Pembrolizumab and Blinatumomab in Treating Patients with Recurrent or Refractory Acute Lymphoblastic Leukemia

Inclusion Criteria

• >= 18 years of age
• Previously treated ALL including philadelphia chromosome (BCR-Ab1) positive ALL who meet all of the following criteria: * Diagnosis of CD19-positive B-cell ALL based on the flow cytometry and histology * Previously treated subjects with primary refractory disease OR after first or subsequent relapse * Subjects with detectable lymphoblasts in bone marrow (BM) or extramedullary disease (EMD) that is radiographically measurable and amenable to repeat biopsies
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Required screening laboratory data (within 28 days prior to administration of treatment day 0)
• Left ventricular ejection fraction (LVEF) > 45%
• Pulmonary function tests diffusing capacity of the lungs for carbon monoxide (DLCO) (adjusted for hemoglobin) > 50% predicted
• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 ml/min for subject with creatinine levels > 1.5 x institutional ULN
• Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine transaminase (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases
• Albumin >= 2.5 mg/dL
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• Beta human chorionic gonadotropin (beta HCG) negative
• Human immunodeficiency virus (HIV): negative HIV antibody/polymerase chain reaction (PCR)
• Hepatitis B virus (HBV): negative hepatitis B surface antigen (HBsAg) and negative hepatitis B core (HBc) antibody or positive HBc and negative HBV deoxyribonucleic acid (DNA) by quantitative PCR
• Hepatitis C virus (HCV): negative viral ribonucleic acid (RNA) (if HCV antibody is positive)
• Discontinuation of all anticancer therapy within 2 weeks or at least 5 half-lives (whichever is shorter) prior to study day 1 with the following exceptions: * Medications that are typically part of a maintenance therapy for ALL, such as glucocorticoids, mercaptopurine, hydroxyurea, cyclophosphamide, methotrexate, vincristine or tyrosine-kinase inhibitors (TKIs) (e.g. imatinib, dasatinib) may be administered up to at least 5 half-lives or 3 days (whichever is longer) prior to the first dose * Intrathecal (IT) chemotherapy may be dosed up to 7 days prior to first dose of study drug (Ara-C recommended). IT chemotherapy is allowed for CNS prophylaxis per treating physician recommendation in between cycles throughout the study. * Radiotherapy may be administered up to 2 weeks prior to the start of treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease * For biologics (e.g. monoclonal antibodies), washout period of 1 month beyond the recommended dosing interval and at least 4 weeks or 5 half-lives (whichever is longer) since the last dose
• All acute toxic effects of any prior antitumor therapy must be resolved to grade =< 1 before enrollment, with the exception of alopecia (any grade permitted), neuropathy (=< grade 2) or bone marrow parameters (any grades permitted). Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• For female subjects of childbearing potential, willingness to abstain from heterosexual intercourse or use 2 concurrent protocol recommended methods of contraception from the screening visit throughout the study treatment period and to 120 days from the last dose of pembrolizumab. A negative serum pregnancy test is required for female subjects at screening. Lactating females must agree to discontinue nursing before administration of study drugs and 120 days post last dose of pembrolizumab
• For male subjects having intercourse with females of childbearing potential, willingness to abstain from heterosexual intercourse or use 2 protocol-recommended methods of contraception from the start of study throughout the study treatment period and for 120 days following the last dose of pembrolizumab. Also, male subjects should refrain from sperm donation from the start of pembrolizumab throughout the study treatment period and for 120 days following the last dose of pembrolizumab
• In the judgment of the investigator, participation in the protocol offers an acceptable benefit-to-risk ratio when considering current disease status, medical condition, and the potential benefits and risks of alternative treatments for the subject’s ALL
• Willingness to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions; Note: psychological, social, familial or geographical factors that might preclude adequate study participation should be considered
• Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures

Exclusion Criteria

• Diagnosis of mature B-cell ALL (Burkitt’s leukemia) or mixed phenotype acute leukemia according to World Health Organization (WHO) classification, or lymphoid blast crisis of chronic myelogenous leukemia (CML)
• A life threatening illness, medical condition or organ system dysfunction which, in the investigators’ opinion, could compromise the subject’s safety or interfere with the absorption or metabolism of pembrolizumab
• Active or symptomatic central nervous system (CNS) disease * For study purposes, a subject will NOT be considered as having active CNS disease if the subject has documentation of prior CNS disease and has received prior treatment (IT or radiation) and is: ** Asymptomatic for the last 28 days prior to screening and ** Has documented at least 2 negative cerebrospinal fluid (CSF) cytology (which must include 1 lumbar puncture [LP] within the study screening window)
• Uncontrolled undercurrent illness including but not limited to unstable angina pectoris or psychiatric illness/social situations that would limit compliance with study requirements; as infection is a common feature of ALL, subjects with active infection are permitted to enroll provided that the infection is documented to be under control
• History of myelodysplastic syndrome or organ transplantation
• History of non-lymphoid malignancy except for the following: * Adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requirement only hormonal therapy and with normal prostate specific antigen for > 1 year prior to the start of pembrolizumab, or any other cancer that has been in complete remission without treatment for >= 5 years prior to enrollment
• Known hypersensitivity or intolerance to any of the active substance or excipients in the formulations for pembrolizumab and blinatumomab
• Ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic active hepatitis B (HBV), HIV, alcoholic liver disease, non-alcoholic steatohepatitis, cirrhosis of the liver, or portal hypertension
• Prior allogeneic bone marrow transplantation
• Pregnancy or breastfeeding
• Has known history of, or any evidence of active, non-infectious pneumonitis/interstitial lung disease.
• Has 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
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is 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 pembrolizumab
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or blinatumomab
• Has received a live vaccine or live attenuated vaccine within 30 days of planned start of study therapy. Administration of killed vaccines is allowed.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug