Carcinoma of the Head and NeckPhase 2FAMOSONCT03001570
Accelerated Modulated Fractionation (SIB-IMRT) for Head and Neck District
A Phase 2 study testing Cetuximab plus Radiotherapy in people with Carcinoma of the Head and Neck, run by European Institute of Oncology at 1 site in Italy.
Trial summary
Nowadays the association between radiotherapy and the anti- Epidermal Growth Factor Receptor (anti-EGFR) monoclonal antibody Cetuximab represents a valid option in the treatment of head and neck locally advanced squamous neoplasm and, particularly, of oropharynx carcinoma. Read more about this study
- Who is it for?
- Ages 18 to 90 years
- Conditions the study is for
- Carcinoma of the Head and Neck
- What is being tested?
- Cetuximab plus Radiotherapy
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteItaly
- Study dates
- Jan 2014to Dec 2023
- Phase
- Phase 2
- 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 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with histological proof of locally advanced squamous carcinoma of oropharynx, larynx, hypopharynx (stage III and Iva)
- Overexpression of EGFR (>50%)
- Patients previously considered non-eligible for curative radio-chemotherapy for clinical reasons.
- Performance Status (ECOG) ≤ 2
- Age ≥ 18 years
- Possibility of correct administration of treatment
- Written informed consent
Who cannot join
- Distant metastases
- Oral cavity or rhinopharynx neoplasm
- Need of cutaneous bolus
- Previous treatments on head and neck district
- Collagenopathies or other severe systemic disease
- Severe cardiopathies or myocardial infarction in the previous 12 months, serious hepatopathies or other diseases with heavy impact on general conditions.
- Psychiatric disorders or other conditions preventing from expressing informed consent.
Trial locations and contacts
1 site in 1 country.
Roberto Orecchia, Prof. contact
Daniela Alterio, MD contact
Italy1 site, 1 recruiting
- Recruiting
Division of Radiotherapy European Institute of Oncology
Milan, MI, 20141
Daniela Alterio, MD, daniela.alterio@ieo.it
About this study
Official title: Accelerated Modulated Fractionation (SIB-IMRT) for the Treatment of Locally Advanced Squamous Cell Carcinoma From Head and Neck District
Nowadays the association between radiotherapy and the anti- Epidermal Growth Factor Receptor (anti-EGFR) monoclonal antibody Cetuximab represents a valid option in the treatment of head and neck locally advanced squamous neoplasm and, particularly, of oropharynx carcinoma. Up to date we have only indirect comparison with the standard curative treatment (i.e. concurrent radiochemotherapy) and the preliminary data show equivalent efficacy of both regimens. For this reason, concurrent Cetuximab and radiotherapy is administered in patients not eligible to chemoradiotherapy. The introduction of Cetuximab has been associated to new kind of toxicities, especially cutaneous, that have increasingly reported.
The aim of our study is to improve the toxicity/benefit ratio in patients receiving concurrent radiotherapy and cetuximab for locally advanced head and neck neoplasm. Hence, this improvement could be achieved by modulating radiation therapy dose per fraction following Cetuximab pharmacokinetics.
Read the detailed description
Radiobiological rationale Overexpression of EGFR has been found to be involved into two different mechanisms of response to ionizing radiations: the former is related to the increased cell proliferation rate, the latter leading to lower radiosensitivity.
- Increasing of cell proliferation rate From an analysis of the already reported evidences, we quantified the effect of a higher cell proliferation rate due to overexpression of EGFR. These findings were reported in patients affected with squamous carcinoma of head and neck district and evaluated for EGFR status. In those patients, local recurrence was compared in patients with different length of treatment but at the same fractionation. Consequently, the real doubling time in the subgroups with high and low EGFR expression was extrapolated . From these extrapolated values, equivalent doses of each day of non-delivered treatment have been calculated for patients who received accelerated schedule. Furthermore, doses were reported in relation to the different primary sites (oropharynx, larynx, oral cavity, hypopharynx). Modification of doubling time (TD) of neoplastic cell population in patients with Low and High EGFR expression.
- Reduction of radiosensitivity Unfortunately, how radiosensitizing drugs can modify radiosensitivity cannot be evaluated retrospectively. Actually, the efficacy is evaluated on the basis of an overall effect of the treatment but radiosensitivity changes day by day in radiation and pharmacological concurrent treatment. However, these changing in radiosensitivity can be analysed in pre-clinical setting. In many reports, a progressively higher radiosensitivity has been shown in cellular survival curves by increasing EGFR inhibitor concentration. Nevertheless, the concentrations of EGFR inhibitor do not correspond to in vivo concentration during radiotherapy delivery. Fortunately, this data is obtainable from Cetuximab pharmacokinetic curve. Therefore, cell survival curves corresponding to drug concentration were obtained by performing a graphic interpolation. From these curves, daily radiosensitivity parameters were found.
Subsequently, daily doses with respect to daily radiosensitivity were identified by radiobiological calculation model. This fractionation, designed on Cetuximab pharmacokinetics, have been calculated to be equivalent to curative treatment (70Gy given with conventional schedule).
At the same time, lower cutaneous toxicity is expected with this "modulated" schedule due to the possibly increased cellular repair. Pharmacokinetics data of Cetuximab we found on the population: Vmax 4.38mg/h (15.4%), Km 74g/ml, central compartment volume Vl 2.83 l (18.6%), peripheral compartment volume 2.43 l (56.4%) and intercompartmental clearance 0.103 l/h (97.2%). Those parameters remain unmodified also during prolonged therapies. Administrated doses have been found to be adequate to cell wall receptors saturation.
A definition of overexpression of EGFR is still lacking. Different cut-offs have been proposed to distinguish patients with "high expression" from patients with "low expression" of EGFR. In a recent study the adoption of accelerated fractionation showed an advantage for those patients with an expression of EGFR>50%. Thus, we adopted this cut-off in our study.
- Conditions
- Carcinoma of the Head and Neck
- Being tested
- Cetuximab plus Radiotherapy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Cetuximab plus RadiotherapyDrug
Also called Radiotherapy, IMRT
Standard dose of a curative radiotherapy treatment is 70Gy given with conventional fractionation (2G daily) in an overall length of 7 weeks. In this study, the fractionation has been modified accordingly Cetuximab pharmacokinetics. Cetuximab will be administered with standard schedule: charge dose of 400mg/mq a week before the beginning of concurrent treatment, then weekly doses of 250mg/mq intravenous for 7 administration. This schedule to obtain the same biological efficacy on tumour with lower toxicity on healthy tissues.
| Study group | Role | What they receive |
|---|---|---|
| Arm 1 | Experimental | Radiotherapy treatment associated with concurrent Cetuximab administration.
Patients candidate to curative concurrent Cetuximab and Radiotherapy are eligible for this study. After expressing written informed consent, patients will perform CT simulation. Then an IMRT-SIB (Simultaneous Integrated Boost) treatment plan will be elaborated and deliver the following Cetuximab pharmacokinetic:
Length: 6 weeks; 1 fraction daily (From Monday to Friday) 30 Total Fractions (5 per week, 6 weeks of treatment). Cetuximab will be administered weekly from a week before starting radiotherapy until the end of treatment for 7 subsequent administration accordingly to the standard schedule (1 before and 6 during radiotherapy). Receives: Drug: Cetuximab plus Radiotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of patients who experienced acute toxicity with Grade 3 or Grade 4 adverse events according to Scala CTCAE v4.0 toxicity criteria and scale Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG / EORTC)
During radiotherapy, patients will be assessed weekly for acute toxicity using validated international scales.acute toxicity will be assessed with CTCAE V 4.03 (Common Terminology Criteria of Adverse Events Version 4.03) scale.
Furthermore pain (NRS pain scale) nutritional assessment (weight in kilograms ) will be performed.
Measured: up to 7 days during RT treatment
Secondary outcomes (2)
Number of patients who experienced late toxicity with Grade 3 or Grade 4 adverse events according to Scala CTCAE v4.0 toxicity criteria and scale RTOG / EORTC
Patients will be assessed weekly for late toxicity using validated international scales.acute toxicity will be assessed with CTCAE V 4.03 (Common Terminology Criteria of Adverse Events Version 4.03) scale.
Measured: up to 6-8 weeks after treatment completion and then up to 2 years
Number of patients who experienced local or distance recurrence of disease assessed through clinical and radiological controls
Clinical assessment will be performed through:
- Otolaryngology examination and laryngoscopy Radiological assessment will be performed through:
- Facial skeleton and neck MRI with and without contrast or CT with and without contrast if MRI is unfeasible.
Measured: up to 6-8 weeks after treatment completion and then up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Dec 2016 (estimated)
- Study startJan 2014
- Primary completionDec 2018
- Study completionDec 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Carcinoma of the Head and NeckStudies of the same condition, open and under way.
- More trials run by European Institute of OncologyThe 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
- 10 participants (estimated)
Sponsor and investigators
- Lead sponsor
- European Institute of Oncology
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Roberto Orecchia, Prof, Study director, European Institute of Oncology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03001570
- Sponsor's protocol ID
- European Institute of Oncology
- Acronym
- FAMOSO
- Status last verified
- Jun 2023
- First submitted
- 12 Dec 2016
- Last updated
- 28 Jun 2023
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 28 Jun 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Accelerated Modulated Fractionation (SIB-IMRT) for the Treatment of Locally Advanced Squamous Cell Carcinoma From Head and Neck District
- ClinicalTrials.gov ID
- NCT03001570
- Acronym / sponsor ID
- FAMOSO / European Institute of Oncology
- Conditions
- Carcinoma of the Head and Neck
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 10 participants (estimated)
- Lead sponsor
- European Institute of OncologyUniversity, hospital or other
- Study start
- Jan 2014
- Primary completion
- Dec 2018 (actual)
- Study completion
- Dec 2023 (estimated)
- First posted
- 23 Dec 2016 (estimated)
- 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.
