Accelerator-based Boron Neutron Capture Therapy (BNCT) in the Treatment of Locally Recurrent Head and Neck Carcinoma: A Phase I Study.
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
研究概览
简要总结
This phase I study of an accelerator-based boron neutron capture therapy (BNCT) in the treatment of locally recurrent head and neck carcinoma, is sponsored by HUS, Haartmaninkatu 4, Helsinki, Finland and Neutron Therapeutics Finland OY, Kanavaranta 9 FIN-00290 Helsinki.
The indication is for patients with head and neck carcinoma that has recurred locally after conventional radiation therapy.
The primary objective is to demonstrate the safety of accelerator-based neutron radiation using the nuBeam Suite in delivering BNCT.
The secondary objective is the ability to deliver the planned radiation dose to the target site and the ability to plan the trial treatment using the trial treatment planning software, position and target the tumor site using the robotic table in conjunction with the CT scanner and calculate the required radiation dose for each planned BNCT trial treatment.
To establish these objectives, the following parameters will be controlled:
- Objective response rate
- Duration of response.
- The clinical benefit rate (includes complete response, partial response, and stabilized disease for a minimum of 8 weeks since the date of the first BNCT).
- Locoregional recurrence-free survival.
- Progression-free survival.
- Overall survival.
- Quality of life.
The maximum sample size is 10 study subjects evaluable for safety.
The study does not involve randomization.
Regarding the target population, the study subjects must fulfill each of the inclusion criteria:
- Patient has provided a written informed consent as approved by the EC prior to study specific screening procedures, with the understanding that the patient has the right to withdraw from the study at any time, without prejudice.
- ≥ 18 years of age at the time of enrollment.
- Histologically confirmed head and neck carcinoma.
- Inoperable cancer, prior surgery may or may not have been done.
- Prior radiotherapy or chemoradiotherapy has been given.
- Anticipated life expectancy of at least 6 months
Patients who fulfill any of the following criteria will be excluded:
- Presence of distant metastases.
- World Health Organization (WHO) performance status > 2
- Concurrent uncontrolled localized cancer other than head and neck carcinoma or overtly metastatic cancer.
- The patient has access to a non-experimental, effective treatment option and is a suitable candidate for such therapy.
- Concomitant chemotherapy.
- Concurrent experimental therapy or participation in a trial with an experimental therapy within 3 months prior to study inclusion.
- Less than 3 months since prior radiation therapy.
- Major surgery within 4 weeks prior to study inclusion.
- Unremovable metal implants present in the head and neck region that will interfere with CT/MRI-based dose-planning.
- Known sensitivity to the study drug.
- One or more of the following:
- Blood hemoglobin < 100 g/L, neutrophils < 1.5 x 109/L, platelet count < 120 x 109/L
- Serum/plasma creatinine > 1.5 x Upper Limit of Normal (ULN)
- Serum bilirubin 2.0 > ULN
- Serum ALT and/or AST > 2.0 x ULN
- Serum alkaline phosphatase > 2.5 x ULN
- Serious uncontrolled infection or other serious uncontrolled concomitant disease.
- Collagen vascular disease or a disease that is considered to increase radiosensitivity of normal tissues to radiation (e.g., ataxia-telangiectasia)
- Patient is unwilling or unable to comply with the CIP required follow-up visits for the duration of the study.
- Untreated or severe treated congestive heart failure, cardiac pacemaker, or renal failure.
- Restlessness or inability to lie in a cast for about 30 minutes.
- Clinical follow-up after therapy cannot be arranged or the patient is not willing to participate in the follow-up.
- Known pregnancy, breastfeeding, or planning of pregnancy; for women of childbearing potential, a negative pregnancy test must be obtained prior to enrollment.
- The patient is not able to understand the nature of the study and trial treatment options.
- Phenylketonuria
- Fructose intolerance.
There is one investigational device included as part of this study. The nuBeam Suite has two main components, the Treatment Delivery System and the nuBeam Dose Engine.
