MATCHPOINT - Medulloblastoma Adoptive T Cell Therapy, DC Vaccines, and Hematopoietic Stem Cells Combined With Immune checkPOINT Blockade
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 12
- 试验地点
- 3
- 主要终点
- Number of participants with immunotherapy-related dose-limiting toxicities after treatment with TTRNA-DCs, TTRNA-xALT and HSCs plus PD1 blockade
研究概览
简要总结
This is a pilot study in a small number of children and young adults with suspected recurrent/progressive medulloblastoma (MB) looking at the feasibility and safety of adoptive cell therapy plus PD-1 blockade.
详细描述
This is a multi-site, single arm, unblinded, uncontrolled pilot study to evaluate the feasibility and safety of ACT + PD-1 blockade in children and young adults with suspected recurrence/progression of Group 3 or 4 (non-SHH/non-WNT) medulloblastoma since completion of definitive focal +/- craniospinal irradiation who are a candidate for surgical resection or biopsy.
After a screening consent is obtained, subjects will undergo standard of care resection for tumor debulking or biopsy for confirmatory diagnosis of disease progression. Tumor tissue will be collected during surgery for tumor debulking or biopsy for total tumor RNA and generation of investigational DC vaccine in parallel. Following biopsy and confirmatory pathologic diagnosis of recurrent MB, patients will be enrolled in the treatment phase of the trial.
After surgery, patients will undergo a mobilized pheresis to collect PBMCs for DC generation and CD34+ HSCs. Amplified tumor RNA obtained from surgically resected or biopsied specimens will be used to generate total tumor RNA-pulsed DCs (TTRNA-DCs) manufactured while patients initiate post-surgical salvage chemotherapy regimen.
Salvage therapy prescribed by treating neuro-oncologist will initiate 1-2 weeks after G-CSF mobilized leukapheresis for 1-3 cycles after which, treatment cycles will be paused, and the patients will receive 3 priming TTRNA-DCs vaccines bi-weekly and undergo a non-mobilized leukapheresis to collect vaccine-boosted lymphocytes for ex vivo T cell expansion and generation of additional TTRNA-DC vaccines. Treatment with salvage therapy will resume with monthly TTRNA-DC vaccines for an additional 1-3 cycles until ex vivo expanded T cells are manufactured and released from the UF cGMP facility.
For ACT, patients will undergo non-myeloablative conditioning with cyclophosphamide/fludarabine followed by infusion of ex vivo expanded tumor-reactive lymphocytes at 3 x 108 cells/Kg, infusion of autologous CD34+ HSCs (targeted dose of 2 x 106 CD34+ HSCs/Kg), PD-1 blockade and three biweekly intradermal TTRNA-DC vaccines to boost T cell engraftment and expansion.
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
- 4 Years 至 30 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Children and young adults ages 4-30 years with suspected recurrence/progression of Group 3 or 4 (non-SHH/non-WNT) MB since completion of definitive focal +/- craniospinal irradiation who are a candidate for surgical resection or biopsy. Of the 6 evaluable subjects, a minimum of 3 slots must be reserved for patients with confirmed Group 4 MB. Patients who are unable to receive radiation therapy due to genetic disorders that put them at significant risk for radiation-induced secondary malignancies (i.e. Gorlin's syndrome or NF1 mutation) are eligible for enrollment at first disease recurrence/progression.
- •Patients must currently be prescribed and approved to receive pembrolizumab therapy (patients who have progressed on anti-PD-1 targeting therapy but are otherwise eligible may be enrolled to receive combination with immunotherapy. Patients who have been previously treated with anti-PD-1 targeting therapy alone or in combination with other agents and discontinued for reasons other than toxicity may be enrolled).
- •Must be a candidate for surgery/biopsy Or tumor tissue obtained clinically, has been previously stored in a qualified site in a manner suitable for tumor RNA extraction and amplification and sample is made available to the PI.
- •Karnofsky or Lansky Performance Status (KPS) ≥ 60% (KPS for > 16 years of age) or Lansky performance Score (LPS) of ≥ 60 (LPS for < 16 years of age)
- •Adequate bone marrow and organ function as defined below:
- •ANC ≥ 1,000/mcL (unsupported)
- •Platelets ≥ 100,000/mcL (unsupported for at least 3 days)
- •Hemoglobin ≥ 9 g/dL (may be supported)
- •Serum creatinine ≤ 1.5 x IULN OR Creatinine clearance by Cockcroft-Gault ≥ 60 mL/min for patients with serum creatinine > 1.5 x IULN
- •Serum total bilirubin ≤ 1.5 x IULN for age OR Direct bilirubin ≤ IULN for patients with total bilirubin > 1.5 x IULN for age
- •AST (SGOT) and ALT (SGPT) ≤ 3 x IULN for age
- •Cardiac shortening fraction ≥27% or LVEF ≥50% by echocardiogram
- •Adequate pulmonary function defined as baseline pulse oximetry of ≥92% on room air
- •For females of childbearing potential, negative serum pregnancy test at enrollment
- •For women of childbearing potential (WOCBP) must be willing to use acceptable contraceptive methods to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug.
