This is a Phase I/II study of blinatumomab in combination with pembrolizumab in adult patients with relapsed or refractory B-lineage ALL (B-ALL). The primary objective of this study is to determine if the addition of pembrolizumab to blinatumomab improves the Complete Response Rate (CR) and Complete Remission with Partial Hematologic Recovery (CRh) relative to blinatumomab alone in adult subjects with relapsed or refractory B-cell acute lymphoblastic leukemia with high bone marrow lymphoblast percentage (\>50% lymphoblasts).
This is a Phase I/II study of blinatumomab in combination with pembrolizumab in adult patients with relapsed or refractory B-lineage ALL (B-ALL). The primary objective of this study is to determine if the addition of pembrolizumab to blinatumomab improves the Complete Response Rate (CR) and Complete Remission with Partial Hematologic Recovery (CRh) relative to blinatumomab alone in adult subjects with relapsed or refractory B-cell acute lymphoblastic leukemia with high bone marrow lymphoblast percentage (\>50% lymphoblasts). Mechanisms of resistance to blinatumomab are not well understood although inhibition of or suboptimal T-cell activation may play an important role. Programmed Death-Ligand 1 (PD-L1) and Programmed Death-Ligand 2 (PD-L2) expression and upregulation in lymphoblasts and the bone marrow microenvironment at baseline and in response to cytokines including those released upon blinatumomab exposure may inhibit T-cell function through the Programmed Death 1 (PD-1) receptor and lead to resistance to blinatumomab. The investigators hypothesize that part of the resistance to therapy with blinatumomab is mediated by the exuberant cytokine release seen with higher disease burden leading to increased expression of PD-L1 and PD-L2. Enhancing T-cell activity through use of the PD-1 inhibitor pembrolizumab is predicted to augment the activity of blinatumomab and convert more patients to complete remission and prolong remission durations. This study will also act to expand knowledge of PD-L1 and PD-L2 dynamics in response to blinatumomab. It will also be a paradigm for the addition of checkpoint inhibitors to therapy with bifunctional T-cell engaging antibodies currently in development for targeting other liquid and solid tumors. The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an attractive target for therapeutic intervention. Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the Immunoglobulin G4 (IgG4/kappa) isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. The study will be conducted in 2 stages: Stage 1 is to ensure safety of pembrolizumab in combination with blinatumomab. Stage 2 of the study will include an expansion cohort of up to 21 additional subjects (for a total of 24 subjects) to evaluate the efficacy of the combination of blinatumomab and pembrolizumab in adults with relapsed/refractory B-cell ALL
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
16
Cycle 1 Blinatumomab Day 1-7 Continuous IV infusion for 28 days (9 mcg/day) Blinatumomab Day 8-28 Continuous IV infusion for 28 days (28 mcg/day) Cycle 2-5 Blinatumomab Day 1-28 Continuous IV infusion for 28 days (28 mcg/day) Cycle length 42 days
Cycle 1 Pembrolizumab Day 15 and 36 IV infusion over 30 minutes (200mg) Cycle 2-5 Pembrolizumab Day 15 and 36 IV infusion over 30 minutes (200mg)
UCSF Fresno Community Cancer Institute
Clovis, California, United States
UC San Diego Moores Cancer Center
La Jolla, California, United States
UC Irvine Health Chao Family Comprehensive Cancer Center
Orange, California, United States
UCSF Comprehensive Cancer Center
San Francisco, California, United States
Best Overall Response Rate (ORR)
Best overall response rate (ORR) with the combination of blinatumomab and pembrolizumab in adult subjects with relapsed or refractory B-cell acute lymphoblastic leukemia will be defined as the Complete Response (CR) rate plus the Complete Response with Hematologic Recovery (CRh) rate after treatment of combination therapy. According to the National Comprehensive Cancer Network (NCCN) Guidelines for Acute Lymphoblastic Leukemia (version 1, 2015), CR is defined as \<5% lymphoblast in the bone marrow without evidence of circulating lymphoblasts or extramedullary disease. CRh is defined as for CR except with platelet count \>50,000/microliter, hemoglobin \>7 g/dL, and neutrophil (ANC) \>500/microliter.
Time frame: 28 weeks
Complete Response Rate (CR)
CR is defined as \<5% lymphoblast in the bone marrow without evidence of circulating lymphoblasts or extramedullary disease.
Time frame: 28 weeks
Minimal Residual Disease (MRD) Negativity Rate in Subjects Achieving a CR or CRh
Minimal residual disease (MRD) negativity in subjects achieving a CR or CRh will be defined as less than 0.01% residual lymphoblasts by multiparameter flow cytometry.
Time frame: 28 weeks
2 Year Relapse-free Survival Rate
The number of patients achieving relapse free survival at 2 years. Relapse-free survival (RFS) will be defined as the time from achieving CR or CRh to relapse defined as the reappearance of lymphoblasts in bone marrow or blood at \>5% of cells or reappearance of extramedullary disease.
Time frame: 2 years
2-year Overall Survival Rate
The number of participants achieving survival at 2 years. 2-year overall survival (OS) will be defined as the time from starting study therapy to death from any cause.
Time frame: 2 years
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