Ethical reflections on phase I clinical trials of anticancer drugs:from a Chinese IRB’s empirical perspective

Purpose With the rapid development of Phase I clinical trials for anticancer drugs in China,addressing ethical con-cerns is imperative.In order to safeguard the rights,interests,and well-being of research participants,this paper aims to illustrate vital ethical issues that should not be neglected by institutional review boards as well as other relevant stakeholders for Phase I clinical trials of anticancer drugs.Methods This study retrospectively collects documents on Phase I clinical trials for anticancer drugs that were sub-mitted to the Institutional Review Board at Zhejiang Cancer Hospital from 2021 to 2023.Based on Chinese and inter-national research regulations and guidelines,these documents,as well as initial and follow-up review resolutions,have been classified and analyzed.Results Given the additional risks of potentially toxic effects in Phase I clinical trials for anticancer drugs and the vul-nerability of participants enrolled with advanced cancer status,it is important to review investigator qualifica-tions,preliminary findings,research methods,inclusion and exclusion criteria in the protocol,as well as the validity and readability of informed consent.Additionally,attention should be given to follow-up reviews,particularly regard-ing safety reports and protocol deviations.Conclusion To effectively protect the rights,interests and safety of research participants.Relevant stakeholders,including sponsors,researchers,and regulatory bodies,should diligently evaluate potential risks and provision contin-gency plan to minimize the latent risk.

Nab-paclitaxel plus capecitabine as first-line treatment for advanced biliary tract cancers:An open-label,non-randomized,phase II clinical trial

BACKGROUND Biliary tract cancers(BTCs)are a heterogeneous group of tumors with high malignancy,poor prognosis,and limited treatment options.AIM To explore the efficacy and safety of nab-paclitaxel plus capecitabine as first-line treatment for advanced and metastatic BTCs.METHODS This open-label,non-randomized,double-center,phase II clinical trial recruited systemic therapy-naive patients with unresectable or metastatic BTCs between April 2019 and June 2022 at Beijing Cancer Hospital and the First Hospital of China Medical University.Eligible patients were administered nab-paclitaxel(150 mg/m^(2),day 1)and capecitabine(2000 mg/m^(2),twice daily,days 1-7)in 14-day cycles until experiencing intolerable toxicity or disease progression.The primary outcome was the objective response rate(ORR).The secondary outcomes included the disease control rate(DCR),overall survival(OS),progression-free survival(PFS),and safety.RESULTS A total of 44 patients successfully completed the trial,with a median age of 64.00 years(interquartile range,35.00-76.00),and 26(59.09%)were females.Tumor response assessment was impeded for one patient due to premature demise from tumor hemorrhage.Among the remaining 43 patients undergoing at least one imaging assessment,the ORR was 23.26%[95%confidence interval(CI):11.80%-38.60%],and the DCR was 69.77%(95%CI:53.90%-82.80%).The median OS was 14.1 months(95%CI:8.3-19.9),and the median PFS was 4.4 months(95%CI:2.5-6.3).A total of 41 patients(93.18%)experienced at least one adverse event(AE),with 10 patients(22.73%)encountering grade≥3 AEs,and the most frequent AEs of any grade were alopecia(79.50%),leukopenia(54.55%),neutropenia(52.27%),and liver dysfunction(40.91%),and no treatment-related deaths were documented.CONCLUSION Nab-paclitaxel plus capecitabine may be an effective and safe first-line treatment strategy for patients with advanced or metastatic BTCs.

Quality Management Model for Phase I Clinical Drug Trials:A Structural Equation Model

This study aimed to construct a quality management model for phase I clinical drug trials.A cross-sectional survey was conducted and data were collected from 604 respondents at 69 institutions in China engaged in phase I clinical drug trials.Exploratory and confirmatory factor analyses were used to develop the survey tool.Structural equation modeling was used to construct a quality management model for phase I clinical drug trials.The results showed that the final survey tool had good reliability and validity(Cronbach’sα=0.938,root mean square error of approximation=0.074,comparative fit index=0.962,and Tucker—Lewis index=0.955).The model included five dimensions:government regulation,industry management,medical institution management,research team management,and contract research organization(CRO)management.In total,22 measurement items were obtained.The structural equation model indicated government regulation,industry management,medical institution management,and CRO management significantly affected the quality of phase I clinical drug trials(β=0.195,β=0.331,β=0.279,andβ=−0.267,respectively;P<0.05).Research team management had no effect on the quality of trials(β=0.041,P=0.610).In conclusion,the model is valuable for identifying factors influencing phase I clinical drug trials and guiding quality management practices.

