Head and Neck Squamous Cell CarcinomaHYDRANCT05364411
HYpofractionated, Dose-redistributed RAdiotherapy With Protons and Photons in HNSCC
A study testing HYpofractionated, Dose-redistributed RAdiotherapy (HYDRA) and conventional fractionated radiotherapy in people with Head and Neck Squamous Cell Carcinoma and Hypofractionation, run by Joris B.W. Elbers at 1 site in Netherlands.
Trial summary
Radiotherapy for advanced-stage head and neck squamous cell carcinoma (HNSCC) results in an unfavorable 5-year overall survival of 40%, and there is a strong biological rationale for improving outcome by combinatorial treatment with immunotherapy. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Head and Neck Squamous Cell Carcinoma, Hypofractionation, Radiotherapy
- What is being tested?
- HYpofractionated, Dose-redistributed RAdiotherapy (HYDRA) and conventional fractionated radiotherapy
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 100 participants
- Where
- 1 siteNetherlands
- Study dates
- 10 Oct 2022to 1 Jun 2026
- 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
None listed.
Who cannot join
- Patients who do not meet the inclusion criteria as specified in paragraph 4.2, and/or who meet the following additional criteria:
- Previously treated by irradiation on the same target volume
- Chronic inflammatory disease or immune disorders which, according to the principal investigator, may disturb the translational immune-read out.
- Patients currently under treatment for other malignant disease (unless in situ carcinoma or basal cell carcinoma of the skin), or treated for other malignant disease within the last 2 years.
- Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule in the participating hospitals.
- Any other serious medical condition that could interfere with follow-up.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site, 1 recruiting
- Recruiting
Erasmus MC
Rotterdam, South Holland, 3015 GL
Jos Elbers, 0031107041249, j.elbers@erasmusmc.nl
About this study
Official title: HYpofractionated, Dose-redistributed RAdiotherapy With Protons and Photons to Combat Radiation-induced Immunosuppression in Head and Neck Squamous Cell Carcinoma (HYDRA)
Radiotherapy for advanced-stage head and neck squamous cell carcinoma (HNSCC) results in an unfavorable 5-year overall survival of 40%, and there is a strong biological rationale for improving outcome by combinatorial treatment with immunotherapy. However, also immunosuppressive effects of radiotherapy have been reported and recently a randomized phase-III trial failed to show any survival benefit following the combination of a PD-L1 inhibitor with chemoradiotherapy. The hypothesis is that the combination of these individually effective treatments failed because of radiation-induced lymphodepletion and that the key therefore lies in reforming conventional radiotherapy, which typically consists of large lymphotoxic radiation fields of 35 fractions. By integrating modern radiobiology and individually established innovative radiotherapy concepts, the patient's immune system could be maximally retained. This will be achieved by 1) increasing the radiation dose per fraction so that the total number of fractions can be reduced (HYpofractionation), 2) by redistributing the radiation dose towards a higher peak dose within the tumor center and a lowered elective-field dose (Dose-redistribution) and 3) by using RAdiotherapy with protons instead of photons (HYDRA).
The objectives of this study are to determine the safety of HYDRA with protons and photons by conducting two parallel phase-I trials. HYDRA's efficacy will be compared to standard of care (SOC). The immune effects of HYDRA-protons will be evaluated by longitudinal immune profiling and compared to HYDRA-photons and SOC (with protons and photons). There will be a specific focus on actionable immune targets and their temporal patterns that can be tested in future hypofractionated-immunotherapy combination trials. This trial therefore is an important step towards future personalized immuno-radiotherapy combinations with the ultimate goal to improve survival for patients with HNSCC.
Read the detailed description
The HYDRA dose prescriptions are, in 20 fractions (instead of the conventional 35 fractions):
- Inhomogeneous focal boost on the macroscopic gross tumor volume (GTVprimary tumor and GTVnodes) on FDG-PET: mean dose 59Gy, max dose 63Gy.
- The mean dose of 59Gy corresponds to an equal late normal tissue toxicity probability after conventionally fractionated radiotherapy of 70Gy in 35 fractions, considering an α/β=3 for normal tissue.
- Simultaneous integrated boost (SIB) on the clinical target volume (CTV-P1 = GTV+5mm): 55Gy
- Elective field / CTV-P2 (GTV+10mm): 40Gy
Patients who receive the HYDRA intervention treatment, as well as patients who receive standard of care may require the addition of a concurrent radiosensitizer based on clinicopathological features according to standard of care. Currently, the only two registered radiosensitizers are platinum-based chemotherapy (cisplatin/carboplatin) and cetuximab. These radiosensitizers should be administered according to standard care treatment protocols.
