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.
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 Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Maximum tolerated dose of ipilimumab
Time frame: Up to 2 years
Dose limiting toxicities
DLT is defined as clinically significant non-hematologic adverse event or abnormal laboratory value assessed as unrelated to disease, intercurrent illness, or concomitant medications and occurring during the first 21 days.
Time frame: During first 21 days on study intervention
Overall response rate
Defined as complete response (CR) + complete response with incomplete marrow recovery (CRi) + partial response (PR). Response will be assessed by the investigator, based on physical examinations, computed tomography scans, laboratory results, and bone marrow examinations, according to the modified 2008 International Workshop on Chronic Lymphocytic Leukemia response criteria for chronic lymphocytic leukemia. The overall response rate (i.e., CR/CRi/PR) will be estimated along with the exact 95% confidence interval.
Time frame: Up to 2 years
Progression-free survival
Assessed using Kaplan-Meier method.
Time frame: From treatment start date until the date of disease progression date or death due to any cause, whichever occurred first, assessed up to 2 years
Overall survival
Assessed using Kaplan-Meier method.
Time frame: From treatment start date until the date of death due to any cause, assessed up to 2 years
Incidence of adverse events
Will be summarized by treatment, category, severity and attribution.
Time frame: Up to 2 years
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