Nivolumab and Ibrutinib in Treating Patients With Relapsed, Refractory, or High-Risk Untreated Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Richter Transformation

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Brief Title

Nivolumab and Ibrutinib in Treating Patients With Relapsed, Refractory, or High-Risk Untreated Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Richter Transformation

Official Title

Nivolumab Combined With Ibrutinib for Relapsed, Refractory or High-Risk Untreated Patients With Chronic Lymphocytic Leukemia (CLL)

Brief Summary

      This phase II trial studies how well nivolumab and ibrutinib work when given together in
      treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or Richter
      transformation that has come back after a period of improvement (relapsed), does not respond
      to treatment (refractory), or is at high risk of spreading and has not been treated.
      Immunotherapy with monoclonal antibodies, such as niolumab, may help the body's immune system
      attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
      Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell
      growth. Giving nivolumab together with ibrutinib may kill more cancer cells.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the efficacy (response rate) of nivolumab in combination with ibrutinib in
      patients with relapsed/refractory or high-risk untreated chronic lymphocytic leukemia (CLL).

      II. Determine the response rate (complete response [CR]/complete response with incomplete
      marrow recovery [CRi]) by 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL)
      criteria. (Cohort I) III. Determine the conversion rate from partial response (PR) to CR/CRi
      by 2008 IWCLL criteria. (Cohort II) IV. Determine the response rate (CR/CRi). (Cohort III)

      SECONDARY OBJECTIVES:

      I. To determine the safety of nivolumab in combination with ibrutinib in patients with
      relapsed, refractory or high-risk untreated CLL/Richter transformation (RT).

      II. To determine the progression-free survival of patients with relapsed, refractory or
      high-risk untreated CLL/RT treated with nivolumab in combination with ibrutinib.

      III. To determine the overall survival of patients with relapsed, refractory or high-risk
      untreated CLL/RT treated with nivolumab in combination with ibrutinib.

      EXPLORATORY OBJECTIVES:

      I. To study immunological and molecular changes in peripheral blood, lymph node, and bone
      marrow in response to nivolumab and ibrutinib therapy.

      OUTLINE: Patients are assigned to 1 of 3 treatment cohorts.

      COHORT I (NO CURRENT IBRUTINIB TREATMENT): Patients receive nivolumab intravenously (IV) over
      1 hour on days 1 and 15 and ibrutinib orally (PO) once daily (QD) on days 1-28 of courses
      2-24. Treatment repeats every 28 days for up to 24 courses in the absence of disease
      progression or unacceptable toxicity.

      COHORT II (IBRUTINIB TREATMENT > 9 MONTHS): Patients receive nivolumab as in Cohort I and
      continue previous ibrutinib treatment.

      COHORT III (RICHTER TRANSFORMATION): Patients receive nivolumab and ibrutinib as in cohort I.
      Ibrutinib may be given earlier than course 2 in case of worsening disease after discussion
      with study principal investigator. Treatment repeats every 28 days for up to 24 courses in
      the absence of disease progression or unacceptable toxicity

      * Note: After 3 cycles of treatment, nivolumab administration may be decreased to once every
      4 weeks in all cohorts, in consultation with the study principal investigator.

      After completion of study treatment, patients are followed up monthly for 1 year.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Best response (BR) defined as complete response (CR) or complete response with incomplete marrow recovery (CRi) that occurs during the first 12 months of treatment (Cohort I and Cohort III)

Secondary Outcome

 Incidence of toxicity defined as any grade 3 or higher non-hematological toxicity at least possibly related to treatment graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0

Condition

Loss of Chromosome 17p

Intervention

Ibrutinib

Study Arms / Comparison Groups

 Cohort I (nivolumab, ibrutinib)
Description:  Patients receive nivolumab IV over 1 hour on days 1 and 15 and ibrutinib PO QD on days 1-28 of courses 2-24. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

72

Start Date

June 19, 2015

Completion Date

February 14, 2022

Primary Completion Date

February 14, 2022

Eligibility Criteria

        Inclusion Criteria:

          -  Patients will have a diagnosis of CLL or small lymphocytic lymphoma (SLL), refractory
             to or relapsed after at least one prior standard therapy or untreated with deletion
             (del)(17p) by fluorescence in-situ hybridization (FISH) (high-risk cytogenetics) and
             have an indication for treatment by IWCLL 2008 criteria (Cohort 1) OR have been on
             ibrutinib for at least 9 months with measurable persistent disease (absolute
             lymphocyte count [ALC] > 4 K/muL, any lymph node > 1.5 cm by computed tomography [CT]
             scan, or > 30% lymphocytes on bone marrow aspirate differential) (Cohort 2), OR
             patients will have a diagnosis of RT, refractory to and/or relapsed after at least one
             prior standard therapy or untreated with del(17p) by FISH (high-risk cytogenetics)
             (Cohort 3)

