PRIMARY OBJECTIVES:
I. To determine the safety of administering the combination of autologous peripheral blood
mononuclear cells (PBMC) and CD34+ peripheral blood stem cells (PBSC) following a melphalan
conditioning regimen, both of which have been genetically modified to express NY-ESO-1 TCR.
SECONDARY OBJECTIVES:
I. To determine the feasibility of delivering the combination of T-cell receptor (TCR)
transduced autologous PBMC and CD34+ PBSC to patients.
II. To determine the persistence of NY-ESO-1 TCR transduced PBMC and the progeny of TCR
transduced PBSC in serial peripheral blood samples.
III. Objective response rate (ORR).
TERTIARY OBJECTIVES:
I. To explore the use of positron emission tomography (PET)-based imaging using the PET
tracer 9-4-[18F]fluoro-3-(hydroxymethyl)butylguanine ([18F]FHBG) with the goal of determining
whether the adoptively transferred NY-ESO-1 TCR transduced PBSC home to bone marrow,
differentiate into T cells and expand in secondary lymphoid organs and extramedullary disease
sites.
OUTLINE:
G-CSF AND PLERIXAFOR MOBILIZED LEUKAPHERESIS: Between 6 months and 3 weeks before infusion of
cells, participants undergo G-CSF and plerixafor mobilization of CD34+ peripheral blood stem
cells. Participants receive filgrastim subcutaneously (SC) on mobilization days 1-4 and up to
mobilization day 8 and plerixafor SC starting on mobilization day 4 up to day 8. During
mobilization, participants will undergo mobilized leukapheresis to obtain PBSC. Participants
also undergo an unmobilized leukapheresis on day -5 before infusion of cells in order to
obtain PBMC.
CHEMOTHERAPY CONDITIONING REGIMEN: Participants receive melphalan intravenously (IV) on days
-3 to -2.
Participants receive LV-NYESO TCR/sr39TK PBSC IV on day 0, and RV-NYESO TCR PBMC IV on day 1.
Beginning on day 2, participants receive aldesleukin (interleukin-2 or IL-2) SC twice daily
(BID) for up to 7 days. Participants receive the 18F-FHBG IV, and after 1 hour, undergo
PET/computed tomography (CT) on days 30 and 90. After day 100, participants receive
lenalidomide orally (PO) once daily (QD) for 21 days. Courses of lenalidomide repeat every 28
days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up monthly after day 90 until
disease progression and annually for up to 15 years.
Inclusion Criteria:
- Relapsed, relapsed and refractory or refractory multiple myeloma patients who have
received > 3 prior lines of therapy including a proteasome inhibitor, an
immunomodulatory agent, and an anti-CD28 monoclonal antibody
- NY-ESO-1 positive by immunohistochemistry (IHC) utilizing commercially available
NY-ESO-1 antibodies
- HLA-A*0201 (HLA-A2.1) positivity by molecular subtyping
- Measurable disease defined by at least one of the following:
- Serum monoclonal protein (serum protein electrophoresis [SPEP]) > 1gm/dL
- Serum free light chain (sFLC): involved free light chain (FLC) >= 10mg/dL AND
abnormal kappa to lambda serum free light chain ratio
- >= 200mg of monoclonal protein in the urine on 24 hour electrophoresis (urine
protein electrophoresis [UPEP])
- Adequate bone marrow and major organ function to undergo a PBSC transplant determined
within 30-60 days prior to enrollment using standard phase 1 criteria for organ
function defined as:
- Absolute neutrophil count (ANC) >= 1.5 x 10^9 cells/L
- Platelets >= 75 x 10^9/L
- Hemoglobin >= 8 g/dL
- Aspartate and alanine aminotransferases (AST, ALT) =< 2.5 x upper limit of normal
(ULN) (=< 5 x ULN, if documented liver metastases are present)
- Total bilirubin =< 2 x ULN (except patients with documented Gilbert?s syndrome)
- Creatinine < 2 mg/dl (or a glomerular filtration rate > 60)
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
- Must be willing and able to accept at least three leukapheresis procedures
- Must be willing and able to undergo three research PET scans
- Must be willing and able to provide written informed consent
Exclusion Criteria:
- Inability to purify >= 2.5 x 10^6 CD34-enriched cells/kg of patient weight from the
pooled granulocyte-colony stimulating factor (G-CSF) mobilized leukapheresis products
- Previous allogeneic transplant
- Previously known hypersensitivity to any of the agents used in this study; known
sensitivity to melphalan
- Received systemic treatment for multiple myeloma, including immunotherapy, within 14
days prior to initiation of study procedures
- Potential requirement for systemic corticosteroids or concurrent immunosuppressive
drugs based on prior history or received systemic steroids within the last 2 weeks
prior to enrollment (inhaled or topical steroids at standard doses are allowed)
- Human immunodeficiency virus (HIV) seropositivity or other congenital or acquired
immune deficiency state, which would increase the risk of opportunistic infections and
other complications during chemotherapy-induced lymphodepletion; if there is a
positive result in the infectious disease testing that was not previously known, the
patient will be referred to their primary physician and/or infectious disease
specialist
- Hepatitis B or C seropositivity with evidence of ongoing liver damage, which would
increase the likelihood of hepatic toxicities from the chemotherapy conditioning
regimen and supportive treatments; if there is a positive result in the infectious
disease testing that was not previously known, the patient will be referred to their
primary physician and/or infectious disease specialist
- Dementia or significantly altered mental status that would prohibit the understanding
or rendering of informed consent and compliance with the requirements of this protocol
- Known clinically active central nervous system (CNS) involvement; prior evidence of
CNS involvement successfully treated with surgery or radiation therapy will not be
exclusion for participation as long as they are deemed under control at the time of
study enrollment and there are no neurological signs of potential CNS involvement
- Pregnancy or breast-feeding; female patients must be surgically sterile or be
postmenopausal for two years, or must agree to use effective contraception during the
period of treatment and for 6 months afterwards; all female patients with reproductive
potential must have a negative pregnancy test (serum/urine) within 14 days from
starting the conditioning chemotherapy; the definition of effective contraception will
be based on the judgment of the study investigators
- Since IL-2 is administered following cell infusion:
- Patients will be excluded if they have a history of clinically significant
electrocardiogram (ECG) abnormalities, symptoms of cardiac ischemia with evidence
of ischemia on a cardiac stress test (stress thallium, stress multigated
acquisition [MUGA], dobutamine echocardiogram or other stress test)
- Similarly, patients with a baseline left ventricular ejection fraction (LVEF) <
45 percent (%) will be excluded
- Patients with ECG results of any conduction delays (PR interval > 200 ms,
corrected QT [QTC] > 480 ms), sinus bradycardia (resting heart rate < 50 beats
per minute), sinus tachycardia (heart rate > 120 beats per minute) will be
evaluated by a cardiologist prior to starting the trial; patients with any
arrhythmias, including atrial fibrillation/atrial flutter, excessive ectopy
(defined as > 20 premature ventricular contractions [PVCs] per minute),
ventricular tachycardia or 3rd degree heart block will be excluded from the study
unless cleared by a cardiologist
- Patients with pulmonary function test abnormalities as evidenced by a forced
expiratory volume in 1 (FEV1) / forced vital capacity (FVC) < 70% of predicted
for normality will be excluded
- Active or recent herpes simplex virus (HSV) infection or cytomegalovirus (CMV) based
on symptoms with positive swab culture and/or positive Immunoglobulin M (IgM)
screening, which would complicate the post-conditioning period
