Clinical Trials /

AU2 In Relapsed and Untreated CLL

NCT04624633

Description:

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)

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: AU2 In Relapsed and Untreated CLL
  • Official Title: A Phase 2 Study of Acalabrutinib, Umbralisib, and Ublituximab (AU2) in Relapsed and Previously Untreated CLL Patients

Clinical Trial IDs

  • ORG STUDY ID: 20-394
  • NCT ID: NCT04624633

Conditions

  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
  • Relapsed Chronic Lymphocytic Leukemia
  • Refractory Chronic Lymphocytic Leukemia

Interventions

DrugSynonymsArms
AcalabrutinibCalquenceCohort 1-Relapsed Disease
UmbralisibRP5264Cohort 1-Relapsed Disease
UblituximabLFB-R603Cohort 1-Relapsed Disease

Purpose

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)

Detailed Description

      In this research study, Investigators are exploring the combination of acalabrutinib,
      umbralisib, and ublituximab and hoping to determine if the combination is effective at
      controlling cancer growth in participants with CLL.

      The research study procedures include screening for eligibility and study treatment including
      evaluations and follow up visits.

      Participants will receive the study drugs for a maximum of 24 cycles (2 years) and will be
      followed for a maximum of 5 years after discontinuing the study drugs.

      The names of the study drugs involved in this study are/is:

        -  Acalabrutinib (CALQUENCE®, ACP-196)

        -  Umbralisib (TGR-1202)

        -  Ublituximab (TG-1101)

      It is expected that about 60 people will take part in this research study.

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational drugs to learn whether the drugs work in treating a
      specific disease. "Investigational" means that the drugs are being studied.

        -  The U.S. Food and Drug Administration (FDA) has not approved umbralisib or ublituximab
           as a treatment for any disease.

        -  The U.S. Food and Drug Administration (FDA) has approved acalabrutinib for CLL, but not
           in this combination.

             -  Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of
                protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow. By
                blocking BTK, acalabrutinib may kill cancer cells or stop them from growing.

             -  Umbralisib is an investigational drug which blocks a protein called PI3K. PI3K is a
                protein that helps CLL cells grow.

             -  Ublituximab is a type of investigational drug called a monoclonal antibody. A
                monoclonal antibody is a type of protein made in the laboratory that can locate and
                bind to substances in the body, including tumor cells. By binding to the tumor
                cells, the antibody might prevent the tumor cell from growing and spreading.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1-Relapsed DiseaseExperimentalParticipants 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
  • Acalabrutinib
  • Umbralisib
  • Ublituximab
Cohort 2-Treatment NaiveExperimentalParticipants 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
  • Acalabrutinib
  • Umbralisib
  • Ublituximab

Eligibility Criteria

        Inclusion Criteria:

          -  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

               -  Absolute neutrophil count (ANC) ≥ 750 mm3

               -  Hemoglobin (Hgb) > 8 g/dL

          -  Participants 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, participants should be class 2B or better.

          -  The effects of umbralisib, acalabrutinib, or ublituximab on the developing human fetus
             are unknown. For this reason and because anti-cancer agents are known to be
             teratogenic, women of child-bearing potential and men must agree to use highly
             effective methods of contraception. 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 and women treated on this protocol must agree
             to use highly effective contraception prior to the study, for the duration of study
             participation, and 4 months after completion of umbralisib, acalabrutinib, or
             ublituximab administration.

          -  Ability to understand and the willingness to sign a written informed consent document.

          -  Ability to swallow and retain oral medication.

          -  Participants must be able to receive prophylactic anti-pneumocystis jiroveci pneumonia
             (PJP) and anti-viral therapy

        Exclusion Criteria:

          -  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.

          -  Participants with a history of inflammatory bowel disease (e.g. Crohn's disease or
             ulcerative colitis).

          -  Participants with irritable bowel syndrome (IBS) with greater than 3 loose stools per
             day at baseline.

          -  Participants with evidence of ongoing systemic bacterial, fungal, or viral infection,
             except localized fungal infections of the skin or nails. NOTE: participants may be
             receiving prophylactic antiviral or antibacterial therapies at the treating
             investigator's discretion. Use of anti-pneumocystis and antiviral prophylaxis is
             required.

          -  Participants with a known history of progressive multifocal leukoencephalopathy (PML).

          -  Participants with evidence of chronic active Hepatitis B (HBV, not including patients
             with prior hepatitis B vaccination or positive serum Hepatitis B antibody), chronic
             active

        Hepatitis C infection (HCV), active cytomegalovirus (CMV), or known history of human
        immunodeficiency virus (HIV):

          -  If HBc antibody is positive, the subject must be evaluated for the presence of HBV DNA
             by PCR (see Appendix B). Subjects with positive HBc antibody and negative HBV DNA by
             PCR are eligible but serial monitoring of HBV DNA by PCR is required, see Section 5.4.
             Subjects with positive HBV DNA by PCR are not eligible.

