A Phase I/II GVHD Prevention Trial Combining Pacritinib With Sirolimus-Based Immune Suppression

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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A Phase I/II GVHD Prevention Trial Combining Pacritinib With Sirolimus-Based Immune Suppression

Conditions
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Graft Vs Host Disease, GVHD

Intervention / Treatment
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* Drug: Pacritinib
* Drug: Sirolimus
* Drug: Tacrolimus
* Procedure: Allogenic hematopoietic cell transplant (alloHCT)


Participation Criteria
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Eligibility Criteria
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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.

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: Prevention
Allocation: Non-Randomized
Intervention 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<br>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. | Drug: Pacritinib<br>* 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).<br>* Other names: tyrosine kinase inhibitor (TKI);Drug: Sirolimus<br>* 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.<br>* Other names: Rapamune;Drug: Tacrolimus<br>* 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.<br>* Other names: Prograf;Procedure: Allogenic hematopoietic cell transplant (alloHCT)<br>* Patients will undergo allogenic hematopoietic cell transplant (alloHCT) as a part of their standard of care treatment.<br>|
| Experimental: Phase 1, Level 2: Pacritinib with Sirolimus and Tacrolimus<br>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. | Drug: Pacritinib<br>* 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).<br>* Other names: tyrosine kinase inhibitor (TKI);Drug: Sirolimus<br>* 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.<br>* Other names: Rapamune;Drug: Tacrolimus<br>* 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.<br>* Other names: Prograf;Procedure: Allogenic hematopoietic cell transplant (alloHCT)<br>* Patients will undergo allogenic hematopoietic cell transplant (alloHCT) as a part of their standard of care treatment.<br>|
| Experimental: Phase 2: Pacritinib with Sirolimus and Tacrolimus<br>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. | Drug: Pacritinib<br>* 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).<br>* Other names: tyrosine kinase inhibitor (TKI);Drug: Sirolimus<br>* 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.<br>* Other names: Rapamune;Drug: Tacrolimus<br>* 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.<br>* Other names: Prograf;Procedure: Allogenic hematopoietic cell transplant (alloHCT)<br>* Patients will undergo allogenic hematopoietic cell transplant (alloHCT) as a part of their standard of care treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| STAT Activity | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Acute GVHD | 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. | up to 100 days |