Accelerator-based BNCT (Boron Neutron Capture Therapy) for Head and Neck Carcinoma.

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.

In sum, although the treatment of locoregionally recurred head and neck carcinoma has evolved substantially during the recent years, the disease is frequent ultimately lethal, and the current therapies may be associated with substantial morbidity. Therefore, there is a clinical need to improve the treatment results in locally recurred head and neck carcinoma, and novel approaches are urgently needed.

Boron Neutron Capture Therapy (BNCT)

BNCT has several potential advantages compared to conventional radiation therapy. First, BNCT has the capability of treating tumors that are highly infiltrating into sensitive tissues where surgery with effective margins would be impossible or mutilating. In addition to the potentially increased effectiveness, this approach as delivered by the nuBeam System is anticipated to provide quality of life benefits due to the reduced side-effects, simplified procedure and reduced cosmetic consequences of the trial treatment as seen in research.

The high-LET (Linear Energy Transfer) radiation produced by BNCT also conveys several advantages. It produces double-strand DNA breaks and should do so even in hypoxic conditions where conventional radiation therapy loses effectiveness. The mechanism of action of high-LET radiation has also been shown to be effective in treating radio-resistant cancers. High-LET in combination with BNCT's ability to effectively spare healthy tissue also allows trial treatments to be carried out in only one or two fractions, which leads to improved patient quality of life as well as the potential for cost reduction when compared to conventional courses of radiation therapy, typically requiring as many as 35 fractions.

BNCT is based on the neutron capture and fission reactions that occur when non-radioactive boron (10B) is irradiated with neutrons of low (thermal) energy (0.025 eV). This causes boron nuclear decay, which yields high linear energy transfer (LET) α particles (4He) and recoiling lithium (7Li) nuclei. Alternatively, to improve neutron tissue penetration, epithermal (10 keV) neutrons that become thermalized (lost energy) in tissue may be used. Since α and 7Li have only a short range in tissue (5 to 9 µm) and they produce dense ionization along their tracks, most radiation effect is local and occurs within the cells that contain boron. The success of BNCT depends upon a selective uptake of sufficient amounts of 10B into cancer cells compared with normal tissues (approximately 20 to 50 µg/g; 109 atoms per cancer cell).

Selective accumulation of boron into cancerous tissue can be achieved using a boron carrier compound that is preferentially taken up by cancer. The most frequently used agents to deliver boron are a derivative of the amino acid phenylalanine, L-boronophenylalanine (L-BPA), sodium borocaptate (BSH), or their combination. After administration of the boron carrier compound (usually using an intravenous infusion), the tumor is irradiated with neutrons.

Until recently, the source of the neutrons needed for BNCT has been a nuclear reactor. This has been a limitation, since nuclear reactors are an expensive neutron source, they are often located at remote sites and are only infrequently available for medical use, and the beam obtained from nuclear reactors requires moderation to obtain neutrons with a suitable flux and energy for BNCT. At present, nuclear reactor-based BNCT is only rarely available for clinical purposes. However, neutron beams with characteristics suitable for BNCT can now be obtained with particle accelerators. A few companies, including three Japanese companies, Hitachi, Sumitomo Heavy Industries, and Mitsubishi Heavy Industry Co., and one American company, Neutron Therapeutics, have built an accelerator neutron source for BNCT. Phase I/II clinical BNCT trials, based on accelerator technology, have been conducted in Japan with promising antitumor effects and good safety, and are planned to be initiated in Finland with this clinical investigation.

Several hundreds of patients have been treated with BNCT using neutrons obtained from a nuclear facility and with L-BPA and/or BSH as the boron carrier. Most patients have had either malignant glioma, head and neck carcinoma, melanoma, or meningioma, but a few patients with other types of tumors have also been treated. In general, BNCT has been relatively well tolerated even in patients who have already been treated with conventional radiation therapy or chemoradiation, the most frequent adverse events being similar to those associated with conventional radiation therapy. The adverse events related to L-BPA and BSH have been few, and both agents thus seem generally well tolerated boron carriers when administered intravenously at the dosages used in clinical trials.

The median survival time of patients with newly diagnosed glioblastoma has been approximately 1 year when they have been treated with surgery and BNCT. This duration is approximately similar to that obtained with surgery followed by conventional radiotherapy when administered without temozolomide. L-BPA-mediated BNCT can be administered also to patients who have glioblastoma that has recurred after surgery and conventional radiotherapy. Such patients survived for a median of about 7 months, and BNCT was generally well tolerated.

Most patients with locally recurred, inoperable head and neck cancer treated in nonrandomized Phase I/II trials with BNCT respond to BNCT. The response rate was about 70 % (range, from 58% to 90%) with a complete response (CR) achieved in 55%. The most common adverse events were mucositis, oral pain, and fatigue. As with other therapies, recurrence is frequent in this patient population. In a trial carried out in Finland the 2-year locoregional recurrence-free survival was 27%, 2-year progression-free survival 20%, and 2-year overall survival 30%. In sum, these data suggest that BNCT is effective and moderately well tolerated in the treatment of locally recurrent, inoperable head and neck cancer leading to relatively high response rates.

Limited data suggest that BNCT can be combined with conventional radiotherapy and with some systemic agents in the treatment of head and neck cancer, but in the absence of clinical trials such an approach remains experimental. Besides head and neck carcinoma, BNCT appears effective also in the treatment of some other human tumor types, such as melanomas of the extremities, and aggressive meningiomas.

Rationale of the Clinical Study Locally recurred head and neck carcinoma poses a substantial therapeutic challenge. Most such cancers eventually progress regardless of the type of therapy, and the majority of cancer progressions eventually lead to death resulting from either local cancer progression, distant metastases, or both. There is a clear unmet need for more effective treatments and for novel treatment options.

As discussed above, L-BPA-mediated BNCT has resulted in promising clinical results in prior clinical studies using reactor-based neutron sources in Finland, Japan, Taiwan and elsewhere. Recent technical innovations have led to the development of proton accelerator-based neutron sources that are suitable for BNCT and can be installed in hospital environments. Such neutron sources can be designed specifically for hospital use, with a focus on reliability and simplicity of operation. Their performance characteristics can be tailored to closely mirror the proven FiR-1 reactor BNCT installation, with similar radiation quality and moderately improved epithermal neutron flux. Accelerator-based systems can be outfitted with automated patient imaging and positioning features to allow for improved targeting of radiation to the tumor and cost-effective treatment of a large number of patients. Next-generation BNCT devices can also be linked to modern treatment planning software platforms, enabling optimized planning of the radiation fields to minimize collateral dose and

• Trial Irradiation Success for the nuBeam TDS [Time frame: 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 [Time frame: 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 [Time frame: 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.]