Clinical trial NCT05120570: PTCy + Sirolimus/VIC-1911 as GVHD Prophylaxis in Myeloablative PBSC Transplantation
Official title: PTCy + Sirolimus/VIC-1911 as GVHD Prophylaxis in Myeloablative PBSC Transplantation
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Acute Leukemia
Myelodysplastic Syndromes
Myeloproliferative Neoplasm
Lymphoma
Keywords: VIC-1911
PTCy
Myeloablative
Allogeneic
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
First posted: 2021-11-15
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: SUPPORTIVE_CARE

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.

Eligibility criteria: 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

Primary outcomes:
measure: Determine the optimal dose of VIC-1911 when given in combination with standard immunosuppressive therapy in adult patients undergoing myeloablative stem cell transplantation.
timeFrame: 21 days post treatment
measure: Confirm safety and obtain an estimate of long-term efficacy as measured by aGVHD assessed (Phase II)
timeFrame: Day 100
measure: Relapsed assessment (Phase II)
timeFrame: 12 months
Secondary outcomes:
measure: Analyze markers of mTOR and IL-2 activity cells
timeFrame: Pre-condition, before Day 1 (Day 0)
measure: Analyze markers of mTOR and IL-2 activity cells
timeFrame: Day 21
measure: Analyze markers of mTOR and IL-2 activity cells
timeFrame: Day 100
measure: To determine the cumulative incidences of acute GVHD
timeFrame: Day 100
measure: To determine the cumulative incidences of chronic GVHD
timeFrame: 12 months
measure: Compare Graft-Versus-Host Disease-Free (GRFS) to the standard PTCY plus tacrolimus/mycophenolate mofetil regimen from MT2015-29
timeFrame: 12 months
measure: Compare duration of initial transplant hospitalization to patients age 18+ who received treatment on MT2015-29
timeFrame: 12 months
measure: To measure Quality of life
timeFrame: Through day 100
measure: To analyze the frequency of CMV reactivation and disease
timeFrame: Through day 180
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center at University of Minnesota
state: Minnesota
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Sherman Holtan, MD
role: PRINCIPAL_INVESTIGATOR
References: