A Phase I Trial of Lymphodepletion Intensification With Low Dose Total Body Irradiation With Dose Expansion for Standard-of-Care Tisagenlecleucel in Patients With Large B-Cell Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Dose-limiting toxicities
研究概览
简要总结
This phase I trial tests the safety, side effects, and best dose of total body irradiation (TBI) in combination with standard of care lymphodepletion with cyclophosphamide and fludarabine before tisagenlecleucel (Tisa-cel) and how well the combination works in patients with large B-cell lymphoma (LBCL) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). TBI is a common treatment that sends radiation (for example, through x-rays) to the entire body. Lymphodepleting chemotherapy, such as cyclophosphamide and fludarabine, along with TBI helps kill cancer cells in the body and helps prepare the body for the Tisa-cel infusion. Tisagenlecleucel is made using a patient's T cells (a type of immune system cell). A gene for a special receptor called chimeric antigen receptor (CAR) is added to the T cells in the laboratory. These changed T cells called CAR T cells are grown in large numbers in the laboratory and given to the patient by infusion. Tisa-cel binds to a protein called CD19, which is found on some leukemia and lymphoma cells. This helps the body's immune system kill cancer cells. Tisa-cel is a type of CAR T-cell therapy. Giving low dose TBI in combination with standard of care lymphodepletion therapy and Tisa-cel may be safe, tolerable, and/or effective in treating patients with relapsed or refractory (R/R) LBCL.
详细描述
PRIMARY OBJECTIVE:
I. To determine the safety and maximum tolerated dose (MTD) of total body irradiation (TBI) as lymphodepletion intensification for Tisa-cel in R/R large B-cell lymphoma.
SECONDARY OBJECTIVE:
I. To determine the efficacy, toxicity, and pharmacokinetics of Tisa-cel with intensified lymphodepletion by low dose TBI.
II. To compare pharmacokinetics of Tisa-cel with intensified to historic control from JULIET trial, provided by Novartis and Navigate.
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
- •Eligible for standard of care anti-CD19 CAR-T treatment with Tisa-cel
- •Age ≥ 18 years
- •Biopsy-confirmed relapsed or refractory large B-cell lymphoma after 2 lines of prior therapy
- •Qualitative CD19 expression by either immunohistochemistry (IHC) or flow cytometry
- •Measurable disease prior to lymphodepletion as determined by Lugano criteria
- •Non-RT bridging therapy allowed, but requires re-staging prior to lymphodepletion (LD) to confirm measurable disease
- •Adequate performance status Eastern Cooperative Oncology Group (ECOG) ≤ 2
- •Platelets above 75K
- •Hemoglobin above 8.0 g/dL without transfusion within 1 week
- •Absolute neutrophil count (ANC) above 1,000 without granulocyte colony-stimulating factor (G-CSF) within 1 week
- •Total bilirubin < 1.5 x upper limit of normal (ULN)
- •Alanine aminotransferase (ALT) =< 3 x ULN
- •Glomerular filtration rate (GFR) > 60 ml/min calculated by the Cockcroft - Gault formula
- •Oxygen saturation (SpO2) > 92% without supplemental oxygen
- •Ejection fraction more than 45%
- •Patients must have the ability to understand and the willingness to sign a written informed consent document
- •For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of < 1% per year during the treatment period and for at least 12 months after Tisa-cel and until CAR T-cells are no longer present by quantitative polymerase chain reaction (qPCR) on two consecutive tests
- •A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (< 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptive s that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices
- •The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
- •For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
- •With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 12 months after Tisa-cel infusion and until CAR T-cells are no longer present by qPCR on two consecutive tests. Men must refrain from donating sperm during this same period
- •With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 6 months after Tisa-cel infusion to avoid potential embryonal or fetal exposure. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
- •For patients with prior irradiation: the study radiation oncologist co-investigator will review the patient's prior history of radiation to confirm that the investigational low dose total body irradiation is feasible and safe to respect the maximum cumulative organ radiation exposure
排除标准
- •Active central nervous system (CNS) disease at screening or prior to lymphodepletion
- •Prior therapy with autologous or allogenic CAR-T or CAR-natural killer (NK) cell therapy
- •Prior anti-CD19 therapies (such as, but not limited to tafasitamab or loncastuximab)
- •Prior allogeneic stem cell transplant
- •Bridging therapy with radiation not allowed
- •Any contra-indications to receive low-dose TBI, standard of care lymphodepleting chemotherapy or Tisa-cel per treating physician
- •A minimum of 28 days must have elapsed between prior treatment with investigational agent(s) and start of lymphodepletion
- •Uncontrolled major medical problem as infections
- •Active malignancy, other than non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast). Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial (e.g. low Gleason score prostate cancer)
- •Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements
- •Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Women of childbearing potential must have a negative serum pregnancy test. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study
- •Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy
- •Active hepatitis B or C as indicated by serology (for details please refer to Novartis Leukapheresis Reference Manual version [v] 4)
- •Patients with history of clinically relevant CNS pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease
- •History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) with requirement of systemic immunosuppressive medication within 6 months
- •Live vaccines given in 28 days prior to lymphodepleting chemotherapy
- •Active substance use disorders
结局指标
主要结局
Dose-limiting toxicities
时间窗: Up to 30 days after infusion
Adverse events will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Cytokine release syndrome and immune effector cell associated neurotoxicity syndrome are graded using American Society for Transplantation and Cellular Therapy (ASTCT) Consensus grading.
Maximum tolerated dose or recommended phase 2 dose (RP2D)
时间窗: Up to 30 days after infusion
Will define the dose as the RP2D for which the isotonic estimate of the toxicity rate is closest to the targeted toxicity rate (i.e., 25%). If there is a tie, the higher dose level when the isotonic estimate is lower than the targeted toxicity rate; and will choose the lower dose level when the isotonic estimate is greater than the targeted toxicity rate.
次要结局
- Incidence of adverse events(Up to 1 year)
- Complete remission rate(At days 30 and 90 from tisagenlecleucel (Tisa-cel) infusion)
- Objective response rate(At 30 and 90 days and 6 months)
- Median duration of response(Up to 1 year)
- Progression-free survival(From Tisa-cel infusion to clinical progression or death as a result of any cause, assessed at 6 months and 1 year)
- Overall survival(From Tisa-cel infusion to death from any cause, assessed at 6 months and 1 year)
- Rate and grade of cytokine release syndrome(Within the first 30 days post-infusion)
- Rate and grade of immune effector cell associated neurotoxicity syndrome(Within the first 30 days post-infusion)
- Rates of grade IV cytopenias(At days 30 and 90 from Tisa-cel infusion)
研究者
Nathan Denlinger
Principal Investigator
Ohio State University Comprehensive Cancer Center