Acute Leukemia, Acute Lymphoid Leukemia, Acute Myeloid Leukemia, Mixed Phenotype Acute Leukemia, Myelodysplastic Syndrome, Therapy-Related Myelodysplastic Syndrome, Undifferentiated Leukemia
Conditions
Keywords
hematopoietic stem cell transplantation, acute leukemia, Myelodysplastic syndromes, matched related donor, matched unrelated donor, myelodysplastic syndrome
Brief summary
This study will evaluate the safety, tolerability, and efficacy of Orca-T, an allogeneic stem cell and T-cell immunotherapy biologic manufactured for each patient (transplant recipient) from the mobilized peripheral blood of a specific, unique donor. It is composed of purified hematopoietic stem and progenitor cells (HSPCs), purified regulatory T cells (Tregs), and conventional T cells (Tcons) in participants undergoing myeloablative allogeneic hematopoietic cell transplant transplantation for hematologic malignancies. This posting represents the Phase III component of Precision-T. The Precision-T Ph1b component is described under NCT04013685.
Detailed description
Cross reference NCT04013685
Interventions
BIOLOGICALOrca-T
an allogeneic stem cell and T-cell immunotherapy biologic
BIOLOGICALStandard-of-Care
unmanipulated donor allograft
Sponsors
Orca Biosystems, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The Phase III is a randomized, open-label, multicenter study comparing outcomes between patients receiving Orca-T followed by single-agent tacrolimus or standard-of-care (SOC) control followed by dual agent, tacrolimus-based Graft-versus-Host-Disease (GVHD) prophylaxis regimen
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Matched to a related or unrelated donor who is an 8/8 match for HLA-A, -B, -C, and DRB1 * Diagnosed with one of the following diseases: * Acute myeloid, lymphoid or mixed phenotype leukemia in complete remission (CR) or CR with incomplete hematologic recovery (CRi), with or without the presence of known minimal residual disease * Myelodysplastic syndromes (MDS) that are indicated for alloHSCT per 2017 International Expert Panel recommendations and/or have therapy-related/secondary MDS, with ≤ 10% blast burden in the bone marrow * Planned to undergo MA-alloHCT including one of the following myeloablative conditioning regimens: * TBI/Cy * TBI/Etoposide * BFT * Cardiac ejection fraction at rest ≥ 45% or shortening fraction of ≥ 27% by echocardiogram or radionuclide scan (MUGA) * Diffusing capacity of the lung for carbon monoxide (DLCO) (adjusted for hemoglobin) ≥ 50% * Negative serum or urine beta-HCG test in females of childbearing potential * ALT/AST \< 3 times ULN * Recipients in screening must screen negative for SARS-CoV-2 RNA using a PCR-based test * Disease Risk Index (DRI) overall risk categorization of intermediate or high * Total bilirubin ≤ upper limit of normal (ULN) * Estimated glomerular filtration rate (eGFR) ≥ 60 mL/minute Key
Exclusion criteria
* Prior allogeneic HCT * Currently receiving corticosteroids or other immunosuppressive therapy. Topical corticosteroids or oral systemic corticosteroid doses less than or equal to 10 mg/day are allowed. * Planned donor lymphocyte infusion (DLI) * Planned pharmaceutical in vivo or ex vivo T cell depletion * Recipient positive anti-donor HLA antibodies against a mismatched allele in the selected donor * Karnofsky performance score \< 70% * Hematopoietic cell transplantation-specific Comorbidity Index (HCT-CI) \> 4 * Uncontrolled bacterial, viral or fungal infections at time of enrollment * Seropositive for HIV-1 or -2, HTLV-1 or -2, Hepatitis B sAg, Hepatitis C antibody * Known allergy or hypersensitivity to, or intolerance of, tacrolimus * Documented allergy or hypersensitivity to iron dextran or bovine, murine, algal or Streptomyces avidinii proteins * Any uncontrolled autoimmune disease requiring active immunosuppressive treatment * Concurrent malignancies or active disease within 1 year, except non-melanoma skin cancers that have been curatively resected * Psychosocial circumstances that preclude the patient being able to go through transplant or participate responsibly in follow up care * Women who are pregnant or breastfeeding * Women of childbearing potential (WOCBP) or men who have sexual contact with WOCBP unwilling to use effective forms of birth control or abstinence for one year after transplantation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free at 12 Months for Moderate or Severe Chronic Graft-versus-Host-Disease-free Survival (cGFS) Per Endpoint Adjudication Committee (EAC) | Day 0 through 730 days after transplantation | Event-free rate estimated at 12 months for cGFS per EAC, which is defined as the time from date of allogeneic hematopoietic cell transplantation (alloHCT) (ie, day 0) to date of death from any cause or first onset of moderate or severe chronic graft-versus-host disease (cGVHD) (graded per NIH consensus criteria), whichever was earliest, within 2 years after day 0. cGVHD was assessed and graded by EAC blinded to treatment assignment. Each participant in the study is followed for up to 730 days after transplant. Primary analysis was event driven (ie, when 56 participants had died or had moderate or severe cGVHD) and was not based on duration of follow-up. The analysis was conducted using all available data at the time that the 56th event occurred, and event-free rate at 12 months was estimated regardless of length of follow-up for individual participants. At the time of analysis, not all participants have reached 730 days of follow-up because they enrolled at different times. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event Rate at 12 Months for Time to Moderate or Severe cGVHD Per EAC | Day 0 through 730 days after transplantation | Event rate estimated at 12 months for time from alloHCT to first onset of moderate or severe cGVHD defined by NIH consensus criteria within 2 years after day 0. Death within 2 years after day 0 without prior moderate or severe cGVHD was considered a competing event. cGVHD was assessed and graded by an independent EAC. Each participant in the study is followed for up to 730 days after transplant. The primary analysis was triggered by the 56th cGFS event (ie, when 56 participants had died or had moderate or severe chronic GVHD) and was not based on the duration of follow-up. Therefore, the analysis was conducted using all available data at the time that the 56th cGFS event occurred, and the event rate of moderate or severe cGVHD at 12 months was estimated regardless of the length of follow-up for individual participants. At the time of analysis, not all participants have reached 730 days of follow-up because they enrolled at different times. |
| Event-free at 12 Months for Overall Survival (OS) | Up to 730 days after end of enrollment | Event-free rate estimated at 12 months for OS, which is defined as time from randomization to death from any cause. Each participant in the study is followed for up to 730 days after transplant. The analysis was triggered by the 56th cGFS event (ie, when 56 participants had died or had moderate or severe chronic GVHD) and was not based on the duration of follow-up. Therefore, the analysis was conducted using all available data at the time that the 56th cGFS event occurred, and the event-free rate of OS at 12 months was estimated regardless of the length of follow-up for individual participants. At the time of analysis, not all participants have reached 730 days of follow-up because they enrolled at different times. |
| Event-free Rate at 12 Months for Graft-versus-host Disease-free and Relapse-free Survival (GRFS) Per EAC | Day 0 through 730 days after transplantation | Event-free rate estimated at 12 months for GRFS, which is defined as time from alloHCT to death from any cause, relapse, the first onset of grade 3 or 4 acute GVHD (graded per Mount Sinai aGVHD International Consortium \[MAGIC\] criteria), or the first onset of moderate or severe cGVHD (graded per NIH consensus criteria), whichever is earliest, within 2 years from day 0 as assessed by independent EAC. Each participant in the study is followed for up to 730 days after transplant. The analysis was triggered by the 56th cGFS event (ie, when 56 participants had died or had moderate or severe cGVHD) and not based on duration of follow-up. Therefore, analysis was conducted using all available data at the time that the 56th cGFS event occurred, and event-free rate of GRFS at 12 months was estimated regardless of length of follow-up for individual participants. At time of analysis, not all participants have reached 730 days of follow-up because they enrolled at different times. |
Countries
United States
Participant flow
Recruitment details
187 participants were randomized to treatment from 19 study centers, of which 182 participants were treated
Participants by arm
| Arm | Count |
|---|---|
| Orca-T Orca-T administered after myeloablative conditioning followed by single-agent tacrolimus | 93 |
| Standard of Care Unmanipulated allograft from peripheral blood of a matched donor after myeloablative conditioning followed by tacrolimus and methotrexate | 94 |
| Total | 187 |
Baseline characteristics
| Characteristic | Standard of Care | Total | Orca-T |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 94 Participants | 187 Participants | 93 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants | 50 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 59 Participants | 121 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants | 16 Participants | 5 Participants |
| Primary Disease Acute Lymphoid Leukemia (ALL) | 27 Participants | 57 Participants | 30 Participants |
| Primary Disease Acute Myeloid Leukemia (AML) | 51 Participants | 100 Participants | 49 Participants |
| Primary Disease High-risk Myelodysplastic Syndrome (MDS) | 11 Participants | 23 Participants | 12 Participants |
| Primary Disease Mixed Phenotype Acute Leukemia (MPAL) | 5 Participants | 7 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 18 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 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 | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 18 Participants | 22 Participants | 4 Participants |
| Race (NIH/OMB) White | 63 Participants | 139 Participants | 76 Participants |
| Region of Enrollment United States | 94 participants | 187 participants | 93 participants |
| Sex: Female, Male Female | 44 Participants | 84 Participants | 40 Participants |
| Sex: Female, Male Male | 50 Participants | 103 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 88 | 9 / 94 |
| other Total, other adverse events | 88 / 88 | 94 / 94 |
| serious Total, serious adverse events | 34 / 88 | 53 / 94 |
Outcome results
Primary
Event-free at 12 Months for Moderate or Severe Chronic Graft-versus-Host-Disease-free Survival (cGFS) Per Endpoint Adjudication Committee (EAC)
Event-free rate estimated at 12 months for cGFS per EAC, which is defined as the time from date of allogeneic hematopoietic cell transplantation (alloHCT) (ie, day 0) to date of death from any cause or first onset of moderate or severe chronic graft-versus-host disease (cGVHD) (graded per NIH consensus criteria), whichever was earliest, within 2 years after day 0. cGVHD was assessed and graded by EAC blinded to treatment assignment. Each participant in the study is followed for up to 730 days after transplant. Primary analysis was event driven (ie, when 56 participants had died or had moderate or severe cGVHD) and was not based on duration of follow-up. The analysis was conducted using all available data at the time that the 56th event occurred, and event-free rate at 12 months was estimated regardless of length of follow-up for individual participants. At the time of analysis, not all participants have reached 730 days of follow-up because they enrolled at different times.
