a hematologic malignancy following a T-cell depleted stem cell graft from a related haploidentical donor. All patients are planned to receive two ATIR101 doses of 2×10E6 viable T-cells/kg, unless the second dose is reduced or halted for safety reasons.
Detailed description
Study CR-AIR-008 is an exploratory, open-label, multicenter study. After signing informed consent, patients will receive a hematopoietic stem cell transplantation (HSCT) from a related, haploidentical donor, followed by a first ATIR101 infusion at a dose of 2×10E6 viable T-cells/kg between 28 and 32 days after the HSCT. Patients will receive a second ATIR101 infusion at a dose of 2×10E6 viable T-cells/kg between 70 and 74 days after the HSCT. To evaluate safety of the second dose administration, the first 6 patients treated will be evaluated for the occurrence of dose limiting toxicity (DLT), defined as acute GvHD grade III/IV within 120 days post HSCT (or within 42 days after the second ATIR101 infusion in case of prior dose delays). If within the first 6 patients no DLT is observed, treatment of the remaining 9 patients will continue with two ATIR101 doses of 2×10E6 viable T cells/kg. If within the first 6 patients at least 2 patients show DLT, the second ATIR101 infusion will be adjusted to a dose of 1×10E6 viable T cells/kg. If in one of the next 3 patients treated at this lower dose again DLT is observed, the second ATIR101 infusion will be halted and the remaining patients will be given only a single dose of ATIR101. All patients treated with ATIR101 will be followed up until 12 months after the HSCT. Assessments will be performed at weekly visits from the day of the first ATIR101 infusion (Week 4) until 6 weeks after the second ATIR101 infusion (Week 16), at monthly visits from 4 until 6 months after the HSCT, and every 3 months from 6 until 12 months after the HSCT.
Interventions
BIOLOGICALATIR101
T-lymphocyte enriched leukocyte preparation depleted ex vivo of host alloreactive T-cells (using photodynamic treatment). Two intravenous infusions with 2x10E6 viable T-cells/kg approximately 42 days apart (unless the second dose is reduced or halted for safety reasons).
PROCEDUREHaploidentical hematopoietic stem cell transplantation (HSCT)
CD34-selected HSCT from a haploidentical donor. In order to prepare the patient for the HSCT one of the following myeloablative conditioning regimens is recommended: * Total Body Irradiation (TBI) regime * Non-TBI regime (See below for details)
PROCEDURETBI regime
* Fractionated TBI 200 cGy twice daily for 3 days on Day -10 to -8 (1200 cGy in 6 fractions) * Fludarabine 30 mg/m2 IV once daily for 5 days on Day -7 to -3 * Thiotepa; 5 mg/kg IV twice daily for 1 day on Day -7 * Anti-thymocyte globulin (ATG; Thymoglobulin®); 2.5 mg/kg once daily for 4 days on Day -5 to -2, as a continuous IV infusion for 8 hours. During the course of ATG, patients will receive methylprednisolone 2 mg/kg/day IV.
PROCEDURENon-TBI regime
* Fludarabine; 30 mg/m2 IV once daily for 5 days on Day -8 to -4 * Thiotepa; 5 mg/kg IV twice daily for 1 day on Day -7 * Melphalan; 60 mg/m2 IV once daily for 2 days on Day -2 and -1 * ATG (Thymoglobulin®); 2.5 mg/kg once daily for 4 days on Day -5 to -2, as a continuous IV infusion for 8 hours. During the course of ATG, patients will receive methylprednisolone 2 mg/kg/day IV.
