Trial of Activated Marrow Infiltrating Lymphocytes Alone or in Conjunction With an Allogeneic Granulocyte Macrophage Colony-stimulating Factor (GM-CSF)-Based Myeloma Cellular Vaccine in the Autologous Transplant Setting in Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
Patient Population: Patients with active myeloma (Stage II/III) that have completed induction therapy and are eligible for an autologous stem cell transplant. Number of Patients: Will treat a total of 32 evaluable patients in a 1:1 randomization of aMILs vs aMILs plus vaccine. An evaluable patient is defined as one which has received the activated MILs and is at least 6 months post-transplant. Study Objectives: Disease response as determined by the Blade' criteria will be the primary endpoint of the trial at one year. Additional study endpoints include progression free survival, parameters of T cell reconstitution, anti-tumor immune responses as well as the effect on osteoclastogenesis and clonogenic myeloma precursor cells.

Official Title
-----------------
Randomized Trial of Activated Marrow Infiltrating Lymphocytes Alone or in Conjunction With an Allogeneic GM-CSF-based Myeloma Cellular Vaccine in the Autologous Transplant Setting in Multiple Myeloma

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Biological: Activated marrow infiltrating lymphocytes
* Biological: Allogeneic Myeloma Vaccine
* Drug: Cyclophosphamide
* Biological: Filgrastim
* Procedure: Leukapheresis
* Drug: Melphalan
* Biological: Autologous stem cell transplant


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Durie-Salmon Stage II or III multiple myeloma Newly diagnosed either prior to receiving treatment or having completed induction therapy Relapsed myeloma not previously transplanted within the past 5 years Measurable serum and/or urine M-protein from prior to induction therapy documented and available. A positive serum free lite assay is acceptable Age greater than 18 years old ECOG performance status of 0 - 2 Meet all institutional requirements for autologous stem cell transplantation The patient must be able to comprehend and have signed the informed consent Exclusion Criteria: Diagnosis of any of the following plasma cell disorders: POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein [M-protein] and skin changes) Non-secretory myeloma (no measurable protein on Serum Free Lite Assay) Plasma cell leukemia Amyloidosis Use of corticosteroids (glucocorticoids) within 21 days of pre-transplant vaccine or bone marrow collection Use of any myeloma-specific therapy other than lenalidomide within 21 days of pre-transplant vaccine In a complete remission at the time of bone marrow collection Infection requiring treatment with antibiotics, antifungal, or antiviral agents within seven days of vaccination or bone marrow collection Participation in any clinical trial, within four weeks prior to vaccination or bone marrow collection on this trial, which involved an investigational drug or device History of malignancy other than multiple myeloma within five years of vaccination or bone marrow collection, except adequately treated basal or squamous cell skin cancer Active autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosis) requiring systemic treatment. Hypothyroidism without evidence of Grave's Disease or Hashimoto's thyroiditis is permitted Evidence of spinal cord compression at time of transplant