Time frame: Day 0 through 730 days after transplantation
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Orca-T | Event-free at 12 Months for Moderate or Severe Chronic Graft-versus-Host-Disease-free Survival (cGFS) Per Endpoint Adjudication Committee (EAC) | 78.0 Percentage of participants |
| Standard of Care | Event-free at 12 Months for Moderate or Severe Chronic Graft-versus-Host-Disease-free Survival (cGFS) Per Endpoint Adjudication Committee (EAC) | 38.4 Percentage of participants |
Comparison: Log-rank test was stratified by randomization stratification factors.p-value: <0.0000195% CI: [0.14, 0.47]Log Rank
Secondary
Event-free at 12 Months for Overall Survival (OS)
Event-free rate estimated at 12 months for OS, which is defined as time from randomization to death from any cause. Each participant in the study is followed for up to 730 days after transplant. The analysis was triggered by the 56th cGFS event (ie, when 56 participants had died or had moderate or severe chronic GVHD) and was not based on the duration of follow-up. Therefore, the analysis was conducted using all available data at the time that the 56th cGFS event occurred, and the event-free rate of OS at 12 months was estimated regardless of the length of follow-up for individual participants. At the time of analysis, not all participants have reached 730 days of follow-up because they enrolled at different times.
Time frame: Up to 730 days after end of enrollment
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Orca-T | Event-free at 12 Months for Overall Survival (OS) | 93.9 Percentage of participants |
| Standard of Care | Event-free at 12 Months for Overall Survival (OS) | 83.1 Percentage of participants |
Comparison: Log-rank test was stratified by randomization stratification factors.p-value: 0.1182395% CI: [0.2, 1.22]Log Rank
Secondary
Event-free Rate at 12 Months for Graft-versus-host Disease-free and Relapse-free Survival (GRFS) Per EAC
Event-free rate estimated at 12 months for GRFS, which is defined as time from alloHCT to death from any cause, relapse, the first onset of grade 3 or 4 acute GVHD (graded per Mount Sinai aGVHD International Consortium \[MAGIC\] criteria), or the first onset of moderate or severe cGVHD (graded per NIH consensus criteria), whichever is earliest, within 2 years from day 0 as assessed by independent EAC. Each participant in the study is followed for up to 730 days after transplant. The analysis was triggered by the 56th cGFS event (ie, when 56 participants had died or had moderate or severe cGVHD) and not based on duration of follow-up. Therefore, analysis was conducted using all available data at the time that the 56th cGFS event occurred, and event-free rate of GRFS at 12 months was estimated regardless of length of follow-up for individual participants. At time of analysis, not all participants have reached 730 days of follow-up because they enrolled at different times.
Time frame: Day 0 through 730 days after transplantation
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Orca-T | Event-free Rate at 12 Months for Graft-versus-host Disease-free and Relapse-free Survival (GRFS) Per EAC | 63.1 Percentage of participants |
| Standard of Care | Event-free Rate at 12 Months for Graft-versus-host Disease-free and Relapse-free Survival (GRFS) Per EAC | 30.9 Percentage of participants |
Comparison: Log-rank test was stratified by randomization stratification factors.p-value: 0.0000395% CI: [0.23, 0.6]Log Rank
Secondary
Event Rate at 12 Months for Time to Moderate or Severe cGVHD Per EAC
Event rate estimated at 12 months for time from alloHCT to first onset of moderate or severe cGVHD defined by NIH consensus criteria within 2 years after day 0. Death within 2 years after day 0 without prior moderate or severe cGVHD was considered a competing event. cGVHD was assessed and graded by an independent EAC. Each participant in the study is followed for up to 730 days after transplant. The primary analysis was triggered by the 56th cGFS event (ie, when 56 participants had died or had moderate or severe chronic GVHD) and was not based on the duration of follow-up. Therefore, the analysis was conducted using all available data at the time that the 56th cGFS event occurred, and the event rate of moderate or severe cGVHD at 12 months was estimated regardless of the length of follow-up for individual participants. At the time of analysis, not all participants have reached 730 days of follow-up because they enrolled at different times.
Time frame: Day 0 through 730 days after transplantation
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Orca-T | Event Rate at 12 Months for Time to Moderate or Severe cGVHD Per EAC | 12.6 Percentage of participants |
| Standard of Care | Event Rate at 12 Months for Time to Moderate or Severe cGVHD Per EAC | 44.0 Percentage of participants |
Comparison: Gray's test was stratified by randomization stratification factors.p-value: 0.0000295% CI: [0.08, 0.43]Gray's test