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CARPALL: Immunotherapy With CD19 CAR T-cells for CD19+ Haematological Malignancies

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ClinicalTrials.gov Identifier: NCT02443831
Recruitment Status : Recruiting
First Posted : May 14, 2015
Last Update Posted : October 17, 2018
Sponsor:
Information provided by (Responsible Party):
University College, London

Brief Summary:
This study aims to evaluate the safety, efficacy and duration of response of CD19 Chimeric Antigen Receptor (CAR) redirected autologous T-cells in children with high risk, relapsed CD19+ haematological malignancies.

Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Burkitt Lymphoma Procedure: Leukapheresis Drug: Lymphodepletion with fludarabine Drug: Lymphodepletion with cyclophosphamide Biological: CD19 CAR T-cells Phase 1

Detailed Description:
This is a multi-centre, non-randomised, open label Phase I clinical trial of an Advanced Therapy Investigational Medicinal Product named CD19 Chimeric Antigen Receptor (CAR) T-cells (CD19 CAR T-cells) in children and young adults (age <24 years) with high risk, relapsed CD19+ haematological malignancies (Acute Lymphoblastic Leukemia and Burkitt's lymphoma). Following informed consent and registration to the trial, patients will undergo an unstimulated leukapheresis for the generation of the CD19 CAR T-cells. Patients will receive the CD19CAR T-cells following lymphodepleting chemotherapy. The study will evaluate the safety, efficacy and duration of response of the CD19 CAR T-cells in children with high risk relapsed CD19+ malignancies.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Immunotherapy With CD19 CAR Redirected T-cells for High Risk, Relapsed Paediatric CD19+ Acute Lymphoblastic Leukaemia and Other Haematological Malignancies
Study Start Date : April 2016
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : December 2030


Arm Intervention/treatment
Experimental: CD19 CAR T-cells
Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19CAR T-cells. Patients will receive lymphodepletion with fludarabine and cyclophosphamide prior to infusion of the CD19CAR T-cells.
Procedure: Leukapheresis
Patients will undergo an unstimulated leukapheresis to isolate the required immune cells to produce the CD19 CAR T-cells

Drug: Lymphodepletion with fludarabine
Patients will receive lymphodepleting chemotherapy with iv fludarabine 30 mg/m2 on days -7 to -3 prior to CD19CAR T-cell infusion.

Drug: Lymphodepletion with cyclophosphamide
Patients will receive lymphodepleting chemotherapy with iv cyclophosphamide 0.5 g/m2 on days -4 to -2 prior to CD19CAR T-cell infusion.

Biological: CD19 CAR T-cells
A single dose of 1 x 10^6/kg CD19CAR transduced T-cells will be given as an intravenous injection through a Hickman line or PICC line(peripherally inserted central catheter) on day 0.




Primary Outcome Measures :
  1. Toxicity evaluation following CD19CAR T-cell infusion [ Time Frame: 1 month ]
    The incidence of grade 3-5 toxicity occurring within 60 days of CD19CAR T-cell infusion. In particular, the incidence of Severe Cytokine Release Syndrome and Grade 3-5 neurotoxicity occurring within 30 days of CD19CAR T-cell infusion.

  2. Molecular remission [ Time Frame: 1 month ]
    Efficacy will be assessed by determining Minimal Residual Disease in the bone marrow aspirate using immunoglobulin heavy chain (IgH) quantitative polymerase chain reaction (qPCR) and/or Next Generation Sequencing in all patients. The proportion of patients achieving molecular remission at 1 month post CD19CAR T-cell infusion will be determined.


Secondary Outcome Measures :
  1. Long term molecular remission [ Time Frame: 2 years ]
    Number of patients in molecular remission without further therapy at 2 years

  2. Frequency of circulating CD19 CAR T-cells [ Time Frame: 2 years ]
    Persistence and frequency of circulating CD19CAR T-cells in the peripheral blood by flow cytometry and qPCR analyses.

  3. Incidence of hypogammaglobulinaemia [ Time Frame: 2 years ]
    Incidence and duration of hypogammaglobulinaemia

  4. Relapse rate [ Time Frame: 10 years ]
    Relapse rate monitored during interventional phase and long term follow up for a total of10 years post cell infusion. Number of patients who relapsed can be summarized as a percentage or rate(for all patients registered to the trial, and also only for those who received the cell infusion).

