SBRT + Immunomodulating Systemic Therapy for Inoperable, Recurrent H&N

February 16, 2021 updated by: Radiotherapie, University Hospital, Ghent

Combined Hypofractionated Stereotactic Body Radiotherapy With Immunomodulating Systemic Therapy for Inoperable Recurrent Head and Neck Cancer: Detection of the Maximum Tolerated Dose.

To derive the maximum tolerated dose of hypofractionated stereotactic body radiotherapy (SBRT) using dose painting by numbers with immunomodulating systemic therapy in patients that are reirradiated for recurrent squamous cell carcinoma of the head and neck.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The standard treatment in inoperable locally or regionally recurrent head and neck cancer has long been palliative systemic therapy using the so-called EXTREME-scheme: a combination of cisplatin, 5-fluorouracil and cetuximab. This therapy remains without realistic chances of cure. More recently, immunotherapy using nivolumab has demonstrated to result in long-term disease control of 1-2 year in cisplatin-refractory recurrent or metastatic head and neck cancer, however only in a small portion of patients (13%).

Fractionated high-dose local or regional re-irradiation is mostly given in a 6-7 weeks scheme. Using stereotactic body radiotherapy (SBRT), high radiotherapy doses can be given in a short time span. Severe late adverse events have been reported using SBRT but seem less frequent than in patients re-treated with conventional schedules. A possible solution to be able to administer higher doses is combining SBRT with dose painting, thus giving these high doses on small subvolumes only.

Addition of concomitant therapy to reirradiation may further improve outcomes due to radiosensitization and direct cytotoxicity. Therefore the investigator aims to combine high doses with concomitant therapy in the proposed study.

The immunomodulatory effect caused by radiation has been demonstrated both in animal models and clinical trials and leads to an enhanced local control as well as to eradication of distant metastasis. This so-called abscopal effect is reached through a systemic immune response evoked by the release of damage-associated molecular patterns (DAMPs) by the dying tumor-cells, also called immunogenic cell death (ICD).

The investigator hypothesizes that an abscopal effect could be present for patients presenting locoregional recurrent disease with asymptomatic distant metastases, thereby offering at least symptom control at the primary site while palliative systemic treatment could be postponed.

The proposed protocol focuses on patients with bad prognosis, as determined by a short timespan between primary therapy and recurrence (defined as 6-24 months after the end of the primary radiotherapy). It would bring the practical advantage of only 2-3 patient visits for the radiotherapy instead of ± 30-35 visits over 6-7 weeks. This shorter treatment schedule is expected to result in a direct gain in quality-of-life due to locoregional symptom control. It can also be expected that rescue systemic therapy will be postponed to a later stage of disease development, thereby prolonging overall survival.

The combination with systemic agents that are involved in immunogenic cell death bear the potential to result in a higher number of patients with longer periods of disease control and survival. The current standard of care, i.e. the combined systemic treatment with cisplatin - 5-fluorouracil - cetuximab, or nivolumab in case of former cisplatin use, can be used as a rescue regimen in case of therapy failure. In that sense, better overall survival from time of diagnosis of the index locoregional recurrent disease is expected.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
6

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
      • Leuven, Belgium
        • UZ Leuven
      • Namur, Belgium
        • CHU Namur
    • Oost-Vlaanderen
      • Ghent, Oost-Vlaanderen, Belgium, 9000
        • Radiotherapy department, University Hospital Ghent

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Histologically confirmed local, regional or combined locoregional recurrence of squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx or cancer of unknown primary (CUP) in the neck in previously irradiated tissue, with former irradiation with curative intent.
  • Patients with non-symptomatic distant metastases and local, regional or combined locoregional recurrence can be included.
  • In case of non-metastatic disease, the recurrence must be primarily unresectable recurrence and/or patients refused surgery.
  • Time interval 6-24 months after the end of the initial radio(chemo)therapy for primary head and neck cancer.
  • Decision of the Head and Neck Tumor Boards at the recruiting centre to offer salvage radio(chemo)therapy, palliative chemotherapy or anti-PD-1 antibody treatment with nivolumab for cisplatin-refractory locoregional recurrent head and neck squamous cell carcinoma.
  • Karnofsky performance status ≥ 70.
  • Age ≥ 18 years old.
  • Informed consent obtained, signed and dated before specific protocol procedures.

