Blinatumomab, Pembrolizumab, and Methotrexate in Treating Patients with Relapsed or Refractory CD19 Positive B Acute Lymphoblastic Leukemia
- Relapsed or refractory CD19-positive B-lineage acute lymphoblastic leukemia having received at least 1 prior line of therapy
- Philadelphia chromosome/BCR-ABL1-positive B-lineage acute lymphoblastic leukemia (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
- Evidence of CD19 expression via flow cytometry (peripheral blood or bone marrow) or immunohistochemistry (bone marrow biopsy) from a sample obtained from the current relapse
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Bilirubin < 1.5 x upper limit of normal (ULN) unless believed due to leukemic infiltration
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x ULN unless believed due to leukemic infiltration
- Creatinine clearance >= 60 mL/min/1.73 m^2 unless reduced creatinine clearance felt by investigator to be acute and reversible
- Absence of unstable cardiac disease defined as myocardial infarction with 6 months, uncontrolled heart failure, or uncontrolled cardiac arrhythmia
- Ability to understand and the willingness to sign a written informed consent
- 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; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * 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)
- Women of child-bearing potential has negative pregnancy test within 72 hours of initiating study drug dosing
- 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
- Corticosteroids and hydroxyurea are permitted after screening bone marrow biopsy is performed and for up to 7 days prior to starting study therapy
- 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-PD1, anti-PD-L1, anti-CTLA4, anti- CD137, or anti-PD-L2 therapy
- Prior treatment with any CD19-directed therapy (e.g. blinatumomab, CD19-directed chimeric antigen receptor T-cell therapy, anti-CD19 antibodies)
- Active central nervous system (CNS) or testicular involvement by leukemia
- History of neurologic disorder including but not limited to: prior seizure, epilepsy, structural brain abnormality, benign brain tumor, stroke, brain injuries, dementia, movement disorder or other significant CNS abnormalities
- 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 TB (Bacillus tuberculosis)
- Known human immunodeficiency virus (HIV) infection
- Active hepatitis B or hepatitis C infection
- Any uncontrolled 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
- Non-pregnant, non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are considered highly unlikely to conceive; highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is >= 45 years of age and has not had menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the duration of the study; the two birth control methods can be either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy; subjects should start using birth control from study day 1 throughout the study period up to 120 days after the last dose of study therapy
- 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
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to blinatumomab or pembrolizumab or other agents used in study
- Known impaired cardiac function including any of the following: * History or presence of clinically significant ventricular or atrial tachyarrhythmias; * Clinically significant resting bradycardia (< 50 beats per minute); * Myocardial infarction within 1 year of starting study drug; * Other clinically significant heart disease (e.g., unstable angina, congestive heart failure, or uncontrolled hypertension)
- Any condition that requires the use of corticosteroids outside of corticosteroids defined in the protocol after day 1 of therapy
- Severe or uncontrolled medical disorder that would, in the investigator’s opinion, impair ability to receive study treatment (i.e., uncontrolled diabetes, chronic renal disease, chronic pulmonary disease or active, uncontrolled infection, psychiatric illness/social situations that would limit compliance with study requirements
I. To determine if the addition of pembrolizumab to blinatumomab improves the overall response rate (complete response [CR] + complete response 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.
I. To estimate CR rate.
II. To estimate the minimal residual disease (MRD) negativity rate in subjects achieving a CR or CRh.
III. To estimate 2-year relapse-free survival.
IV. To estimate 2-year overall survival.
V. To estimate overall response rate (ORR), CR, CRh, 2-year relapse free survival (RFS), and 2-year overall survival (OS) in the Philadelphia (Ph)/BCR-ABL1-negative and Ph/BCR-ABL1–positive populations separately.
VI. To determine the allogeneic hematopoietic cell transplantation rate in transplant-eligible subjects.
VII. To determine the safety and tolerability of blinatumomab in combination with pembrolizumab.
I. To determine PD-1 expression on T-cells and PD-L1 and PD-L2 protein expression on lymphoblasts at diagnosis and in response to therapy.
II. To determine changes in bone marrow and peripheral blood T-cell populations in response to therapy with blinatumomab and the combination of blinatumomab and pembrolizumab.
III. To determine changes in PD-1, PD-L1 and PD-L2 expression with blinatumomab exposure and correlation with disease response.
IV. To determine changes in cytokine response with therapy and correlate with PD-1, PD-L1 and PD-L2 expression changes.
Patients receive blinatumomab intravenously (IV) continuously on days 1-28 and pembrolizumab IV over 30 minutes on days 15 and 36. Patients also receive methotrexate intrathecally or intraventricularly on days 29-36. Treatment repeats every 42 days for up to 5 cycles in the absence of disease progression or unaccepted toxicity.
After completion of study treatment, patients are followed up every 3 months for a minimum of 2 years.
Trial Phase Phase I/II
Trial Type Treatment
University of California San Diego
Matthew Joseph Wieduwilt
- Primary ID UCHMC1504
- Secondary IDs NCI-2017-01385
- Clinicaltrials.gov ID NCT03160079