Acute Lymphoblastic Leukemia, Leukemia, Myelogenous, Chronic, Leukemia, Myeloid, Acute, Lymphoma, Non-Hodgkin, Myelodysplasia
Conditions
Brief summary
The main purpose of this trial is to study whether the drug sitagliptin can be given safely to patients undergoing umbilical cord blood transplantation to speed up engraftment (recovery of blood counts after transplant).
Detailed description
Umbilical cord blood (UCB) is increasingly used as a source of stem cells for patients with blood cancers who need an allogeneic stem cell transplant (a transplant with stem cells from another person) but who have no suitably matched donors. The advantages of UCB are that (1) it is associated with less risk of transmitting an infection from a donor, (2) it can be more safely given even if not completely matched compared to bone marrow or blood stem cells, and (3) it is much more quickly available than unrelated donor bone marrow or blood stem cells. While more commonly used for transplantation in children, UCB is increasingly being used in adults. However, because they are larger than children, the relatively smaller stem cell dose in UCB is major limitation for transplantation in adults, and engraftment can be delayed. This study is investigating whether the drug sitagliptin can be used to increase and speed up engraftment in adults receiving UCB transplantation, overcoming the limitation of small stem cell doses associated with umbilical cord blood. Sitagliptin is a drug given in tablet form that has been recently approved by the Food and Drug Administration (FDA) for the treatment of certain patients with diabetes mellitus (a disease that results in high blood sugar). Sitagliptin has been given to both normal healthy volunteers and diabetic patients and has been found to be safe and well-tolerated. The drug improves control of blood sugar in diabetics by inhibiting an enzyme called CD26/DPP-IV. Recent studies at Indiana University (and other centers) have shown that this same enzyme plays an important role in the way transplanted stem cells find their way to the bone marrow and engraft. Transplant studies in mice have found that inhibiting CD26/DPP-IV significantly increases the engraftment of stem cells. Based on these studies, it is believed that drugs that inhibit CD26/DPP-IV, such as sitagliptin, may also increase engraftment in patients who receive clinical stem cell transplants.
Interventions
DRUGSitagliptin
600 mg sitagliptin taken orally per the schedule listed in each of the three separate arms.
Sponsors
Indiana University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 59 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have one of the following disease types with disease-specific features as outlined in the protocol: * Acute myeloid leukemia (AML) * Acute lymphoblastic leukemia (ALL) * Myelodysplasia * Chronic myelogenous leukemia * Patients with aggressive non-Hodgkin's lymphoma (NHL), including diffuse large cell lymphoma, mediastinal B-cell lymphoma, transformed lymphoma, mantle cell lymphoma, and peripheral T cell lymphoma * Hodgkin's lymphoma * Relapsed Multiple Myeloma * At least 35 days following start of preceding leukemia induction cytotoxic chemotherapy * Patient age 18-55 years * Karnofsky Performance status ≥ 70% * No availability of a consenting HLA-matched related donor who is either matched fully matched or mismatched at only one locus of HLA-A, -B, and DRB1. * No availability of a readily available HLA-matched volunteer unrelated donor (8 of 8 allele match at HLA-A, -B, -C and -DRB1). Patients with unstable disease who are in danger of significant disease progression while waiting to procure volunteer donor cells will be eligible to be treated on this protocol, even if a matched donor is available. * Patients must have a matched or partially matched UCB unit with greater than 1.8 x10-7 nucleated cells/kg of recipient weight at the time of cryopreservation. * No current uncontrolled bacterial, viral or fungal infection (defined as currently taking medication and progression of clinical symptoms). * No HIV disease. Patients with immune dysfunction are at a significantly higher risk of infection from intensive immunosuppressive therapies. * Non pregnant and non-nursing. Treatment under this protocol would expose a fetus to significant risks. * Required baseline laboratory values as defined in the protocol
Exclusion criteria
