Combination of an Anti-PD1 Antibody With Tisagenlecleucel Reinfusion in Children, Adolescents and Young Adults With Acute Lymphoblastic Leukemia After Loss of Persistence
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 26
- 试验地点
- 12
- 主要终点
- Efficacy assessed by Minimal residual disease (MRD) negative Complete remission (CR) and B cell aplasia.
研究概览
简要总结
Tisagenlecleucel (CTL019) is an anti-CD19 autologous Chimeric Antigen Receptor (CAR) T-cell therapy, which has shown dramatic early results in advanced ALLs. Early loss of B-cell aplasia (recovery of B-cells in marrow/ peripheral blood within 6 months after infusion), a marker of the loss or non-functionality of the CAR T-cells, is associated to a very high risk of relapse. A reinfusion of CTL019, even after Fludarabine-Cyclophosphamide reconditioning, frequently fails to induce further expansion as observed in UPENN studies and in the Robert Debré Hospital experience.
Non-persistence of CAR T-cells may be due to immune- mediated rejection or environment-mediated suppression of their growth. Evidence for increased PD-1 expression in CAR T-cells between infusion and peak expansion has been demonstrated in clinical samples.
Preclinical data and few clinical data support a role of PD- 1-PD-L1 blockade in improving the effectiveness of CAR T-cell therapy.
The objectives of this phase I/II study is to determine the safety, efficacy and feasibility of Nivolumab (Opdivo®)- an anti-PD1 treatment- combined to tisagenlecleucel in a cohort of relapsed or refractory B-ALL patients, aged 1-25 years old, previously treated by tisagenlecleucel (Kymriah®), with a demonstrated early loss of B-cell aplasia (within 6 months), a surrogate marker of the loss of CAR T-cells or their non- functionality.
More specifically, the main objectives are:
• In cohort 1 that includes patients with a MRD negative disease status combined to an early loss (within 6 months) of B-cell aplasia :
To determine the optimal starting time of Nivolumab (Opdivo®) in terms of safety and efficacy among 4 candidate time points (day 14, day 11, day 5, and day - 1).
• In cohort 2 that includes relapsed patients with an early loss (within 6 months) of B-cell aplasia :
To estimate the feasibility in terms of safety and efficacy of a very early start of nivolumab (day-1), prior to the reinfusion of tisagenlecleucel
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients aged from 1 to 25 years (pediatric and young adults) with a history of CD19+ relapsed or refractory B-ALL (any relapse after HSCT, 2nd relapse or later, refractory ALL).
- •Patient must have a second tisagenlecleucel (Kymriah ®) product available
- •Cohort 1: previously treated by tisagenlecleucel (Kymriah ®), and who present an early loss of B-cell aplasia defined by blood B lymphocytes < 10 /mm3 and/ or < 3% of total lymphocytes (< 6 months after infusion) while still being in CR with undetectable MRD
- •Cohort 2: previously treated by tisagenlecleucel (Kymriah ®), who present a loss of B-cell aplasia defined by blood B lymphocytes < 10 /mm3 and/ or < 3% of total lymphocytes and a CD19+ ALL detectable disease in the marrow and/or Blood
- •Life expectancy > 12 weeks.
- •Karnofsky (age > 16) Lansky (age < 16) > 70 at screening.
- •No organ dysfunction
- •Who have signed an informed consent
- •Affiliation to social security or any health insurance (as a beneficiary or assignee)
排除标准
- •Patient has received intervening therapy for leukemia after first tisagenlecleucel infusion (chemotherapy, anti leukemic immunotherapy, ITK, allogeneic HSCT).
- •Patient has an active autoimmune disease requiring systemic treatment within the past 2 years.
- •Patient has known history of, or any evidence of active, non-infectious pneumonitis.
- •Patient has a history of non-infectious pneumonitis that required steroid or has current pneumonitis.
- •Had receive prior therapy with an anti-PD1, Anti- PDL1 or anti-PDL2 agent.
- •Patient has hypersensivity to pembrolizumab/ nivolumab or one of its excipients
- •Patient has received a live vaccine injection within 45 days of planned start of study therapy.
- •Patients with concomitant genetic syndromes associated with bone marrow failure states: such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down syndrome will not be excluded.
- •Patients with Burkitt's lymphoma/leukemia
- •Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
- •Prior treatment with any gene therapy product except first tisagenlecleucel (Kymriah ®) injection.
- •Prior treatment with any anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy, except for patients pre-treated with blinatumomab and/or tisagenlecleucel (Kymriah®)
- •Prior anti-cancer monoclonal antibody within 4 weeks before starting the study.
- •Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade1 or at baseline) from adverse events due to a previously administered agent.
- •Active or latent hepatitis B or active hepatitis C (test within 8 weeks of Screening), or any uncontrolled infection at Screening.
- •Human immunodeficiency virus (HIV) positive test within 8 weeks of Screening.
- •Presence of grade 2 to 4 acute or extensive chronic GVHD.
- •Active CNS involvement by malignancy, defined as CNS-3 per NCCN guidelines. Note: Patients with history of CNS disease that has been effectively treated will be eligible.
- •Uncontrolled acute life threatening bacterial, viral or fungal infection at Screening.
- •Previous or concurrent malignancy with the following exceptions:
- •Adequately treated basal cell or squamous cell carcinoma
- •in situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study.
- •A primary malignancy completely resected and in CR for ≥ 5 years
- •Pregnant or lactating women (female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion)
- •Patient with hypersensivity to Fludarabine and/or cyclophosphamide and/or tisagenlecleucel and/or nivolumab or one of their excipients.
研究组 & 干预措施
Patients with MRD negative disease status: Time to Event Continual Reassessment Method (TITE-CRM)
干预措施: Decreasing starting times for beginning nivolumab (Time to Event Continual Reassessment Method (TITE-CRM) ) (Drug)
For relapsed patients
干预措施: Nivolumab starting at day -1 (Drug)
结局指标
主要结局
Efficacy assessed by Minimal residual disease (MRD) negative Complete remission (CR) and B cell aplasia.
时间窗: at 3 months
MRD negative CR is defined by undetectable disease at a 10-4 sensitivity threshold B cell aplasia is defined by blood B lymphocytes \< 10 /mm3 and/or \< 3% of total lymphocytes
Proportion of patients with limiting-toxicities
时间窗: at day 28
Limiting toxicities are defined by the occurrence of either - Related to CAR-T cells infusion: CRS or aGVH: limiting toxicity will be defined as toxicity ≥ 4 ICANs: limiting toxicity will be defined as toxicity ≥ 3 (excepted grade 3 seizure, ie focal, generalized seizure that resolves rapidly) - Related to nivolumab: immune related myocarditis, pneumonitis, encephalitis: limiting toxicity will be defined as toxicity ≥ 4
次要结局
- Incidence of Grade 3, 4 or 5 nivolumab-related adverse events(up to 2 years)
- Proportion of patients with Minimal residual disease(at 12 months)
- Incidence of B cell aplasia(at 6 months)
- Proportion of patients with Disease best response(up to three months)
- Overall survival(at 2 years)
- Proportion of patients with Complete remission(at 12 months)
- Incidence of GVHD(up to one year)
- Incidence of Grade 3 adverse events(up to 2 years)
- Increase of B cell aplasia duration compared to the previous one observed(up to 24 months)
- Event Free Survival (EFS)(at 2 years)