Study of TG-1801 in Subjects With B-Cell Lymphoma

Phase 1 first in human Study to Assess the Bispecific Antibody TG-1801 in Subjects with B-Cell Lymphoma

This is an open-label, multi-center, accelerated titration design study. Planned enrollment includes 1 subject at low dose levels. Subjects will receive weekly infusions of TG-1801 in a 4 week-cycles.

Eligibility Criteria:
Inclusion Criteria:

1. Histologically confirmed B-cell lymphoma, relapsed to or refractory after at least one prior standard therapy. For subjects with aggressive lymphoma: those who are non-candidates for high-dose therapy or autologous stem cell transplant. Refractory is defined as disease progression during or within 6 months of the most recent prior therapy, while relapsed is defined as disease progression greater than 6 months after the most recent prior therapy.
2. Measurable disease defined as at least 1 measurable disease lesion ≥ 1.5 cm in at least one diameter by CT/CT-PET or magnetic resonance imaging (MRI) in an area of no prior radiation therapy, or in an area that was previously irradiated that has documented progression.
3. Be able to provide a core or excisional lymph node biopsy for biomarker analysis from an archival or newly obtained biopsy at Screening.
4. Adequate organ function defined as:

   1. Absolute neutrophil count (ANC) \> 1,000/µL and platelet count \> 75,000/µL. Platelet requirements cannot be met by use of recent transfusion (within 30 days of study treatment initiation \[Cycle 1 Day 1\]). Growth factor support (e.g. G-CSF) is not allowed within 2 weeks prior to treatment initiation.
   2. Total bilirubin ≤ 1.5 times the ULN, or direct bilirubin ≤ ULN for subjects with total bilirubin \> 1.5 ULN.
   3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN if no liver involvement or ≤ 5 x the ULN if known liver involvement.
   4. Calculated creatinine (Cr) clearance (CL) \> 30 mL/min (as calculated by the Cockcroft-Gault or MDRD formula, 24-hour urine Cr CL also acceptable).
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
6. Male or female ≥ 18 years of age.
7. Female subjects who are not of child-bearing potential, and female subjects of child-bearing potential who have a negative serum pregnancy test within 3 days prior to Cycle 1, Day 1. Female subjects of child-bearing potential, and male partners must consent to use a medically acceptable method of contraception throughout the study period and for 4 months after the last administration of ublituximab and 30 days after last administration of TG-1801. Men of reproductive potential may not participate unless they agree to use medically acceptable contraception.
8. Willingness and ability to comply with trial and follow-up procedures and provide written informed consent.

Exclusion Criteria:

1. Prior therapy with any agent blocking the CD47/SIRPα pathway or any previous CD19 targeting therapy, including but not limited to: antibodies, fragments, bispecific bodies, or chimeric antigen receptor (CAR) T-cells.
2. Subjects receiving cancer therapy (i.e. chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization) or any investigational drug within 21 days of Day 1 of Cycle 1 (42 days for prior mitomycin C or a nitrosourea).

   a. Corticosteroid therapy started at least 7 days prior to Cycle 1 Day 1 (prednisone ≤ 10 mg daily or equivalent) is allowed as clinically warranted. Topical or inhaled corticosteroids are permitted.
3. Prior autologous stem cell transplant within 6 months. Prior allogeneic hematologic stem cell transplant within 1 year and excluded if there is active graft versus host disease.
4. Subjects who have not recovered (≤ Grade 1 or at baseline) from adverse events due to previous therapy, except for alopecia and Grade 2 neuropathy due to previous cancer therapy.

   Note: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets the inclusion requirements for laboratory parameters defined above.
5. Any severe or uncontrolled illness or other conditions that could affect their participation in the study including, but not limited to:

   1. Symptomatic, or history of documented congestive heart failure (NY Heart Association functional classification III-IV).
   2. Myocardial infarction within 6 months of enrollment.
   3. Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident, transient ischemic attack, angioplasty, cardiac/vascular stenting within 6 months of enrollment, angina not well controlled by medication.
   4. Ongoing or active infection, except localized fungal infection of skin or nails.
6. Known active Hepatitis B (e.g. HBsAg reactive), Hepatitis C (e.g. HCV RNA \[qualitative\] is detected), cytomegalovirus (CMV DNA by PCR), or known history of HIV.
7. Malignancy within 2 years of study enrollment except for adequately treated basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, superficial bladder cancer, or localized prostate cancer.
8. Known clinically active CNS involvement.
9. History of anaphylaxis or severe allergy to a monoclonal antibody; or known or suspected hypersensitivity to the excipients contained in the study drug formulation.
10. Lactating or pregnant.