  5. Overall Survival [ Time Frame: 10 years ]
    Overall survival is monitored during interventional phase and long term follow up for 10 years post-CD19CAR T-cell infusion. Number of patients alive can be summarized as a percentage (for all patients registered to the trial, and also only for those who received the cell infusion).



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Ages Eligible for Study:   up to 24 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Children and young adults (age 24 years or younger) with high risk/relapsed CD19+ haematological malignancy:

    1. Resistant disease (>25% blasts) at end of UKALL 2011 or equivalent induction
    2. ALL with persistent high level MRD at 2nd time point of frontline national protocol (currently > 5 x 10-3 at week 14 UKALL2011 or equivalent)
    3. High risk infant ALL (age < 6 months at diagnosis with MLL gene rearrangement and either presenting white cell count > 300 x 109/L or poor steroid early response (i.e circulating blast count >1x109/L following 7 day steroid pre-phase of Interfant 06)
    4. Intermediate risk infant ALL with MRD > 10-3 at end of Interfant06 induction
    5. Very early (< 18 months from diagnosis) bone marrow or extramedullary relapse of acute lymphoblastic leukaemia (ALL)
    6. Early (within 6 months of finishing therapy) bone marrow, or combined extramedullary relapse of ALL with bone marrow minimal residual disease (MRD) > 10-3 at end of re-induction
    7. Any on therapy relapse of ALL in patients age 16-24
    8. Any relapse of infant ALL
    9. ALL post ≥ 2nd relapse
    10. Any refractory relapse of ALL
    11. ALL with MRD >10-4 prior to planned stem cell transplant
    12. Any relapse of ALL eligible for stem cell transplant but no available HLA matched donor or other contraindication to transplant
    13. Any relapse of ALL after stem cell transplant
    14. Any relapse of Burkitt's or other CD19+ lymphoma
  2. Agreement to have a pregnancy test, use adequate contraception (if applicable)
  3. Written informed consent

Exclusion Criteria:

  • Exclusion Criteria for registration:

    1. CD19 negative disease
    2. Active hepatitis B, C or HIV infection
    3. Oxygen saturation ≤ 90% on air
    4. Bilirubin > 3 x upper limit of normal
    5. Creatinine > 3 x upper limit of normal
    6. Women who are pregnant or lactating
    7. Stem Cell Transplant patients only: active acute graft-versus-host disease (GVHD) overall Grade ≥ II (Seattle criteria) or moderate/severe chronic GVHD (NIH consensus criteria) requiring systemic steroids
    8. Inability to tolerate leucapheresis
    9. Karnofsky (age ≥ 10 years) or Lansky (age < 10) score ≤ 50%

Exclusion criteria for CD19CAR T-cell infusion:

  1. Severe intercurrent infection at the time of scheduled CD19CAR T-cell infusion
  2. Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19CAR T-cell infusion
  3. Allogeneic transplant recipients with active acute GVHD overall grade >2 or moderate/severe chronic GVHD requiring systemic steroids at the time of scheduled CD19CAR T-cell infusion

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): NCT02443831


Contacts
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Contact: Fernanda Castro 02076799860 ctc.carpall@ucl.ac.uk

Locations
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United Kingdom
Great Ormond Street Hospital Recruiting
London, United Kingdom
Contact: Prof. Persis Amrolia         
University College Hospital Recruiting
London, United Kingdom
Contact: Dr Rachael Hough         
Royal Manchester Infirmary Not yet recruiting
Manchester, United Kingdom
Contact: Eleni Tholouli         
Royal Manchester Royal Children's Hopsital (part of MRI) Recruiting
Manchester, United Kingdom
Contact: Dr Rob Wynn         
Sponsors and Collaborators
University College, London
Investigators
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Study Chair: Persis Amrolia UCL Institute of Child Health

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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT02443831     History of Changes
Other Study ID Numbers: UCL 14/0529
First Posted: May 14, 2015    Key Record Dates
Last Update Posted: October 17, 2018
Last Verified: May 2018

Keywords provided by University College, London:
high risk relapsed CD19+ hematological malignancies

Additional relevant MeSH terms:
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Burkitt Lymphoma
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Hematologic Neoplasms
Neoplasms
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Lymphoma, B-Cell
Lymphoma, Non-Hodgkin
Lymphoma
Neoplasms by Site
Hematologic Diseases
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents