Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Cyclophosphamide

Fludarabine

Fludarabine phosphate

The first 3 subjects enrolled in the study will receive 5x10\^6 CAR138 T-cells/m\^2 via infusion. The number of cells for the infusion will be increased to 1x10\^7 CAR138 T-cells/m\^2 and then, 2.5x10\^7 CAR138 T-cells/m\^2, 5x10\^7 CAR138 T-cells/m\^2, 1x10\^8 CAR138 T-cells/m\^2 and 2x10\^8 CAR138 T-cells/m\^2 in subsequent cohorts of 3 subjects provided no dose limiting toxicities (DLTs) are observed within 4 weeks of the cell infusion. Cohort enrollment will be staggered, requiring each subject to complete at least 2 weeks of safety monitoring following CAR138 T-cell infusion at the designated dose level for the cohort before another subject is allowed to enroll in the cohort.

The MTD is defined as the dose at which approximately 0.20 of subjects experience DLT dose escalation guided by the continual reassessment method (CRM).

Six dose levels will be evaluated:

Dose level 1: 5X10\^6 cells/m\^2 Dose level 2: 1X10\^7 cells/m\^2 Dose level 3: 2.5X10\^7 cells/m\^2 Dose level 4: 5X10\^7 cells/m\^2 Dose level 5: 1x10\^8 cells/m\^2 Dose level 6: 2x10\^8 cells/m\^2

Six subjects will be enrolled at the MTD to better characterize safety at that dose level.

Cell Administration: CAR138 T cells will be given by intravenous injection over through either a peripheral or a central line.

The lymphodepletion regimen will consist of intravenous cyclophosphamide 300 mg/m\^2 and fludarabine 30 mg/m\^2 given once daily for three days.

CAR138 T Cells

Catherine Cheng

Kelly Hoye

Sascha Tuchman, MD, MPS

Sascha Tuchman, MD, MHS

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 subjects with cancers. They both have shown promise, but neither alone has been sufficient to cure most subjects. 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 subject'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 subjects. 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 subjects for cell procurement. In subjects 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 subject decides to withdraw from the study, OR
* General or specific changes in the subject's condition render the subject unacceptable for further treatment in the judgment of the investigator.

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

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

Arms and Interventional ArmTitle : CAR138 T cells Description: The first 3 subjects enrolled in the study will receive 5x10\^6 CAR138 T-cells/m\^2 via infusion. The number of cells for the infusion will be increased to 1x10\^7 CAR138 T-cells/m\^2 and then, 2.5x10\^7 CAR138 T-cells/m\^2, 5x10\^7 CAR138 T-cells/m\^2, 1x10\^8 CAR138 T-cells/m\^2 and 2x10\^8 CAR138 T-cells/m\^2 in subsequent cohorts of 3 subjects provided no dose limiting toxicities (DLTs) are observed within 4 weeks of the cell infusion. Cohort enrollment will be staggered, requiring each subject to complete at least 2 weeks of safety monitoring following CAR138 T-cell infusion at the designated dose level for the cohort before another subject is allowed to enroll in the cohort.

Study of ATLCAR.CD138 Cells for Relapsed/Refractory Multiple Myeloma

Phase I Study of Autologous CAR T-Cells Targeting the CD138 Antigen for Relapsed or Refractory Multiple Myeloma

The maximum tolerated dose will be determined through assessment of dose limiting toxicity (DLT) experienced during the safety evaluation period. Severity and categorization of adverse events will be determined in accordance with the National Cancer Institute's Common Terminology for Adverse Events (CTCAE, version 5.0). A DLT is defined as any of the following that may, after consultation with the FDA, be considered possibly, probably, or definitely related to the study cellular products: Grade 3 and 4 cytokine release syndrome (CRS) that persists beyond 72 hours, or any Grade 5 CRS event; Grade 4 neutropenia or thrombocytopenia lasting more than 28 days from the time of CAR138 T-cell infusion. Any other ≥ Grade 3 non- hematologic toxicity (exceptions include: alopecia; grade 3 electrolyte abnormalities, hyperglycemia, diarrhea, or nausea and vomiting that can be managed with supportive care and do not persist as Grade 3 toxicities for \> 72 hours)).

Persistence of CAR138 T-cells in vivo determined by quantitative polymerase chain reaction (PCR) and flow cytometry in samples of peripheral blood.

To determine the overall survival (OS) after infusion of CAR138 T cells in subjects with relapsed or refractory multiple myeloma. OS will be measured from the date of administration of CAR138 T-cells to the date of death.

Progression Free Survival (PFS) is the time from infusion of CAR138 T cells to progression or death from any cause. Subjects not known to have progressed or died at last follow-up are censored on the date of last contact. Revised Uniform Response Criteria by the International Myeloma Working Group defines progression as: Increase of 25% from lowest response value in: Serum M component with absolute increase (AI) ≥0.5 g/dL; serum M component increase ≥1 g/dL if starting M component is ≥5 g/dL and/or; Urine M component (AI ≥200 mg/24 h) and/or; in subjects without measurable serum \& urine M-protein levels: difference between involved \& uninvolved FLC levels (AI \> 10 mg/dL); in subjects without measurable serum \& urine M-protein levels, without measurable disease by FLC level, bone marrow; Development of new or definite increase in size of existing bone lesions or soft tissue plasmacytoma; Development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder.

ORR, percentage of subjects achieving a partial response or better: Complete response (CR) is Negative immunofixation of serum and urine, disappearance of soft tissue plasmacytomas, and \<5% plasma cells in bone marrow (BM); stringent complete response (sCR) CR plus normal FLC ratio and absence of clonal plasma cells; Immunophenotypic CR- sCR plus absence of phenotypically aberrant plasma cells in BM with minimum of 1 million total BM cells; Molecular CR -CR plus negative allele-specific oligonucleotide polymerase chain reaction. Very good partial response -Serum and urine M component detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M component plus urine M component \<100/24h; Partial response ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to \<200 mg per 24 hr; no known evidence of progressive or new bone lesions if radiographic studies were performed.

Spots Global Cancer Trial Database for car138 t cells