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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02891603
Recruitment Status : Recruiting
First Posted : September 7, 2016
Last Update Posted : July 7, 2020
Sponsor:
Collaborator:
CTI BioPharma
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute

Tracking Information
First Submitted Date  ICMJE September 1, 2016
First Posted Date  ICMJE September 7, 2016
Last Update Posted Date July 7, 2020
Actual Study Start Date  ICMJE June 8, 2017
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 6, 2016)
STAT Activity [ Time Frame: up to 21 days ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 6, 2016)
Incidence of Acute GVHD [ Time Frame: up to 100 days ]
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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase I/II GVHD Prevention Trial Combining Pacritinib With Sirolimus-Based Immune Suppression
Official Title  ICMJE A Phase I/II GVHD Prevention Trial Combining Pacritinib With Sirolimus-Based Immune Suppression
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 single-arm, 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • Graft Vs Host Disease
  • GVHD
Intervention  ICMJE
  • Drug: Pacritinib
    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:
    • PAC
    • tyrosine kinase inhibitor (TKI)
  • Drug: Sirolimus
    In addition to the study drug, pacritinib, sirolimus and tacrolimus (SIR/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 SIR/TAC taper. SIR/TAC levels will be monitored according to program standard operating procedures. Dose modifications of SIR/TAC for concurrent use of CYP3A4 inhibitors or inducers will be based on program standard operating procedures.
    Other Name: Rapamune
  • Drug: Tacrolimus
    In addition to the study drug, pacritinib, sirolimus and tacrolimus (SIR/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 SIR/TAC taper. SIR/TAC levels will be monitored according to program standard operating procedures. Dose modifications of SIR/TAC for concurrent use of CYP3A4 inhibitors or inducers will be based on program standard operating procedures.
    Other Name: Prograf
Study Arms  ICMJE Experimental: Pacritinib with Sirolimus and Tacrolimus

Pacritinib added to standard treatment with Sirolimus and Tacrolimus (PAC/SIR/TAC).

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.

Interventions:
  • Drug: Pacritinib
  • Drug: Sirolimus
  • Drug: Tacrolimus
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 6, 2016)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Michelle Burton 813-745-1537 michelle.burton@moffitt.org
Contact: Joseph Pidala 813-745-2069 joseph.pidala@moffitt.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02891603
Other Study ID Numbers  ICMJE MCC-18783
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party H. Lee Moffitt Cancer Center and Research Institute
Study Sponsor  ICMJE H. Lee Moffitt Cancer Center and Research Institute
Collaborators  ICMJE CTI BioPharma
Investigators  ICMJE
Principal Investigator: Joseph Pidala, M.D. H. Lee Moffitt Cancer Center and Research Institute
PRS Account H. Lee Moffitt Cancer Center and Research Institute
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP