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

Sponsor

Masonic Cancer Center, University of Minnesota (Other)

Overall Status

Recruiting

CT.gov ID

NCT05120570

Collaborator

(none)

Enrollment

Location

Arm

72.5

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Acute Leukemia Myelodysplastic Syndromes Myeloproliferative Neoplasm Lymphoma	Drug: VIC- 1911	Phase 1/Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

75 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Supportive Care

Official Title:

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

Actual Study Start Date :

Mar 17, 2022

Anticipated Primary Completion Date :

Mar 31, 2025

Anticipated Study Completion Date :

Mar 31, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PTCy/sirolimus plus VIC-1911 Patients enrolled and treated with PTCy/sirolimus plus VIC-1911	Drug: VIC- 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.

Arm

Intervention/Treatment

Experimental: PTCy/sirolimus plus VIC-1911

Patients enrolled and treated with PTCy/sirolimus plus VIC-1911

Drug: VIC- 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.

Outcome Measures

Primary Outcome Measures

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.
Confirm safety and obtain an estimate of long-term efficacy as measured by aGVHD assessed (Phase II) [Day 100]
Assessment for aGVHD
Relapsed assessment (Phase II) [12 months]
Assessment to determine if patient has relapse

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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