Venetoclax for the Treatment of Patients With Relapsed Hairy Cell Leukemia

A Phase 2 Study of Venetoclax in Relapsed Classic or Variant Hairy Cell Leukemia

This phase II trial tests how well venetoclax works in treating patients with hairy cell leukemia that has come back after a period of improvement (relapsed). Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival.

Study Overview

• Status: Not yet recruiting
• Conditions: Recurrent Hairy Cell Leukemia; Recurrent Hairy Cell Leukemia Variant
• Intervention / Treatment: Procedure: Magnetic Resonance Imaging; Procedure: Biospecimen Collection; Drug: Venetoclax; Procedure: Computed Tomography; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the objective response rate (ORR) of venetoclax.

SECONDARY OBJECTIVES:

I. To determine the complete remission (CR) and minimal residual disease (MRD)-negative CR rates of venetoclax in relapsed hairy cell leukemia/hairy cell leukemia variant (HCL/HCLv).

II. To determine the rates of MRD-negative by blood flow cytometry with venetoclax.

III. To determine the safety of venetoclax in relapsed HCL/HCLv. IV. To determine the response and CR duration and MRD-negative survival in relapsed HCL/HCLv receiving venetoclax.

EXPLORATORY OBJECTIVES:

I. To correlate response to TP53 mutations and other mutations, particularly for BRAF wild-type (WT) relapsed HCL/HCLv.

II. To perform whole exome sequencing (WES) of relapsed HCL/HCLv samples to look for mutations, to correlate with response.

OUTLINE:

Patients receive venetoclax orally (PO) once daily (QD) on days 1-28 of each cycle. Treatment repeats every 28 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) and blood sample collection throughout the study. Patients may undergo bone marrow biopsy and/or aspiration on study.

After completion of study treatment, patients are followed up at 30 days.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed HCL/HCLv after purine analog therapy who are relapsed from or are ineligible for BRAF therapy and have not received prior venetoclax
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
• Total bilirubin ≤ 3 x institutional upper limit of normal (ULN) unless consistent with Gilbert's (ration between total and direct bilirubin > 5)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 × institutional ULN
• Serum creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 45 mL/min/1.73m^2
• 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
• 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
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• Patients must have had no HCL/HCLv treatment for ≥ 4 weeks prior to enrollment, and those with treatment > 4 weeks prior to enrollment must not be responding to their last treatment with decreasing tumor burden or improving drug-related cytopenias
• Patients must have a need for treatment due to absolute neutrophil count (ANC) < 1/nL, hemoglobin (Hgb) < 10g/dL, platelets (Plt) < 100/nL, symptomatic splenomegaly, enlarging HCL mass > 2cm in short axis, enlarging HCL mass > 0.5 cm in the central nervous system (CNS) in short axis, or leukemic count > 5/nL
• The effects of venetoclax on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during treatment and for 30 days after the last dose of venetoclax. 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. Men treated or enrolled on this protocol must also agree to use adequate contraception during treatment and for 30 days after the last dose of venetoclax
• Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants
• Ability and willingness to swallow pills

Exclusion Criteria:

• Patients who have received prior venetoclax
• Patients who are receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to venetoclax
• 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 venetoclax is a B-cell lymphoma-2 (BCL-2) inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with venetoclax, breastfeeding should be discontinued if the mother is treated with venetoclax
• Malabsorption syndrome or other conditions that would interfere with intestinal absorption
• Live attenuated vaccines should not be administered within 4 weeks prior to, during, or 30 days after study treatment and recovery has occurred

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (venetoclax); Patients receive venetoclax PO QD on days 1-28 of each cycle. Treatment repeats every 28 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI and blood sample collection throughout the study. Patients may undergo bone marrow biopsy and/or aspiration on study.

Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Drug: Venetoclax; Given PO; Other Names: Venclexta; ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclyxto; Procedure: Computed Tomography; Undergo CT scan; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy; Other Names: Biopsy of Bone Marrow; Biopsy, Bone Marrow

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	Will be determined with 95% confidence intervals for each group.	Up to 30 days after the last dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete remission (CR) rate	CR will be defined as resolution of cytopenias with neutrophils > 1.5/nL, platelets > 100/nL, and hemoglobin > 11g/dL at least 4 weeks from last transfusion or growth factor, resolution of splenomegaly by exam or by spleen size < 17 cm by imaging, resolution of hairy cell leukemia (HCL)/hairy cell leukemia variant (HCLv)-related lymphadenopathy/masses to < 2cm in short axis (< 0.5 cm in short axis in the central nervous system [CNS]), and absence of morphological evidence of HCL/HCLv in the blood and bone marrow.	Up to 30 days after the last dose
Minimal residual disease (MRD)-negative CR rate	Defined as meeting the criteria for CR plus absence of HCL/HCLv cells in the bone marrow aspirate and blood by flow cytometry, and negative immunochemistry of the bone marrow biopsy. Positive IHC involves B-cells > T-cells and most of the B-cells being consistent with HCL. Patients with CNS disease who achieve CR with positive cerebrospinal fluid flow cytometry will be considered CR with MRD.	Up to 30 days after the last dose
MRD negativilty	Will determine the rates of MRD-negative by blood flow cytometry.	Up to 30 days after the last dose
Incidence of adverse events		Up to 30 days after the last dose
Complete response duration		Up to 30 days after the last dose
MRD-negative survival		Up to 30 days after the last dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
TP53 mutations and other mutations	Will correlate response to TP53 mutations and other mutations.	Up to 30 days after the last dose
Whole exome sequencing of relapsed HCL/HCLv samples	Will perform whole exome sequencing of relapsed HCL/HCLv samples to look for mutations, to correlate with response.	Up to 30 days after the last dose

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Robert J Kreitman, National Cancer Institute LAO

Study record dates

Study Major Dates

• Study Start (Estimated): May 20, 2024
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: March 13, 2024
• First Submitted That Met QC Criteria: March 13, 2024
• First Posted (Actual): March 15, 2024

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Leukemia; Recurrence; Leukemia, Hairy Cell; Antineoplastic Agents; Venetoclax
• Other Study ID Numbers: NCI-2024-01904 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 10637 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: "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."

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No