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, Overall survival, GRFS, GVHD
Brief summary
The primary objective of this study is to compare safety and efficacy of a haploidentical T-cell depleted HSCT and adjunctive treatment with ATIR101 versus a haploidentical T cell replete HSCT with post-transplant administration of high dose cyclophosphamide (PTCy) in patients with a hematologic malignancy. An additional objective of the study is to compare the effect of the two treatments on quality of life.
Detailed description
Study CR-AIR-009 is a Phase III randomized controlled multicenter open-label study comparing two parallel groups. After signing informed consent, a total of 250 patients will be randomized in a 1:1 fashion to receive either a T-cell depleted hematopoietic stem cell transplantation (HSCT; CD34 selection) from a related, haploidentical donor, followed by ATIR101 infusion, or a T-cell replete HSCT, followed by a high dose of post-transplant cyclophosphamide (PTCy). Randomization will use minimization to balance treatment groups with respect to underlying disease (AML, ALL, or MDS), Disease Risk Index (DRI; intermediate risk, high risk, or very high risk) and center. A stochastic treatment allocation procedure will be used so that the treatment assignment is random for all patients entered in the study. Patients randomized in the ATIR101 group will receive a single ATIR101 dose of 2×10E6 viable T-cells/kg between 28 and 32 days after the HSCT. Patients randomized in the PTCy group will receive cyclophosphamide 50 mg/kg/day at 3 and 4/5 days after the HSCT. All patients will be followed up for at least 24 months post HSCT.
Interventions
BIOLOGICALATIR101
ATIR101 is a T-lymphocyte enriched leukocyte preparation depleted ex vivo of host alloreactive T-cells using photodynamic treatment; single dose of 2×10E6 viable T-cells/kg body weight between 28 and 32 days after the HSCT (intravenous infusion)
DRUGCyclophosphamide
High dose post-transplant cyclophosphamide 50 mg/kg/day at 3 and 4/5 days after the HSCT (powder for intravenous infusion)
PROCEDURET-cell depleted HSCT from a related, haploidentical donor
T-cell depleted graft prepared from peripheral blood stem cells using the CD34+ cell selection method; infused after a total body irradiation (TBI) or non-TBI conditioning regimen
PROCEDURET-cell replete HSCT from a related, haploidentical donor
T-cell replete (full, non-manipulated) graft prepared from either bone marrow or peripheral blood stem cells; infused after a total body irradiation (TBI) or non-TBI conditioning regimen
Sponsors
Kiadis Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Any of the following hematologic malignancies: * Acute myeloid leukemia (AML) in first cytomorphological remission (with \< 5% blasts in the bone marrow) with Disease Risk Index (DRI) intermediate or above, or in second or higher cytomorphological remission (with \< 5% blasts in the bone marrow) * Acute lymphoblastic leukemia (ALL) in first or higher remission (with \< 5% blasts in the bone marrow) * Myelodysplastic syndrome (MDS): transfusion-dependent (requiring at least one transfusion per month), or intermediate or higher Revised International Prognostic Scoring System (IPSS-R) risk group * Clinical justification of allogeneic stem cell transplantation where a suitable HLA matched sibling or unrelated donor is unavailable in a timely manner * Availability of a related haploidentical donor with one fully shared haplotype and 2 to 4 mismatches at the HLA-A, -B, -C, and -DRB1 loci of the unshared haplotype, as determined by high resolution human leukocyte antigen (HLA)-typing * Karnofsky Performance Status (KPS) ≥ 70% * Male or female, age ≥ 18 years and ≤ 70 years. Patients aged ≥ 65 years must have a Sorror score ≤ 3 * Patient weight ≥ 25 kg and ≤ 130 kg * Availability of a donor aged ≥ 16 years and ≤ 75 years who is eligible according to local requirements and regulations. Donors aged \< 16 years are allowed if they are the only option for an HSCT, if they are permitted by local regulations, and if the IRB/IEC approves participation in the study. * For females of childbearing potential who are sexually active and males who have sexual contact with a female of childbearing potential: willingness to use of reliable methods of contraception (oral contraceptives, intrauterine device, hormone implants, contraceptive injection or abstinence) during study participation * Given written informed consent (patient and donor)
