Chronic lymphocytic leukemia (CLL) is a cancer of white blood cells. It is also called small lymphocytic lymphoma (SLL). It causes tiredness, night sweats, weight loss, swollen lymph nodes, easy bruising or bleeding, and frequent infections. Researchers want to test if a drug combination is effective and safe for people with CLL/SLL.
To test how safe and effective a combination of ibrutinib, short-course fludarabine, and pembrolizumab is for people with chronic lymphocytic leukemia (CLL), also known as small lymphocytic lymphoma (SLL).
Adults at least 18 years old who have CLL or SLL, with certain genetic changes.
Participants will be screened with:
Blood and lab tests
Small lymph node sample removed by needle
Sample of bone marrow taken by needle in the hipbone. The area will be numbed.
CT or PET scan. They will lie in a machine that takes pictures. They may have a radioactive sugar injected before the scan.
Phase 1 will be 12 weeks. Participants will take ibrutinib by mouth once a day. For weeks 5 and 9 they will also take fludarabine. It will be infused in a vein for half an hour each day for 5 days in a row.
Phase 2 will be 2 years. Participants will take ibrutinib by mouth once a day. They will also get pembrolizumab by vein for half an hour once every 3 weeks.
After that, the study team will decide if participants should continue therapy.
During the study, participants will have regular visits. They will repeat some or all screening tests.
Chronic lymphocytic leukemia and small lymphocytic lymphoma (hereby referred as CLL) are tumors of B cells. A subset of patients categorized as high-risk CLL has a poor clinical outcome when treated with conventional chemotherapy. High-risk CLL is defined by relapsed/refractory disease status, or the presence of high-risk mutations, such as deletion 17p, TP53, and NOTCH1. While the cause of CLL is still unclear, studies have indicated critical factors required for the tumor cells. First, CLL cells grow and survive because they receive signals through the B-cell receptor (BCR); and second, CLL cells benefit from interactions with other cells, especially T cells.
The stimulation through the BCR can be blocked by ibrutinib, which is an oral drug that selectively inhibits Bruton s tyrosine kinase (BTK). In clinical trials, ibrutinib demonstrated safety and high response rates in patients with high-risk disease. Ibrutinib has gained FDA approval as a treatment for CLL regardless of prior treatment or cytogenetic status. However, single-agent ibrutinib has limitations; the drug does not eliminate all tumor cells and, with time, the tumor cells may become resistant. Therefore, combination of ibrutinib with other drugs could be beneficial.
This study investigates the combination of ibrutinib, fludarabine and pembrolizumab for treatment of CLL. Fludarabine is a well-tolerated drug that has been used widely to treat CLL. Also, fludarabine can kill both malignant B cells and T cells that support the growth of leukemia cells. Pembrolizumab targets immune checkpoint molecules and enhances the cell-killing activity of T cells. With this approach we hope to achieve a greater reduction in CLL cells than with single agent ibrutinib and to restore healthier immune system that could contribute to durable responses.
To investigate the rate of complete response to ibrutinib, short course fludarabine and pembrolizumab.
Key eligibility criteria:
Patients with active CLL meeting treatment indications defined by 2008 International Workshop on CLL (IWCLL) consensus guideline.
High-risk CLL defined by one of the following:
Relapsed/refractory disease status (except patients with deletion 13q AND mutated IgHV), or
Presence of high-risk mutations regardless of prior treatment status: deletion 17p, TP53 mutation, NOTCH1 mutation, or complex cytogenetics.
This is a single-arm, open-label phase II study.
Timeline: Treatment on this study is given in cycles from cycle -3 to 17, then in months beyond cycle 17. Cycles -3 to -1 are 28-day cycles. Cycles 1 to 17 are 21-day cycles. After completion of 1 year of pembrolizumab, the time on study is by chronological months on study from starting pembrolizumab.
Treatment plan: Ibrutinib is given daily until disease progression or intolerable side effects occur. Fludarabine is given on cycle -2 only. Pembrolizumab is given every 3 weeks starting from cycle 1 for 1 year. Minimal residual disease will be measured at 2 years from cycle 1 to determine the need for long- term treatment with ibrutinib.
CLL, Fevers Higher Than 100.5 Degress F or 38.0 Degrees C for 2 or More Weeks, Progressive Marrow Failure, Night Sweats for More Than 1 Month Without Evidence of Infection, SLL, Chronic Lymphocytic Leukemia, Weight Loss of 10% or More Within the Previous 6 Months, SmallLymphocytic Lymphoma
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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