First-line therapy with Loncastuximab Tesirine and Rituximab for PTLD after transplant

Inclusion Criteria:

* Subject aged ≥ 18 years.
* Histologically confirmed B-cell PTLD (monomorphic and polymorphic) following solid organ transplantation; with or without EBV association.

  --Note: Subjects with classic Hodgkin-like PTLD are excluded.
* Measurable disease as defined by the 2014 Lugano Classification as assessed by positron-emission tomography (PET)- computed tomography (CT) or by CT or magnetic resonance imaging (MRI) if the tumor is not fluorodeoxyglucose (FDG)-avid on screening
* ECOG Performance Status ≤ 2.
* Adequate organ function as defined as:

  * Hematologic:

    * Absolute neutrophil count (ANC) ≥ 1000/mm3
    * Platelet count ≥ 75,000/mm3
    * Hemoglobin ≥ 8 g/dL
  * Hepatic:

    * Bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN with document liver involvement and/ or Gilbert's disease
    * Transaminases (AST or ALT) ≤ 3 x ULN or ≤ 5 x ULN with documented liver involvement
  * Renal:

    * Estimated creatinine clearance ≥ 60 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 or having undergone surgical sterilization (bilateral oophorectomy or hysterectomy). 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 and the lactation requirements as described in Sections 5.4.1 and 5.4.2.
* Subjects or their legal representatives must be able to read, understand, and provide informed consent to participate in the trial.
* Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol

Exclusion Criteria:

* PTLD following liquid transplantation
* CNS involvement
* Prior treatment for PTLD with the exception of radiation, antivirals, steroids and reduced immunosuppression
* Human immunodeficiency virus (HIV) infection
* Major surgery within 4 weeks prior to enrolment
* History of bleeding diathesis (e.g., von Willebrand's disease), hemophilia, or active bleeding.
* Subjects with chronic liver disease with hepatic impairment Child-Pugh class C
* Pregnant or lactating or intending to become pregnant during the study
* Active autoimmune disease which, in the opinion of the investigator, may negatively impact subject safety or interfere with study participation.
* The diagnosis of another malignancy which, in the opinion of the investigator, is likely to negatively impact subject safety or interfere with study participation.
* Significant medical diseases or conditions including those requiring substantial changes in concomitant medications, as assessed by the investigator, that would substantially increase the risk-to-benefit ratio of participating in the study. This includes, but is not limited to the following conditions:

  * Cardiovascular disorders:

    * Congestive heart failure New York Heart Association Class III or IV, unstable angina pectoris, serious cardiac arrhythmias.
    * Myocardial infarction (MI) within 6 months before the first dose.
    * QTc prolongation defined as a QTcF \> 480 ms.
    * Congenital long QT syndrome or a corrected QT measure (QTc) interval of \>480 ms at screening (unless secondary to pacemaker or bundle branch block).
    * Grade 2 or higher edema (peripheral, pleural or ascites)
    * Grade 1 or higher pericardial effusion
  * Severe pulmonary disease
  * Uncontrolled diabetes mellitus
  * Severely immunocompromised state
  * 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.
* Active systemic bacterial, viral, fungal, or other infection requiring systemic treatment at time of screening
* Subjects with evidence of active hepatitis B infection, based on positive surface antigen or Hepatitis B DNA PCR are excluded. Subjects who are Hepatitis B core antibody positive must take prophylaxis with entecavir or equivalent and be willing to undergo monthly Hepatitis B DNA PCR testing
* Active hepatitis C infection
* Grade 2 or higher rash
* Clinically significant fluid accumulation in the third space
* Subjects taking prohibited medications as described in Section 6.8.1. 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.