The study drug included in this study is L-boronophenylalanine fructose (L-BPA Fructose)
详细描述
CLINICAL STUDY BACKGROUND AND RATIONALE
Disease Background and Unmet Clinical Need Head and neck carcinoma accounts for about 5% of all cancers and is the sixth most common type of cancer in humans. More than 650,000 new cases are detected annually worldwide, leading to more than 350,000 deaths. Head and neck carcinoma comprise carcinomas located in the oral cavity, the nasopharynx, the oropharynx, the hypopharynx, the larynx, the paranasal sinuses, and the salivary glands. Some carcinomas are related to smoking or alcohol abuse, but an increasing proportion of oropharynx and tonsil carcinomas, in particular, are related to human papilloma virus (HPV) infection. Cancer HPV status is often determined with immunohistochemistry from the cancerous tissue by demonstrating positive immunostaining for p16, an inhibitor of cyclin-dependent kinases 4 and 6. p16 is upregulated in HPV-infected tissues with inactivated retinoblastoma protein. Nasopharynx carcinomas are also frequently associated with oncogenic viruses.
Most patients with head and neck carcinomas have squamous cell carcinoma of the head and neck (HNSCC), and present with locally advanced stage disease. Several factors need to be considered when selecting for the trial treatment, including the primary tumor size and location, presence of metastases, the histological type and histological features of cancer, depth of cancer invasion, patient performance status and comorbidities, and whether cancer is HPV infection related or not. In general, early carcinomas may be treated with a single treatment modality, whereas advanced carcinomas require a multimodality approach for achieving optimal outcomes. Surgery and radiation therapy are the mainstay of locoregional treatment. Radiation therapy is often given concomitantly with certain chemotherapy agents, notably platin salts, to improve efficacy. Precision radiotherapy, such as intensity modulated radiotherapy (IMRT), reduces some adverse effects including xerostomia, and improves locoregional cancer control. New radiotherapy techniques such stereotactic ablative radiotherapy (SABR) and proton therapy are under active evaluation.
Although substantial advances have been made in the treatment of HNSCC, still 20% to 50% of the patients treated with chemoradiotherapy for unresectable HNSCC have locoregional cancer recurrence. Distant metastases are not uncommon, and survival outcomes remain relatively poor also in locally advanced disease. The overall long-term survival of patients with head and neck carcinoma is about 50% but varies greatly depending on factors such as tumor size, site, and the histological type.
Locoregionally recurrent HNSCC is usually treated with surgery, radiation therapy, and/or systemic therapy. The preferred option for operable patients is salvage surgery, which leads to 5-year survival up to 40%. Many recurrent cancers are, however, considered inoperable, or surgery is anticipated to lead to substantial morbidity. Reirradiation is an option for selected. The reported survival outcomes vary depending on patient selection and the techniques used with 2-year overall survival ranging from 10% to 35%. Cumulative doses greater than 60 Gy are usually recommended for reirradiation despite the relative high frequency of severe adverse events associated with such treatments. In recent years, a growing body of literature has reported on the safety and feasibility of hypofractionated radiotherapy for tumors of the head and neck. Most of these series include patients with recurrent, unresectable head and neck carcinomas who had been previously irradiated. These studies have found promising overall response rates up to 80% and 1-year local control rates in the range of 50% Chemotherapy with or without an agent targeted for the epidermal growth factor receptor (EGFR, HER1) has moderate efficacy, but is not considered curative if administered alone. Some patients respond to immune therapy obtaining clinically meaningful objective responses.
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 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The patient considered for the study has provided a written informed consent as approved by the EC prior to study specific screening procedures, with the understanding that the patient has the right to withdraw from the study at any time, without prejudice.
- •≥ 18 years of age at the time of enrollment.
- •Histologically confirmed head and neck carcinoma.
- •Inoperable cancer, prior surgery may or may not have been done.
- •Prior radiotherapy or chemoradiotherapy has been given.
- •Anticipated life expectancy of at least 6 months.
排除标准
- •Patients who fulfill any of the following criteria will be excluded:
- •Presence of distant metastases.
- •World Health Organization (WHO) performance status > 2 (see Appendix 2).
- •Concurrent uncontrolled localized cancer other than head and neck carcinoma or overtly metastatic cancer.
