Study to Assess Safety and Immune Response of Stage IIB-IV Resected Melanoma After Treatment With MAGE-A3 ASCI

Study Overview
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Brief Summary
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The goals of this study are to 1) assess the safety of recombinant MAGE-A3 protein combined with AS15 Immunological Adjuvant System (recMAGE-A3 + AS15) as an Antigen-Specific Cancer Immunotherapeutic (MAGE-A3 ASCI) when administered in two different administration sites, intramuscular (IM) or intradermal/subcutaneous (ID/SC), and 2) to provide preliminary data on the immunological response to ASCI in the injection site microenvironment, in the node draining the vaccine site (sentinel immunized node) and in the blood and whether there are large differences in the magnitude, persistence, or type of immune response induced as a function of the ASCI injection. Evaluation of immune responses to the ASCI will include, amonth others antiMAGE-A3 antibody responses and CD4+ and CD8+ T cell responses.

Detailed Description
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This was an open-label randomized single institution pilot study to evaluate the safety and immunologic response to MAGE-A3 immunotherapeutic administered by either of two injection routes (i.m. or i.d./s.c.). Patients were studied following IRB approval (IRB #15398) and documentation of informed consent. The trial was registered in clinicaltrials.gov (NCT01425749), and was performed at the University of Virginia. MAGE-A3 immunotherapeutic (0.5 ml) was administered five times (weeks 0, 3, 6, 9, 12) in extremities uninvolved with melanoma. Vaccines 1 and 3 were administered at the same site: other vaccine sites were rotated among available extremities. Subjects were randomized 1:1, within each stratum (AJCC stage II/III or IV), to i.m. (Group A) or i.d./s.c. (Group B) administration. The randomization code was generated by the study statistician using varying block sizes of 2 to 4. For group B patients, half of the dose was injected s.c., then the needle was withdrawn to the dermis, then advanced intradermally from that same puncture site and the remaining half dose was injected i.d. Immune responses were evaluated in a SIN and PBMC.

Official Title
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T Cell Activation and Immune Cell Function in Melanoma Patients Treated With recMAGE-A3 + AS15 Immunological Adjuvant System

Conditions
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Melanoma

Intervention / Treatment
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* Biological: recMAGE-A3 + AS15 ASCI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven melanoma that meets one of the following two criteria: Stage IIB-IV melanoma rendered clinically free of disease by surgery, other therapy, or spontaneous remission within 6 months prior to registration. Stage III or IV melanoma with disease. Patients may be eligible if there are definite or equivocal findings of persistent or metastatic disease as long as those findings do not meet RECIST criteria for measurable disease. Expression of MAGE-A3 by the tumor (primary or metastasis). Patients may have had multiple primary melanomas. Patients may have had, or may have, a metastasis from a cutaneous, mucosal, unknown primary site. Patients with brain metastases may be eligible if all of the following are true: The total number of brain metastases ever is less than or equal to 3. The brain metastases have been completely removed by surgery or have been treated completely by stereotactic radiotherapy. Stereotactic radiotherapy, such as gamma knife, can be used up to 1 week prior to study entry. There has been no evident growth of any brain metastasis since treatment. No treated brain metastasis is greater than 2 cm in diameter at the time of protocol entry. Patients must have at least two intact axillary and/or inguinal lymph node basins. The interferon education packet must be completed satisfactorily for those who are eligible for, but refuse, interferon therapy. All patients must have: ECOG performance status of 0 or 1. Ability and willingness to give informed consent. Laboratory parameters as follows: ANC > 1000/mm3, and Platelets > 75,000/mm3 and Hgb > 9 g/dL Hepatic: AST and ALT up to 2.5 x upper limits of normal (ULN) Bilirubin up to 2.5 x ULN Alkaline phosphatase up to 2.5 x ULN LDH up to 2x ULN Renal: Creatinine up to 1.5 x ULN Serology: HIV negative (antibody screening), Hepatitis C negative HGBA1C level of < 7.5% Patients must be 18 years or older at study entry Exclusion Criteria: Patients with primary ocular melanoma. Patients who have had brain metastases unless they meet the criteria outlined in the inclusion criteria Patients who are currently receiving systemic cytotoxic chemotherapy, radiation, monoclonal antibody therapy, or other experimental therapy, or who have received this therapy within the preceding 4 weeks. Patients who are currently receiving nitrosoureas or who have received this therapy within the preceding 6 weeks. Patients who have received isolated limb infusion (ILI) or isolated limb perfusion (ILP) for melanoma will not be eligible unless they have experienced tumor progression after the ILI/ILP, and the ILI/ILP was not performed within the prior 12 weeks. Patients will not be eligible if there is clinically detectable melanoma deemed likely by the investigator to require intervention during the first 12 weeks of the study that would require premature discontinuation. Patients with known or suspected allergies to any component of the MAGE-A3 ASCI. Patients receiving the following medications at study entry or within the preceding 4 weeks are excluded, except as specified below: Agents with putative immunomodulating activity, but with the exception of non-steroidal anti-inflammatory agents and topical steroids. Antibodies to CTLA-4, PD-1, PD-L1, or CD137 may not have been received in the past 12 weeks, and patients will be eligible only if there has been melanoma progression since that therapy was administered. Allergy desensitization injections. Systemic corticosteroids, administered parenterally or orally. Inhaled steroids are not permitted. Topical corticosteroids are acceptable, including steroids with very low solubility administered nasally for local effects only. Any growth factors (e.g. GM-CSF, G-CSF, erythropoietin). Interferon therapy. Interleukin-2 or other interleukins. Targeted therapies designed to inhibit BRAF, MAPKinase, mTOR, or their signaling pathways. Prior active immunotherapy or vaccines for melanoma may be an exclusion criterion in some circumstances. Exceptions to this exclusion criterion are as follows: Patients who have recurred or progressed either after or during administration of a melanoma vaccine may be eligible to enroll in this study 12 weeks following their last vaccination. Patients may not have been previously administered the synthetic MAGE-A3 protein, though prior vaccinations with up to 4 synthetic MAGE-A3 peptides (up to 16 amino acids in length, each) is allowed. Pregnancy or the possibility of becoming pregnant during vaccine administration. Female patients of child-bearing potential must have a negative pregnancy test (urinary or serum beta-HCG) prior to administration of the first MAGE-A3 ASCI dose. Males and females must agree, in the consent form, to use effective birth control methods during the course of vaccination. Women must also not be breast feeding. This is consistent with existing standards of practice for vaccine and chemotherapy protocols. Patients in whom there is a medical contraindication or potential problem in complying with the requirements of the protocol, in the opinion of the investigator. Patients classified according to the New York Heart Association classification as having Class III or IV heart disease. Patients with a body weight < 110 lbs because of the amount and frequency with which blood will be drawn, and because of the biopsies required. Patients must not have had prior autoimmune disorders requiring cytotoxic or immunosuppressive therapy, or autoimmune disorders with visceral involvement. Patients with an active autoimmune disorder requiring these therapies are also excluded. The following will not be exclusionary: Laboratory evidence of autoimmune disease (e.g. positive ANA titer) without symptoms Clinical evidence of vitiligo Other forms of depigmenting illness Mild arthritis requiring NSAID medications

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Intramuscular injections of recMAGE-A3 + AS15 ASCI. | Biological: recMAGE-A3 + AS15 ASCI<br>* Injections of recMAGE-A3 + AS15 ASCI will be given 5 times at 3-week intervals. This will either be administered cutaneously or intramuscularly depending on the study group. The injected doses will be administered in alternating extremities at each visit.<br>* Other names: recMAGE-A3 + AS15 ASCI ID/SC;|
| Experimental: Arm B<br>Intradermal/Subcutaneous injections of recMAGE-A3 + AS15 ASCI. Requires an injection site biopsy at Day 8 and Day 50. | Biological: recMAGE-A3 + AS15 ASCI<br>* Injections of recMAGE-A3 + AS15 ASCI will be given 5 times at 3-week intervals. This will either be administered cutaneously or intramuscularly depending on the study group. The injected doses will be administered in alternating extremities at each visit.<br>* Other names: recMAGE-A3 + AS15 ASCI ID/SC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-related Adverse Events as a Measure of Safety and Tolerability | grade 2 treatment-related adverse events graded by CTCAE v4 | Over 6 months | 
| Enumeration of CD4 and CD8 T Cell Responses to MAGE-A3 Epitopes in the Injection Site-draining Lymph Node (Sentinel Immunized Node, SIN) as a Measure of Immunogenicity. | Flow cytometry on in vitro stimulated lymphocytes. A positive immune response was identified as one with bifunctional CD4+ or CD8+ T cells, producing both TNF alpha and IFN-gamma after exposure to antigen. | One week after 3 doses of study drug, on day 22. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Enumeration of CD4+ and CD8+ T Cells Reactive to MAGE-A3 Epitopes in Peripheral Blood as a Measure of Immunogenicity. | The analysis determined the proportion of CD4+ (and/or CD8+) T cells producing IFN-gamma or TNFα, or both, in response to MAGE-A3 peptide pools (with irrelevant peptide as negative control). T cell response was defined when T cells producing both IFNγ and TNFα in response to MAGE-A3 peptides exceeded (a) twice the maximum of 2 negative controls (PRAME peptides, media only), corrected for pre-existing response; and (b) exceeded the negative controls by at least 0.2% of the T cell population. These criteria also were used to define immunogenicity by ELIspot (IFNγ only). If the negative control values for a given sample were zero, a meaningful fold-increase could not be calculated; so, in those cases, we used the minimum detectable value among all similar assays (0.06%) as the negative control value for that sample. | Over 6 months | 
| Identification of Antibody Responses to MAGE-A3 After MAGE-A3 ASCI Administration as a Measure of Immunogenicity. | Antibody responses were assessed in serum by ELISA, assay for IgG. Seroconversion was defined as a detectable Ab response by ELISA (>20 EU/ml). | Over 6 months, typically weeks 1, 7, 13, 26 | 
| Characterization of the Maturation and Activation of Dendritic Cell (DC) Populations in the Sentinel Immunized Node (SIN) After Treatment With MAGE-A3 ASCI. | Number of CD83+ cells (mature DC) and CD1a+ cells (immature DC/Langerhans cells) per mm^2 in cross-sections of sentinel immunized nodes | Over 3 weeks | 
| A Preliminary Evaluation of Cellular Components of the Injection Site Microenvironment for Cutaneous Immunization With MAGE-A3 ASCI (Activated T Cells, Th1,Th2, Th17 Infiltrating CD4 Cells, Regulatory T Cells, and Myeloid-derived Suppressor Cells). | Cells per mm^2 in the superficial dermis at the vaccine site microenvironment, by enumeration of immunohistochemically stained slides. Biopsies of the vaccine sites were taken at week 1 (1 week after the first vaccine) and week 7 (1 week after the 3rd vaccine). This only was evaluable in Arm B patients. | Over 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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melanoma, MAGE-A3, immunotherapy, adjuvant, skin cancer, skin diseases, immunology