PTCy + Sirolimus/VIC-1911 as GVHD Prophylaxis in Myeloablative PBSC Transplantation

Study Overview
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Brief Summary
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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
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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.

Official Title
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PTCy + Sirolimus/VIC-1911 as GVHD Prophylaxis in Myeloablative PBSC Transplantation

Conditions
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Acute Leukemia, Myelodysplastic Syndromes, Myeloproliferative Neoplasm, Lymphoma

Intervention / Treatment
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* Drug: VIC- 1911


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PTCy/sirolimus plus VIC-1911<br>Patients enrolled and treated with PTCy/sirolimus plus VIC-1911 | Drug: VIC- 1911<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 21 days post treatment | 
| Confirm safety and obtain an estimate of long-term efficacy as measured by aGVHD assessed (Phase II) | Assessment for aGVHD | Day 100 | 
| Relapsed assessment (Phase II) | Assessment to determine if patient has relapse | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analyze markers of mTOR and IL-2 activity cells | Determine the frequency of CD4+, pS6+ [marker of mTOR activity] and CD4+, pSTAT5+ [marker of IL-2 activity] cells | Pre-condition, before Day 1 (Day 0) | 
| Analyze markers of mTOR and IL-2 activity cells | Determine the frequency of CD4+, pS6+ [marker of mTOR activity] and CD4+, pSTAT5+ [marker of IL-2 activity] cells | Day 21 | 
| Analyze markers of mTOR and IL-2 activity cells | Determine the frequency of CD4+, pS6+ [marker of mTOR activity] and CD4+, pSTAT5+ [marker of IL-2 activity] cells | Day 100 | 
| To determine the cumulative incidences of acute GVHD | Assessment of aGVHD | Day 100 | 
| To determine the cumulative incidences of chronic GVHD | Assessment of cGVHD | 12 months | 
| Compare Graft-Versus-Host Disease-Free (GRFS) to the standard PTCY plus tacrolimus/mycophenolate mofetil regimen from MT2015-29 | GRFS defined as grade III-IV acute GVHD, chronic GVHD requiring immunosuppression, relapse, or death by 1 year | 12 months | 
| Compare duration of initial transplant hospitalization to patients age 18+ who received treatment on MT2015-29 | Comparison hospitalization days with another trial's data (MT2015-29) | 12 months | 
| To measure Quality of life | Use quality of life questionnaire to measure patients' quality of life. | Through day 100 | 
| To analyze the frequency of CMV reactivation and disease |  | Through day 180 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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VIC-1911, PTCy, Myeloablative, Allogeneic