- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02891603
A Phase I/II GVHD Prevention Trial Combining Pacritinib With Sirolimus-Based Immune Suppression
The purpose of this study is to examine a new approach to preventing a serious problem after transplant called graft vs. host disease (abbreviated as GVHD).
This is a 3 arm sequential phase I/II, study of Pacritinib with Sirolimus and Tacrolimus (PAC/SIR/TAC) for the prevention of acute GVHD after matched related and unrelated allogeneic hematopoietic cell transplantation (alloHCT).
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
GVHD is a common problem that occurs after transplant despite the use of standard immune suppressive medications (these are called sirolimus and tacrolimus). GVHD can result in skin rash, nausea, vomiting, diarrhea, and liver damage. Severe GVHD can be life-threatening.
In this study, investigators will add a medication called pacritinib to the combination of sirolimus and tacrolimus to see if this approach can more effectively prevent GVHD. Pacritinib is a medicine used to treat a disease of the bone marrow called myelofibrosis Pacritinib turns off a switch in cells called Janus Kinase 2 (JAK2). Pacritinib is an investigational medicine used in several clinical trials and not FDA approved. JAK2 is an important regulator of inflammation. This inflammation is thought to contribute to GVHD. Pacritinib is able to turn this inflammation off by inhibiting JAK2. Research has shown that blocking JAK2 prevents GVHD in mice and also reduces severe GVHD in transplant patients. Doctors at Moffitt have identified that inflammation from JAK2 is an important cause of GVHD, and is present well before patients develop GVHD symptoms. This trial will study how well pacritinib turns off inflammation during the transplant and if it prevents GVHD when added to our standard medicines.
Pacritinib will begin the day of the participant's transplant (Day 0) and will continue until 70 days after the transplant.
Sirolimus will be given the day before transplant and continued daily for at least one year.
Tacrolimus will begin 3 days before transplant and will be given for at least 50 days.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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Florida
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Tampa, Florida, United States, 33612
- H. Lee Moffitt Cancer Center and Research Institute
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Minnesota
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Minneapolis, Minnesota, United States, 55455
- University of Minnesota
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Must have an available 8/8 HLA-A, -B, -C, and -DRB1 matched-related or unrelated donor allogeneic hematopoietic peripheral blood stem cell graft.
- Signed informed consent.
- Acute myeloid leukemia, myelodysplasia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, myeloproliferative neoplasms, Hodgkin lymphoma, or non-Hodgkin lymphoma requiring a matched allogeneic hematopoietic stem cell transplantation (HSCT). Acute Leukemia (AML or ALL) must be in complete remission defined as: <5% marrow blasts with no morphologic evidence of leukemia, no peripheral blasts, marrow >20% cellular, and peripheral absolute neutrophil count >1000/uL (platelet recovery is not required). Myelodysplasia (MDS) and chronic myeloid leukemia (CML): Must have <5% marrow blasts. Myeloproliferative neoplasms (MPN): Must have <5% peripheral / marrow blasts. Note: Prior use of a JAK2 inhibitor is allowed up to 4 weeks before day 0 of alloHCT. Hodgkin and non-Hodgkin lymphoma: Must have chemosensitive disease.
- Adequate vital organ function.
- Performance status: Karnofsky Performance Status Score ≥ 80%.
Donor Eligibility:
- Eligible donors will include healthy sibling, relative or unrelated donors that are matched with the patient at HLA-A, B, C, and DRB1 by high resolution typing as defined by the Collaborative Trials Network.
Exclusion Criteria:
- Active infection not controlled with appropriate antimicrobial therapy.
- History of HIV, hepatitis B, or active hepatitis C infection.
- Anti-thymocyte globulin, alemtuzumab, bortezomib, or post-transplant cyclophosphamide as part of GVHD prophylaxis.
- Sorror's co-morbidity factors with total score >4.
- Any patient anticipating or scheduled to receive a tyrosine kinase inhibitor, FLT3 inhibitor, or JAK2 inhibitor (outside of this study) post-HCT.
- QTc>450ms per Fridericia's correction.
- Thrombin time (TT), prothrombin time (PT), or partial thromboplastin time (PTT) >2x upper limit of normal (ULN).
