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

Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05120570
• Other study ID #: 2021LS006
• Secondary ID: MT2021-01
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: March 17, 2022
• Est. completion date: March 31, 2028

Study information

• Verified date: April 2024
• Source: Masonic Cancer Center, University of Minnesota
• Contact: Cancer Center Clinical Trials Office
• Phone: 612 624 2620
• Email: ccinfo[@]umn.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 75
• Est. completion date: March 31, 2028
• Est. primary completion date: March 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Leukemia
• Lymphoma
• Myelodysplastic Syndromes
• Myeloproliferative Disorders
• Myeloproliferative Neoplasm

Intervention

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.

Locations

Country	Name	City	State
United States	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
Masonic Cancer Center, University of Minnesota

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	21 days post treatment
Primary	Confirm safety and obtain an estimate of long-term efficacy as measured by aGVHD assessed (Phase II)	Assessment for aGVHD	Day 100
Primary	Relapsed assessment (Phase II)	Assessment to determine if patient has relapse	12 months
Secondary	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)
Secondary	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
Secondary	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
Secondary	To determine the cumulative incidences of acute GVHD	Assessment of aGVHD	Day 100
Secondary	To determine the cumulative incidences of chronic GVHD	Assessment of cGVHD	12 months
Secondary	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
Secondary	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
Secondary	To measure Quality of life	Use quality of life questionnaire to measure patients' quality of life.	Through day 100
Secondary	To analyze the frequency of CMV reactivation and disease		Through day 180