This phase I/II trial tests the safety, side effects, and effectiveness of tovorafenib in combination with rituximab in patients with classical hairy cell leukemia (cHCL) that has come back after a period of improvement (recurrent) or that has not responded to previous treatment (refractory) and compares the effect of tovorafenib and rituximab to current standard treatment of cladribine and rituximab in cHCL patients that have not yet received treatment. Tovorafenib blocks certain proteins made by the mutated BRAF gene, which may help keep cancer cells from growing. It is a type of kinase inhibitor. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Cladribine damages the cell's deoxyribonucleic acid and may kill cancer cells. It is a type of antimetabolite. Giving tovorafenib in combination with rituximab may be safe and tolerable and more effective than cladribine with rituximab in treating patients with untreated, recurrent or refractory cHCL.
Patients must have histologically or cytologically confirmed diagnosis of classical hairy cell leukemia (HCL), including demonstration of BRAF V600E mutation by immunohistochemistry, molecular diagnostic testing, or polymerase chain reaction (PCR)
PHASE 1 ONLY: Prior therapy with at least one purine nucleoside analog-containing regimen (fludarabine, pentostatin, or cladribine) unless contraindicated. Prior vemurafenib alone is allowed in the relapsed/refractory cohort
PHASE 2 ONLY: No prior HCL-directed treatment for front-line cohort. The design of this cohort is such that the patients will need to be treatment naïve
Age ≥ 18 years. Because no dosing or adverse event (AE) data are currently available on the use of tovorafenib (DAY101) or cladribine in combination with rituximab in patients < 18 years of age, children are excluded from this study
Central nervous system (CNS) involvement with HCL is very rare, and therefore the biology of the disease in patients with CNS involvement may not be representative of the disease under study as a whole. Patients with treated brain metastases are eligible if follow-up brain imaging after CNS-directed therapy shows no evidence of progression
Patients with HCL who are BRAF V600E mutation negative and those with the variant HCL
Patients with platelets < 50,000/mCL
Patients on warfarin and direct oral anticoagulants (due to risk of bleeding)
Parallel
Biospecimen Collection
Procedure/SurgeryUndergo blood sample and buccal swab collection
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrow biopsy and aspiration
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow biopsy and aspiration
Cladribine
DrugGiven IV
Computed Tomography
Procedure/SurgeryUndergo CT
Rituximab
Biological/VaccineGiven IV
Tovorafenib
DrugGiven PO
Incidence of adverse events (Phase 1)
Adverse events (AEs) will be documented and summarized by type, grade, severity, and attribution using the Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 criteria for non-hematologic toxicities and table of criteria for hematologic toxicities. In addition, the number of treatment cycles received and reasons for going off treatment will be summarized to assess treatment tolerability. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
Minimal residual disease negative complete remission (MRD [-] CR) rate (Phase 2)
Will be calculated as the proportion of patients who achieve MRD (-) CR to therapy divided by the total number of patients for each treatment arm. All randomized patients or evaluable patients will be included in calculating the rate of MRD (-) CR for the study along with corresponding 95% binomial confidence intervals (CIs) (assuming that the number of patients who respond is binomially distributed). The MRD (-) CR rate will be compared between the untreated classical hairy cell leukemia (cHCL) patients with tovorafenib plus rituximab treatment and the patients with cladribine plus rituximab using the chi-square test or Fisher's exact test.
MRD (-) CR rate (Phase 1)
Will be calculated along with corresponding 95% binomial CIs (assuming that the number of patients who respond is binomially distributed).
Overall response rate (ORR) (Phase 1)
Will be calculated along with corresponding 95% binomial CIs (assuming that the number of patients who respond is binomially distributed). For the phase 2 portion, the ORR will be compared between the untreated cHCL patients with tovorafenib plus rituximab treatment and the patients with cladribine plus rituximab using the chi-square test or Fisher's exact test.
Progression-free survival (Phase 1)
Will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.
Overall survival (Phase 1)
Will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.
Mitogen-activated protein kinase activation status (Phase 1)
Graphical analyses will be largely used to assess potential patterns and relationships. All continuous measurements will be summarized using mean with standard deviations or median with range at each time point. Changes in these measurements from baseline to after treatment or baseline to progression will be assessed using paired t-tests or corresponding bob-parametric tests. The changes will also be compared between the treatment groups using two sample t-tests or Wilcoxon tests.
Changes in T and natural killer cell function (Phase 1)
Graphical analyses will be largely used to assess potential patterns and relationships. All continuous measurements will be summarized using mean with standard deviations or median with range at each time point. Changes in these measurements from baseline to after treatment or baseline to progression will be assessed using paired t-tests or corresponding bob-parametric tests. The changes will also be compared between the treatment groups using two sample t-tests or Wilcoxon tests.
Click on the lead sponsor to view all of their trials.
