Ipilimumab, Ibrutinib, and Nivolumab for the Treatment of Chronic Lymphocytic Leukemia and Richter Transformation

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Brief Title

Ipilimumab, Ibrutinib, and Nivolumab for the Treatment of Chronic Lymphocytic Leukemia and Richter Transformation

Official Title

Ipilimumab Combined With Ibrutinib and Nivolumab for Patients With Chronic Lymphocytic Leukemia (CLL) and Richter Transformation (RT)

Brief Summary

      This phase I/Ib trial evaluates the best dose and side effects of ipilimumab in combination
      with either ibrutinib alone or with ibrutinib and nivolumab in treating patients with chronic
      lymphocytic leukemia (CLL) and Richter transformation (RT). Immunotherapy with monoclonal
      antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the
      cancer, and 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 ipilimumab with either ibrutinib alone or with ibrutinib and nivolumab may help
      control CLL and RT.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of
      ipilimumab in combination with ibrutinib in patients with CLL/small lymphocytic lymphoma
      (SLL)/RT. (Part A) II. To determine the MTD and DLT of ipilimumab in combination with
      nivolumab and ibrutinib in patients with CLL/SLL/RT. (Part B)

      SECONDARY OBJECTIVES:

      I. To determine the efficacy (response rate, defined as complete response [CR] + complete
      response with incomplete marrow recovery [CRi] + partial response [PR]) of the combination
      therapy.

      II. To determine the progression-free survival and overall survival of the combination
      therapy.

      EXPLORATORY OBJECTIVE:

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

      OUTLINE: This is a dose-escalation study of ipilimumab followed by a dose-expansion study.
      Patients are assigned to 1 of 2 parts.

      PART A: Patients receive ipilimumab intravenously (IV) over 90 minutes on day 1. Treatment
      repeats every 3 weeks for up to 4 cycles in the absence of disease progression or
      unacceptable toxicity. Beginning day 1 of cycle 1, patients also receive ibrutinib orally
      (PO) once daily (QD) in the absence of disease progression or unacceptable toxicity. Patients
      who complete 4 doses of ipilimumab and are deriving benefit from it, without severe
      toxicities, may continue to receive ipilimumab every 12 weeks for up to a total of 2 years.

      PART B: Patients receive ipilimumab IV over 90 minutes and nivolumab IV over 30 minutes on
      day 1. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease
      progression or unacceptable toxicity. Beginning day 7 of cycle 1, patients also receive
      ibrutinib PO QD in the absence of disease progression or unacceptable toxicity. Patients who
      complete 4 doses of ipilimumab and nivolumab, and are deriving benefit from it, without
      severe toxicities, may continue to receive ipilimumab every 12 weeks and nivolumab every 4
      weeks for up to a total of 2 years.

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

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Maximum tolerated dose of ipilimumab

Secondary Outcome

 Overall response rate

Condition

Hematopoietic and Lymphoid Cell Neoplasm

Intervention

Ibrutinib

Study Arms / Comparison Groups

 Part A (ipilimumab, ibrutinib)
Description:  Patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning day 1 of cycle 1, patients also receive ibrutinib PO QD in the absence of disease progression or unacceptable toxicity. Patients who complete 4 doses of ipilimumab and are deriving benefit from it, without severe toxicities, may continue to receive ipilimumab every 12 weeks for up to a total of 2 years.

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

50

Start Date

April 30, 2022

Completion Date

December 31, 2024

Primary Completion Date

December 31, 2024

Eligibility Criteria

        Inclusion Criteria:

          -  Cohort 1: Patients with a diagnosis of CLL or SLL, refractory to and/or relapsed after
             at least one prior therapy (prior therapy could be a chemoimmunotherapy regimen, or a
             targeted therapy such as a BTK inhibitor, a BCL2 inhibitor, or a PI3 kinase inhibitor)
             or untreated with del(17p) by fluorescence in situ hybridization (FISH) (high-risk
             cytogenetics) and have an indication for treatment by International Workshop on
             Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria

          -  Cohort 2: Patients with a diagnosis of CLL or SLL who have been on ibrutinib for at
             least 9 months with measurable persistent disease (absolute lymphocyte count [ALC] >
             4K/uL, any lymph node > 1.5 cm by computed tomography [CT] scan, or > 30% lymphocytes
             on bone marrow aspirate differential)

          -  Cohort 3: Patients with a diagnosis of RT

          -  Age 18 years or older

          -  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 (unless
             deemed to be disease related)

          -  Females of childbearing potential must have a negative serum or urine beta human
             chorionic gonadotrophin (beta-human chorionic gonadotropin [hCG]) pregnancy test
             result within 14 days 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 CD20 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.
             For patients who are on ibrutinib at study entry - may continue ibrutinib without
             interruption

          -  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 >= 140 mmHg or diastolic >= 90 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 steroids (> 10 mg daily of prednisone or equivalent) or
             immune suppression medications. Note: Patients on high-dose steroids (doses > 10
             mg/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) 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

NCT04781855

Organization ID

2020-0571

Secondary IDs

NCI-2020-14161

Responsible Party

Sponsor

Study Sponsor

M.D. Anderson Cancer Center


Study Sponsor

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


Verification Date

March 2022