Study of ATLCAR.CD138 Cells for Relapsed/Refractory Multiple Myeloma
Study of ATLCAR.CD138 Cells for Relapsed/Refractory Multiple Myeloma
The body has different ways of fighting infection and disease. No single way seems perfect
 for fighting cancer. This research study combines two different ways of fighting disease:
 antibodies and T cells. Antibodies are proteins that protect the body from disease caused by
 bacteria or toxic substances. Antibodies work by binding those bacteria or substances, which
 stops them from growing and causing bad effects. T cells, also called T lymphocytes, are
 special infection-fighting blood cells that can kill other cells, including tumor cells or
 cells that are infected. Both antibodies and T cells have been used to treat patients with
 cancers. They both have shown promise, but neither alone has been sufficient to cure most
 patients. This study is designed to combine both T cells and antibodies to create a more
 effective treatment. The treatment that is being researched is called autologous T lymphocyte
 chimeric antigen receptor cells targeted against the CD138 antigen (CAR138 T cells).

 In previous studies, it has been shown that a new gene can be put into T cells that will
 increase their ability to recognize and kill cancer cells. A gene is a unit of DNA. Genes
 make up the chemical structure carrying the patient's genetic information that may determine
 human characteristics (i.e., eye color, height and sex). The new gene that is put in the T
 cells in this study makes a piece of an antibody called anti-CD138. This antibody floats
 around in the blood and can detect and stick to cancer cells called multiple myeloma cells
 because they have a substance on the outside of the cells called CD138. Anti-CD138 antibodies
 have been used to treat people with multiple myeloma, but have not been strong enough to cure
 most patients. For this study, the anti-CD138 antibody has been changed so that instead of
 floating free in the blood part of it is now joined to the T cells. Only the part of the
 antibody that sticks to the multiple myeloma cells is attached to the T cells instead of the
 entire antibody. When an antibody is joined to a T cell in this way it is called a chimeric
 receptor. These CD138 chimeric (combination) receptor-activated T cells seem to kill some of
 the tumor, but they do not last very long in the body and so their chances of fighting the
 cancer are unknown.
Cell Procurement Up to 300 mL total of peripheral blood (up to 3 collections) will be
 obtained from patients for cell procurement. In patients with a low CD3 count in the
 peripheral blood (less than 200/μl by flow cytometry), a leukopheresis may be performed to
 isolate sufficient T-cells. The parameters for pheresis will be 2 blood volumes.

 CAR138 T-cell Administration Autologous CAR138 T-cells will be administered 2-14 days
 following lymphodepletion. The lymphodepletion regimen will consist of Cyclophosphamide 300
 mg/m^2 and Fludarabine 30 mg/m^2 IV each given daily over 3 consecutive days.

 Duration of Therapy Autologous CAR138 T-cells will be administered 2-14 days following
 lymphodepletion with cyclophosphamide and fludarabine by a licensed provider (oncology
 registered nurse or physician) via intravenous injection over 5-10 minutes through either a
 peripheral or central line. The expected volume is 1-50cc.

 Treatment with one infusion will be administered unless:

 -  The patient decides to withdraw from the study, OR

 -  General or specific changes in the patient's condition render the patient unacceptable
 for further treatment in the judgment of the investigator.

 Duration of Follow-up Patients will be followed for up to 15 years for replication-competent
 retrovirus evaluation or until death, whichever occurs first. Patients removed from study for
 unacceptable adverse events will continue follow up for evaluation of progression free
 survival, overall survival and replication-competent retrovirus monitoring.

 Patients who experience disease progression after receiving a cell infusion will still be
 required to complete abbreviated follow up procedures.
Eligibility Criteria:

 -  Written informed consent and HIPAA authorization for release of personal health
 information. Patients must sign a consent to undergo cell procurement. Written
 informed consent to enroll in the CAR T-cell therapy trial must be obtained prior to
 lymphodepletion.

 -  Age ≥ 18 years at the time of consent.

 -  Karnofsky score of ≥ 60%.

