Clinical Trials /

Pembrolizumab and Blinatumomab in Treating Participants With Recurrent or Refractory Acute Lymphoblastic Leukemia

NCT03512405

Description:

This phase I/II studies the side effects of pembrolizumab and blinatumomab and to see how well they work in treating participants with acute lymphoblastic leukemia that has come back or has not responded to the treatment. Monoclonal antibodies, such as pembrolizumab and blinatumomab, may interfere with the ability of tumor cells to grow and spread.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Blinatumomab in Treating Participants With Recurrent or Refractory Acute Lymphoblastic Leukemia
  • Official Title: A Phase 1/2 Trial of Pembrolizumab in Combination With Blinatumomab in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 17135
  • SECONDARY ID: NCI-2018-00526
  • SECONDARY ID: 17135
  • NCT ID: NCT03512405

Conditions

  • CD19 Positive
  • Philadelphia Chromosome Positive
  • Recurrent Acute Lymphoblastic Leukemia
  • Refractory Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
BlinatumomabAnti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody, Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103, Blincyto, MEDI-538, MT-103Treatment (pembrolizumab, blinatumomab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, blinatumomab)

Purpose

This phase I/II studies the side effects of pembrolizumab and blinatumomab and to see how well they work in treating participants with acute lymphoblastic leukemia that has come back or has not responded to the treatment. Monoclonal antibodies, such as pembrolizumab and blinatumomab, may interfere with the ability of tumor cells to grow and spread.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Assess the safety and tolerability of combination immunotherapy with blinatumomab and
      pembrolizumab by evaluation of toxicities including: type, frequency, severity, attribution,
      time course and duration. (Phase 1) II. Determine the recommended phase 2 schedule of
      combination immunotherapy with pembrolizumab and blinatumomab. (Phase 1) III. Evaluate the
      anti-leukemia activity of combination immunotherapy blinatumomab and pembrolizumab as
      assessed by overall response rate (complete response [CR] or CR with incomplete recovery
      [CRi]). (Phase 2)

      SECONDARY OBJECTIVES:

      I. Estimate time to response (CR or CRi) and response duration. (Phase 2) II. Estimate
      overall survival and event-free survival. (Phase 2) III. Determine the number and proportion
      of patients who underwent hematopoietic stem cell transplantation (HSCT) after treatment of
      pembrolizumab and blinatumomab. (Phase 2) IV. Determine the number and proportion of patients
      who receive pembrolizumab maintenance and the proportion continuing for up to 1 year. (Phase
      2) V. Estimate the minimal residual disease rate. (Phase 2)

      CORRELATIVE OBJECTIVES:

      I. Explore evolution of T cell subsets at various points in treatment (T naive, T effector, T
      effector memory, T central memory, CD4, CD8). (Phase 2) II. Evaluate PD-L1 expression levels
      on acute lymphoblastic leukemia (ALL) blasts and blasts counts overtime. (Phase 2) III.
      Evaluate PD-1/PD-L1 expression on subsets of T cells. (Phase 2) IV. Evaluate the clonal
      evolution of leukemic blasts in response to treatment. (Phase 2)

      OUTLINE:

      Participants receive pembrolizumab intravenously (IV) over 30 minutes on day 15 of course 1
      and days 1 and 22 of courses 2 -4, and blinatumomab IV on days 1-28. Treatment repeats every
      35-42 days for up to 4 courses in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, participants are followed up at 30 days and then every 3
      months for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, blinatumomab)ExperimentalParticipants receive pembrolizumab IV over 30 minutes on day 15 of course 1 and days 1 and 22 of courses 2 -4, and blinatumomab IV on days 1-28. Treatment repeats every 35-42 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  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
    
              -  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)
    
              -  Required screening laboratory data (within 28 days prior to administration of
                 pembrolizumab)
    
              -  Discontinuation of all therapy (including radiotherapy, chemotherapy, tyrosine-kinase
                 inhibitors [TKIs], immunotherapy or investigational therapy) for the treatment of
                 cancer as follows:
    
                   -  At least 1 week or 5 half-lives (whichever is longer) from the last dose of prior
                      anti-cancer therapy and the initiation of study therapy
    
                   -  Exceptions or modifications to the above are as follows:
    
                        -  Medications that are typically part of a maintenance therapy for ALL, such
                           as glucocorticoids or mercaptopurine, may be administered up to 3 days prior
                           to the first dose, except vinca alkaloids which must be discontinued at
                           least 14 days prior to the start of study treatment; TKIs are not permitted
                           to be continued at screening (e.g. Gleevec)
    
                   -  Intrathecal (IT) chemotherapy may be dosed up to 7 days prior to first dose of
                      pembrolizumab (cytarabine [Ara-C] recommended)
    
                   -  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), or bone
                 marrow parameters (any grades permitted)
    
              -  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 30
                 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
    
              -  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 pembrolizumab throughout the study
                 treatment period and for 90 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 3 months following the last dose of study drugs
    
              -  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;
                 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) 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; 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
    
              -  Concurrent participation in an investigational drug trial with therapeutic intent
                 defined as prior study therapy within 28 days prior to start of this study
    
              -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
                 within 2 weeks prior to study day 1 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
    
              -  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 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
    
              -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or
                 blinatumomab
    
              -  Has received a live vaccine within 30 days of planned start of study therapy
    
              -  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
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Incidence of toxicity graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5 (Phase 1)
    Time Frame:Up to 42 days
    Safety Issue:
    Description:Evaluated using Simon two-stage optimal design.

    Secondary Outcome Measures

    Measure:Incidence of adverse events
    Time Frame:Up to 1 year
    Safety Issue:
    Description:Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, attribution, time of onset, duration, probable association with the study treatment and reversibility or outcome. Baseline information (e.g. the extent/type of prior therapy).
    Measure:Duration of remission
    Time Frame:From the date of first documented response (CR/CRi) up to 1 year
    Safety Issue:
    Description:
    Measure:Time to response
    Time Frame:From date of first dose of study drug up to 1 year
    Safety Issue:
    Description:Will be estimated using the product-limit method of Kaplan and Meier.
    Measure:Overall survival
    Time Frame:From date of first dose of study drug up to 1 year
    Safety Issue:
    Description:Will be estimated using the product-limit method of Kaplan and Meier.
    Measure:Event-free survival
    Time Frame:From date of first dose of study drug up to 1 year
    Safety Issue:
    Description:Will be estimated using the product-limit method of Kaplan and Meier.
    Measure:Allogeneic stem cell transplantation (SCT) realization rate measured by number of patients who underwent SCT after treatment of pembrolizumab and blinatumomab.
    Time Frame:Up to 1 year
    Safety Issue:
    Description:
    Measure:Allogeneic stem cell transplantation (SCT) realization rate measured by proportion of patients who underwent SCT after treatment of pembrolizumab and blinatumomab.
    Time Frame:Up to 1 year
    Safety Issue:
    Description:
    Measure:Number of patients who start pembrolizumab maintenance
    Time Frame:Up to 1 year
    Safety Issue:
    Description:
    Measure:Proportion of patients who start pembrolizumab maintenance
    Time Frame:Up to 1 year
    Safety Issue:
    Description:
    Measure:Number of patients who complete pembrolizumab maintenance
    Time Frame:Up to 1 year
    Safety Issue:
    Description:
    Measure:Proportion of patients who complete pembrolizumab maintenance
    Time Frame:Up to 1 year
    Safety Issue:
    Description:
    Measure:Minimal residual disease rate measured by number of patients with CR who have confirmed minimal residual disease
    Time Frame:Up to 1 year
    Safety Issue:
    Description:
    Measure:Minimal residual disease rate measured by proportion of patients with CR who have confirmed minimal residual disease
    Time Frame:Up to 1 year
    Safety Issue:
    Description:

    Details

    Phase:Phase 1/Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:City of Hope Medical Center

    Last Updated

    April 19, 2018