Specification of phase Ⅰ of new drugs' clinical tolerance trials

Phase Ⅰ of clinical trials is the first stage of clinical pharmacology and body safety evaluation,including body tolerance test and pharmacokinetics test.The aim is providing evidence for dosage regimen and be the cornerstone of the preliminary assessment of efficacy and safety of phase Ⅱ of clinical trials.This text discussed the technique and requirement of phase Ⅰ of new drugs' clinical tolerance trials.

Progress in phase III clinical trials of molecular targeted therapy and immunotherapy for glioblastoma

Glioblastoma(GBM)is the most common primary central nervous system tumor,whose prognosis remains poor under the sequential standard of care,such as neurosurgery followed by concurrent temozolomide radiochemotherapy and adjuvant temozolomide chemotherapy in the presence or absence of tumor treating fields.Accordingly,the advent of molecular targeted therapy and immunotherapy has opened a new era of tumor management.A diverse range of targeted drugs have been tested in patients with GBM in phase III clinical trials.However,these drugs are ineffective for all patients,as evidenced by the fact that only a minority of patients in these trials showed prolonged survival.Furthermore,there are several published phase III clinical trials that involve immune checkpoint inhibitors,peptide vaccines,dendritic cell vaccines,and virotherapy.Accordingly,this review comprehensively overviews existing studies of targeted drugs and immunotherapy for glioma and discusses the challenge and perspective of targeted drugs and immunotherapy for glioma to clarify future directions.

Human umbilical cord mesenchymal stem cells to treat spinal cord injury in the early chronic phase: study protocol for a prospective, multicenter, randomized, placebo-controlled, single-blinded clinical trial

Human umbilical cord mesenchymal stem cells(hUC-MSCs)support revascularization,inhibition of inflammation,regulation of apoptosis,and promotion of the release of beneficial factors.Thus,they are regarded as a promising candidate for the treatment of intractable spinal cord injury(SCI).Clinical studies on patients with early chronic SCI(from 2 months to 1 year post-injury),which is clinically common,are rare;therefore,we will conduct a prospective,multicenter,randomized,placebo-controlled,single-blinded clinical trial at the Third Affiliated Hospital of Sun Yat-sen University,West China Hospital of Sichuan University,and Shanghai East Hospital,Tongji University School of Medicine,China.The trial plans to recruit 66 early chronic SCI patients.Eligible patients will undergo randomization at a 2:1 ratio to two arms:the observation group and the control group.Subjects in the observation group will receive four intrathecal transplantations of stem cells,with a dosage of 1×106/kg,at one calendar month intervals.Subjects in the control group will receive intrathecal administrations of 10 mL sterile normal saline in place of the stem cell transplantations.Clinical safety will be assessed by the analysis of adverse events and laboratory tests.The American Spinal Injury Association(ASIA)total score will be the primary efficacy endpoint,and the secondary efficacy outcomes will be the following:ASIA impairment scale,International Association of Neural Restoration-Spinal Cord Injury Functional Rating Scale,muscle tension,electromyogram,cortical motor and cortical sensory evoked potentials,residual urine volume,magnetic resonance imaging–diffusion tensor imaging,T cell subtypes in serum,neurotrophic factors and inflammatory factors in both serum and cerebrospinal fluid.All evaluations will be performed at 1,3,6,and 12 months following the final intrathecal administration.During the entire study procedure,all adverse events will be reported as soon as they are noted.This trial is designed to evaluate the clinical safety and efficacy of subarachnoid transplantation of hUC-MSCs to treat early chronic SCI.Moreover,it will establish whether cytotherapy can ameliorate local hostile microenvironments,promote tracking fiber regeneration,and strengthen spinal conduction ability,thus improving overall motor,sensory,and micturition/defecation function in patients with early chronic SCI.This study was approved by the Stem Cell Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University,China(approval No.[2018]-02)on March 30,2018,and was registered with ClinicalTrials.gov(registration No.NCT03521323)on April 12,2018.The revised trial protocol(protocol version 4.0)was approved by the Stem Cell Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University,China(approval No.[2019]-10)on February 25,2019,and released on ClinicalTrials.gov on April 29,2019.

A Phase II Study of Antineoplastons A10 and AS2-1 in Children with High-Grade Glioma. Final Report (Protocol BT-06), and Review of Recent Trials

Standard treatment for high-grade glioma involves surgical resection followed by radiation therapy and temozolomide. Unfortunately, there are no standard treatment recommendations after recurrence and new therapies are needed for patients whose tumor recurs after first-line treatment. This single-arm, two-stage, interventional Phase II study evaluated the efficacy and safety of a combination of antineoplastons A10 and AS2-1. Nineteen patients were enrolled in the study (safety population), but fifteen patients with a median age of 9.4 years who met eligibility criteria were evaluated. The majority of subjects (12/15) were Caucasian and 8/15 (53%) were female. More than half (53%) of patients were diagnosed with glioblastoma and 33% with anaplastic astrocytoma. All patients had failed standard therapy including surgery, radiation, and chemotherapy. Antineoplastons were administered intravenously every four hours (median dose of A10 6.9 g/kg/d and AS2-1 0.30 g/kg/d) until objective response was documented and thereafter for a further 8 months. Clinical evaluations were performed every 8 weeks. All patients enrolled in the study were included in the safety analysis but only patients fulfilling the inclusion criteria were included in the efficacy evaluation. The duration of treatment with antineoplastons ranged from 2 weeks to 120 weeks. A complete response was documented in 2/15 (13%), partial response in 2/15 (13%), stable disease in 3/15 (20%). Progression-free survival at six months was 47% and overall survival (OS) at one year was 33.3%. One patient (6.7%) survived 10 years from treatment start. A small group of patients suffered reversible Grade 3 and 4 toxicities including hypernatremia 2/19 (11%) and decrease of neutrophils 1/19 (5%). There were no chronic toxicities. There was improvement of quality of life in patients who had objective response. It is concluded that antineoplastons show efficacy with an acceptable profile in this cohort of patients with recurrent high-grade glioma.

PHASE II CLINICAL TRIAL OF LASTET CAPSULE IN COMBINATION CHEMOTHERAPY OF MALIGNANT TUMORSIN CHINA

This study reports the efficacy of prolonged administration of oral etoposide in the treatment of 86 cases with solid tumor,malignant lymphoma and other cancer.The oral etoposide used was the Lastet capsule (Las-c).An overall response rate(RR)of 62.8% was achieved with CR rate being 23.3% and PR rate 39.5%. Different combination chemotherapy regimens led to different response rates but no significant difference was found. The Las-C containing regimens used in this study have not caused any serious side effects.

Clinical Trial Phases

Developers of drugs, biologicals, and medical devices must ensure product safety, demonstrate medical benefit in people, and mass produce the product. Preclinical development starts before clinical trials and the main goals are to determine safety and effectiveness of the intervention. If preclinical studies show that the therapy is safe and effective, clinical trials are started. Clinical trial phases are steps in the research to determine if an intervention would be beneficial or detrimental to humans and include Phases 0, I, II, III, IV, and V clinical studies. Understanding the basis of clinical trial phases will help researchers plan and implement clinical study protocols and, by doing so, improve the number of therapies coming to market for patients.

Toward phase 4 trials in heart failure: A social and corporate responsibility of the medical profession

Congestive heart failure(CHF) is a chronic condition, requiring polypharmacy, allied health supports and regular monitoring. All these factors are needed to ensure compliance and to deliver the positive outcomes demonstrated from randomized controlled trials. Unfortunately many centers around the world are unable to match trial level support. The outcomes for many communities are thus unclear. Research design factors in post-marketing surveillance to address this issue. Phase 4 studies is the name given to trials designed to obtain such community level data and thus address issues of external validity. CHF phase 4 studies are relatively underutilized. We feel the onus for this research lies with the health profession. In this commentary we provide arguments as to why phase 4 studies should be viewed as a social and corporate responsibility of health professional that care for clients with CHF.

FDA儿童药物临床试验规范化对我国的启示

对美国食品药品监督管理局(Food and Drug Administration,FDA)儿童药物临床试验的规范化进行界定,发现我国面临儿童用药方面存在安全隐患、儿童药物临床试验存在需求缺口、儿童药物临床试验审查不够规范等现实困境,引发规范儿童药物临床试验的关键性思考。借鉴FDA对儿童药物临床试验的规范化实践,总结FDA儿童药物临床试验相关法案、临床试验指南文件以及对伦理审查委员会的监管措施,得出完善儿童药物临床试验专门法规和指南、加强相关伦理委员会监管和指导、规范儿童药物临床试验伦理审查、加大儿童受试者保护力度等对我国的启示。

