WT1 Analog Peptide Vaccine in Patients With Multiple Myeloma Following Autologous Stem Cell Transplantation

Study Overview
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Brief Summary
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The purpose of this study is to see if the investigator can help the immune system to work against myeloma through the use/administration of a peptide vaccine (immunotherapy agent) directed against the Wilms Tumor 1 (WT1) protein called galinpepimut-S (or GPS, for brief). Because cancer is produced by the patient's own body, the immune system does not easily recognize and fight cancer cells. The immune system needs to be trained to do this; the latter goal is accomplished by using a vaccine consisting of selected fragments of the target antigen, in this case, WT1. This disease has been selected for this study because the WT1 protein is often present in myeloma cells. WT1 is a gene that is involved in the normal development of kidneys and other organs. When the WT1 gene becomes abnormal, it can make proteins involved in the development of cancer, i.e., can acquire the properties of a true oncogene. This study will determine whether the vaccine against the WT1 antigen (present in malignant plasmacytes) can cause an immune response which is safe, but also able to keep the myeloma from either coming back or progressing.

Detailed Description
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Key Features: - This is a Phase 1/2 clinical study conducted in patients with newly diagnosed high-risk multiple myeloma to examine the effects of GPS immunotherapy on clinical and immunobiological indices. The study is titled A Pilot Trial of a WT1 Analog Peptide Vaccine (Galinpepimut-S) in Patients With Multiple Myeloma Following Autologous Stem Cell Transplantation and is designed as a single-arm, single-institution, open-label study. Rationale: - Overexpression of WT1 in multiple myeloma (MM) cells has been demonstrated by immunocytochemistry (IHC) and in HLA-A*0201 patients by staining with a high-affinity fully human IgG1 mAb (ESK1) specific to the RMFPNAPYL/HLA-A*0201 complex on malignant plasma cells. WT1 also serves as a target for antigen-specific directly immunizing immunotherapeutic approaches, such as peptide vaccines (in this case, galinpepimut-S), in patients with multiple myeloma. Patients with persistent plasma cell leukemia following CD34+-selected allografts treated with adoptive transfer of donor-derived WT1-specific cytotoxic T cells are capable of achieving long-lasting complete remission (CR) status, thus underscoring the therapeutic potential of activated T-cells specifically immunized against WT1 peptides. The above provide the theoretical basis for the possibility of successful immunization after exposure to a WT1-specific vaccine (such as galinpepimut-S), whereby WT1-sensitized T-lymphocytes (both CD8+ and CD4+) from vaccinated MM could be directed to antigen (WT1) expressed on malignant plasma cells. Galinpepimut-S (GPS) - Key features: - GPS is a tetravalent peptide vaccine, consisting of an equiweight mixture of 4 WT1-derived peptides which have been chosen to strengthen antigenicity, but also broaden immunogenicity over a wide range of HLA subtypes, being able to stimulate both CD8+ (MHC Class I)- and CD4+ (MHC Class II)-dependent responses. Of note, 2 of the 4 peptides are heteroclitic, i.e., carry by-design introduced missense mutations, in order to decrease tolerogenicity (as these modified peptides are no longer identified as self moieties by the vaccinated host's immune system. GPS contains one heteroclitic peptide (WT1-A1) to stimulate CD8+ responses, two longer native peptides (427 long and 331 long) to stimulate CD4+ responses and one longer heteroclitic peptide (122A1 long) that is capable of stimulating both CD8+ and CD4+ cells (with the CD8-activating shorter sequence/locus 'buried' with the lengthier CD4-activating one). Galinpepimut-S is always mixed in emulsion with the immunological adjuvant Montanide™ and is administered after granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostine; Leukine®) pre-stimulation. Putative Mechanism of action (MOA) of galinpepimut-S in MM: - Galinpepimut-S (GPS) is a peptide immunogen of the vaccine type, capable of inducing in the treated host WT1-specific antigenicity and eventual systemic immunogenicity against WT1-expressing deposits of cancerous cells. The above principles are applicable in MM patients treated with this immunotherapeutic. It is very likely that the antigen presenting cell (APC)-CD8-CD4 cross-activating circuits are markedly amplified in subjects receiving galinpepimut-S, leading to specific and direct immunization against WT1 and eventual killing of WT1-expressing malignant plasma cells via activated immunocytes (mainly lymphocytes and natural killer [NK] cells). This MOA represents a plausible model for the immunobiological basis of the observed clinical activity of galinpepimut-S against various tumor types (other than MM) tested to-date, and is poised to be applicable in MM as well.

Official Title
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A Pilot Trial of a WT1 Analog Peptide Vaccine in Patients With Multiple Myeloma Following Autologous Stem Cell Transplantation

Conditions
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Multiple Myeloma, Minimal Residual Disease, High-Risk Cancer

Intervention / Treatment
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* Biological: WT1 Analog Peptide Vaccine
* Biological: Sargramostim (GM-CSF)
* Drug: lenalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Symptomatic multiple myeloma, ISS stage 1-3 with confirmed diagnosis of multiple myeloma at MSKCC Patients must be eligible to undergo autologous stem cell transplantation by standard institutional criteria Patients must have documented WT1 positive disease. For purpose of this study, this is defined as detectable presence of WT1 expression by immunohistochemistry or by WT1 transcript via RT-PCR on a bone marrow or other plasma cell-related biopsy specimen prior to autologous stem cell transplantation. Bone marrow or other biopsy specimen from time of diagnosis from patients diagnosed at MSKCC or outside hospital may be requested for assessment of WT1 expression by IHC Age > or = to 18 years Karnofsky performance status > or = to 50% Hematologic parameters: Absolute neutrophil count (ANC) > or = to 1,000/μl Platelets > 50,000/μl Biochemical parameters: Total bilirubin < than or = to 2.0 mg/dl AST and ALT < than or = to 2.5 x upper limits of normal (ULN) Creatinine < than or = to 2.0 mg/dl Exclusion Criteria: Pregnant or lactating women Patients with active infection requiring systemic antimicrobials Patients taking systemic corticosteroids Patients with serious unstable medical illness Concurrent malignancies

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: vaccine<br>Galinpepimut-S (GPS) inoculations are started 12-22 d following autologous stem cell transplantation (ASCT). GPS (1.0 ml of emulsion) is given s.c. on weeks 0, 2, 4, 6, 8, & 10 (i.e., x 6). Injection sites are pre-stimulated with Sargramostim (GM-CSF; 70 μg) s.c. on d -2 (± 1 d ) & d 0 of each GPS inoculation. N.B.: during each GPS inoculation, the Sargramostim & GPS are administered to the same anatomical site. Subjects are observed for >/= 30 minutes after vaccination. Non-progressing subjects who are clinically stable (no active infection with fevers & no cardiovascular/respiratory compromise) may receive up to 6 more vaccinations q-month. The use of post-ASCT maintenance therapy with either lenalidomide or bortezomib is allowed starting >/= 3 months after ASCT. | Biological: WT1 Analog Peptide Vaccine<br>* Preparation of a suspension of liquid vaccine drug product preparation (100 mcg of each peptide x 4 WT1 peptides within the GPS mixture; total weight: 400 mcg) 1:1 v/v with Montanide (oil depot emulsifier) to a total volume of  1 ml, which is then injected s.c. to the patient. GPS is administered subcutaneously with Montanide adjuvant, with the first dose within 22 days of ASCT with melphalan conditioning (200 mg/sq.m.) and biweekly administration thereafter, for a total of 6 initial doses. Subsequently, patients continued to receive booster GPS administrations every 4 weeks, for an additional set of 6 doses, assuming they remain non-progressors per International Myeloma Working Group (IMW) criteria and are also clinically stable.<br>* Other names: Galinpepimut-S (GPS);Biological: Sargramostim (GM-CSF)<br>* Granulocyte-macrophage colony-stimulating factor (GM-CSF; Leukine®) is administered s.c. at a dose of 70 μg on day -2 and day 0 of each GPS administration.<br>* Other names: GM-CSF;Drug: lenalidomide<br>* IMiD (lenalidomide; 10 mg p.o. daily) OR -in select patients- proteasome inhibitor (bortezomib; 1.3 mg/sq.m. s.c. every 2 weeks) maintenance starting 3-months post auto SCT.<br>* Other names: Revlimid®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antigen-specific T-cell immune response (IR) - early | The level of induction of T-cell (CD4+ and CD8+) immune responses against WT1 peptides within the galinpepimut-S vaccine mixture - as compared to baseline (t=0; before vaccine administration)- will be measured by intracellular interferon-γ production assay and MHC tetramer analyses - the latter, if available for patient's HLA-type. | 12 weeks after the initial GPS vaccine (end of first series [GPS x 6 administrations]) | 
| Antigen-specific T-cell immune response (IR) - late | The level of induction of T-cell (CD4+ and CD8+) immune responses against WT1 peptides within the galinpepimut-S vaccine mixture - as compared to baseline (t=0; before vaccine administration) - will be measured by intracellular interferon-γ production assay and MHC tetramer analyses - the latter, if available for patient's HLA-type. | 38 weeks after the initial GPS vaccine (end of booster series [GPS x 12 administrations]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | From time of registration to the time of documented myeloma progression (as defined by the International Myeloma Working Group [IMW] consensus criteria; Kumar S et al. Lancet Oncol. 2016) or subject death. | 2 years | 
| Overall survival (OS) | From time of registration to the time of subject death. | 2 years | 
| Toxicity profile | Toxicity will be graded in accordance with Common Toxicity Criteria, version 4.0 (CTCAE 4.0) The only toxicities captured outside of the SAEs reported will be all Grade 1-5 toxicities deemed definitely, probably, or possibly related to the portion of the study. relevant to the active administration of galinpepimut-S. | 2 years | 
| WT1 expression level quantification | Protein expression analysis for WT antigens will be done by immunohistochemistry (IHC) as follows: Monoclonal antibodies to CD138/Syndecan, co-express WT1 when staining WT1 mAB 6F-H2 will employed by the study specified research lab on MSKCC S-631. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Maintenance therapy, Autologous Stem Cell Transplant (ASCT), Lenalidomide, Immune Response, Wilms Tumor 1, Prevention of progression, Prevention of relapse, Immuno-Oncology, Immunotherapeutic Agent, Direct Immunizer, Heteroclitic, Multivalent, Post-ASCT maintenance, High-risk cytogenetics, WT1 Analog Peptide Vaccine, 12-288, Galinpepimut-S, GPS