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: 19017
  • SECONDARY ID: NCI-2018-00526
  • SECONDARY ID: 19017
  • 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 cycle 1
      and days 1 and 22 of cycles 2 -5, and blinatumomab IV on days 1-28. Treatment repeats every
      35-42 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.
      Patients who achieve complete response have the option to receive blinatumomab IV for up to 4
      additional cycles.

      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.
  • Blinatumomab
  • Pembrolizumab

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 (Phase 1)
Time Frame:Up to 42 days
Safety Issue:
Description:Will be graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5

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
Time Frame:Up to 1 year
Safety Issue:
Description:Will be measured by number and proportion of patients who underwent SCT after treatment of pembrolizumab and blinatumomab
Measure:Number and proportion of patients who start pembrolizumab maintenance
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Number and proportion of patients who complete pembrolizumab maintenance
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Minimal residual disease rate confirmed minimal residual disease
Time Frame:Up to 1 year
Safety Issue:
Description:Will be measured by number and proportion of patients with CR who have confirmed minimal residual disease.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated