Acute Leukemia, Lymphoma, Myelodysplastic Syndromes, Myeloproliferative Neoplasm
Conditions
Keywords
VIC-1911, PTCy, Myeloablative, Allogeneic
Brief summary
This is a single-arm, phase I/II, study of PTCy/sirolimus plus VIC-1911 to prevent GVHD and relapse after Allogeneic Hematopoietic Cell Transplantation (alloHCT).
Detailed description
Determination of the optimal dose during the Phase I trial is based on Dose Limiting Toxicity for safety and reduction of CD4+, pH3ser10+ T cells (phosphorylated histone 3 serine 10 is a biomarker of Aurora kinase A activity) for efficacy. Phase II will be powered to improve grade III-IV acute graft-versus-host disease and relapse after alloHCT, compared to historical estimates at the University of Minnesota. Patients will receive myeloablative conditioning (MAC) with total body irradiation (TBI) followed by infusion of HLA-matched related or unrelated peripheral blood stem cells (PBSC) on day 0. Cyclophosphamide will be administered on days +3 and +4. Sirolimus targeting 8-12ng/ml will begin on day +5 until day +365. VIC-1911 will be administered as 25 mg, 50 mg, or 75 mg orally BID from day +5 to day +45 according to the rules of our phase I study. The lowest biologically active and safe dose of VIC-1911 will be identified as the recommended phase II dose.
Interventions
DRUGVIC- 1911
25 mg, 50 mg, or 75 mg administered twice a day from day 5 post HCT to day 45, and the dose escalation will stop once we identify the lowest biologically active and safe dose of VIC.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of * acute leukemia in complete remission, or * myelodysplasia with \<5% blasts, or * myeloproliferative neoplasm/myelofibrosis with \<5% marrow or circulating blasts * chemosensitive Hodgkin or non-Hodgkin lymphoma * Age 18 years or older * Performance status of ≥ 80% Karnofsky * Adequate organ function within 28 days of study registration defined as: * left ventricular ejection fraction ≥ 45% * pulmonary function with FEV1, FVC, and DLCO ≥ 50% predicted * AST and ALT \< 2 times upper limit of normal * Total bilirubin \<1.5 times the upper limit of normal. If the patient is suspected of having Gilbert syndrome, they require prior approval of the medical monitor * creatinine clearance ≥ 50cc/min * no active/uncontrolled infection * negative HIV, HBV and HCV * ferritin \< 2000 ng/ml * Patients able to tolerate oral medication * Women of childbearing potential and men with partners of child-bearing potential must agree to use of contraception for the duration of treatment through 60 days after the last treatment of VIC-1911 or sirolimus * Able to provide written voluntary consent prior to the performance of any research related tests or procedures
Exclusion criteria
* HCT-CI \> 4 or unable to receive myeloablative TBI * Use of planned post-transplant maintenance therapy to begin prior to day +75. Patients may receive standard of care maintenance therapies starting at day +75 or later * Patients with a history of hypersensitivity to any of the investigational products * Pregnant or breastfeeding as agents used in this study are Pregnancy Category o C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations, and Pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Females of childbearing potential must have a negative pregnancy test (serum or urine) within 28 days of study registration. * Women or men of childbearing potential unwilling to take adequate precautions to avoid unintended pregnancy from the start of protocol treatment through 60 days after the last treatment of VIC-1911 or sirolimus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determine the Optimal Dose of VIC-1911 When Given in Combination With Standard Immunosuppressive Therapy in Adult Patients Undergoing Myeloablative Stem Cell Transplantation. | 21 days post treatment | The optimal dose will be identified using the EffTox design. The proportion of patients with an average CD4+, pH3ser10+ T cell of \<54%. The minimum desired biologic efficacy is 65% of patients by day 21 (+/- 3 days) with \<30% of patients experiencing a DLT. Data only to reported from arm with maximum tolerated dose. |
| Progression-free Survival | 1 Year | Participant progression-free survival assessed using aGVHD data. |
| Relapsed Assessment (Phase I) | 12 months | Assessment to determine if patient has relapse in MTD arm. Data only to reported from arm with maximum tolerated dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival Comparing Graft-Versus-Host Disease-Free (GRFS) to the Standard PTCY Plus Tacrolimus/Mycophenolate Mofetil Regimen From MT2015-29 | 12 months | Progression-free Survival assessed using GRFS defined as grade III-IV acute GVHD, chronic GVHD requiring immunosuppression, relapse, or death by 1 year |
| Overall Survival (OS) | 1 year | Overall Survival for participants on MTD arm. Data only to reported from arm with maximum tolerated dose. |
| Frequency of CMV Reactivation and Disease | Day 100 | Analyze the frequency of CMV reactivation and disease for MTD arm. Data only to reported from arm with maximum tolerated dose. |
| Progression Free Survival | 1 Year | Percentage of participants with progression free survival at 1 year for MTD arm. Data only to reported from arm with maximum tolerated dose. |
| To Determine the Cumulative Incidences of Acute GVHD | Day 100 | Assessment of aGVHD for MTD arm. Data only to reported from arm with maximum tolerated dose. |
| To Determine the Cumulative Incidences of Chronic GVHD | 12 months | Assessment of cGVHD |
Countries
United States
Participant flow
Pre-assignment details
No participants were enrolled into the Phase II portion of the study. We concluded the trial when Phase Ia was completed, rather than proceeding to Phase Ib, due to funding constraints and the goal of focusing on developing a new randomized study.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level A1 25 mg administered twice a day from day 5 post HCT to day 45. Dose escalation will stop once we identify the lowest biologically active and safe dose of VIC. | 4 |
| Dose Level A2 50 mg administered twice a day from day 5 post HCT to day 45. Dose escalation will stop once we identify the lowest biologically active and safe dose of VIC. | 3 |
| Dose Level A3 75 mg administered twice a day from day 5 post HCT to day 45. Dose escalation will stop once we identify the lowest biologically active and safe dose of VIC. | 9 |
| Total | 16 |
Baseline characteristics
| Characteristic | Dose Level A1 | Dose Level A2 | Dose Level A3 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 3 Participants | 8 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 3 Participants | 9 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 4 Participants | 1 Participants | 8 Participants | 13 Participants |
| Region of Enrollment United States | 4 participants | 3 participants | 9 participants | 16 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 4 Participants | 1 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 4 | 0 / 3 | 0 / 9 |
| other Total, other adverse events | 1 / 4 | 3 / 3 | 3 / 9 |
| serious Total, serious adverse events | 1 / 4 | 2 / 3 | 3 / 9 |
Outcome results
Primary
Determine the Optimal Dose of VIC-1911 When Given in Combination With Standard Immunosuppressive Therapy in Adult Patients Undergoing Myeloablative Stem Cell Transplantation.
The optimal dose will be identified using the EffTox design. The proportion of patients with an average CD4+, pH3ser10+ T cell of \<54%. The minimum desired biologic efficacy is 65% of patients by day 21 (+/- 3 days) with \<30% of patients experiencing a DLT. Data only to reported from arm with maximum tolerated dose.
Time frame: 21 days post treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCy/Sirolimus Plus VIC-1911 | Determine the Optimal Dose of VIC-1911 When Given in Combination With Standard Immunosuppressive Therapy in Adult Patients Undergoing Myeloablative Stem Cell Transplantation. | 75 mg of VIC |
Primary
Progression-free Survival
Participant progression-free survival assessed using aGVHD data.
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCy/Sirolimus Plus VIC-1911 | Progression-free Survival | 100 Percentage of participants |
| Dose Level A2 | Progression-free Survival | 100 Percentage of participants |
| Dose Level A3 | Progression-free Survival | 100 Percentage of participants |
Primary
Relapsed Assessment (Phase I)
Assessment to determine if patient has relapse in MTD arm. Data only to reported from arm with maximum tolerated dose.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCy/Sirolimus Plus VIC-1911 | Relapsed Assessment (Phase I) | 0 Percentage of participants |
Secondary
Frequency of CMV Reactivation and Disease
Analyze the frequency of CMV reactivation and disease for MTD arm. Data only to reported from arm with maximum tolerated dose.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCy/Sirolimus Plus VIC-1911 | Frequency of CMV Reactivation and Disease | 0 Percentage of participants |
Secondary
Overall Survival (OS)
Overall Survival for participants on MTD arm. Data only to reported from arm with maximum tolerated dose.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCy/Sirolimus Plus VIC-1911 | Overall Survival (OS) | 100 Percent of participants |
Secondary
Progression Free Survival
Percentage of participants with progression free survival at 1 year for MTD arm. Data only to reported from arm with maximum tolerated dose.
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCy/Sirolimus Plus VIC-1911 | Progression Free Survival | 100 Percent of participants |
Secondary
Progression-free Survival Comparing Graft-Versus-Host Disease-Free (GRFS) to the Standard PTCY Plus Tacrolimus/Mycophenolate Mofetil Regimen From MT2015-29
Progression-free Survival assessed using GRFS defined as grade III-IV acute GVHD, chronic GVHD requiring immunosuppression, relapse, or death by 1 year
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCy/Sirolimus Plus VIC-1911 | Progression-free Survival Comparing Graft-Versus-Host Disease-Free (GRFS) to the Standard PTCY Plus Tacrolimus/Mycophenolate Mofetil Regimen From MT2015-29 | 100 Percentage of participants |
| Dose Level A2 | Progression-free Survival Comparing Graft-Versus-Host Disease-Free (GRFS) to the Standard PTCY Plus Tacrolimus/Mycophenolate Mofetil Regimen From MT2015-29 | 100 Percentage of participants |
| Dose Level A3 | Progression-free Survival Comparing Graft-Versus-Host Disease-Free (GRFS) to the Standard PTCY Plus Tacrolimus/Mycophenolate Mofetil Regimen From MT2015-29 | 67 Percentage of participants |
Secondary
To Determine the Cumulative Incidences of Acute GVHD
Assessment of aGVHD for MTD arm. Data only to reported from arm with maximum tolerated dose.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCy/Sirolimus Plus VIC-1911 | To Determine the Cumulative Incidences of Acute GVHD | 6 number of new cases per 900 person-days |
Secondary
To Determine the Cumulative Incidences of Chronic GVHD
Assessment of cGVHD
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCy/Sirolimus Plus VIC-1911 | To Determine the Cumulative Incidences of Chronic GVHD | 0 Percentage of participants |
| Dose Level A2 | To Determine the Cumulative Incidences of Chronic GVHD | 0 Percentage of participants |
| Dose Level A3 | To Determine the Cumulative Incidences of Chronic GVHD | 33 Percentage of participants |