Sponsors
Kiadis Pharma
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Any of the following hematologic malignancies: * Acute myeloid leukemia (AML) in first remission with high-risk features or in second or higher remission * Acute lymphoblastic leukemia (ALL) in first remission with high-risk features or in second or higher remission * Myelodysplastic syndrome (MDS): transfusion-dependent, or intermediate or higher IPSS-R risk group * Karnofsky performance status ≥ 70% * Eligible for haploidentical stem cell transplantation according to the investigator * Male or female, age ≥ 18 years and ≤ 65 years
Exclusion criteria
* Availability of a fully matched related or unrelated donor following a donor search * Diffusing capacity for carbon monoxide (DLCO) \< 50% predicted * Left ventricular ejection fraction \< 50% (evaluated by echocardiogram or MUGA) * AST \> 2.5 x ULN (CTCAE grade 2) * Bilirubin \> 1.5 x ULN (CTCAE grade 2) * Creatinine clearance \< 50 mL/min (calculated or measured) * Positive HIV test * Positive pregnancy test (women of childbearing age only) * Prior allogeneic HSCT * Estimated probability of surviving less than 3 months * Known allergy to any of the components of ATIR101 (e.g., dimethyl sulfoxide) * Known presence of HLA antibodies against the non-shared donor haplotype * Any other condition which, in the opinion of the investigator, makes the patient ineligible for the study Inclusion Criteria Donor: * Haploidentical family donor with 2 to 3 mismatches at the HLA-A, -B and/or -DR loci of the unshared haplotype * Male or female, age ≥ 16 and ≤ 75 years (If applicable, local legal requirements for donors under the age of 18 will be followed) * Eligible for donations of human blood and blood components according to local requirements and regulations * Eligible for donation according to the transplantation center
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of Acute Graft Versus Host Disease (GVHD) Grade III/IV | 180 days post HSCT |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved T-Cell Reconstitution at 6 and 12 Months Post HSCT | 6 and 12 months post HSCT | Defined as CD3+ in peripheral blood higher than 0.2×10E9/L at 6 and 12 months post HSCT. |
| Viral, Fungal, and Bacterial Infections | From 6 months to 1 year after HSCT | Infection was defined as (1) a clinically apparent infectious disease with symptoms or (2) a viral reactivation. Severity was graded according to CTCAE vs. 4.0 |
| Transplant-related Mortality (TRM) | 12 months post HSCT | Defined as death due to causes other than disease relapse or progression, or other causes which are unrelated to the transplantation procedure (e.g. accident, suicide) |
| Incidence and Severity of Acute and Chronic GVHD | Between 6 and 12 months after HSCT | — |
| Overall Survival (OS) | 12 months post HSCT | Defined as the time from HSCT until death from any cause |
| Progression-free Survival (PFS) | 12 months post HSCT | Defined as the time from HSCT until relapse, disease progression, or death, whichever occurs first |
| GVHD-free, Relapse-free Survival (GRFS) | 12 months post HSCT | Defined as the time until acute GVHD grade III/IV, chronic GVHD requiring systemic treatment, relapse, or death, whichever occurs first |
| Relapse-related Mortality (RRM) | 12 months post HSCT | Defined as death due to disease relapse or disease progression |
Countries
Belgium, Canada, Croatia, Germany, Portugal, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ATIR101 ATIR101: T-lymphocyte enriched leukocyte preparation depleted ex vivo of host alloreactive T-cells (using photodynamic treatment). Two intravenous infusions with 2x10E6 viable T-cells/kg approximately 42 days apart (unless the second dose is reduced or halted for safety reasons).
Haploidentical hematopoietic stem cell transplantation (HSCT): CD34-selected HSCT from a haploidentical donor. In order to prepare the patient for the HSCT one of the following myeloablative conditioning regimens is recommended:
* Total Body Irradiation (TBI) regime
* Non-TBI regime
(See below for details)
TBI regime: • Fractionated TBI 200 cGy twice daily for 3 days on Day -10 to -8 (1200 cGy in 6 fractions)
* Fludarabine 30 mg/m2 IV once daily for 5 days on Day -7 to -3
* Thiotepa; 5 mg/kg IV twice daily for 1 day on Day -7
* Anti-thymocyte globulin (ATG; Thymoglobulin®); 2.5 mg/kg once daily for 4 days on Day -5 to -2, as a continuous IV infusion for 8 hours. During the course of ATG, patients will receive methylprednisolone 2 mg/kg/day IV.