Exclusion Criteria:

  • Previous radiotherapy was for cT1-2 cN0 M0 glottic cancer.
  • Grade ≥ 4 late toxicity after the initial radio(chemo)therapy.
  • Brachytherapy as treatment for second primary / recurrence.
  • Previous (combination with) immunotherapy for the primary or the recurrent squamous cell carcinoma.
  • Impossibility of oral intake of cyclophosphamide.
  • For patients receiving cyclophosphamide: necessary intake during therapy of allopurinol, amiodarone, digoxin, hydrochlorothiazide, indomethacin, phenobarbital, phenytoin, warfarin. clopidogrel, ticlopidine, carbamazepine, efavirenz, rifampicin, ritonavir

  • High risk for arterial blow-out: 1 of following criteria is sufficient to exclude patients:

    1. soft tissue necrosis
    2. skin invasion of the recurrent cancer
    3. circumferential involvement of > 180° of a carotid artery
  • Symptomatic distant metastases.
  • Other uncontrolled second primary tumors.
  • Pregnant or lactating women.
  • Mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the study.
  • Patient unlikely to comply with protocol, i.e. uncooperative attitude, inability to return for follow-up visits, and unlikely to complete the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Stereotactic body radiotherapy + IM
Single arm phase I trial with 3 Stereotactic Body Radiation Therapy dose-escalation arms.
Radiation: Stereotactic body radiotherapy

The range of dose-painting will be escalated in following levels:

  • 2x 6-8Gy (day 1-4)
  • 3x 6-8Gy (day 1-4-7)
  • 3x 6-10Gy (day 1-4-7)
  • 3x 6-12Gy (day 1-4-7)

Patients will take cyclophosphamide orally 50 mg tablets, 1 tablet a day from the first day of irradiation for 8 consecutive weeks.

Nivolumab will be considered as standard therapy in patients with cisplatin refractory locoregional disease recurrence. Nivolumab will be administered as per current standard of care. In case patients that are treated with nivolumab will be included in the trial, they will not be treated with cyclophosphamide.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
maximum tolerated dose
Time Frame: 3 months after radiotherapy
maximum tolerated dose of hypofractionated stereotactic body radiotherapy (SBRT) using dose painting by numbers with immunomodulating systemic therapy in patients that are reirradiated for recurrent squamous cell carcinoma of the head and neck
3 months after radiotherapy

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
symptom palliation - pain
Time Frame: through study completion, an average of 12 months
reduction in pain
through study completion, an average of 12 months
symptom palliation - dysphagia
Time Frame: through study completion, an average of 12 months
reduction in grade of dysphagia
through study completion, an average of 12 months
local control
Time Frame: 3 months after SBRT and thereafter through study completion, an average of 12 months

Assessment of:

  1. diameter of target lesion of SBRT (and, if present, non-target lesions) in mm
  2. tumor response according to recist criteria
3 months after SBRT and thereafter through study completion, an average of 12 months
Overall survival
Time Frame: through study completion, an average of 12 months
To estimate overall survival
through study completion, an average of 12 months
Progression free survival
Time Frame: through study completion, an average of 12 months
To estimate progression-free survival
through study completion, an average of 12 months
grade ≥ 3 toxicity-free survival
Time Frame: through study completion, an average of 12 months
To estimate grade ≥ 3 toxicity-free survival (anemia, febrile neutropenia, fatigue, dysphagia, oral mucositis, laryngeal mucositis, pharyngeal mucositis, pharyngeal hemorrhage, pharyngeal necrosis, pharyngeal stenosis, pharyngolaryngeal pain, dry mouth)
through study completion, an average of 12 months
QOL - general
Time Frame: before therapy, week 3, week 6, week 10, week 14
To assess quality-of-life: EORTC QLQ
before therapy, week 3, week 6, week 10, week 14
QOL - H&N specific
Time Frame: before therapy, week 3, week 6, week 10, week 14
To assess quality-of-life: H&N35
before therapy, week 3, week 6, week 10, week 14
topographic distribution of recurrence
Time Frame: through study completion, an average of 12 months
To assess the topographic distribution of recurrence (inside/outside FDG-avid GTV)
through study completion, an average of 12 months
time to further treatment
Time Frame: through study completion, an average of 12 months
To assess time to further treatment
through study completion, an average of 12 months
immune response
Time Frame: using serum taken before treatment and at each fraction of SBRT, at weeks 6-14
To assess the immune response
using serum taken before treatment and at each fraction of SBRT, at weeks 6-14

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University Hospital, Ghent

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Fréderic Duprez, MD, PhD, Gent University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 31, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 3, 2020

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 3, 2020

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
November 20, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 10, 2018

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 18, 2018

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 18, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 16, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • EC/2017/0636
  • 2017-000133-31 (EudraCT Number)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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