Hairy Cell LeukemiaPhase 1/2NCT06965114
Testing the Combination of Anti-cancer Drugs, Tovorafenib Plus Rituximab, in Patients With Hairy Cell Leukemia
A Phase 1/2 study testing Biospecimen Collection, Bone Marrow Aspiration and Bone Marrow Biopsy in people with Hairy Cell Leukemia and Recurrent Hairy Cell Leukemia, run by National Cancer Institute (NCI) at 4 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hairy Cell Leukemia, Recurrent Hairy Cell Leukemia, Refractory Hairy Cell Leukemia
- What is being tested?
- Biospecimen Collection, Bone Marrow Aspiration and Bone Marrow Biopsy
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 84 participants
- Where
- 4 sitesUnited States
- Study dates
- 29 May 2026to 1 Mar 2030
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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)
- Creatinine clearance (ClCr) ≥ 30 mL/min
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load for > 6 months
- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- Electrocardiogram (ECG) without evidence of clinically significant ventricular arrhythmias or ischemia as determined by the investigator and a rate-corrected QT interval (QTc, Bazett's formula) of < 480 msec
- The effects of tovorafenib (DAY101), cladribine, and rituximab on the developing human fetus are unknown. For this reason and because BRAF kinase inhibitor agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential (WOCBP) and men must agree to use two forms of adequate contraception (including a highly effective birth control method in addition to a barrier method) during treatment prior to study entry and for the duration of study treatment participation and 12 months after the last dose of the study medication
- WOCBP should use effective non-hormonal contraception during treatment and for 12 months after the last dose of the study medication. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. For male patients with a female partner of childbearing potential, a condom should be used for contraception in addition to one of the highly effective contraception methods prior to the study, for the duration of study treatment, and 12 months after the last dose of the study medication. Male patients must not father a child or donate sperm while participating in this study
- Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives (LARs) may sign and give informed consent on behalf of study participants
Who cannot join
- 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
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- 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
Trial locations and contacts
4 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States4 sites, 4 recruiting
- Recruiting
NCI - Center for Cancer Research
Bethesda, Maryland, 20892
Site Public Contact, 800-411-1222
Robert J. Kreitman
- Recruiting
University of Virginia Cancer Center
Charlottesville, Virginia, 22908
Site Public Contact, 434-243-6303, uvacancertrials@hscmail.mcc.virginia.edu
Nathan L. Roberts
- Recruiting
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
Site Public Contact, 800-293-5066, Jamesline@osumc.edu
Seema A. Bhat
- Recruiting
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, 15232
Site Public Contact, 412-647-8073
Robert L. Redner
About this study
Official title: A Phase 1 Study of Combination Tovorafenib (DAY101) and Rituximab Treatment in Relapsed or Refractory Classical Hairy Cell Leukemia and Phase 2 Randomized Study Comparing Tovorafenib (DAY101) and Rituximab With Cladribine and Rituximab for Front-Line Treatment of Classical Hairy Cell Leukemia
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.
Read the detailed description
PRIMARY OBJECTIVES:
- 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:
- 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:
- 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.
- Being tested
- Biospecimen Collection, Bone Marrow Aspiration, Bone Marrow Biopsy, Cladribine, Computed Tomography
- Medical subject headings
- Leukemia, Hairy Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Biospecimen CollectionProcedure or surgery
Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection
Undergo blood sample and buccal swab collection
Bone Marrow AspirationProcedure or surgery
Undergo bone marrow biopsy and aspiration
Bone Marrow BiopsyProcedure or surgery
Also called Biopsy of Bone Marrow, Biopsy, Bone Marrow
Undergo bone marrow biopsy and aspiration
CladribineDrug
Also called 2-CdA, 2CDA, CdA, Cladribina
Given IV
Computed TomographyProcedure or surgery
Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography
Undergo CT
RituximabBiological
Also called ABP 798, ABP-798, ABP798, BI 695500
Given IV
TovorafenibDrug
Also called BIIB 024, BIIB-024, BIIB024, DAY 101
Given PO
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Biological: Rituximab; Drug: Tovorafenib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: At completion of tovorafenib plus rituximab treatment versus cladribine plus rituximab
Secondary outcomes (7)
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).
Measured: At completion of tovorafenib plus rituximab
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.
Measured: At completion of tovorafenib plus rituximab
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.
Measured: From initiation of therapy to documented progression or death without progression, assessed up to 10 years
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.
Measured: From initiation of therapy to death from any cause, assessed up to 10 years
Incidence of AEs (Phase 2)
Will be documented and summarized by type, grade, severity, and attribution using the CTCAE v 5.0 criteria for non-hematologic toxicities and the table on Criteria for Hematologic Toxicities. Will review all AE data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing. The incidence of severe (grade 3+) AEs or toxicities will be described. The number of treatment cycles received and reasons for going off treatment will be summarized to assess treatment tolerability. Will assess tolerability of the regimens through assessing the number of patients who required dose modifications and/or dose delays. Tolerability measures will be assessed within each treatment arm, and will explore differences in these measures between the arms. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
Measured: 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
Rate of durable complete remission (CR) (Phase 2)
Will be defined as achieving a CR and not experiencing relapse at 12 months after completing treatment.
Measured: Up to 12 months after completing treatment
Mutations or changes in transcription profile (Phase 1)
Will be assessed using whole exome and ribonucleic acid sequencing.
