A Phase 1/1b Study of Autologous b7-h3 Chimeric Antigen Receptor t Cells (b7-h3.cd28z.Cart) in Children and Young Adults With Recurrent or Progressive Cns Neoplasms Expressing b7-h3 Target
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 70
- 试验地点
- 4
- 主要终点
- Manufacturing Success Rate of Autologous B7-H3.CD28Z CAR T Cells
研究概览
简要总结
The purpose of this research study is to test the safety and effectiveness of a cell therapy at different doses for children and young adults with recurrent or progressive brain tumors. Recurrent/recurred means a tumor that has gone away and then came back. This cell therapy is called B7- H3.CD28Z.CART, referred to as B7-H3 CAR T cells. B7-H3 is a protein that is over-expressed on many tumor cells, making it a good target for cancer cell therapy.
The names of the study investigational therapies involved in this study are:
- Fludarabine (a type of chemotherapy)
- Cyclophosphamide (a type of chemotherapy)
- B7-H3 CAR T cells (a type of cellular therapy)
详细描述
This is a single-institution, Phase 1/1b, open-label study to test the safety and effectiveness of a cell therapy at different doses for children and young adults with recurrent or progressive brain tumors. Recurrent/recurred means a tumor that has gone away and then came back. This cell therapy is called B7- H3.CD28Z.CART, referred to as B7-H3 CAR T cells. B7-H3 is a protein that is over-expressed on many tumor cells, making it a good target for cancer cell therapy.
The U.S. Food and Drug Administration (FDA) has not approved B7-H3 CAR T cells as a treatment for any disease.
Fludarabine and cyclophosphamide are standard lymphodepleting chemotherapy medications that are being used in this study to prepare the body for cell therapy. They are approved by the U.S. Food & Drug Administration (FDA) for this purpose and are not intended to be treatment for recurrent or progressive brain tumors.
The structure of the study will be by dose-escalation using a modified 3+3 design in two risk strata (standard risk, high risk), followed by a two-stage Phase 1b expansion at the recommended Phase 2 dose.
Participation in this study is expected to last up to 15 years.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Pre-screening Inclusion Criteria:
- •Participants must have histologically and/or molecularly confirmed CNS embryonal tumor (see eligible tumor types below), OR ependymoma that is recurrent/progressive following standard of care treatment.
- •-Eligible CNS embryonal tumor types include:
- •Medulloblastoma
- •Atypical Teratoid Rhabdoid Tumor (ATRT)
- •Embryonal Tumor with Multilayered Rosettes (ETMR) Pineoblastoma
- •Other CNS embryonal tumor types, at the discretion of the study chair (or designee)
- •Participants must have adequate pre-trial tumor material available to determine B7- H3 expression status. Tumor tissue from the most recent resection or biopsy of recurrent disease is preferred. If unavailable, tumor tissue from prior recurrences or from time of initial diagnosis is acceptable. Biopsies will not be performed for participation in this research trial or for research purposes.
- •Pre-screening IHC Consent: All participants ≥ 18 years of age must be able to give informed consent. For participants <18 years of age, their legal authorized representative (LAR) (i.e. parent or guardian) must give informed consent. Pediatric participants will be included in age-appropriate discussion and written assent will be obtained for those ≥10 years of age, where appropriate. If a minor becomes of age during participation of this study, they will be asked to reconsent as an adult.
- •Inclusion Criteria:
- •Participants must have histologically and/or molecularly confirmed CNS embryonal tumor (see eligible tumor types below), OR ependymoma that is recurrent/progressive following standard of care treatment.
- •-Eligible CNS embryonal tumor types include:
- •Medulloblastoma
- •Atypical Teratoid Rhabdoid Tumor (ATRT)
- •Embryonal Tumor with Multilayered Rosettes (ETMR)
- •Pineoblastoma
- •Other CNS embryonal tumor types, at the discretion of the study chair (or designee)
- •B7-H3 expression: Demonstration of B7-H3 expression with H score greater than 100 by immunohistochemistry (IHC) is required.
