Back to resultsMAGE-A3 Protein + AS15 as Consolidation for Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation
Primary Purpose
Multiple Myeloma
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
recMAGE-A3 Protein + AS15 Adjuvant
Sponsored by
About this trial
This is an interventional treatment trial for Multiple Myeloma focused on measuring multiple myeloma, MAGE-A3, autologous stem cell transplant
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.
Sites / Locations
- New York University School of Medicine
- Mount Sinai Hospital
- Memorial Sloan-Kettering Cancer Center
- Fox Chase Cancer Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
recMAGE-A3 Protein + AS15 Adjuvant
Arm Description
Subjects received a total of 8 pre- and post-auto-SCT immunizations with recMAGE-A3 + AS15.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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
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.
Full Information
NCT ID
NCT01380145
First Posted
June 20, 2011
Last Updated
October 3, 2022
Sponsor
Ludwig Institute for Cancer Research
Collaborators
GlaxoSmithKline, MOUNT SINAI HOSPITAL, NYU Langone Health, Fox Chase Cancer Center, Memorial Sloan Kettering Cancer Center
1. Study Identification
Unique Protocol Identification Number
NCT01380145
Brief Title
MAGE-A3 Protein + AS15 as Consolidation for Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation
Official Title
Pilot Study of recMAGE-A3 + AS15 ASCI as Consolidation for Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation
Study Type
Interventional
2. Study Status
Record Verification Date
October 2022
Overall Recruitment Status
Completed
Study Start Date
September 2011 (undefined)
Primary Completion Date
July 2014 (Actual)
Study Completion Date
November 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ludwig Institute for Cancer Research
Collaborators
GlaxoSmithKline, MOUNT SINAI HOSPITAL, NYU Langone Health, Fox Chase Cancer Center, Memorial Sloan Kettering Cancer Center
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma
Keywords
multiple myeloma, MAGE-A3, autologous stem cell transplant
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
13 (Actual)
8. Arms, Groups, and Interventions
Arm Title
recMAGE-A3 Protein + AS15 Adjuvant
Arm Type
Experimental
Arm Description
Subjects received a total of 8 pre- and post-auto-SCT immunizations with recMAGE-A3 + AS15.
Intervention Type
Biological
Intervention Name(s)
recMAGE-A3 Protein + AS15 Adjuvant
Other Intervention Name(s)
Antigen-specific cancer immunotherapeutic (ASCI)
Intervention Description
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.
Primary Outcome Measure Information:
Title
Assessment of Safety of recMAGE-A3 + AS15
Description
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.
Time Frame
Continuously for up to 14 months
Secondary Outcome Measure Information:
Title
Induction or Augmentation of MAGE-A3-Specific Humoral Immunity
Description
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.
Time Frame
Baseline, first immunization, and first and second leukopheresis prior to auto-SCT; Days 31, 73, 194, 284, and 374 after auto-SCT
Title
Induction or Augmentation of MAGE-A3-Specific Cellular Immunity
Description
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.
Time Frame
Baseline, first immunization, and first and second leukopheresis prior to auto-SCT; Days 31, 73, 194, 284, and 374 after auto-SCT
Title
Assessment of Tumor Response
Description
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
Time Frame
At 3 and 12 months after auto-SCT
Title
Assessment of Survival and Time to Subsequent Therapy
Description
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.
Time Frame
Continuously on study and for up to 5 years post-study
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hearn J Cho, MD, PhD
Organizational Affiliation
MOUNT SINAI HOSPITAL
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Michael Millenson, MD
Organizational Affiliation
Fox Chase Cancer Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Nikoletta Lendvai, MD, PhD
Organizational Affiliation
Memorial Sloan Kettering Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
New York University School of Medicine
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Mount Sinai Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Memorial Sloan-Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Fox Chase Cancer Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19111
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
30745365
Citation
Cohen AD, Lendvai N, Nataraj S, Imai N, Jungbluth AA, Tsakos I, Rahman A, Mei AH, Singh H, Zarychta K, Kim-Schulze S, Park A, Venhaus R, Alpaugh K, Gnjatic S, Cho HJ. Autologous Lymphocyte Infusion Supports Tumor Antigen Vaccine-Induced Immunity in Autologous Stem Cell Transplant for Multiple Myeloma. Cancer Immunol Res. 2019 Apr;7(4):658-669. doi: 10.1158/2326-6066.CIR-18-0198. Epub 2019 Feb 11.
Results Reference
derived
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MAGE-A3 Protein + AS15 as Consolidation for Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation
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