Exclusion criteria
* Diagnosis of chronic myelomonocytic leukemia (CMML) * Availability of a suitable HLA-matched sibling or unrelated donor in a donor search * Prior allogeneic hematopoietic stem cell transplantation * Diffusing capacity for carbon monoxide (hemoglobin corrected DLCO) \< 50% predicted * Left ventricular ejection fraction \< 45% (evaluated by echocardiogram or MUGA scan) * Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 2.5 × upper limit of normal (CTCAE grade 2) * Creatinine clearance \< 50 ml/min (calculated or measured) * Positive pregnancy test or breastfeeding of patient or donor (women of childbearing age only) * Estimated probability of surviving less than 3 months * Known allergy to any of the components of ATIR101 (e.g., dimethyl sulfoxide) * Known hypersensitivity to cyclophosphamide or any of its metabolites * Any contraindication for GVHD prophylaxis with mycophenolate mofetil, cyclosporine A, or tacrolimus * Known presence of HLA antibodies against the non-shared donor haplotype * Positive viral test of the patient or donor for human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B virus (HBV), hepatitis C virus (HCV), Treponema pallidum, human T-lymphotropic virus (HTLV)-1 (if tested), HTLV-2 (if tested), West Nile virus (WNV; if tested), or Zika virus (if tested) * Any other condition that, in the opinion of the investigator, makes the patient or donor ineligible for the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Graft-versus-host Disease-free, Relapse-free Survival (GRFS) | 24 months post-HSCT | Defined as the time until acute GVHD grade III/IV, chronic GVHD requiring systemic treatment, relapse, or death, whichever occurs first. Kaplan-Meier estimates (percentage of participants) of GRFS were calculated at 24 months post HSCT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 24 months post-HSCT | OS is defined as the time from HSCT until death from any cause. Kaplan-Meier estimates (percentage of participants) of OS were calculated at 24 months post HSCT. |
| Progression-free Survival (PFS) | 24 months post-HSCT | Defined as the time from HSCT until relapse, disease progression, or death, whichever occurs first. Kaplan-Meier estimates (percentage of participants) of PFS were calculated at 24 months post HSCT. |
| Relapse-related Mortality (RRM) | Through study completion, at least two years post HSCT | Time from randomization to death due to disease relapse or disease progression |
| Transplant-related Mortality (TRM) | 24 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). Kaplan-Meier estimates (percentage of participants) of PFS were calculated at 24 months post HSCT. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Incidence of NCI CTCAE Grade 2-5 and Grade 3-5 Infections | Until 2 years after the HSCT | Viral, fungal, and bacterial infections |
| Cumulative Incidence of NCI CTCAE Grade 3-5 Adverse Events | Until 2 years after the HSCT | Viral, fungal, and bacterial infections |
| FACT-BMT Total Score (Change From Screening) | Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT) | Quality of life: Foundation for the Accreditation of Cellular Therapy - Bone Marrow Transplantation questionnaire (FACT-BMT) |
| Immune Reconstitution | Through study completion, at least two years post HSCT | Time to CD3+ \> 0.2×10E9/l in peripheral blood (at two consecutive measurements; time to first measurement) |
| MDASI Total Score (Change From Screening) | Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT) | Quality of life: MD Anderson Symptom Inventory (MDASI) |
| EQ-5D-5L (Change From Screening) | Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT) | Quality of life: EQ-5D-5L |
| SF-36 Total Score (Change From Screening) | Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT) | Quality of life: Short Form 36-item health survey (SF-36) |
| Cumulative Incidence of Grade II-IV and Grade III-IV Acute Graft-versus-host-disease (GVHD) | Through study completion, at least two years post HSCT | — |
| Cumulative Incidence of Moderate/Severe Chronic GVHD | Through study completion, at least two years post HSCT | — |
| Cumulative Incidence of Chronic GVHD Requiring Systemic Immunosuppressive Treatment | Through study completion, at least two years post HSCT | — |
| Duration of GVHD Episodes | Through study completion, at least two years post HSCT | — |
Countries
Belgium, Canada, Croatia, France, Germany, Israel, Italy, Netherlands, Portugal, Spain, Sweden, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ATIR101 T-cell depleted HSCT from a related, haploidentical donor, followed by IV infusion with ATIR101 at a single dose of 2×10E6 viable T-cells/kg body weight between 28 and 32 days after the HSCT
ATIR101: ATIR101 is a T-lymphocyte enriched leukocyte preparation depleted ex vivo of host alloreactive T-cells using photodynamic treatment; single dose of 2×10E6 viable T-cells/kg body weight between 28 and 32 days after the HSCT (intravenous infusion)
T-cell depleted HSCT from a related, haploidentical donor: T-cell depleted graft prepared from peripheral blood stem cells using the CD34+ cell selection method; infused after a total body irradiation (TBI) or non-TBI conditioning regimen | 16 |
| PTCy T-cell replete HSCT from a related, haploidentical donor, followed by IV infusion of post-transplant cyclophosphamide (PTCy) 50 mg/kg/day at 3 and 4/5 days after the HSCT
Cyclophosphamide: High dose post-transplant cyclophosphamide 50 mg/kg/day at 3 and 4/5 days after the HSCT (powder for intravenous infusion)
T-cell replete HSCT from a related, haploidentical donor: T-cell replete (full, non-manipulated) graft prepared from either bone marrow or peripheral blood stem cells; infused after a total body irradiation (TBI) or non-TBI conditioning regimen | 27 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Active Study Phase (up to 18 Months) | Completed 2 year follow-up | 1 | 0 |
| Active Study Phase (up to 18 Months) | Death | 7 | 5 |
| Active Study Phase (up to 18 Months) | Discontinued before HSCT | 8 | 2 |
| Active Study Phase (up to 18 Months) | End of study after HSCT but before treatment | 1 | 0 |
| Active Study Phase (up to 18 Months) | Screen failures | 7 | 2 |
| Long Term Safety FU (up to 24 Months) | Death | 1 | 1 |
| Long Term Safety FU (up to 24 Months) | Lost to Follow-up | 1 | 1 |
| Long Term Safety FU (up to 24 Months) | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | ATIR101 | PTCy | Total |
|---|---|---|---|
| Age, Continuous | 36.2 years STANDARD_DEVIATION 9.63 | 32.8 years STANDARD_DEVIATION 13.2 | 34.5 years STANDARD_DEVIATION 11.42 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 22 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 5 Participants |
| Hematologic malignancy Acute lymphatic leukemia (ALL) | 4 Participants | 2 Participants | 6 Participants |
| Hematologic malignancy Acute myeloid leukemia (AML) | 9 Participants | 18 Participants | 27 Participants |
| Hematologic malignancy Myelodysplastic syndrome (MDS) | 3 Participants | 7 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) White | 14 Participants | 23 Participants | 37 Participants |
| Sex: Female, Male Female | 10 Participants | 20 Participants | 30 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 16 | 6 / 27 |
| other Total, other adverse events | 0 / 16 | 0 / 27 |
| serious Total, serious adverse events | 13 / 16 | 19 / 27 |
Outcome results
Primary
Graft-versus-host Disease-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. Kaplan-Meier estimates (percentage of participants) of GRFS were calculated at 24 months post HSCT.
Time frame: 24 months post-HSCT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATIR101 | Graft-versus-host Disease-free, Relapse-free Survival (GRFS) | 25 Percentage of participants |
| PTCy | Graft-versus-host Disease-free, Relapse-free Survival (GRFS) | 62 Percentage of participants |
Secondary
Overall Survival (OS)
OS is defined as the time from HSCT until death from any cause. Kaplan-Meier estimates (percentage of participants) of OS were calculated at 24 months post HSCT.