          -  Participants with positive HBsAg are to be excluded.

          -  If HCV antibody is positive, the subject must be evaluated for the presence of HCV RNA
             by PCR. Subjects with positive HCV antibody and negative HCV RNA by PCR are eligible.
             Subjects with positive HCV RNA by PCR are not eligible.

          -  If the subject is CMV IgG or CMV IgM positive, the subject must be evaluated for the
             presence of CMV DNA by PCR. Subjects who are CMV IgG or CMV IgM positive but who are
             CMV DNA negative by PCR are eligible, anti-viral prophylaxis should be considered per
             treating investigator discretion.

               -  History of allergic reactions attributed to study drugs including active product
                  or excipients, or compounds of similar chemical or biologic composition to
                  acalabrutinib, umbralisib, or ublituximab, including participants with a history
                  of anaphylaxis (excluding infusion-related reactions) in association with
                  previous anti-CD20 administration.

               -  Participants requiring concomitant treatment with any medications or substances
                  that are strong inhibitors or inducers of CYP3A4 at the time of study enrollment.
                  Because the lists of these agents are constantly changing, it is important to
                  regularly consult a frequently-updated medical reference. As part of the
                  enrollment/informed consent procedures, the participant will be counseled on the
                  risk of interactions with other agents, and what to do if new medications need to
                  be prescribed or if the participant is considering a new over-the-counter
                  medicine or herbal product.

               -  Participants requiring concomitant treatment with proton pump inhibitors
                  (e.g.omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or
                  pantoprazole) at the time of study enrollment. Note: participants receiving
                  proton pump inhibitors who switch to H2-receptor antagonists or antacids prior to
                  the first dose of study medication are eligible.

               -  Participants with psychiatric illness/social situations that would limit
                  compliance with study requirements.

               -  Pregnant women are excluded from this study because acalabrutinib, umbralisib,
                  and ublituximab are anti-cancer agents 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
                  acalabrutinib, umbralisib, or ublituximab, breastfeeding must be discontinued
                  prior to the initiation of study treatment. A negative serum pregnancy test is
                  required for women of childbearing potential within 3 days prior to Cycle 1 Day
                  1.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of Complete Remission after 24 Cycles
Time Frame:2 Years
Safety Issue:
Description:The primary endpoint is the rate of CR after 24 cycles of treatment with acalabrutinib, umbralisib, and ublituximab in previously untreated and relapsed CLL patients, assessed per 2018 IW-CLL criteria.1

