Overview

The purpose of this study is to determine the correct dose and safety of combining two new cancer drugs, loncastuximab tesirine and venetoclax, as a treatment for relapsed or refractory B cell lymphoma.These drugs are used to treat some lymphomas, but have not yet been tested in combination for the treatment of lymphoma. The main goal of this study is to determine the safety of the combination.

Eligibility

Inclusion Criteria:

        -Participants must have histologic or cytologic diagnosis of non-Hodgkin lymphoma, with the
        exclusion of small lymphocytic lymphoma/chronic lymphocytic leukemia.
          -  Patients with mantle cell lymphoma are not eligible for the dose escalation part of
             the study. Inclusion of patients with mantle cell lymphoma to the dose expansion part
             of the study will be done after an amendment delineates a MCL - specific venetoclax
             ramp up and tumor lysis syndrome prophylaxis and monitoring regimen.
             -Participants must have received ≥2 prior systemic therapies for their lymphoma.
             -Participants must have measurable disease as defined by the 2014 Lugano
             Classification.
             -Participants must meet clinical indications for treatment.
             -ECOG performance status ≤ 2 (see Appendix I)
             -Adequate bone marrow function, defined by the following laboratory parameters
          -  Absolute neutrophil count of 1.0 x 109/L
          -  Platelet count of 75 x 109/L; platelet count of 50 - 75 x 109/L are permitted in
             participants with marrow involvement by the lymphoma. Platelets must not have received
             a platelet transfusion in 7 days.
             -Adequate organ function, defined by the following laboratory parameters
          -  Adequate hepatic function, with transaminases (alanine aminotransferase [ALT],
             aspartate aminotransferase [AST], and gamma glutammyltransferase [GGT]) ≤ 2.5 times
             the upper limit of normal;
          -  Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of
             non-hepatic origin)
          -  Serum creatinine ≤ 1.5 times the upper limit of normal. -For women of childbearing
             potential: agreement to remain abstinent (refrain from heterosexual intercourse) or
             use a contraceptive method with a failure rate of < 1% per year during the treatment
             period and for at least 30 days after the last dose of venetoclax and at least 9
             months after the last dose of loncastuximab tesirine for women.
          -  A woman is considered to be of childbearing potential if she is postmenarcheal, has
             not reached a postmenopausal state (< 12 continuous months of amenorrhea with no
             identified cause other than menopause), and has not undergone surgical sterilization
             (removal of ovaries and/or uterus).
        Examples of contraceptive methods with a failure rate of < 1% per year include bilateral
        tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation,
        hormone-releasing intrauterine devices, and copper intrauterine devices.
        The reliability of sexual abstinence should be evaluated in relation to the duration of the
        clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence
        (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not
        acceptable methods of contraception.
        -For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
        contraceptive measures, and agreement to refrain from donating sperm, as defined below:
        --With female partners of childbearing potential, men must remain abstinent or use a condom
        plus an additional contraceptive method that together result in a failure rate of < 1% per
        year during the treatment period and for at least 6 months after the last dose of
        loncastuximab. Men must refrain from donating sperm during this same period.
        With pregnant female partners, men must remain abstinent or use a condom during the
        treatment period and for at least 6 months after the last dose of loncastuximab to avoid
        exposing the embryo.
        The reliability of sexual abstinence should be evaluated in relation to the duration of the
        clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence
        (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not
        acceptable methods of contraception.
        Exclusion Criteria:
          -  Prior treatment toxicities not resolved to grade <2 according to NCI CTCAE 5.0 (with
             the exception of alopecia or grade 2 sensory peripheral neuropathy).
          -  Patients with spontaneous tumor lysis syndrome.
          -  Autologous stem cell transplant within 30 days of start of study drug (C1D1).
          -  Allogeneic stem cell transplant within 60 days of start of study drug (C1D1).
          -  Women who are pregnant or breastfeeding.
          -  Active graft versus host disease
          -  Active autoimmune disease
          -  Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV)
             virus. Note: Testing is not mandatory to be eligible.
          -  Malabsorption syndrome or other condition that precludes enteral route of
             administration.
          -  Known allergy to both xanthine oxidase inhibitors and rasburicase. Allergy to only one
             of these agents does not constitute an exclusion criterion.
          -  Use of strong CYP3A inhibitors or inducers.
             --All medications that fall in these categories should be discontinued 7 days prior to
             the first dose of study drug.
          -  Administration or consumption of any of the following within 3 days prior to the first
             dose of study drug:
               -  Grapefruit or grapefruit products
               -  Seville oranges (including marmalade containing Seville oranges)
               -  Star fruit
          -  Evidence of other clinically significant uncontrolled condition(s) including, but not
             limited to:
               -  Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
               -  Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note:
                  subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B
                  surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B
                  core (HBc) antibody negative) or positive anti-HBc antibody from intravenous
                  immunoglobulins (IVIG) may participate.
               -  Other uncontrolled conditions including uncontrolled cardiovascular disease or
                  arrythmia, decompensated diabetes or COPD.