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

Phase 2

Completed

Conditions: Recurrent Small Lymphocytic Lymphoma
Recurrent Chronic Lymphocytic Leukemia
Refractory Chronic Lymphocytic Leukemia
Loss of Chromosome 17p
Refractory Small Lymphocytic Lymphoma
Richter Syndrome

Interventions: Drug: Ibrutinib
Other: Laboratory Biomarker Analysis
Biological: Nivolumab

Registration Number: NCT02420912

Lead Sponsor: M.D. Anderson Cancer Center

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 37

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort II (nivolumab, previous ibrutinib) Chronic Lymphocytic Leukemia (CLL)	Laboratory Biomarker Analysis	Patients receive nivolumab as in Cohort I and continue previous ibrutinib treatment.
Cohort II (nivolumab, previous ibrutinib) Chronic Lymphocytic Leukemia (CLL)	Nivolumab	Patients receive nivolumab as in Cohort I and continue previous ibrutinib treatment.
Cohort III (nivolumab, ibrutinib) Richters Transformation (RT)	Ibrutinib	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.
Cohort III (nivolumab, ibrutinib) Richters Transformation (RT)	Laboratory Biomarker Analysis	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.
Cohort III (nivolumab, ibrutinib) Richters Transformation (RT)	Nivolumab	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.
Cohort I (nivolumab, ibrutinib) Chronic Lymphocytic Leukemia (CLL)	Ibrutinib	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.
Cohort I (nivolumab, ibrutinib) Chronic Lymphocytic Leukemia (CLL)	Laboratory Biomarker Analysis	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.
Cohort I (nivolumab, ibrutinib) Chronic Lymphocytic Leukemia (CLL)	Nivolumab	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.
Cohort II (nivolumab, previous ibrutinib) Chronic Lymphocytic Leukemia (CLL)	Ibrutinib	Patients receive nivolumab as in Cohort I and continue previous ibrutinib treatment.

Primary Outcome Measures

Name	Time	Method
Number of Participants With a Response for Cohorts 1 and 3	Up to 12 months	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.
Number of Participants in Cohort 2 to Convert From a Partial Response (PR) to Complete Response (CR)	Up to 12 months	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.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	Up to 6 years, 7 months	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%.
Progression-free Survival (PFS)	Up to 6 years, 7 months	Time from date of treatment start until the date of first objective documentation of disease-relapse.