- •Age: greater than or equal to two (2) years of age and less than or equal to 21 years of age. The first participant treated at each dose level within each stratum (Standard Risk and High Risk) will be ≥ 6 years of age when feasible.
- •Disease status: Participants must have evaluable disease in the central nervous system to be eligible. Evaluable disease includes either measurable OR non-measurable disease, defined as follows:
- •-Measurable disease (contrast-enhancing or non-enhancing tumor)
- •Clearly defined lesional margins with two perpendicular diameters of at least 10mm, OR
- •At least two times (in both perpendicular diameters) the MRI slice thickness, plus the interslice gap
- •-Non-measurable disease (tumor that is too small to be accurately measured)
- •Lesion that is measurable in only one perpendicular dimension, OR
- •Lesion that is less than 10mm in at least one perpendicular dimension, OR
- •Lesion that is less than two times the MRI slice thickness, plus the interslice gap
- •Note: Leptomeningeal (LM) disease is considered non-measurable but evaluable.
- •Performance status: Karnofsky performance status ≥60% for participants ≥16 years of age and Lansky performance status ≥60% for participants <16 years of age (see APPENDIX A PERFORMANCE STATUS CRITERIA). NOTE: Participants with neurologic deficits must have a stable neurologic exam for seven (7) days prior to enrollment. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
- •Life expectancy of greater than 12 weeks
- •Prior therapy: Participants must have received prior standard of care therapy, including maximal safe surgical resection, radiation therapy and/or standard chemotherapy, and is recovered from all acute treatment-related toxicities (defined as ≤ Grade 1 or stable) from all prior therapy before entering this study There is no upper limit to the number of prior therapies allowed, but must have received all standard curative options for their tumor type.
- •Participants must meet the following washouts prior to enrollment:
- •Radiation therapy - Participants must have had their last fraction of:
- •--Craniospinal irradiation, whole brain radiation therapy, or radiation therapy to >50% of the pelvis or spine >28 days prior to enrollment
- •--Focal irradiation (small port) >14 days prior to enrollment
- •At least 14 days since any prior cytotoxic chemotherapy
- •At least 7 days since any biologic antineoplastics, tyrosine kinase inhibitor, targeted agent
- •At least 21 days or 5 half-lives (whichever is shorter) since any investigational antineoplastic or disease-directed agent (but at least 28 days from prior investigational antineoplastic vaccine therapy)
- •At least 21 days since any monoclonal antibody therapy
- •At least 90 days since any systemic inhibitor/stimulatory immune checkpoint therapy
- •At least 28 days from prior autologous stem cell transplantation, with no ongoing toxicities
- •At least 14 days after peg-filgrastim and 7 days for hematopoietic growth factor support
- •Steroid use: Must not require concurrent systemic steroid therapy, although physiologic corticosteroid replacement therapy for management of pituitary/adrenal insufficiency and/or topical administration (e.g. inhaled or dermatologic) is allowed. Use of topical, ocular, intranasal, or inhaled corticosteroids are permitted per PI
- •discretion.
- •Participants must have adequate organ function, as defined below
- •-Adequate bone marrow function
- •Hemoglobin ≥ 8 g/dL
- •Absolute neutrophil count (ANC) ≥ 1000 cells/uL
- •Absolute lymphocyte count (ALC) ≥ 150 cells/uL
- •Platelets ≥100,000/uL (unsupported, defined as no platelet transfusion within 4 days)
- 另有 20 项未显示
排除标准
- •Participants with bulky tumor are ineligible. Bulky tumor is defined as:
- •Tumor with diameter of >5cm in one dimension on T2/FLAIR sequence
- •Tumor with evidence of clinically significant midline shift or uncal herniation
- •Tumor that, in opinion of the site investigator, shows significant mass effect in either the brain or spine
- •Participants with clinical or radiological evidence of brain herniation.
- •Participants who have received other B7-H3 targeted cellular therapies. Other prior cellular therapies are eligible, including immune checkpoint inhibition and vaccine therapy. These prior therapies should be discussed with the study chair (or designee) prior to participant enrollment.
- •Concurrent illness
- •Participants with any prior immunodeficiency or history of autoimmune disease requiring systemic steroids/ immunosuppressive medication/ disease-modifying agents within the last two (2) years.
- •Uncontrolled (Grade 3) bacterial, viral, fungal, or other infection.
- •Ongoing infection with HIV or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive). A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing.
- •Evidence of severe or uncontrolled systemic disease (e.g. Grade 3 significant cardiac, pulmonary, hepatic, renal or other organ dysfunction) that in the judgement of the principal investigator is likely to interfere with assessment of safety or efficacy of the investigational regimen and its requirements.
- •Known sensitivity or allergy to any of the agents/reagents used in this study (i.e. DSMO, cyclophosphamide, fludarabine)
- •History of severe hypersensitivity reaction to compounds of similar chemical or biologic compositions to any agent used in the study or in the manufacturing of cells.
- •Concomitant medications
- •Current systemic corticosteroid therapy
- •Note, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency will be allowed.
- •Participants who are receiving any other anti-cancer or investigational drug therapy are ineligible.
- •Participants who have received the last vaccination of a live vaccine ≤ 30 days prior to the start of treatment are ineligible.
- •Ongoing use of dietary supplements, alternative therapies or extreme diets, or any medication not approved by the study chair (or designee).
- •Any other condition which in the principal investigator's opinion makes the individual clinically unsuitable to participate in this trial, or which would jeopardize compliance with the protocol, or would make it difficult to interpret adverse events or study data.
研究组 & 干预措施
Dose Expansion for B7-H3.CD28Z.CART in Standard Risk Stratum
Dose expansion will occur per dose-limiting toxicity rules.
- Baseline visit
- Apheresis to obtain T cells
- Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily
- Day 0: B7-H3 CAR T cell infusion 1x daily
- 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response
- Follow up every 3 months after last infusion up until 2 years
- Long term follow annually for an additional 13 years
干预措施: B7-H3.CD28Z.CART (Biological)
Dose Expansion for B7-H3.CD28Z.CART in Standard Risk Stratum
Dose expansion will occur per dose-limiting toxicity rules.
- Baseline visit
- Apheresis to obtain T cells
- Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily
- Day 0: B7-H3 CAR T cell infusion 1x daily
- 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response
- Follow up every 3 months after last infusion up until 2 years
- Long term follow annually for an additional 13 years
干预措施: Fludarabine (Drug)
Dose Escalation for B7-H3.CD28Z.CART in Standard Risk Stratum
Participants will be enrolled in a staggered, sequential fashion using a modified 3 + 3 dose escalation design, assigning participants to one of three intravenous dose levels to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of IV B7-H3.CD28Z.CART. Dose escalation will occur per dose-limiting toxicity rules.
- Baseline visit
- Apheresis to obtain T cells
- Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily
- Day 0: B7-H3 CAR T cell infusion 1x daily
- 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response
- Follow up every 3 months after last infusion up until 2 years
- Long term follow annually for an additional 13 years
干预措施: B7-H3.CD28Z.CART (Biological)
Dose Escalation for B7-H3.CD28Z.CART in Standard Risk Stratum
Participants will be enrolled in a staggered, sequential fashion using a modified 3 + 3 dose escalation design, assigning participants to one of three intravenous dose levels to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of IV B7-H3.CD28Z.CART. Dose escalation will occur per dose-limiting toxicity rules.
