The main purpose of this study is to determine the effectiveness of the study drug pacritinib in people with relapsed or refractory lymphoproliferative disorders.

Patients will receive single-agent treatment with pacritinib 200mg orally twice daily until any condition for treatment discontinuation has been met. Patients will be enrolled into one of four cohorts: Peripheral T-Cell Lymphoma, not otherwise specified (PTCL, NOS) (cohort 1); angioimmunoblastic T-cell lymphoma/follicular helper T-cell (AITL/TFH) PTCL (cohort 2); Cutaneous T-Cell Lymphoma (CTCL) - mycosis fungoides (MF) and Sezary syndrome (SS) (cohort 3); and other eligible, less common PTCL subtypes (cohort 4).

14NOV2025- Updates were made to the inclusion and exclusion criteria to align with the pacritinib IB v19 and the funders guidance.

Selected Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Subject must have the ability to understand and the willingness to sign a written informed consent.
2. ECOG performance status ≤ 2
3. A histologically confirmed diagnosis, per the WHO 2016 classification, of any PTCL or CTCL subtype listed in the protocol.
4. Relapsed or refractory disease. Refractory disease is defined as progression during treatment or recurrent/progressive disease within 6 months of completing a treatment regimen that achieved either stable disease or a PR/CR. Relapsed disease is defined as progression or recurrence at least 6 months after a prior documented response (PR or CR).
5. Adequate organ and hematopoietic function as defined in the protocol.
6. Sufficient archival tissue (15 unstained slides obtained within 90 days prior to registration) is required. If available, this tissue should be identified at screening and shipped prior to C2D1.If not available, a lymph node or tissue biopsy (core-needle or excisional) or skin biopsy (for CTCL) is required. The type of tissue obtained is at the discretion of the investigator based on disease. NOTE: If archival tissue is not available and a fresh biopsy is inaccessible or technically challenging (per site investigator discretion) at the site, the subject may be eligible for the study.
7. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Testing is based on known history and local policies.
8. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. Testing is based on known history and local policies.
9. Ability to take oral medication without crushing, dissolving or chewing tablets.
10. In the investigator's opinion, the patient requires treatment, has an anticipated life expectancy of at least 3 months, and the patient has the ability to communicate satisfactorily with the investigator and the study team, to participate fully in the study, and comply with all requirements.

Selected Exclusion Criteria:

1. History of, or a concurrent, clinically significant illness, medical condition or laboratory abnormality that, in the investigator's opinion, could affect the conduct of the study

2. Pregnant or breast feeding women. NOTE: women may not breast feed or store breast milk during treatment and for 3 months after pacritinib discontinuation.

3. Unwilling or unable to use a medically acceptable form of contraception during the time of participation in the trial (sexual abstinence is permissible) unless documented successful vasectomy, hysterectomy, bilateral oophorectomy or post-menopausal for at least 2 years. Women of childbearing potential must use highly effective methods of birth control from the time of informed consent, for the duration of pacritinib treatment and for 30 days after discontinuation of pacritinib. This timeframe also applies to breast-feeding and egg donation. Fertile males must use contraception from the time of study treatment initiation, for the duration of pacritinib treatment and for 30 days after discontinuation of pacritinib. This timeframe is also applicable to sperm donation. Participants should be informed of the risk of unintended pregnancy due to potential reduced effectiveness of hormonal contraceptives sensitive to CYP3A4 metabolism (i.e. progestin) during treatment with pacritinib.

4. Uncontrolled current illness, including, but not limited to the following:

   1. Ongoing or active infections requiring intravenous antimicrobials
   2. Symptomatic congestive heart failure (CHF) defined as NYHA class II, III or IV (Appendix II), or ejection fraction <45% in any patient.
   3. Unstable angina pectoris within 6 months of study enrollment
   4. Unstable cardiac arrhythmia
   5. History of myocardial infarction, stroke or intracranial hemorrhage within 6 months prior to enrollment
   6. Moderate to severe hepatic impairment (Child-Pugh class B or C).
   7. Psychiatric illness or social situations that would limit compliance with study requirements.

5. Recent (within 21 days of initiation of therapy, day 1) major surgery

6. Less than 14 days have elapsed since last radiation therapy or chemotherapy treatment or patient has not recovered from all clinically significant treatment related toxicity; less than 90 days have passed since date of autologous stem cell transplant and patient has not recovered to ≤grade 1 toxicity related to this procedure.

7. Use of systemic steroids at a dose equivalent to >10 mg/day of prednisone

8. Prior treatment with pacritinib

9. Requires use of a medication that increases the risk of bleeding, including anticoagulation or antiplatelet therapy with the exception of aspirin at doses of ≤ 100mg daily.

10. History of significant bleeding (≥ Grade 2 by CTCAE), bleeding diatheses, or bleeding complications within the past 3 months.

11. Hypersensitivity or allergic reaction to compounds related to pacritinib.

12. Treatment with strong CYP3A4 inducers or strong CYP3A4 inhibitors (See Appendix III), for which no alternative is available. Treatment with strong CYP3A4 inducers or strong CYP3A4 inhibitors requires a washout period of 2 weeks prior to initiation of therapy, Cycle 1 Day 1.

13. Uncontrolled diarrhea. NOTE: patients with chronic diarrhea that is well controlled with supportive care measure (e.g. anti-motility agents) are eligible

14. Any gastrointestinal or metabolic condition that in the opinion of the investigator could interfere with the absorption of an oral medication.

15. Prior allogeneic stem-cell transplant.