Testing the Combination of Anti-cancer Drugs, Tovorafenib Plus Rituximab, in Patients With Hairy Cell Leukemia

NCT06965114 | Recruiting Phase 1 FDA Drug

• 3 other identifiers: NCI-2025-0328110664UM1CA186712
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Refractory Hairy Cell Leukemia; Recurrent Hairy Cell Leukemia; Hairy Cell Leukemia

Outcome Measures

Primary Outcomes (2)

• 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.

  During cycles 1-3 (cycle length = 28 days)

• 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.

  At completion of tovorafenib plus rituximab treatment versus cladribine plus rituximab

Secondary Outcomes (7)

• MRD (-) CR rate (Phase 1)

  At completion of tovorafenib plus rituximab

• Overall response rate (ORR) (Phase 1)

  At completion of tovorafenib plus rituximab

• Progression-free survival (Phase 1)

  From initiation of therapy to documented progression or death without progression, assessed up to 10 years

• Overall survival (Phase 1)

  From initiation of therapy to death from any cause, assessed up to 10 years

• Incidence of AEs (Phase 2)

  From first dose of study treatment up to 30 days after the last dose of study medication, or until the start of subsequent antineoplastic therapy, whichever occurs first

Other Outcomes (2)

• Mitogen-activated protein kinase activation status (Phase 1)

  During cycle 1 (cycle length = 28 days)

• Changes in T and natural killer cell function (Phase 1)

  Prior to and after tovorafenib and after tovorafenib plus rituximab, assessed up to 10 years

Study Arms (3)

Phase 1 (tovorafenib, rituximab)

EXPERIMENTAL

Patients receive tovorafenib PO QW for up to 16 weeks and rituximab 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, CT as clinically indicated, and bone marrow biopsy and aspiration throughout the study. Additionally, patients undergo buccal swab collection pre-study.

Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Biological: Rituximab; Drug: Tovorafenib

Phase 2 Arm A (cladribine, rituximab)

ACTIVE COMPARATOR

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.

Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Drug: Cladribine; Procedure: Computed Tomography; Biological: Rituximab

Phase 2 Arm B (tovorafenib, rituximab)

EXPERIMENTAL

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.

Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Biological: Rituximab; Drug: Tovorafenib

Interventions

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow biopsy and aspiration

Phase 1 (tovorafenib, rituximab); Phase 2 Arm A (cladribine, rituximab); Phase 2 Arm B (tovorafenib, rituximab)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow biopsy and aspiration

Also known as: Biopsy of Bone Marrow, Biopsy, Bone Marrow

Phase 1 (tovorafenib, rituximab); Phase 2 Arm A (cladribine, rituximab); Phase 2 Arm B (tovorafenib, rituximab)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Phase 1 (tovorafenib, rituximab); Phase 2 Arm A (cladribine, rituximab); Phase 2 Arm B (tovorafenib, rituximab)

Rituximab BIOLOGICAL

Given IV

Also known as: ABP 798, ABP-798, ABP798, BI 695500, BI-695500, BI695500, Blitzima, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT P10, CT-P10, CTP10, GP 2013, GP-2013, GP2013, IDEC 102, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, IDEC102, Ikgdar, Mabtas, MabThera, Monoclonal Antibody IDEC-C2B8, PF 05280586, PF-05280586, PF05280586, Riabni, Ritemvia, Rituxan, Rituximab ABBS, Rituximab ARRX, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar GP2013, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, Rituximab Biosimilar SIBP-02, rituximab biosimilar TQB2303, Rituximab PVVR, Rituximab-abbs, Rituximab-arrx, Rituximab-blit, Rituximab-pvvr, Rituximab-rite, Rituximab-rixa, Rituximab-rixi, Rixathon, Riximyo, RTXM 83, RTXM-83, RTXM83, Ruxience, Truxima

Phase 1 (tovorafenib, rituximab); Phase 2 Arm A (cladribine, rituximab); Phase 2 Arm B (tovorafenib, rituximab)

Tovorafenib DRUG

Given PO

Also known as: BIIB 024, BIIB-024, BIIB024, DAY 101, DAY-101, DAY101, MLN 2480, MLN-2480, MLN2480, Ojemda, pan-RAF Kinase Inhibitor DAY101, TAK 580, TAK-580, TAK580

Phase 1 (tovorafenib, rituximab); Phase 2 Arm B (tovorafenib, rituximab)

Cladribine DRUG

Given IV

Also known as: 2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251

Phase 2 Arm A (cladribine, rituximab)

Biospecimen Collection PROCEDURE

Undergo blood sample and buccal swab collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Phase 1 (tovorafenib, rituximab); Phase 2 Arm A (cladribine, rituximab); Phase 2 Arm B (tovorafenib, rituximab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Patients must meet indications for treatment of cHCL:
• Absolute neutrophil count \< 1,000/mcL
• Platelets \< 100,000/mcL
• Hemoglobin \< 10 g/dL
• Recurrent infections
• Symptomatic and/or progressive extramedullary disease including lymph nodes and bone lesions
• Progressive or symptomatic splenomegaly or hepatomegaly
• Disease-related constitutional symptoms consisting of unexplained weight loss exceeding 10% body weight during the preceding 6 months, Cancer Therapy Evaluation Program (CTEP) active version of the Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or 3 fatigue, and/or fever \> 100.5 F or night sweats for \> 2 weeks without evidence of active infection
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%); ECOG performance status \> 2 (Karnofsky \< 60%) will be allowed if considered due to HCL
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x institutional ULN (unless related to Gilbert's disease or HCL; patients with documented Gilbert's disease may be enrolled with sponsor approval provided total bilirubin is ≤ 2.0 x ULN)

You may not qualify if:

• 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)
• Patients who have not recovered from AEs as a result of prior anti-cancer therapy (i.e., have residual toxicities \> grade 1), with the exception of alopecia
• Patients who are receiving any other investigational agents
• Patients who are receiving strong CYP2C8 inhibitors, inducers, and breast cancer resistance protein (BCRP) substrates with narrow therapeutic index
• Patients who are pregnant, breastfeeding, and/or unwilling to use adequate contraception during the study period and for 12 months after completion of the study
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to tovorafenib (DAY101) or other agents used in the study, including those with a previous history of severe infusion-related reaction (anaphylaxis) with rituximab administration
• Patients with known hypersensitivity to any of the study drugs
• Patients with an inability to swallow oral medications or with gastrointestinal impairment
• Live or live-attenuated vaccines within 28 days of randomization
• Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
• Pregnant women are excluded from this study because tovorafenib (DAY101) is a BRAF kinase inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with tovorafenib (DAY101), breastfeeding should be discontinued if the mother is treated with tovorafenib (DAY101). These potential risks may also apply to other agents used in this study

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (4)

NCI - Center for Cancer Research

Bethesda, Maryland, 20892, United States

RECRUITING

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

RECRUITING

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

University of Virginia Cancer Center

Charlottesville, Virginia, 22908, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Hairy Cell

Interventions

Specimen Handling; Biopsy; Cladribine; Rituximab; CT-P10; tovorafenib

Condition Hierarchy (Ancestors)

Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; 2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Seema A Bhat

  Ohio State University Comprehensive Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 8, 2025
• First Posted: May 11, 2025
• Study Start (Estimated): June 27, 2026
• Primary Completion (Estimated): March 1, 2030
• Study Completion (Estimated): March 1, 2030
• Last Updated: April 30, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share

Locations

US (4)