Clinical Trials /

Blinatumomab Plus HLA-Mismatched Cellular Therapy for Relapsed/Refractory CD19+ ALL

NCT03751709

Description:

Single center Phase 1 dose escalation trial of the combination of standard-of-care blinatumomab plus Haplo-Mismatched Cellular Therapy (HMCT). HMCT refers to the infusion of donor peripheral blood mononuclear cells collected via pheresis from a haploidentical family member - the procedure is analogous to giving a donor lymphocyte infusion outside of the setting of an allogeneic stem cell transplant; also known as 'microtransplantation'. The HMCT is an unselected mix of lymphocytes and leukocytes, but the product dose escalation will be done based on the T cell content. Ten recipients are planned. Each subject will be administered one infusion of HMCT during the first cycle of blinatumomab and two infusions during cycle two of blinatumomab; the CD3+ cell dose of the HMCT infusion is governed by dose escalation / de-escalation following a Bayesian method.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Blinatumomab Plus HLA-Mismatched Cellular Therapy for Relapsed/Refractory CD19+ ALL
  • Official Title: IIT2017-05-MERIN-BLINHMCT: Blinatumomab Plus HLA-Mismatched Cellular Therapy (HMCT) for Relapsed/Refractory CD19+ ALL

Clinical Trial IDs

  • ORG STUDY ID: IIT2017-05-MERIN-BLINHMCT
  • NCT ID: NCT03751709

Conditions

  • B-Cell Acute Lymphoblastic Leukaemia
  • ALL, Adult
  • B-ALL

Interventions

DrugSynonymsArms
BlinatumomabBlincytoSubjects

Purpose

Single center Phase 1 dose escalation trial of the combination of standard-of-care blinatumomab plus Haplo-Mismatched Cellular Therapy (HMCT). HMCT refers to the infusion of donor peripheral blood mononuclear cells collected via pheresis from a haploidentical family member - the procedure is analogous to giving a donor lymphocyte infusion outside of the setting of an allogeneic stem cell transplant; also known as 'microtransplantation'. The HMCT is an unselected mix of lymphocytes and leukocytes, but the product dose escalation will be done based on the T cell content. Ten recipients are planned. Each subject will be administered one infusion of HMCT during the first cycle of blinatumomab and two infusions during cycle two of blinatumomab; the CD3+ cell dose of the HMCT infusion is governed by dose escalation / de-escalation following a Bayesian method.

Detailed Description

      This single center, phase 1 study will examine the safety, side effects, and effectiveness of
      combining the investigational use of Haplo-Mismatched Cellular Therapy (HMCT) in combination
      with blinatumomab. Investigators plan to give HMCT starting on day 15, after the initial CRS
      caused by blinatumomab has resolved. The investigational treatment will start with 1% of the
      typical HMCT dose (10e6 CD3+ cells/kg) and will employ a modified dose escalation design as
      an additional safety measure. The primary end points will be DLT of the combination of
      blinatumomab and HMCT.
    

Trial Arms

NameTypeDescriptionInterventions
SubjectsExperimentalBlinatumomab+Haplo-Mismatched Cell Therapy (HMCT)
  • Blinatumomab

Eligibility Criteria

        Inclusion Criteria:

          -  Relapsed/Refractory CD19+ Acute Lymphoblastic Leukemia. Patients with minimal residual
             disease detected by NGS > 10e-6 or multiparameter flow cytometry > 10e-5 in blood or
             bone marrow are eligible.

          -  Patients must belong to one of the following 'high risk' categories: (i) at least 2nd
             relapse or refractory to at least one salvage therapy (ii) relapse after autologous
             stem cell transplantation, (iii) any relapse in a patient with no immediate allogeneic
             transplant option (such as advanced age, comorbidity, lack of identified donor, or
             patient refusal) (iv) Patients with Ph+ ALL will be allowed on the trial at the
             discretion of the treating physician if they are no longer candidates for further TKI
             based therapy. Prior therapy with a minimum of 2 prior 2nd/3rd generation TKI is
             required. (TKI therapy is not allowed while on trial).

          -  Patients with prior blinatumomab treatment are eligible if last treatment was at least
             3 months prior to C1D1, patient's blasts are confirmed to express CD19, and patient
             did not develop Grade 4 toxicities with prior blinatumomab therapy.

          -  Age ≥ 18 years.

          -  Patient has at least one medically fit first- or second-degree family member who is a
             potential haploidentical donor. In addition, the prospective donor is willing to
             voluntarily donate peripheral blood cells, and sign consent forms. For minors, consent
             will be obtained from parent/guardian (assent from the minor is required).

          -  Patients must have adequate organ function as defined below (note there are no marrow
             function criteria, cytopenias will not result in exclusion):

               -  Serum creatinine ≤ 2.0 x the upper limits of institutional normal (ULN)

               -  Total bilirubin ≤ 1.5x the upper limits of institutional normal, unless elevated
                  bilirubin is attributed to liver involvement of leukemia or Gilbert's disease.

               -  AST/ALT ≤ 2.5 x the upper limits of institutional normal (≤ 5 x ULN for patients
                  with suspected liver involvement of leukemia).

          -  ECOG performance status of 0, 1, or 2, and estimated survival of at least 3 months.

          -  Patients must be able to understand and agree to sign an IRB-approved informed consent
             form.

          -  The effects of treatment on the developing human fetus are unknown. For this reason,
             women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control or complete abstinence) prior to study
             entry, for the duration of study, and for two months after study participation. Should
             a woman become pregnant or suspect she is pregnant while participating in this study,
             she should inform her treating physician immediately.

          -  Written informed consent obtained from subject and ability for subject to comply with
             the requirements of the study.

        Exclusion Criteria:

          -  Prior allogeneic stem cell transplant

          -  Prior treatment with fludarabine or cladribine within the last six months prior to
             C1D1, or treatment with antithymocyte globulin (ATG) or alemtuzumab within the last 1
             year.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  Pregnant and/or lactating.

          -  Who have had non-biopsy surgery in the last 10 days.

          -  Who have active CNS disease. Patients with previously treated leptomeningeal disease
             without evidence of remaining leukemia cells by spinal fluid will be eligible.
             Intrathecal chemo may be given for prophylaxis for patients who previously had CNS
             involvement but have now cleared the CSF, at the discretion of the treating physician.
             Recommend to avoid IT chemotherapy for a few days before or after HMCT infusion.

          -  History or presence of clinically relevant CNS pathology such as epilepsy, childhood
             or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia,
             Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis
             (patients with minor prior stroke who are cognitively intact and capable of performing
             all ADLs are permitted).

          -  Patients with known active autoimmune disorder.

          -  Known infection with HIV virus.

          -  Patients concurrently taking the following drugs are excluded: mycophenolate,
             cyclosporine, prednisone > 20mg/day, or immunosuppressive agents (low dose maintenance
             chemotherapy - POMP, hydroxyurea, low dose prednisone - is allowed until 24 hours
             prior to starting blinatumomab).

          -  Patients known to have active hepatitis B or C (Hepatitis B positive patients are
             allowed if they are on appropriate antiviral agents such as lamivudine).

          -  Subject likely to not be available to complete all protocol-required study visits or
             procedures, including follow-up visits, and/or to comply with all required study
             procedures to the best of the subject and Investigator's knowledge.

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of DLTs
Time Frame:up to 6 months
Safety Issue:
Description:Number of Dose Limiting Toxicities experienced by patients undergoing HLA mismatched cellular therapy (HMCT) of allogenic CD3+ cells in combination with blinatumomab.

Secondary Outcome Measures

Measure:Number of participants experiencing complete response (CR) from time of transplant to one day following the second treatment
Time Frame:up to 3 months
Safety Issue:
Description:Bone marrow aspiration and local peripheral blood counts will be used to measure response. CR is defined as the following: Less than or equal to 5% blasts in the bone marrow No evidence of disease, AND Full recovery of peripheral blood counts: platelets > 100,000/ul, and ANC > 1000/ul
Measure:Number of participants experiencing complete response with partial recovery of peripheral blood counts (CRh) from time of transplant to one day following the second treatment
Time Frame:up to 3 months
Safety Issue:
Description:Bone marrow aspiration and local peripheral blood counts will be used to measure response. CRh is defined as the following: Less than or equal to 5% blasts in the bone marrow No evidence of disease, AND Full recovery of peripheral blood counts: platelets > 50,000/ul, and ANC > 500/ul
Measure:Number of participants experiencing complete response with incomplete count recovery (CRi) from time of transplant to one day following the second treatment
Time Frame:up to 3 months
Safety Issue:
Description:Bone marrow aspiration and local peripheral blood counts will be used to measure response. CRi is defined as the following: Less than or equal to 5% blasts in the bone marrow No evidence of disease, AND Full recovery of peripheral blood counts: platelets > 100,000/ul, and ANC > 1000/ul
Measure:Response blast-free hypoplastic or aplastic bone marrow from time of transplant to one day following the second treatment
Time Frame:up to 3 months
Safety Issue:
Description:Bone marrow aspiration and local peripheral blood counts will be used to measure response. Blast-free hypoplastic or aplastic bone marrow response is defined as the following: Less than or equal to 5% blasts in the bone marrow No evidence of disease, AND Full recovery of peripheral blood counts: platelets > 50,000/ul, and ANC > 500/ul
Measure:Disease burden measured as the minimal residual disease (MRD) response from time of transplant to one day following the second treatment
Time Frame:up to 3 months
Safety Issue:
Description:MRD remission is defined as the occurrence of an MRD level below 10^-4 measured by quantitative reverse transcription polymerase chain reaction (PCR) or flow cytometry. Complete response defined as: no detectable leukemic cells by PCR or flow cytometry.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Cedars-Sinai Medical Center

Trial Keywords

  • Haplo-Mismatched Cellular Therapy
  • Acute Lymphoblastic Leukemia
  • ALL
  • B-ALL
  • donor lymphocyte
  • DLI
  • blinatumomab
  • bispecific
  • microtransplantation
  • microtransplant

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