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HYpofractionated, Dose-redistributed RAdiotherapy With Protons and Photons in HNSCC (HYDRA)

Primary Purpose

Head and Neck Squamous Cell Carcinoma, Hypofractionation, Radiotherapy

Status

Recruiting

Phase

Not Applicable

Locations

Netherlands

Study Type

Interventional

Intervention

HYpofractionated, Dose-redistributed RAdiotherapy (HYDRA)

conventional fractionated radiotherapy

About this trial

This is an interventional treatment trial for Head and Neck Squamous Cell Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

In order to be eligible to participate in this study, a subject must meet all of the following criteria:

≥ 18 years old at time of signing informed consent.
WHO 0-2
Squamous cell carcinoma of the oropharynx, hypopharynx and larynx* proven by cytology / histology
Patients amenable for curative intent proton therapy (by model-based selection criteria, according to the Dutch standard of care) or photon therapy.
Radiotherapy with or without concurrent radiosensitizer.
Ability to understand the requirements of the study and to give written informed consent, as determined by the treating physician.
Written informed consent obtained.
- Note: The HYDRA dose prescriptions should be applicable for all HNSCC patients and should therefore ideally be tested within the full range of treatment indications, e.g. multiple tumor subsites and both chemoradiotherapy and radiotherapy alone. There are several reports about acceptable acute toxicity following hypofractionated chemoradiotherapy in advanced stage HNSCC. However, concerns about late toxicity remain, especially for laryngeal carcinoma. Patients with laryngeal carcinoma are therefore initially excluded, until these patients are also considered eligible for treatment with HYDRA. The statistical considerations and interim safety analyses for this purpose and the decision-making / consultation are further described elsewhere.

Exclusion criteria

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.

Sites / Locations

Erasmus MCRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Experimental

Active Comparator

Arm Label

HYDRA-protons

Conventional fractionated proton therapy

HYDRA-photons

Conventional fractionated photon therapy

Arm Description

group 1, n=25, run at HollandPTC

group 2, n=25, run at HollandPTC

group 3, n=25 run at Erasmus MC

group 4, n=25 run at Erasmus MC

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

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.

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.

Full Information

NCT ID

NCT05364411

First Posted

April 28, 2022

Last Updated

December 7, 2022

Sponsor

Joris B.W. Elbers

Collaborators

Erasmus Medical Center, HollandPTC

1. Study Identification

Unique Protocol Identification Number

NCT05364411

Brief Title

HYpofractionated, Dose-redistributed RAdiotherapy With Protons and Photons in HNSCC

Acronym

HYDRA

Official Title

HYpofractionated, Dose-redistributed RAdiotherapy With Protons and Photons to Combat Radiation-induced Immunosuppression in Head and Neck Squamous Cell Carcinoma (HYDRA)

Study Type

Interventional

2. Study Status

Record Verification Date

December 2022

Overall Recruitment Status

Recruiting

Study Start Date

October 10, 2022 (Actual)

Primary Completion Date

June 1, 2024 (Anticipated)

Study Completion Date

June 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Joris B.W. Elbers

Collaborators

Erasmus Medical Center, HollandPTC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Head and Neck Squamous Cell Carcinoma, Hypofractionation, Radiotherapy, Proton Therapy, Immune System Suppression

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

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)

Allocation

Randomized

Enrollment

100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

HYDRA-protons

Arm Type

Experimental

Arm Description

group 1, n=25, run at HollandPTC

Arm Title

Conventional fractionated proton therapy

Arm Type

Active Comparator

Arm Description

group 2, n=25, run at HollandPTC

Arm Title

HYDRA-photons

Arm Type

Experimental

Arm Description

group 3, n=25 run at Erasmus MC

Arm Title

Conventional fractionated photon therapy

Arm Type

Active Comparator

Arm Description

group 4, n=25 run at Erasmus MC

Intervention Type

Radiation

Intervention Name(s)

HYpofractionated, Dose-redistributed RAdiotherapy (HYDRA)

Intervention Description

20 daily fractions, 5 times per week

Intervention Type

Radiation

Intervention Name(s)

conventional fractionated radiotherapy

Intervention Description

35 daily fractions, 5 times per week

Primary Outcome Measure Information:

Title

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.

Description

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.

Time Frame

month 1-36

Secondary Outcome Measure Information:

Title

Objective response after HYDRA defined by radiological response on CT-scans or MRI in comparison to standard of care

Description

Time Frame

month 1-27

Title

Efficacy of HYDRA in terms of in-field and nodal elective field tumor control at 1 year

Description

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.

Time Frame

month 24-36

Title

Immune profile (changes) between all 4 treatment groups

Description

Time Frame

month 1-27

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

In order to be eligible to participate in this study, a subject must meet all of the following criteria: ≥ 18 years old at time of signing informed consent. WHO 0-2 Squamous cell carcinoma of the oropharynx, hypopharynx and larynx* proven by cytology / histology Patients amenable for curative intent proton therapy (by model-based selection criteria, according to the Dutch standard of care) or photon therapy. Radiotherapy with or without concurrent radiosensitizer. Ability to understand the requirements of the study and to give written informed consent, as determined by the treating physician. Written informed consent obtained. Note: The HYDRA dose prescriptions should be applicable for all HNSCC patients and should therefore ideally be tested within the full range of treatment indications, e.g. multiple tumor subsites and both chemoradiotherapy and radiotherapy alone. There are several reports about acceptable acute toxicity following hypofractionated chemoradiotherapy in advanced stage HNSCC. However, concerns about late toxicity remain, especially for laryngeal carcinoma. Patients with laryngeal carcinoma are therefore initially excluded, until these patients are also considered eligible for treatment with HYDRA. The statistical considerations and interim safety analyses for this purpose and the decision-making / consultation are further described elsewhere. Exclusion criteria 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Joris BW Elbers, MD, PhD

Phone

0031207041249

j.elbers@erasmusmc.nl

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Joris BW Elbers, MD, PhD

Organizational Affiliation

Erasmus MC, Rotterdam / HollandPTC, Delft - The Netherlands

Official's Role

Principal Investigator

Facility Information:

Facility Name

Erasmus MC

City

Rotterdam

State/Province

Zuid Holland

ZIP/Postal Code

3015 GL

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jos Elbers

Phone

0031107041249

j.elbers@erasmusmc.nl

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

tba

Learn more about this trial

HYpofractionated, Dose-redistributed RAdiotherapy With Protons and Photons in HNSCC

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