Acute Myeloid Leukemia, Chronic Myeloid Leukemia, Myelodysplastic Syndrome, Myeloid Malignancies
Conditions
Brief summary
The goal of this clinical research study is to learn about the safety and effectiveness of giving KDS-1001 in combination with a standard stem cell transplant to patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myeloid leukemia (CML). KDS-1001 is a study product created using certain immune cells called natural killer (NK) cells collected from a third-party donor.
Detailed description
Primary Objective Assess the safety and effectiveness of off the shelf third party NK cells in combination with allogeneic SCT in patients with myeloid malignancies. Secondary Objectives To assess NK cell related toxicities To estimate the proportion of patients with engraftment/graft failure. To assess the rate of leukemia relapse, disease-free survival (DFS), overall survival (OS), and GVHD-free, Relapse-free survival (GRFS) after transplantation by one year. To estimate the non-relapse mortality (NRM) at day 100, day 180 and 1 year post-transplant. To estimate the cumulative incidence of grade 2-4 and grades 3-4 aGVHD at day 100. To assess the rate of chronic GVHD within the first-year post transplantation. To assess rate of BK, CMV, and Adenovirus infections. To assess MRD. To assess immune reconstitution post-transplant
Interventions
DRUGCyclophosphamide
Given by IV
DRUGMesna
Given by IV
DRUGFilgrastim
Given by IV
DRUGMelphalan
Given by IV
DRUGFludarabine phosphate
Given by IV
DRUGTacrolimus
Given by IV
DRUGMycophenolate mofetil
Given by IV
DRUGTotal Body Irradiation One Dose
Given by IV
Sponsors
M.D. Anderson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Patients ages 18 to 70 years old at the time of enrollment. 2. Patients weighing at least 42 kg 3. Patient with the hematologic malignancies described below, as well as an HLA matched related donor, HLA matched unrelated donor, a haploidentical related donor, or a one antigen mismatched unrelated donor. HLA matching includes HLA A, B, C, and DR-B1. 4. Patients must have one of the following diseases: Acute myeloid leukemia (AML): a. With one or more high-risk features defined as: (i) Greater than 1 cycle of induction therapy required to achieve remission; (ii) Preceding myelodysplastic syndrome (MDS); Presence of FLT3 mutations or internal tandem duplication or other mutations designated as adverse-risk by the ELN Leukemia Net AML Classification (see Appendix 2): Adverse: * t(6;9)(p23;q34.1); DEK-NUP214 * t(v;11q23.3); KMT2A rearranged * t(9;22)(q34.1;q11.2); BCR-ABL1 * inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1) * -5 or del(5q); -7; -17/abn(17p) * Complex karyotype, monosomal karyotype * Wild-type NPM1 and FLT3-ITDhigh * Mutated RUNX1 * Mutated ASXL1 * Mutated TP53 (iv) FAB M6 or M7 classification; (v) Adverse cytogenetics: -5, del 5q, -7, del7q, abnormalities involving 3q, 9q, 11q, 20q, 21q, 17, +8 or complex karyotype \[\> 3 abnormalities\]; or other mutations designated as adverse-risk by the ELN criteria; (vi) Treatment-related AML (vii) Primary induction failure with partial response to therapy who achieve adequate cytoreduction (viii) Aplastic/hypoplastic marrow with or without detectable persistent disease after induction chemotherapy or after salvage chemotherapy. (ix) Have minimal residual disease by flow cytometry, FISH, detection of disease related mutations or cytogenetic abnormality after first course of induction chemotherapy (x) Have relapsed after prior allogeneic hematopoietic transplant AND b. Patients must be in one of the following (i) CR: complete remission, (ii) CRi: CR with incomplete hematologic recovery, or (iii) MLFS: morphological leukemia-free state with less than 5% bone marrow blasts. (iv) If not in either of the above i-iii, then may be in either of the following: 1. Primary induction failure with partial response to therapy who achieve adequate cytoreduction 2. Aplastic/hypoplastic marrow with or without detectable persistent disease after induction chemotherapy or after salvage chemotherapy Myelodysplastic syndromes (MDS): a. De novo MDS with intermediate or high-risk IPSS scores, chronic myelomonocytic leukemia (CMML) or treatment-related MDS. Patients with intermediate-1 features should have failed to respond to hypomethylating agent therapy. . Patients must have less than 10% bone marrow blasts Chronic myeloid leukemia (CML): 1. Failed to achieve cytogenetic remission or have cytogenetic relapse after treatment with at least 2 tyrosine kinase inhibitors, or 2. Accelerated phase or blast phase at any time, or 3. Intolerant of available TKIs 5. Performance score of at least 70% by Karnofsky or 0 to 1 by ECOG. 6. Adequate major non-hematopoietic organ system function as demonstrated by: 1. Serum creatinine clearance equal or more than 50 ml/min (calculated with Cockcroft-Gault formula). 2. Bilirubin equal or less than 1.5 mg/dL except for Gilbert's disease. ALT or AST equal or less than 200 U/L for adults. Conjugated (direct) bilirubin less than 2x upper limit of normal. 3. Left ventricular ejection fraction equal or greater than 45%. 4. Diffusing capacity for carbon monoxide (DLCO) equal or greater than 60% predicted corrected for hemoglobin. 7. Ability to understand and willingness to sign the written informed consent document. 8. Sexually active males and females of childbearing potential must agree to use a form of contraception considered effective and medically acceptable by the Investigator while on study.
Exclusion criteria
1. HIV positive; active hepatitis B or C. 2. Uncontrolled infections; PI is the final arbiter of this criterion. 3. Liver cirrhosis. 4. CNS involvement within 3 months prior to the transplant. 5. Positive pregnancy test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization. 6. Inability to comply with medical therapy or follow-up. 7. Patient with a known history of allergic reactions to any constituents of the product, including a known history of allergic reactions to cellular products or DMSO. 8. Other malignancy/cancer diagnosis with active disease or in remission and \<2 years ago, not including nonmelanoma skin cancer 9. Requiring systemic corticosteroids with prednisone dose \>10 mg or equivalent. 10. KDS-1001 Donor specific antibodies (dsa) \>3000 MFI units or C1q positive
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Graft Failure | 28 days post-transplant | Primary Graft failure is defined as failure to achieve an ANC \> 0.5 x 109/L for 3 consecutive days by day 28 post SC infusion, with no evidence of donor derived cells by bone marrow chimerism studies and no evidence of persistent or relapsing disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experienced Non-relapsed Mortality at 100 Day Post Transplant | 100 days post-transplant | Number of participants died from any cause other than relapse disease. |
| Number of Participants in Subsequent Transplant Prior to NK Cell Infusions/Stem Cell Transplant | On the day of study consent | Number participants had prior allogeneic transplants before study enrollment |
Countries
United States
Participant flow
Recruitment details
All participants were registered in MD Anderson Cancer Center
Participants by arm
| Arm | Count |
|---|---|
| NK Cell Infusion in Combination With Fludarabine Melphalan and TBI for Participants Undergoing SCT D-7 to D-6 Melphalan Administration: Patients \< age 60 receive melphalan 140 mg/m2 IV split into two doses (70 mg/m2 IV each day).
Patients age 60-70 receive melphalan 100 mg/m2 IV (infused per package insert) split into two doses (50 mg/m2 IV each day).
D-7 to D-4 Fludarabine Administration. Fludarabine will be administered at the dose of 40 mg/m2 IV daily for four doses on days -7 to -4.
D-3 TBI 200 cGy on D-3. D-2 NK cell (KDS-1001) administration D+3 and D+4 Post Transplant D+5 GvHD prophylaxis with Tacrolimus and Mycophenolate Mofetil | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Due to Bacteremia | 1 |
| Overall Study | Due to COVID19 | 1 |
| Overall Study | Due to viral infection | 1 |
Baseline characteristics
| Characteristic | NK Cell Infusion in Combination With Fludarabine Melphalan and TBI for Participants Undergoing SCT |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 12 / 21 |
| other Total, other adverse events | 20 / 21 |
| serious Total, serious adverse events | 5 / 21 |
Outcome results
Primary
Number of Participants Who Experienced Graft Failure
Primary Graft failure is defined as failure to achieve an ANC \> 0.5 x 109/L for 3 consecutive days by day 28 post SC infusion, with no evidence of donor derived cells by bone marrow chimerism studies and no evidence of persistent or relapsing disease.
Time frame: 28 days post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NK Cell Infusion in Combination With Fludarabine Melphalan and TBI for Participants Undergoing SCT | Number of Participants Who Experienced Graft Failure | 0 Participants |
Secondary
Number of Participants Experienced Non-relapsed Mortality at 100 Day Post Transplant
Number of participants died from any cause other than relapse disease.
Time frame: 100 days post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NK Cell Infusion in Combination With Fludarabine Melphalan and TBI for Participants Undergoing SCT | Number of Participants Experienced Non-relapsed Mortality at 100 Day Post Transplant | 4 Participants |
Secondary
Number of Participants in Subsequent Transplant Prior to NK Cell Infusions/Stem Cell Transplant
Number participants had prior allogeneic transplants before study enrollment
Time frame: On the day of study consent
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NK Cell Infusion in Combination With Fludarabine Melphalan and TBI for Participants Undergoing SCT | Number of Participants in Subsequent Transplant Prior to NK Cell Infusions/Stem Cell Transplant | 10 Participants |