Measured: At baseline and at time of relapse, assessed up to 10 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 May 2025
- Study start29 May 2026
- Primary completion1 Mar 2030 (estimated)
- Study completion1 Mar 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hairy Cell LeukemiaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 84 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Seema A Bhat, Principal investigator, Ohio State University Comprehensive Cancer Center LAO
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06965114
- Sponsor's protocol ID
- NCI-2025-03281
- Other IDs
- NCI-2025-03281, 10664, 10664, UM1CA186712
- Status last verified
- Jul 2026
- First submitted
- 8 May 2025
- Last updated
- 31 Jul 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
Study at a glance
From the registry record, last updated by the sponsor on 31 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1 Study of Combination Tovorafenib (DAY101) and Rituximab Treatment in Relapsed or Refractory Classical Hairy Cell Leukemia and Phase 2 Randomized Study Comparing Tovorafenib (DAY101) and Rituximab With Cladribine and Rituximab for Front-Line Treatment of Classical Hairy Cell Leukemia
- ClinicalTrials.gov ID
- NCT06965114
- Acronym / sponsor ID
- NCI-2025-03281
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 84 participants (estimated)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 29 May 2026 (actual)
- Primary completion
- 1 Mar 2030 (estimated)
- Study completion
- 1 Mar 2030 (estimated)
- First posted
- 11 May 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
PRIMARY OBJECTIVES:
- 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:
- 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:
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Phase 1 (tovorafenib, rituximab) | Experimental | Procedure: Biospecimen Collection, Procedure: Bone Marrow Aspiration, Procedure: Bone Marrow Biopsy, Procedure: Computed Tomography, Biological: Rituximab, Drug: TovorafenibPatients 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. |
| Phase 2 Arm A (cladribine, rituximab) | Active comparator | Procedure: Biospecimen Collection, Procedure: Bone Marrow Aspiration, Procedure: Bone Marrow Biopsy, Drug: Cladribine, Procedure: Computed Tomography, Biological: RituximabPatients 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. |
| Phase 2 Arm B (tovorafenib, rituximab) | Experimental | Procedure: Biospecimen Collection, Procedure: Bone Marrow Aspiration, Procedure: Bone Marrow Biopsy, Procedure: Computed Tomography, Biological: Rituximab, Drug: TovorafenibPatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (24 listed)
- 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:
Key exclusion criteria (14 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Biospecimen CollectionAlso: Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen CollectionUndergo blood sample and buccal swab collection | Procedure or surgery | Phase 1 (tovorafenib, rituximab), Phase 2 Arm A (cladribine, rituximab), Phase 2 Arm B (tovorafenib, rituximab) |
| Bone Marrow AspirationUndergo bone marrow biopsy and aspiration | Procedure or surgery | Phase 1 (tovorafenib, rituximab), Phase 2 Arm A (cladribine, rituximab), Phase 2 Arm B (tovorafenib, rituximab) |
| Bone Marrow BiopsyAlso: Biopsy of Bone Marrow, Biopsy, Bone MarrowUndergo bone marrow biopsy and aspiration | Procedure or surgery | Phase 1 (tovorafenib, rituximab), Phase 2 Arm A (cladribine, rituximab), Phase 2 Arm B (tovorafenib, rituximab) |
| CladribineAlso: 2-CdA, 2CDA, CdA, CladribinaGiven IV | Drug | Phase 2 Arm A (cladribine, rituximab) |
| Computed TomographyAlso: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial TomographyUndergo CT | Procedure or surgery | Phase 1 (tovorafenib, rituximab), Phase 2 Arm A (cladribine, rituximab), Phase 2 Arm B (tovorafenib, rituximab) |
| RituximabAlso: ABP 798, ABP-798, ABP798, BI 695500Given IV | Biological | Phase 1 (tovorafenib, rituximab), Phase 2 Arm A (cladribine, rituximab), Phase 2 Arm B (tovorafenib, rituximab) |
| TovorafenibAlso: BIIB 024, BIIB-024, BIIB024, DAY 101Given PO | Drug | Phase 1 (tovorafenib, rituximab), Phase 2 Arm B (tovorafenib, rituximab) |
Primary outcome
Incidence of adverse events (Phase 1)
Time frame: During cycles 1-3 (cycle length = 28 days)
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)
Time frame: At completion of tovorafenib plus rituximab treatment versus cladribine plus rituximab
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.
7 secondary outcomes
MRD (-) CR rate (Phase 1)
Time frame: At completion of tovorafenib plus rituximab
Overall response rate (ORR) (Phase 1)
Time frame: At completion of tovorafenib plus rituximab
Progression-free survival (Phase 1)
Time frame: From initiation of therapy to documented progression or death without progression, assessed up to 10 years
Overall survival (Phase 1)
Time frame: From initiation of therapy to death from any cause, assessed up to 10 years
Incidence of AEs (Phase 2)
Time frame: 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
Rate of durable complete remission (CR) (Phase 2)
Time frame: Up to 12 months after completing treatment
Mutations or changes in transcription profile (Phase 1)
Time frame: At baseline and at time of relapse, assessed up to 10 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Jul 2026.
- Individual participant dataSharing planned: Yes. NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Ohio State University Comprehensive Cancer Center
Columbus, United States
Seema A Bhat principal investigator
Ohio State University Comprehensive Cancer Center LAO
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Biospecimen Collection, Bone Marrow Aspiration and Bone Marrow Biopsy in people with Hairy Cell Leukemia and Recurrent Hairy Cell Leukemia, run by National Cancer Institute (NCI) at 4 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 24 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 31 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of adverse events (Phase 1) (time frame: During cycles 1-3 (cycle length = 28 days)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jul 2026.