* Symptomatic uncontrolled coronary artery disease or congestive heart failure. * Severe hypoxemia with room air PaO2 less than 70, supplemental oxygen dependence, or DLCO less than 50 percent predicted * Patients with central nervous system (CNS) involvement refractory to intrathecal chemotherapy * Prior allogeneic or autologous hematopoietic stem cell transplant in the last 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Incidence of Patients With Engraftment by Day +30 Following Transplant | Transplant (Day 0) through Day +30 | Evaluate the efficacy of CD26/DPP-IV inhibition in increasing the cumulative incidence of adult patients with hematological malignancies engrafting by day +30 following transplantation of UCB by 30 percent. The cumulative incidence of patients achieving this will be reported. The value of the estimate will be from bootstrapping 1000 samples with replacement of the data and the 95% confidence interval will be calculated using the percentile method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Neutrophil Engraftment | Transplant (Day 0) up to 1 year | Time to neutrophil engraftment will be analyzed by the Kaplan-Meier method. The time to engraftment of neutrophils is defined as the time from day 0 to the date of the first of three consecutive days after transplantation during which the absolute neutrophils count (ANC) is at least 0.5 x109/l. Patients who did not have neutrophil engraftment before death will be censored at the date of death. The median and 95% confidence intervals will be provided. For the RCD group, all patients engrafted before day +30, except one patient who died at day 28 before engraftment. For the PD group, all patients engrafted before day +100, except one patient who died on day +103 before engraftment. For the 600 mg sitagliptin/12 hours group, two patients engrafted before day +100, and the other two patients died before day +100 before engraftment. The one patient on 600 mg sitagliptin/8 hours died on day +14 before engraftment. |
| Time to Platelet Engraftment | Transplant (Day 0) up to 1 year | Time to platelet engraftment will be analyzed by the Kaplan-Meier method. The time to engraftment of platelets is defined as the time from day 0 to the first of seven consecutive days after transplantation during which the platelet count is at least 20 x109/l without transfusion support. Only patients who achieved engraftment of platelets will be included in the analysis. The median and 95% confidence intervals will be provided. |
| Treatment Related Adverse Events Grade 3 or Higher for Non-hematological Toxicity | Transplant (Day 0) up to 3 years | Number of unique patients who had a treatment related (possible, probable or definite) non-hematological adverse event that was graded 3 or greater. |
Countries
United States
Participant flow
Recruitment details
Initially based on single arm 2 stage design using 600 mg sitagliptin/24 hrs in RBC replete and RBC depleted UCB units. In an unplanned interim analysis after 1st 20 enrolled pts, protocol was amended to exclude RBC replete UCB units due to worse outcomes and to test more frequent dosing of sitagliptin due to suboptimal inhibition of plasma DPP-IV.
Participants by arm
| Arm | Count |
|---|---|
| Red Cell-Depleted (RCD) - 600 mg Sitagliptin/24 Hrs 600 mg sitagliptin/day PO starting on Day -1 for a total of 4 doses in red cell-depleted patients | 17 |
| Red Cell-Replete, Plasma-Depleted (PD) - 600 mg Sitagliptin/24 600 mg sitagliptin/day PO starting on Day -1 for a total of 4 doses in red cell-replete patients | 7 |
| 600 mg Sitagliptin/12 Hrs 600 mg sitagliptin/bid PO starting on Day -1 for a total of 8 doses | 4 |
| 600 mg Sitagliptin/8 Hrs 600 mg sitagliptin/tid PO starting on Day -1 for a total of 12 doses | 1 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 5 | 6 | 1 | 1 |
| Overall Study | Disease Progression | 5 | 0 | 1 | 0 |
| Overall Study | Engraftment failure | 0 | 0 | 1 | 0 |
| Overall Study | Veno-Occlusive Disease | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Red Cell-Depleted (RCD) - 600 mg Sitagliptin/24 Hrs | Red Cell-Replete, Plasma-Depleted (PD) - 600 mg Sitagliptin/24 | 600 mg Sitagliptin/12 Hrs | 600 mg Sitagliptin/8 Hrs | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 7 Participants | 4 Participants | 1 Participants | 29 Participants |
| Age, Continuous | 40.6 years STANDARD_DEVIATION 10.86 | 34.8 years STANDARD_DEVIATION 8.95 | 46.9 years STANDARD_DEVIATION 7.94 | 54.9 years STANDARD_DEVIATION 0 | 40.6 years STANDARD_DEVIATION 10.62 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 7 Participants | 4 Participants | 1 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 5 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 | 14 Participants | 5 Participants | 4 Participants | 1 Participants | 24 Participants |
| Sex: Female, Male Female | 12 Participants | 4 Participants | 2 Participants | 1 Participants | 19 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 2 Participants | 0 Participants | 10 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 17 / 17 | 7 / 7 | 4 / 4 | 1 / 1 |
| serious Total, serious adverse events | 11 / 17 | 6 / 7 | 2 / 4 | 1 / 1 |
Outcome results
Primary
Cumulative Incidence of Patients With Engraftment by Day +30 Following Transplant
Evaluate the efficacy of CD26/DPP-IV inhibition in increasing the cumulative incidence of adult patients with hematological malignancies engrafting by day +30 following transplantation of UCB by 30 percent. The cumulative incidence of patients achieving this will be reported. The value of the estimate will be from bootstrapping 1000 samples with replacement of the data and the 95% confidence interval will be calculated using the percentile method.