- •The patient has access to a non-experimental, effective treatment option and is a suitable candidate for such therapy.
- •Concomitant chemotherapy.
- •Concurrent experimental therapy or participation in a trial with an experimental therapy within 3 months prior to study inclusion.
- •Less than 3 months since prior radiation therapy.
- •Major surgery within 4 weeks prior to study inclusion.
- •Unremovable metal implants present in the head and neck region that will interfere with CT/MRI-based dose-planning.
- •Known sensitivity to the study drug.
- •One or more of the following:
- •Blood hemoglobin < 100 g/L, neutrophils < 1.5 x 109/L, platelet count < 120 x 109/L
- •Serum/plasma creatinine > 1.5 x Upper Limit of Normal (ULN)
- •Serum bilirubin 2.0 > ULN
- •Serum ALT and/or AST > 2.0 x ULN
- •Serum alkaline phosphatase > 2.5 x ULN
- •Serious uncontrolled infection or other serious uncontrolled concomitant disease.
- •Collagen vascular disease or a disease that is considered to increase radiosensitivity of normal tissues to radiation (e.g., ataxia-telangiectasia)
- •The patient is unwilling or unable to comply with the CIP required follow-up visits for the duration of the study.
- •Untreated or severe treated congestive heart failure, cardiac pacemaker, or renal failure.
- •Restlessness or inability to lie in a cast for about 30 minutes.
- •Clinical follow-up after therapy cannot be arranged or the patient is not willing to participate in the follow-up.
- •Known pregnancy, breastfeeding, or planning of pregnancy; for women of childbearing potential, a negative urine pregnancy test must be obtained prior to enrollment.
- •The patient is not able to understand the nature of the study and trial treatment options.
- •Phenylketonuria.
- •Fructose intolerance.
研究组 & 干预措施
Single group - Dose escalation study
Two BNCT trial treatments are scheduled to be administered to each study subject with a 4-week time interval between the 2 trial treatments (a range from 3.0 to 6.0 weeks is allowed for the interval). Neutron irradiations are given at the Helsinki University Hospital BNCT facility (Helsinki, Finland) using the nuBeam Suite. The nuBeam Treatment Delivery System within the nuBeam Suite delivers a neutron beam that has suitable energy and flux for clinical BNCT.
The Instructions for Use/User Guide(s) containing the detailed instructions for using the system will be followed for the delivery of neutron irradiation for each BNCT trial treatment.
The basic steps for the irradiation procedure are:
- Neutron source preparation/calibration
- CT imaging of the target region
- Positioning of the study subject
- Irradiation to the planned trial treatment dose
- Close-out/Shutdown Each BNCT trial treatment will be carried out according to the trial treatment plan.
干预措施: L-Boronophenylalanine intravenous administration (Drug)
结局指标
主要结局
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
时间窗: The expected duration to the primary outcome is 13 months. The primary safety endpoint is 1 month after the final/2nd BNCT trial treatment of the last study subject. Study subject enrollment is anticipated to take 12 months.
The primary objective is to assess the safety of accelerator-based neutron radiation using the nuBeam Suite, and explicitly, the nuBeam Treatment Delivery System (TDS) in delivering BNCT to treat cancer patients. Safety/toxicity of neutron radiation delivered by the nuBeam TDS will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 at one month after the last BNCT trial treatment.
次要结局
- Trial Irradiation Success for the nuBeam TDS(The expected duration to the primary outcome is 13 months. The primary safety endpoint is 1 month after the final/2nd BNCT trial treatment of the last study subject. Study subject enrollment is anticipated to take 12 months.)
- Procedure success of the nuBeam Suite(The expected duration to the primary outcome is 13 months. The primary safety endpoint is 1 month after the final/2nd BNCT trial treatment of the last study subject. Study subject enrollment is anticipated to take 12 months.)
- Treatment effectiveness(The expected duration to the primary outcome is 13 months. The primary safety endpoint is 1 month after the final/2nd BNCT trial treatment of the last study subject. Study subject enrollment is anticipated to take 12 months.)