Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Study Overview
=================
Brief Summary
-----------------
Background: 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. This single-arm, phase II study investigates the combination of ibrutinib, fludarabine and pembrolizumab for treatment of CLL. Ibrutinib is an orally administered therapy for CLL. Fludarabine is a well-tolerated drug that has been widely used to treat CLL. Also, fludarabine can modulate CLL cells as well as immune cells that support the growth of CLL cells. Pembrolizumab recruits immune cells to attack CLL 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. Objective: To investigate the rate of complete response to ibrutinib, short course fludarabine and pembrolizumab. Eligibility: 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, or Presence of high-risk mutations regardless of prior treatment status: deletion 17p, TP53 mutation, NOTCH1 mutation, SF3B1 mutation, MYC aberration, or complex cytogenetics. Design: 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 starting from cycle -3 and continuously until disease progression or intolerable side effects occur. Fludarabine is given on D1-D5 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. Previously-untreated patients who achieve minimal residual disease negativity will stop ibrutinib. Patients who do not achieve minimal residual disease negativity or who has Relapsed/refractory CLL will continue ibrutinib.

Detailed Description
-----------------
Background: This study investigates the combination of ibrutinib, fludarabine and pembrolizumab for treatment of CLL. 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. Objectives: -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, or Presence of high-risk mutations regardless of prior treatment status: deletion 17p, TP53 mutation, NOTCH1 mutation, SF3B1 mutation, MYC aberration, or complex cytogenetics.

Official Title
-----------------
A Phase II Study Of Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Conditions
-----------------
B-Cell Chronic Lymphocytic Leukemia, B-Lymphocytic Leukemia, Chronic, Chronic Lymphocytic Leukemia, Leukemia, Chronic Lymphatic, Leukemia, Chronic Lymphocytic, B-Cell, Leukemia, Lymphocytic, Chronic, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphocytic Leukemia, Chronic, B Cell, Lymphocytic Leukemia, Chronic, B-Cell

