SBRT-based PArtial Tumor Irradiation of HYpoxic Segment

NCT04168320 | Terminated Phase 1 DMC

• 1 other identifier: A21/18
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Bystander Effect; Abscopal Effect; Unresectable Malignant Solid Neoplasm; Bulky Tumors

Keywords

Phase I; Bystander effect; Abscopal effect; Tumor hypoxia

Outcome Measures

Primary Outcomes (1)

• Bystander and abscopal effects

  Rates of significant (30% or more) tumor regression at the level of both the partially treated bulky tumors (bystander effects) and unirradiated oligometastases and/or regional lymph nodes (abscopal effect).

  6 months

Secondary Outcomes (6)

• Overall survival

  Up to 100 weeks

• Progression-free survival

  Up to 100 weeks

• Patient-reported outcome (PRO)

  3 months

• Common Terminology Criteria for Adverse Events (CTCAE) v5.0

  Up to 100 weeks

• Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

  Up to 6 months

Study Arms (2)

Less favorable time-position in immune cycle

ACTIVE COMPARATOR

Starting two weeks prior to the initiation of radiotherapy serial, 7x blood samples will be taken every two days, excluding the weekend (for example, if starting on a Monday: Monday-Wednesday-Friday-Monday-Wednesday-Friday and Monday), but also on the day of the first radiotherapy treatment, to define the serial high-sensitivity C-reactive protein (hs-CRP) test, LDH and white cell differential count (leucocytes: neutrophils, basophils, eosinophils, lymphocytes, monocytes). Data from the assays will be assembled in a spreadsheet and analyzed for levels and cyclical fluctuations to determine each patient's idiosyncratic immune cycle's periodicity and then each patient's time-position of initiation of treatment and response to therapy. SBRT-PATHY will be administered to this arm at an estimated "less favorable time-Position in immune cycle".

Radiation: SBRT-PATHY (SBRT-based PArtial Tumor irradiation targeting HYpoxic segment)

Most favorable time-position in immune cycle

EXPERIMENTAL

Starting two weeks prior to the initiation of radiotherapy serial, 7x blood samples will be taken every two days, excluding the weekend (for example, if starting on a Monday: Monday-Wednesday-Friday-Monday-Wednesday-Friday and Monday), but also on the day of the first radiotherapy treatment, to define the serial high-sensitivity C-reactive protein (hs-CRP) test, LDH and white cell differential count (leucocytes: neutrophils, basophils, eosinophils, lymphocytes, monocytes). Data from the assays will be assembled in a spreadsheet and analyzed for levels and cyclical fluctuations to determine each patient's idiosyncratic immune cycle's periodicity and then each patient's time-position of initiation of treatment and response to therapy. SBRT-PATHY will be administered to this arm at an estimated "most favorable time-position in immune cycle".

Radiation: SBRT-PATHY (SBRT-based PArtial Tumor irradiation targeting HYpoxic segment)

Interventions

SBRT-PATHY (SBRT-based PArtial Tumor irradiation targeting HYpoxic segment) RADIATION

Novel stereotactic high-dose partial irradiation of the hypoxic segment of bulky tumors.

Less favorable time-position in immune cycle; Most favorable time-position in immune cycle

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Metastatic biopsy proven malignant cancer with at least one "bulky" (diameter of at least 6 cm or greater) lesion, or in the case of a biopsy missing for any reason-progression of the suspicious lesion evaluated on at least 2 consecutive radiological examinations,
• Written informed consent obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluation,
• Ineligibility for systemic therapy or being in progression under systemic therapy,
• A minimum time interval of four weeks from the last dose of systemic therapy before radiotherapy,
• Median life expectancy of \>3 months,
• Age \> 18 years at the time of study entry,
• Adequate bone marrow function: Haemoglobin ≥ 9.0 g/dL, absolute neutrophil count (ANC) ≥ 1.5 x 109/L (\> 1500 per mm3), platelet count ≥ 100 x 109/L (\>100,000 per mm3),
• Female subjects must either be of non-reproductive potential (i.e. post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry,
• Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up.

You may not qualify if:

• Patients without metastatic cancer (regional metastatic lymph nodes considered as metastatic),
• Patients without bulky lesions,
• Median life expectancy of less than three months,
• Patients with prior radiation therapy to the same site,
• Contraindication to IV iodine contrast medium administration, particularly estimated glomerular filtration rate (GFR) less than 45 mL/min/1.73 m2,
• History of autoimmune disease,
• Current or prior use of immunosuppressive medication within 28 days before enrollment with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid,
• History of primary immunodeficiency,
• History of allogeneic organ transplant,
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent,
• Known history of previous clinical diagnosis of tuberculosis,
• History of leptomeningeal carcinomatosis,
• Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control,
• Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results,
• Subjects with uncontrolled seizures.

Sponsors & Collaborators

• Klinikum Klagenfurt am Wörthersee: lead

Study Sites (1)

KABEG Klinikum Klagenfurt, Institute for Radiation Oncology

Klagenfurt, Carinthia, 9020, Austria

Location

Study Officials

• Slavisa Tubin, M.D.

  KABEG Klinikum Klagenfurt

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Vice-Chairman of the Radiation Oncology Institute, Klinikum Klagenfurt am Wörthersee

Model Details: Starting two weeks prior to the initiation of radiotherapy serial, 7x blood samples will be taken every two days, excluding the weekend (for example, if starting on a Monday: Monday-Wednesday-Friday-Monday-Wednesday-Friday and Monday), but also on the day of the first radiotherapy treatment, to define the serial high-sensitivity C-reactive protein (hs-CRP) test, LDH and white cell differential count (leucocytes: neutrophils, basophils, eosinophils, lymphocytes, monocytes). Data from the assays will be assembled in a spreadsheet and analyzed for levels and cyclical fluctuations to determine each patient's idiosyncratic immune cycle's periodicity and then each patient's time-position of initiation of treatment and response to therapy. Radiotherapy will be administered to the arm 1 (13 patients) at an estimated "less favorable time-position", while it will be administered to the arm 2 (13 patients) at an estimated "most favorable time-position in immune cycle".

Study Record Dates

• First Submitted: November 14, 2019
• First Posted: November 19, 2019
• Study Start: October 30, 2018
• Primary Completion: February 14, 2022
• Study Completion: December 14, 2022
• Last Updated: November 2, 2023

Record last verified: 2023-10

Locations

AU (1)