 -  Diagnosis of relapsed or refractory multiple myeloma (as defined by the Revised
 Uniform Response Criteria outlined by the IMWG

 -  Measurable disease as defined by one or more of the following: 1) serum M-protein ≥1.0
 g/dL (≥0.5 g/dL for immunoglobulin A myeloma); 2) urine M-protein ≥200 mg/24 hours; 3)
 involved serum free light chain level ≥10 mg/dL AND an abnormal serum free light chain
 ratio. Patients with non-secretory disease and a baseline marrow burden of myeloma of
 at least 30% will also be eligible to participate.

 -  Two lines of therapy will be allowed if the patient has disease that is
 refractory to both an immunomodulatory agent (lenalidomide or pomalidomide) and a
 proteasome inhibitor.

 -  Received high dose melphalan followed by autologous stem-cell transplant or is not
 eligible for or has declined the procedure.

 -  Allogeneic stem cell transplantation is allowed provided the patient is ≥ 1 year from
 transplant, not on immunosuppressive therapy to treat/prevent graft-versus-host
 disease, has no evidence of active graft-versus-host disease, and has no evidence of
 active graft-versus-host disease or infection.

 -  Demonstrate adequate organ function prior to cell procurement as defined below:

 -  Creatinine Clearance using the Cockcroft-Gault formula: ≥ 50 mL/min

 -  Bilirubin: ≤ 1.5 × upper limit of normal (ULN)

 -  Aspartate aminotransferase (AST): ≤ 2.5 × ULN

 -  Alanine aminotransferase (ALT): ≤ 2.5 × ULN

 -  Oxygen saturation: ≥ 92% on room air

 -  Forced expiratory volume at 1 second (FEV1), forced vital capacity (FVC), total
 lung capacity (TLC), diffusion capacity of lung for carbon monoxide (DLCO): ≥ 50%
 of predicted values

 -  Ejection fraction: ≥ 50%

 -  Hemoglobin: ≥ 8.0 g/dL; transfusion of red blood cells within 1 weeks will be
 permitted

 -  Platelets: ≥ 50,000 /mm^3; Patients should not have received platelet
 transfusions within 1 week of screening

 -  ANC: ≥ 1000 /mm^3; Patients should not have received Granulocyte-colony
 stimulating factor (G-CSF) or Granulocyte macrophage colony-stimulating factor
 (GM-CSF) within 1 week or pegylated G-CSF (Neulasta) within 2 weeks of screening

 -  Negative serum pregnancy test within 72 hours prior to procurement and again 72 hours
 prior to lymphodepleting therapy for female participants of child bearing potential.
 NOTE: Females are considered of child bearing potential unless they are surgically
 sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral
 oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.

 -  Women of childbearing potential (WOCBP) should be willing to use 2 methods of birth
 control or be surgically sterile, or abstain from heterosexual activity for the course
 of the study, and for 6 months after the study is concluded. WOCBP are those who have
 not been surgically sterilized or have not been free from menses for > 1 year. The two
 birth control methods can be composed of: two barrier methods or a barrier method plus
 a hormonal method to prevent pregnancy. The male partner of WOCBP patients enrolled
 into the trial should use a condom and female participants must take the
 responsibility to inform their partners of the need to use a condom. As determined by
 the enrolling physician or protocol designee, ability of the patient to understand and
 comply with study procedures for the entire length of the study.

 -  Male patients with female partners must have had a prior vasectomy or agree to use an
 adequate method of contraception (i.e., double barrier method: condom plus spermicidal
 agent) prior to lymphodepletion through 3 months after the last dose of study therapy.

 -  No active infection (fungal, bacterial or viral) including Human Immunodeficiency
 Virus (HIV), Human T-lymhotropic virus (HTLV), Hepatits B virus (HBV), Hepatitis C
 virus (HCV) (tests can be pending at the time of cell procurement; only those samples
 confirming lack of active infection will be used to generate transduced cells). Note:
 To meet eligibility, patients are required to be negative for HIV antibody or HIV
 viral load, negative for HTLV1 and 2 antibody or PCR negative for HTLV1 and 2,
 negative for Hepatitis B surface antigen, and negative for HCV antibody or HCV viral
 load.

 -  Not pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while
 the mother is being treated on study).

