Clinical Trials /

Daratumumab and Ibrutinib in Treating Patients With Symptomatic Chronic Lymphocytic Leukemia

NCT03447808

Description:

This phase Ib trials studies the side effects of daratumumab and ibrutinib and how well they work in treating patients with symptomatic chronic lymphocytic leukemia. Monoclonal antibodies, such as daratumumab, may interfere with the ability of cancer cells to grow and spread. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving daratumumab and ibrutinib may work better in treating patients with chronic lymphocytic leukemia.

Related Conditions:
  • Chronic Lymphocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Daratumumab and Ibrutinib in Treating Patients With Symptomatic Chronic Lymphocytic Leukemia
  • Official Title: Daratumumab and Ibrutinib for Symptomatic, Treatment-Naive CLL: A Phase 1b Proof-of-Concept Study

Clinical Trial IDs

  • ORG STUDY ID: OSU-17143
  • SECONDARY ID: NCI-2018-00159
  • SECONDARY ID: P30CA016058
  • NCT ID: NCT03447808

Conditions

  • Chronic Lymphocytic Leukemia

Interventions

DrugSynonymsArms
DaratumumabAnti-CD38 Monoclonal Antibody, Darzalex, HuMax-CD38, JNJ-54767414Treatment (daratumumab, ibrutinib)
IbrutinibBTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765Treatment (daratumumab, ibrutinib)

Purpose

This phase Ib trials studies the side effects of daratumumab and ibrutinib and how well they work in treating patients with symptomatic chronic lymphocytic leukemia. Monoclonal antibodies, such as daratumumab, may interfere with the ability of cancer cells to grow and spread. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving daratumumab and ibrutinib may work better in treating patients with chronic lymphocytic leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To characterize the safety of treatment with daratumumab and ibrutinib for previously
      untreated chronic lymphocytic leukemia (CLL).

      II. To determine the complete response rate (CR) at the post cycle 12 response assessment
      following treatment with daratumumab and ibrutinib for previously untreated chronic
      lymphocytic leukemia (CLL).

      SECONDARY OBJECTIVES:

      I. To characterize the activity of daratumumab and ibrutinib as measured by overall response
      rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival
      (OS), and time-to-next treatment.

      TERTIARY OBJECTIVES:

      I. To measure pharmacodynamic parameters in B cells including drug occupancy of BTK and B
      cell receptor signaling during treatment.

      II. To determine the influence of this combination on T cell and natural killer (NK) cell
      number and function.

      III. To assess for development of mutations that may confer resistance to this combination.

      IV. To assess the ability of daratumumab to clear CLL in the peripheral blood and association
      of CD38 expression on CLL cells with response.

      OUTLINE:

      Patients receive daratumumab intravenously (IV) on days 1, 8, 15, and 22 of courses 1-2, days
      1 and 15 of courses 3-6, and day 1 of subsequent courses. Treatment repeats every 28 days for
      up to 12 courses in the absence of disease progression or unacceptable toxicity. Beginning
      course 2, patients also receive ibrutinib orally (PO) once daily (QD) on days 1-28. Courses
      repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 12 weeks for up to 2
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (daratumumab, ibrutinib)ExperimentalPatients receive daratumumab IV on days 1, 8, 15, and 22 of courses 1-2, days 1 and 15 of courses 3-6, and day 1 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Beginning course 2, patients also receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Daratumumab
  • Ibrutinib

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of chronic lymphocytic leukemia (CLL) meeting criteria established in the
             International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for the
             diagnosis and treatment of CLL

          -  Requires therapy for symptomatic CLL in the opinion of the treating physician as
             defined by:

               -  Evidence of marrow failure as manifested by the development or worsening of
                  anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or
                  thrombocytopenia)

               -  Massive (>= 6 cm below the costal margin), progressive or symptomatic
                  splenomegaly

               -  Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy

               -  Constitutional symptoms, which include any of the following:

                    -  Unintentional weight loss of 10% or more within 6 months

                    -  Significant fatigue limiting activity

                    -  Fevers >= 100.5 degrees Fahrenheit (F) for 2 weeks or more without evidence
                       of infection

                    -  Night sweats > 1 month without evidence of infection

          -  No prior chemotherapy, immunotherapy, or targeted therapy for the treatment of CLL
             with the exception of palliative loco-regional radiotherapy and corticosteroids for
             symptom control

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Hemoglobin >= 8 g/dL

          -  Absolute neutrophil count (ANC) >= 1000/mm^3

          -  Platelets >= 30,000/mm^3

          -  Prothrombin time (PT)/partial thromboplastin time (PTT) =< 1.5 x ULN

          -  Total bilirubin =<1.5 x ULN (excepting Gilbert?s syndrome)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (unless
             due to liver involvement)

          -  Serum creatinine < 2.0 mg/dL OR creatinine clearance (Cockcroft) >= 40 mL/min/1.73 m^2

