An interventional study of External beam radiotherapy in Squamous Cell Carcinoma of the Head and Neck, sponsored by International Atomic Energy Agency. Status unknown at 11 sites in 9 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-08-08.
Sponsored by International Atomic Energy Agency · Not applicable, Interventional, and Treatment
The aim of the study is to test whether a resource-sparing 4-week, 20-fraction course of accelerated hypofractionated radiotherapy is non-inferior to accelerated radiotherapy delivering 33 fractions over 5.5 weeks in the treatment of patients with Stage I-IV squamous cell carcinoma of the pharynx, larynx and oral cavity with the exception of paranasal sinus, nasopharyngeal and stage I-II glottic carcinomas.
Worldwide, head and neck squamous cell carcinomas (HNSCC) constitute approximately 7% of all incident cancers, and 75% of these are seen in low- and middle-income countries. Life-style factors, in particular tobacco and alcohol consumption, are major etiological factors although an increasing number of HNSCC cases are associated with viral infections (Epstein Barr Virus and Human Papilloma Virus). Radiation therapy (RT) alone or combined with cytotoxic or molecular targeted agents is a mainstay as definitive treatment for previously untreated locally advanced disease. This therapy offers organ and functional preservation in many cases with an approximate 30 to 50% of cases obtaining longterm loco-regional tumor control. Accelerated RT, that is increasing the weekly delivered radiation dose above the conventional 10 Gy per week, has been shown in a large number of randomized controlled trials to be associated with an improved efficacy to toxicity ratio relative to standard fractionation provided a careful balance between total dose, dose per fraction and overall treatment time is chosen. The Danish Head and Neck Cancer Group trial DAHANCA 6/7 tested a schedule of accelerated normofractionated radiation therapy for HNSCC delivering 6 fractions of 2.0 Gy per week to a total dose of 66-68 Gy. This schedule gave a 10% improvement in loco-regional tumor control compared with the same dose delivered with 5 fractions per week. The DAHANCA 6/7 schedule was tested in the IAEA ACC trial, comparing again 6 vs. 5 fractions per week but allowing the total dose to range from 66 Gy to 70 Gy. The outcome of the IAEA ACC trial also showed a significant 13% improvement in loco-regional control in the accelerated arm. Thus, accelerating RT by delivering 6 fractions per week may reasonably be considered a standard of care for definitive RT alone. Clinical evidence points in the direction of a 4 week accelerated, hypofractionated schedule as being a radiobiologically interesting alternative to accelerated schedules using more fractions for treatment of HNSCC. A series of exploratory calculations suggested that an attractive schedule could be 55 Gy in 20 fractions (2.75 Gy per fraction) delivered over 4 weeks and this schedule was chosen for the test arm of HYPNO. There is historical experience with this schedule in the North of UK and in many countries in the British Commonwealth. The aim of this study is to test whether this resource-sparing 4-week course of accelerated hypofractionated radiotherapy is non-inferior to radiotherapy delivering 33 fractions over 5.5 weeks.
The study design is a stratified, balanced, and randomized study (phase III) recruiting patients with Stage I to IV squamous cell carcinoma of the pharynx, larynx and oral cavity with the exception of paranasal sinus, nasopharyngeal and stage I to II glottic carcinomas. Patients will be assigned to the test arm or the control arm by central, randomization, stratified according to the following characteristics:
Patients are reviewed at least once a week during treatment. Time and severity of early radiation reactions in mucosa and skin are noted. These data are registered on the Treatment Response Form. Patients are seen about 2 months after the end of treatment to record persistent early toxicities and early tumor response, both at the primary and nodal site. Afterwards, the patients are seen every 3 months for 2 years and 6 monthly for 3 years bringing the total trial follow-up to just over 5 years. CRFs are designed to record all the information for an individual study subject required by the study protocol. The purpose of the CRF is threefold: i) to ensure data collection in accordance with the study protocol; ii) to fulfill the regulatory requirements for data collection; iii) to facilitate the effective, comprehensive data processing and analysis, results reporting, and to promote structured collection of safety and efficacy data. The completed CRF's are submitted by email to the Data Center: hypno@humonc.wisc.edu where the data will be electronically transferred to the central trial database. HYPNO uses a rather novel design as a non-inferiority trial with dual primary endpoints. The primary efficacy endpoint is 3 year loco-regional control (LRC) - even though 5 year disease status will also be collected - and the primary toxicity endpoint is 3 year grade 2 or higher (moderate or severe) side effects (TOX). All times to events will be measured from the date of randomization. The test arm (HYPNO -T) will be declared non-inferior to the control arm if both i) LRC in the test arm is non-inferior to that of the control arm AND ii) Late toxicity in the test arm is non-inferior (i.e. not worse) than in the control arm. This design has been developed in collaboration with the HYPNO trial statistician, Prof. Richard Chappell, Department of Biostatistics and Medical Informatics, University of Wisconsin - Madison.