- •or For males with female partners of childbearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 24 weeks following the last dose of study drug.
- •Signed informed consent by patient and/or legally authorized representative
排除标准
- •this study:
- •Prior discontinuation of PD-1 inhibitor treatment due to toxicity.
- •Corticosteroids equivalent to ≥ 4mg dexamethasone daily.
- •Known HIV, Hepatitis B, or Hepatitis C seropositive.
- •Known active infection or immunosuppressive disease.
- •Known autoimmune disease requiring medical management with immunosuppressant.
- •Pregnancy or lactation, due to possible adverse effects on the developing fetus or infant.
- •Treatment with another investigational drug or other intervention within 30 days prior to projected first dose of study treatment (Priming phase with TTRNA-DC).
- •Known severe, active co-morbidity, defined as follows:
- •Unstable angina and/or congestive heart failure requiring hospitalization.
- •Transmural myocardial infarction within the last 6 months.
- •Acute bacterial or fungal infection requiring intravenous antibiotics at time of enrollment.
- •Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy.
- •Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects.
- •Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive.
- •Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy.
研究组 & 干预措施
Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab
ACT + PD-1 blockade consists of the intravenous delivery of ex vivo expanded tumor-reactive lymphocytes and autologous hematopoietic stem cells (HSCs) with concomitant tumor RNA-pulsed DC vaccines followed by intravenous delivery of PD-1 blocking antibodies.
干预措施: TTRNA-DC vaccines with GM-CSF (Biological)
Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab
ACT + PD-1 blockade consists of the intravenous delivery of ex vivo expanded tumor-reactive lymphocytes and autologous hematopoietic stem cells (HSCs) with concomitant tumor RNA-pulsed DC vaccines followed by intravenous delivery of PD-1 blocking antibodies.
干预措施: Td vaccine (Drug)
Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab
ACT + PD-1 blockade consists of the intravenous delivery of ex vivo expanded tumor-reactive lymphocytes and autologous hematopoietic stem cells (HSCs) with concomitant tumor RNA-pulsed DC vaccines followed by intravenous delivery of PD-1 blocking antibodies.
干预措施: autologous HSCs (Biological)
Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab
ACT + PD-1 blockade consists of the intravenous delivery of ex vivo expanded tumor-reactive lymphocytes and autologous hematopoietic stem cells (HSCs) with concomitant tumor RNA-pulsed DC vaccines followed by intravenous delivery of PD-1 blocking antibodies.
干预措施: TTRNA-xALT (Biological)
Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab
ACT + PD-1 blockade consists of the intravenous delivery of ex vivo expanded tumor-reactive lymphocytes and autologous hematopoietic stem cells (HSCs) with concomitant tumor RNA-pulsed DC vaccines followed by intravenous delivery of PD-1 blocking antibodies.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Number of participants with immunotherapy-related dose-limiting toxicities after treatment with TTRNA-DCs, TTRNA-xALT and HSCs plus PD1 blockade
时间窗: enrollment to completion of DLT window; up to 12 months
Number of subjects with immunotherapy-related dose-limiting toxicities including 1) Grade III or greater non-neurologic toxicity; 2) Grade III neurologic toxicity that does not improve to Grade II or better within 5 days; or 3) Grade IV neurologic toxicity. For the purposes of evaluating the safety of ACT combined with PD-1 blockade, dose limiting toxicities will be assessed during the period beginning with administration of ex vivo expanded tumor-reactive (TTRNA- xALT) through 2 weeks post TTRNA -DC vaccine #9. Safety will be defined as \< 1 DLT out of six enrolled and treated subjects.
Number of enrolled participants who receive qualified immunotherapy products out of the total number of participants enrolled.
时间窗: enrollment up to 12 months
Feasibility will be defined as capacity to enroll, manufacture, and administer qualified immunotherapy products (TTRNA-DCs, TTRNA-xALT and HSCs) to at least 66.7% of enrolled subjects.
次要结局
未报告次要终点