Pemigatinib in Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphomas

Inclusion Criteria:

• Subjects aged ≥ 18 years.

• ECOG Performance Status ≤ 2.

• Histologically confirmed MCL or MZL, including EMZL/MALT lymphoma, SMZL, and NMZL.

--Patients with gastric MALT lymphoma and those who are H. Pylori positive need tohave failed a trial of H. Pylori eradication and are either ineligible, haverefused, or have failed gastric radiation therapy.

• Have received at least two prior lines of systemic therapy and do not have FDAapproved available therapies or have refused them.

• Prior autologous hematopoietic cell transplantation (auto-HCT) and CAR-T celltherapy are eligible.

• Patients with prior auto-HCT may be eligible if treatment completed after atleast 3 months prior to first treatment

• Patients with CAR T-cell therapy may be eligible if treatment completed afterat 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 atleast one lesion >1.5 cm in size or assessable disease in the opinion of theinvestigator.

• Life expectancy >3 months, in the opinion of the investigator.

• Adequate organ function as defined as:

• Hematologic:

• Absolute neutrophil count (ANC) ≥ 1000/mm3 (≥1.0 x 10^9/L) independent ofG-CSF support (i.e., no G-CSF within the past 3 days), unless there isdocumented bone marrow involvement or splenomegaly with ensuing cytopeniain which case ANC of 750 cells/mm3 (0.75 x 10^9/L) is permissible. Also,there should be no evidence of myelodysplasia or hypoplastic bone marrow.

• Platelet count ≥ 75,000/mm3 (≥75 x 10^9/L) independent of transfusionsupport (i.e., no transfusion within the past 3 days) unless there isdocumented bone marrow involvement in which case platelet count of 50,000cells/mm3 (0.5 x 10^9/L) is permissible. Patients must be responsive totransfusion support if given for thrombocytopenia and patients refractoryto transfusion support are not eligible. Also, there should be no evidenceof myelodysplasia or hypoplastic bone marrow.

• Hemoglobin ≥ 8 g/dL independent of transfusion support (i.e., notransfusion within the past 3 days) unless there is documented bone marrowinvolvement or splenomegaly with ensuing cytopenia in which casehemoglobin of 7 g/dL is permissible. Patients must be responsive totransfusion support if given for anemia and patients refractory totransfusion support are not eligible. Also, there should be no evidence ofmyelodysplasia or hypoplastic bone marrow.

• Hepatic:

• Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN). or <2.5x ULN with document liver involvement and/ or Gilbert's disease

• AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN ----Subjects with liverinvolvement will be allowed to enroll with AST and ALT levels ≤ 5 x ULN.

• Renal: ----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 monthswithout an alternative medical cause. The following age-specific requirements apply:

• Women < 50 years of age: ---Amenorrheic for ≥ 12 months following cessation of exogenous hormonaltreatments; and ---Luteinizing hormone and follicle-stimulating hormone levels in thepost-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 exogenoushormonal 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, bilateralsalpingectomy, or hysterectomy).

• Female subjects of childbearing potential and male subjects with a sexual partner ofchildbearing potential must agree to use a highly effective method of contraceptionas described in Section 5.3.1.

• Ability to swallow oral tablets.

• Recovery to baseline or ≤ Grade 2 CTCAE v5 from toxicities related to any priortreatments, unless AE(s) are clinically nonsignificant and/or stable on supportivetherapy per the treating investigator.

• Patients or their legal representatives must be able to read, understand, andprovide informed consent to participate in the trial.

Exclusion Criteria:

• Prior receipt of FGFR inhibitor.

• Clinically significant active malabsorption syndrome or other condition likely toaffect gastrointestinal (GI) absorption of the study drug.

• Concurrent anticancer therapy except as listed in section 6.7.2 for prostate andbreast cancer.

• Prior systemic anti-cancer therapy or any investigational therapy within thetimeframes listed below:

• Cytotoxic chemotherapy within 4 weeks prior to treatment.

• Monoclonal antibody within 3 weeks prior to treatment

• BTK inhibitor within 2 weeks prior to treatment. ---Note: The wash out intervalis based on the last day of the prior therapy to the start of the study drug (C1D1).

• Prior radiotherapy within 4 weeks prior to the first dose of study treatment.

--Note: Subjects must have recovered from all radiation-related toxicities, notrequire corticosteroids, and not have radiation pneumonitis. A 2-week washout ispermitted for palliative radiation to non-CNS disease.

• Major surgery 4 weeks prior to starting study drug or who have not fully recoveredfrom major surgery.

• Active second malignancy which is expected to impact study participation, in theopinion of the investigator.

• Known CNS involvement.

• Current evidence of uncontrolled, significant intercurrent illness including, butnot limited to, the following conditions:

--Cardiovascular disorders:

• Congestive heart failure New York Heart Association Class III or IV or seriouscardiac arrhythmias.

• Unstable angina pectoris or acute coronary syndrome within the past 2 monthsprior to study enrolment

• History of myocardial infarction (MI) within 3 months prior to enrollment.

• QTcF prolongation defined as a QTcF > 470 ms

• Correction of suspected drug induced QTcF prolongation can be attempted atthe investigator's discretion and only if clinically safe to do so witheither discontinuation of the offending drug or switch to another drug notknown 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 offainting or clinically relevant arrhythmias while using the pacemaker.

• Left ventricular ejection fraction < 40% in the 12 months prior to studyenrollment

• Any other condition that would, in the Investigator's judgment,contraindicate the subject's participation in the clinical study due tosafety concerns or compliance with clinical study procedures (e.g.,infection/inflammation, intestinal obstruction, unable to swallowmedication, [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 hepatitisC.

--Note: Subjects with a past or resolved HBV infection (defined as the presence ofhepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjectspositive for hepatitis C (HCV) antibody are eligible only if polymerase chainreaction is negative for HCV RNA. Subjects with SMZL who have chronic HCV will needto have undergone antiviral treatment to participate.

• History and/or current evidence of ectopic mineralization/calcification, includingbut not limited to soft tissue, kidneys, intestine, myocardia, or lung, exceptingcalcified lymph nodes and asymptomatic arterial or cartilage/tendon calcification.

• Current evidence of clinically significant corneal or retinal disorder confirmed byophthalmologic 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 Dfood supplements are allowed.

• Current evidence of clinically significant corneal (including but not limited tobullous/band keratopathy, corneal abrasion, inflammation/ulceration, andkeratoconjunctivitis) or retinal disorder (including but not limited tomacular/retinal degeneration, diabetic retinopathy, and retinal detachment) asconfirmed by ophthalmologic examination.

• Medical, psychiatric, cognitive, or other conditions that may compromise thesubject'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 componentin its formulations (NCI CTCAE v5.0 Grade ≥ 3).

• Subjects taking prohibited medications as described in Section 6.7.4. A washoutperiod of prohibited medications for a period of at least five half-lives or asclinically indicated should occur before the start of treatment.