Phase I/II Study of Pacritinib, A JAK2/IRAK1/CSF1R Inhibitor, in Refractory Chronic Graft-Versus-Host Disease (cGVHD) After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Phase I/II Study of Pacritinib, A JAK2/IRAK1/CSF1R Inhibitor, in Refractory Chronic Graft-Versus-Host Disease (cGVHD) After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Background:

Chronic graft-versus-host disease (cGVHD) is an immune system disorder that can occur in people who have had a stem cell transplant. cGVHD can affect multiple organs and increase risk of disability and death. New treatments are needed to treat cGVHD after stem cell transplant.

Objective:

To test a drug (pacritinib) in people with moderate or severe cGVHD that has not responded to previous treatment.

Eligibility:

People aged 18 years and older with moderate or severe cGVHD that has not responded to 2 or more lines of previous treatment.

Design:

Participants will be screened. They will have blood and urine tests. They will have tests of their heart and lung function. They may also have a CT scan. Some may have other specialized tests.

Participants will take the study drug at home every day. Pacritinib is a capsule taken by mouth. The study doctor will determine the dosage and schedule.

Participants will keep a medication diary. They will record the date and time of each drug dose and any missed doses.

Participants will visit the clinic every 2 weeks for the first 4 months. Then they will visit the clinic once every 4 weeks. They will have blood and urine tests. During some visits, other screening tests will be repeated, and participants will fill out questionnaires about their quality of life. Photographs may be taken of skin rashes and joints affected by cGVHD.

Participants will give saliva samples. Optional biopsies may be taken of the skin and mouth.

Participants will take pacritinib for 6 to 12 months if no side effects develop. Follow-up visits will continue for up to 2 years.

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Background:

• Chronic GVHD (cGVHD) is a multi-organ disorder characterized by immune dysregulation, impaired organ function, and decreased survival for hematopoietic stem cell transplantation (HSCT) patients.
• The JAK-STAT pathway plays an important role in immune cell development and function, including antigen presenting cells, B- and T-cells, and its activation leads to a cascade promoting a proinflammatory cytokine milieu.
• Pacritinib is a JAK2/IRAK1/CSF1R/FLT3 inhibitor, with an established safety and efficacy profile in the treatment of myeloproliferative neoplasms (myelofibrosis) and of acute GVHD.
• Pacritinib s immunomodulatory effects suggest therapeutic benefit for cGVHD, without abrogating the graft-versus-leukemia effect after HSCT.

Objectives:

• Phase I: to determine the safety of pacritinib in participants with refractory cGVHD
• Phase II: to determine the efficacy of pacritinib in participants with refractory cGVHD

Eligibility:

• Moderate or severe cGVHD (after allogeneic hematopoietic stem cell transplantation) diagnosed and staged per NIH criteria.
• cGVHD that did not respond to at least two prior lines of systemic therapy.
• Age >=18 years.
• If participant is taking systemic therapy for cGVHD at the time of enrollment, they must be on stable or tapering doses in the preceding 4 weeks.
• Participants must have adequate organ and marrow function.

Design:

• This Phase I/II study will use a modified 3+3 dose-escalation design, with two planned dose levels of pacritinib, followed by a small efficacy evaluation in a randomized phase II design.
• Pacritinib will be given taken orally once or twice daily (based on dose level) on days 1- 28 of a 28-day cycle.
• Pacritinib treatment will continue for up to 24 months. cGVHD response will be evaluated at 6 weeks, and 3, 6, 9 and 12 months from the start of pacritinib. If patient continues treatment beyond 12 months, cGVHD will be evaluated at 15, 18, 21 and 24 months (off treatment timepoint) from the start of pacritinib. All participants will be followed through 3 years post-initiation of pacritinib.
• The accrual ceiling is set at 50 participants.

-INCLUSION CRITERIA:

1. Moderate or severe cGVHD (after allogeneic hematopoietic stem cell transplantation) diagnosed and staged per NIH criteria

2. cGVHD that did not respond to >=2 lines of prior systemic therapy.

