Clinical Trials /

Acalabrutinib With or Without Obinutuzumab in Treating Participants With Early-Stage Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

NCT03516617

Description:

This phase II trials studies how well acalabrutinib with or without obinutuzumab works in treating participants with early-stage chronic lymphocytic leukemia or small lymphocytic lymphoma. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as obinutuzumab, may interfere with the ability of cancer cells to grow and spread. It is not yet known whether giving acalabrutinib with or without obinutuzumab will work better in treating participants with early-stage chronic lymphocytic leukemia or small lymphocytic lymphoma.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Acalabrutinib With or Without Obinutuzumab in Treating Participants With Early-Stage Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
  • Official Title: Randomized Phase 2 Study Comparing Acalabrutinib to Acalabrutinib and Obinutuzumab in the Treatment of Patients With Early-Stage Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Who Are at High Risk of Disease Progression

Clinical Trial IDs

  • ORG STUDY ID: MC168E
  • SECONDARY ID: NCI-2018-00591
  • SECONDARY ID: MC168E
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03516617

Conditions

  • CCND1 Negative
  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
  • t(11;14) Negative

Interventions

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

Purpose

This phase II trials studies how well acalabrutinib with or without obinutuzumab works in treating participants with early-stage chronic lymphocytic leukemia or small lymphocytic lymphoma. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as obinutuzumab, may interfere with the ability of cancer cells to grow and spread. It is not yet known whether giving acalabrutinib with or without obinutuzumab will work better in treating participants with early-stage chronic lymphocytic leukemia or small lymphocytic lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare the bone marrow minimal residual disease (MRD)-negative complete response (CR)
      rate of acalabrutinib alone and acalabrutinib/obinutuzumab in early stage asymptomatic
      chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients who are high and
      very high risk by CLL-International Prognostic Index (IPI). (Arms A and B) II. To evaluate
      time to first therapy (TFT) in early stage asymptomatic CLL/SLL patients with low and
      intermediate-risk by CLL-IPI. (Arm C)

      SECONDARY OBJECTIVES:

      I. To compare the safety of acalabrutinib alone and acalabrutinib/obinutuzumab in early stage
      asymptomatic CLL/SLL patients who are high and very high risk by CLL-IPI.

      II. To compare the overall response rate (ORR), progression-free survival (PFS), time to next
      therapy (TNT) and overall survival (OS) of acalabrutinib alone and acalabrutinib/obinutuzumab
      in early stage asymptomatic CLL/SLL patients who are at high and very high risk by CLL-IPI.

      III. To determine the progression-free survival (PFS) and overall survival (OS) in early
      stage asymptomatic CLL/SLL patients with low and intermediate risk by CLL-IPI.

      EXPLORATORY OBJECTIVES:

      I. To evaluate the quality of life using Functional Assessment of Cancer Therapy-General
      (FACT-G) quality of life (QOL) survey.

      CORRELATIVE RESEARCH:

      I. To compare the peripheral blood immune profile using 8-color flow cytometry, to assess
      changes in T-cells, natural killer (NK)-cells, and NK-T cells at baseline and during active
      treatment among patients receiving either acalabrutinib alone or acalabrutinib and
      obinutuzumab.

      II. To determine changes in the peripheral blood immune profile using 8-color flow cytometry
      to assess changes in T-cells, NK-cells, and NK-T cells at baseline and during event
      monitoring in patients with low and intermediate risk by CLL-IPI.

      III. Signal pathway studies-BTK, ERK, PLC gamma and S6 protein levels and phosphorylation
      status will be assessed by Western blot methodology using specific antibodies to pull down
      specific proteins from cell lysates.

      IV. To confirm if in vitro cell killing is via apoptosis we will also assess PARP and caspase
      3 cleavage.

      V. Apoptotic protein studies-MCL-1, XIAP levels will be determined by Western blot
      methodology using specific antibodies to pull down these specific proteins from cell lysates.

      VI. Bone marrow aspirates will be studied for hematopoietic function in two ways: estimation
      of colony forming capacity by purified hematopoietic stem cells (HSCs) and evaluation of the
      levels of HSCs and their differentiated progeny (i.e. MPP, CMP, CLP).

      VII. Paired bone marrow and blood samples will be evaluated for the levels of innate effector
      cells.

      VIII. Perform targeted sequencing of 59 genes mainly grouped in 8 biological pathways:
      NOTCH1, B-cell signaling, deoxyribonucleic acid (DNA) damage response, chromatin modifiers,
      ribonucleic acid (RNA) metabolism, NF-kappaB pathway, cell cycle and apoptosis.

      OUTLINE: Participants with high or very high risk CLL-IPI are randomized to Arm A or Arm B.
      Participants with intermediate or low risk are assigned to Arm C.

      ARM A: Participants receive acalabrutinib orally (PO) twice daily (BID) on days 1-28.
      Treatment repeats every 28 days for 6 courses in the absence of disease progression or
      unacceptable toxicity. Participants then receive acalabrutinib PO BID on days 1-84. Treatment
      repeats every 84 days for 6 courses in the absence of disease progression or unacceptable
      toxicity. Participants may continue treatment with acalabrutinib If MRD negative CR/CR with
      incomplete marrow recovery (CRi) is not achieved after 12 courses.

      ARM B: Participants receive acalabrutinib orally (PO) twice daily (BID) on days 1-28 and
      obinutuzumab intravenously (IV) on days 1, 2, 8, and 15 of course 1 and days 1 of subsequent
      courses. Treatment repeats every 28 days for 6 courses in the absence of disease progression
      or unacceptable toxicity. Participants then receive acalabrutinib PO BID on days 1-84.
      Treatment repeats every 84 days for 6 courses in the absence of disease progression or
      unacceptable toxicity. Participants may continue treatment with acalabrutinib If MRD negative
      CR/CRi is not achieved after 12 courses.

      ARM C: Participants will be observed every 6 months for up to 2 years.

      After completion of study treatment, participants are followed up every 6 months for up to 5
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (acalabrutinib)ExperimentalParticipants receive acalabrutinib PO BID on days 1-28. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Participants then receive acalabrutinib PO BID on days 1-84. Treatment repeats every 84 days for 6 courses in the absence of disease progression or unacceptable toxicity. Participants may continue treatment with acalabrutinib If MRD negative CR/CRi is not achieved after 12 courses.
  • Acalabrutinib
Arm B (acalabrutinib, obinutuzumab)ExperimentalParticipants receive acalabrutinib PO BID on days 1-28 and obinutuzumab IV on days 1, 2, 8, and 15 of course 1 and days 1 of subsequent courses. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Participants then receive acalabrutinib PO BID on days 1-84. Treatment repeats every 84 days for 6 courses in the absence of disease progression or unacceptable toxicity. Participants may continue treatment with acalabrutinib If MRD negative CR/CRi is not achieved after 12 courses.
  • Acalabrutinib
Arm C (observation)Active ComparatorParticipants will be observed every 6 months for up to 2 years.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Diagnosis of:
    
                   -  Biopsy-proven small lymphocytic lymphoma (SLL) , or
    
                   -  Diagnosis of chronic lymphocytic leukemia (CLL) with a clonal B-cell population
                      in the peripheral blood with immunophenotyping consistent with CLL as follows:
    
                        -  The population of lymphocytes share both B-cell antigens (CD19, CD20
                           [typically dim expression], or CD23) as well as CD5 in the absence of other
                           pan-T-cell markers (CD3, CD2, etc.)
    
                        -  Clonality as evidenced by kappa or lambda light chain expression (typically
                           dim immunoglobulin expression) or other genetic method (e.g. IGHV analysis)
    
                        -  Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by
                           demonstrating a negative fluorescence in situ hybridization (FISH) analysis
                           for t(11;14)(IgH/CCND1)
    
              -  Patients must be previously untreated
    
                   -  Note: Prior chemotherapy or monoclonal antibody based therapy for treatment of
                      CLL or SLL will be considered prior therapy; nutraceutical treatments with no
                      established benefit in CLL (such as epigallocatechin gallate or EGCG, found in
                      green tea or other herbal treatments or supplemental vitamins) will not be
                      considered ?prior treatment?; prior corticosteroid therapy for an indication
                      other than CLL/SLL will not be considered ?prior treatment?
    
              -  All patients will undergo testing for prognostic factors according to the CLL-IPI
                 (testing obtained ? 120 days prior to registration)
    
                   -  Note: Patients with CLL-IPI risk category of high risk or very high risk (total
                      score of 4-10) will be randomized to Arms A or B
    
                   -  Note: Patients with CLL-IPI risk category of low risk or intermediate risk (total
                      score of 0-3) will be registered to Arm C
    
              -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
    
              -  Provide written informed consent
    
              -  Willing to provide blood and saliva samples for correlative research purposes
    
              -  Willing to return to enrolling institution for follow-up (during the active monitoring
                 phase of the study)
    
              -  For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ? 30 days prior
                 to randomization: Absolute neutrophil count (ANC) ? 1500/mm^3
    
              -  For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ? 30 days prior
                 to randomization: Platelet count ? 100,000/mm^3
    
              -  For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ? 30 days prior
                 to randomization: Hemoglobin ? 11.0 g/dL
    
              -  For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ? 30 days prior
                 to randomization: Aspartate aminotransferase (aspartate transaminase [AST]) ? 3 x
                 upper limit of normal (ULN)
    
              -  For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ? 30 days prior
                 to randomization: Creatinine ? 1.5 X ULN
    
              -  For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ? 30 days prior
                 to randomization: Total bilirubin ? 1.5 x upper limit of normal (ULN) (or total
                 bilirubin ? 3.0 x ULN with direct bilirubin ? 1.5 x ULN in patients with
                 well-documented Gilbert?s syndrome)
    
              -  For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ? 30 days prior
                 to randomization: prothrombin time (PT), international normalized ratio (INR), and
                 partial thromboplastin time (PTT) ? 1.5 X ULN OR if patient is receiving anticoagulant
                 therapy and PT or PTT is within therapeutic range of intended use of coagulants
    
              -  Negative serum pregnancy test done ? 7 days prior to registration, for persons of
                 childbearing potential only
    
              -  Will provide bone marrow aspirate sample for correlative research purposes
    
            Exclusion Criteria:
    
              -  Date of CLL/SLL diagnosis ? 24 months prior to registration
    
              -  Prior exposure to ibrutinib or to a BCR inhibitor (eg Btk or PI3 kinase or Syk
                 inhibitors) or a BCL-2 inhibitor (eg venetoclax)
    
              -  Known central nervous system (CNS) lymphoma or leukemia
    
              -  Patients with any of the following indications for chemotherapy:
    
                   -  Evidence of progressive marrow failure as manifested by the development of or
                      worsening anemia (? 11 g/dL) and/or thrombocytopenia (? 100 x 10^9/L) not due to
                      autoimmune disease
    
                   -  Symptomatic or progressive lymphadenopathy, splenomegaly or hepatomegaly
    
                   -  One or more of the following disease-related symptoms:
    
                        -  Weight loss ? 10% within the previous 6 months
    
                        -  Extreme fatigue attributed to CLL
    
                        -  Fevers ? 100.4 degree Fahrenheit (F) for 2 weeks without evidence of
                           infection
    
                        -  Drenching night sweats without evidence of infection
    
              -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
                 of the investigator, would make the patient inappropriate for entry into this study or
                 interfere significantly with the proper assessment of safety and toxicity of the
                 prescribed regimens
    
              -  Patients known to be human immunodeficiency virus (HIV) positive and currently
                 receiving antiretroviral therapy; NOTE: Patients known to be HIV positive, but without
                 clinical evidence of an immunocompromised state, are eligible for this trial
    
              -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
                 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
                 arrhythmia, or psychiatric illness/social situations that would limit compliance with
                 study requirements
    
              -  Receiving any other investigational agent which would be considered as a treatment for
                 the primary neoplasm
    
              -  Other active malignancy ? 2 years prior to registration; EXCEPTIONS: Non-melanotic
                 skin cancer, carcinoma-in-situ of the cervix, or early stage prostate cancer
    
              -  History of myocardial infarction ? 6 months prior to registration, or congestive heart
                 failure requiring use of ongoing maintenance therapy for life-threatening ventricular
                 arrhythmias
    
              -  For high risk and very high risk CLL-IPI (Arms A and B) only:
    
                   -  Any of the following:
    
                        -  Pregnant persons
    
                        -  Nursing persons
    
                        -  Persons of childbearing potential who are unwilling to employ highly
                           effective contraception
    
                   -  Serologic status reflecting active hepatitis B or C infection
    
                        -  NOTE: Subjects with hepatitis B core antibody positive who are surface
                           antigen negative or who are hepatitis C antibody positive will need to have
                           a negative polymerase chain reaction (PCR) result before randomization;
                           those who are hepatitis B surface antigen positive or hepatitis B PCR
                           positive and those who are hepatitis C PCR positive will be excluded
    
                   -  History of stroke or intracranial hemorrhage within 6 months before randomization
    
                   -  History of bleeding diathesis (e.g. hemophilia, von Willebrand disease)
    
                   -  Requires or receiving anticoagulation with warfarin or equivalent vitamin K
                      antagonists (e.g. phenprocoumon) within 7 days of first dose of study drug and
                      while on study
    
                   -  Requires treatment with a strong CYP3A inducer
    
                   -  Requires treatment with proton-pump inhibitors (e.g. omeprazole, esomeprazole,
                      lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole)
    
                   -  Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months
                      before screening
    
                   -  History of confirmed progressive multifocal leukoencephalopathy (PML)
    
                   -  Received a vaccination with a live vaccine ? 28 days prior to randomization
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Rate of minimal residual disease (MRD)-negative complete response (Arm A and Arm B)
    Time Frame:After 12 cycles (2 Years)
    Safety Issue:
    Description:Defined as an objective status of complete response (CR) or CR with incomplete marrow recovery (CRi) along with MRD negativity in the bone marrow by flow cytometry. Will be compared between the two arms. The proportion of successes will be estimated in each arm by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated in each arm based on the normal approximation. Comparison of MRD-negative complete response rates between the two treatment groups will be performed using a one-sided z-test (based on normal approximation with pooled variance of standardized test statistics) at significance level 0.10.

    Secondary Outcome Measures

    Measure:Overall response rate (Arms A and B)
    Time Frame:Up to 5 years
    Safety Issue:
    Description:Will be estimated in each arm by the number of patients who achieve a CR, CRi, clinical complete response (CCR), nodular partial response (nPR), or partial response (PR) at any time during treatment divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success rate will be calculated.
    Measure:Progression-free survival (Arms A and B)
    Time Frame:From randomization up to 5 years
    Safety Issue:
    Description:Will be estimated in each arm using the method of Kaplan-Meier. Progression-free survival will be compared between the two arms using log-rank statistics.
    Measure:Time to next therapy (Arms A and B)
    Time Frame:From the date of randomization up to 5 years
    Safety Issue:
    Description:Will be estimated in each arm using the method of Kaplan-Meier. Time to next therapy will be compared between the two arms using log-rank statistics.
    Measure:Overall survival (Arms A and B)
    Time Frame:From randomization up to 5 years
    Safety Issue:
    Description:Will be estimated in each arm using the method of Kaplan-Meier. Overall survival will be compared between the two arms using log-rank statistics.
    Measure:Progression-free survival (Arm C)
    Time Frame:From randomization up to 5 years
    Safety Issue:
    Description:Will be estimated in using the method of Kaplan-Meier.
    Measure:Overall survival (Arm C)
    Time Frame:From randomization up to 5 years
    Safety Issue:
    Description:Will be estimated in using the method of Kaplan-Meier.
    Measure:Incidence of adverse events rates according to Common Terminology Criteria for Adverse Events version 4.0 (Arms A and B)
    Time Frame:Up to 5 years
    Safety Issue:
    Description:The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed for each arm to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Mayo Clinic

    Last Updated

    May 3, 2018