FDA与EMA关于化学药申请Ⅰ期临床试验相关药学质量文件要求简介

FDA与EMA先后颁布了关于临床试验申请申报资料技术要求的指导原则,本文主要介绍其中关于新药I期临床试验申请药学研究技术要求的相关内容,期望能对相关工作提供参考和借鉴,以加速我国创新药进入临床试验的时间。

FDA对药物基因组学早期临床研究的建议

药物基因组学是当前一个热点话题。FDA于2013年发布了"临床药物基因组学指导原则:早期临床研究的上市前评价和对说明书的建议",本文介绍其中第IV部分基因组学的临床评价。我国还没有类似的指导原则,期待本文对我国这方面的研究和监管有益。

基于FDA新版指南草案浅谈适应性设计的发展

在过去的二、三十年中,适应性设计一直是临床研究设计的热点。继2010年美国食品药品管理局(FDA)发布第一版适应性设计指南草案后,2018年9月FDA再次发布了第二版适应性设计指南草案:'Adaptive Designs for Clinical Trials of Drugs and Biologics Guidance for Industry'(以下简称'新版指南草案')。此次颁布的指南草案在2010年版的基础上增加了临床试验中适应性设计的原则、适应性设计的类型、与适应性设计有关的注意事项及主题,如适应性设计计划中的模拟问题、贝叶斯适应性设计以及终点考虑和安全性考虑等内容,为临床试验的研究者们提供了非常重要的蓝本。本文将基于该新版指南草案内容,同时结合国内外适应性设计的发展概况,对适应性设计类型等相关的问题进行浅析,以期为相关研究人员提供参考。

FDA警告信中关于研究者总体职责缺陷项的分析

目的:分析FDA警告信中研究者总体职责缺陷项的问题,为加强中国临床试验研究者充分履行其职责提出科学建议。方法:收集FDA警告信中关于'研究者总体职责'缺陷项的具体问题,进一步汇总和分析。结果:共检索2013-2017年发给研究者警告信38封,其中35封涉及缺陷项'研究者总体职责',具体问题归纳为14类。发生频次从高到低分别是违反入组或排除标准、未按方案给予药物或器械、漏做检查或评估、违反筛选流程、未按时报告不良事件或严重不良事件、主要研究者不尽责或不合理授权等。有4位研究者针对警告信回复采取措施,该措施被FDA认可,故有4项被终止。结论:FDA警告信中关于'研究者总体职责'缺陷项的问题,对我国临床试验的实施起到警示作用。建议药品监管部门加强信息透明度完善奖惩制度、加强培训提高研究者意识、授权合格的研究者并加强监督,从而进一步提高我国临床试验整体质量。

A Phase II Study of Antineoplastons A10 and AS2-1 in Adult Patients with Recurrent Glioblastoma Multiforme: Final Report (Protocol BT-21)

Treatment of recurrent glioblastoma multiforme (RGBM) creates one of the most difficult challenges to neuro-oncology. The purpose of this study is to evaluate the outcome of adults with high-grade glioma with special attention to RGBM patients treated with Antineoplastons (ANP) A10 and AS2-1 injections. The study was conducted according to Protocol BT-21, which accrued patients who failed standard radiation therapy (RT) and chemotherapy. There were 40 candidates registered in the study. Among the intent-to-treat (ITT) population, there were 30 cases of RGBM that progressed during and after prior treatment, 4 patients with anaplastic astrocytoma (AA), 1 with anaplastic mixed glioma (AMG), and 5 with persistent GBM. The aim of this paper is to evaluate the responses, survival and toxicity of all 40 patients, the efficacy in 30 patients with RGBM, and in 24 patients with RGBM who received at least 28 days of ANP (ERGBM). All RGBM patients were treated before with RT and chemotherapy, except one patient who only had surgery (patient refused radiation). In this group, 63% had one recurrence, 30% had two recurrences, and 7% had three recurrences. The median duration of ANP and ITT was 12 weeks and the median dosage of ANP A10 was 6.52 g/kg/d and ANP AS2-1 was 0.23 g/kg/d. Responses were assessed by gadolinium-enhanced magnetic resonance imaging (MRI) repeated every eight weeks. In the ITT population, objective responses (ORs) were determined in 10% of cases (complete response—CR, and partial response—PR in 5% each). Progression-free survival (PFS) in ITT at six months was 17.5%. Overall survival (OS) was 28.3% at one year, 2.6% at two years, five and ten years. In the RGBM population, objective responses (ORs) were determined in 13.3% of cases (CR and PR in 6.7% each). PFS in RGBM at six months was 16.7%. OS was 34.7% at one year, 3.47% at two years, five?and ten years. In the ERGBM population, ORs were determined in 16.7% of cases (CR and PR in?8.3% each). PFS in ERGBM at six months was 20.8%, OS was 39.3% at one year, 4.4% at two years, five and ten years. The treatment was well-tolerated with reversible Grades 3 and 4 toxicity in 17.5% of patients (7 patients who experienced multiple toxicities) and no chronic toxicity. In conclusion, the study reached efficacy endpoint. ANP is well-tolerated and compares favorably to the current treatment for RGBM.