          -  Women of childbearing potential and men who are sexually active must be practicing a
             highly effective method of birth control during and after the study consistent with
             local regulations regarding the use of birth control methods for subjects
             participating in clinical trials; men must agree to not donate sperm during and after
             the study; for females, these restrictions apply for 1 month after the last dose of
             study drug; for males, these restrictions apply for 3 months after the last dose of
             study drug

          -  Women of childbearing potential must have a negative serum (beta-human chorionic
             gonadotropin [beta-hCG]) or urine pregnancy test at screening; women who are pregnant
             or breastfeeding are ineligible for this study

          -  Sign (or their legally-acceptable representatives must sign) an informed consent
             document indicating that they understand the purpose of and procedures required for
             the study, including biomarkers, and are willing to participate in the study

          -  Positive hepatitis serology:

               -  Hepatitis B virus (HBV): Patients with positive serology for hepatitis B defined
                  as positivity for hepatitis B surface antigen (HBsAg) or hepatitis B virus core
                  antibody (anti-HBc); patients who are positive for anti-HBc may be considered for
                  inclusion in the study on a case-by-case basis if they are hepatitis B viral
                  deoxyribonucleic acid (DNA) negative and are willing to undergo ongoing HBV DNA
                  testing by real-time polymerase chain reaction (PCR); patients with positive
                  serology may be referred to a hepatologist or gastroenterologist for appropriate
                  monitoring and management

                    -  Patients with positive hepatitis B surface antigen (HBSAg) consistent with
                       prior vaccination to HBV (i.e., hepatitis B virus surface antibody
                       [anti-HBs]+, anti-HBc-) may participate

                    -  Patients suspected to have false positive serologic studies because of IV
                       immunoglobulin administration are potentially eligible after negative PCR
                       studies for viral DNA/ribonucleic acid (RNA) and discussion with the
                       principal investigator

               -  Hepatitis C virus (HCV): Patients with positive hepatitis C serology unless HCV
                  RNA is confirmed negative and may be considered for inclusion in the study on a
                  case-by-case basis (e.g., patients with negative viral load after HCV-specific
                  treatment)

        Exclusion Criteria:

          -  Patients who have had chemotherapy, immunotherapy, radiotherapy, or investigational
             therapy within 28 days prior to entering the study or those who have not recovered
             from adverse events due to agents administered more than 28 days earlier; steroids for
             control of disease related symptoms are permitted

          -  Patients who are receiving any other investigational agents

          -  History of stroke or intracranial hemorrhage within 6 months prior to randomization

          -  Uncontrolled autoimmune hemolytic anemia or thrombocytopenia

          -  Active Richter's transformation

          -  Known active involvement of the central nervous system by lymphoma or leukemia

          -  Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg,
             phenprocoumon); patients may be eligible if able to be taken off warfarin and started
             on an alternative anticoagulant

          -  Requires chronic treatment with strong CYP3A inhibitors

          -  Known infection with the human immunodeficiency virus (HIV) virus

          -  Clinically significant cardiovascular disease such as uncontrolled or symptomatic
             arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
             screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by
             the New York Heart Association functional classification

          -  History of severe (defined as grade 4 and/or requiring permanent discontinuation of
             prior antibody therapy) allergic or anaphylactic reactions to human, humanized,
             chimeric, or murine monoclonal antibodies

          -  A female patient who is pregnant or breast-feeding

          -  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

          -  Known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory
             volume in 1 second [FEV1] < 50% of predicted normal), persistent asthma, or a history
             of poorly controlled asthma within the last 2 years (controlled intermittent asthma or
             controlled mild persistent asthma is allowed)

          -  History of other active malignancies other than CLL within the past 3 years prior to
             study entry, with the exception of adequately treated in situ carcinoma or the cervix
             uteri or breast, basal cell or localized squamous cell carcinoma of the skin, previous
             malignancy confirmed and surgically resected (or treated with other modalities) with
             curative intent or without relapse for >= 2 years

          -  Vaccination with a live vaccine < 28 days prior to the start of treatment

          -  Any life-threatening illness, medical condition, or organ system dysfunction which, in
             the investigator?s opinion, could compromise the subject?s safety, interfere with the
             absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue
             risk
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete response (CR) + complete response with incomplete marrow recovery (CRi) defined by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria
Time Frame:Up to 2 years
Safety Issue:
Description:Will be tabulated by type and grade and displayed in summary form.

Secondary Outcome Measures

Measure:Duration of response (DOR)
Time Frame:From the date of first response until the date of progression or death presumed attributable to disease progression, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Will be summarized by the Kaplan-Meier method.
Measure:Overall survival
Time Frame:From the first treatment date until the date of death or date last known alive, assessed up to 2 years
Safety Issue:
Description:Will be summarized by the Kaplan-Meier method.
Measure:Overall survival (CR + CRi + partial response [PR])
Time Frame:Up to 2 years
Safety Issue:
Description:With a 95% confidence interval (CI) will be reported for all evaluable patients, assuming a binomial distribution.
Measure:Progression-free survival
Time Frame:From the first treatment date until the date of progression or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Will be summarized by the Kaplan-Meier method.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Jennifer Woyach

Last Updated

August 22, 2019