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

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ClinicalTrials.gov Identifier: NCT03516617
Recruitment Status : Recruiting
First Posted : May 4, 2018
Last Update Posted : October 9, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Tracking Information
First Submitted Date  ICMJE April 23, 2018
First Posted Date  ICMJE May 4, 2018
Last Update Posted Date October 9, 2019
Actual Study Start Date  ICMJE September 10, 2018
Estimated Primary Completion Date March 15, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 3, 2018)
  • Rate of minimal residual disease (MRD)-negative complete response (Arm A and Arm B) [ Time Frame: After 12 cycles (2 Years) ]
    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.
  • Time to first therapy in patients (Arm C) [ Time Frame: From the date of registration, assessed after 12 cycles (2 Years) ]
    Will be estimated using the method of Kaplan-Meier.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 3, 2018)
  • Overall response rate (Arms A and B) [ Time Frame: Up to 5 years ]
    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.
  • Progression-free survival (Arms A and B) [ Time Frame: From randomization up to 5 years ]
    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.
  • Time to next therapy (Arms A and B) [ Time Frame: From the date of randomization up to 5 years ]
    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.
  • Overall survival (Arms A and B) [ Time Frame: From randomization up to 5 years ]
    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.
  • Progression-free survival (Arm C) [ Time Frame: From randomization up to 5 years ]
    Will be estimated in using the method of Kaplan-Meier.
  • Overall survival (Arm C) [ Time Frame: From randomization up to 5 years ]
    Will be estimated in using the method of Kaplan-Meier.
  • 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 ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: May 3, 2018)
  • Quality of life measures used Functional Assessment of Cancer Therapy-General (FACT-G) [ Time Frame: Up to 5 years ]
    Descriptive statistics by arm at each time point will include means, standard deviations, medians, and ranges for each scale. Descriptive graphical techniques will include mean plots by arm over time for each scale. For evaluating changes over time in each score, a minimally important difference will be defined as a change of 7 points, based on previously established cutoffs for the transformed FACT-G scores. Changes from baseline will be assessed using a paired sample t-test.
  • T-cells, natural killer (NK)-cells, and NK-T cells assess in peripheral blood immune profile using 8-color flow cytometry [ Time Frame: Baseline ]
    Values over time will be summarized graphically and descriptively. Paired sample approaches (Wilcoxon signed rank test) for these types of quantitative measures will be used to assess differences over time. Differences between treatments (Arms A and B only) will be assessed.
  • Bone marrow hematopoiesis (Arms A and B) [ Time Frame: Up to 5 years ]
    will be evaluated by estimation of colony forming capacity by purified hematopoietic stem cells (HSCs) and their differentiated progeny (i.e. MPP, CMP, CLP) as continuous measures. Degree of cytopenia in the peripheral blood will be evaluated on a continuous scale for each blood cell component (hemoglobin, platelets, etc.). In each arm, correlation between each blood cell component and its corresponding pre-cursor will be evaluated using Spearman?s rank correlation coefficients.
  • Percent killing of chronic lymphocytic leukemia (CLL) B-cells (Arms A and B) [ Time Frame: After 12 cycles (2 years) ]
    Will be measured as a continuous measure. In each arm, the relationship between percent killing and response (responder versus [vs.] non-responder) after 12 cycles of treatment will be evaluating using Wilcoxon?s rank sum test.
  • Somatic genetic mutations (Arms A and B) [ Time Frame: After 12 cycles (2 years) ]
    Will be evaluated as present vs. absent for each gene. In each arm, the relationship between each mutation and response (responder vs. non-responder) after 12 cycles of treatment will be evaluated using Fisher?s exact test.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Acalabrutinib With or Without Obinutuzumab in Treating Participants With Early-Stage Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Official Title  ICMJE 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
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • CCND1 Negative
  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
  • t(11;14) Negative
Intervention  ICMJE
  • Drug: Acalabrutinib
    Given PO
    Other Names:
    • ACP-196
    • Bruton Tyrosine Kinase Inhibitor ACP-196
    • Calquence
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: Obinutuzumab
    Given IV
    Other Names:
    • Anti-CD20 Monoclonal Antibody R7159
    • GA-101
    • GA101
    • Gazyva
    • huMAB(CD20)
    • R7159
    • RO 5072759
  • Other: Patient Observation
    Undergo observation
    Other Names:
    • Active Surveillance
    • deferred therapy
    • expectant management
    • observation
    • Watchful Waiting
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
Study Arms  ICMJE
  • Experimental: Arm A (acalabrutinib)
    Participants 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.
    Interventions:
    • Drug: Acalabrutinib
    • Other: Laboratory Biomarker Analysis
    • Other: Quality-of-Life Assessment
  • Experimental: Arm B (acalabrutinib, obinutuzumab)
    Participants 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.
    Interventions:
    • Drug: Acalabrutinib
    • Other: Laboratory Biomarker Analysis
    • Biological: Obinutuzumab
    • Other: Quality-of-Life Assessment
  • Active Comparator: Arm C (observation)
    Participants will be observed every 6 months for up to 2 years.
    Interventions:
    • Other: Laboratory Biomarker Analysis
    • Other: Patient Observation
    • Other: Quality-of-Life Assessment
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 3, 2018)
120
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 15, 2025
Estimated Primary Completion Date March 15, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 (see Note)

    • 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), as shown in Appendix V.

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03516617
Other Study ID Numbers  ICMJE MC168E
NCI-2018-00591 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC168E ( Other Identifier: Mayo Clinic )
P30CA015083 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mayo Clinic
Study Sponsor  ICMJE Mayo Clinic
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Sameer Parikh Mayo Clinic
PRS Account Mayo Clinic
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP