MAGE-A3 Protein + AS15 as Consolidation for Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation

Study Overview
=================
Brief Summary
-----------------
This was an open-label, single-arm, pilot study of the recombinant MAGE-A3 protein plus the immunological adjuvant AS15 (recMAGE-A3 + AS15) in subjects with symptomatic multiple myeloma who had completed induction therapy with at least a Very Good Partial Response (VGPR) by the International Myeloma Working Group (IMWG) criteria and who were eligible for high-dose chemotherapy with autologous stem cell transplant (auto-SCT). The primary objective was to determine the safety and tolerability of immunizations when administered prior to stem cell mobilization and multiple times after stem cell reinfusion. Secondary objectives were to assess the humoral and cellular immunogenicity and clinical outcomes of immunization.

Detailed Description
-----------------
Subjects were enrolled sequentially following confirmation of eligibility criteria, including International Staging System (ISS) stage 1, 2, or 3 multiple myeloma with MAGE-A3 tumor antigen expression. Subjects received a total of 8 immunizations with 300 µg of recMAGE-A3 + AS15. The first immunization was administered approximately 6 to 15 weeks prior to auto-SCT (Day 0), with subsequent immunizations administered every 3 weeks (± 3 days) starting 10 days after auto-SCT (ie, Days 10, 31, 52, 73, and 94). Two additional immunizations were administered at 3-month intervals (± 7 days, ie, Days 180 and 270). No dose adjustments were allowed. Platelet counts must have been ≥ 50 x 10E9/L prior to immunization, with blood product transfusions permitted as necessary. The process for auto-SCT comprised the following: (1) up to 3 steady-state leukopheresis procedures to collect and freeze a sufficient quantity of peripheral blood mononuclear cells (PBMCs), with the first leukopheresis performed 3 weeks (± 6 days) after the first immunization; (2) stem cell mobilization with cyclophosphamide, granulocyte-colony stimulating factor (G-CSF) and/or plerixafor; (3) high-dose melphalan (total dose 200 mg/m2) on Days -3 through -1; (4) auto-SCT on Day 0; and (5) re-infusion with thawed PBMCs on Day 3.

Official Title
-----------------
Pilot Study of recMAGE-A3 + AS15 ASCI as Consolidation for Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation

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

Intervention / Treatment
-----------------
* Biological: recMAGE-A3 Protein + AS15 Adjuvant


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Symptomatic multiple myeloma, ISS stage 1, 2 or 3 within 12 months of starting therapy. Completion of induction therapy with VGPR, or better, by IMWG criteria. All induction myeloma therapy (oral or intravenous, including steroids) must have been discontinued for 3 weeks prior to the first immunization. Subjects did not need to have measurable disease at the time of the screening visit. Signed separate informed consent for stem cell mobilization and high-dose chemotherapy/auto-SCT, and was found to be eligible for SCT by standard institutional criteria. MAGE-A3 expression determined by immunohistochemistry (IHC) present in a bone marrow specimen or plasmacytoma specimen. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1. The following laboratory parameters within the ranges specified: Neutrophil count: ≥ 1.5 x 109/L Lymphocyte count: ≥ 0.5 x 109/L Platelet count: ≥ 50 x 109/L Serum creatinine: ≤ 2 mg/dL Serum bilirubin: < 1.5 x the upper limit of normal (ULN) Aspartate and alanine aminotransferase (AST and ALT): < 2 x ULN Hemoglobin: ≥ 8.0 g/dL International normalized ratio (INR): ≤ 1.5 Partial thromboplastin time: ≤ 1.5 x ULN (unless known history of anti-phospholipid antibody or lupus anticoagulant) Age ≥ 18 years. Able and willing to give valid written informed consent. Exclusion Criteria: Prior treatment with melphalan (Alkeran®), other than 1 cycle (4 days) of oral melphalan. Prior autologous or allogeneic SCT. Prior immunization against MAGE-A3 or other cancer-testis antigens. Concurrent malignancies, except for treated non-melanoma skin cancer and cervical carcinoma in situ. Known immunodeficiency, human immunodeficiency virus (HIV) positivity, or active hepatitis B or C. Known allergy or history of life-threatening reaction to G-CSF or GM-CSF. History of autoimmune disease (eg., rheumatoid arthritis, lupus), other than vitiligo, diabetes, or treated thyroiditis. History of severe allergic reactions to vaccines or unknown allergens. History of myocardial infarction, angina, congestive heart failure, ventricular tachyarrhythmia, stroke or transient ischemic attack within the previous 6 months. Other serious illnesses or co-morbid conditions (e.g., serious infections requiring antibiotics, bleeding disorders, other heart or lung conditions) that, in the opinion of the investigator, made the subject inappropriate for high-dose melphalan and auto-SCT. Pregnancy and breastfeeding. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to first immunization. Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study. Lack of availability for immunological and clinical follow-up assessments.

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

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

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: recMAGE-A3 Protein + AS15 Adjuvant<br>Subjects received a total of 8 pre- and post-auto-SCT immunizations with recMAGE-A3 + AS15. | Biological: recMAGE-A3 Protein + AS15 Adjuvant<br>* recMAGE-A3 + AS15 was administered intramuscularly at a dose of 300 µg recMAGE-A3, with no dose adjustments permitted. The first immunization was administered 6 to 15 week prior to auto-SCT, with subsequent immunizations administered on Days 10, 31, 52, 73, and 94 (± 3 days) and Days 180 and 270 (± 7 days) after auto-SCT.<br>* Other names: Antigen-specific cancer immunotherapeutic (ASCI);|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Safety of recMAGE-A3 + AS15 | Analysis of treatment-emergent adverse events (TEAEs) reported from clinical laboratory tests, physical examinations, and vital signs, with severity graded according to the NCI CTCAE, Version 4.0. | Continuously for up to 14 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction or Augmentation of MAGE-A3-Specific Humoral Immunity | Humoral immunity was determined by enzyme-linked immunosorbent assay (ELISA) to measure the presence of circulating antibodies to MAGE-A3. Titers against an antigen were considered significant if they were >100. Induction of responses was considered significant if there was a change from undetectable (<100) to detectable (>100) or if there was an at least 4-fold increase in titers over time. | Baseline, first immunization, and first and second leukopheresis prior to auto-SCT; Days 31, 73, 194, 284, and 374 after auto-SCT | 
| Induction or Augmentation of MAGE-A3-Specific Cellular Immunity | Cellular immunity was determined by enzyme-linked immunosorbent spot assay (ELISPOT) or intracellular flow cytometry to determine peripheral blood levels of interferon gamma-producing CD4+ and CD8+ T cells specific for MAGE-A3. Results were considered significant if > 50 spots and > 2 times the number of spots to negative control were observed. | Baseline, first immunization, and first and second leukopheresis prior to auto-SCT; Days 31, 73, 194, 284, and 374 after auto-SCT | 
| Assessment of Tumor Response | Tumor responses were evaluated using appropriate imaging methods and were categorized according to the IMWG criteria, which includes the following response designations: Complete Response (CR): negative immunofixation on serum/urine, disappearance of soft tissue plasmacytomas, <5% plasma cells in bone marrow; Stringent CR (sCR): CR + normal free light chain (FLC) ratio and absence of clonal cells in bone marrow; Very Good Partial Response (VGPR): Serum/urine M-component detectable by immunofixation but not electropheresis OR ≥90% reduction in serum M-component + urine M-component <100 mg/24 hrs; Partial Response (PR): ≥50% reduction of serum M-protein and reduction in 24-hr urinary M-protein by ≥90% or to <200 mg/24 hrs Stable disease: not response or progression | At 3 and 12 months after auto-SCT | 
| Assessment of Survival and Time to Subsequent Therapy | Progression-free survival (PFS) was calculated as the date from first immunization to first observation of disease progression or death due to any cause, censored on the start date of subsequent therapy or at the last date of disease assessment for subjects without a PFS event. Overall survival (OS) was calculated as the date from first immunization to death due to any cause, censored at the date of last follow-up for subjects who were alive at the time of the analysis. Time to subsequent therapy was calculated as the date from first immunization to start of subsequent therapy for myeloma, censored at the date of death or last follow-up for subjects who did not receive subsequent therapy. | Continuously on study and for up to 5 years post-study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
multiple myeloma, MAGE-A3, autologous stem cell transplant