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Immunotherapy With BCMA CAR-T Cells in Treating Patients With BCMA Positive Relapsed or Refractory Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT03338972
Recruitment Status : Recruiting
First Posted : November 9, 2017
Last Update Posted : March 5, 2019
Sponsor:
Collaborators:
Juno Therapeutics, Inc.
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Brief Summary:
This phase I trial studies the side effects and best dose of BCMA CAR-T cells in treating patients with BCMA positive multiple myeloma that has come back or does not respond to treatment. T cells are a type of white blood cell and a major component of the immune system. T-cells that have been genetically modified in the laboratory express BCMA and may kill cancer cells with the protein BCMA on their surface. Giving chemotherapy before BCMA CAR-T cells may reduce the amount of disease and to cause a low lymphocyte (white blood cell) count in the blood, which may help the infused BCMA CAR-T cells survive and expand.

Condition or disease Intervention/treatment Phase
Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma TNFRSF17 Positive Biological: Autologous Anti-BCMA-CAR-expressing CD4+/CD8+ T-lymphocytes FCARH143 Drug: Cyclophosphamide Drug: Fludarabine Other: Laboratory Biomarker Analysis Procedure: Leukapheresis Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the safety of adoptive therapy with ex vivo expanded autologous CD8+ plus CD4+ T cells transduced to express a human B cell maturation antigen (BCMA-)-targeting chimeric antigen receptor (CAR) for patients with relapsed or treatment refractory multiple myeloma.

SECONDARY OBJECTIVES:

I. To determine the degree to which adoptively transferred T cells traffic to multiple myeloma (MM) cells in the bone marrow (BM) and function in vivo.

II. To determine the degree to which adoptively transferred T cells traffic to MM cells in the BM and function in vivo.

III. To estimate the antitumor activity of adoptively transferred BCMA-specific CAR-expressing T lymphocytes (BCMA CAR-T cells).

OUTLINE: This is a dose-escalation study of BCMA-specific CAR-expressing T lymphocytes.

Patients undergo leukapheresis to obtain their immune cells, from which CAR-T cells are produced. A few weeks later, patients then receive cyclophosphamide and fludarabine on days -4 to -2. Beginning 36-96 hours after chemotherapy, patients receive BCMA-specific CAR-expressing T lymphocytes intravenously (IV) over 20-30 minutes on day 0.

After completion of study treatment, patients are followed up at 60, 90, 120, 180, and 365 days and then up to 15 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Adoptive Immunotherapy for Advanced B-Cell Maturation Antigen (BCMA)+ Multiple Myeloma With Autologous CD4+ and CD8+ T Cells Engineered to Express a BCMA-Specific Chimeric Antigen Receptor
Actual Study Start Date : November 29, 2017
Estimated Primary Completion Date : December 15, 2020
Estimated Study Completion Date : December 15, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
Experimental: Treatment (chemotherapy, BCMA CAR-T cells)
Patients undergo leukapheresis. Patients then receive cyclophosphamide and fludarabine on days -4 to -2. Beginning to 36-96 days after chemotherapy, patients receive BCMA-specific CAR-expressing T lymphocytes IV over 20-30 minutes on day 0. Patients may receive a second BCMA-specific CAR-expressing T lymphocytes infusion at the highest cell dose or the next highest dose level.
Biological: Autologous Anti-BCMA-CAR-expressing CD4+/CD8+ T-lymphocytes FCARH143
Given IV
Other Names:
  • Autologous Anti-BCMA-CAR CD4+/CD8+ Cells
  • Autologous Anti-BCMA-CAR-expressing CD8+ and CD4+ T-lymphocytes
  • BCMA CAR-CD4+/CD8+ T-cells
  • BCMA-specific CAR-expressing CD4+/CD8+ T-lymphocytes
  • FCARH143

Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Drug: Fludarabine
Given IV
Other Name: Fluradosa

Other: Laboratory Biomarker Analysis
Correlative studies

Procedure: Leukapheresis
Undergo leukapheresis
Other Names:
  • Leukocytopheresis
  • Therapeutic Leukopheresis




Primary Outcome Measures :
  1. Dose-limiting toxicity (DLT) [ Time Frame: Up to 21 days after T cell infusion ]
    Observed DLT rates will be summarized based on the DLT-Evaluable analysis set. Final DLT rates at each dose level will be estimated by the Continual Reassessment Method (CRM) algorithm.

  2. Incidence of toxicity graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 [ Time Frame: Up to 42 days after T cell infusion ]
    All adverse events (AEs) will be listed and summarized. Summaries of laboratory data will include, at a minimum, treatment-emergent laboratory abnormalities. Summaries of AEs and laboratory abnormalities will be based on the All Treated analysis set.


Secondary Outcome Measures :
  1. Duration of persistence of adoptively transferred BCMA CAR-T cells [ Time Frame: Baseline up to 15 years ]
  2. Migration of adoptively transferred BCMA CAR-T cells [ Time Frame: Baseline up to 15 years ]
  3. Objective response rate (ORR) [ Time Frame: Baseline up to 3 months after T cell infusion ]
    Proportion of patients with a best response of either complete response or partial response, assessed using modified International Myeloma Working group response criteria.

  4. Progression-free survival (PFS) [ Time Frame: Assessed up to 15 years ]
    Assessed using modified International Myeloma Working Group response criteria

  5. Overall survival (OS) [ Time Frame: Assessed up to 15 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   22 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Have the capacity to give informed consent
  • Have measurable disease by International Myeloma Working Group (IMWG) criteria based on one or more of the following findings:

    • Serum M-protein >= 1 g/dL
    • Urine M-protein >= 200 mg/24 hour
    • Involved serum free light chain (sFLC) level >= 10 mg/dL with abnormal kappa/lambda ratio
    • Measurable biopsy-proven plasmacytomas (>= 1 lesion that has a single diameter >= 2 cm)
    • Bone marrow plasma cells >= 30%
  • Have a diagnosis of BCMA+ MM (>= 5% BCMA+ by flow cytometry on CD138 co-expressing plasma cells obtained within 45 days of study enrollment); the MM diagnosis must be confirmed by internal pathology review of a fresh biopsy specimen at the Fred Hutchinson Cancer Research Center (FHCRC)/Seattle Cancer Care Alliance (SCCA)
  • Have relapsed or treatment refractory disease with >= 10% CD138+ malignant plasma cells (IHC) on BM core biopsy, either:

    • Following autologous stem cell transplant (ASCT)
    • Or, if a patient has not yet undergone ASCT, the individual must:

      • Be transplant ineligible, due to age, comorbidity, patient choice, insurance reasons, concerns of rapidly progressive disease, and/or discretion of attending physician, and,
      • Demonstrate disease that persists after > 4 cycles of induction therapy and that is double refractory (persistence/progression) after therapy with both a proteasome inhibitor and immunomodulatory drug (IMiD) administered either in tandem, or in sequence; > 4 cycles of therapy are not required for patients with a diagnosis of plasma cell leukemia
  • Male and female patients of reproductive potential must be willing to use an effect contraceptive method before, during, and for at least 4 months after the CAR T cell infusion

Exclusion Criteria:

  • History of another primary malignancy that requires intervention beyond surveillance or that has not been in remission for at least 1 year (the following are exempt from the 1 year limit: non-melanoma skin cancer, curatively treated localized prostate cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on papanicolaou [PAP] smear)
  • Active hepatitis B, hepatitis C at the time of screening
  • Patients who are (human immunodeficiency virus [HIV]) seropositive
  • Subjects with uncontrolled active infection
  • > 1 hospital admission (lasting 5 days or more) for documented infection in prior 6 months
  • Presence of acute or chronic graft-versus-host disease (GVHD) requiring active treatment unless limited to skin involvement and managed with topical steroid therapy alone
  • History of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease as determined by the principal investigator (PI) or designee
  • History or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis, active central nervous system MM involvement and/or carcinomatous meningitis; subjects with previously treated central nervous systems involvement may participate, provided they are free of disease in the CNS (documented by flow cytometry performed on the cerebrospinal fluid [CSF] within one week of enrollment) and have no evidence of new sites of CNS activity
  • Pregnant or breastfeeding females
  • Use of any of the following:

    • Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis; physiologic replacement, topical, and inhaled steroids are permitted
    • Cytotoxic chemotherapeutic agents within 1 week of leukapheresis; oral chemotherapeutic agents are allowed if at least 3 half-lives have elapsed prior to leukapheresis
    • Lymphotoxic chemotherapeutic agents within 2 weeks of leukapheresis
    • Daratumumab (or other anti-CD38 therapy) within 30 days of leukapheresis
    • Experimental agents within 4 weeks of leukapheresis unless progression is documented on therapy and at least 3 half-lives have elapsed prior to leukapheresis
  • Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the investigator; or unwillingness or inability to follow the procedures required in the protocol
  • Absolute neutrophil count (ANC) < 1000/mm^3, per PI discretion if thought to be related to underlying myeloma
  • Hemoglobin (Hgb) < 8 mg/dl, per PI discretion if thought to be related to underlying myeloma
  • Platelet count < 50,000/mm^3, per PI discretion if thought to be related to underlying myeloma
  • Active autoimmune disease requiring immunosuppressive therapy
  • Major organ dysfunction defined as:

    • Creatinine clearance < 20 ml/min
    • Significant hepatic dysfunction (serum glutamic-oxaloacetic transaminase [SGOT] > 5 x upper limit of normal; bilirubin > 3.0 mg/dL)
    • Forced expiratory volume in 1 second (FEV1) of < 50% predicted or diffusion capacity of the lung for carbon monoxide (DLCO) (corrected) < 40% (patients with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing)
  • Anticipated survival of < 3 months
  • Contraindication to cyclophosphamide or fludarabine chemotherapy
  • Patients with known AL subtype amyloidosis
  • Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the PI; or unwillingness or inability to follow the procedures required in the protocol

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03338972


Locations
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United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Immunotherapy Trials Intake, SCCA    206-606-4668    immunotherapy@seattlecca.org   
Principal Investigator: Damian J. Green         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Juno Therapeutics, Inc.
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Damian Green Fred Hutch/University of Washington Cancer Consortium

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Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT03338972     History of Changes
Other Study ID Numbers: 9762
NCI-2017-01932 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9762 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
RG9217023 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
First Posted: November 9, 2017    Key Record Dates
Last Update Posted: March 5, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites