Phase I/II Study of SLAMF7 FPBMC/CS-1 FPBMC in Relapsed/Refractory Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to understand the safety and estimate the efficacy of combining anti-CD3 x anti-SLAMF7 bispecific antibody fresh peripheral blood mononuclear cells (SLAMF7 FPBMC/CS1 FPBMC) for patients with relapsed and/or refractory multiple myeloma. Patients receive 8 weekly doses and then 8 more doses every 2 weeks of SLAMF7 FPBMC by intravenous infusion.

Detailed Description
-----------------
Once subjects are determined eligible, white blood cells (lymphocytes) are collected via leukapheresis procedure. The white blood cells, specifically T cells, are then mixed with two proteins, OKT3 and IL-2, which activate the cells to multiply. The activated T cells are coated with the OKT3 and elotuzumab (an anti-SLAMF7 drug) to produce bispecific fresh peripheral blood mononuclear cells (FPBMC). About 72 hours after the leukapheresis procedure, SLAMF7 FPBMC infusions will start. After about 8-9 weeks, participants will have another leukapheresis procedure and then receive doses every 2 weeks for 8 more doses. Before, throughout and following SLAMF7 FPBMC, research blood will be collected to better understand immune response. Disease status will be checked regularly during and after study treatment.

Official Title
-----------------
Phase I/II Study of Anti-CD3 x Anti-SLAMF7 (Anti-CS-1) Bispecific Antibody Armed Fresh Peripheral Blood Mononuclear Cells (SLAMF7 FPBMC) in Relapsed/Refractory Multiple Myeloma

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

Intervention / Treatment
-----------------
* Drug: SLAMF7 FPBMC


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must have received ≥ 2 consecutive cycles of treatment which include an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody either used individually or in combination Documented refractory or relapsed myeloma Refractory is defined as progression while on treatment or within 60 days of last treatment Measurable disease based on at least one of the following lab results within 28 days of enrollment Serum IgG, IgA, or IgM M-protein ≥ 1.0 g/dL Urine M-protein ≥ 200 mg excreted in a 24-hr collection sample Involved serum free light chain (FLC) ≥ 100 mg/L provided the FLC ratio is abnormal ECOG Performance Status 0 -2 Left Ventricular Ejection Fraction (LVEF) ≥ 45% at rest (MUGA or Echocardiogram) Age ≥ 18 years at the time of consent (Written informed consent and HIPAA authorization for release of personal health information) Females of childbearing potential, and males, must be willing to use an effective method of contraception for the duration of the treatment with study drug plus 90 days (duration of sperm turnover). Adequate cardiac function as defined as: No EKG evidence of acute ischemia No EKG evidence of clinically significant conduction system abnormalities in the opinion of the treating investigator No EKG evidence of > Grade 2 (> 480 ms) QTc prolongation No uncontrolled angina or severe ventricular arrhythmias No clinically significant pericardial disease No history of myocardial infarction (MI) in the last 6 months No Class 3 or higher New York Heart Association Congestive Heart Failure Demonstrate adequate organ function as defined below; all screening labs should be performed within 14 days prior to enrollment. Absolute lymphocyte count ≥ 400/mm3 Absolute neutrophil count ≥ 1,000/mm3 Platelets ≥ 75,000/mm3 Calculated Creatinine Clearance ≥ 30 ml/min Serum total bilirubin ≤ 1.5 x upper limit of normal AST and ALT < 2.5 times normal Exclusion Criteria: Known hypersensitivity to elotuzumab (Elo) Amyloidosis, Waldenstrom's macroglobulinemia, POEMS syndrome, or known central nervous system (CNS) involvement Receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to enrollment. NOTE: Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Active autoimmune disease that has required systemic treatment in the past 2 years before enrollment (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Serious non-healing wound, ulcer, bone fracture, major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to enrollment Active liver disease (such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis) HIV positive or known active Hepatitis C (e.g., HCV RNA [qualitative] is detected) or Hepatitis B (e.g. HBsAg reactive) virus Active bleeding or a pathological condition that is associated with a high risk of bleeding (therapeutic anticoagulation is allowed) Has an active infection requiring systemic therapy History of active TB (Bacillus Tuberculosis) Has received a live vaccine within 30 days of enrollment. Anti-myeloma drug therapy (including radiation therapy) ≤ 14 days prior to apheresis History of myocardial infarction (within 6 months of enrollment), stable or unstable angina History of another malignancy within the past 3 years before enrollment. -- Exceptions include: Basal cell carcinoma of the skin or squamous cell carcinoma of the skin, In situ cancers that have undergone potentially curative therapy Prisoners or patients who are incarcerated Patients who are compulsorily detained for treatment of either a psychiatric or physical illness Pregnant or breastfeeding females: Females of childbearing potential must have a negative pregnancy test within 7 days prior to enrollment.

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
Interventional Model Description: SLAMF7 FPBMC
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SLAMF7 FPBMC<br>Participants will undergo apheresis to collect cells to make SLAMF7 fresh peripheral blood mononuclear cells (FPBMC). These cells will be activated in the lab to fight against multiple myeloma. About 3-4 days after apheresis, participants will start receiving infusions of SLAMF7 FPBMC. Throughout treatment, participants will have blood taken for labs, to check disease status and also to look at immune response. Study treatment will stop if the participant has disease progression. | Drug: SLAMF7 FPBMC<br>* Participants will receive 8 weekly infusions of SLAMF7 FPBMC, then 8 additional infusions every 2 weeks.<br>* Other names: CS-1 FPBMC;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicities (DLTs) | An adverse event that is considered at least possibly related to SLAMF7 FPBMC and meets at least one of the protocol-defined criteria | From time of informed consent through one week following 8th FPBMC infusion | 
| Adverse event profile | Severity, frequency, category, seriousness and duration of adverse events | From time of informed consent through 30 days following last FPBMC infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | As defined by International Myeloma Working Group (IMWG) response criteria (partial response (PR), very good partial response (VGPR), complete response (CR), stringent CR (sCR) | About once a month during study treatment (for about 6 months), then about every 3 months for 3 years or until first progression | 
| Minimal Residual Disease (MRD) status | Assessed by ClonoSeq, only for patients who achieve stringent CR or CR | Through first progression of disease (maximum of 3 years from first infusion) | 
| Overall Survival (OS) | Duration of time from consent through death or 3 years after first FPBMC infusion | Through 3 years after first FPBMC infusion | 
| Cellular anti-myeloma responses | IFN-gamma Elispots stimulated by a multiple myeloma cell line | Multiple timepoints through 12 months after last FPBMC infusion | 
| Progression-free survival (PFS) | Duration of time from consent through first progression (or end of follow-up) | From informed consent through first progression or 3 years after enrollment | 
| Humoral anti-myeloma responses | Anti-SOX2 IgG antibodies in the serum by specific ELISA | Multiple timepoints through 12 months after last FPBMC infusion | 
| Lymphocyte response following infusions of SLAMF7 FPBMC | T cell count and count for T cell subpopulations | Blood samples collected prior to first infusion and then before the second through fifth infusions | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Multiple myeloma, Relapsed, Refractory, Fresh Peripheral Blood Mononuclear Cells (FPBMC), Bispecific antibodies