Acalabrutinib, Umbralisib, and Ublituximab (AU2) In Relapsed and Untreated CLL

NCT04624633 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 1 other identifier: 20-394
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

This study is testing the effectiveness of the study drug combination of acalabrutinib, umbralisib, and ublituximab in participants with Chronic Lymphocytic leukemia (CLL). The names of the study drugs involved in this study are/is:

• Acalabrutinib (CALQUENCE®, ACP-196)
• Umbralisib (TGR-1202)
• Ublituximab (TG-1101)

Conditions

Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Relapsed Chronic Lymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia

Keywords

Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Relapsed Chronic Lymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia

Outcome Measures

Primary Outcomes (1)

• Complete Remission (CR) Rate After 24 Cycles

  The CR Rate is defined as the proportion of participants achieving complete remission (CR) based on 2018 IW-CLL criteria.

  According to this endpoint is after 24 cycles. Overall median number of cycles is 24 with range 1-25.

Secondary Outcomes (2)

• Partial Remission (PR) Rate After 24 Cycles

  According to this endpoint is after 24 cycles. Overall median number of cycles is 24 with range 1-25.

• Median Progression-Free Survival (PFS)

  Disease will be evaluated through imaging at cycle 1 day 1, 8, and 15, cycle 2-6 and cycle 8-25 day 1, and cycle 7 day 1, 2 and 8. Observation on treatment up to approximately 25 cycles. In long-term follow-up, survival follow-up up to 5 years.

Study Arms (2)

Cohort 1-Relapsed Disease

EXPERIMENTAL

Participants with relapsed disease * Treatment with Acalabrutinib \& Umbralisib beginning C1D1, * Ublituximab beginning C7D1 * Assessment of treatment response * Treatment continues for a maximum of 24 cycles. Participants followed post treatment for a maximum of 5 years

Drug: Acalabrutinib; Drug: Umbralisib; Drug: Ublituximab

Cohort 2-Treatment Naive

EXPERIMENTAL

Participants with previously untreated disease * Treatment with Acalabrutinib \& Umbralisib beginning C1D1, * Ublituximab beginning C7D1 * Assessment of treatment response * Treatment continues for a maximum of 24 cycles. Participants followed post treatment for a maximum of 5 years

Drug: Acalabrutinib; Drug: Umbralisib; Drug: Ublituximab

Interventions

Acalabrutinib DRUG

Oral, twice a day, predetermined dosage

Also known as: Calquence

Cohort 1-Relapsed Disease; Cohort 2-Treatment Naive

Umbralisib DRUG

Oral, once a day, predetermined dosage, each 28 day cycle up to 24 cycles

Also known as: RP5264

Cohort 1-Relapsed Disease; Cohort 2-Treatment Naive

Ublituximab DRUG

28 day cycle, starting cycle 7 via iv, on at predetermined dosage and timepoints in each cycle

Also known as: LFB-R603

Cohort 1-Relapsed Disease; Cohort 2-Treatment Naive

Eligibility Criteria

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

You may qualify if:

• Confirmed diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) per International Workshop on CLL (iwCLL) 2018 criteria.1
• Participants must have an indication for treatment as defined by iwCLL 2018 criteria.1
• Participants must have measurable disease, defined as lymphocytosis \> 5,000 / μL, or palpable or CT measurable lymphadenopathy ≥ 1.5 cm, or bone marrow involvement ≥ 30%.
• For enrollment to Cohort 1: Participants must have relapsed or refractory disease as per iwCLL 2018 criteria,1 and must have received no more than 2 prior lines of anti-cancer therapy.
• For enrollment to Cohort 2: Participants must have previously untreated disease (i.e.
• must not have received any prior systemic therapy for CLL or SLL).
• Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of umbralisib, acalabrutinib, and ublituximab in participants \< 18 years of age and CLL is extremely rare in this population, children are excluded from this study.
• ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix A).
• Participants must have adequate organ and marrow function as defined below:
• Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) (unless due to hemolysis or Gilbert's disease, in which ≤ 3 × institutional ULN is acceptable)
• AST (SGOT) and ALT (SGPT) ≤ 2.5 × institutional ULN, OR
• AST (SGOT) and ALT (SGPT) ≤ 5 × institutional ULN if there is hemolysis or documented disease involvement in the liver
• Calculated creatinine clearance ≥ 30 mL/min (as calculated by the Cockcroft-Gault formula)
• Platelet count ≥ 50,000/mcL, unless there is bone marrow involvement with disease
• PT-INR or aPTT ≤ 2 × institutional ULN

You may not qualify if:

• Participants with progressive or refractory disease while receiving either a BTK inhibitor or PI3K inhibitor. Prior exposure to either a BTK inhibitor, PI3K inhibitor, or both is acceptable as long as the participant's disease did not progress during active therapy with the agent(s).
• Participants who have undergone a major surgical procedure within 28 days of the first dose of study drug. If a participant had major surgery greater than 28 days prior to the first dose of study drug, they must have recovered adequately from any adverse event and/or complications from the intervention prior to the first dose (as judged by the treating investigator). For enrollment to Cohort 1: receipt of prior BTK inhibitor treatment within 7 days, or any other anti-cancer therapy (e.g. chemotherapy, immunotherapy, radiation, biologic therapy or any investigational agent) within 21 days of the first dose of study drug.
• Participants who are receiving any other investigational agents.
• History of prior allogeneic stem cell transplant.
• History of autologous hematologic stem cell transplant within 6 months of the first dose of study drug.
• Participants with known Richter's transformation, or histological transformation from CLL to large cell lymphoma.
• Participants with known CNS involvement, because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with no known history of CNS leukemia are not required to undergo CT scan or lumbar puncture (LP) for trial eligibility unless the participant is symptomatic as judged by the treating investigator.
• Participants with uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP).
• Participants with active clinically significant bleeding or history of bleeding diathesis (e.g. hemophilia or von Willebrand disease).
• Participants requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (other anticoagulants are permitted).
• Participants with a history of significant cerebrovascular disease/event within 6 months before the first dose of study drug, including stroke or intracranial hemorrhage.
• Participants with uncontrolled intercurrent illness, including but not limited to: unstable angina pectoris, cardiac arrhythmia, or poorly controlled and clinically significant atherosclerotic vascular disease (including patients who required angioplasty, cardiac or vascular stenting within 6 months prior to the first dose of study agent), myocardial infarction within 6 months of screening, congestive heart failure, or patients with Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification. Note: participants with controlled, asymptomatic atrial fibrillation are permitted to enroll on study. Concomitant use of medication known to cause QT prolongation or torsades de pointes should be used with caution and at investigator discretion.
• Individuals with a history of a different malignancy are ineligible with the following exceptions: individuals who have been treated and are disease-free for a minimum of 2 years prior to study enrollment, or individuals who are deemed by the treating investigator to be at low risk for disease recurrence. Additionally, individuals with the following cancers are eligible if diagnosed and curatively treated within the past 2 years: basal or squamous cell carcinomas of the skin, and breast or cervical carcinomas in situ.
• Prostate cancer on observation, with stable PSA for 6 months, is also eligible.
• Participants who require ongoing immunosuppressive therapy including systemic corticosteroids (prednisone or equivalent ≤ 10 mg daily is permitted). Topical, inhaled, and ophthalmologic steroids are permitted.

Sponsors & Collaborators

• Jennifer R. Brown, MD, PhD: lead
• AstraZeneca: collaborator
• TG Therapeutics, Inc.: collaborator

Study Sites (1)

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Related Publications (1)

• Yin Y, Xu H, He L, Brown JR, Mato AR, Aittokallio T, Skanland SS. Protein Profiles Predict Treatment Responses to the PI3K Inhibitor Umbralisib in Patients with Chronic Lymphocytic Leukemia. Clin Cancer Res. 2025 May 15;31(10):1943-1955. doi: 10.1158/1078-0432.CCR-24-2911.

  PMID: 40085050 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

acalabrutinib; umbralisib; ublituximab; LFB-R603

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Jennifer R Brown MD PhD
• Organization: Dana-Farber Cancer Institute

Jennifer_Brown@dfci.harvard.edu

617-632-4894

Study Officials

• Jennifer R Brown, MD, PhD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor Investigator

Study Record Dates

• First Submitted: November 5, 2020
• First Posted: November 12, 2020
• Study Start: December 15, 2020
• Primary Completion: December 21, 2023
• Study Completion (Estimated): January 1, 2028
• Last Updated: February 25, 2026
• Results First Posted: February 27, 2025

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (1)