NCT06965114 | RECRUITING | Hairy Cell Leukemia

Detailed Description:

PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of tovorafenib (DAY101) plus rituximab treatment in patients with relapsed or refractory classical hairy cell leukemia (cHCL). (Relapsed/Refractory Classical Hairy Cell Leukemia) II. To determine the minimal residual disease negative complete remission (MRD \[-\] CR) rate at completion of tovorafenib (DAY101) plus rituximab treatment versus cladribine plus rituximab for untreated cHCL. (Front-line Classical Hairy Cell Leukemia) SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. (Relapsed/Refractory Classical Hairy Cell Leukemia) II. To determine the overall response rate (ORR) and rate of minimal residual disease negative complete remission (MRD \[-\] CR) at completion of tovorafenib (DAY101) plus rituximab treatment for relapsed or refractory cHCL. (Relapsed/Refractory Classical Hairy Cell Leukemia) III. To determine the complete remission (CR) rate at completion of tovorafenib (DAY101) plus rituximab treatment in patients with relapsed or refractory cHCL. (Relapsed/Refractory Classical Hairy Cell Leukemia) IV. To estimate progression-free and overall survival after tovorafenib (DAY101) and rituximab treatment for patients with relapsed or refractory cHCL. (Relapsed/Refractory Classical Hairy Cell Leukemia) V. To determine the rate of durable CR after combination tovorafenib (DAY101) plus rituximab treatment, where durable CR is defined as achieving a CR and not experiencing relapse at 12 months after completing treatment. (Front-line Classical Hairy Cell Leukemia) VI. To determine the safety of the combination of tovorafenib (DAY101) plus rituximab. (Front-line Classical Hairy Cell Leukemia) VII. To determine the clonal evolution of cHCL at the time of relapse by whole exome sequencing (WES) and ribonucleic acid sequencing (RNAseq). (Front-line Classical Hairy Cell Leukemia) EXPLORATORY OBJECTIVES: I. To evaluate mitogen-activated protein kinase (MAPK) activation status pre- and post-treatment in peripheral blood circulating cells (multiple timepoints during cycle 1: pre-dose \[cycle (C) 1 day (D) 1\], at 24 \[C1D2\] and 72 \[C1D4\] hours after first dose of tovorafenib \[DAY101\] and pre-dose on C1D8) to demonstrate that the drug did what it is expected to do and to assess the kinetics of phosphorylated-extracellular signal-regulated kinase (pERK) clearance. (Front-line Classical Hairy Cell Leukemia) II. To describe changes in T- and natural killer (NK)-cell function prior to, after tovorafenib (DAY101) single agent treatment, and after tovorafenib (DAY101) plus rituximab combination treatment in patients with cHCL. (Front-line Classical Hairy Cell Leukemia) III. To identify mutations or changes in transcription profile through whole exome and RNA sequencing of leukemia cell samples at baseline and at time of relapse after combination treatment, which can be used to guide analysis in larger cohorts or with future functional studies to determine mechanisms of resistance (or sensitivity) to the therapy. (Front-line Classical Hairy Cell Leukemia) OUTLINE: PHASE 1: Patients receive tovorafenib orally (PO) once weekly (QW) for up to 16 weeks and rituximab intravenously (IV) QW on weeks 5-9 and 11, 13, and 15 in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, computed tomography (CT) as clinically indicated, and bone marrow biopsy and aspiration throughout the study. Additionally, patients undergo buccal swab collection pre-study. PHASE 2: Patients are randomized to 1 of 2 arms. ARM A: Patients receive cladribine IV over 2 hours on days 1-5 of cycle 1 and rituximab IV on days 1, 8, 15, and 22 of cycles 2 and 3. Cycles repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, CT as clinically indicated, and bone marrow biopsy and aspiration throughout the study. ARM B: Patients receive tovorafenib PO on days 1, 8, 15, and 22 of each cycle and rituximab IV on days 1, 8, 15, and 22 of cycle 2 and on days 1 and 15 of cycles 3 and 4. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, CT as clinically indicated, and bone marrow biopsy and aspiration throughout the study. After completion of study treatment, patients are followed up every 6 months.