Pemigatinib for the Treatment of Patients with Relapsed or Refractory B-cell Non-Hodgkin Lymphomas

Inclusion Criteria

• Subjects aged >= 18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status =< 2
• Histologically confirmed MCL or MZL, including extranodal MZL (EMZL)/mucosa-associated lymphoid tissue (MALT) lymphoma, splenic MZL (SMZL), and nodal MZL (NMZL) * Patients with gastric MALT lymphoma and those who are Helicobacter (H.) Pylori positive need to have failed a trial of H. Pylori eradication and are either ineligible, have refused, or have failed gastric radiation therapy
• Have received at least two prior lines of systemic therapy and do not have Food and Drug Administration (FDA) approved available therapies or have refused them
• Prior autologous hematopoietic cell transplantation (auto-HCT) and chimeric antigen receptor (CAR)-T cell therapy are eligible * Patients with prior auto-HCT may be eligible if treatment completed after at least 3 months prior to first treatment * Patients with CAR T-cell therapy may be eligible if treatment completed after at least 1 month prior to first treatment
• Subject must have an indication for systemic treatment
• Radiographically measurable disease by computed tomography (CT) scan, defined as at least one lesion > 1.5 cm in size or assessable disease in the opinion of the investigator
• Life expectancy >3 months, in the opinion of the investigator
• Absolute neutrophil count (ANC) >= 1000/mm^3 (>= 1.0 x 10^9/L) independent of granulocyte colony-stimulating factor (G-CSF) support (i.e., no G-CSF within the past 3 days), unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case ANC of 750 cells/mm^3 (0.75 x 10^9/L) is permissible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow
• Platelet count >= 75,000/mm^3 (>=75 x 10^9/L) independent of transfusion support (i.e., no transfusion within the past 3 days) unless there is documented bone marrow involvement in which case platelet count of 50,000 cells/mm^3 (0.5 x 10^9/L) is permissible. Patients must be responsive to transfusion support if given for thrombocytopenia and patients refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow
• Hemoglobin 8 >= g/dL independent of transfusion support (i.e., no transfusion within the past 3 days) unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case hemoglobin of 7 g/dL is permissible. Patients must be responsive to transfusion support if given for anemia and patients refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow
• Total bilirubin =< 1.5x institutional upper limit of normal (ULN) or <2.5 x ULN with document liver involvement and/ or Gilbert’s disease
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 × institutional ULN * Subjects with liver involvement will be allowed to enroll with AST and ALT levels =< 5 x ULN
• Estimated creatinine clearance >= 30 mL/min by Cockcroft-Gault formula
• For female subjects: Negative pregnancy test or evidence of post-menopausal status. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * Women < 50 years of age: ** Amenorrheic for >= 12 months following cessation of exogenous hormonal treatments; and ** Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution; or ** Underwent surgical sterilization (bilateral oophorectomy or hysterectomy) * Women >= 50 years of age: ** Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or ** Had radiation-induced menopause with last menses > 1 year ago; or ** Had chemotherapy-induced menopause with last menses > 1 year ago; or ** Underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy)
• Female subjects of childbearing potential and male subjects with a sexual partner of childbearing potential must agree to use a highly effective method of contraception. Acceptable highly effective contraceptive methods include: * Bilateral tubal occlusion * Vasectomized partner * Intra-uterine devise (IUD) or hormone-releasing system (IUS) * Any hormonal (estrogen combined with progesterone or progesterone alone) contraception associated with inhibition of ovulation: implanted, oral, intravaginal, transdermal, or injectable * Spermicide with a compatible barrier method (i.e. diaphragm, sponge, or male or female condoms) * Abstinence from heterosexual intercourse
• Ability to swallow oral tablets
• Recovery to baseline or =< Grade 2 Common Terminology Criteria for Adverse Events (CTCAE) (v)5 from toxicities related to any prior treatments, unless adverse events (AE[s]) are clinically nonsignificant and/or stable on supportive therapy per the treating investigator
• Patients or their legal representatives must be able to read, understand, and provide informed consent to participate in the trial

