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MB-CART19.1 in Patients With R/R ALL

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03321123
Recruitment Status : Unknown
Verified October 2017 by Shanghai Children's Medical Center.
Recruitment status was:  Not yet recruiting
First Posted : October 25, 2017
Last Update Posted : October 25, 2017
Sponsor:
Collaborator:
Miltenyi Biomedicine GmbH
Information provided by (Responsible Party):
Shanghai Children's Medical Center

Brief Summary:
Precursor-B acute lymphoblastic leukemia (ALL) is the most common cancer in childhood. Despite major advances in ALL therapy, 20% of children and 40-50% of adults fail state-of-the art first-line treatment. But there is a strong need for alternative treatments to cure chemotherapy-refractory and relapsed B cell malignancies in pediatric patients. Relapsed and refractory B cell malignancies remain a therapeutic challenge, as these diseases are characterized by adverse survival. These cancers share a cell origin from the B-cell lineage and consequent surface expression of B-lineage markers such as CD19 and CD22. Chimeric antigen receptor (CAR) engineered T cell therapy has recently emerged as a new modality to target B cell malignancies. CARs couple a single-chain Fv (scFv) domain directed against a B-lineage-specific antigen to T-cell activating intracellular signaling domains. CAR gene-modified T cell interaction with target cells occurs in a HLA-independent fashion, so that a single vector can be used to treat all patients with cancers that express the target antigen. Miltenyi Biotec has established a semi-automated manufacturing process that can be made available to academic settings for systematic exploration of CAR strategies in advanced clinical studies. Closed-system operation, improved robustness, simplified work flows, and reduced labor intensity, while maintaining strict adherence to regulatory guidelines, allows for decentralized manufacturing. In the proposed phase II study, the investigator will explore autologous 2nd generation CD19 CAR T cell products in patients with relapsed and refractory disease incurable with standard therapies.

Condition or disease Intervention/treatment Phase
Precursor B-Lymphoblastic Lymphoma/Leukaemia Refractory Drug: MB-CART19.1 Phase 2

Detailed Description:

This is an open-label, non-randomized phase II paediatric study. In this study, eligible patients will receive autologous T cells transduced with the lentiviral vector pLTG1563 (MB-CART19.1) at a doesage of 2x10e6 ~2x10e7 CAR-transduced T cells/kg.

Upon enrollment, leukapheresis will be performed for MB-CART19.1 generation. Patients with high disease burden at screening (e.g. ALL with M3 marrow and 10.000/L blasts in peripheral blood) may receive bridging chemotherapy after leukapheresis, to avoid critical tumor lysis syndrome and cytokine release syndrome (CRS) by subsequent lymphodepleting chemotherapy and CAR transfer.

All patients will receive lymphodepleting chemotherapy with fludarabine 30 mg/m2/d intravenously (iv) on days -5,-4,-3 and -2 cyclophosphamide 500 mg/m2/d iv on day -3,-2 before CAR T cell transfer to enhance the in vivo expansion of CAR T cells.

Patients will receive freshly prepared MB-CART19.1 on day 0, corresponding to day 12 (48 hours) of manufacturing, at a dose of 2x10e6 ~2x10e7/kg MB-CART19.1 T cells as defined in the study design section. The appropriate volume for the target cell dose will be drawn up and given as an IV injection over 30 minutes through a large vein peripherally or centrally.

The primary objectives are:

  • To assess the safety and tolerability of MB-CART19.1.
  • To evaluate the biological activity of adoptive transfer of autologous MB-CART19.1 in patients with R/R CD19-positive B cell lymphoblastic leukemia.

The primary endpoint is Overall response rate (ORR):ORR in ALL patients is defined as the rate of complete remission (CR, CRh) on day 28.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Adoptive Therapy With MB-CART19.1 in Patients With Relapsed/Refractory CD19-positive B Cell Acute Lymphoblastic Leukemia
Estimated Study Start Date : December 1, 2017
Estimated Primary Completion Date : July 1, 2019
Estimated Study Completion Date : December 31, 2019


Arm Intervention/treatment
Experimental: CRA treatment

The drug for this trial is autologous T cells transduced with the lentiviral vector pLTG1563 (MB-CART19.1). The dose is 2x10e6 ~2x10e7 MB-CART19.1/kg.

A leukapheresis for the patient will be performed for MB-CART19.1 generation. All patients will receive lymphodepleting chemotherapy with fludarabine 30 mg/m2/d intravenously (iv) on days -5,-4,-3 and -2 cyclophosphamide 500 mg/m2/d iv on day -3,-2 before CAR T cell transfer to enhance the in vivo expansion of CAR T cells.

Drug: MB-CART19.1
Miltenyi Biotec has established a semi-automated manufacturing process that can be made available to academic settings for systematic exploration of CAR strategies in advanced clinical studies. Closed-system operation, improved robustness, simplified work flows, and reduced labor intensity, while maintaining strict adherence to regulatory guidelines, allows for decentralized manufacturing. In this study, we will explore autologous 2nd generation CD19 CAR T cell products in patients with relapsed and refractory disease incurable with standard therapies.
Other Name: Miltenyi CD-19 CAT-T cell




Primary Outcome Measures :
  1. Overall response rate [ Time Frame: 1 Month ]
    ORR in ALL patients is defined as the rate of complete remission (CR, CRh) on day 28


Secondary Outcome Measures :
  1. Overall incidence and severity of adverse events. [ Time Frame: 1 Months ]
    Overall incidence and severity of adverse events will measure in this trial. Including: 1,Risks related to targeting of CD19+ normal B-cells; 2,Allergic reactions to CAR T cell infusion; 3, Cytokine release syndrome (CRS); 4, neurological toxicities; 5,Risks related to transfer of donor T cells after previous alloSCT; 6, Risks related to lentiviral gene transfer into human cells.

  2. Rate of ALL patients achieving MRD negative CR [ Time Frame: 12 Months ]
    The rate of ALL patients achieving MRD negative CR in D28; 3,6,12months.

  3. Relapse rate and time to relapse [ Time Frame: 12 Months ]
    Overall rate of relapse and the time to relapse from CART cell transfused.


Other Outcome Measures:
  1. Disease-free and overall survival at 1 year after adoptive immunotherapy with MB-CART19.1 in patients not receiving alloSCT [ Time Frame: 12 Months ]
    CART treatment is an adoptive immunotherapy, and the CART cells will disaper after infusion. Then the patient relapsed. Allo-SCT can rebuild a new immune system to detec and destory cancer cell.

  2. Level of circulating CAR T cells [ Time Frame: 12 Months ]
    CART treatment is an adoptive immunotherapy, and the CART cells will disaper after infusion. The investigator need to detec the circulating CAR-T cell after infusion regularly.



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Months to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≤18 years (if deemed fit by treating investigator)
  • CD19 expression must be detected on the malignant cells by flow cytometry.
  • Patients with relapsed disease with >5% blasts in BM (M2 or M3) after at least one standard chemotherapy and one salvage regimen who are ineligible for allogeneic stem cell transplant (alloSCT)
  • Patients have refractory disease activity precluding alloSCT at this time, or patients who have relapsed post alloSCT at least 100 days post-transplant, with no evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30 days prior to enrollment.
  • Patients with combined extramedullary ALL are eligible if extramedullary disease has been successfully cleared by conventional therapy at the time of inclusion (e.g. intrathecal chemotherapy, orchiectomy). This includes patients with combined CNS-2 (<5 WBC/µl CSF, with blasts on cytospin) or CNS-3 (5WBC/µl CSF, with blasts on cytospin) disease and patients with combined testicular relapse.
  • Patients and/or parents must give their written informed consent/assent.

Exclusion Criteria:

  • Rapidly progressive disease that in the estimation of live less than 12 weeks
  • Isolated extramedullary relapse (CNS and/or testicular) in ALL
  • Current autoimmune disease, or history of autoimmune disease with potential CNS involvement
  • Active clinically significant CNS dysfunction (including but not limited to uncontrolled seizure disorders, cerebrovascular ischemia or hemorrhage, dementia, paralysis)
  • History of an additional malignancy other than non-melanoma skin cancer or carcinoma in situ unless disease free for ≥3 years.
  • Pulmonary function: Patients with pre-existing severe lung disease (FEV1 or FVC < 65%) or an oxygen requirement of >28% O2 supplementation or active pulmonary infiltrates on chest X-ray at the time scheduled for T cell infusion
  • Cardiac function: Fractional shortening <28% or left ventricular ejection fraction <50% by echocardiography
  • Renal function: Creatinine clearance <50 mL/min/1.73 m2

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03321123


Contacts
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Contact: Jing Chen, MD, PhD 86 18930830632 chenjing@scmc.com.cn
Contact: Benshang Li, MD, PhD 86 18101893712 libenshang@scmc.com.cn

Sponsors and Collaborators
Shanghai Children's Medical Center
Miltenyi Biomedicine GmbH
Investigators
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Principal Investigator: Jing Chen, MD,PhD Shanghai Children Medicine Center
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Responsible Party: Shanghai Children's Medical Center
ClinicalTrials.gov Identifier: NCT03321123    
Other Study ID Numbers: SCMC CART 20170920
First Posted: October 25, 2017    Key Record Dates
Last Update Posted: October 25, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Shanghai Children's Medical Center:
B cell Acute Lymphoblastic Leukemia
relapsed or refractory
CD-19 Positive
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases