Clinical Trials /

Acalabrutinib and Obinutuzumab for the Treatment of Chronic Lymphocytic Leukemia

NCT04505254

Description:

This phase II trial investigates the how well acalabrutinib and obinutuzumab work in treating patients with chronic lymphocytic leukemia (CLL). Acalabrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with obinutuzumab may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving acalabrutinib and obinutuzumab may help to control disease progression in CLL patients who have not received treatment for CLL.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Acalabrutinib and Obinutuzumab for the Treatment of Chronic Lymphocytic Leukemia
  • Official Title: Intermittent Therapy With the BTK Inhibitor Acalabrutinib (Calquence) in Combination With Obinutuzumab in Treatment Naive (Tn) Patients With Chronic Lymphocytic Leukemia (CLL)

Clinical Trial IDs

  • ORG STUDY ID: 2019-1141
  • SECONDARY ID: NCI-2020-05262
  • SECONDARY ID: 2019-1141
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04505254

Conditions

  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma

Interventions

DrugSynonymsArms
AcalabrutinibACP-196, Bruton Tyrosine Kinase Inhibitor ACP-196, CalquenceTreatment (acalabrutinib, obinutuzumab)
ObinutuzumabAnti-CD20 Monoclonal Antibody R7159, GA-101, GA101, Gazyva, huMAB(CD20), R7159, RO 5072759, RO-5072759, RO5072759Treatment (acalabrutinib, obinutuzumab)

Purpose

This phase II trial investigates the how well acalabrutinib and obinutuzumab work in treating patients with chronic lymphocytic leukemia (CLL). Acalabrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with obinutuzumab may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving acalabrutinib and obinutuzumab may help to control disease progression in CLL patients who have not received treatment for CLL.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the proportion of patients who have treatment-free remission 6 months after
      discontinuation of acalabrutinib in patients who complete 24 cycles of frontline therapy.

      SECONDARY OBJECTIVES:

      I. To determine clinical factors associated with a treatment-free remission of more than 6
      months after discontinuation of acalabrutinib.

      II. To determine the treatment-free remission length. III. To evaluate the efficacy of
      re-treatment with acalabrutinib plus obinutuzumab in patients who relapse.

      EXPLORATORY OBJECTIVES:

      I. To characterize the effects of limited-duration acalabrutinib plus obinutuzumab therapy on
      the clonal architecture as determined by genome-wide genotyping and analysis (GWAs) and whole
      exome sequencing (WES).

      II. To determine the frequency of BTK and PLCG2 mutation in patients relapsing after
      limited-duration acalabrutinib plus obinutuzumab therapy.

      OUTLINE:

      Patients receive acalabrutinib orally (PO) twice a day (BID) every 12 hours starting on day 1
      of cycle 1, and obinutuzumab intravenously (IV) over 4-6 hours on days 1 and 2 of cycle 3,
      and day 1 of cycles 4-8. Patients who do not achieve a complete response or remission after
      cycle 8 may receive single-agent acalabrutinib therapy PO BID for an additional 6 cycles at
      the discretion of their treating physician. Patients who are in partial response or who have
      stable disease receive an additional 6 cycles of acalabrutinib PO BID and obinutuzumab IV.
      Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days then every 3 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (acalabrutinib, obinutuzumab)ExperimentalPatients receive acalabrutinib PO BID every 12 hours starting on day 1 of cycle 1, and obinutuzumab IV over 4-6 hours on days 1 and 2 of cycle 3, and day 1 of cycles 4-8. Patients who do not achieve a complete response or remission after cycle 8 may receive single-agent acalabrutinib therapy PO BID for an additional 6 cycles at the discretion of their treating physician. Patients who are in partial response or who have stable disease receive an additional 6 cycles of acalabrutinib PO BID and obinutuzumab IV. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
  • Acalabrutinib
  • Obinutuzumab

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis CLL/small lymphocytic lymphoma (SLL) and be untreated

          -  Patients must have an indication for treatment by 2018 International Workshop on
             Chronic Lymphocytic Leukemia (IWCLL) Criteria

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

          -  Patients of childbearing potential must be willing to practice highly effective birth
             control during treatment and for 2 days after the last dose of acalabrutinib or 18
             months after the last dose of obinutuzumab, whichever is later

          -  A negative urine pregnancy test (within 7 days of day 1) is required for women with
             childbearing potential

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) except for patients
             with bilirubin elevation due to Gilbert's disease who will be allowed to participate

          -  An alanine transferase (ALT) =< 2.5 x ULN

          -  An estimated creatinine clearance (CrCl) of > 30 mL/min, as calculated by the
             Cockcroft-Gault equation unless disease related

