Clinical Trials /

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

NCT03672318

Description:

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.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of ATLCAR.CD138 Cells for Relapsed/Refractory Multiple Myeloma
  • Official Title: Phase I Study of Autologous CAR T-Cells Targeting the CD138 Antigen for Relapsed or Refractory Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: LCCC 1603-ATL
  • NCT ID: NCT03672318

Conditions

  • Multiple Myeloma
  • Immune System Diseases

Interventions

DrugSynonymsArms
CAR138 T CellsATLCAR.CD138, CAR.CD138 T cellsCAR138 T cells

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
CAR138 T cellsExperimentalThe first 3 patients 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 patients provided no dose limiting toxicities (DLTs) are observed within 4 weeks of the cell infusion. Cohort enrollment will be staggered, requiring each patient to complete at least 2 weeks of safety monitoring following CAR138 T-cell infusion at the designated dose level for the cohort before another patient is allowed to enroll in the cohort.
  • CAR138 T Cells

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of participants with dose limiting toxicities as a measure of maximum tolerated dose of CAR138 T cells
Time Frame:4 weeks from infusion of the CAR138 T cells
Safety Issue:
Description: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)).

Secondary Outcome Measures

Measure:Survival of CAR138 T cells in vivo as assessed by PCR and flow cytometry
Time Frame:15 years
Safety Issue:
Description:Persistence of CAR138 T-cells in vivo determined by quantitative polymerase chain reaction (PCR) and flow cytometry in samples of peripheral blood.
Measure:Overall survival after infusion of CAR138 T cells
Time Frame:15 years
Safety Issue:
Description:To determine the overall survival (OS) after infusion of CAR138 T cells in patients with relapsed or refractory multiple myeloma. OS will be measured from the date of administration of CAR138 T-cells to the date of death
Measure:Progression free survival after infusion of CAR138 T cells
Time Frame:15 years
Safety Issue:
Description:Progression Free Survival (PFS) is the time from infusion of CAR138 T cells to progression or death from any cause. Patients 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 patients without measureable serum & urine M-protein levels: difference between involved & uninvolved FLC levels (AI > 10 mg/dL); in patients 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.
Measure:Overall response rate (ORR) as defined as the percentage of patients achieving a confirmed partial response or better based on the International Myeloma Working Group (IMWG) response criteria.
Time Frame:15 years
Safety Issue:
Description:ORR, percentage of patients 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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • CAR T cells
  • CD138
  • Multiple Myeloma

Last Updated

May 10, 2019