Clinical trial NCT01380145: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Multiple Myeloma
Keywords: multiple myeloma
MAGE-A3
autologous stem cell transplant
Lead sponsor: Ludwig Institute for Cancer Research
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
name: MOUNT SINAI HOSPITAL
name: NYU Langone Health
name: Fox Chase Cancer Center
name: Memorial Sloan Kettering Cancer Center
First posted: 2011-06-27
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Symptomatic multiple myeloma, ISS stage 1, 2 or 3 within 12 months of starting therapy.
2. 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.
3. 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.
4. MAGE-A3 expression determined by immunohistochemistry (IHC) present in a bone marrow specimen or plasmacytoma specimen.
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
6. 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)
7. Age ≥ 18 years.
8. Able and willing to give valid written informed consent.

Exclusion Criteria:

1. Prior treatment with melphalan (Alkeran®), other than 1 cycle (4 days) of oral melphalan.
2. Prior autologous or allogeneic SCT.
3. Prior immunization against MAGE-A3 or other cancer-testis antigens.
4. Concurrent malignancies, except for treated non-melanoma skin cancer and cervical carcinoma in situ.
5. Known immunodeficiency, human immunodeficiency virus (HIV) positivity, or active hepatitis B or C.
6. Known allergy or history of life-threatening reaction to G-CSF or GM-CSF.
7. History of autoimmune disease (eg., rheumatoid arthritis, lupus), other than vitiligo, diabetes, or treated thyroiditis.
8. History of severe allergic reactions to vaccines or unknown allergens.
9. History of myocardial infarction, angina, congestive heart failure, ventricular tachyarrhythmia, stroke or transient ischemic attack within the previous 6 months.
10. 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.
11. Pregnancy and breastfeeding.
12. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to first immunization.
13. Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study.
14. Lack of availability for immunological and clinical follow-up assessments.

Primary outcomes:
measure: Assessment of Safety of recMAGE-A3 + AS15
timeFrame: Continuously for up to 14 months
Secondary outcomes:
measure: Induction or Augmentation of MAGE-A3-Specific Humoral Immunity
timeFrame: Baseline, first immunization, and first and second leukopheresis prior to auto-SCT; Days 31, 73, 194, 284, and 374 after auto-SCT
measure: Induction or Augmentation of MAGE-A3-Specific Cellular Immunity
timeFrame: Baseline, first immunization, and first and second leukopheresis prior to auto-SCT; Days 31, 73, 194, 284, and 374 after auto-SCT
measure: Assessment of Tumor Response
timeFrame: At 3 and 12 months after auto-SCT
measure: Assessment of Survival and Time to Subsequent Therapy
timeFrame: Continuously on study and for up to 5 years post-study
Other outcomes:
Locations:
city: New York
country: United States
facility: New York University School of Medicine
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
Study officials:
affiliation: MOUNT SINAI HOSPITAL
name: Hearn J Cho, MD, PhD
role: STUDY_CHAIR
affiliation: Fox Chase Cancer Center
name: Michael Millenson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Memorial Sloan Kettering Cancer Center
name: Nikoletta Lendvai, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.