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

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

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Richter Syndrome; Recurrent Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma; Loss of Chromosome 17p
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Biological: Nivolumab; Drug: Ibrutinib

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 Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort I (nivolumab, ibrutinib) Chronic Lymphocytic Leukemia (CLL); 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Drug: Ibrutinib; Given PO; Other Names: PCI-32765; Imbruvica; BTK Inhibitor PCI-32765; CRA-032765
Experimental: Cohort II (nivolumab, previous ibrutinib) Chronic Lymphocytic Leukemia (CLL); Patients receive nivolumab as in Cohort I and continue previous ibrutinib treatment.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Drug: Ibrutinib; Given PO; Other Names: PCI-32765; Imbruvica; BTK Inhibitor PCI-32765; CRA-032765
Experimental: Cohort III (nivolumab, ibrutinib) Richters Transformation (RT); 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Drug: Ibrutinib; Given PO; Other Names: PCI-32765; Imbruvica; BTK Inhibitor PCI-32765; CRA-032765

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Response for Cohorts 1 and 3	Response is Complete Response (CR) + Partial Response (PR). CR = Peripheral blood Lymphocytes <4000/uL, no lymphadenopathy, no hepatomegaly or splenomegaly by exam or scan, absence of symptoms, neutrophils > 1,500/uL, Platelets > 1000,000/uL, hemoglobin > 11.0 g/dl (untransfused) and normocellular bone marrow < 30% nucleated cells being lymphocytes, no lymphoid nodules. PR = 1 for >/= 2 months: >/= 50% decrease in peripheral lymphocyte count from baseline, >/= 50% reduction in lymphadenopathy, >/= 50% reduction in pretreatment enlargement of the spleen or liver by scan. Additionally for PR must have 1 of the following for >/= 2 months: Neutrophils > 1,500/uL, Platelets > 100,000/uL or >/= 50% improvement over baseline or Hemoglobin > 11.0 g/dl (untransfused) or >/= 50% improvement over baseline. Additionally if patients fufill CR but have one of the following, be considered a PR: bone marrow nodules or persistent anemia, thrombocytopenia, neutropenia unrelated to disease.	Up to 12 months
Number of Participants in Cohort 2 to Convert From a Partial Response (PR) to Complete Response (CR)	Complete Response (CR) = Peripheral blood Lymphocytes <4000/uL, no lymphadenopathy, no hepatomegaly or splenomegaly by exam or scan, absence of symptoms, neutrophils > 1,500/uL, Platelets > 1000,000/uL, hemoglobin > 11.0 g/dl (untransfused) and normocellular bone marrow < 30% nucleated cells being lymphocytes, no lymphoid nodules. Partial Response (PR) = 1 for >/= 2 months: >/= 50% decrease in peripheral lymphocyte count from baseline, >/= 50% reduction in lymphadenopathy, >/= 50% reduction in pretreatment enlargement of the spleen or liver by scan. Additionally for PR must have 1 of the following for >/= 2 months: Neutrophils > 1,500/uL, Platelets > 100,000/uL or >/= 50% improvement over baseline or Hemoglobin > 11.0 g/dl (untransfused) or >/= 50% improvement over baseline. Additionally if patients fufill CR but have one of the following, be considered a PR: bone marrow nodules or persistent anemia, thrombocytopenia, neutropenia unrelated to disease.	Up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Time from date of treatment start until date of death due to any cause or last Follow-up. Survival will be presented by median survival, which is the time point at which the cumulative survival drops below 50%. If there is no median survival (not reached), it means the cumulative survival was more than 50%.	Up to 6 years, 7 months
Progression-free Survival (PFS)	Time from date of treatment start until the date of first objective documentation of disease-relapse.	Up to 6 years, 7 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in biomarkers	Assessed through fitting linear or non-linear mixed effect models. Descriptive statistics including plots, mean, median & standard deviations will be used to summarize data. T-test & analysis of variance will be used to compare outcome measures across patient characteristics. Dunnett's & Tukey's test that properly adjust for multiplicity in multiple tests will be implemented. Pair-wise comparisons will be performed using pre- & post-therapy samples from each patient. The chi-square test or Fisher's exact test will be used to test the association between two categorical variables.	Baseline up to 1 year

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Nitin Jain, M.D. Anderson Cancer Center

Publications and helpful links

General Publications

• Jain N, Senapati J, Thakral B, Ferrajoli A, Thompson P, Burger J, Basu S, Kadia T, Daver N, Borthakur G, Konopleva M, Pemmaraju N, Parry E, Wu CJ, Khoury J, Bueso-Ramos C, Garg N, Wang X, Lopez W, Ayala A, O'Brien S, Kantarjian H, Keating M, Allison J, Sharma P, Wierda W. A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL. Blood Adv. 2023 May 23;7(10):1958-1966. doi: 10.1182/bloodadvances.2022008790.

Helpful Links

• University of Texas MD Anderson Cancer Center Website

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2015
• Primary Completion (Actual): February 14, 2022
• Study Completion (Actual): February 14, 2022

Study Registration Dates

• First Submitted: April 15, 2015
• First Submitted That Met QC Criteria: April 15, 2015
• First Posted (Estimated): April 20, 2015

Study Record Updates

• Last Update Posted (Actual): March 20, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Leukemia, B-Cell; Chronic Disease; Lymphoma; Leukemia; Recurrence; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Tyrosine Kinase Inhibitors; Nivolumab; Ibrutinib
• Other Study ID Numbers: 2014-0931 (Other Identifier: M D Anderson Cancer Center); NCI-2015-00844 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No