ALL, AML - Acute Myeloid Leukemia, Hodgkin's Lymphoma, MDS (Myelodysplastic Syndrome), Mixed Phenotype Acute Leukemia, NHL - Non-Hodgkin's Lymphoma
Conditions
Keywords
Pediatric, GvHD, Hematopoietic Stem Cell Transplantation, Stem Cells, Transplant, BMT - bone marrow transplant
Brief summary
A significant number of patients with hematologic malignancies need a hematopoietic stem cell transplant (HSCT) to be cured. Only about 50% of these patients have a fully matched donor, the remaining patients will require an HSCT from a mismatched related or unrelated donor. Almost 60% of these mismatched donor HSCTs will result in graft-versus-host disease (GvHD), which can cause significant morbidity and increased non-relapse mortality. GvHD is caused by the donor effector T cells present in the HSC graft that recognize and react against the mismatched patient's tissues. Researchers and physicians at Lucile Packard Children's Hospital, Stanford are working to prevent GvHD after HSCT with a new clinical trial. The objective of this clinical program is to develop a cell therapy to prevent GvHD and induce graft tolerance in patients receiving mismatched unmanipulated donor HSCT. The cell therapy consists of a cell preparation from the same donor of the HSCT (T-allo10) containing T regulatory type 1 (Tr1) cells able to suppress allogenic (host-specific) responses, thus decreasing the incidence of GvHD. This is the first trial of its kind in pediatric patients and is only available at Lucile Packard Children's Hospital, Stanford. The purpose of this phase 1 study is to determine the safety and tolerability of a cell therapy, T-allo10, to prevent GvHD in patients receiving mismatched related or mismatched unrelated unmanipulated donor HSCT for hematologic malignancies.
Detailed description
Patients ages 3-30 years, with hematologic malignancies undergoing mismatched related or unrelated donor transplant will receive conditioning chemotherapy with Total body radiation and cyclophosphamide, according to the standard procedure. The investigators plan to infuse the donor T-allo10 product one day before HSCT so that the Tr1 cells contained within the T-allo10 product will be able to prevent anti-host alloreactivity of the T cells present within the unmanipulated HSC graft. Indeed, Tr1 cells best exert their suppressive activity at the time of effector T cell activation, occurring when the T cells present in the HSC graft will be transferred to the patient ; therefore, the investigators expect that the early infusion of T-allo10 cells will optimally modulate anti-host alloreactivity of the donor T cells and prevent GvHD. Immunosuppression will also be administered at the time of HSCT. Up to 27 eligible patients will be given the T-allo10 product sequentially in 3 escalating dose cohorts to determine the maximum tolerated dose (or the highest dose tested if no maximum tolerated dose is reached). Each cohort will begin by evaluating 3 patients. The patients in each cohort will be staggered by 28 days and each succeeding patient will be enrolled no sooner than the 29 day after the preceding patient's infusion of T-allo10. * If no patient in a cohort develops a dose limiting toxicity (DLT) following infusion of the investigational cellular product, the investigators will start enrolling patients at the next higher cell dose after completing the 28-day safety evaluation of the 3rd patient in the dose cohort. * If one out of 3 patients in a cohort has a DLT, 3 additional patients will be evaluated at the same dose level. * If one out of 6 patients experiences a DLT, dose escalation will occur. * If 2 out of ≤ 6 patients experience a DLT, dose escalation will cease and that dose will be designated the maximally administered dose. * Up to three (3) additional patients will be entered at the next lowest dose level if only 3 patients were treated previously at that dose
Interventions
BIOLOGICALT-allo10
The T-allo10 drug product consists of donor derived, host (patient) alloantigen hyporesponsive (anergic) CD4+ (cluster of differentiation 4) cells containing Type 1 regulatory T (Tr1) cells induced in vitro in the presence of IL-10 (interleukin-10), which are also defined as IL-10 anergized T cells. T-allo10 cell infusion is being developed to prevent acute Graft-versus-Host Disease (GvHD) and induce graft tolerance in patients with hematologic malignancies receiving mismatched related and unrelated unmanipulated hematopoietic stem cell transplant (HSCT).