- Grade 3 or higher recent (within the past 6 months) or ongoing non-QTc cardiac adverse events/comorbidities.
- Grade 3 or higher recent or ongoing cardiac dysrhythmias, family history of long QT.
syndrome, or serum potassium <3.0 mEq/L that is persistent and refractory to correction.
- Grade 3 or higher recent or ongoing bleeding events.
- Symptomatic or uncontrolled cardiovascular disease, myocardial infarction or severe/unstable angina within the past 6 months, or New York Heart Association (NYHA) Class III or IV congestive heart failure.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Non-Randomized
- Interventional Model: Sequential Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Phase 1, Level 1: Pacritinib with Sirolimus and Tacrolimus
After standard of care allogenic hematopoietic cell transplantation, Pacritinib will be added to standard treatment with Sirolimus and Tacrolimus (PAC/SIR/TAC). 100 mg Pacritinib will begin taken by mouth the day of the participant's transplant (Day 0) and will continue until 70 days after the transplant.. Sirolimus will be given the day before transplant and continued daily for at least one year. Tacrolimus will begin 3 days before transplant and will be given for at least 50 days. |
Pacritinib Dose and Schedule: 200 mg twice a day (BID) orally from day 0 until day +100.
PAC will be tapered to 50% of the total dose at day +70, then 25% of total dose at day +84, then stop at day +100 (+/- 7 days).
Other Names:
Sirolimus (SIR) will be administered and dosed according to Moffitt Cancer Center, Department of Blood and Marrow Transplantation standard practice.
Attending physician discretion is permitted with regard to timing, rapidity, and completion of SIR taper.
SIR levels will be monitored according to program standard operating procedures.
Dose modifications of SIR for concurrent use of CYP3A4 inhibitors or inducers will be based on program standard operating procedures.
Other Names:
Tacrolimus (TAC) will be administered and dosed according to Moffitt Cancer Center, Department of Blood and Marrow Transplantation standard practice.
Attending physician discretion is permitted with regard to timing, rapidity, and completion of TAC taper.
TAC levels will be monitored according to program standard operating procedures.
Dose modifications of TAC for concurrent use of CYP3A4 inhibitors or inducers will be based on program standard operating procedures.
Other Names:
Patients will undergo allogenic hematopoietic cell transplant (alloHCT) as a part of their standard of care treatment.
|
Experimental: Phase 1, Level 2: Pacritinib with Sirolimus and Tacrolimus
After standard of care allogenic hematopoietic cell transplantation, Pacritinib will be added to standard treatment with Sirolimus and Tacrolimus (PAC/SIR/TAC). 100 mg Pacritinib will begin taken by mouth twice daily starting the day of the participant's transplant (Day 0) and continuing until 70 days after the transplant.. Sirolimus will be given the day before transplant and continued daily for at least one year. Tacrolimus will begin 3 days before transplant and will be given for at least 50 days. |
Pacritinib Dose and Schedule: 200 mg twice a day (BID) orally from day 0 until day +100.
PAC will be tapered to 50% of the total dose at day +70, then 25% of total dose at day +84, then stop at day +100 (+/- 7 days).
Other Names:
Sirolimus (SIR) will be administered and dosed according to Moffitt Cancer Center, Department of Blood and Marrow Transplantation standard practice.
Attending physician discretion is permitted with regard to timing, rapidity, and completion of SIR taper.
SIR levels will be monitored according to program standard operating procedures.
Dose modifications of SIR for concurrent use of CYP3A4 inhibitors or inducers will be based on program standard operating procedures.
Other Names:
Tacrolimus (TAC) will be administered and dosed according to Moffitt Cancer Center, Department of Blood and Marrow Transplantation standard practice.
Attending physician discretion is permitted with regard to timing, rapidity, and completion of TAC taper.
TAC levels will be monitored according to program standard operating procedures.
Dose modifications of TAC for concurrent use of CYP3A4 inhibitors or inducers will be based on program standard operating procedures.
Other Names:
Patients will undergo allogenic hematopoietic cell transplant (alloHCT) as a part of their standard of care treatment.
|
Experimental: Phase 2: Pacritinib with Sirolimus and Tacrolimus
After standard of care allogenic hematopoietic cell transplantation, Pacritinib will be added to standard treatment with Sirolimus and Tacrolimus (PAC/SIR/TAC). Patients will take Pacritinib at the MTD: 100 mg Pacritinib will begin taken by mouth twice daily starting the day of the participant's transplant (Day 0) and continuing until 70 days after the transplant.. Sirolimus will be given the day before transplant and continued daily for at least one year. Tacrolimus will begin 3 days before transplant and will be given for at least 50 days. |
Pacritinib Dose and Schedule: 200 mg twice a day (BID) orally from day 0 until day +100.
PAC will be tapered to 50% of the total dose at day +70, then 25% of total dose at day +84, then stop at day +100 (+/- 7 days).
Other Names:
Sirolimus (SIR) will be administered and dosed according to Moffitt Cancer Center, Department of Blood and Marrow Transplantation standard practice.
Attending physician discretion is permitted with regard to timing, rapidity, and completion of SIR taper.
SIR levels will be monitored according to program standard operating procedures.
Dose modifications of SIR for concurrent use of CYP3A4 inhibitors or inducers will be based on program standard operating procedures.
Other Names:
Tacrolimus (TAC) will be administered and dosed according to Moffitt Cancer Center, Department of Blood and Marrow Transplantation standard practice.
Attending physician discretion is permitted with regard to timing, rapidity, and completion of TAC taper.
TAC levels will be monitored according to program standard operating procedures.
Dose modifications of TAC for concurrent use of CYP3A4 inhibitors or inducers will be based on program standard operating procedures.
Other Names:
Patients will undergo allogenic hematopoietic cell transplant (alloHCT) as a part of their standard of care treatment.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
STAT Activity
Time Frame: up to 21 days
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STAT3 activity in circulating CD4+ T-cells. This is equivalent to 5.5 tablespoons of blood for each assessment. Peripheral blood mononuclear cells (PBMC) will be isolated by Ficoll density gradient. PBMCs will be stimulated with IL-6 for 20 minutes to activate STAT3. Phosphoproteins will be analyzed within T-cells by flow cytometry. Result reported is %pSTAT3+CD4+T cells at day +21. |
up to 21 days
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of Acute GVHD
Time Frame: up to 100 days
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Cumulative incidence of acute GVHD .
Participants will be monitored for clinical signs of acute GVHD.
Acute GVHD will be graded per the 1995 consensus guidelines.
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up to 100 days
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Collaborators and Investigators
Investigators
- Principal Investigator: Joseph Pidala, M.D., H. Lee Moffitt Cancer Center and Research Institute
Publications and helpful links
General Publications
- Pidala J, Walton K, Elmariah H, Kim J, Mishra A, Bejanyan N, Nishihori T, Khimani F, Perez L, Faramand RG, Davila ML, Nieder ML, Sagatys EM, Holtan SG, Lawrence NJ, Lawrence HR, Blazar BR, Anasetti C, Sebti SM, Betts BC. Pacritinib Combined with Sirolimus and Low-Dose Tacrolimus for GVHD Prevention after Allogeneic Hematopoietic Cell Transplantation: Preclinical and Phase I Trial Results. Clin Cancer Res. 2021 May 15;27(10):2712-2722. doi: 10.1158/1078-0432.CCR-20-4725. Epub 2021 Mar 22.
- Betts BC, Bastian D, Iamsawat S, Nguyen H, Heinrichs JL, Wu Y, Daenthanasanmak A, Veerapathran A, O'Mahony A, Walton K, Reff J, Horna P, Sagatys EM, Lee MC, Singer J, Chang YJ, Liu C, Pidala J, Anasetti C, Yu XZ. Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation. Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):1582-1587. doi: 10.1073/pnas.1712452115. Epub 2018 Jan 30.
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Immune System Diseases
- Graft vs Host Disease
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Enzyme Inhibitors
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Anti-Bacterial Agents
- Protein Kinase Inhibitors
- Antibiotics, Antineoplastic
- Antifungal Agents
- Calcineurin Inhibitors
- Tacrolimus
- Sirolimus
- Tyrosine Kinase Inhibitors
Other Study ID Numbers
- MCC-18783
- 5R01HL133823-02 (U.S. NIH Grant/Contract)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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