   Disease that has failed prior systemic therapy will be defined as follows:

   a) For prior corticosteroid-containing regimens, disease that:

   i) recurs after achievement of a CR, or

   ii) progresses after achievement of a PR, or

   iii) progresses after at least 1 week of prednisone equivalent of 1 mg/kg/day, or

   iv) is stable and persistent after at least 4 weeks of a prednisone equivalent of 0.5 mg/kg/day

   OR,

   b) For other systemic therapies, disease that:

   i) recurs after achievement of CR, or

   ii) progresses after achievement of a PR, or

   iii) is stable and persistent despite 4 weeks of therapeutic dosing of systemic therapy

3. Karnofsky performance score >=60%

4. Age >=18 years.

5. If participant is taking systemic therapy for cGVHD at the time of enrollment, they must be on a stable or tapering dose in the preceding 4 weeks.

6. Participants must have adequate organ and marrow function as defined below:

   • absolute neutrophil count >=1,000/mcL
   • platelets >=50,000/mcL
   • total bilirubin <=1.5 X institutional upper limit of normal

   OR

   <=3 X institutional upper limit of normal in participants with Gilbert's syndrome

   • AST(SGOT)/ALT(SGPT) <=3 X institutional upper limit of normal
   • eGFR >= 35 mL/min per CKD-EPI 2021

7. Primary malignancy for which the participant received transplant has been in complete clinical remission and stable for 3 months prior to enrollment on study.

8. Individuals of child-bearing potential (IOCBP) and individuals able to father a child with a partner able to become pregnant who are sexually active must agree to use one (1) highly effective (e.g., intrauterine system containing levonorgestrel intrauterine devices, surgical) or two (2) effective forms of contraception (e.g., barrier method) at study entry, for the duration of study treatment, and for at least 30 days after last study drug exposure.

9. Ability of participant to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

1. Acute GVHD that is active as defined by exhibiting current signs or symptoms of disease without any chronic GVHD (classic and late-acute GVHD per NIH consensus criteria); participants with a clinical presentation consistent with overlapping acute GVHD with concurrent chronic GVHD will be eligible

2. Treatment with ruxolitinib within 24 hours, or ibrutinib within the <=14 days prior to treatment initiation.

3. Active HIV-1 (detectable HIV viral load), or Hepatitis B (HBV) and/or Hepatitis C (HCV) infection (positive HBV or HCV viral load in the setting of positive HBV core antibody or surface antibody or HCV antibody).

4. Participants with the following cardiac conditions at screening:

   • symptomatic congestive heart failure
   • unstable angina pectoris
   • uncontrolled cardiac dysrhythmias
   • QTc(F) prolongation >450 ms or other factors that increase the risk for QT prolongation (i.e., heart failure, or a history of long QT interval syndrome).

5. Left ventricular ejection fraction <= 50% by transthoracic echocardiogram (TTE) at screening.

6. Participants with poor pulmonary function as defined by a forced expiratory volume in the first second (FEV1) <= 39% calculated using the USA-ITS-NIH equation.

7. Participants with evidence of ongoing hemorrhage, active signs/symptoms of bleeding, or history of severe bleeding complications in the one year prior to enrollment.

8. Concurrent treatment with any other investigational agents.

9. Concurrent use of strong CYP3A4 inducers or inhibitors, must stop 2 weeks prior study drug initiation.

10. Known hypersensitivity to JAK inhibitors.

11. Participants who are unwilling to accept blood transfusions.

12. Pregnancy or breastfeeding.

13. Participants with any active, uncontrolled viral, bacterial, or fungal infection are excluded.

14. Other malignancy except non-melanoma skin cancer or carcinoma in situ of the cervix or breast which requires active treatment.

15. Uncontrolled intercurrent illness evaluated by history, physical exam and chemistries or situation that would limit compliance with study requirements.