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASCT + MILs<br>Cyclophosphamide and filgrastim will be given to mobilize peripheral blood stem cells. Leukapheresis will be performed to collect peripheral blood from which activated marrow infiltrating lymphocytes will be produced. A melphalan conditioning regimen will be used prior to autologous stem cell transplant, and the MILs product will be administered on Days 3 and 4. | Biological: Activated marrow infiltrating lymphocytes<br>* Administered on Days 3 and 4.<br>* Other names: aMILs;Drug: Cyclophosphamide<br>* Administered at 2.5 g/m^2.<br>* Other names: Cytoxan;Biological: Filgrastim<br>* Administered post cyclophosphamide daily until leukapheresis.<br>* Other names: G-CSF;Procedure: Leukapheresis<br>* Performed approximately 12 days post cyclophosphamide. Exact date depends on peripheral blood CD34+ cell counts.<br>* Other names: Apheresis;Drug: Melphalan<br>* 100 mg/m^2/day given on Days -2 and -1.<br>* Other names: Alkeran;Biological: Autologous stem cell transplant<br>* Infused on Day 0.<br>* Other names: ASCT;|
| Experimental: ASCT + MILs + vaccine<br>Cyclophosphamide and filgrastim will be given to mobilize peripheral blood stem cells. Leukapheresis will be performed to collect peripheral blood from which activated marrow infiltrating lymphocytes will be produced. A melphalan conditioning regimen will be used prior to autologous stem cell transplant, and the MILs product will be administered on Days 3 and 4. The allogeneic myeloma vaccine will be administered on Days 21, 60, 180, and 300. | Biological: Activated marrow infiltrating lymphocytes<br>* Administered on Days 3 and 4.<br>* Other names: aMILs;Biological: Allogeneic Myeloma Vaccine<br>* Allogeneic granulocyte macrophage colony-stimulating factor (GM-CSF)-based myeloma cellular vaccine. Administered on Days 21, 60, 180, and 300.<br>Drug: Cyclophosphamide<br>* Administered at 2.5 g/m^2.<br>* Other names: Cytoxan;Biological: Filgrastim<br>* Administered post cyclophosphamide daily until leukapheresis.<br>* Other names: G-CSF;Procedure: Leukapheresis<br>* Performed approximately 12 days post cyclophosphamide. Exact date depends on peripheral blood CD34+ cell counts.<br>* Other names: Apheresis;Drug: Melphalan<br>* 100 mg/m^2/day given on Days -2 and -1.<br>* Other names: Alkeran;Biological: Autologous stem cell transplant<br>* Infused on Day 0.<br>* Other names: ASCT;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rates by Blade Criteria | Number of participants with each disease response category utilizing the Blade criteria: Complete Response (CR): Defined as negative serum and urine immunofixation and a bone marrow aspirate with < 5% plasma cells. Near Complete Response (nCR): Defined as negative serum and urine paraprotein, positive serum and/or urine immunofixation, and a bone marrow aspirate with < 5% plasma cells. Very Good Partial Response (VGPR): Defined as negative serum and urine paraprotein with positive serum and/or urine immunofixation; or a 90% decrease in serum paraprotein with urine paraprotein < 100 mg/24 hours. Partial Response (PR): Defined as a 50-89% decrease in serum paraprotein. Minimal Response (MR): Defined as a 25-49% decrease in serum paraprotein. Stable Disease (SD): Defined as not falling into any other response category. Overall response rate (ORR): Total of CR, nCR, VGPR, and PR. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Median number of months that participants were alive without disease relapse or progression (progression-free survival). | Up to 5 years | 
| Overall Survival | Number of participants alive at 5 years (overall survival). | Up to 5 years | 
| Feasibility as Measured by Participant Withdrawal or Removal | Number of participants who withdrew or were removed from the study for reasons other than lack of efficacy prior to completion. | Up to 1 year | 
| Safety as Measured by Grade 3-5 Adverse Events | Number of participants who experienced at least one grade 3-5 adverse event by CTCAE 3.0 that was attributed to MILs or the myeloma vaccine. | Up to 1 year | 
| Anti-tumor Immune Response | Evaluate tumor specific responses in blood and bone marrow Examine T cell responses to DC-pulsed myeloma cell lines Examine induction of novel antibody responses | Days 60, 180, and 360 | 
| The Effect of aMILs on Osteoclastogenesis as Measured by Bone Turnover (RANKL/OPG Ratio) |  | Days 60, 180, and 360 | 
| The Effect of aMILs on Osteoclastogenesis as Measured by Bone Turnover (Serum C Telopeptide Levels) | Serum C Telopeptide | Days 60, 180, 360 | 
| The Effect of aMILs on Osteoclastogenesis as Measured by Bone Turnover (bAlkaline Phosphatase Levels) | bAlkaline phosphatase | Days 60, 180, 360 | 
| The Effect of aMILs on Osteoclastogenesis as Measured by Bone Turnover (Osteocalcin Levels) | Osteocalcin | Days 60, 180, 360 | 
| Effect of aMILs on Clonogenic Myeloma Precursors | • Examine side population of CD19 enriched PBLs throughout study. | Days 60, 180, and 360 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
multiple myeloma