- Conditions
- Head and Neck Squamous Cell Carcinoma, Hypofractionation, Radiotherapy, Proton Therapy, Immune System Suppression
- Being tested
- HYpofractionated, Dose-redistributed RAdiotherapy (HYDRA), conventional fractionated radiotherapy
- Medical subject headings
- Squamous Cell Carcinoma of Head and Neck
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HYpofractionated, Dose-redistributed RAdiotherapy (HYDRA)Radiation
20 daily fractions, 5 times per week
conventional fractionated radiotherapyRadiation
35 daily fractions, 5 times per week
| Study group | Role | What they receive |
|---|---|---|
| HYDRA-protons | Experimental | group 1, n=25, run at HollandPTC Receives: Radiation: HYpofractionated, Dose-redistributed RAdiotherapy (HYDRA) |
| Conventional fractionated proton therapy | Active comparator | group 2, n=25, run at HollandPTC Receives: Radiation: conventional fractionated radiotherapy |
| HYDRA-photons | Experimental | group 3, n=25 run at Erasmus MC Receives: Radiation: HYpofractionated, Dose-redistributed RAdiotherapy (HYDRA) |
| Conventional fractionated photon therapy | Active comparator | group 4, n=25 run at Erasmus MC Receives: Radiation: conventional fractionated radiotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety of HYDRA-protons and HYDRA-photons in terms of radiation-induced grade 3-4 late toxicity, physician-reported by CTCAE v5.0, monitored until 1 year after the last patient has completed HYDRA.
HYDRA is randomized with standard of care for translational research purposes; a direct comparison of toxicity will statistically not be conclusive and is outside the scope of this study.
Measured: month 1-36
Secondary outcomes (3)
Objective response after HYDRA defined by radiological response on CT-scans or MRI in comparison to standard of care
Objective response rate 3 months after HYDRA (group 1 and 3), defined by radiological response on CT-scans or MRI using RECIST version 1.1 and/or histopathological confirmation of residual disease, in comparison to standard of care (group 2 and 4, respectively), 3 months after end of treatment
Measured: month 1-27
Efficacy of HYDRA in terms of in-field and nodal elective field tumor control at 1 year
Efficacy of HYDRA (group 1 and 3) in terms of in-field and nodal elective field tumor control, 1 year after the last patient is included, in comparison to group 2 and 4, respectively.
Measured: month 24-36
Immune profile (changes) between all 4 treatment groups
Numbers and phenotype of peripheral immune cell populations in blood at baseline, related to patient- and tumor characteristics, and differences between temporal changes of these immune markers during/after treatment at 6 timepoints in group 1-4.
Measured: month 1-27
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 May 2022
- Study start10 Oct 2022
- Primary completion1 Jun 2025 (estimated)
- Study completion1 Jun 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Head and Neck Squamous Cell CarcinomaStudies 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
- Randomised
- Intervention model
- Parallel groups
- Model description
- Two parallel, non-comparative phase-I trials of HYDRA-protons run at HollandPTC (group 1, n=25) and HYDRA-photons (group 3, n=25) run at the Erasmus MC. Toxicity will be monitored until 1 year after the last patient has completed HYDRA. This will result in a median follow-up of approximately 2 years. Patients will subsequently receive follow-up according to standard of care up to 5 years after treatment for the evaluation of very late-onset toxicity. For translational immune profiling, HYDRA-protons and HYDRA-photons will be randomized by minimization (1:1 ratio) against SOC: conventional fractionated proton therapy in HPTC (group 2, n=25) and conventional fractionated photon therapy in the Erasmus MC (group 4, n=25), respectively.
- Masking
- None (open label)
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Joris B.W. Elbers
- Sponsor type
- University, hospital or other
- Collaborators
- Erasmus Medical Center, HollandPTC
- Responsible party
- Sponsor-investigator, Joris B.W. Elbers, Erasmus Medical Center
- Investigators
- Joris BW Elbers, MD, PhD, Principal investigator, Erasmus MC, Rotterdam / HollandPTC, Delft - The Netherlands
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05364411
- Sponsor's protocol ID
- HYDRA
- Acronym
- HYDRA
- Status last verified
- Feb 2024
- First submitted
- 28 Apr 2022
- Last updated
- 20 Feb 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: tba
Publications
Gunsch PA, Kroesen M, Debets R, Keereweer S, van Meerten E, Zindler J, van Werkhoven E, Hoogeman M, Verduijn GM, Nout RA, Elbers JBW. HYpofractionated, dose-redistributed RAdiotherapy (HYDRA) versus conventional radiotherapy for head and neck cancer: planned interim analysis and dosimetric comparison from the phase I HYDRA trial. Clin Transl Radiat Oncol. 2026 Jan 25;58:101113. doi: 10.1016/j.ctro.2026.101113. eCollection 2026 May.
