SBRT-based PArtial Tumor Irradiation of HYpoxic Segment

Overview

This study uses an unconventional radiotherapy schedule developed at our institute, consisting of a short course high-dose partial irradiation targeting exclusively the hypoxic segment of a bulky tumors, which in our preliminary study has shown to be capable of inducing abscopal and bystander effects. This approach is delivered by using a stereotactic radiotherapy technique so as to spare nearby organs at risk including the peritumoral immune microenvironment from irradiation as much as possible. Our approach consists of a single or up to 3 radiotherapy doses of at least 10 Gy per fraction prescribed to the 70% isodose line encompassing the hypoxic target volume. Radiotherapy will be administered at the precise timing determined specifically for each patient based on the serially mapped homeostatic immune fluctuations by monitoring the blood levels of the cytokines and inflammatory markers over the 2 weeks prior to irradiation. This is done in order to synchronize the radiation treatment with the favorable, most active anti-tumor immune system phase, so as to stimulate and increase anti-tumor immune system activity. This is a monocentric, prospective, two-arm, phase I proof of principle study in which the investigator will enroll subjects with oligometastatic and/or locally advanced (N+) cancers with at least one "bulky" lesion (maximum diameter of at least 6 cm or greater). Patients with life expectancy of at least 3 months, who are ineligible for systemic therapy or experience disease progression with systemic therapies will be included. Radiotherapy will be administered to arm 1 at an estimated "less favorable time-position in immune cycle", while the second arm will have it administered at the estimated "most favorable time-position in immune cycle". The primary endpoint will be the response rate of the non-targeted effects both bystander (local, at the level of the partially treated bulky tumor) and abscopal (distant, at the non-treated metastatic sites), defined as a tumor regression of at least 30%. Secondary endpoints will be safety, survival and analysis of the best timing for the administration of radiotherapy.

The purpose of this study is to evaluate the effectiveness of our new method for high dose partial irradiation of the hypoxic tumor segment of bulky masses in terms of the intentional induction of the non-targeted effects of radiotherapy in patients with metastatic or locally advanced (N+) malignancies who are ineligible for, or currently in progression under systemic therapies. By mapping the homeostatic immune fluctuations serially, and by monitoring the blood levels of the cytokines and inflammatory markers over the 2 weeks prior to irradiation, radiotherapy will be administered at the precise, optimal timing in order to stimulate and to increase anti-tumor immune system activity. Primary endpoint: bystander (local) and abscopal (distant, metastatic or lymph nodal sites) response rates. Secondary endpoints: overall safety and tolerability profile of our new radiotherapy method, progression-free survival rates at local and distant sites, as well as overall survival rates, efficacy of this regimen in palliating symptoms, neoadjuvant potential of this novel radiotherapy for unresectable/borderline resectable bulky lesions, optimal timing for radiotherapy to be administered based on the fluctuating/oscillating suppressed anti-tumor immune response. This monocentric, two-arm prospective phase I proof of principle trial will enroll 26 patients from a single institution: KABEG Klinikum Klagenfurt am Woerthersee, Austria. During the visit, and after clinical examination, patients will be eligible if they satisfy the inclusion criteria for participation in this pilot study on the use of the novel stereotactic radiotherapy technique which will consist of partial irradiation of exclusively hypoxic segments of their bulky tumors, with 1-3 high dose fractions of radiotherapy based on the tumor's site, volume and its relationship with nearby organs. The irradiation will take place within 3 weeks of clinical examination. After the treatment, the patient will be regularly followed for the evaluation of all endpoints. If any severe toxicity (grade ≥3 per CTCAE v 4.3 criteria) occurs in the first 7 evaluable patients, the trial will stop. Safety reviews will continue on an ongoing basis, provided that severe toxicities do not occur in more than 15% of patients. In the case of eventual disease progression during the follow-up, the patients will be offered additional local (radiotherapy) or systemic (chemotherapy, immunotherapy, hormonal therapy) treatment if indicated by current NCCN (National Comprehensive Cancer Network) treatment recommendations and guidelines. Routine surveillance computerized axial tomography (CT) imaging of the whole body will be performed beginning at 1 month (+/- 3 days) after treatment to allow for endpoint assessment - or before in any case of clinical suspicion of disease progression. Routine CT imaging surveillance will continue per standard of care. Patients will also be followed clinically with physical and laboratory examinations as indicated. Tumor assessments will be completed on the CRF using RECIST v1.1. criteria. Radiographic and clinical evaluations will be conducted with the same schedule. The investigator will assess anti-tumor activity based on radiological assessments and clinical evaluations of patients using RECIST v1.1 at baseline, 1 and 2 months post-treatment, and every 3 months thereafter until confirmed disease progression per RECIST v1.1, regardless of the discontinuation of study treatment or the initiation of subsequent anti-cancer therapy. Radiological tumor assessments will also be conducted whenever disease progression is suspected (e.g. symptomatic deterioration or physical examination findings suggestive of mucosal recurrence).