Exclusion Criteria

• Prior receipt of FGFR inhibitor
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug
• Concurrent anticancer therapy except including, but not limited to: * Hematopoietic growth factors to treat neutropenia, anemia, or thrombocytopenia in accordance with American Society for Clinical Oncology (ASCO) or European Society for Medical Oncology (ESMO) guidelines * Red blood cell and platelet transfusions * Anti-emetic, analgesic, and antidiarrheal medications * Electrolyte repletion (e.g., calcium and magnesium) to correct low electrolyte levels * Glucocorticoid use on study (less than 20 mg per day prednisone or equivalent) are allowed preferably for a duration of approximately 14 days or less unless there is a compelling clinical rationale for a higher dose or longer duration articulated by the investigator and approved by the sponsor. Anticipated uses include short courses to treat conditions such as asthma or chronic obstructive pulmonary disease * Thyroid replacement therapy for hypothyroidism * Continuation of medications that the patient has been on for the previous 28 days is allowed, provided they are not on the list of prohibited concomitant medications. Such therapy may include hormonal therapy for patients with prior: ** Prostate cancer (e.g., gonadotropin-releasing hormone [GnRH] or luteinizing hormone-releasing hormone [LHRH] agonists), or ** Breast cancer (e.g., GnRH/LHRH agonists, aromatase inhibitors, selective estrogen receptor modulators, or degraders) * Vaccines that do not contain live virus are allowed and all data/information relevant to the vaccines will be collected ** Note: If prohibited concomitant medications are required to treat an acute adverse event (e.g., monoclonal antibodies for acute COVID infection), they may be utilized as necessary and deemed clinically appropriate. However, the required medications should not be given in the context of enrollment into a concurrent clinical trial and should be recorded as a concomitant medication as required by protocol
• Prior systemic anti-cancer therapy or any investigational therapy within the timeframes listed below: * Cytotoxic chemotherapy within 4 weeks prior to treatment * Monoclonal antibody within 3 weeks prior to treatment * Bruton tyrosine kinase (BTK) inhibitor within 2 weeks prior to treatment ** Note: The wash out interval is based on the last day of the prior therapy to the start of the study drug (cycle 1 day 1 [C1D1])
• Prior radiotherapy within 4 weeks prior to the first dose of study treatment * Note: Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have radiation pneumonitis. A 2-week washout is permitted for palliative radiation to non-central nervous system (CNS) disease
• Major surgery 4 weeks prior to starting study drug or who have not fully recovered from major surgery
• Active second malignancy which is expected to impact study participation, in the opinion of the investigator
• Known CNS involvement
• Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions: * Cardiovascular disorders: ** Congestive heart failure New York Heart Association Class III or IV or serious cardiac arrhythmias ** Unstable angina pectoris or acute coronary syndrome within the past 2 months prior to study enrollment ** History of myocardial infarction (MI) within 3 months prior to enrollment ** Corrected QT interval by Fridericia's formula (QTcF) prolongation defined as a QTcF > 470 ms *** Correction of suspected drug induced QTcF prolongation can be attempted at the investigator’s discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation *** Correction for underlying bundle branch block (BBB) allowed *** Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker ** Left ventricular ejection fraction < 40% in the 12 months prior to study enrollment * Any other condition that would, in the Investigator’s judgment, contraindicate the subject’s participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, [subjects may not receive the drug through a feeding tube], etc.)
• Known HIV infection
• Active hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C * Note: Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA) * Subjects with SMZL who have chronic HCV will need to have undergone antiviral treatment to participate
• History and/or current evidence of ectopic mineralization/calcification, including but not limited to soft tissue, kidneys, intestine, myocardia, or lung, excepting calcified lymph nodes and asymptomatic arterial or cartilage/tendon calcification
• Current evidence of clinically significant corneal or retinal disorder confirmed by ophthalmologic examination
• Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14 days or 5 half-lives (whichever is longer) before the first dose of study drug. Moderate CYP3A4 inhibitors are not prohibited but should be avoided
• Subject with history of hypovitaminosis D requiring supraphysiologic dose (such as 50,000 IU of vitamin D3) to replenish the deficiency. Subjects receiving vitamin D food supplements are allowed
• Current evidence of clinically significant corneal (including but not limited to bullous/band keratopathy, corneal abrasion, inflammation/ulceration, and keratoconjunctivitis) or retinal disorder (including but not limited to macular/retinal degeneration, diabetic retinopathy, and retinal detachment) as confirmed by ophthalmologic examination
• Medical, psychiatric, cognitive, or other conditions that may compromise the subject's ability to understand the subject information, give informed consent, comply with the study protocol or complete the study
• Known prior severe hypersensitivity to investigational product (IP) or any component in its formulations (National Cancer Institute [NCI] CTCAE v5.0 Grade >= 3)
• Subjects taking prohibited medications. A washout period of prohibited medications for a period of at least five half-lives or as clinically indicated should occur before the start of treatment * The concomitant administration of potent CYP3A4 inhibitors and inducers and moderate CYP3A4 inducers is prohibited. Based on the low overall bioavailability of topical ketoconazole, there are no restrictions on topical ketoconazole. * Patients should not receive concomitant systemic anticancer agents, therapeutic monoclonal antibodies, drugs with immunosuppressant properties, or any other investigational agents except as required for an acute adverse event and only when deemed clinically necessary and safe * Live vaccines should not be administered while on study treatment or within 90 days after the last dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, H1N1 flu, rabies, bacillus Calmette-Guérin, and typhoid. COVID-19 and seasonal flu vaccines that do not contain live virus are permitted. * Additionally, patients should not take herbal medications while participating in this study * If a subject requires treatment with one or more of the listed prohibited medications, the subject may need to be taken off study therapy. Each case will be considered and if possible, the investigator should discuss with the Data Safety Monitoring Committee (DSMC) and Medical Monitor prior to initiating prohibited therapy