Safety, PK, PD, Clinical Activity of KT-333 in Adult Patients With Refractory Lymphoma, Large Granular Lymphocytic Leukemia, Solid Tumors

This is an open-label Phase 1a (dose escalation)/1b (dose expansion) first-in-human study of KT-333 in adult patients. Patients with relapsed/refractory (R/R) lymphomas, LGL-L, T-PLL, and solid tumors will be enrolled in Phase 1a. Phase 1b will consist of separate cohorts of patients with R/R PTCL, CTCL, LGL-L, and solid tumors.

Inclusion criteria

• Phase 1a Only: Cytologically or pathologically confirmed Lymphomas (including Hodgkin's, B-cell, T-cell, Small Lymphocytic, or Natural-Killer (NK)-cell Lymphomas and LGL-L), T-PLL and solid tumors with the exception of chronic lymphocytic leukemia (CLL) Note: Patients with indolent non-Hodgkin's lymphoma (NHL) and small lymphocytic lymphoma (SLL) are only eligible if not require immediate cytoreductive therapy or if there are no available treatments with potential benefit.
• Phase 1b Only: Histologically or pathologically confirmed PTCL, CTCL, LGL-L [T-cell LGL-L or Chronic Lymphoproliferative Disorder of NK-cells (CLPD-NK)], or solid tumors.
• Fresh or archival formalin fixed paraffin embedded (FFPE) tumor tissue or 15 slides preferably collected within 6 months or 2 years prior to first dose of the study drug (for lymphoma and solid tumor patients respectively).
• Phase 1a only: Lymphoma and Solid Tumor: Relapsed and/or refractory disease to at least 2 prior systemic standard of care treatments or for whom standard therapies are not available.
• Phase 1a: LGL-L/T-PLL only: Relapsed and/or refractory disease to at least 1 prior systemic standard of care treatment or for whom standard therapies are not available.
• Phase 1b only: All disease types: Relapsed and/or refractory disease to at least 1 prior systemic standard of care treatments or for whom standard therapies are not available.
• LGL-L patients only (hematology specific criteria):

• One of the following:

• Severe neutropenia < 500/mm3, or,
• Symptomatic anemia and/or,
• Transfusion-dependent anemia.
• ANC ≥ 200/μL at Screening and C1D1 (pre dose)
• Platelet count ≥ 100,000/μL (assessed ≥ 7 days following last platelet transfusion in patients with thrombocytopenia requiring platelets).
• LGL-L Patients Only (baseline disease characteristics):

• CD3+CD8+ cell population >650/mm3;
• CD3+CD8+CD57+ population >500/mm3;
• Presence of a clonal T-cell receptor (within 1 month of diagnosis);
• Note: patients with T-LGLL may be included with PI approval even if CD3+CD8+ cell population is<650/mm3 or CD3+CD8+CD57+ population is <500/mm3, though +TCR is required;
• NK LGL is also permitted, provided there is a clonal NK-cell population noted with>500 cells/mm3
• PTCL and solid tumors Only: Measurable disease at Screening. Solid tumor patients with non-measurable disease are allowed in Phase1a
• T-PLL: Measurable disease per Lugano and/or atypical T lymphocytes quantifiable by flow cytometry or morphology in the peripheral blood or bone marrow.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at Screening and C1D1 (pre-dose).
• Adequate bone marrow function at Screening and C1D1 (pre-dose) for all patients except those with LGL-L Adequate liver/kidney organ function at Screening and C1D1 (pre-dose) for all patients.
• Women of childbearing potential (WOCBP) must agree to use highly effective contraceptive methods for the duration of study treatment and 6 months after the last dose of KT333.

Exclusion criteria

• Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth.

Note: Patients with solid tumors are eligible if their CNS metastases or cord compression have been treated (e.g., radiotherapy, stereotactic surgery) and they are clinically stable, off steroids for at least 4 weeks before first dose of study drug and have no evidence of progression at time of study enrollment.

Note: Patients with lymphomas are eligible if their CNS metastases or cord compression have been treated effectively (i.e. achieved CR) and there is no clinical or radiographic evidence of active lymphoma.

• Diagnosis of Chronic Lymphocytic Leukemia (CLL).
• History of or active concurrent malignancy other than lymphoma or solid tumors unless the patient has been disease-free for ≥ 2 years.
• Patient has not recovered from any clinically significant adverse events (AEs) of previous treatments to pretreatment baseline or Grade 1 prior to first dose of study drug.
• Ongoing unstable cardiovascular function.
• Autologous hematopoietic stem cell transplant less than 3 months prior to first dose of study drug.
• Prior allogenic hematopoietic or bone marrow transplant.