Non-TBI regime: • Fludarabine; 30 mg/m2 IV once daily for 5 days on Day -8 to -4
* Thiotepa; 5 mg/kg IV twice daily for 1 day on Day -7
* Melphalan; 60 mg/m2 IV once daily for 2 days on Day -2 and -1
* ATG (Thymoglobulin®); 2.5 mg/kg once daily for 4 days on Day -5 to -2, as a continuous IV infusion for 8 hours. During the course of ATG, patients will receive methylprednisolone 2 mg/kg/day IV. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 7 |
Baseline characteristics
| Characteristic | ATIR101 | — |
|---|---|---|
| Age, Continuous | 41 years | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Belgium | 5 Participants | — |
| Region of Enrollment Canada | 7 Participants | — |
| Region of Enrollment Germany | 1 Participants | — |
| Region of Enrollment United Kingdom | 2 Participants | — |
| Sex: Female, Male Female | 10 Participants | — |
| Sex: Female, Male Male | 5 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 15 |
| other Total, other adverse events | 8 / 15 |
| serious Total, serious adverse events | 7 / 15 |
Outcome results
Primary
Incidence of Acute Graft Versus Host Disease (GVHD) Grade III/IV
Time frame: 180 days post HSCT
Population: The primary study endpoint, grade III/IV acute GVHD within 180 days after HSCT, was met for two patients treated with two doses of ATIR101.~Two patients developed grade III/IV acute GVHD within 180 days after HSCT treated with a single dose of ATIR101.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATIR101 | Incidence of Acute Graft Versus Host Disease (GVHD) Grade III/IV | Single dose of ATIR101, grade III/IV acute GVHD within 180 days after HSCT | 2 participants |
| ATIR101 | Incidence of Acute Graft Versus Host Disease (GVHD) Grade III/IV | Two doses of ATIR101, Grade III/IV acute GVHD within 180 days after HSCT | 2 participants |
Secondary
GVHD-free, Relapse-free Survival (GRFS)
Defined as the time until acute GVHD grade III/IV, chronic GVHD requiring systemic treatment, relapse, or death, whichever occurs first
Time frame: 12 months post HSCT
Population: Nine subjects received a single dose of ATIR101 and 6 subjects received a double dose of ATIR101.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATIR101 | GVHD-free, Relapse-free Survival (GRFS) | Single dose, Kaplan-Meier estimates of GRFS | 55.6 Percentage of participants |
| ATIR101 | GVHD-free, Relapse-free Survival (GRFS) | Double dose, Kaplan-Meier estimates of GRFS | 16.7 Percentage of participants |
Secondary
Incidence and Severity of Acute and Chronic GVHD
Time frame: Between 6 and 12 months after HSCT
Population: 7 patients in the single dose and 4 patients in the double dose were analysed to make a total of 11 patients analysed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATIR101 | Incidence and Severity of Acute and Chronic GVHD | Single dose group acute GVHD between 6 and 12 months after HSCT | 0 Participants |
| ATIR101 | Incidence and Severity of Acute and Chronic GVHD | Double dose group acute GVHD between 6 and 12 months after HSCT | 0 Participants |
| ATIR101 | Incidence and Severity of Acute and Chronic GVHD | Single dose group chronic GVHD between 6 and 12 months after HSCT | 0 Participants |
| ATIR101 | Incidence and Severity of Acute and Chronic GVHD | Double dose group chronic GVHD between 6 and 12 months after HSCT | 2 Participants |
Secondary
Overall Survival (OS)
Defined as the time from HSCT until death from any cause
Time frame: 12 months post HSCT
Population: Nine participants received a single dose of ATIR101 and 6 participants received a double dose of ATIR101
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATIR101 | Overall Survival (OS) | Single dose group, Kaplan-Meier estimates of OS 12 months post HSCT | 66.7 Percentage of participants |
| ATIR101 | Overall Survival (OS) | Double dose group, Kaplan-Meier estimates of OS 12 months post HSCT | 33.3 Percentage of participants |
Secondary
Percentage of Participants Who Achieved T-Cell Reconstitution at 6 and 12 Months Post HSCT
Defined as CD3+ in peripheral blood higher than 0.2×10E9/L at 6 and 12 months post HSCT.
