Pacritinib for the Treatment of Relapsed or Refractory T-Cell Lymphomas

Inclusion Criteria

• Written informed consent and Health Insurance Portability and Accountability Act (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
• Age >= 18 years at the time of consent
• Eastern Cooperative Oncology Group (ECOG) Performance Status of =< 2
• A histologically confirmed diagnosis, per the 2016 World Health Organization (WHO) classification, of any PTCL subtype or CTCL (mycosis fungoides and Sezary syndrome) is included in this study
• Subjects must have relapsed or refractory disease (after ≥ 1 line of prior therapy). 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) * NOTE: Subjects with relapsed or refractory ALCL (ALK+ or ALK-) must have received prior brentuximab vedotin
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times upper limit of normal (ULN) or =< 5 x ULN in the presence of known hepatic involvement * Patients satisfying diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH), who are otherwise eligible, remain eligible irrespective of ECOG performance status, AST/ALT, hemoglobin, and absolute neutrophil count (ANC), eligibility criteria, if poor performance status, elevated AST/ALT, anemia, and neutropenia, are, in the opinion of the principal investigator (PI)/co-investigator (Co-I), secondary to HLH, and the patient otherwise satisfies HLH-specific eligibility criteria
• Total bilirubin =< 3.0 times ULN (=< 5.0 times ULN if disease involvement or Gilbert's disease)
• Creatinine clearance (CrCl) >= 30mL/min utilizing the Cockcroft-Gault formula
• Hemoglobin ≥ 8 g/dL (without erythropoietin or transfusion support within past 2 weeks) * Patients satisfying diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH), who are otherwise eligible, remain eligible irrespective of ECOG performance status, AST/ALT, hemoglobin, and ANC, eligibility criteria, if poor performance status, elevated AST/ALT, anemia, and neutropenia, are, in the opinion of the PI/Co-I, secondary to HLH, and the patient otherwise satisfies HLH-specific eligibility criteria
• ANC >= 1,000 cells/uL (or >= 750 cells/uL if bone marrow involvement) * Patients satisfying diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH), who are otherwise eligible, remain eligible irrespective of ECOG performance status, AST/ALT, hemoglobin, and ANC, eligibility criteria, if poor performance status, elevated AST/ALT, anemia, and neutropenia, are, in the opinion of the PI/Co-I, secondary to HLH, and the patient otherwise satisfies HLH-specific eligibility criteria
• Platelets >= 100,000 (or >= 75,000 in the setting of bone marrow involvement) cells/uL * Patients satisfying diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH), who are otherwise eligible, remain eligible irrespective of ECOG performance status, AST/ALT, hemoglobin, and ANC, eligibility criteria, if poor performance status, elevated AST/ALT, anemia, and neutropenia, are, in the opinion of the PI/Co-I, secondary to HLH, and the patient otherwise satisfies HLH-specific eligibility criteria
• Q-T interval Bazett-correct interval =< 0.48 sec
• International normalized ratio (INR) =< 1.5
• Patients with T-cell lymphoma-associated HLH must meet the diagnostic criteria for HLH, including at least 5 of the following: * Fever * Splenomegaly * Cytopenias involving at least 2 cell lines ** Hemoglobin < 9 g/dL ** Platelets < 100,000/uL ** Absolute neutrophil count < 1000/uL * Hypertriglyceridemia or hypofibrinogenemia * Tissue demonstration of hemophagocytosis * Low or absent NK cell activity * Serum ferritin >= 3000 ug/L * Soluble IL-2 receptor (CD25) > 2400 U/mL NOTE: Subjects with T-cell lymphoma-associated HLH are eligible independent of any prior HLH-directed therapies received, so long as they have relapsed/refractory PTCL (after >= 1 line of prior PTCL-directed therapy). Patients with relapsed or refractory ALCL (ALK+ or ALK-) must have received prior brentuximab vedotin
• 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 cycle 2 day 1 (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
• Human immunodeficiency virus (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
• 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
• Ability to take oral medication without crushing, dissolving or chewing tablets
• In the investigator’s opinion, the patient requires treatment
• In the investigator’s opinion, has an anticipated life expectancy of at least 3 months
• In the investigator’s opinion, 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

Exclusion Criteria

• 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
• Pregnant or breast-feeding women. NOTE: women may not breast feed or store breast milk during treatment and for 3 months after pacritinib discontinuation
• 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. Women of childbearing potential should be cautioned that hormonal contraceptives alone are not considered highly effective methods of contraception. One of the following alternative contraceptives are recommended: (1) Contraceptives not affected by inducers and inhibitors of CYP3A4 metabolism (e.g., intrauterine devices) and (2) Additional nonhormonal contraception (e.g., condom, diaphragm with spermicidal gel or condoms with spermicide). Subjects should discuss the contraception options with their doctor
• Uncontrolled current illness, including, but not limited to the following: * Ongoing or active infections requiring intravenous antimicrobials. NOTE: subjects who complete IV antimicrobials 14 days prior to cycle 1 day 1 (C1D1) treatment are eligible * Symptomatic congestive heart failure (CHF) defined as New York Heart Association (NYHA) class II, III, or IV, or ejection fraction =< 45% * Angina pectoris within 6 months of study registration * Unstable cardiac arrhythmia within 6 months of study registration * History of myocardial infarction, stroke or intracranial hemorrhage within 6 months prior to registration * Moderate to severe hepatic impairment (Child-Pugh class B or C) * Psychiatric illness or social situations that would limit compliance with study requirements
• Recent (within 21 days of initiation of therapy) major surgery
• Less than 14 days have elapsed since last radiation therapy or chemotherapy treatment and the initiation of therapy (day 1), or patient has not recovered from clinically significant (> grade 2) 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
• Use of systemic steroids at a dose > 10 mg/day of prednisone. NOTE: subjects able to taper down to ≤ 10 mg of prednisone or equivalent within 7 days prior to C1D1 treatment are eligible.(Patients with T-cell lymphoma-associated HLH, if on steroids at the time of registration, may continue corticosteroids, albeit without dose escalation. Systemic steroids should be tapered as deemed clinically appropriate by the co-investigator [Co-I]/principal investigator [PI] after registration)
• Prior treatment with pacritinib
• Requires anti-platelet agents (other than aspirin [ASA] at doses of ≤ 100mg daily) * NOTE: Subjects on anticoagulation therapy are eligible
• History of significant bleeding (>= grade 2 by Common Terminology Criteria for Adverse Events [CTCAE]), bleeding diatheses, or bleeding complications within past 3 months
• Hypersensitivity or allergic reaction to compounds related to pacritinib
• Treatment with strong CYP3A4 inducers or strong CYP3A4 inhibitors, 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
• Uncontrolled diarrhea * NOTE: patients with chronic diarrhea that is well controlled with supportive care measure (e.g. anti-motility agents) are eligible
• Any gastrointestinal or metabolic condition that in the opinion of the investigator could interfere with the absorption of an oral medication
• Prior allogeneic stem-cell transplant