UB-VV400 in Combination With Rapamycin in Relapsed or Refractory B-cell Malignancies

Inclusion criteria

• Age ≥ 18 at time of consent.
• Provide voluntary written informed consent.
• Relapsed/refractory disease for subjects that are either CAR T-naive or CAR T-exposed.
• Measurable disease according to Lugano 2014 criteria.
• No serious concomitant diseases or active/uncontrolled infections.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Cardiac function: left ventricular ejection fraction (LVEF) ≥ 40%.
• Pulmonary function: pulse oximetry ≥ 90% on room air at rest.
• Renal function: serum creatinine ≤ 1.5 × age-adjusted upper limit of normal (ULN) or creatinine clearance ≥ 45 mL/min.
• Absolute lymphocyte count (ALC) ≥ 0.2×10^9/L.
• Alanine aminotransferase (ALT) ≤ 2.5 × ULN, aspartate aminotransferase (AST) ≤ 2.5 × ULN, AND total bilirubin < 1.5 × ULN.
• No ongoing coagulopathies requiring periodic replacement of clotting factors (eg, fresh frozen plasma, cryoprecipitate).
• Women of childbearing potential must:

• Have 2 negative pregnancy tests verified (one negative serum beta human chorionic gonadotropin [β-hCG] at screening and another within 48 hours prior to treatment withUB-VV400).
• Commit to "true abstinence" from heterosexual intercourse or agree to use and complywith highly effective, uninterrupted contraception for 12 months after administration of UB-VV400 .
• Abstain from breastfeeding for 12 months following administration of UB-VV400.
• Men with partners of childbearing potential must commit to "true abstinence" from heterosexual intercourse or agree to use a highly effective form of contraception duringheterosexual contact with a pregnant individual or any individual of childbearing potential for 12 months after administration of UB-VV400, regardless of past vasectomy.
• Subjects must agree not to donate blood, organs, sperm/semen, and/or egg cells for use for at least 1 year following treatment with UB-VV400 alone or in combination with rapamycin. Insufficient data are available to define a duration of time sufficient to make a recommendation on when it is safe to donate any tissue; therefore, subjects should not donate any tissue after administration of UB-VV400.

Exclusion criteria

• Women who are pregnant or breastfeeding.
• Subjects with current isolated central nervous system (CNS) tumor involvement.
• Subjects with a prior malignancy whose clinical course or management has the potential to interfere with the safety and/or efficacy evaluation of the clinical trial.
• Prior treatment with any of the following: allogeneic bone marrow transplantation, gene therapy, or adoptive cell transfer of any kind except for CAR T-cell therapy.
• Treatment with prior CD22-directed therapy except for UB-VV400.
• History of or active human immunodeficiency virus (HIV).
• Active hepatitis B (HepB) or hepatitis C (HepC).
• For subjects receiving rapamycin: a. History of angioedema; b. Pneumonitis (Grade 3 or greater).
• Ongoing Grade > 2 toxicities from the last line of anticancer therapy.
• Use of the following:

• Therapeutic systemic doses of corticosteroids (defined as > 20 mg prednisone equivalent) within 72 hours before dosing with UB-VV400.
• Approved targeted therapies:

i. Small molecules: within 3 half-lives before dosing with UB-VV400 (see package insert). ii. Antibodies: within 14 days before dosing with UB-VV400. iii. CAR T therapy: within 28 days before dosing with UB-VV400. c. Autologous stem cell transplant within 28 days before dosing with UB-VV400. d. Cytotoxic chemotherapy (eg, alkylators, anthracyclines) within 14 days before dosing with UB-VV400.

e. Any experimental agent (ie, not approved for disease/indication or with accepted consensus guidelines recommendation) within 4 weeks before dosing with UB-VV400 unless progression has been documented and a minimum of 3 half-lives has elapsed.

f. Any immune-suppressing agent within 28 days before dosing with UB-VV400 (eg, tacrolimus, mycophenolate mofetil, immunosuppressive antibodies such as anti-tumor necrosis factor [TNF]/IL-6).

g. Radiation within 4 weeks before dosing with UB-VV400 (palliative radiation to a symptomatic lesion[s] is allowed if at least one additional, non-irradiated, measurable lesion remains present to assess response).

h. Prophylactic treatment with short-acting oral antiretroviral medications within 7 days before UB-VV400 administration. Long-acting antiretroviral prophylaxis is not allowed within 2 years of UB-VV400 treatment.

• Allergies to rapamycin or supportive medications required for CAR T-cell toxicity management (eg, tocilizumab).
• Systemic autoimmune diseases or immunodeficiency diseases (except for well-controlled type I diabetes with hemoglobin A1C [HbA1c] less than 8% or well-controlled thyroid disease, as assessed by the treating physician).
• Ongoing CNS diseases (eg, seizure disorder, tremor, history of cerebral vascular accident [CVA]/recurrent transient ischemic attack [TIA]) that would preclude evaluation of immune effector cell-associated neurotoxicity syndrome (ICANS).
• Presence of uncontrolled angina or other acute uncontrolled heart disease. Myocardial infarction within the previous 6 months. New York Heart Association (NYHA) Class III or IV. History of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
• Actively receiving treatment in other interventional clinical trials. Note: continued follow-up on previous trials is allowed for survivorship, but no further investigational agents or assessments will be allowed.