Sponsors
National Cancer Institute (NCI)
Roncarolo, Maria Grazia, MD
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
1. Eligible diseases include: A. Acute Lymphoblastic Leukemia (B- or T-ALL) 1. Complete Response (CR)1-ultra high risk features * Unfavorable cytogenetics * Hypodiploidy * Induction failure * Minimal Residual Disease (MRD) positive after consolidation 2. CR-2: * Any of the high risk features listed in CR1 * B-ALL: any relapse considered eligible for transplant * T- ALL 3. CR-3-any B. Acute Myeloid Leukemia 1. MRD \>5% at day 22 induction 1 2. MRD \>0.1% after induction 2 3. FLT/ITD with allelic ratio \> 0.4 and MRD \>0.1% at day 22 or 29 induction 1 4. Translocation (6:9), (8:6), (16:21), monosomy 7, monosomy 5, 5q 5. M7 with KMT2A rearrangements, inv(16)(p13.3q24.3) \[CBFA2T3-GLIS2\] or t(11;12)(p15;p13) \[NUP98-KDM5A\] 6. AML in 2nd or subsequent CR 7. Therapy related or Secondary AML 8. Refractory anemia with excess blasts (RAEB)2 C. Myelodysplastic syndrome D. Mixed Phenotype Acute Leukemia MRD\>1% after consolidation E. Non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma (HL) beyond first remission 2. Age ≥3 to ≤45 years old. Subjects 1 and 2 (in Cohort 1) will be ≥ 12 years old 3. Available mismatched related donor (mMRD) or mismatched unrelated donor (mMUD), Human leukocyte antigen (HLA) matched 8/10 or 9/10 4. Lansky (age \<16) or Karnofsky (age ≥16) performance status ≥80% 5. Able and willing to provide written, signed informed consent (assent as appropriate) 6. Have adequate organ function defined as the following: * Serum Creatinine \<1.5 X upper limit of normal (ULN) or 24-hour creatinine clearance \>50 ml/min * Serum bilirubin ≤ 2 x ULN * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤10 x ULN * Diffusion Capacity of the Lungs (DLCO) \>60% predicted (in children, O2 saturation \>92% on room air) * Left ventricular ejection fraction \>45% (in children, shortening fraction \>26%) 7. Male and female subjects of child bearing potential must agree to use an effective method of birth control to avoid pregnancy throughout the transplant procedure, while on immunosuppression, and if the subject experiences any chronic GvHD.
Exclusion criteria
1. Prior bone marrow or peripheral blood HSCT within the last 6 (six) months 2. HLA-matched related or unrelated donor available 3. Any active, uncontrolled infection at the time of enrollment 4. Pregnant or lactating females 5. Any severe concurrent disease which, in the judgement of the investigator, would place the patient at increased risk during participation in the study 6. Any subject with a history of significant renal, hepatic, pulmonary, or cardiac dysfunction or on treatment to support cardiac dysfunction 7. HIV positive 8. Non-cooperative behavior or non-compliance of the patient and/or of his/her family 9. Received another investigational agent within 30 days of enrollment 10. Patients with Down's syndrome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Successful T-allo10 Products Manufactured for Patients Enrolled | By Day -2 | Feasibility defined by the rate of successful manufacture of the T-allo10 product to satisfy the targeted dose level and meet the required release specifications. Number of products meeting specifications out of total products manufactured is reported. |
| Number of Participants Experiencing Treatment Emergent Adverse Events (TEAE) | Time of T-allo10 cell infusion until 28 days following the infusion. | Number of participants experiencing TEAEs. Assessments of TEAE will include laboratory abnormalities, changes in vital signs, and changes in physical examination related to the infusion of T-allo10 cells in order to assess the tolerability of T-allo10. |
| Severity of Treatment Emergent Adverse Events (TEAE) | Time of T-allo10 cell infusion until 28 days following the infusion. | Number of participants experiencing TEAEs related to infusion, by severity graded according to the CTCAE grading system, from grade 1 (least severe) to grade 5 (death). Assessments of TEAE will include laboratory abnormalities, changes in vital signs, and changes in physical examination following infusion of T-allo10 cells in order to assess the safety of T-allo10. |
| Number of Participants Who Achieved Stem Cell Engraftment After Hematopoietic Stem Cell Transplant (HSCT). | +42 days post HSCT | Stem cell engraftment is evaluated by clinical laboratory studies including absolute neutrophil count above 500/mm3 for three consecutive days, hematopoiesis at bone marrow examination, with cellularity \>5 % and donor chimerism \>90% by short tandem repeat (STR) analysis for the presence of donor cells, and minimal residual disease (MRD) assay \< 0.1%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Grade III and/or IV Acute GvHD | Study visits through Day +100 | The number of patients who experienced grade III and IV acute GvHD at Day +100 following infusion of Tallo10 cells, assessed using the Modified Keystone scale administered by an independent evaluator on study visits through Day +100 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Developed Chronic GvHD | After Day +100 through Day +365 | The number of participants who experienced chronic GvHD and severity will be assessed by an independent evaluator. Outcome is reported as the highest level of chronic GVHD reported. |
| Number of Days to Reach Immune Reconstitution | Up to Day 365 | Immune reconstitution will be evaluated by clinical laboratory studies of CD3+ T cells, assessed by the number of days to reach \>200/microliter CD3+ T cells. |
| Number of Participants Who Experienced Disease Free Survival | At Day +365 | Disease free survival is defined as the absence of minimal residual disease in the bone marrow. The investigators will use bone marrow aspirate examination, minimal residual disease (MRD) assay, and donor chimerism by STR analysis to evaluate disease free survival. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Participants receive 1 X 10\^6/kg (± 10%) T-allo10 cells infused intravenously on Day -1 (day before transplant). | 3 |
| Cohort 2 Participants receive 3 X 10\^6/kg (± 10%) T-allo10 cells infused intravenously on Day -1 (day before transplant). | 2 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Relapse of primary disease | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 2 | Cohort 1 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 4 Participants |
| Diagnosis Acute Lymphoid Leukemia (ALL) | 0 Participants | 1 Participants | 1 Participants |
| Diagnosis Acute Myeloid Leukemia (AML) | 2 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 2 |
| other Total, other adverse events | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 3 / 3 | 2 / 2 |
Outcome results
Primary
Number of Participants Experiencing Treatment Emergent Adverse Events (TEAE)
Number of participants experiencing TEAEs. Assessments of TEAE will include laboratory abnormalities, changes in vital signs, and changes in physical examination related to the infusion of T-allo10 cells in order to assess the tolerability of T-allo10.
Time frame: Time of T-allo10 cell infusion until 28 days following the infusion.
Population: One participant who had no post-transplant data is excluded from analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Participants Experiencing Treatment Emergent Adverse Events (TEAE) | 1 Participants |
| Cohort 2 | Number of Participants Experiencing Treatment Emergent Adverse Events (TEAE) | 0 Participants |
Primary
Number of Participants Who Achieved Stem Cell Engraftment After Hematopoietic Stem Cell Transplant (HSCT).
Stem cell engraftment is evaluated by clinical laboratory studies including absolute neutrophil count above 500/mm3 for three consecutive days, hematopoiesis at bone marrow examination, with cellularity \>5 % and donor chimerism \>90% by short tandem repeat (STR) analysis for the presence of donor cells, and minimal residual disease (MRD) assay \< 0.1%.
Time frame: +42 days post HSCT
Population: One participant who had no post-transplant data is excluded from analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Participants Who Achieved Stem Cell Engraftment After Hematopoietic Stem Cell Transplant (HSCT). | 3 Participants |
| Cohort 2 | Number of Participants Who Achieved Stem Cell Engraftment After Hematopoietic Stem Cell Transplant (HSCT). | 1 Participants |
Primary
Number of Successful T-allo10 Products Manufactured for Patients Enrolled
Feasibility defined by the rate of successful manufacture of the T-allo10 product to satisfy the targeted dose level and meet the required release specifications. Number of products meeting specifications out of total products manufactured is reported.
Time frame: By Day -2
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Cohort 1 | Number of Successful T-allo10 Products Manufactured for Patients Enrolled | 3 Products |
| Cohort 2 | Number of Successful T-allo10 Products Manufactured for Patients Enrolled | 0 Products |
Primary
Severity of Treatment Emergent Adverse Events (TEAE)
Number of participants experiencing TEAEs related to infusion, by severity graded according to the CTCAE grading system, from grade 1 (least severe) to grade 5 (death). Assessments of TEAE will include laboratory abnormalities, changes in vital signs, and changes in physical examination following infusion of T-allo10 cells in order to assess the safety of T-allo10.
Time frame: Time of T-allo10 cell infusion until 28 days following the infusion.
Population: One participant who had no post-transplant data is excluded from analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Severity of Treatment Emergent Adverse Events (TEAE) | Grade 1 | 1 Participants |
| Cohort 1 | Severity of Treatment Emergent Adverse Events (TEAE) | >=Grade 2 | 0 Participants |
| Cohort 2 | Severity of Treatment Emergent Adverse Events (TEAE) | Grade 1 | 0 Participants |
| Cohort 2 | Severity of Treatment Emergent Adverse Events (TEAE) | >=Grade 2 | 0 Participants |
Secondary
Number of Participants Who Experienced Grade III and/or IV Acute GvHD
The number of patients who experienced grade III and IV acute GvHD at Day +100 following infusion of Tallo10 cells, assessed using the Modified Keystone scale administered by an independent evaluator on study visits through Day +100
Time frame: Study visits through Day +100
Population: One participant who had no post-transplant data is excluded from analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Participants Who Experienced Grade III and/or IV Acute GvHD | 2 Participants |
| Cohort 2 | Number of Participants Who Experienced Grade III and/or IV Acute GvHD | 0 Participants |
Other Pre-specified
Number of Days to Reach Immune Reconstitution
Immune reconstitution will be evaluated by clinical laboratory studies of CD3+ T cells, assessed by the number of days to reach \>200/microliter CD3+ T cells.
Time frame: Up to Day 365
Population: One participant who had no post-transplant data is excluded from analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Number of Days to Reach Immune Reconstitution | 22 Days |
| Cohort 2 | Number of Days to Reach Immune Reconstitution | 56 Days |
Other Pre-specified
Number of Participants Who Experienced Disease Free Survival
Disease free survival is defined as the absence of minimal residual disease in the bone marrow. The investigators will use bone marrow aspirate examination, minimal residual disease (MRD) assay, and donor chimerism by STR analysis to evaluate disease free survival.
Time frame: At Day +365
Population: One participant who had no post-transplant data is excluded from analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Participants Who Experienced Disease Free Survival | 3 Participants |
| Cohort 2 | Number of Participants Who Experienced Disease Free Survival | 1 Participants |
Other Pre-specified
Number of Patients Who Developed Chronic GvHD
The number of participants who experienced chronic GvHD and severity will be assessed by an independent evaluator. Outcome is reported as the highest level of chronic GVHD reported.
Time frame: After Day +100 through Day +365
Population: One participant who had no post-transplant data is excluded from analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Number of Patients Who Developed Chronic GvHD | Mild | 2 Participants |
| Cohort 1 | Number of Patients Who Developed Chronic GvHD | Moderate | 1 Participants |
| Cohort 1 | Number of Patients Who Developed Chronic GvHD | Severe | 0 Participants |
| Cohort 1 | Number of Patients Who Developed Chronic GvHD | Overall Incidence | 3 Participants |
| Cohort 2 | Number of Patients Who Developed Chronic GvHD | Overall Incidence | 1 Participants |
| Cohort 2 | Number of Patients Who Developed Chronic GvHD | Severe | 0 Participants |
| Cohort 2 | Number of Patients Who Developed Chronic GvHD | Mild | 0 Participants |
| Cohort 2 | Number of Patients Who Developed Chronic GvHD | Moderate | 1 Participants |