- Baseline visit
- Apheresis to obtain T cells
- Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily
- Day 0: B7-H3 CAR T cell infusion 1x daily
- 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response
- Follow up every 3 months after last infusion up until 2 years
- Long term follow annually for an additional 13 years
干预措施: Fludarabine (Drug)
Dose Escalation for B7-H3.CD28Z.CART in Standard Risk Stratum
Participants will be enrolled in a staggered, sequential fashion using a modified 3 + 3 dose escalation design, assigning participants to one of three intravenous dose levels to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of IV B7-H3.CD28Z.CART. Dose escalation will occur per dose-limiting toxicity rules.
- Baseline visit
- Apheresis to obtain T cells
- Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily
- Day 0: B7-H3 CAR T cell infusion 1x daily
- 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response
- Follow up every 3 months after last infusion up until 2 years
- Long term follow annually for an additional 13 years
干预措施: Cyclophosphamide (Drug)
Dose Escalation for B7-H3.CD28Z.CART in High Risk Stratum
Participants will be enrolled in a staggered, sequential fashion using a modified 3 + 3 dose escalation design, assigning participants to one of three intravenous dose levels to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of IV B7-H3.CD28Z.CART. Dose escalation will occur per dose-limiting toxicity rules.
- Baseline visit
- Apheresis to obtain T cells
- Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily
- Day 0: B7-H3 CAR T cell infusion 1x daily
- 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response
- Follow up every 3 months after last infusion up until 2 years
- Long term follow annually for an additional 13 years
干预措施: B7-H3.CD28Z.CART (Biological)
Dose Escalation for B7-H3.CD28Z.CART in High Risk Stratum
Participants will be enrolled in a staggered, sequential fashion using a modified 3 + 3 dose escalation design, assigning participants to one of three intravenous dose levels to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of IV B7-H3.CD28Z.CART. Dose escalation will occur per dose-limiting toxicity rules.
- Baseline visit
- Apheresis to obtain T cells
- Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily
- Day 0: B7-H3 CAR T cell infusion 1x daily
- 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response
- Follow up every 3 months after last infusion up until 2 years
- Long term follow annually for an additional 13 years
干预措施: Fludarabine (Drug)
Dose Escalation for B7-H3.CD28Z.CART in High Risk Stratum
Participants will be enrolled in a staggered, sequential fashion using a modified 3 + 3 dose escalation design, assigning participants to one of three intravenous dose levels to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of IV B7-H3.CD28Z.CART. Dose escalation will occur per dose-limiting toxicity rules.
- Baseline visit
- Apheresis to obtain T cells
- Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily
- Day 0: B7-H3 CAR T cell infusion 1x daily
- 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response
- Follow up every 3 months after last infusion up until 2 years
- Long term follow annually for an additional 13 years
干预措施: Cyclophosphamide (Drug)
Dose Expansion for B7-H3.CD28Z.CART in Standard Risk Stratum
Dose expansion will occur per dose-limiting toxicity rules.
- Baseline visit
- Apheresis to obtain T cells
- Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily
- Day 0: B7-H3 CAR T cell infusion 1x daily
- 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response
- Follow up every 3 months after last infusion up until 2 years
- Long term follow annually for an additional 13 years
干预措施: Cyclophosphamide (Drug)
Dose Expansion for B7-H3.CD28Z.CART in High Risk Stratum
Dose expansion will occur per dose-limiting toxicity rules.
- Baseline visit
- Apheresis to obtain T cells
- Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily
- Day 0: B7-H3 CAR T cell infusion 1x daily
- 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response
- Follow up every 3 months after last infusion up until 2 years
- Long term follow annually for an additional 13 years
干预措施: B7-H3.CD28Z.CART (Biological)
Dose Expansion for B7-H3.CD28Z.CART in High Risk Stratum
Dose expansion will occur per dose-limiting toxicity rules.
- Baseline visit
- Apheresis to obtain T cells
- Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily
- Day 0: B7-H3 CAR T cell infusion 1x daily
- 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response
- Follow up every 3 months after last infusion up until 2 years
- Long term follow annually for an additional 13 years
干预措施: Fludarabine (Drug)
Dose Expansion for B7-H3.CD28Z.CART in High Risk Stratum
Dose expansion will occur per dose-limiting toxicity rules.
- Baseline visit
- Apheresis to obtain T cells
- Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily
- Day 0: B7-H3 CAR T cell infusion 1x daily
- 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response
- Follow up every 3 months after last infusion up until 2 years
- Long term follow annually for an additional 13 years
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Manufacturing Success Rate of Autologous B7-H3.CD28Z CAR T Cells
时间窗: Participants will receive the CART cell infusion on Day 0.
Each participant's product will be tested for the following criteria: cell viability ≥ 70%; cell number within ± 20% of the planned dose; CD3+ T cells ≥ 80% of leukocytes; CAR-positive cells ≥ 10% of CD3+ T cells; endotoxin ≤ 5 EU/kg; mycoplasma not detected; vector copy number (VCN) per transduced cell ≤ 10; replication-competent retrovirus (RCR) not detected; and sterility confirmed as "No Growth to Date" (NGTD) after a minimum of 5 days in culture. A participant will be classified as a manufacturing success if the final product satisfies all release criteria. If any criterion is not met, the participant will be classified as a manufacturing failure. The manufacturing success rate is defined as the proportion of participants classified as a success.
Maximum Tolerated Dose (MTD) of B7-H3.CD28Z.CART Cells
时间窗: 28 days
The MTD is defined as the highest dose level of B7-H3.CD28Z.CART cells at which the rate of dose-limiting toxicity (DLT) is considered acceptable according to the modified 3+3 rules. Additional details are provided in Protocol Section 13.1. Definition of DLT is outlined in protocol. The definition of DLT uses NCI's Common Terminology Criteria for Adverse Events (CTCAEv6.0).
Recommended Phase 2 Dose (RP2D) of B7-H3.CD28Z.CART Cells
时间窗: 28 days
The recommended phase 2 dose (RP2D) is the dose of B7-H3.CD28Z.CAR T cells selected for Phase 2 based on Phase 1 results, considering safety, tolerability, manufacturing feasibility, and observed clinical activity, and may be at or below the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD).
次要结局
- Number of Participants Experience Dose-Limiting Toxicity (DLT) during Dose Escalation(28 years)
- Number of Participants Experience Dose-Limiting Toxicity (DLT) at Maximum Tolerated Dose (MTD) / Recommend Phase 2 Dose (RP2D)(28 days)
- Number of Participants with Two Additional ICV B7-H3.CD28Z.CAR T Infusions(From Day 0 (initial IV infusion) through Day 56 (third ICV infusion))
- Adverse Events of Special Interest (AESIs) Rate(From Day 0 (initial IV infusion) through Day 56 (third ICV infusion) plus a 28-day follow-up period, for a total of 74 days.)
- Complete Response Rate (CRR) at Day 28(Day 28)
- Partial Response Rate (PRR) at Day 28(Day 28)
- Stable Disease Rate (SDR) at Day 28(Day 28)
- 3 Month Complete Response Rate (CRR3)(3 months)
- 3 Month Partial Response Rate (PRR3)(3 months)
- 3 Month Stable Disease Rate (SDR3)(3 months)
- Best Overall Response Rate (BORR)(Treatment duration may be up to 224 days, and disease evaluations will be performed at Day 28 (±4 days), at Months 2 and 3 (±1 week), and every 3 months thereafter through Month 24 (±4 weeks) after the end of treatment.)
- Median Duration of Response (DOR)(Treatment duration may be up to 224 days, and disease evaluations will be performed at Day 28 (±4 days), at Months 2 and 3 (±1 week), and every 3 months thereafter through Month 24 (±4 weeks) after the end of treatment.)
- 2 Year Progression-Free Survival (PFS2)(2 years)
- Median Overall Survival (OS)(15 years)
研究者
Robbie Majzner
Sponsor-Investigator
Dana-Farber Cancer Institute