Blinatumomab and Pembrolizumab for Adults With Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia With High Marrow Lymphoblasts

Blinatumomab and Pembrolizumab for Adults With Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia With High Marrow Lymphoblasts

A Phase I/II Study of Blinatumomab in Combination With Pembrolizumab (MK-3475) for Adults With Relapsed or Refractory B-lineage Acute Lymphoblastic Leukemia With High Bone Marrow Lymphoblast Percentage

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

blinatumomab, pembrolizumab, MK-3475, relapsed, refractory, B-lineage acute lymphoblastic leukemia, ALL

Drug: blinatumomab 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 Other Names: Blincyto Drug: pembrolizumab 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) Other Names: Keytruda MK-3475

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)

Inclusion Criteria: Relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL) having received at least 1 prior line of therapy Philadelphia chromosome positive (Ph+), or Breakpoint Cluster Region Protein-Abelson Murine Leukemia Viral Oncogene Homolog 1 (BCR-ABL1) positive B-lineage ALL must have failed at least 1 second or third generation tyrosine kinase inhibitor (TKI) or be intolerant to TKIs Greater than 50% lymphoblasts on screening bone marrow aspirate or biopsy Adequate organ function Women of child-bearing potential and men with partners of child-bearing potential must agree to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy; or Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential even if they have had a successful vasectomy starting with the first dose of study therapy through 120 days after the last dose of study therapy. Exclusion Criteria: Allogeneic hematopoietic cell transplantation within 5 years of study drug administration Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) or Granulocyte Colony-Stimulating Factor (G-CSF) use within 2 weeks of study treatment and throughout the study Prior checkpoint inhibitor therapy including anti Programmed Death Receptor 1 (anti-PD1), anti-PD-L1, anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4), anti tumor necrosis factor receptor superfamily, member 9 (anti-CD137), or anti-PD-L2 therapy Active Central Nervous System (CNS) or testicular involvement by leukemia History of neurologic disorder Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. Burkitt lymphoma/leukemia Has a diagnosis of congenital immunodeficiency Has a known history of active Bacillus Tuberculosis (TB) Known Human Immunodeficiency Virus (HIV) infection Active hepatitis B or hepatitis C infection Has received a live vaccine within 30 days prior to first dose 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 120 days after the last dose of trial treatment. History of autoimmune disease Known interstitial lung disease Any evidence of active, non-infectious pneumonitis or has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis Patients who have received chemotherapy or radiotherapy within 2 weeks prior to entering the study or has not recovered from adverse events due to agents administered more than 2 weeks earlier. Patients who are less than 4 weeks from surgery or have insufficient recovery from surgical-related trauma or wound healing. Known impaired cardiac function

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