A Phase II Single Center Study Of Naxitamab , Granulocyte Macrophage Colony Stimulating Factor (GM CSF and Ifosfamide Carboplatin Etoposide) For Patients With Relapsed Refractory , Soft Tissue or Anti GD2 Immunotherapy Refractory Neuroblastoma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 47
- 试验地点
- 1
- 主要终点
- Clinical Benefit Rate (at the end of HITS treatment)
研究概览
简要总结
The purpose of this study is to evaluate safety and efficacy of naxitamab, granulocyte macrophage Colony Stimulating Factor (GM CSF) and Isofosfamide/Carboplatin/Etoposide (NICE) for Patients With Relapsed /Refractory, soft tissue or anti GD2 immunotherapy refractory Neuroblastoma
详细描述
The anti-GD2 monoclonal antibody Naxitamab (also known as hu3F8) in combination with macrophage colony-stimulating factor (GM-CSF) is currently under pivotal phase 3 investigation for the treatment of High-Risk Neuroblastoma Patients with Primary or Secondary Refractory Osteomedullary Disease.
A subset of patients with high-risk, resistant disease, i.e., relapsed or refractory Neuroblastoma with soft tissue involvement as measured by 123I-Meta-iodobenzylguanidine (MIBG), 18F-FDG avid or measurable computed tomography (CT)/ magnetic resonance imaging (MRI) tumors outside of the bone marrow, or disease refractory to Naxitamab in combination with GM-CSF has shown significant response rates to a chemoimmunotherapy combination of Naxitamab, GM-CSF, irinotecan and temozolomide (HITS- Hu3F8, irinotecan, temozolomide and sargramostim) (NCT03189706). Treatment is administered on an outpatient basis and toxicities include those expected from I/T (myelosuppression and diarrhea) as well as pain and hypertension expected with Naxitamab. No other greater than grade 2 related toxicities occurred in this study (n=46). Early responses, assessed after 2 cycles, were documented in 18 (39%) patients and here complete (n = 9), partial (n = 8), and mixed (n = 1) and 13 patients had stable disease. Responses were achieved in refractory (3/7;43%) and progressive disease (15/39;38%) subgroups, in patients who had previously received I/T (12/34;35%) and/or anti-GD2 MoAb (14/36;39%), and in soft tissue (6/22; 27%) MIBG-avid skeletal sites (20/36;56%) and on bone marrow histology (9/12;75%). While encouraging, new strategies are warranted to further treat resistant disease.
A high-dose combination of ifosfamide, carboplatin, and etoposide (ICE) has activity against Neuroblastoma without cross-resistance to widely used chemotherapy regimens.
Through compassionate use, 4 patients with progression of disease or refractory disease after HITS therapy, have been further treated with two cycles of a combination of naxitamab, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and ifosfamide/Carboplatin/Etoposide (NICE). The first patient showed a complete response.
Toxicity included G2 prolonged aplasia and G3 hypertension, both expected from the chemotherapy agents and hu3F8. One patient progressed after the 2 cycles and the other 2 showed stable disease, according to the revised (2017) International Neuroblastoma Response Criteria (INRC).
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 Months 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of neuroblastoma (NB) as defined per INRC as
- •histopathology of tumor biopsy, or
- •BM aspirate or biopsy indicative of NB by histology plus high blood or urine catecholamine metabolite levels or MYCN amplification, or
- •Fluorodeoxyglucose (FDG), MIBG avid lesion(s)
- •High-risk NB as defined as any of the following:
- •Stage 4 with MYCN amplification
- •Stage 4 without MYC amplification >1.5 y of age
- •Stage 3 with MYCN amplification
- •Relapsed/refractory Neuroblastoma with
- •Evidence of soft tissue disease or
- •Progessive disease/incomplete response/relapsed to previous treatment with Naxitamab plus GM-CSF
- •Prior treatment with murine and hu3F8 is allowed
- •Prior treatment with irinotecan or temozolomide or ICE is permitted
- •Evaluable (microscopic marrow metastasis, elevated tumor markers, positive MIBG or PET scans) or measurable (CT, MRI) disease documented after completion of prior systemic therapy
- •Age ≥18 months
- •Acceptable hematological status defined as:
- •Hemoglobin ≥8 g/dL (5.0 mmol/L)
- •White blood cell count ≥1000/μL
- •Absolute Neutrophil Count (ANC) ≥500/μL
- •Platelet count ≥50,000/μL
- •Acceptable liver function defined as:
- •alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 times Upper Limit of Normal (ULN)
- •Bilirubin ≤1.5 x ULN
- •Acceptable kidney function defined as:
- •a. estimated Glomerular Filtration Rate (eGFR) >60 mL/min/1.73 m2 calculated by the 2009 revised Bedside Schwartz Equation
- •Written informed consent from legal guardian(s) and/or patient in accordance with local regulations. Children must provide assent as required by local regulations (≥ 12 years old).
排除标准
- •Existing major organ dysfunction > grade 2, with the exception of hearing loss and hematologic toxicity (defined as suppression of all subtypes of WBCs, RBCs, and platelets).
- •Active life-threatening infection.
- •Pregnant women or women who are breast-feeding.
- •Inability to comply with protocol requirements, including genetic studies.