Time frame: Transplant (Day 0) through Day +30
Population: Modified Intent to treat population (mITT) - all patients receiving at least one dose of study drug and receiving REB depleted UCB units only
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Red Cell-Depleted (RCD) - 600 mg Sitagliptin/24 Hrs | Cumulative Incidence of Patients With Engraftment by Day +30 Following Transplant | 88 percentage of participants |
Secondary
Time to Neutrophil Engraftment
Time to neutrophil engraftment will be analyzed by the Kaplan-Meier method. The time to engraftment of neutrophils is defined as the time from day 0 to the date of the first of three consecutive days after transplantation during which the absolute neutrophils count (ANC) is at least 0.5 x109/l. Patients who did not have neutrophil engraftment before death will be censored at the date of death. The median and 95% confidence intervals will be provided. For the RCD group, all patients engrafted before day +30, except one patient who died at day 28 before engraftment. For the PD group, all patients engrafted before day +100, except one patient who died on day +103 before engraftment. For the 600 mg sitagliptin/12 hours group, two patients engrafted before day +100, and the other two patients died before day +100 before engraftment. The one patient on 600 mg sitagliptin/8 hours died on day +14 before engraftment.
Time frame: Transplant (Day 0) up to 1 year
Population: All patients enrolled and received treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Red Cell-Depleted (RCD) - 600 mg Sitagliptin/24 Hrs | Time to Neutrophil Engraftment | 21 days |
| Red Cell-Replete, Plasma-Depleted (PD) - 600 mg Sitagliptin/24 | Time to Neutrophil Engraftment | 35 days |
| 600 mg Sitagliptin/12 Hrs | Time to Neutrophil Engraftment | 51 days |
| 600 mg Sitagliptin/8 Hrs | Time to Neutrophil Engraftment | 14 days |
Secondary
Time to Platelet Engraftment
Time to platelet engraftment will be analyzed by the Kaplan-Meier method. The time to engraftment of platelets is defined as the time from day 0 to the first of seven consecutive days after transplantation during which the platelet count is at least 20 x109/l without transfusion support. Only patients who achieved engraftment of platelets will be included in the analysis. The median and 95% confidence intervals will be provided.
Time frame: Transplant (Day 0) up to 1 year
Population: All patients enrolled and received treatment who achieved platelet recovery/engraftment of platelets.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Red Cell-Depleted (RCD) - 600 mg Sitagliptin/24 Hrs | Time to Platelet Engraftment | 77 days |
| Red Cell-Replete, Plasma-Depleted (PD) - 600 mg Sitagliptin/24 | Time to Platelet Engraftment | 91 days |
| 600 mg Sitagliptin/12 Hrs | Time to Platelet Engraftment | NA days |
| 600 mg Sitagliptin/8 Hrs | Time to Platelet Engraftment | NA days |
Secondary
Treatment Related Adverse Events Grade 3 or Higher for Non-hematological Toxicity
Number of unique patients who had a treatment related (possible, probable or definite) non-hematological adverse event that was graded 3 or greater.
Time frame: Transplant (Day 0) up to 3 years
Population: All patients enrolled and received treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Red Cell-Depleted (RCD) - 600 mg Sitagliptin/24 Hrs | Treatment Related Adverse Events Grade 3 or Higher for Non-hematological Toxicity | 0 participants |
| Red Cell-Replete, Plasma-Depleted (PD) - 600 mg Sitagliptin/24 | Treatment Related Adverse Events Grade 3 or Higher for Non-hematological Toxicity | 0 participants |
| 600 mg Sitagliptin/12 Hrs | Treatment Related Adverse Events Grade 3 or Higher for Non-hematological Toxicity | 0 participants |
| 600 mg Sitagliptin/8 Hrs | Treatment Related Adverse Events Grade 3 or Higher for Non-hematological Toxicity | 1 participants |