Adoptive Transfer of NY-ESO-1 TCR Engineered Peripheral Blood Mononuclear Cells (PBMC) and Peripheral Blood Stem Cells (PBSC) After a High Dose Melphalan Conditioning Regimen, With Administration of Interleukin-2, in Patients With Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Incidence of dose limiting toxicity
研究概览
简要总结
This phase I trial studies the side effects of NY-ESO-1 TCR engineered peripheral blood mononuclear cells (PBMC) and peripheral blood stem cells (PBSC) after melphalan conditioning regimen in treating participants with multiple myeloma that has come back or does not respond to treatment. The melphalan conditioning chemotherapy makes room in the patient?s bone marrow for new blood cells (PBMC) and blood-forming cells (stem cells) to grow. Giving NY-ESO-1 TCR PBMC and stem cells after the conditioning chemotherapy is intended to replace the immune system with new immune cells that have been redirected to attack and kill the cancer cells and thereby improve immune system function against cancer. Giving NY-ESO-1 TCR PBMC and PBSC after melphalan may work better at treating multiple myeloma.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Treatment (Genetically engineered PBMC and PBSC)
Refer to outline
干预措施: 18F-FHBG (Radiation)
Treatment (Genetically engineered PBMC and PBSC)
Refer to outline
干预措施: Aldesleukin (Biological)
Treatment (Genetically engineered PBMC and PBSC)
Refer to outline
干预措施: Cellular Therapy (Biological)
Treatment (Genetically engineered PBMC and PBSC)
Refer to outline
干预措施: Computed Tomography (Procedure)
Treatment (Genetically engineered PBMC and PBSC)
Refer to outline
干预措施: Filgrastim (Biological)
Treatment (Genetically engineered PBMC and PBSC)
Refer to outline
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (Genetically engineered PBMC and PBSC)
Refer to outline
干预措施: Lenalidomide (Drug)
Treatment (Genetically engineered PBMC and PBSC)
Refer to outline
干预措施: Leukapheresis (Procedure)
Treatment (Genetically engineered PBMC and PBSC)
Refer to outline
干预措施: Melphalan (Drug)
Treatment (Genetically engineered PBMC and PBSC)
Refer to outline
干预措施: Plerixafor (Drug)
Treatment (Genetically engineered PBMC and PBSC)
Refer to outline
干预措施: Positron Emission Tomography (Procedure)
结局指标
主要结局
Incidence of dose limiting toxicity
时间窗: Up to 90 days
Safety will be assessed by monitoring and recording potential adverse effects of the treatment using the Common Toxicity Criteria at each study visit. Subjects will be monitored by medical histories, physical examinations and blood studies to detect potential toxicities from the treatment. If there are no dose limiting toxicities observed, the cohort will be expanded to 12 subjects. If 1/3 are observed, up to 6 subjects will be recruited. If less than 2/6 are observed, the cohort will be expanded to a total of 12 subjects. If a dose limiting toxicity is observed in 2 or more of 6 subjects, then this dose level will have exceeded the 33% rate, and the study will be terminated.
次要结局
- Persistence of transduced T cells(Up to 2 years after transgenic cell adoptive transfer)
- Feasibility of NY-ESO-1 TCR transgenic cells(Up to 1 month after transgenic cell adoptive transfer)
- Engraftment and persistence of transduced progeny T cells(Up to 2 years after transgenic cell adoptive transfer)
- Engraftment and persistence of transduced T cells and progeny T cells(Up to 2 years after transgenic cell adoptive transfer)
- Persistence of TCR gene transduced cells(Up to 15 years)
- Long term monitoring for replication competence of retrovirus (RCR) and lentivirus (RCL)(Up to 12 months post cell administration)
- Duration of overall response(From the time measurement criteria is met for complete response/partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 15 years)
- Time to disease progression(Time from the date of cell infusion (day 0) to the date of progressive disease first documented, or death whichever occurs first, assessed up to 15 years)
- Immunological monitoring(Up to 15 years)
- Objective response(Up to 15 years)
- Duration of overall complete response(From the time measurement criteria has been first met for complete response until the first date that recurrent or progressive disease is objectively documented, assessed up to 15 years)