Study protocol of the Asian XELIRI ProjecT(AXEPT):a multinational,randomized,non-inferiority,phase Ⅲ trial of second-line chemotherapy for metastatic colorectal cancer, comparing the eicacy and safety of XELIRI with or without bevacizumab versus FOLFIRI w

Background: Capecitabine and irinotecan combination therapy(XELIRI) has been examined at various dose levels to treat metastatic colorectal cancer(m CRC). Recently, in the Association of Medical Oncology of the German Cancer Society(AIO) 0604 trial, tri?weekly XELIRI plus bevacizumab, with reduced doses of irinotecan(200 mg/m^2 on day 1) and capecitabine(1600 mg/m^2 on days 1–14), repeated every 3 weeks, has shown favorable tolerability and eicacy which were comparable to those of capecitabine and oxaliplatin(XELOX) plus bevacizumab. The doses of capecit?abine and irinotecan in the AIO trial are considered optimal. In a phase I/II study, XELIRI plus bevacizumab(BIX) as second?line chemotherapy was well tolerated and had promising eicacy in Japanese patients.Methods: The Asian XELIRI Projec T(AXEPT) is an East Asian collaborative, open?labelled, randomized, phase Ⅲ clinical trial which was designed to demonstrate the non?inferiority of XELIRI with or without bevacizumab versus standard FOLFIRI(5?fluorouracil, leucovorin, and irinotecan combination) with or without bevacizumab as second?line chemo?therapy for patients with m CRC. Patients with 20 years of age or older, histologically conirmed m CRC, Eastern Coop?erative Oncology Group performance status 0–2, adequate organ function, and disease progression or intolerance of the irst?line regimen will be eligible. Patients will be randomized(1:1) to receive standard FOLFIRI with or with?out bevacizumab(5 mg/kg on day 1), repeated every 2 weeks(FOLIRI arm) or XELIRI with or without bevacizumab(7.5 mg/kg on day 1), repeated every 3 weeks(XELIRI arm). A total of 464 events were estimated as necessary to show non?inferiority with a power of 80% at a one?sided α of 0.025, requiring a target sample size of 600 patients. The 95% conidence interval(CI) upper limit of the hazard ratio was pre?speciied as less than 1.3.Conclusion: The Asian XELIRI Projec T is a multinational phase III trial being conducted to provide evidence for XELIRI with or without bevacizumab as a second?line treatment option of mCRC.

A Phase II Study of Antineoplastons A10 and AS2-1 in Children with Recurrent, Refractory or Progressive Primary Brain Tumors—Final Report (Protocol BT-22)

Primary malignant brain tumors are a leading cause of cancer-related death in children. This Phase II study evaluated the efficacy and safety of Antineoplastons A10 and AS2-1 (ANP) in children who developed progression during standard treatment. A total of 43 children were recruited to the study, but only 41 met eligibility criteria. There were twelve cases of glioblastoma multiforme (GBM), eight anaplastic astrocytomas (AA), twelve diffuse intrinsic pontine gliomas (DIPG), three supertentorial primitive neuroectodermal tumors (sPNET), three cases of medulloblastoma and one case each of anaplastic ependymoma (AE), atypical teratoid rhabdoid tumor (AT/RT), and disseminated pilocytic astrocytoma (PAD). ANP was administered intravenously daily every four hours (median dose of A10 8.74 g/kg/d and AS2-1 0.35 g/kg/d), until objective response (OR) was documented, and then a further eight months. All enrolled patients were included in safety, but only eligible patients in the efficacy evaluation. A total of 12.2% of patients obtained OR;2.4% complete response (CR) and 9.8% partial response (PR). Stable disease (SD) was determined in 17.1% and progressive disease (PD) in 43.9% of cases. There were 26.8% of nonevaluable (NE) cases due to premature discontinuation. Out of five OR cases, four patients were diagnosed with recurrent DIPG and one with recurrent AA. Median progression-free survival (PFS) was 2.5 months. Median overall survival was 4.8 months. OS at 6 months was 46.3%, one year was 12.2%, and 4.8% at two, five, and ten years. The longest survivor is a patient diagnosed with DIPG and gliosarcoma who remains alive more than 15 years. A group of eleven patients reported grade 3 and 4 toxicity including hypernatremia in eight cases, somnolence in two cases, and hypokalemia in one case. There were no chronic toxicities, and the quality of life was very good. The largest group of patients were represented by DIPG, GBM, and AA. The best results were obtained in the DIPG and AA groups. In the DIPG group, CR was in 8.3%, PR was 25%, median PFS was 4.8 months, median OS was 6.1 months, and OS at 6 months was 58.3%, at one year 25%, and 8.3% at two, five, and ten years. In the AA group, PR was 12.5%, median PFS was 3.7 months, median OS was 4.7 months, and OS at 6 months was 37.5%, and 12.5%, at one, two, five, and ten years. In conclusion, antineoplastons showed efficacy and acceptable toxicity in patients with recurrent, refractory or progressive primary brain tumors.

