Head and Neck Squamous Cell Carcinoma (HNSCC)Phase 2ORIONNCT07888816
Optimizing Response to Immunotherapy With Online Adaptive Pulsed Radiotherapy in Incurable Head and Neck Cancers
A Phase 2 study testing Pulsed Adaptive Radiotherapy Combined with Pembrolizumab with or without chemotherapy in people with Head and Neck Squamous Cell Carcinoma (HNSCC), run by University Health Network, Toronto at 1 site in Canada.
Trial summary
The ORION study will evaluate a novel treatment approach for patients with recurrent, metastatic, oligometastatic, or locoregionally incurable head and neck squamous cell carcinoma (HNSCC). 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 (HNSCC)
- What is being tested?
- Pulsed Adaptive Radiotherapy Combined with Pembrolizumab with or without chemotherapy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 48 participants
- Where
- 1 siteCanada
- Study dates
- 1 Nov 2026to 30 Sep 2029
- Phase
- Phase 2
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
- Age ≥ 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Estimated life expectancy ≥ 6 months
- Histologically confirmed mucosal head and neck squamous cell carcinoma (HNSCC) of the nasal cavity, nasopharynx, oral cavity, oropharynx, hypopharynx, larynx, or other mucosal site
- Disease not amenable to curative-intent local therapy
- Radiographically evident disease at the planned pulsed RT target(s)
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- Patient must meet criteria for one of three cohorts: Cohort 1: Newly diagnosed locoregionally advanced or metastatic HNSCC unfit for curative-intent therapy, Cohort 2: Recurrent and/or metastatic disease after prior local therapy, Cohort 3: Oligoprogression (≤5 sites) on immunotherapy ± chemotherapy
- Candidate for immunotherapy as determined by medical oncologist
- For chemotherapy-eligible patients, candidate for platinum-based chemotherapy
- Planned RT target(s) within the head and neck region amenable to delivery on Varian Ethos with online adaptive replanning for at least one site.
- For patients with RT target(s) outside head and neck, they may be treated with online or offline adapted pulsed RT
- Adequate organ function for initiation of immunotherapy as determined by the medical oncologist.
- Women of childbearing potential must have a negative serum pregnancy test within 7 days of fifirst study treatment
- Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life and/or health utility questionnaires in English. Inability (lack of comprehension in English, or other equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible.
- Written informed consent obtained prior to any study-specific procedures.
Who cannot join
- Two or more prior courses of radiotherapy to a planned re-irradiation site
- Laryngeal local recurrence requiring RT after prior ≥ 50 Gy to the larynx
- Previous RT to the target lesion(s) completed within 6 months before enrollment
- Uncontrolled brain metastases (controlled/treated brain metastases are permitted)
- Active second malignancy requiring treatment, with the exception of localized cutaneous malignancy or in-situ disease
- Head and neck target not amenable to RT delivery on Varian Ethos with online adaptive replanning
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- Contraindication to immune checkpoint inhibitors, including: Active autoimmune disease requiring systemic immunosuppressive therapy, Prior grade ≥ 3 immune-related adverse event attributable to prior ICI therapy, Active or recent (within 6 months) interstitial lung disease or pneumonitis requiring corticosteroids
- Hypersensitivity to pembrolizumab
- Pregnancy or breastfeeding
- Inability to lie supine for online adaptive radiotherapy delivery
- Any uncontrolled medical condition that, in the opinion of the investigator, would compromise patient safety or study compliance
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Canada1 site
Princess Margaret Cancer Center
Toronto, Ontario, M5A2M9
Nauman Malik, nauman.malik@uhn.ca
About this study
The ORION study will evaluate a novel treatment approach for patients with recurrent, metastatic, oligometastatic, or locoregionally incurable head and neck squamous cell carcinoma (HNSCC). Participants will receive pulsed adaptive radiotherapy delivered in 3 to 5 treatment courses approximately 10 days apart, alongside standard-of-care pembrolizumab with or without chemotherapy. Using advanced imaging and adaptive treatment planning, radiotherapy will be tailored to changes in tumor size and surrounding tissues throughout treatment. The study will assess safety, disease control, progression-free survival, quality of life, and biological markers of treatment response. Researchers hypothesize that combining pulsed radiotherapy with systemic therapy will improve 12-month progression-free survival from 17% to 32%, potentially leading to improved outcomes for patients with advanced head and neck cancer.
- Being tested
- Pulsed Adaptive Radiotherapy Combined with Pembrolizumab with or without chemotherapy
- 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.
Pulsed Adaptive Radiotherapy Combined with Pembrolizumab with or without chemotherapyCombination product
The primary tumor in the head and neck region, or dominant metastatic site, will be treated with pulsed RT consisting of 8 Gy pulses delivered every 10-11 days for a total of 5 pulses, delivered exclusively with online adaptive radiotherapy on the Varian Ethos platform. Concomitantly, patients will be treated with the standard systemic treatment with pembrolizumab with or without chemotherapy.
| Study group | Role | What they receive |
|---|---|---|
| Pulsed Adaptive Radiotherapy Plus Pembrolizumab ± Chemotherapy | Experimental | Not described Receives: Combination Product: Pulsed Adaptive Radiotherapy Combined with Pembrolizumab with or without chemotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
12-Month Progression-Free Survival
12-month progression-free survival will be estimated using the Kaplan-Meier method. The proportion of patients progression-free at 12 months will be compared to the historical benchmark of 17%. The study will be considered positive if the lower bound of the 95% confidence interval exceeds 17%.
Measured: 12 months
Secondary outcomes (13)
12-Month Modified Progression-Free Survival (mPFS)
Modified progression-free survival is defined as the time from study enrollment to disease progression that is no longer amenable to local salvage radiotherapy or death from any cause, whichever occurs first.
Measured: 12 months
Treatment-Related Adverse Events
The incidence, severity, and type of acute and late treatment-related adverse events will be assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 6.0.
Measured: 12 Months
Changes in Patient-Reported Quality of Life
Assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) with higher scores indicating better quality of life. Changes from baseline will be assessed at each study time point.
Measured: 12 Months
Changes in Patient-Reported Quality of Life and Functional Outcomes
Assessed using the EORTC Head and Neck Cancer Module (QLQ-H\&N43). Scores range from 0 to 100 scale where for the functional scales, higher scores indicate better functioning. For symptom scales and symptom items, higher scores indicate greater symptom burden or worse symptoms. Changes from baseline over the study period will be evaluated.
Measured: 12 Months
Swallowing Function
Swallowing function will be assessed using the Functional Oral Intake Scale (FOIS), where scores range from 1 to 7, where 1 indicates no oral intake (nothing by mouth) and 7 indicates a full oral diet with no restrictions. Higher scores indicate better oral intake and swallowing function. Changes from baseline over the study period will be evaluated.
Measured: 12 Months
Changes in Patient-Reported Quality of Life and Functional Outcomes
Assessed using the Performance Status Scale for Head and Neck Cancer (PSS-HN), which evaluates three domains: Normalcy of Diet, Eating in Public, and Understandability of Speech. Each domain is scored separately on a scale from 0 to 100, with higher scores indicating better function and less impairment. Changes from baseline over the study period will be evaluated.
Measured: 12 Months
Median Progression-Free Survival (PFS)
Estimated using the Kaplan-Meier method with 95% confidence intervals
Measured: 12 months
Median Overall Survival (OS)
Estimated using the Kaplan-Meier method with 95% confidence intervals
Measured: 12 months
Objective Response Rate (ORR)
Reported as a proportion with 95% confidence intervals
Measured: 12 months
Duration of Response (DoR)
Estimated using the Kaplan-Meier method with 95% confidence intervals
Measured: 12 months
Time to Next Systemic Therapy
Estimated using the Kaplan-Meier method, with patients censored at last contact if they have not initiated next-line therapy
Measured: 12 months
Health Economic Impact
Health economic outcomes will be assessed through measures of healthcare resource utilization (Total treatment visits, imaging utilization, resource utilization) compared to historical conventional palliative RT cohorts.
Measured: 12 months
Financial Toxicity
Patient-reported financial toxicity using Financial Toxicity Questionnaire, with higher scores indicating less financial distress (better financial well-being) and lower scores indicating greater financial toxicity (worse financial burden).
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Oct 2026
- Study start1 Nov 2026 (estimated)
- Primary completion30 Sep 2029 (estimated)
- Study completion30 Sep 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Head and Neck Squamous Cell Carcinoma (HNSCC)Studies of the same condition, open and under way.
- More trials run by University Health Network, TorontoThe sponsor's other registered studies.
- 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 48 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Health Network, Toronto
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07888816
- Sponsor's protocol ID
- 26-5660
- Acronym
- ORION
- Status last verified
- Oct 2026
- First submitted
- 8 Oct 2026
- Last updated
- 22 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No