Dose Escalation Trial of WT1-specific Donor-derived T Cells Following T-Cell Depleted Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Relapsed/Refractory Multiple Myeloma

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT01758328
First received: December 24, 2012
Last updated: August 19, 2014
Last verified: August 2014
  Purpose

The purpose of this study is to test the safety of specialized white cells from the donor at different doses. They are called WT1 sensitized T cells. They have been grown in the lab and are immunized against a protein. The protein is called the Wilms' tumor protein, or WT1. The multiple myeloma cells make and express this protein". The investigators want to learn whether the WT1 sensitized T cells will attach to the protein and kill the myeloma cells. The investigators want to find out what effects, good and/or bad, it has on the patient and multiple myeloma.


Condition Intervention Phase
Multiple Myeloma
Drug: busulfan
Drug: melphalan
Drug: fludarabine
Biological: anti-thymocyte globulin (ATG)
Procedure: a T cell depleted stem cell transplant
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 Dose Escalation Trial of WT1-specific Donor-derived T Cells Following T-Cell Depleted Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Relapsed/Refractory Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • assess the toxicities [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
    DLT will be defined as a grade III or greater toxicity developing within 3 weeks of the T cell infusion, as graded by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4 or new development of grade II-IV acute GVHD within 3 weeks of the T cell infusion that requires treatment with systemic glucocorticosteroids. Patients will be evaluated for 21 days for grade III or greater toxicities.

  • maximum tolerated dose (MTD) [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    Patients will also be monitored for secondary or immune-mediated graft rejection and or onset of grade II-IV acute GVHD following the administration of WT1-specific T-cell infusions. Because patients may still have transplantation associated cytopenia or may have residual disease that may be associated with cytopenias, hematologic toxicity will be excluded in assessing DLT. All patients will be observed for a minimum of 3 weeks after the first WT-1 peptide sensitized T-cell infusion before the dose can be escalated.


Secondary Outcome Measures:
  • serologic response [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    In addition, patients will be monitored for serologic responses of their myelomas. The time at which the response was achieved will be recorded for all patients and summarized by dose level. The data derived from these studies will provide an initial assessment of the effects of the T cell infusions.

  • survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To quantitate the number of WT1-specific T cells in the blood and marrow at defined intervals post infusion


Estimated Enrollment: 21
Study Start Date: December 2012
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pts with Mutiple myeloma
Patients will undergo a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor. Hematopoietic stem cell donors for this trial will include individuals who are 10/10 HLA matched or one antigen or allele mismatched at the HLA-A, B, C, DRB1 or DQB1 locus, as defined by high resolution methods. The administration of WT1-specific cytotoxic T cells (WT1 CTLs) post transplantation is integrated to induce complete remissions in patients with residual disease and to decrease the rate of relapse following the allogeneic transplant.
Drug: busulfan Drug: melphalan Drug: fludarabine Biological: anti-thymocyte globulin (ATG) Procedure: a T cell depleted stem cell transplant

  Eligibility

Ages Eligible for Study:   21 Years to 72 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Diagnosis:

  • Patient must have multiple myeloma that has either relapsed or remains refractory following autologous stem cell transplantation and patients who have plasma cell leukemia at diagnosis.
  • Patients with relapsed multiple myeloma following autologous stem cell transplantation who achieved < partial response following additional chemotherapy or who achieved < PR at 3 months following autologous stem cell transplantation and patients with plasma cell leukemia at diagnosis.

DONOR: Patients must have a healthy HLA matched or mismatched related or unrelated donor who is willing to receive G-CSF injections and undergo apheresis for PBSC collection, or undergo a marrow harvesting procedure.

  • HLA-matched related and unrelated donors Patients who have an HLA-matched related or unrelated donor are eligible for entry on this protocol. This will include a healthy donor who is genotypically matched at all A, B, C, DRB1 and DQB1 loci, as tested by DNA analysis.
  • HLA- mismatched related and unrelated donors
  • Patients who do not have an HLA-matched donor but have a related or unrelated donor who have one antigen or one allele mismatch at the HLA A, B, C, DRB1 or DQB1 loci, will be eligible for entry on this protocol.

The following inclusion criteria are also required:

  • Patients should be ≥ 21, < 73 years old.
  • Patients may be of either gender or any ethnic background.
  • Patients must have a Karnofsky (adult) or Performance Status > 70%
  • Patients must have adequate organ function measured by:

    1. Cardiac: asymptomatic or if symptomatic then LVEF at rest must be > 50% and must improve with exercise.
    2. Hepatic: < 3x ULN ALT and < 1.5 total serum bilirubin, unless there is congenital benign hyperbilirubinemia.
    3. Renal: serum creatinine <1.2 mg/dl or if serum creatinine is outside the normal range, then CrCl > 40 ml/min (measured or calculated/estimated) with dose adjustment of Fludarabine for <70ml/min.
    4. Pulmonary: asymptomatic or if symptomatic, DLCO > 50% of predicted (corrected for hemoglobin)
  • Each patient must be willing to participate as a research subject and must sign an informed consent form.

Exclusion Criteria:

  • Female patients who are pregnant or breast-feeding
  • Active viral, bacterial or fungal infection
  • Patient seropositive for HIV-I/II; HTLV -I/II
  • Patients who have had a previous malignancy that is not in remission.
  • Patients with known hypersensitivity to mouse proteins (murine antibodies in ISOLEX) if receiving SBA-E- bone marrow, or chicken egg products.
  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: NCT01758328

Contacts
Contact: Guenther Koehne, M.D., Ph.D. 212-639-8599
Contact: Richard O'Reilly, MD 212-639-5957

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Guenther Koehne, MD, PhD    212-639-8599      
Contact: Richard O'Reilly, MD    212-639-5957      
Principal Investigator: Guenther Koehne, MD, PhD         
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Investigators
Principal Investigator: Guenther Koehne, MD, PhD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT01758328     History of Changes
Other Study ID Numbers: 12-175
Study First Received: December 24, 2012
Last Updated: August 19, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Memorial Sloan-Kettering Cancer Center:
BUSULFAN
FLUDARABINE
G-CSF
MELPHALAN
RABBIT ATG WT1
PEPTIDE SPECIFIC T CELLS
12-175

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
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
Antilymphocyte Serum
Busulfan
Melphalan
Fludarabine phosphate
Fludarabine
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Immunosuppressive Agents
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists
Antimetabolites, Antineoplastic

ClinicalTrials.gov processed this record on September 14, 2014