Head and Neck NeoplasmNCT03402737
SBRT + Immunomodulating Systemic Therapy for Inoperable, Recurrent H&N
A study testing Stereotactic body radiotherapy in people with Head and Neck Neoplasm, run by University Hospital, Ghent at 3 sites in Belgium.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Head and Neck Neoplasm
- What is being tested?
- Stereotactic body radiotherapy
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 3 sitesBelgium
- Study dates
- 31 Jul 2017to 3 Dec 2020
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
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- High risk for arterial blow-out: 1 of following criteria is sufficient to exclude patients:
- soft tissue necrosis
- skin invasion of the recurrent cancer
- 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.
Trial locations and contacts
3 sites in 1 country.
Belgium3 sites
Radiotherapy department, University Hospital Ghent
Ghent, Oost-Vlaanderen, 9000
UZ Leuven
Leuven
CHU Namur
Namur
About this study
Official title: 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.
Read the 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.
- Conditions
- Head and Neck Neoplasm
- Being tested
- Stereotactic body radiotherapy
- Keywords
- Stereotactic body radiotherapy, Immunomodulating systemic therapy
- Medical subject headings
- Head and Neck Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Stereotactic body radiotherapyRadiation
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.
| Study group | Role | What they receive |
|---|---|---|
| Stereotactic body radiotherapy + IM | Experimental | Single arm phase I trial with 3 Stereotactic Body Radiation Therapy dose-escalation arms. Receives: Radiation: Stereotactic body radiotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
maximum tolerated dose
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
Measured: 3 months after radiotherapy
Secondary outcomes (11)
symptom palliation - pain
reduction in pain
Measured: through study completion, an average of 12 months
symptom palliation - dysphagia
reduction in grade of dysphagia
Measured: through study completion, an average of 12 months
local control
Assessment of:
- diameter of target lesion of SBRT (and, if present, non-target lesions) in mm
- tumor response according to recist criteria
Measured: 3 months after SBRT and thereafter through study completion, an average of 12 months
Overall survival
To estimate overall survival
Measured: through study completion, an average of 12 months
Progression free survival
To estimate progression-free survival
Measured: through study completion, an average of 12 months
grade ≥ 3 toxicity-free survival
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)
Measured: through study completion, an average of 12 months
QOL - general
To assess quality-of-life: EORTC QLQ
Measured: before therapy, week 3, week 6, week 10, week 14
QOL - H&N specific
To assess quality-of-life: H\&N35
Measured: before therapy, week 3, week 6, week 10, week 14
topographic distribution of recurrence
To assess the topographic distribution of recurrence (inside/outside FDG-avid GTV)
Measured: through study completion, an average of 12 months
time to further treatment
To assess time to further treatment
Measured: through study completion, an average of 12 months
immune response
To assess the immune response
Measured: using serum taken before treatment and at each fraction of SBRT, at weeks 6-14
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jan 2018
- Study start31 Jul 2017
- Primary completion3 Dec 2020
- Study completion3 Dec 2020
Why it stopped: Poor recrual.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Head and Neck NeoplasmStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Model description
- The range of dose-painting will be escalated in following levels: * 2x 6-8Gy * 3x 6-8Gy The standard "3+3" design will be used for the this trial. To obtain more precise toxicity rate of the MTD we will double the number of patients at the first dose prescription that gives totally 6 patients. The 3 remaining dose levels will include 3 patients each. Thus, fifteen (6+3+3+3) patients will be included in this radiotherapy dose finding study investigating the MTD. The number of patients will be doubled in case of 2 DLTs at the dose prescription I and 1 DLT at dose prescriptions II-IV with DLT in a maximum of 10 out of 30 patients. * 3x 6-10Gy * 3x 6-12Gy
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Ghent
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Radiotherapie, University Hospital, Ghent
- Investigators
- Fréderic Duprez, MD, PhD, Principal investigator, Gent University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03402737
- Sponsor's protocol ID
- EC/2017/0636
- Other IDs
- 2017-000133-31, 2017
- Status last verified
- Feb 2021
- First submitted
- 20 Nov 2017
- Last updated
- 18 Feb 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Combined Hypofractionated Stereotactic Body Radiotherapy With Immunomodulating Systemic Therapy for Inoperable Recurrent Head and Neck Cancer: Detection of the Maximum Tolerated Dose.
- ClinicalTrials.gov ID
- NCT03402737
- Acronym / sponsor ID
- EC/2017/0636
- Conditions
- Head and Neck Neoplasm
- Keywords
- Stereotactic body radiotherapy, Immunomodulating systemic therapy
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Poor recrual.
- Enrolment
- 6 participants (actual)
- Lead sponsor
- University Hospital, GhentUniversity, hospital or other
- Study start
- 31 Jul 2017 (actual)
- Primary completion
- 3 Dec 2020 (actual)
- Study completion
- 3 Dec 2020 (actual)
- First posted
- 18 Jan 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- The range of dose-painting will be escalated in following levels: * 2x 6-8Gy * 3x 6-8Gy The standard "3+3" design will be used for the this trial. To obtain more precise toxicity rate of the MTD we will double the number of patients at the first dose prescription that gives totally 6 patients. The 3 remaining dose levels will include 3 patients each. Thus, fifteen (6+3+3+3) patients will be included in this radiotherapy dose finding study investigating the MTD. The number of patients will be doubled in case of 2 DLTs at the dose prescription I and 1 DLT at dose prescriptions II-IV with DLT in a maximum of 10 out of 30 patients. * 3x 6-10Gy * 3x 6-12Gy
| Arm | Type | Receives |
|---|---|---|
| Stereotactic body radiotherapy + IM | Experimental | Radiation: Stereotactic body radiotherapySingle arm phase I trial with 3 Stereotactic Body Radiation Therapy dose-escalation arms. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (15 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Stereotactic body radiotherapyThe 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. | Radiation | Stereotactic body radiotherapy + IM |
Primary outcome
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
11 secondary outcomes
symptom palliation - pain
Time frame: through study completion, an average of 12 months
symptom palliation - dysphagia
Time frame: 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
Overall survival
Time frame: through study completion, an average of 12 months
Progression free survival
Time frame: through study completion, an average of 12 months
grade ≥ 3 toxicity-free survival
Time frame: through study completion, an average of 12 months
QOL - general
Time frame: 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
topographic distribution of recurrence
Time frame: through study completion, an average of 12 months
time to further treatment
Time frame: 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
Results and safety
The study was stopped early (reason given: Poor recrual.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Feb 2021.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Fréderic Duprez, MD, PhD principal investigator
Gent University
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Stereotactic body radiotherapy in people with Head and Neck Neoplasm, run by University Hospital, Ghent at 3 sites in Belgium.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 18 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early (reason given: Poor recrual.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
maximum tolerated dose (time frame: 3 months after radiotherapy). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Feb 2021.