Statistical formulation of the non-inferiority hypotheses with dual primary endpoints:
HYPOTHESIS I:
H0: LRC in the TEST arm less than LRC in the CONTROL arm (Test arm inferior to control arm with respect to LRC). HA: LRC in the TEST arm greater than or equal to LRC in the CONTROL arm (Test arm non-inferior to control arm with respect to LRC).
HYPOTHESIS II:
H0: TOX in the TEST arm greater than TOX in the CONTROL arm (Experimental treatment inferior to control treatment with respect to late toxicity).
HA: TOX in the TEST arm less than or equal to TOX in the CONTROL arm (Experimental treatment non-inferior to control treatment with respect to late toxicity).
The required sample size in this kind of design depends heavily on the choice of the inferiority margin, with decreasing values leading to a steep increase in the sample size. It also depends to some extend on the baseline 3 year LRC and TOX rates. These were selected based on the published results from the IAEA-ACC trial. Thus, the target sample size is 836 patients. The primary analysis will be performed for all randomized patients using the intention-to-treat principle.
A QA committee will be formed and they will be charged with all aspects of quality assurance and credentialing of centers for participation in HYPNO. Each participating center should appoint a contact person for QA issues (physician or physicist).
Data exchange dummy run Before the first patient can be randomized in a center, a 'dry run' of the data exchange is conducted. To this end, a HNSCC patient from the center will be arbitrarily chosen by the local investigator and a set of CRFs filled in for this case and submitted electronically to the Data Center.
Machine level QA An associated GCP and QA program securing compliance with the protocol will be established between the IAEA, the Data Center and involved departments. Participation in the IAEA TLD audit is mandatory for centers participating in the HYPNO trial. A credentialing QA program will be developed for departments using IMRT.
Patient level QA Radiotherapy plans and dose-volume histogram (DVH) data for the first two patients on trial from a center will be submitted for central review, if possible in electronic form. During the period when a center is accruing patients for the trial, the Data Center will randomly select a subset of patients (5-10%, a smaller proportion reviewed for highly accruing centers) for a 'crossed' review where 3-4 centers will review cases. It is expected that the total number of cases reviewed for HYPNO will not exceed 50.
An Independent Data Monitoring Committee (IDMC) will be appointed. Recommendations to stop patient accrual early for safety or efficacy reasons can only be made by the IDMC. Participating centers will not be informed about comparative effectiveness or toxicity in the trial arms as long as the trial is open for accrual.
An associated translational research program is planned. Formally these studies will run as separate research protocol and separate informed consent from patients will have to be obtained according to the relevant national regulations.
2,018 studies on the registry are indexed under Squamous Cell Carcinoma of Head and Neck; 573 are open to participants now.
This study's planned enrollment of 836 is above the median of 48 across 1,653 interventional studies indexed under Squamous Cell Carcinoma of Head and Neck.
Browse Squamous Cell Carcinoma of Head and Neck studies →International Atomic Energy Agency is the lead sponsor of 12 studies on the registry; 1 is open to participants now.
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Impaired function of liver is defined as elevation of liver enzymes by 2.5 times the reference value for the institution and of kidney as serum creatinine by 1.5 times the upper limit of the normal reference value for the institution by routine laboratory examinations or level less than 50 ml/min
Exclusion Criteria
3.5. Additional criterion for patients receiving chemotherapy
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
The study doctor’s estimate of how long someone is likely to live. Criteria use it so that people can stay in the study long enough for it to answer its question.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ECOG performance status
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Creatinine clearance (CrCl)
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Metastases
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Life expectancy
The study doctor’s estimate of how long someone is likely to live. Criteria use it so that people can stay in the study long enough for it to answer its question.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
'Standard' external beam radiotherapy to deliver 66Gy in 33 fractions treating with 6 fractions a week.
Radiation: External beam radiotherapy
The experimental regimen in which patients receive external beam radiotherapy to deliver 55Gy in 20 fractions treating 5 times a week.
Radiation: External beam radiotherapy
External beam radiotherapy using megavoltage radiotherapy with radical intent.
Also known as: Radical radiotherapy
Primary tumor control in T and N position
Time frame: 3 years after date of randomisation in HYPNO
Treatment related late Grade 2+ toxicity (CTCAE 4.0)
Time frame: 3 years after date of randomisation in HYPNO
Overall survival
Time frame: 1, 3 and 5 years after date of randomisation in HYPNO
Disease free survival
Time frame: 1, 3 and 5 years after date of randomisation in HYPNO
Any other treatment related early and late morbidities (CTCAE 4.0)
Time frame: 1 and 3 years after date of randomisation in HYPNO
EORTC QOL-C30/HN-35 (optional)
Time frame: 1 and 3 years after date of randomisation in HYPNO
Plan to share: No
No publications or documents are linked to this record.
The record gives a start of Mar 2014, a primary completion of Nov 2020 and a completion of Nov 2021. It does not say whether these dates are actual or estimated.
How these figures are worked out, and which studies are left out of them.
This study is status unknown, as verified in Aug 2019. You cannot join it, but the record below documents what was studied.
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International Atomic Energy Agency