Time frame: 6 and 12 months post HSCT
Population: Cumulative incidence estimates of T-cell reconstitution at 6 and 12 months post HSCT were analyzed for the single dose group (N=9) and double dose group (N=6).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATIR101 | Percentage of Participants Who Achieved T-Cell Reconstitution at 6 and 12 Months Post HSCT | Cumulative incidence estimates of T-cell reconstitution, 6 months post HSCT. Single dose group. | 44.4 percentage of participants |
| ATIR101 | Percentage of Participants Who Achieved T-Cell Reconstitution at 6 and 12 Months Post HSCT | Cumulative incidence estimates of T-cell reconstitution, 6 months post HSCT. Double dose group. | 50.0 percentage of participants |
| ATIR101 | Percentage of Participants Who Achieved T-Cell Reconstitution at 6 and 12 Months Post HSCT | Cumulative incidence estimates of T-cell reconstitution, 12 months post HSCT. Single dose group. | 77.8 percentage of participants |
| ATIR101 | Percentage of Participants Who Achieved T-Cell Reconstitution at 6 and 12 Months Post HSCT | Cumulative incidence estimates of T-cell reconstitution, 12 months post HSCT. Double dose group. | 50.0 percentage of participants |
Secondary
Progression-free Survival (PFS)
Defined as the time from HSCT until relapse, disease progression, or death, whichever occurs first
Time frame: 12 months post HSCT
Population: Nine participants received a single dose of ATIR101 and 6 participants received a double dose of ATIR101
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATIR101 | Progression-free Survival (PFS) | Single dose group, Kaplan-Meier estimates of PFS 12 months post HSCT | 55.6 Percentage of participants |
| ATIR101 | Progression-free Survival (PFS) | Double dose group, Kaplan-Meier estimates of PFS 12 months post HSCT | 33.3 Percentage of participants |
Secondary
Relapse-related Mortality (RRM)
Defined as death due to disease relapse or disease progression
Time frame: 12 months post HSCT
Population: Nine participants received a single dose of ATIR101 and 6 participants received a double dose of ATIR101
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATIR101 | Relapse-related Mortality (RRM) | Single dose group, cumulative estimates of RRM 12 months post HSCT | 11.1 percentage of participants |
| ATIR101 | Relapse-related Mortality (RRM) | Double dose group, cumulative estimates of RRM 12 months post HSCT | 0 percentage of participants |
Secondary
Transplant-related Mortality (TRM)
Defined as death due to causes other than disease relapse or progression, or other causes which are unrelated to the transplantation procedure (e.g. accident, suicide)
Time frame: 12 months post HSCT
Population: Nine participants received a single dose of ATIR101 and 6 participants received a double dose of ATIR101
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATIR101 | Transplant-related Mortality (TRM) | Single-dose group, cumulative estimates of TRM | 22.2 percentage of participants that died |
| ATIR101 | Transplant-related Mortality (TRM) | Double-dose group, cumulative estimates of TRM | 66.7 percentage of participants that died |
Secondary
Viral, Fungal, and Bacterial Infections
Infection was defined as (1) a clinically apparent infectious disease with symptoms or (2) a viral reactivation. Severity was graded according to CTCAE vs. 4.0
Time frame: From 6 months to 1 year after HSCT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATIR101 | Viral, Fungal, and Bacterial Infections | Any infection | 10 Participants |
| ATIR101 | Viral, Fungal, and Bacterial Infections | Severity, grade 1-2 | 7 Participants |
| ATIR101 | Viral, Fungal, and Bacterial Infections | Severity, grade 3-5 | 3 Participants |