          -  Free of prior malignancies for 2 years with exception of patients diagnosed with basal
             cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or
             breast who are eligible even if they are currently treated or have been treated and/or
             diagnosed in the past 2 years prior to study enrollment. If patients had another
             malignancy of indolent behavior in the past 2 years prior to study enrollment that is
             expected to be cured with treatment they received such patients can be enrolled, after
             consultation with the principal investigator

        Exclusion Criteria:

          -  Pregnant or breast-feeding females

          -  Prior CLL/SLL treatment

          -  Known history of infection with human immunodeficiency virus (HIV) or any uncontrolled
             active significant infection (eg, bacterial, viral or fungal)

          -  Signs of active hepatitis B or C. Subjects who are hepatitis B core antibody
             (anti-HBc) positive and who are surface antigen negative will need to have a negative
             polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HBsAg)
             positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C
             antibody positive will need to have a negative PCR result. Those who are hepatitis C
             PCR positive will be excluded

          -  Patients with uncontrolled autoimmune hemolytic anemia (AIHA) or autoimmune
             thrombocytopenia (ITP)

          -  An absolute neutrophil count of less than 500/uL, unless disease-related at time of
             screening for this protocol

          -  A platelet count of less than 30,000/uL at time of screening for this protocol

          -  Clinically significant cardiovascular disease such as uncontrolled or symptomatic
             arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
             heart failure, or any class 3 or 4 cardiac disease as defined by the New York Heart
             Association Functional Classification. Subjects with controlled, asymptomatic atrial
             fibrillation can enroll. Patients with a history of paroxysmal atrial fibrillation
             (PAF) or deep vein thrombosis or pulmonary embolism (DVT/PE) can be included if they
             had no signs of PAF or DVT/PE in the last 6 months before enrolment. Patients with
             ongoing atrial fibrillation (AFib) or ongoing PAF or DVT/PE should be excluded

          -  History of stroke or cerebral hemorrhage within 6 months

          -  Known history or evidence of bleeding diathesis or coagulopathy within 3 months

          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days

          -  Minor surgical procedures, fine needle aspirations or core biopsies within 7 days
             prior to day 1. Bone marrow aspiration and/or biopsy are allowed

          -  Serious, non-healing wound, ulcer, or bone fracture

          -  Treatment with warfarin (Coumadin) or any other vitamin K antagonist. Patients who
             recently received warfarin must be off warfarin for at least 7 days prior to start of
             the study. Patients receiving novel oral anticoagulant (NOAC), also termed direct oral
             anticoagulant (DOAC) are permitted to enroll. Patients who are currently on a vitamin
             K antagonist must be switched to a non-vitamin K antagonist, such as a NOAC/DOAC

          -  Has difficulty with or is unable to swallow oral medication, or has significant
             gastrointestinal disease that would limit absorption of oral medication

          -  Known history of drug-specific hypersensitivity or anaphylaxis to study drug
             (including active product or excipient components)

          -  Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer

          -  Prothrombin time (PT)/international normalized ratio (INR) or activated partial
             thromboplastin time (aPTT) (in the absence of lupus anticoagulant) > 2 x ULN

          -  Requires treatment with proton pump inhibitors

          -  Concurrent participation in another therapeutic clinical trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Treatment-free remission
Time Frame:At 6 months after discontinuation of acalabrutinib, up to 4 years
Safety Issue:
Description:Defined as the time from discontinuation of acalabrutinib to the date of CLL relapse with active disease.

Secondary Outcome Measures

Measure:Clinical factors associated with a treatment-free remission
Time Frame:Up to 6 months after completion of treatment
Safety Issue:
Description:Will use Cox's proportional hazards analysis of predictors that have a p value < 0.2 in the univariate analysis. Explanatory variables that were highly correlated will be independently entered into the Cox's regression model. Factors significant in at least one model tested will be taken to be possible independent predictors of relapse risk. Demographic and clinical characteristics will be summarized using descriptive statistics, including means with standard deviations, or medians with ranges, histograms and box-plot. Fisher's exact test and Wilcoxon rank test will be used in the data analyses of categorical and continuous variables, respectively.
Measure:Treatment-free remission length
Time Frame:Up to 6 months after completion of treatment
Safety Issue:
Description:The median length of treatment-free remission will be estimated using the Kaplan-Meier method.
Measure:Success rate of re-treatment in patients who relapse
Time Frame:Up to 6 months after completion of treatment
Safety Issue:
Description:The success rate of re-treatment, along with the 95% confidence interval will be computed, and median length of treatment-free remission will be estimated.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

August 5, 2020