A Phase I Study of CD19 Specific T Cells in CD19 Positive Malignancy

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by Christie Hospital NHS Foundation Trust
Sponsor:
Information provided by (Responsible Party):
Professor Robert Hawkins, Christie Hospital NHS Foundation Trust
ClinicalTrials.gov Identifier:
NCT01493453
First received: December 14, 2011
Last updated: November 25, 2013
Last verified: November 2013
  Purpose

In particular circumstances T cells can be an effective treatment for malignant disease, for example, donor lymphocyte infusions following allogeneic transplants or treatment of EBV related lymphomas post allograft. However, many common cancers are poorly recognised by the immune system in part because of a lack of suitable T cell targets and in part because of defects in antigen presentation by tumours (Garrido, et al 1997). Genetically modified T cells engineered to express chimeric immune receptors (CIRs) on their cell surface can bypass the need for MHC presentation and thus represent an attractive approach to immunotherapy (Gross, et al 1989).


Condition Intervention Phase
CD19 Positive Non-Hodgkin Lymphoma
Genetic: aCD19z cells, IL2, pre conditioning Cyclophosphamide & Fludarabine
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Adoptive Transfer of Autologous Tumour Antigen-Specific T Cells With Pre-conditioning Chemotherapy and Intravenous IL2 in Patients With CD19 Positive Malignancy

Resource links provided by NLM:


Further study details as provided by Christie Hospital NHS Foundation Trust:

Primary Outcome Measures:
  • To asses aCD19z T cell survival and aCD19z T cell toxicity in patients, & The dose of aCD19z T cells required to give optimal survival of these cells in the circulation [ Time Frame: Week 6 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To assess whether aCD19z T cells in the circulation are functional [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 24
Study Start Date: March 2008
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single Arm - aCD19z cells, interleukin 2, Chemotherapy Genetic: aCD19z cells, IL2, pre conditioning Cyclophosphamide & Fludarabine
aCD19z T cells IV Day 1. The dose of aCD19z T cells will be determined by dose escalation scheme, starting at 10*9 IL2 given as 15 minute IV infusion every eight hours for up to 12 doses Cyclophosphamide (C) 15mg/kg day -7 and day -6, Fludarabine (F) 25mg/m2 day -5 to day -1.

Detailed Description:

CD19 is an Immunoglobulin-like 95kDa glycoprotein that is expressed on all B lymphocytes until differentiation into terminal effector cells (Tedder and Isaacs 1989). It plays an important role in regulating cell signalling thresholds and also as a costimulatory molecule for B cell receptor signalling (Tedder, et al 1997). CD19 is present on the majority of B-CLL, B-ALL, and both low and high grade non-Hodgkin lymphomas (NHL). It is rarely lost during the process of neoplastic transformation and is not expressed on haematopoetic stem cells. B cell malignancies are often highly responsive to chemotherapy, with cures possible in significant numbers of those with high grade tumours. However, improved treatments are needed for those with low grade tumours and those with high grade tumours who relapse after conventional therapy.

In recent years the introduction of Rituximab, a CD20 monoclonal antibody, into clinical practice has increased the options available for the treatment of NHL (Maloney, et al 1994). The success of Rituximab and other monoclonal antibodies has demonstrated that B cell malignancies may be particularly suitable as a target for immunotherapy. However, there are number of potential advantages of T cells engineered to express a CIR over monoclonal antibody therapies. Firstly, the possibility of in vivo T cell persistence and expansion may enable stable expression of the CIR over a prolonged period of time (Walker, et al 2000). Secondly, homing to the tumour site may mean that T cells need not rely on diffusion to achieve localisation (Balkwill 2004, Mitsuyasu, et al 2000) and thirdly following tumour recognition T cells can produce cytokines that may recruit and activate other effector cells. An alternative to CIR engineered T cells is the generation of peptide specific T cells. Lymphoma models suggest these can be effective (Armstrong, et al 2002, Armstrong, et al 2004), but to produce clinically applicable numbers of T cells is technically demanding and there is a lack of generic peptide target antigens in lymphoma.

One potential problem in the use of CIR engineered T cells in general is that tumour associated antigens are frequently expressed at low levels on normal tissues, thus providing the potential for autoimmunity. Targeting B cell malignancies with CD19 specific T cells is attractive because whilst CD19 is expressed on B cells and the majority of B cell malignancies it is not expressed on any other cell type. It is clear from clinical use of anti-CD20 antibodies that prolonged depletion of B cells (>6 months) is safe (Plosker and Figgitt 2003) and that even in patients with hereditary B cell deficiency immunoglobulin infusion restores normal health in most patients (Ochs and Smith 1996).

The Investigators have therefore propose a clinical trial using T cells expressing a CD19 targeting CIR by retroviral transduction of the CIR into activated T cells in order to target B cell malignancies.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically confirmed CD19 positive non-Hodgkin Lymphoma with evidence of persistent or progressive disease and poor prognosis as discussed in detail in section 1.5
  • Written informed consent and the ability of the patient to co-operate with study treatment, procedures and follow up must be ensured and documented.
  • Age equal to or greater than 18 years.
  • World Health Organisation (WHO) performance status of 0 or 1 (appendix 1).
  • Life expectancy >3months.
  • LVEF > 50% as measured by MUGA scan
  • Haematological and biochemical indices:

Haemoglobin (Hb)≥ 10.0 g/dl neutrophils ≥ 1.0 x 109/L platelets (Plts)≥ 100 x 109/L

Any of the following abnormal baseline liver function tests:

serum bilirubin ≤ 1.5 x upper limit of normal (ULN) alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) and /or alkaline phosphatase (ALP)≤ 5 x ULN Serum creatinine ≤ 0.14 mmol/L

  • Female patients of child-bearing potential are eligible, provided they have a negative serum or urine pregnancy test prior to enrolment and agree to use appropriate medically approved contraceptive precautions for four weeks prior to entering the trial, during the trial, and for six months afterwards.
  • Male patients must agree to use barrier method contraception during the trial and for six months afterwards.
  • Measurable disease as defined by RECIST criteria (appendix 3).

Exclusion Criteria:

  • Radiotherapy, biological therapy, endocrine therapy, immunotherapy, systemic steroids, or chemotherapy during the previous four weeks (six weeks for nitrosoureas and Mitomycin-C) prior to treatment or during the course of the trial.
  • All toxic manifestations of previous treatment must have resolved. Exceptions to this are alopecia or certain Grade 1 toxicities which in the opinion of the Investigator and Trial Sponsor should not exclude the patient.
  • Participation in any other clinical trial within the previous 30 days or during the course of this trial.
  • Previous participation in a Gene Therapy trial.
  • Previous allogeneic transplant.
  • Patients who are high medical risks because of non-malignant systemic disease, including those with active infection, uncontrolled cardiac or respiratory disease, or other serious medical or psychiatric disorders which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
  • Concurrent serious infections within the 28 days prior to entry to the trial.
  • Current malignancies at other sites, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin.
  • Patients known or found to be serologically positive for Hepatitis B, C, HIV or HTLV.
  • History of autoimmune disease.
  • Evidence of CNS involvement.
  • Patients who are likely to require systemic steroids or other immunosuppressive therapy.
  • Pregnant and lactating women.
  • Radiotherapy to >25% skeleton.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01493453

Contacts
Contact: Ian Bottomley, BA Honours +44(0)161 9187443 ext 7443 Ian.Bottomley@christie.nhs.uk

Locations
United Kingdom
The Christie NHS Foundation Trust Recruiting
Manchester, United Kingdom, M20 3EE
Contact: Ian Emerson, BA    01619187443    ian.emerson@christie.nhs.uk   
Principal Investigator: Robert E Hawkins, BA, MB BS, MCRP, Phd, FRCP         
Sub-Investigator: Fiona C Thistlethwaite, MB BChir, PhD, MRCP         
Sponsors and Collaborators
Professor Robert Hawkins
  More Information

No publications provided

Responsible Party: Professor Robert Hawkins, Professor of Medical Oncology, Christie Hospital NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT01493453     History of Changes
Other Study ID Numbers: 05_DOG05_18
Study First Received: December 14, 2011
Last Updated: November 25, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine monophosphate
Fludarabine
Interleukin-2
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Antimetabolites, Antineoplastic
Antimetabolites

ClinicalTrials.gov processed this record on July 29, 2014