Myelodysplastic Syndromes, Secondary Acute Myeloid Leukemia
Conditions
Keywords
MDS, sAML
Brief summary
The purpose of the study is to determine the safety of an investigational treatment for myelodysplastic syndrome (MDS) after the first therapy (such as azacitidine or decitabine) stops working or after progression of MDS to acute myeloid leukemia (AML). Funding source - FDA OOPD.
Detailed description
The purpose of the study is to determine the safety of an investigational treatment for myelodysplastic syndrome (MDS) after the first therapy (such as azacitidine or decitabine) stops working or after progression of MDS to acute myeloid leukemia (AML). Patients with advanced MDS are treated with hypomethylating agents (HMAs) such as azacitidine or decitabine. These medications can be effective for a few months to a few years, but usually lose effect eventually. This study is attempting to design a therapy called "non-engrafting, CD8 depleted donor lymphocyte infusion" or "NE-DLI" as a treatment for these diseases.
Interventions
BIOLOGICALCD8 Depleted, Non-engrafting,HLA mismatched unrelated donor lymphocytes
Infusion of mononuclear cells, apheresis products depleted of CD8+ T cells using the CliniMACS® system with CliniMACS® CD8 reagent
Standard of care cytarabine-based chemotherapy
Sponsors
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
Myelodysplastic Syndrome (MDS) having failed hypomethylating agent (HMA) therapy cohort: * Age 18-79 years, inclusive * Pathologically confirmed MDS or myelodysplastic/myeloproliferative overlap (MDS/MPN) * IPSS-R score intermediate, high or very high * Must have failed therapy with an HMA (defined as lack of response by International Working Group criteria (1) or intolerance of the drug) Secondary Acute Myeloid Leukemia (sAML): * Pathologically confirmed AML according to World Health Organization (WHO) criteria * Evidence of an antecedent hematologic disorder (AHD) prior to acute leukemia including a known prior diagnosis of MDS, MPN or MDS/MPN or data suggestive of an AHD such as cytopenias, fibrosis, macrocytic anemia, cellular or dysplasia at or prior to the time of diagnosis. If available, MDS-defining karyotypes (-7/del(7q), -5/del(5q), del(13q), del(11q), del(12p), t(12p), del(9q), idic(X)(q13), t(17p) (unbalanced translocations) or i(17q) (ie, loss of 17p), t(11;16)(q23;p13.3), t(3;21)(q26.2;q22.1), t(1;3)(p36.3;q21), t(2;11)(p21;q23), inv(3)(q21q26.2), t(6;9)(p23;q34)) or somatic mutations in multiple genes including p53, TET2, JAK2, CALR, MPL, ASXL1, RUNX1, SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 would also confirm eligibility. * Age 60-79 years, inclusive * May be previously untreated For both cohorts: * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Deemed eligible to receive cytotoxic chemotherapy * Creatinine clearance (CrCl)\>50ml/min * Total bilirubin \<2 mg/dL (except for patients with Gilbert's disease), AST and ALT \< 3x ULN * Left Ventricular Ejection Fraction ≥ 50% * Willing and able to participate in study assessments
Exclusion criteria
* Patients who have had systemic chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Hydroxyurea during this period may be given as a bridging therapy to maintain disease stability while awaiting treatment. Intrathecal chemotherapy within this time frame is permitted. Intrathecal chemotherapy may be continued during protocol therapy in order to consolidate or maintain a central nervous system (CNS) remission, but not to treat active CNS disease * Acute promyelocytic leukemia, or the presence of t(15;17) * Patients receiving any other investigational agents * Uncontrolled concurrent illness including, but not limited to, ongoing and uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * Pregnant women are excluded from this study because there is an unknown but potential risk for adverse events in the fetus. Breastfeeding should be discontinued if the mother is treated. These potential risks may also apply to other agents used in this study * Patients who have any debilitating medical or psychiatric illness that would preclude their giving informed consent or their receiving optimal treatment and follow-up * Patients with a poor functional status of ECOG 3-4, or otherwise deemed unfit to tolerate induction chemotherapy. * Patients with blastic transformation of chronic myelogenous leukemia are ineligible * Exposure to a humanized mouse chimeric antibody, as this could sensitize patients to components of the CD8 depletion column that may be present in small amounts in the cell product * Prior allogenic hematopoietic cell transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of CD8 Depleted Non-engrafting HLA-mismatched Unrelated Donor Lymphocytes Infusion (NE-DLI) | Up to 60 days per dose level | Maximum Tolerated Dose will be determined by testing increasing doses of CD8 depleted non-engrafting HLA-mismatched unrelated donor lymphocytes infusion (NE-DLI). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Up to 12 months | Overall Response Rate is defined as Complete Response + Partial Response using RECIST v1.1 criteria. |
| Progression Free Survival | Up to 12 months | Progression Free Survival is defined as the time from enrollment to date of progression or death, or censor at last follow-up date. |
| Overall Survival | Up to 12 months | Overall Survival is defined as the time from study enrollment to death from any cause or censored at last follow up date |
| Hematologic Response | Up to 12 months | Hematologic response will be determined using International Working Group 2006 criteria for MDS patients and the International Working Group 2003 criteria for AML |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJoseph Pidala, MD, PhD
Moffitt Cancer Center
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 Dose Level 1 All participants will receive cytotoxic induction chemotherapy with a standard of care cytarabine-based regimen. 24-36 hours after chemotherapy cessation, participants will receive CD8-depleted non-engrafting HLA-mismatched unrelated donor lymphocyte infusion (NE-DLI) at dose level 1: 1X10\^6 CD4 T Cells/kg
CD8 Depleted, Non-engrafting,HLA mismatched unrelated donor lymphocytes: Infusion of mononuclear cells, apheresis products depleted of CD8+ T cells using the CliniMACS® system with CliniMACS® CD8 reagent
Standard of Care Chemotherapy: Standard of care cytarabine-based chemotherapy | 3 |
| Phase 1 Dose Level 2 All participants will receive cytotoxic induction chemotherapy with a standard of care cytarabine-based regimen. 24-36 hours after chemotherapy cessation, participants will receive CD8-depleted non-engrafting HLA-mismatched unrelated donor lymphocyte infusion (NE-DLI) at dose level 2: 1X10\^7 CD4 T Cells/kg
CD8 Depleted, Non-engrafting,HLA mismatched unrelated donor lymphocytes: Infusion of mononuclear cells, apheresis products depleted of CD8+ T cells using the CliniMACS® system with CliniMACS® CD8 reagent
Standard of Care Chemotherapy: Standard of care cytarabine-based chemotherapy | 3 |
| Phase 1 Dose Level 3 All participants will receive cytotoxic induction chemotherapy with a standard of care cytarabine-based regimen. 24-36 hours after chemotherapy cessation, participants will receive CD8-depleted non-engrafting HLA-mismatched unrelated donor lymphocyte infusion (NE-DLI) at dose level 3: 5 X10\^7 CD4 T Cells/kg
CD8 Depleted, Non-engrafting,HLA mismatched unrelated donor lymphocytes: Infusion of mononuclear cells, apheresis products depleted of CD8+ T cells using the CliniMACS® system with CliniMACS® CD8 reagent
Standard of Care Chemotherapy: Standard of care cytarabine-based chemotherapy | 3 |
| Phase 2 -Treatment at Maximum Tolerated Dose (MTD) All participants will receive cytotoxic induction chemotherapy with a standard of care cytarabine-based regimen. 24-36 hours after chemotherapy cessation, participants will receive CD8-depleted non-engrafting HLA-mismatched unrelated donor lymphocyte infusion (NE-DLI) at MTD.
CD8 Depleted, Non-engrafting,HLA mismatched unrelated donor lymphocytes: Infusion of mononuclear cells, apheresis products depleted of CD8+ T cells using the CliniMACS® system with CliniMACS® CD8 reagent
Standard of Care Chemotherapy: Standard of care cytarabine-based chemotherapy | 10 |
| Total | 19 |
Baseline characteristics
| Characteristic | Total | Phase 1 Dose Level 1 | Phase 1 Dose Level 2 | Phase 1 Dose Level 3 | Phase 2 -Treatment at Maximum Tolerated Dose (MTD) |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 3 Participants | 2 Participants | 2 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 3 Participants | 2 Participants | 3 Participants | 10 Participants |
| Region of Enrollment United States | 19 participants | 3 participants | 3 participants | 3 participants | 10 participants |
| Sex: Female, Male Female | 8 Participants | 2 Participants | 0 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 11 Participants | 1 Participants | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 3 | 2 / 3 | 5 / 10 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 10 / 10 |
| serious Total, serious adverse events | 2 / 3 | 0 / 3 | 3 / 3 | 1 / 10 |
Outcome results
Primary
Maximum Tolerated Dose of CD8 Depleted Non-engrafting HLA-mismatched Unrelated Donor Lymphocytes Infusion (NE-DLI)
Maximum Tolerated Dose will be determined by testing increasing doses of CD8 depleted non-engrafting HLA-mismatched unrelated donor lymphocytes infusion (NE-DLI).
Time frame: Up to 60 days per dose level
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maximum Tolerated Dose (MTD) | Maximum Tolerated Dose of CD8 Depleted Non-engrafting HLA-mismatched Unrelated Donor Lymphocytes Infusion (NE-DLI) | 5 10^7 CD4 cells/kg |
Secondary
Hematologic Response
Hematologic response will be determined using International Working Group 2006 criteria for MDS patients and the International Working Group 2003 criteria for AML
Time frame: Up to 12 months
Population: As specified in the protocol, only participants treated at the MTD are included in this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maximum Tolerated Dose (MTD) | Hematologic Response | 7 Number of Participants achieving CR |
| Participants Treated at MTD - MDS | Hematologic Response | 0 Number of Participants achieving CR |
Secondary
Overall Response Rate
Overall Response Rate is defined as Complete Response + Partial Response using RECIST v1.1 criteria.
Time frame: Up to 12 months
Population: As specified in the protocol, only participants treated at the MTD are included in this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maximum Tolerated Dose (MTD) | Overall Response Rate | 61.5 percentage of Participants with Response |
Secondary
Overall Survival
Overall Survival is defined as the time from study enrollment to death from any cause or censored at last follow up date
Time frame: Up to 12 months
Population: As specified in the protocol, only participants treated at the MTD are included in this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Maximum Tolerated Dose (MTD) | Overall Survival | 11.9 Months |
Secondary
Progression Free Survival
Progression Free Survival is defined as the time from enrollment to date of progression or death, or censor at last follow-up date.
Time frame: Up to 12 months
Population: As specified in the protocol, only participants treated at the MTD are included in this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Maximum Tolerated Dose (MTD) | Progression Free Survival | 8.7 Months |