Time frame: 24 months post-HSCT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATIR101 | Overall Survival (OS) | 49 percentage of participants |
| PTCy | Overall Survival (OS) | 77 percentage of participants |
Secondary
Progression-free Survival (PFS)
Defined as the time from HSCT until relapse, disease progression, or death, whichever occurs first. Kaplan-Meier estimates (percentage of participants) of PFS were calculated at 24 months post HSCT.
Time frame: 24 months post-HSCT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATIR101 | Progression-free Survival (PFS) | 44 percentage of participants |
| PTCy | Progression-free Survival (PFS) | 73 percentage of participants |
Secondary
Relapse-related Mortality (RRM)
Time from randomization to death due to disease relapse or disease progression
Time frame: Through study completion, at least two years post HSCT
Population: Study was pre-maturely terminated. Data not collected.
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). Kaplan-Meier estimates (percentage of participants) of PFS were calculated at 24 months post HSCT.
Time frame: 24 months post-HSCT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATIR101 | Transplant-related Mortality (TRM) | 44 percentage of participants |
| PTCy | Transplant-related Mortality (TRM) | 15 percentage of participants |
Other Pre-specified
Cumulative Incidence of Chronic GVHD Requiring Systemic Immunosuppressive Treatment
Time frame: Through study completion, at least two years post HSCT
Population: Study was pre-maturely terminated. Data not collected.
Other Pre-specified
Cumulative Incidence of Grade II-IV and Grade III-IV Acute Graft-versus-host-disease (GVHD)
Time frame: Through study completion, at least two years post HSCT
Population: Study was pre-maturely terminated. Data not collected.
Other Pre-specified
Cumulative Incidence of Moderate/Severe Chronic GVHD
Time frame: Through study completion, at least two years post HSCT
Population: Study was pre-maturely terminated. Data not collected.
Other Pre-specified
Cumulative Incidence of NCI CTCAE Grade 2-5 and Grade 3-5 Infections
Viral, fungal, and bacterial infections
Time frame: Until 2 years after the HSCT
Population: Study was pre-maturely terminated. Data not collected.
Other Pre-specified
Cumulative Incidence of NCI CTCAE Grade 3-5 Adverse Events
Viral, fungal, and bacterial infections
Time frame: Until 2 years after the HSCT
Population: Study was pre-maturely terminated. Data not collected.
Other Pre-specified
Duration of GVHD Episodes
Time frame: Through study completion, at least two years post HSCT
Population: Study was pre-maturely terminated. Data not collected.
Other Pre-specified
EQ-5D-5L (Change From Screening)
Quality of life: EQ-5D-5L
Time frame: Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT)
Population: Study was pre-maturely terminated. Data not collected.
Other Pre-specified
FACT-BMT Total Score (Change From Screening)
Quality of life: Foundation for the Accreditation of Cellular Therapy - Bone Marrow Transplantation questionnaire (FACT-BMT)
Time frame: Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT)
Population: Study was pre-maturely terminated. Data not collected.
Other Pre-specified
Immune Reconstitution
Time to CD3+ \> 0.2×10E9/l in peripheral blood (at two consecutive measurements; time to first measurement)
Time frame: Through study completion, at least two years post HSCT
Population: Study was pre-maturely terminated. Data not collected.
Other Pre-specified
MDASI Total Score (Change From Screening)
Quality of life: MD Anderson Symptom Inventory (MDASI)
Time frame: Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT)
Population: Study was pre-maturely terminated. Data not collected.
Other Pre-specified
SF-36 Total Score (Change From Screening)
Quality of life: Short Form 36-item health survey (SF-36)
Time frame: Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT)
Population: Study was pre-maturely terminated. Data not collected.