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

Primary Purpose

Graft Vs Host Disease, GVHD

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Pacritinib

Sirolimus

Tacrolimus

Allogenic hematopoietic cell transplant (alloHCT)

About this trial

This is an interventional prevention trial for Graft Vs Host Disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

H. Lee Moffitt Cancer Center and Research Institute
University of Minnesota

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Phase 1, Level 1: Pacritinib with Sirolimus and Tacrolimus

Phase 1, Level 2: Pacritinib with Sirolimus and Tacrolimus

Phase 2: Pacritinib with Sirolimus and Tacrolimus

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Full Information

NCT ID

NCT02891603

First Posted

September 1, 2016

Last Updated

October 24, 2023

Sponsor

H. Lee Moffitt Cancer Center and Research Institute

Collaborators

CTI BioPharma, National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT02891603

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Completed

Study Start Date

June 8, 2017 (Actual)

Primary Completion Date

January 28, 2022 (Actual)

Study Completion Date

April 18, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

H. Lee Moffitt Cancer Center and Research Institute

Collaborators

CTI BioPharma, National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Graft Vs Host Disease, GVHD

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

40 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Phase 1, Level 1: Pacritinib with Sirolimus and Tacrolimus

Arm Type

Experimental

Arm Description

Arm Title

Phase 1, Level 2: Pacritinib with Sirolimus and Tacrolimus

Arm Type

Experimental

Arm Description

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.

Arm Title

Phase 2: Pacritinib with Sirolimus and Tacrolimus

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Pacritinib

Other Intervention Name(s)

PAC, tyrosine kinase inhibitor (TKI)

Intervention Description

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).

Intervention Type

Drug

Intervention Name(s)

Sirolimus

Other Intervention Name(s)

Rapamune

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Tacrolimus

Other Intervention Name(s)

Prograf

Intervention Description

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.

Intervention Type

Procedure

Intervention Name(s)

Allogenic hematopoietic cell transplant (alloHCT)

Intervention Description

Patients will undergo allogenic hematopoietic cell transplant (alloHCT) as a part of their standard of care treatment.

Primary Outcome Measure Information:

Title

STAT Activity

Description

Time Frame

up to 21 days

Secondary Outcome Measure Information:

Title

Incidence of Acute GVHD

Description

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.

Time Frame

up to 100 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Joseph Pidala, M.D.

Organizational Affiliation

H. Lee Moffitt Cancer Center and Research Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

H. Lee Moffitt Cancer Center and Research Institute

City

Tampa

State/Province

Florida

ZIP/Postal Code

33612

Country

United States

Facility Name

University of Minnesota

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55455

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

33753457

Citation

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.

Results Reference

derived

PubMed Identifier

29382747

Citation

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.

Results Reference

derived

Links:

URL

https://moffitt.org/clinical-trials-research/

Description

Moffitt Cancer Center Clinical Trials website

Learn more about this trial

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

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