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

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN); for patients with Gilbert's
             disease, total bilirubin up to =< 3 x ULN is allowed provided normal direct bilirubin

          -  Serum creatinine =< 1.5 x ULN

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN

          -  Females of childbearing potential must have a negative serum or urine beta human
             chorionic gonadotrophin (beta-hCG) pregnancy test result within 24 hours prior to the
             first dose of treatment and must agree to use an effective contraception method during
             the study and for 23 weeks following the last dose of the study drugs; females of
             non-childbearing potential are those who are postmenopausal greater than 1 year or who
             have had a bilateral tubal ligation or hysterectomy; males who have partners of
             childbearing potential must agree to use an effective contraceptive method during the
             study and for 31 weeks following the last dose of study drugs

          -  Patients or their legally authorized representative must provide written informed
             consent

        Exclusion Criteria:

          -  History of another primary invasive malignancy that has not been definitively treated
             or in remission for at least 2 years; patients with non-melanoma skin cancers or with
             carcinomas in situ are eligible regardless of the time from diagnosis (including
             concomitant diagnoses); if patients have another malignancy that was treated within
             the last 2 years, such patients may be enrolled if the likelihood of requiring
             systemic therapy for this other malignancy within 2 years is less than 10%, as
             determined by an expert in that particular malignancy at MD Anderson Cancer Center and
             after consultation with the principal investigator

          -  Any major surgery, radiotherapy, cytotoxic chemotherapy, biologic therapy,
             immunotherapy, immunomodulatory drugs, experimental therapy within 4 weeks prior to
             the first dose of the study drugs; Note: prior therapy with anti cluster of
             differentiation (CD)20 monoclonal antibody, anti CD52 monoclonal antibody, and
             lenalidomide are allowed; for oral targeted therapies (such as idelalisib,
             venetoclax), a washout of 3 days is allowed

          -  Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,
             congestive heart failure, or myocardial infarction within 2 months of screening, or
             any class 3 or 4 cardiac disease as defined by the New York Heart Association
             functional classification

          -  History of stroke or cerebral hemorrhage within 2 month

          -  Patients who have uncontrolled hypertension (defined as sustained systolic blood
             pressure >= 160 mmHg or diastolic >= 100 mmHg)

          -  Known evidence of active cerebral/meningeal CLL; patients may have history of central
             nervous system (CNS) leukemic involvement if definitively treated with prior therapy
             and no evidence of active disease at the time of registration

          -  Active, uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring
             steroid therapy

          -  Patients with autoimmune diseases are excluded: patients with a history of
             inflammatory bowel disease (including Crohn's disease and ulcerative colitis) are
             excluded from this study as are patients with a history of autoimmune disease (e.g.,
             rheumatoid arthritis, systemic progressive sclerosis, systemic lupus erythematosus,
             Wegener's granulomatosis)

          -  Patients with previous allogeneic stem cell transplant (SCT) within 6 months or with
             active acute or chronic graft-versus host disease are excluded; patients must be off
             immunosuppression for graft-versus host disease (GVHD) for at least 30 days before
             cycle 1 day 1

          -  Patients with organ allografts (such as renal transplant) are excluded

          -  History of interstitial lung disease or pneumonitis

          -  Patients who are on high dose steroid (> 10 mg daily of prednisone or equivalent) or
             immune suppression medications; Note: patients on high-dose steroids (doses > 10mg/day
             of prednisone or equivalent) or immune suppression medications are eligible provided
             these drugs are discontinued at least 3 days prior to starting on the study drugs

          -  Patients with uncontrolled active infection (viral, bacterial, and fungal) are not
             eligible

          -  Current or chronic hepatitis B or C infection, or known seropositivity for human
             immunodeficiency virus (HIV)

          -  Patient is pregnant or breast-feeding

          -  Concurrent use of investigational therapeutic agent

          -  Malabsorption syndrome or other condition that precludes enteral route of
             administration

          -  Concomitant use of warfarin or other vitamin K antagonists

          -  Requires treatment with a strong cytochrome P450 (CYP) family 3, subfamily A (3A)
             inhibitor

          -  Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that in the opinion of the investigator may increase the risk associated
             with study participation or investigational product administration or may interfere
             with the interpretation of study results and/or would make the patient inappropriate
             for enrollment into this study
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Nitin Jain, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02420912

Organization ID

2014-0931

Secondary IDs

NCI-2015-00844

Responsible Party

Sponsor

Study Sponsor

M.D. Anderson Cancer Center

Collaborators

 National Cancer Institute (NCI)

Study Sponsor

Nitin Jain, Principal Investigator, M.D. Anderson Cancer Center


Verification Date

March 2022