Effect of Blinatumomab on Minimal Residual Disease (MRD) in Diffuse Large B-Cell Lymphoma (DLBCL) Subjects Post Autologous Hematopoietic Stem Cell Transplantation (aHSCT)
Condition: High-risk Diffuse Large B-cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Neoplasm, Residual
Intervention: Blinatumomab
Intervention description: Blinatumomab is administered as a continuous IV infusion.
Intervention MeSH terms: Blinatumomab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No

Summary:

      The study will estimate the MRD-negative response rate after treatment with blinatumomab in
      subjects with high-risk DLBCL who are MRD-positive following aHSCT. The clinical hypothesis
      is that the MRD-negative response rate will be greater than 10%. Achieving an MRD-negative
      response rate of 30% would be of scientific and clinical interest.
    

Eligibility criteria:

        Inclusion and Exclusion Criteria - Part 1

        Inclusion Criteria - Part 1

          -  Subject has provided informed consent prior to initiation of any study-specific
             activities/procedures or subject's legally acceptable representative has provided
             informed consent prior to any study-specific activities/procedures being initiated
             when the subject has any kind of condition that, in the opinion of the investigator,
             may compromise the ability of the subject to give written informed consent.

          -  Age ≥ 18 at time of informed consent

          -  Biopsy-proven DLBCL excluding DLBCL that represents transformation of indolent
             non-Hodgkin's lymphoma (NHL) Note: Lymphoblastic Lymphoma and Burkitt Lymphoma
             histology are not eligible

          -  Subject has ≥ 1 characteristic feature of high-risk DLBCL:

               -  High-risk first complete remission (defined as interim positron emission
                  tomography - computed tomography (PET-CT) positive or < complete remission to
                  frontline chemotherapy AND achieved complete remission to platinum-containing
                  salvage)

               -  Relapse within 1 year of diagnosis

               -  Secondary age-adjusted international prognostic index > 1

               -  Partial response/partial metabolic response after minimum of 2 cycles of
                  platinum-containing salvage chemotherapy

               -  C-myc rearrangement

          -  aHSCT with high-dose chemotherapy following first (or later) salvage treatment.

          -  PET-CT negative (Deauville score ≤ 3) 90 days (± 30 days) post aHSCT

          -  Available relapsed and/or diagnostic pathology formalin-fixed paraffin-embedded (FFPE)
             tumor block or slide samples at the time of enrollment including the successful
             identification of malignant clone sequences by the central laboratory.

          -  MRD plasma sample collected ≤ 3 weeks after the post aHSCT PET-CT scan

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

          -  Adequate organ function determined ≤ 3 weeks prior to enrollment defined as follows:

               -  Hematological:

        Absolute neutrophil count (ANC) ≥ 1.0 x 109/L Platelet count ≥ 75 x 109/L Hemoglobin ≥ 8
        g/dL

          -  Renal:

        Creatinine clearance ≥ 50 mL/min Cockcroft-Gault equation

          -  Hepatic:

        Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of
        normal (ULN) Total bilirubin < 2 x ULN (unless Gilbert's Disease or if liver involvement
        with lymphoma)

          -  Subject will be available to complete all protocol-required study visits or
             procedures, and/or to comply with all required study procedures to the best of the
             subject's and investigator's knowledge including but not limited to:

          -  Completion of up to a 24-month run-in period

          -  Completion of all regularly scheduled study visits including blood draws for MRD
             assessment, clinical disease state assessment, PET-CT scans (ie, at time of MRD
             positivity or relapse), assignment to treatment with blinatumomab

               -  Other Inclusion criteria may apply. See "Inclusion and Exclusion criteria - Part
                  2".

        Exclusion Criteria - Part 1

          -  Clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure,
             paresis, aphasia,stroke, severe brain injury, dementia, Parkinson's disease,
             cerebellar disease, organic brain syndrome, and psychosis

          -  Evidence of CNS involvement with DLBCL at disease evaluation obtained prior to
             starting blinatumomab

          -  Current autoimmune disease or history of autoimmune disease with potential of CNS
             involvement

          -  Prior anti-CD19 directed therapies

          -  Prior alloHSCT

          -  Received radiation ≤ 2 weeks prior to enrollment

          -  Infection with human immunodeficiency virus or chronic infection with hepatitis B
             virus (hepatitis B surface antigen positive) or hepatitis C virus (anti-hepatitis C
             virus positive)

          -  History of malignancy other than DLBCL within the past 3 years with the following
             exceptions:

               -  Malignancy treated with curative intent and with no known active disease present
                  for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the
                  treating physician

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease

               -  Adequately treated cervical carcinoma in situ without evidence of disease

               -  Adequately treated breast ductal carcinoma in situ without evidence of disease

               -  Prostatic intraepithelial neoplasia without evidence of prostate cancer

               -  Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in
                  situ

          -  Subject has known hypersensitivity to immunoglobulins or any of the products or
             components to be administered during dosing.

          -  History or evidence of any other clinically significant disorder, condition or disease
             (with the exception of those outlined above) that, in the opinion of the investigator
             or Amgen physician, if consulted, would pose a risk to subject safety or interfere
             with the study evaluation, procedures or completion.

          -  Women who are pregnant or breastfeeding or planning to become pregnant or breastfeed
             while receiving blinatumomab and for an additional 48 hours after the last treatment
             dose of blinatumomab. (Females of child bearing potential should only be included
             after a negative highly sensitive urine or serum pregnancy test.)

          -  Women of childbearing potential unwilling to use an acceptable method of effective
             contraception while receiving blinatumomab and for an additional 48 hours after last
             dose of blinatumomab. Note: The pregnancy, breastfeeding and contraceptive
             requirements are specific to blinatumomab. The investigator is responsible for
             providing the subject (male and female) with pregnancy and breastfeeding (female only)
             avoidance requirements for other medications given during the study.

          -  Currently receiving treatment in another investigational device or drug study or less
             than 30 days since ending treatment on another investigational device or drug study.
             Other investigational procedures while participating in this study are excluded.

               -  Other Exclusion criteria may apply. See "Inclusion and Exclusion criteria - Part
                  2".

        Inclusion and Exclusion Criteria - Part 2

        Inclusion Criteria - Part 2

          -  MRD-positive assessment (by NGS analysis) at enrollment or at any time during the
             run-in 1 period

          -  PET-CT negative (defined by Deauville criteria ≤ 3) at run-in 2 performed ≤ 3 weeks
             from MRD test result available to the site at run-in 1. Historical PET-CT are allowed
             if performed ≤ 6 weeks from day 1 (first dose of blinatumomab) and subject has no
             clinical signs or symptoms suggestive of disease progression (eg, increase in lactate
             dehydrogenase [LDH] not otherwise explained)

          -  Adequate organ function determined ≤ 7 days prior to treatment assignment with
             blinatumomab as follows:

               -  Hematological:

        ANC ≥ 1.0 x 109/L Hemoglobin ≥ 8 g/L Platelet count ≥ 75 x 109/L

          -  Renal:

        Creatinine clearance ≥ 50 mL/min Cockcroft-Gault equation

          -  Hepatic:

        AST and ALT < 3 x ULN Total bilirubin < 2 x ULN (unless Gilbert's Disease or if liver
        involvement with lymphoma)

        Exclusion Criteria - Part 2

          -  Subject has active infection requiring systemic therapy

          -  Any change in the part 1 eligibility criteria during the run-in period.