A Dose-Ranging Study of IV BNZ-1 in LGL Leukemia or Refractory CTCL

This study is an open-label, multi-center, dose-ranging study to characterize the safety, tolerability, preliminary efficacy, and PK/PD of up to four dose levels of BNZ-1 administered weekly by IV infusion to adults diagnosed with LGL or CTCL. The study has 5 periods:

* Screening Period
* 4-week Treatment Period
* 3-month Treatment Extension Period
* Long-term Extension Period (open-ended)
* 6-week Follow-up Period Subjects will be screened for eligibility within 30 days of study Day 1 (first dosing day of the 4-Week Treatment Period).

• BNZ132-1-40 (Drug), also known as BNZ-1: Injectable PEGylated peptide antagonist that binds to the common gamma chain (γc) signaling receptor for the cytokines interleukin (IL)-2, IL-9, and IL-15

Primary outcomes

• Incidence, severity and relationship of treatment-emergent adverse events [1 month]
• Incidence, severity and relationship of treatment-emergent adverse events [4 months]

Secondary outcomes

• Pharmacodynamics [16 weeks]: Flow cytometry: Change from baseline over time for Tregs, NK cells and CD8+ central memory T-cells
• Single-dose and steady-state Cmax [16 weeks]: Plasma levels of BNZ-1 will be measured after the 1st and last doses
• Single-dose and steady-state AUC [16 weeks]: Plasma levels of BNZ-1 will be measured after the 1st and last doses
• Steady-state Elimination half-life (t1/2) [16 weeks]: Plasma levels of BNZ-1 will be measured after the last dose

Other outcomes

• Exploratory assessment of changes from baseline in CTCL disease severity (mSWAT) [16 weeks]: mSWAT
• Exploratory assessment of Complete Response in LGL [16 weeks]: Normalization of CBC and LGL count
• Exploratory assessment of Partial Response in LGL [16 weeks]: ANC: >50% improvement from baseline and >500 cells/uL; or >50% reduction in transfusion requirements

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Willing and able to consent and participate in the study.
* Agrees not to receive any other investigational product or therapy while participating in this study.
* Must be:

  * Currently using two forms of effective birth control (one of which is a barrier method) for the duration of the study for both males and females of childbearing potential. Effective methods of birth control include hormonal contraception (i.e., birth control pills, injected hormones, vaginal ring), intrauterine device, or barrier methods with spermicide (i.e., diaphragm with spermicide, condom with spermicide), or
  * Surgically sterile (i.e., hysterectomy, tubal ligation, vasectomy).
* Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2.
* Life expectancy >1 year.

LGL-Specific:

* Phenotypic studies (obtained within 8 weeks prior to study drug administration) from peripheral blood showing CD3+, CD57+ cells >400/mm³ or CD8+ cells >650/mm³.

  * Note: Complete blood count (CBC) and differential should be reported for the phenotyped sample.
* Evidence for clonal T-cell receptor gene rearrangement (obtained within 1 year prior to study drug administration).

CTCL-Specific:

* Histopathologically confirmed mycosis fungoides or Sézary syndrome (CTCL stage IIB or greater according to the European Organization for Research and Treatment of Cancer/International Society for Cutaneous Lymphomas \[EORTC-ISCL\] consensus classification) at study entry with progressive, persistent, or recurrent disease who have no available remaining standard therapeutic options (i.e., Refractory) as determined by the Investigator.

Exclusion Criteria:

* Clinically relevant hepatic, neurological, pulmonary, ophthalmological, endocrine, renal, or other major systemic disease making implementation of the protocol or interpretation of the study results difficult, or that would put the subject at risk by participating in the study in the opinion of the Investigator.
* History of or currently active primary or secondary immunodeficiency.
* Known active bacterial, viral, fungal, mycobacterial infection, or other infection (including tuberculosis \[TB\] or atypical mycobacterial disease \[but excluding fungal infection of nail beds, minor upper respiratory tract infection, and minor skin conditions\]), or any major episode of infection that required hospitalization or treatment with IV antibiotics within 30 days of study drug administration or oral antibiotics within 14 days prior to study drug administration.
* Received other investigational products or therapy in the 60 days prior to study drug administration.

• Results publication: Brammer JE, Ballen K, Sokol L, Querfeld C, Nakamura R, Mishra A, McLaughlin EM, Feith D, Azimi N, Waldmann TA, Tagaya Y, Loughran T. Effective treatment with the selective cytokine inhibitor BNZ-1 reveals the cytokine dependency of T-LGL leukemia. Blood. 2023 Oct 12;142(15):1271-1280. doi: 10.1182/blood.2022017643. PMID 37352612

• Jonathan Brammer, MD, PhD, Principal investigator, Ohio State University