- •History of allergy to GM-CSF ≥ G4 (Common Terminology Criteria for Adverse Events- CTCAE) or does not respond to treatment.
- •Absolute Neutrophil Count (ANC) < 500/uL .
- •Platelet count <50,000/uL.
- •Patients with relapsed/refractory Neuroblastoma with solely bone marrow/bone involvement. Only patients with B/BM compartiment disease who show progressive disease/incomplete response/relapsed to previous treatment with Naxitamab plus GM-CSF may be eligible (inclusion critèrium #3).
研究组 & 干预措施
Arm 1
Treatment involves 2 cycles of HITS: hu3F8, irinotecan, temozolomide, and GM-CSF. Irinotecan and temozolomide are given for 5 days, and hu3F8 and GM-CSF on specific days.
Following this, 5 cycles of Naxitamab + GM-CSF are administered. Patients without a response receive NICE: hu3F8, GM-CSF, carboplatin, ifosfamide, and etoposide for 4 cycles.
Patients with a complete response (CR) move to Naxitamab consolidation (5 cycles). This involves GM-CSF before and after, and hu3F8 on days 1, 3, and 5.
Those with less than CR undergo 2 more NICE cycles, evaluated after the 4th. Lack of response leads to removal from the study.
干预措施: HITS (Drug)
Arm 1
Treatment involves 2 cycles of HITS: hu3F8, irinotecan, temozolomide, and GM-CSF. Irinotecan and temozolomide are given for 5 days, and hu3F8 and GM-CSF on specific days.
Following this, 5 cycles of Naxitamab + GM-CSF are administered. Patients without a response receive NICE: hu3F8, GM-CSF, carboplatin, ifosfamide, and etoposide for 4 cycles.
Patients with a complete response (CR) move to Naxitamab consolidation (5 cycles). This involves GM-CSF before and after, and hu3F8 on days 1, 3, and 5.
Those with less than CR undergo 2 more NICE cycles, evaluated after the 4th. Lack of response leads to removal from the study.
干预措施: Naxitamab + GM-CSF cycles (Drug)
Arm 1
Treatment involves 2 cycles of HITS: hu3F8, irinotecan, temozolomide, and GM-CSF. Irinotecan and temozolomide are given for 5 days, and hu3F8 and GM-CSF on specific days.
Following this, 5 cycles of Naxitamab + GM-CSF are administered. Patients without a response receive NICE: hu3F8, GM-CSF, carboplatin, ifosfamide, and etoposide for 4 cycles.
Patients with a complete response (CR) move to Naxitamab consolidation (5 cycles). This involves GM-CSF before and after, and hu3F8 on days 1, 3, and 5.
Those with less than CR undergo 2 more NICE cycles, evaluated after the 4th. Lack of response leads to removal from the study.
干预措施: NICE (Drug)
结局指标
主要结局
Clinical Benefit Rate (at the end of HITS treatment)
时间窗: From first day of treatment with HITS until completion of HITS (39 days).
Clinical Benefit Rate is defined as the proportion of patients with Best Overall Response of CR (complete response) or PR (partial response) or SD (stable disease) ≥ 24 w
Number of Participants with Serious and Non-Serious Adverse Events
时间窗: 14 months after ICF signature
The safety and tolerability of the treatment will be determined by means of type, incidence, severity, timing, seriousness, and relatedness of reported AEs, physical examinations, and laboratory tests. Toxicity will be graded and tabulated by the NCI CTCA E v 5 .0
Best Overall Response (at the end of NICE treatment)
时间窗: From first day of treatment with NICE until completion of NICE (39 days).
Best Overall Response is defined as the best response recorded from the start of the study treatment
Objective Response Rate (at the end of NICE treatment)
时间窗: From first day of treatment with NICE until completion of NICE (39 days).
Objective Response Rate is defined as the proportion of patients with Best Overall Response of CR (complete response) or PR (partial response).
Best Overall Response (at the end of HITS treatment)
时间窗: From first day of treatment with HITS until completion of HITS (39 days).
Best Overall Response is defined as the best response recorded from the start of the study treatment
Objective Response Rate (at the end of HITS treatment)
时间窗: From first day of treatment with HITS until completion of HITS (39 days).
Objective Response Rate is defined as the proportion of patients with Best Overall Response of CR (complete response) or PR (partial response).
Best Overall Response of Complete Response (CR) (at the end of NICE treatment)
时间窗: From first day of treatment with NICE until completion of NICE (39 days).
The number and proportion of patients with CR as Best Overall Response at the end of NICE treatment
Best Overall Response of Complete Response (CR) (at the end of HITS treatment)
时间窗: From first day of treatment with HITS until completion of HITS(39 days).
The number and proportion of patients with CR as Best Overall Response at the end of HITS treatment
Clinical Benefit Rate (at the end of NICE treatment)
时间窗: From first day of treatment with NICE until completion of NICE (39 days).
Clinical Benefit Rate is defined as the proportion of patients with Best Overall Response of CR (complete response) or PR (partial response) or SD (stable disease) ≥ 24 w
次要结局
- To measure MRD after HITS(From first day of treatment with HITS until completion of HITS (39 days).)
- To evaluate serum cytokines in patients receiving NICE(From first day of treatment with NICE, until day 11 post administration.)
- To measure MRD after NICE(From first day of treatment with NICE until completion of NICE (39 days).)