Intervention / Treatment
-----------------
* Drug: Ibrutinib
* Drug: Fludarabine
* Drug: Pembrolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: Men and women with histologically confirmed CLL or SLL Active disease as defined by at least one of the following IWCLL consensus criteria: Weight loss greater than or equal to 10% within the previous 6 months. Extreme fatigue. Fevers of greater than 100.5 degrees F for greater than or equal to 2 weeks without evidence of infection. Night sweats for more than one month without evidence of infection. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. Massive or progressive splenomegaly. Massive nodes or clusters or progressive lymphadenopathy. Progressive lymphocytosis with an increase of >50% over a 2-month period, or an anticipated doubling time of less than 6 months. High-risk disease defined by meeting at least one of the following three criteria: Relapsed and/or refractory CLL/SLL. Presence of high-risk mutations detected by FISH or targeted sequencing, regardless of prior treatments status. FISH: deletion 17p (or TP53), complex cytogenetics (3 or more abnormalities) Targeted sequencing: TP53 mutations, SF3B1 mutations, or NOTCH1 mutation. Pathologic mutations occurring at the coding regions are accepted as relevant mutations. MYC aberration. Aberration includes rearrangement, amplification, and tissue expression by immunohistochemistry CLL or SLL with disease transformation with Hodgkin-like cells regardless of prior treatment status. Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 1. Adequate organ function as defined by the study protocol. Agreement to use acceptable methods of contraception during the study and for 90 days after the last dose of study drug if sexually active and able to bear or beget children. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information. Individuals greater than or equal to 18 years old EXCLUSION CRITERIA: Transformation of CLL into lymphomas other than those with Hodgkin-like cells. Currently receiving or previously participated to receive an investigational agent within 4 weeks prior to study treatment. Currently receiving or previously received monoclonal antibodies, immunomodulatory therapy, chemotherapy, radiation, or radioimmunotherapy within 4 weeks prior to study treatment, or has not recovered from non-hematologic adverse events due to a previously administered agent. Major surgery within 4 weeks of first dose of study drug Currently receiving systemic steroid therapy (i.e. prednisone) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Prior therapy with BTK inhibitor, anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g.., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Known additional malignancy that is progressing or requires active treatment. Known history of, or any evidence of active, non-infectious pneumonitis that required steroids. Known bleeding disorders (i.e., von Willebrand s disease or hemophilia). Known HIV infection Active hepatitis B or hepatitis C infection. Recent known active infection requiring systemic therapy that was completed less than or equal to 14 days before the first dose of study drug. Known history of active tuberculosis. Any uncontrolled active systemic infection. Known hypersensitivity to ibrutinib, fludarabine, or pembrolizumab. Requires concomitant anticoagulation with Coumadin (warfarin) or other vitamin K antagonists. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to the first dose of ibrutinib or subjects who require continuous treatment with a strong CYP3A inhibitor Currently active, clinically significant cardiovascular disease including uncontrolled or symptomatic arrhythmias, Class 3 or 4 congestive heart failure as defined by New York Heart Association Functional Classification, or a history of myocardial infarction, unstable angina or acute coronary syndrome within 6 months of screening. Life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib and fludarabine, or put the study outcomes at undue risk Female patients who are currently in pregnancy, or unwilling to use acceptable methods of contraception or refrain from pregnancy if of childbearing potential or currently breastfeeding. Male patients who are unwilling to follow the contraception requirements described in this protocol. Psychiatric illness/social situations that would limit the patient s ability to tolerate and/or comply with study requirements. Unable to understand the investigational nature of the study or give informed consent. Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibrutinib, Fludarabine, and Pembrolizumab in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma<br>Ibrutinib, Fludarabine, and Pembrolizumab combination therapy will be administered in participants with High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). Ibrutinib will be administered daily by mouth starting cycle -3 at 420 mg until end study or disease progression or intolerable side effects occur. Fludarabine will be administered intravenously only on cycle -2 at 25mg/m^2 x5 days. Pembrolizumab will be administered intravenously every 3 weeks at 200 mg starting from cycle 1 through cycle 17 or 1 year of immunotherapy phase. | Drug: Ibrutinib<br>* Ibrutinib will be administered daily by mouth starting cycle -3 at 420 mg until end study or disease progression or intolerable side effects occur.<br>* Other names: Imbruvica;Drug: Fludarabine<br>* Fludarabine will be administered intravenously only on cycle -2 at 25mg/m^2 x5 days.<br>* Other names: Fludara;Drug: Pembrolizumab<br>* Pembrolizumab will be administered intravenously every 3 weeks at 200 mg starting from cycle 1 through cycle 17 or 1 year of immunotherapy phase.<br>* Other names: Keytruda;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Response of the Combination of Ibrutinib, Fludarabine, and Pembrolizumab in Patients With High-risk and/or Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Leukemia | Rate of complete response with combination ibrutinib, fludarabine, and pembrolizumab in patients with high-risk and/or relapsed/refractory chronic lymphocytic leukemia and small lymphocytic leukemia. Response assessments defined by IWCLL 2008 guidelines incorporating the 2012 and 2013 clarifications for patients treated with kinase inhibitors. Complete response defined as: Lymphadenopathy is none > 1.5 cm; No Splenomegaly or Hepatomegaly; Blood Lymphocytes <4000/uL; Bone Marrow is normocellular, <30% lymphocytes, no B-lymphoid nodules; Platelet count >100,000/uL; Hemoglobin > 11.0 g/dL and Neutrophils >1500/uL. Partial response is defined by meeting 2 criteria: Lymphadenopathy decrease > or = 50%; Splenomegaly or Hepatomegaly decrease > or = 50%; Blood Lymphocytes decrease > or = 50% from baseline; Platelet is > 100,000/uL or increase > or = 50% over baseline; Hemoglobin is > 11.0 g/dL or increase > or = 50% over baseline; Neutrophils is > 1500/uL or increase > or = 50% over baseline. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability, Response and Best Response, Survival | Tolerability of the combination regimen, Overall response rate (ORR), Duration of response (DOR), Best response, Minimal residual disease (MRD) status, Progression-free survival (PFS), Overall survival (OS), To explore the biologic effects on B- and T-cell subsets and function, To identify predictors of clinical response. | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Deletion 17p, TP53 Mutation, NOTCH1 mutation, Complex Cytogenetics, Bruton's Tyrosine Kinase (BTK) Inhibitor