Multicenter phase Ⅱ trial of modified FOLFIRINOX in gemcitabine-refractory pancreatic cancer

AIM To evaluate the efficacy and safety of modified FOLFIRINOX as a second-line treatment for gemcitabine(GEM)-refractory unresectable pancreatic cancer(PC).METHODS This study was a prospective, multicenter, one-arm, open-label, phase Ⅱ trial. Patients with unresectable PC, who showed disease progression during GEMbased chemotherapy were enrolled. All patients were administered FOLFIRINOX with reduced irinotecan and oxaliplatin(RIO; irinotecan 120 mg/m^2 and oxaliplatin 60 mg/m^2), which was set according to the phase Ⅰ study of FOLFIRINOX. The objective response rate(ORR), disease control rate(DCR), progressionfree survival(PFS), overall survival(OS), adverse events were evaluated. Additionally, changes in quality of life(QoL) were assessed using a questionnaire on QoL.RESULTS Between August 2015 and May 2016, a total of 48 patients were enrolled. The median follow-up time was 259 d with a median of 8.5 cycles. The ORR and DCR were 18.8% and 62.5%, respectively, including one patient who showed complete remission. The median PFS was 5.8 mo [95% confidence interval(CI): 3.7-7.9] and median OS was 9.0 mo(95%CI: 6.4-11.6). Neutropenia(64.6%) was the most common grade 3-4 adverse event, followed by febrile neutropenia(16.7%). Although 14.6% of patients experienced grade 3 fatigue, most non-hematologic AEs were under grade 2. In the QoL analysis, the global health status score before treatment was not different from the score at the last visit after treatment(45.43 ± 22.88 vs 48.66 ± 24.14, P = 0.548).CONCLUSION FOLFIRINOX with RIO showed acceptable toxicity and promising efficacy for GEM-refractory unresectable PC. However, this treatment requires careful observation of treatment-related hematologic toxicities.

A Phase II Study of Antineoplastons A10 and AS2-1 in Patients with Brainstem Gliomas. The Report on Non-Diffuse Intrinsic Pontine Glioma (Protocol BT-11)

Inoperable brainstem gliomas (BSG) are among the most difficult to treat malignancies. In the intent-to-treat (ITT) population of the BT-11 study for BSG, forty patients (median age 11.2 years old) were enrolled. Antineoplastons A10 and AS2-1 (ANP) were administered intravenously daily. The median daily dose of A10 was 8.70 g/kg/day and AS2-1 was 0.32 g/kg/day. Efficacy analyses were conducted in two subgroups: recurrent pediatric diffuse intrinsic pontine glioma (RPDIPG, N?= 17) and non-diffuse intrinsic pontine glioma (NDIPG, N?= 11). This paper reports the results of the study of the efficacy and safety of ANP in patients with NDIPG. The results in the RPDIPG group were reported before;complete response (CR) was 6%, partial response (PR) 23.5%, and stable disease (SD) 17.6%. One year overall survival (OS) was 29.4%, 2 years 11.8%, and 5, 10, and 15 years 6%. In the NDIPG group, there were 36% CR and 27.5% SD. OS at 1, 5, 10, and 15 years was 82%, 73%, 62%, and 50% correspondingly. There was only one serious adverse event (9%) reported in NDIPG represented by hypokalemia, Grade 4. The results suggest that ANP shows efficacy and an acceptable tolerability profile in patients with RPDIPG and NDIPG.