Genetically Engineered T Cells in Treating Patients with Relapsed and / or Refractory Multiple Myeloma
This pilot phase I trial studies the side effects of genetically engineered T cells, called B cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR)-expressing T lymphocytes, in treating patients with multiple myeloma that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). Taking white blood cells, called T cells, from a patient and modifying them in the laboratory may help identify and possibly kill cancerous cells. The modification is a genetic change, or gene transfer, to the normal T cells. These modified cells are called T cells expressing a CAR construct (CART)-BCMA- because they target a marker on multiple myeloma cells called BCMA.
- Subjects must have a confirmed prior diagnosis of active MM as defined by the International Myeloma Working Group (IMWG) criteria
- Subjects must have relapsed or refractory disease after either one of the following: * At least 3 prior regimens, which must have contained an alkylating agent, proteasome inhibitor, and immunomodulatory agent (IMiD) OR * At least 2 prior regimens if “double-refractory” to a proteasome inhibitor and IMiD, defined as progression on or within 60 days of treatment with these agents; Note: induction therapy, stem cell transplant, and maintenance therapy, if given sequentially without intervening progression, should be considered as 1 “regimen”
- Subjects must have signed written, informed consent
- Subjects must be at least 90 days since autologous stem cell transplant, if performed
- Serum creatinine =< 2.5 or estimated creatinine clearance >= 30 ml/min and not dialysis-dependent
- Absolute neutrophil count >= 1000/μl
- Platelet count >= 50,000/μl (>= 30,000/μl if bone marrow plasma cells are >= 50% of cellularity)
- Serum glutamic oxaloacetic transaminase (SGOT) =< 3 x the upper limit of normal
- Total bilirubin =< 2.0 mg/dl (except for patients in whom hyperbilirubinemia is attributed to Gilbert’s syndrome)
- Left ventricular ejection fraction (LVEF) >= 45%; LVEF assessment must have been performed within 8 weeks of enrollment
- Toxicities from prior therapies, with the exception of peripheral neuropathy attributable to bortezomib, must have recovered to grade =< 2 according to the Common Toxicity Criteria (CTC) 4.0 criteria or to the subject’s prior baseline
- Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- Subjects must have measurable disease on study entry, which must include at least 1 of the following: * Serum M-spike >= 0.5 g/dL * 24 hr urine M-spike >= 200 mg * Involved serum free light chain (FLC) >= 50 mg/L with abnormal ratio * Measurable plasmacytoma on exam or imaging * Bone marrow plasma cells >= 20% (bone marrow biopsy only required at screening if no other measurable disease is present) ** Note: patients with immunoglobulin (Ig)A myeloma in whom serum protein electrophoresis is deemed unreliable, due to co-migration of normal serum proteins with the paraprotein in the beta region, may be considered eligible as long as total serum IgA level is elevated above normal range
- Subjects of reproductive potential must agree to use acceptable birth control methods
- Subjects must not be pregnant or lactating
- Subjects must not have inadequate venous access for or contraindications to leukapheresis
- Subjects must not have any active and uncontrolled infection
- Subjects must not have active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection
- Any uncontrolled medical or psychiatric disorder that would preclude participation
- Subjects must not have New York Heart Association (NYHA) class III or IV heart failure, unstable angina, or a history of recent (within 6 months) myocardial infarction or sustained (> 30 seconds) ventricular tachyarrhythmias
- Subjects must not have undergone allogeneic stem cell transplantation
- Subjects must not have received prior gene therapy or gene-modified cellular immunotherapy; subject may have received, however, non-gene-modified autologous T-cells in association with an anti-myeloma vaccine (e.g., human telomerase reverse transcriptase [hTERT] or melanoma-associated antigen 3 [MAGEA3]) or vaccination against infectious agents (e.g., influenza or pneumococcus) as was performed on our previous studies
- Subjects must not have active auto-immune disease, including connective tissue disease, uveitis, sarcoidosis, inflammatory bowel disease, or multiple sclerosis, or have a history of severe (as judged by the principal investigator) autoimmune disease requiring prolonged immunosuppressive therapy
- Subjects must not have a history of neurodegenerative or central nervous system movement disorder
- Subjects must not have prior or active central nervous system (CNS) involvement (e.g. leptomeningeal disease, parenchymal masses) with myeloma; screening for this (e.g. with lumbar puncture) is not required unless suspicious symptoms are present
Locations & Contacts
Contact: Adam David Cohen
Trial Objectives and Outline
I. To evaluate the safety of CART-BCMA cells (BCMA-specific CAR-expressing T lymphocytes) for patients with relapsed/refractory multiple myeloma (MM).
I. To describe clinical outcomes, including response rates, minimal residual disease rates, progression-free and overall survival.
II. To assess the feasibility of manufacturing CART-BCMA cells.
I. To characterize CART-BCMA cells with respect to their expansion, persistence, homing, phenotype and function.
II. To evaluate for development of cellular and/or humoral immunity against CART-BCMA cells.
III. To evaluate effect of CART-BCMA cells on B cell and plasma cell compartments, including immunoglobulin levels.
IV. To determine the impact of CART-BCMA cells on systemic soluble immune factors in patients.
V. To assess BCMA and related surface antigens expression on MM cells, B cells, and plasma cells pre- and post-treatment.
The first cohort of patients will receive CAR T cells alone. If safe, all subsequent cohorts will receive lymphodepleting chemotherapy prior to the first CART-BCMA cell infusion.
LYMPHODEPLETING CHEMOTHERAPY: Patients receive cyclophosphamide intravenously (IV) on day -3.
CART-BCMA T CELL INFUSION: Patients receive autologous BCMA-specific CAR-expressing T lymphocytes IV on days 0, 1, and 2.
After completion of study treatment, patients are followed up at day 28, monthly up to 6 months, every 3 months for up to 2 years, and then periodically for up to 15 years.
Trial Phase & Type
University of Pennsylvania / Abramson Cancer Center
Adam David Cohen
Secondary IDs NCI-2015-01595, bjcdacda, UPCC#14415
Clinicaltrials.gov ID NCT02546167