Ibrutinib and PD-1 Blockade in High Risk Lymphocytic Leukemia

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the impact of sequential overlapping treatment with PD-1 monoclonal antibody (mAb), pembrolizumab/MK-1375, followed by ibrutinib on endogenous immune function in previously untreated, high-risk CLL patients. Immune function will be evaluated through various laboratory correlative tests.

Official Title
-----------------
Phase II Trial of Ibrutinib and PD-1 Blockade in High Risk Chronic Lymphocytic Leukemia to Improve Immune Dysfunction

Conditions
-----------------
Chronic Lymphocytic Leukemia

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Have high risk CLL Have documented previously untreated CLL according to IWCLL criteria Willing and able to provide written informed consent Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Demonstrate adequate organ function Able to take oral medication and willing to adhere to the medication regimen Exclusion Criteria: Currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment Meets IWCLL criteria to start therapy Has had any treatment for CLL including any investigational agent, chemotherapy, mAb, anti-PD-1, anti-PDL-1, or anti-CTLA-4 Transformation of CLL to aggressive NHL (Richter's transformation or pro-lymphocytic leukemia) Known active central nervous system (CNS) metastases and/or carcinomatous meningitis Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 90 days after the last dose of trial treatment Major surgery or a wound that has not fully healed within 4 weeks of first dose Additional criteria may apply

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: Pembrolizumab and Ibrutinib<br>Treatment with pembrolizumab and ibrutinib and follow-up period of up to 24 months. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK). Ibrutinib is a small-molecule inhibitor of BTK. | Drug: Pembrolizumab<br>* Pembrolizumab will be administered intravenously (IV) at 200 mg every 3 weeks for 1 year and up to 2 years.<br>* Other names: Keytruda®;Drug: Ibrutinib<br>* Ibrutinib will be administered orally once daily at approximately the same time each day at the dose of 420 mg daily (3 capsules of 140 mg daily).<br>* Other names: Imbruvica®;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) to the Therapeutic Intervention | Response categories according to The International Workshop on Chronic Lymphocytic Leukemia (IWCLL): Complete remission (CR); Complete remission with incomplete marrow recovery (CRi); Partial remission (PR); Progressive disease (PD); Stable disease (SD), defined as not meeting criteria for CR, CRi, PR or PD. | Up to 2 years | 
| Time to Best Response | Time to best response to chronic lymphocytic leukemia (CLL) to the therapeutic intervention. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progressive disease (PD), defined as ≥ 50% rise in lymphocyte count to > 5 x10^9/L, ≥ 50% increase in lymphadenopathy, ≥ 50% increase in liver or spleen size, Richter's transformation, or new cytopenias due to CLL. | Up to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Lymphocytic, Leukemia, CLL, Blood disease, White blood cells, Bone marrow disease, Immunotherapy