Redirected Auto T Cells for Advanced Myeloma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Adaptimmune
ClinicalTrials.gov Identifier:
NCT01352286
First received: May 4, 2011
Last updated: June 22, 2015
Last verified: June 2015
  Purpose

The purpose of this study is to 1) evaluate the safety and tolerability of autologous genetically modified T cells transduced to express the high affinity NY-ESO-1c259 TCR in HLA-A2+ subjects and 2) measure the incidence of GVHD in patients following infusion of TCR modified autologous T cells.


Condition Intervention Phase
Multiple Myeloma
Genetic: Autologous Genetically modified T cells
Phase 1
Phase 2

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/IIa, Dual-cohort, Two-site, Clinical Trial Evaluating the Safety and Activity of Redirected Autologous T Cells Expressing a High Affinity TCR Specific for NY-ESO-1 Administered Post ASCT in Patients With Advanced Myeloma

Resource links provided by NLM:


Further study details as provided by Adaptimmune:

Primary Outcome Measures:
  • Frequency and severity of adverse events related to study treatment. [ Time Frame: Day -40 visit until relapse/progression or until 1 year, (whichever comes first), then during LTFU (years 1-15), ] [ Designated as safety issue: Yes ]

    Occurrence of study related adverse events, defined as NCI CTC > grade 4 signs/symptoms, laboratory toxicities and clinical events that are probably or definitely related to investigational study treatment at any time from the infusion until 1 year. This will include infusional toxicity, and any toxicity probably or definitely related to the NY-ESO-1c259T including but not limited to:

    1. Fevers
    2. Rash
    3. Neutropenia, thrombocytopenia, anemia, marrow aplasia
    4. Hepatic dysfunction
    5. Pulmonary infiltrates or other pulmonary toxicity
    6. Development of GVHD

    NOTE: transplant-related toxicities, typically occurring within a month post-transplant, are excluded as investigational study-related adverse events.

    Antitumor efficacy will be evaluated in depth through clinical, molecular and immunological secondary endpoints.



Secondary Outcome Measures:
  • Clinical Response Rate [ Time Frame: at day 180 ] [ Designated as safety issue: Yes ]
    Evaluate correlates of treatment efficacy by measuring (i) clinical response rates to treatment and (ii) the appearance of target antigen/MHC loss variants upon disease recurrence, as well as (iii) immunological parameters associated with product persistence, bioactivity and functionality.


Estimated Enrollment: 26
Study Start Date: April 2011
Estimated Study Completion Date: April 2031
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Autologous Genetically modified T cells
Patients with advanced myeloma and who are candidates for autologous stem cell transplants, or syngeneic stem cell transplants (SSCT), will be eligible. Prior to full screening on this study, patients will undergo prescreening to evaluate HLA-A type and presence of NY-ESO-1c259T/LAGE antigen. Patients will undergo a steady-state mononuclear cell apheresis for T cell collection, with an optional second collection. Once mononuclear cells have been collected, patients (or donors in the case of SSCT) will then undergo hematopoietic stem cell mobilization. Patients will receive a dose >0.1-1 x 10¹º anti-CD3/anti-CD28-costimulated autologous T cells which have been genetically modified to express high affinity NY-ESO-1c259 TCRs.
Genetic: Autologous Genetically modified T cells

Patients will undergo myeloma restaging at days +42, +100, 6 months, 9 months and 1 year post infusion. At this point, in accordance with FDA Guidelines, all patients will enter long term follow up (LTFU) and be followed biannually for monitoring for gene transfer delayed adverse events until year 5 post infusion. From year 5, all patients will require annual LTFU visits for monitoring for delayed adverse events until year 15 after receiving the genetically modified T cells.

Patients whose disease progresses prior to year 1 will enter LTFU at time of progression; however these patients will be seen quarterly from progression until year 1 post infusion and then follow the LTFU schedule mentioned above.


Detailed Description:

The primary objective of this study is to evaluate the safety and tolerability of autologous genetically modified T cells. Genetic material is transferred into the subject's previously harvested autologous T cells to redirect them to target myeloma cells rather than their usual target. Study subjects must have systemic or multifocal myeloma requiring autologous stem cell transplantation whose disease has relapsed or incompletely responded to prior therapy or have high-risk features. Subjects must also have measureable disease on study entry, as defined by quantifiable or detectable levels of serum or urine paraprotein or elevated serum free light chains with an abnormal ratio.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Myeloma has relapsed, progressed, or failed to respond after at least one prior course of therapy (consisting of at least 2 treatment cycles or months of therapy)
  • Myeloma has responded partially to initial therapy but a complete response (immunofixation negative and normal serum free light chain) has NOT developed after a minimum of 3 cycles or months of initial therapy
  • Myeloma has high-risk features as defined by the presence of one or more cytogenetic abnormalities known to confer a poor outcome even after standard auto-transplants: complex karyotype (≥ to 3 abnormalities), t(4;14), t(14;16), del (17) (p13.1), and/or chromosome 13 abnormalities. These patients may be enrolled even while in complete or near-complete remission
  • Measurable disease on study entry, as defined by quantifiable or detectable levels of serum or urine paraprotein or elevated serum free light chains with abnormal ratio
  • Patients who are in complete remission at the time of proposed study entry (serum and urine immunofixation consistently negative and normal serum free light chains) are not eligible unless their disease meets the criteria for high-risk as defined in protocol
  • Ages 18-80
  • ECOG performance status 0-2 (unless due solely to bone pain)
  • Prior to Lenalidomide maintenance phase, all study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®
  • Females subjects of childbearing potential must have a negative pregnancy test and both male and female (of childbearing potential) subjects must agree to use reliable methods of contraception during the study.
  • Lenalidomide treatment phase: able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin)
  • HLA-A201 patients must have confirmed expression of NY-ESO-1 and/or LAGE. HLA-A2 patients must have the A-201 allele

Adequate vital organ function as defined below:

  • Serum creatinine ≤3.0 mg/dl and not on dialysis
  • WBC at least 3000/mm³, platelet count at least 100,000/mm³
  • SGOT ≤ to 2 x upper limit of normal and bilirubin ≤ to 2.0 mg/dl (unless due to Gilbert's syndrome)
  • Left ventricular ejection fraction (LVEF) ≥ 45%. A lower LVEF is permissible if a formal cardiologic evaluation reveals no evidence for clinically significant functional impairment
  • Adequate pulmonary function with mechanical parameters ≥ 40% predicted (FEV1, FVC, TLC, DLCO). Patients who are unable to complete PFTs due to bone pain or fracture must have a high resolution CT scan of the chest and must have acceptable arterial blood gases defined as a room air PO2 greater than 70 mmHg
  • Patients should have recovered from any toxicities related to prior therapy or at least returned to their baseline level of organ function.
  • Patients should be off of glucocorticoids for at least 2 weeks and/or other therapies for at least 1 week prior to enrollment

Exclusion Criteria:

  • Pregnant or nursing females
  • HIV or HTLV-1/2 seropositivity
  • History of myelodysplasia
  • History of chronic active hepatitis or liver cirrhosis (if suspected by laboratory studies, should be confirmed by liver biopsy)
  • Active Hepatitis B (as defined by positive Hepatitis B surface antigen); positive Hepatitis C virus (HCV) antibody is NOT an exclusion
  • Prior allogeneic transplant
  • History of severe autoimmune disease requiring steroids or other immunosuppressive treatments
  • Active immune mediated diseases including: connective tissue diseases, uveitis, sarcoidosis, inflammatory bowel disease, multiple sclerosis
  • Evidence or history of other significant cardiac, hepatic, renal, ophthalmologic, psychiatric, or gastrointestinal disease which would likely increase the risks of participating in the study
  • Active bacterial, viral, or fungal infections
  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: NCT01352286

Locations
United States, Maryland
Greenebaum Cancer Center, University of Maryland
Baltimore, Maryland, United States, 21201
United States, Pennsylvania
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Adaptimmune
Investigators
Principal Investigator: Ed Stadtmauer, MD Abramson Cancer Center of the University of Pennsylvania
Principal Investigator: Aaron Rapoport, MD University of Maryland Greenebaum Cancer Center
  More Information

No publications provided

Responsible Party: Adaptimmune
ClinicalTrials.gov Identifier: NCT01352286     History of Changes
Other Study ID Numbers: ADP 01411
Study First Received: May 4, 2011
Last Updated: June 22, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Adaptimmune:
Multiple myeloma
Autologous stem cell transplantation
Received initial treatment previously

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Blood Protein Disorders
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Paraproteinemias
Vascular Diseases

ClinicalTrials.gov processed this record on July 01, 2015