Safety Study of Anti LewisY Chimeric Antigen Receptor in Myeloma, Acute Myeloid Leukemia or Myelodysplastic Syndrome

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Peter MacCallum Cancer Centre, Australia
ClinicalTrials.gov Identifier:
NCT01716364
First received: October 25, 2012
Last updated: December 3, 2012
Last verified: October 2012
  Purpose

Patients with some forms of acute myeloid leukemia (AML) and multiple myeloma (MM) are not cured with conventional therapy and new approaches are needed. For the last 15 years we have investigated the potential of using a patient's own T cells (a type of white blood cell [WBC]) to eradicate the tumor. We have demonstrated the feasibility of this approach in cell culture and animal models of AML and MM. Over the last 5 years we have been preparing to treat patients as part of a Phase I (first in human) clinical trial.

The trial treatment involves collecting the patient's own WBCs from the blood by a standard well established and safe process called apheresis. The cells are then cultured in a specialized laboratory (under Good Manufacturing Practice conditions, similar to standards under which pharmaceuticals are produced) over 12 days to convert the cells to specialized tumor-attacking T cells. Early in that culture process the cells are exposed to a virus (that is modified so that it cannot infect or replicate outside the special culture conditions) that contains a special gene. Via the virus, this gene inserts into the patient's T cells in culture and gets incorporated into the T cell's genetic machinery. As the T cells replicate, the new gene produces a protein receptor that becomes part of the patient's T cells. This protein receptor on the T cells has the capacity to specifically recognize and bind to a protein on the leukemia or myeloma cells called the "Lewis Y" antigen.

After the modified T cells are infused into the patient, they home into the bone marrow (this tracking is monitored by special radiological techniques) where the new protein receptor on the T cell surface can recognize and bind to the cancer cells (which express Lewis Y). Once bound onto the cancer cells, the T cells get activated and subsequently replicate and kill the cancer cells. The novelty of this approach is that the T-cells will only kill cells that have the Lewis Y on their surface - the cancer cells. Moreover, because there are few normal cells in a person's body that carry Lewis Y, this treatment is likely to only have minor side effects.

This gene therapy trial is unique and although the primary purpose is to test the safety of this approach, patients will be monitored closely for anti-tumor responses. As the trial progresses, the dose of T cells infused will increase, in the hope that this will result in a better and stronger immune response to the leukemia or myeloma.


Condition Intervention Phase
Multiple Myeloma
Acute Myeloid Leukaemia
Myelodysplastic Syndrome
Biological: Anti-LeY- scFv-CD28-ζ vector,.
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study Investigating Safety Immunological Effects of Peripheral Blood T Lymphocytes Transduced With Anti LewisY Chimeric Receptor Gene in LewisY Positive Myeloma, Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome

Resource links provided by NLM:


Further study details as provided by Peter MacCallum Cancer Centre, Australia:

Primary Outcome Measures:
  • Number of participants with adverse events. [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Percentage of infused labelled cells localizing in bone marrow [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Percentage of infused labelled cells localizing in soft tissue or plasmacytoma. [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Presence or absence of anti-LeY positive T-cells in peripheral blood and bone marrow. [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Percentage of anti LeY positive T-cells in peripheral blood and bone marrow. [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Serum IFN-γ and IL-2 levels. [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Presence or absence of autoimmune disease. [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Overall response. [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Time to progression [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Time to treatment failure [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Duration of response [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Location of labelled re-infused T-cells [ Time Frame: Up to 1 month ] [ Designated as safety issue: No ]
  • LewisY expression assessed with Flow Cytometry in Peripheral Blood and Bone Marrow. [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • LewisY expression assessed with Flow Cytometry in Peripheral Blood and Bone [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 6
Study Start Date: January 2010
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Anti-LeY- scFv-CD28-ζ vector.
Anti-LeY- scFv-CD28-ζ vector, a non-pathogenic, replication-incompetent retroviral vector specifically designed for this study and produced by EUFETS under GMP-conditions.
Biological: Anti-LeY- scFv-CD28-ζ vector,.

  Eligibility

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

Inclusion Criteria:

  • Applicable to all Patients
  • Patient is able to undergo apheresis of peripheral blood mononuclear cells (PBMC) within eight weeks following registration.
  • White cell count (WCC) <30/nL as higher WCC could interfere with the apheresis of PBMC.
  • Patient has an ECOG performance status of 0 - 1.
  • Patient is deemed capable of undergoing the planned study procedures
  • Patient has adequate organ function:

    • bilirubin <1.5x upper limit of normal (ULN), AST/ALT ≤2.5 x ULN except in patients with Gilbert's syndrome
    • Serum Creatinine < 1.5 ×ULN or creatinine clearance > 50ml/min
    • Amylase, lipase ≤1.5xULN
  • Lymphocyte count of ≥0.5x109/L
  • > 18 years of age.
  • Patient has provided written informed consent.
  • No chemotherapy or treatment with G-CSF within 4 weeks prior to the planned apheresis.
  • Applicable to patients with multiple myeloma
  • Patient has histologically or cytologically confirmed diagnosis of multiple myeloma plus one or more of the criteria set out below must apply:
  • Presence of the following features that are known to be associated with an adverse prognosis with conventional chemotherapy, high-dose chemotherapy and autologous stem cell transplant (AUSCT):

Chromosomal abnormalities:

  • 13q deletion
  • 17p deletion as p53-deletion by IHC on the bm trephine
  • Translocation (4:14)
  • Translocation (14:16)

Clinical features:

  • Progressive disease within 12 months after previous AUSCT
  • Plasmablastic morphology
  • Plasma cell leukaemia

    • Patient planned for high-dose melphalan chemotherapy with AUSCT having had at least two prior treatment regimens (which can include prior high-dose chemotherapy and AUSCT and must include at least one of thalidomide, lenalidomide or bortezomib).
    • Patient has previously proven LewisY expression on the plasma cells prior to study entry in an analysis as defined in study criteria
    • Patient is planned to receive high dose melphalan and autograft (after apheresis of PBMC)
    • Additional inclusion Criteria applied to patients with acute myeloid leukaemia (AML)/high-risk myelodysplastic syndrome (MDS)

All of the following must apply:

  • Patient must either have newly diagnosed AML/high-risk MDS with a poor prognosis or relapsed/refractory AML/high-risk MDS
  • Patient has previously proven LewisY expression on the myeloblasts prior to study entry in an analysis as defined in study criteria
  • Patient is planned to receive fludarabine containing regime (FCR) chemotherapy (after apheresis of PBMC) which is planned to be the last cycle of FCR chemotherapy, no further FCR chemotherapy should be planned within 3 months after this cycle of FCR

Definition of poor prognosis in AML/high-risk MDS

A patient with AML has a poor prognosis if any of the following is satisfied:

  • Age > 65 years
  • Age 56 - 65 years with any of the following single cytogenetic abnormalities: -7, -5, trisomy 8, abnormal 3q, t(6;9), t(9;22) or t(9;11), normal karyotype with FLT3-ITD
  • Age 56 - 65 years with a complex aberrant karyotype defined as >4 cytogenetic abnormalities
  • Any age with relapsed or refractory disease

Exclusion Criteria

None of the following should apply:

  • Patient has had immunotherapy including corticosteroids (except Prednisolone <10mg or equivalent) within the last 4 weeks or is planned to receive such therapy prior to apheresis of PBMC.
  • Patient has been given chemotherapy and/or G-CSF in the last 4 weeks.
  • Patient has been planned to receive chemotherapy and/or growth factors of any type before planned apheresis of PBMC
  • Patient has been given experimental therapy within the last 4 weeks or is planned to receive experimental therapy prior to apheresis of PBMC
  • Patient has known clinically significant autoimmune disease with positive serology for RHF (>20kU/L) or ANA (titre >1:40)
  • Patient has a history of idiopathic pancreatitis Patient has known, biopsy proven autoimmune inflammatory disease of the gastrointestinal tract
  • Women of child bearing potential (WOCBP) who are unwilling or unable to use an effective method of contraception to avoid pregnancy for the entire study period and for at least 3 months after completion of study treatment.
  • Women who are pregnant or breastfeeding.
  • Men who are unwilling or unable to use an acceptable method of contraception for the entire study period and for at least 3 months after completion of study treatment if their sexual partners are WOCBP.
  • Patient has known central nervous system (CNS) disease.
  • Patient has a serious uncontrolled medical disorder which would impair the ability to receive protocol therapy.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01716364

Locations
Australia, Victoria
Peter MacCallum Cancer Centre
Melbourne, Victoria, Australia, 3002
Sponsors and Collaborators
Peter MacCallum Cancer Centre, Australia
Investigators
Principal Investigator: Miles Prince, MD Peter MacCallum Cancer Centre, Australia
  More Information

No publications provided

Responsible Party: Peter MacCallum Cancer Centre, Australia
ClinicalTrials.gov Identifier: NCT01716364     History of Changes
Other Study ID Numbers: LeYPh1
Study First Received: October 25, 2012
Last Updated: December 3, 2012
Health Authority: Australia: Therapeutic Goods Administration, Department of Health and Aging, Australian Government

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Multiple Myeloma
Neoplasms, Plasma Cell
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases
Precancerous Conditions

ClinicalTrials.gov processed this record on April 17, 2014