 -  No tumor in a location where enlargement could cause airway obstruction.

 -  No history of hypersensitivity reactions to murine protein-containing products.

 -  No known sensitivity to mouse monoclonal antibodies.

 -  Has not received treatment with any investigational drug within 21 days or any tumor
 vaccines within the previous six weeks prior to lymphodepletion.

 -  No major surgery within 28 days prior to lymphodepletion.

 -  No diagnosis of any of the following conditions: amyloidosis, POEMS syndrome or
 multiple myeloma with central nervous system involvement.

 -  Patients with plasma cell leukemia are allowed to participate.

 -  No active inflammatory or infectious gastrointestinal disorder (e.g. infectious
 colitis, diverticulitis or inflammatory bowel disease).

 -  No psychiatric illness which would prevent the patient from giving informed consent.

 -  No medical condition which, in the opinion of the treating physician, would make this
 protocol unreasonably hazardous for the patient.

 -  No other prior or concomitant malignancies with the exception of:

 -  Non-melanoma skin cancer

 -  In-situ malignancy

 -  Low-risk prostate cancer after curative therapy

 -  Other cancer for which the patient has been disease free for ≥ 3 years.

 -  Adequate cardiac function, defined as:

 -  No EKG evidence of acute ischemia

 -  No EKG evidence of active, clinically significant conduction system abnormalities

 -  Prior to study entry, any EKG abnormality at screening not felt to put the
 patient at risk has to be documented by the investigator as not medically
 significant

 -  No uncontrolled angina or severe ventricular arrhythmias

 -  No clinically significant pericardial disease

 -  No history of myocardial infarction within the last 6 months prior to
 registration

 -  No Class 3 or higher New York Heart Association Congestive Heart Failure

 -  To qualify for lymphodepletion and CAR138 T-cell infusion, patients must meet all of
 the above eligibility criteria. A repeat EKG, echocardiogram or multigated acquisition
 scan, pulmonary function tests and viral serologies do not need to be repeated unless
 clinically indicated. In addition:

 -  Patients must have autologous transduced activated CAR 138 T-cells with
 appropriate transduction efficiency (as discussed with FDA)

 -  Patients must have autologous transduced activated CAR138 T-cells with ≥15%
 expression of CAR138

 -  Patients must have stopped taking corticosteroids for at least 48 hours prior to
 lymphodepleting chemotherapy; (those receiving <10mg/day prednisone equivalent may be
 enrolled at discretion of investigator)

 -  Patients must have stopped systemic chemotherapy for at least 14 days prior to
 lymphodepletion

 -  Patients must have stopped radiation therapy for at least 7 days prior to
 lymphodepletion

 -  Patients should have repeat multiple myeloma serologies performed within 7 days of
 lymphodepletion. If markers of measurable disease no longer fall within the guidelines
 outlined above (eligibility criterion #5), the Principal Investigator should be
 contacted. In such an event, the patient may be allowed to receive lymphodepletion and
 CAR138 T-cell infusion if it is felt to be in the patient's best interests. The
 patient would not be evaluable for response (disease not measurable) but would be
 evaluable for all other safety and efficacy measures.

 -  Patients must demonstrate adequate organ function prior to lymphodepletion as defined
 in the table below; all tests must be obtained within 48 hours prior to
 lymphodepletion.

 -  Hemoglobin: ≥ 8 g/dL

 -  Absolute Neutrophil Count (ANC): ≥ 1000 cells/mm^3; patients should not have
 received G-CSF or GM-CSF within 1 week or pegylated G-CSF (Neulasta) within 2
 weeks of screening for lymphodepletion

 -  Platelets: ≥ 50,000 cells/mm^3; patients should not have received platelet
 transfusion within 1 week of screening for lymphodepletion

 -  Calculated creatinine clearance: ≥ 50 mL/min using the Cockcroft-Gault formula

 -  Bilirubin: ≤ 1.5 × upper limit of normal (ULN)

 -  Aspartate aminotransferase (AST): ≤ AST ≤ 2.5 × ULN

 -  Alanine aminotransferase (ALT): ≤ AST ≤ 2.5 × ULN

 -  Pulse oximetry: ≥92% on room air