Secondary Outcome Measures

Measure:Rate of Partial Remission after 24 cycles
Time Frame:2 Years
Safety Issue:
Description:Response of CLL participants will be evaluated using the 2018 iwCLL criteria
Measure:Rate of Complete Remission with Incomplete Recovery (CRi) after 24 Cycles
Time Frame:2 Years
Safety Issue:
Description:Some patients fulfill all the criteria for a CR, but have a persistent anemia, thrombocytopenia or neutropenia apparently unrelated to CLL, but related to drug toxicity. These patients should be considered as a different category of remission, CR with incomplete marrow recovery (CRi). The marrow evaluation should be performed with scrutiny and not show any clonal disease infiltrate. Response of CLL participants will be evaluated using the 2018 iwCLL criteria
Measure:Median Progression Free Survival at 2 Years
Time Frame:2 Years
Safety Issue:
Description:progression of CLL participants will be evaluated using the 2018 iwCLL criteria for CLL. The Kaplan Meier method will be used to estimate the median PFS time.
Measure:Median Progression Free Survival at 3 Years
Time Frame:3 Years
Safety Issue:
Description:progression of CLL participants will be evaluated using the 2018 iwCLL criteria for CLL.The Kaplan Meier method will be used to estimate the median PFS time
Measure:Median Progression Free Survival at 5 Years
Time Frame:5 Years
Safety Issue:
Description:progression of CLL participants will be evaluated using the 2018 iwCLL criteria for CLL. The Kaplan Meier method will be used to estimate the median PFS time
Measure:Time to Next Treatment (TTNT) at 2 Years
Time Frame:2 Years
Safety Issue:
Description:Defined as the interval between the first treatment day until the patient starts an alternative therapy for progressive CLL. The Kaplan Meier method will be used to estimate TTNT.
Measure:Time to Next Treatment (TTNT) at 3 Years
Time Frame:3 Years
Safety Issue:
Description:Defined as the interval between the first treatment day until the patient starts an alternative therapy for progressive CLL. The Kaplan Meier method will be used to estimate TTNT.
Measure:Time to Next Treatment (TTNT) at 5 Years
Time Frame:5 Years
Safety Issue:
Description:Defined as the interval between the first treatment day until the patient starts an alternative therapy for progressive CLL. The Kaplan Meier method will be used to estimate TTNT.
Measure:Overall Survival Rate at 2 Years
Time Frame:2 Years
Safety Issue:
Description:Defined as the time from first treatment day to death due to any cause, or censored at date last known alive. The Kaplan Meier method will be used to estimate median OS time.
Measure:Overall Survival Rate at 3 Years
Time Frame:3 Years
Safety Issue:
Description:Defined as the time from first treatment day to death due to any cause, or censored at date last known alive. The Kaplan Meier method will be used to estimate median OS time.
Measure:Overall Survival Rate at 5 Years
Time Frame:5 Years
Safety Issue:
Description:Defined as the time from first treatment day to death due to any cause, or censored at date last known alive. The Kaplan Meier method will be used to estimate median OS time.
Measure:Rate of undetectable MRD in bone marrow
Time Frame:6 months
Safety Issue:
Description:Blood or marrow with < 1 CLL cell per 10,000 leukocytes assessed by at least four color flow cytometry (MRD flow), allele-specific oligonucleotide PCR, or high-throughput sequencing using the ClonoSEQ assay
Measure:Rate of undetectable MRD in bone marrow
Time Frame:12 months
Safety Issue:
Description:Blood or marrow with < 1 CLL cell per 10,000 leukocytes assessed by at least four color flow cytometry (MRD flow), allele-specific oligonucleotide PCR, or high-throughput sequencing using the ClonoSEQ assay
Measure:Rate of undetectable MRD in bone marrow
Time Frame:24 months
Safety Issue:
Description:Blood or marrow with < 1 CLL cell per 10,000 leukocytes assessed by at least four color flow cytometry (MRD flow), allele-specific oligonucleotide PCR, or high-throughput sequencing using the ClonoSEQ assay
Measure:Rate of peripheral blood undetectable MRD
Time Frame:6 Months
Safety Issue:
Description:Blood or marrow with < 1 CLL cell per 10,000 leukocytes assessed by at least four color flow cytometry (MRD flow), allele-specific oligonucleotide PCR, or high-throughput sequencing using the ClonoSEQ assay
Measure:Rate of peripheral blood undetectable MRD
Time Frame:12 Months
Safety Issue:
Description:Blood or marrow with < 1 CLL cell per 10,000 leukocytes assessed by at least four color flow cytometry (MRD flow), allele-specific oligonucleotide PCR, or high-throughput sequencing using the ClonoSEQ assay
Measure:Rate of peripheral blood undetectable MRD
Time Frame:24 Months
Safety Issue:
Description:Blood or marrow with < 1 CLL cell per 10,000 leukocytes assessed by at least four color flow cytometry (MRD flow), allele-specific oligonucleotide PCR, or high-throughput sequencing using the ClonoSEQ assay
Measure:Correlation between undetectable MRD in the peripheral blood and bone marrow
Time Frame:2 year
Safety Issue:
Description:MRD should be performed on the marrows to evaluate response at years 1 and 2.
Measure:Correlation between undetectable MRD in the peripheral blood and bone marrow
Time Frame:1year
Safety Issue:
Description:MRD should be performed on the marrows to evaluate response at years 1 and 2.
Measure:Time to MRD Positive Disease Recurrence in the Peripheral Blood
Time Frame:2 Year
Safety Issue:
Description:MRD should be performed on the marrows to evaluate response at years 1 and 2.
Measure:Time to Clinical Disease Progression
Time Frame:5 Years
Safety Issue:
Description:Defined as evidence of disease progression in a patient who has previously achieved the above criteria of a CR or PR for ≥ 6 months.
Measure:Number of Participants with Treatment Related Adverse Events as Assessed by CTCAE v 5.0
Time Frame:first dose of study medication to up to 5 years
Safety Issue:
Description:The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications of non-hematologic toxicity.
Measure:Rates of Therapy Discontinuation by cycle 12
Time Frame:1 Year
Safety Issue:
Description:A descriptive analysis of rates of therapy discontinuation by cycle 12 will be performed, with subjects grouped by reasons for discontinuation (e.g. achievement of CR, progressive disease, or intolerability). Rates of discontinuation of individual components of the regimen will also be included in this analysis.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jennifer R. Brown, MD, PhD

Trial Keywords

  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
  • Relapsed Chronic Lymphocytic Leukemia
  • Refractory Chronic Lymphocytic Leukemia

Last Updated

November 12, 2020