PubMed 41685200Elbers JBW, Gunsch PA, Debets R, Keereweer S, van Meerten E, Zindler J, van Norden Y, Hoogeman MS, Verduijn GM, Kroesen M, Nout RA. HYpofractionated, dose-redistributed RAdiotherapy with protons and photons to combat radiation-induced immunosuppression in head and neck squamous cell carcinoma: study protocol of the phase I HYDRA trial. BMC Cancer. 2023 Jun 13;23(1):541. doi: 10.1186/s12885-023-11031-w.
PubMed 37312053
Study at a glance
From the registry record, last updated by the sponsor on 20 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- HYpofractionated, Dose-redistributed RAdiotherapy With Protons and Photons to Combat Radiation-induced Immunosuppression in Head and Neck Squamous Cell Carcinoma (HYDRA)
- ClinicalTrials.gov ID
- NCT05364411
- Acronym / sponsor ID
- HYDRA / HYDRA
- Conditions
- Head and Neck Squamous Cell Carcinoma, Hypofractionation, Radiotherapy, Proton Therapy, Immune System Suppression
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- Joris B.W. ElbersUniversity, hospital or other
- Collaborators
- Erasmus Medical Center, HollandPTC
- Study start
- 10 Oct 2022 (actual)
- Primary completion
- 1 Jun 2025 (estimated)
- Study completion
- 1 Jun 2026 (estimated)
- First posted
- 6 May 2022 (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.
Radiotherapy for advanced-stage head and neck squamous cell carcinoma (HNSCC) results in an unfavorable 5-year overall survival of 40%, and there is a strong biological rationale for improving outcome by combinatorial treatment with immunotherapy. However, also immunosuppressive effects of radiotherapy have been reported and recently a randomized phase-III trial failed to show any survival benefit following the combination of a PD-L1 inhibitor with chemoradiotherapy. The hypothesis is that the combination of these individually effective treatments failed because of radiation-induced lymphodepletion and that the key therefore lies in reforming conventional radiotherapy, which typically consists of large lymphotoxic radiation fields of 35 fractions. By integrating modern radiobiology and individually established innovative radiotherapy concepts, the patient's immune system could be maximally retained. This will be achieved by 1) increasing the radiation dose per fraction so that the total number of fractions can be reduced (HYpofractionation), 2) by redistributing the radiation dose towards a higher peak dose within the tumor center and a lowered elective-field dose (Dose-redistribution) and 3) by using RAdiotherapy with protons instead of photons (HYDRA).
The objectives of this study are to determine the safety of HYDRA with protons and photons by conducting two parallel phase-I trials. HYDRA's efficacy will be compared to standard of care (SOC). The immune effects of HYDRA-protons will be evaluated by longitudinal immune profiling and compared to HYDRA-photons and SOC (with protons and photons). There will be a specific focus on actionable immune targets and their temporal patterns that can be tested in future hypofractionated-immunotherapy combination trials. This trial therefore is an important step towards future personalized immuno-radiotherapy combinations with the ultimate goal to improve survival for patients with HNSCC.
Detailed description
The HYDRA dose prescriptions are, in 20 fractions (instead of the conventional 35 fractions):
- Inhomogeneous focal boost on the macroscopic gross tumor volume (GTVprimary tumor and GTVnodes) on FDG-PET: mean dose 59Gy, max dose 63Gy.
- The mean dose of 59Gy corresponds to an equal late normal tissue toxicity probability after conventionally fractionated radiotherapy of 70Gy in 35 fractions, considering an α/β=3 for normal tissue.
- Simultaneous integrated boost (SIB) on the clinical target volume (CTV-P1 = GTV+5mm): 55Gy
- Elective field / CTV-P2 (GTV+10mm): 40Gy
Patients who receive the HYDRA intervention treatment, as well as patients who receive standard of care may require the addition of a concurrent radiosensitizer based on clinicopathological features according to standard of care. Currently, the only two registered radiosensitizers are platinum-based chemotherapy (cisplatin/carboplatin) and cetuximab. These radiosensitizers should be administered according to standard care treatment protocols.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
- Model description
- Two parallel, non-comparative phase-I trials of HYDRA-protons run at HollandPTC (group 1, n=25) and HYDRA-photons (group 3, n=25) run at the Erasmus MC. Toxicity will be monitored until 1 year after the last patient has completed HYDRA. This will result in a median follow-up of approximately 2 years. Patients will subsequently receive follow-up according to standard of care up to 5 years after treatment for the evaluation of very late-onset toxicity. For translational immune profiling, HYDRA-protons and HYDRA-photons will be randomized by minimization (1:1 ratio) against SOC: conventional fractionated proton therapy in HPTC (group 2, n=25) and conventional fractionated photon therapy in the Erasmus MC (group 4, n=25), respectively.
| Arm | Type | Receives |
|---|---|---|
| HYDRA-protons | Experimental | Radiation: HYpofractionated, Dose-redistributed RAdiotherapy (HYDRA)group 1, n=25, run at HollandPTC |
| Conventional fractionated proton therapy | Active comparator | Radiation: conventional fractionated radiotherapygroup 2, n=25, run at HollandPTC |
| HYDRA-photons | Experimental | Radiation: HYpofractionated, Dose-redistributed RAdiotherapy (HYDRA)group 3, n=25 run at Erasmus MC |
| Conventional fractionated photon therapy | Active comparator | Radiation: conventional fractionated radiotherapygroup 4, n=25 run at Erasmus MC |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (0 listed)
Key exclusion criteria (6 listed)
- Patients who do not meet the inclusion criteria as specified in paragraph 4.2, and/or who meet the following additional criteria:
- Previously treated by irradiation on the same target volume
- Chronic inflammatory disease or immune disorders which, according to the principal investigator, may disturb the translational immune-read out.
- Patients currently under treatment for other malignant disease (unless in situ carcinoma or basal cell carcinoma of the skin), or treated for other malignant disease within the last 2 years.
- Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule in the participating hospitals.
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 |
|---|---|---|
| HYpofractionated, Dose-redistributed RAdiotherapy (HYDRA)20 daily fractions, 5 times per week | Radiation | HYDRA-photons, HYDRA-protons |
| conventional fractionated radiotherapy35 daily fractions, 5 times per week | Radiation | Conventional fractionated photon therapy, Conventional fractionated proton therapy |
Primary outcome
Safety of HYDRA-protons and HYDRA-photons in terms of radiation-induced grade 3-4 late toxicity, physician-reported by CTCAE v5.0, monitored until 1 year after the last patient has completed HYDRA.
Time frame: month 1-36
HYDRA is randomized with standard of care for translational research purposes; a direct comparison of toxicity will statistically not be conclusive and is outside the scope of this study.
3 secondary outcomes
Objective response after HYDRA defined by radiological response on CT-scans or MRI in comparison to standard of care
Time frame: month 1-27
Efficacy of HYDRA in terms of in-field and nodal elective field tumor control at 1 year
Time frame: month 24-36
Immune profile (changes) between all 4 treatment groups
Time frame: month 1-27
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Feb 2024.
- Derived from this study: PubMed 41685200Gunsch PA, Kroesen M, Debets R, Keereweer S, van Meerten E, Zindler J, van Werkhoven E, Hoogeman M, Verduijn GM, Nout RA, Elbers JBW. HYpofractionated, dose-redistributed RAdiotherapy (HYDRA) versus conventional radiotherapy for head and neck cancer: planned interim analysis and dosimetric comparison from the phase I HYDRA trial. Clin Transl Radiat Oncol. 2026 Jan 25;58:101113. doi: 10.1016/j.ctro.2026.101113. eCollection 2026 May.
- Derived from this study: PubMed 37312053Elbers JBW, Gunsch PA, Debets R, Keereweer S, van Meerten E, Zindler J, van Norden Y, Hoogeman MS, Verduijn GM, Kroesen M, Nout RA. HYpofractionated, dose-redistributed RAdiotherapy with protons and photons to combat radiation-induced immunosuppression in head and neck squamous cell carcinoma: study protocol of the phase I HYDRA trial. BMC Cancer. 2023 Jun 13;23(1):541. doi: 10.1186/s12885-023-11031-w.
- Individual participant dataSharing planned: No. tba
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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.
Joris BW Elbers, MD, PhD principal investigator
Erasmus MC, Rotterdam / HollandPTC, Delft - The Netherlands
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing HYpofractionated, Dose-redistributed RAdiotherapy (HYDRA) and conventional fractionated radiotherapy in people with Head and Neck Squamous Cell Carcinoma and Hypofractionation, run by Joris B.W. Elbers at 1 site in Netherlands.
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 0 inclusion and 6 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: status not confirmed, as of the sponsor's last update on 20 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Joris BW Elbers, MD, PhD (0031207041249, j.elbers@erasmusmc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety of HYDRA-protons and HYDRA-photons in terms of radiation-induced grade 3-4 late toxicity, physician-reported by CTCAE v5.0, monitored until 1 year after the last patient has completed HYDRA. (time frame: month 1-36). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05364411, which also lists 2 linked publications.
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 20 Feb 2024.