A Phase II Study of Anti-PD-1 Antibody (MK-3475) in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) and Other Low Grade B Cell Non-Hodgkin Lymphoma (NHL)
Overview
- Phase
- Phase 2
- Intervention
- Ibrutinib
- Conditions
- Recurrent B-Cell Non-Hodgkin Lymphoma
- Sponsor
- Mayo Clinic
- Enrollment
- 65
- Locations
- 2
- Primary Endpoint
- Proportion of Patients Who Achieve a Confirmed Response
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This phase II trial studies how well pembrolizumab alone or with idelalisib or ibrutinib works in treating patients with chronic lymphocytic leukemia or other low-grade B-cell non-Hodgkin lymphomas that have returned after a period of improvement (relapsed) or have not responded to treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Idelalisib and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab alone or with idelalisib or ibrutinib may be an effective treatment in patients with chronic lymphocytic leukemia or other low-grade B-cell non-Hodgkin lymphomas.
Detailed Description
PRIMARY OBJECTIVE: I. Test the efficacy (overall response rate) of single-agent MK-3475 (pembrolizumab) in relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (Arm A) other low grade B-cell non-Hodgkin lymphoma (B-NHL), and CLL with Richter's transformation (Arm C). SECONDARY OBJECTIVES: I. Test the safety of single-agent MK-3475 in relapsed CLL/SLL (Arm A), other low grade B-NHL (Arm B), and CLL with Richter's transformation (Arm C). II. Test the overall survival, progression free survival, treatment free survival, duration of response and time to next therapy of single-agent MK-3475 in relapsed CLL/SLL (Arm A), other low grade B-NHL (Arm B), and CLL with Richter's transformation (Arm C). III. Test the complete response rate of single MK-3475 in relapsed CLL/SLL (Arm A), other low grade B-NHL (Arm B), and CLL with Richter's transformation (Arm C). IV. Test the safety of MK-3475 in combination with the signal inhibitor (either idelalisib or ibrutinib) in relapsed CLL/SLL (Arm A) and CLL with Richter's transformation (Arm C). V. Test the progression-free survival, treatment-free survival, duration of response and time to next therapy, as well as overall survival of MK-3475 in combination with the signal inhibitor (either idelalisib or ibrutinib) in relapsed CLL/SLL (Arm A) and CLL with Richter's transformation (Arm C). VI. Test the overall and complete response rates of MK-3475 in combination with the signal inhibitor (either idelalisib or ibrutinib) in relapsed CLL/SLL (Arm A) and CLL with Richter's transformation (Arm C). CORRELATIVE RESEARCH OBJECTIVES: I. To assess the potential association between programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1)/PD-L2 expression on tumor and T cells and/or PD-L1 soluble levels in plasma with clinical efficacy of PD-1 blockade. II. To investigate the effects of MK-3475 on selected markers of immune modulation and immune profiles in peripheral blood and tumor samples. III. Examine T-cell immune synapse function and expression/location of co-stimulatory and co-inhibitory molecules (including effector molecules) as potential biomarkers to response for anti-PD-1 immune checkpoint blockade immunotherapy. OUTLINE: ALL PATIENTS (ARMS A, B, and C): Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator. Patients with CLL or CLL with Richter's transformation experiencing stable disease without partial remission or progressive disease at 3 months of treatment with pembrolizumab proceed to the treatment continuation phase. CONTINUATION PHASE (ARMS A and C): Patients receive pembrolizumab IV over 30 minutes on day 1. Patients also receive idelalisib orally (PO) twice daily (BID) on days 1-21 OR ibrutinib PO once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 12 or 24 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator. After completion of study treatment, patients are followed up every 3 months for 1 year.
Investigators
Eligibility Criteria
Inclusion Criteria
- •CLL/SLL PATIENTS (ARM A) ONLY
- •Diagnosis of CLL according to the National Cancer Institute (NCI) criteria or SLL according to the World Health Organization (WHO) criteria; this includes previous documentation of:
- •Biopsy-proven small lymphocytic lymphoma or
- •Diagnosis of CLL according to NCI working group criteria as evidenced by all of the following:
- •Peripheral blood B cell count of \> 5 x 10\^9/L consisting of small to moderate size lymphocytes
- •Immunophenotyping consistent with CLL defined as:
- •The predominant population of lymphocytes share both B-cell antigens (cluster of differentiation \[CD\]19, CD20 \[typically dim expression\] or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.)
- •Clonality as evidenced by kappa or lambda light chain expression (typically dim immunoglobulin expression) or other genetic method (e.g. immunoglobulin heavy chain variable \[IGHV\] analysis)
- •NOTE: splenomegaly, hepatomegaly, or lymphadenopathy are not required for the diagnosis of CLL
- •Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by demonstrating a negative fluorescent in situ hybridization (FISH) analysis for t(11;14) (immunoglobulin H \[IgH\]/cyclin D1 \[CCND1\]) on peripheral blood or tissue biopsy or negative immunohistochemical stains for cyclin D1 on involved tissue biopsy
Exclusion Criteria
- •Currently participating in or has participated in a study of an investigational agent or using an investigational device =\< 28 days prior to registration
- •Receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy =\< 7 days prior to registration; EXCEPTIONS:
- •Low doses of steroids (=\< 20 mg of prednisone or equivalent dose of other steroid/day)
- •Previous use of corticosteroids is allowed
- •After initiation of MK-3475 therapy, steroid can be used for management of potential immune mediated adverse events (AE) for less than 8 weeks of therapy
- •Topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption) are permitted
- •Prior anti-cancer monoclonal antibody =\< 28 days prior to registration or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
- •Prior chemotherapy or radiation therapy =\< 14 days prior to registration or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to a previously administered agent
- •Note: subjects with =\< grade 2 neuropathy are an exception to this criterion and may qualify for the study
- •Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
Arms & Interventions
Treatment (pembrolizumab, idelalisib, or ibrutinib)
Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator. Patients with CLL or CLL with Richter's transformation experiencing stable disease without partial remission or progressive disease at 3 months of treatment with pembrolizumab proceed to the treatment continuation phase. CONTINUATION PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1. Patients also receive idelalisib PO BID on days 1-21 OR ibrutinib PO QD on days 1-21. Treatment repeats every 21 days for up to 12 or 24 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator.
Intervention: Ibrutinib
Treatment (pembrolizumab, idelalisib, or ibrutinib)
Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator. Patients with CLL or CLL with Richter's transformation experiencing stable disease without partial remission or progressive disease at 3 months of treatment with pembrolizumab proceed to the treatment continuation phase. CONTINUATION PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1. Patients also receive idelalisib PO BID on days 1-21 OR ibrutinib PO QD on days 1-21. Treatment repeats every 21 days for up to 12 or 24 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator.
Intervention: Idelalisib
Treatment (pembrolizumab, idelalisib, or ibrutinib)
Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator. Patients with CLL or CLL with Richter's transformation experiencing stable disease without partial remission or progressive disease at 3 months of treatment with pembrolizumab proceed to the treatment continuation phase. CONTINUATION PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1. Patients also receive idelalisib PO BID on days 1-21 OR ibrutinib PO QD on days 1-21. Treatment repeats every 21 days for up to 12 or 24 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator.
Intervention: Laboratory Biomarker Analysis
Treatment (pembrolizumab, idelalisib, or ibrutinib)
Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator. Patients with CLL or CLL with Richter's transformation experiencing stable disease without partial remission or progressive disease at 3 months of treatment with pembrolizumab proceed to the treatment continuation phase. CONTINUATION PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1. Patients also receive idelalisib PO BID on days 1-21 OR ibrutinib PO QD on days 1-21. Treatment repeats every 21 days for up to 12 or 24 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Proportion of Patients Who Achieve a Confirmed Response
Time Frame: 1 year
Confirmed response is defined to be a partial response, nodular partial response, clinical complete response, confirmed response with incomplete blood count recovery or confirmed response (Arm A and B), or complete metabolic response, partial metabolic response, partial response, or confirmed response (Arm C). The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial confidence intervals for the true success proportion will be calculated.
Secondary Outcomes
- Progression-free Survival of Patients Treated in Single Agent Phase(5 years)
- Treatment-free Survival of Patients Treated With Single-agent Pembrolizumab(5 years)
- Time to Next Treatment for Patients on Combination Therapy(5 years)
- Time to Next Treatment for Patients Treated With Single-agent Pembrolizumab(5 years)
- Complete Response Rate(1 year)
- Progression-free Survival of Patients Treated With Combination Therapy(5 years)
- Treatment-free Survival of Patients Treated With Combination Therapy(5 years)
- Duration of Response(5 years)
- Overall Survival(5 years)
- Confirmed All Response Rate of Patients Treated With Combination Therapy(1 year)
- Incidence of Adverse Events(1 year)