Nowadays the association between radiotherapy and the anti- Epidermal Growth Factor Receptor (anti-EGFR) monoclonal antibody Cetuximab represents a valid option in the treatment of head and neck locally advanced squamous neoplasm and, particularly, of oropharynx carcinoma. Up to date we have only indirect comparison with the standard curative treatment (i.e. concurrent radiochemotherapy) and the preliminary data show equivalent efficacy of both regimens. For this reason, concurrent Cetuximab and radiotherapy is administered in patients not eligible to chemoradiotherapy. The introduction of Cetuximab has been associated to new kind of toxicities, especially cutaneous, that have increasingly reported.
The aim of our study is to improve the toxicity/benefit ratio in patients receiving concurrent radiotherapy and cetuximab for locally advanced head and neck neoplasm. Hence, this improvement could be achieved by modulating radiation therapy dose per fraction following Cetuximab pharmacokinetics.
Detailed description
Radiobiological rationale Overexpression of EGFR has been found to be involved into two different mechanisms of response to ionizing radiations: the former is related to the increased cell proliferation rate, the latter leading to lower radiosensitivity.
- Increasing of cell proliferation rate From an analysis of the already reported evidences, we quantified the effect of a higher cell proliferation rate due to overexpression of EGFR. These findings were reported in patients affected with squamous carcinoma of head and neck district and evaluated for EGFR status. In those patients, local recurrence was compared in patients with different length of treatment but at the same fractionation. Consequently, the real doubling time in the subgroups with high and low EGFR expression was extrapolated . From these extrapolated values, equivalent doses of each day of non-delivered treatment have been calculated for patients who received accelerated schedule. Furthermore, doses were reported in relation to the different primary sites (oropharynx, larynx, oral cavity, hypopharynx). Modification of doubling time (TD) of neoplastic cell population in patients with Low and High EGFR expression.
- Reduction of radiosensitivity Unfortunately, how radiosensitizing drugs can modify radiosensitivity cannot be evaluated retrospectively. Actually, the efficacy is evaluated on the basis of an overall effect of the treatment but radiosensitivity changes day by day in radiation and pharmacological concurrent treatment. However, these changing in radiosensitivity can be analysed in pre-clinical setting. In many reports, a progressively higher radiosensitivity has been shown in cellular survival curves by increasing EGFR inhibitor concentration. Nevertheless, the concentrations of EGFR inhibitor do not correspond to in vivo concentration during radiotherapy delivery. Fortunately, this data is obtainable from Cetuximab pharmacokinetic curve. Therefore, cell survival curves corresponding to drug concentration were obtained by performing a graphic interpolation. From these curves, daily radiosensitivity parameters were found.
Subsequently, daily doses with respect to daily radiosensitivity were identified by radiobiological calculation model. This fractionation, designed on Cetuximab pharmacokinetics, have been calculated to be equivalent to curative treatment (70Gy given with conventional schedule).
At the same time, lower cutaneous toxicity is expected with this "modulated" schedule due to the possibly increased cellular repair. Pharmacokinetics data of Cetuximab we found on the population: Vmax 4.38mg/h (15.4%), Km 74g/ml, central compartment volume Vl 2.83 l (18.6%), peripheral compartment volume 2.43 l (56.4%) and intercompartmental clearance 0.103 l/h (97.2%). Those parameters remain unmodified also during prolonged therapies. Administrated doses have been found to be adequate to cell wall receptors saturation.
A definition of overexpression of EGFR is still lacking. Different cut-offs have been proposed to distinguish patients with "high expression" from patients with "low expression" of EGFR. In a recent study the adoption of accelerated fractionation showed an advantage for those patients with an expression of EGFR>50%. Thus, we adopted this cut-off in our study.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Arm 1 | Experimental | Drug: Cetuximab plus RadiotherapyRadiotherapy treatment associated with concurrent Cetuximab administration. Patients candidate to curative concurrent Cetuximab and Radiotherapy are eligible for this study. After expressing written informed consent, patients will perform CT simulation. Then an IMRT-SIB (Simultaneous Integrated Boost) treatment plan will be elaborated and deliver the following Cetuximab pharmacokinetic: Length: 6 weeks; 1 fraction daily (From Monday to Friday) 30 Total Fractions (5 per week, 6 weeks of treatment). Cetuximab will be administered weekly from a week before starting radiotherapy until the end of treatment for 7 subsequent administration accordingly to the standard schedule (1 before and 6 during radiotherapy). |
Who may qualify
- Ages
- 18 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Patients with histological proof of locally advanced squamous carcinoma of oropharynx, larynx, hypopharynx (stage III and Iva)
- Overexpression of EGFR (>50%)
- Patients previously considered non-eligible for curative radio-chemotherapy for clinical reasons.
- Performance Status (ECOG) ≤ 2
- Age ≥ 18 years
Key exclusion criteria (7 listed)
- Distant metastases
- Oral cavity or rhinopharynx neoplasm
- Need of cutaneous bolus
- Previous treatments on head and neck district
- Collagenopathies or other severe systemic disease
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 |
|---|---|---|
| Cetuximab plus RadiotherapyAlso: Radiotherapy, IMRTStandard dose of a curative radiotherapy treatment is 70Gy given with conventional fractionation (2G daily) in an overall length of 7 weeks. In this study, the fractionation has been modified accordingly Cetuximab pharmacokinetics. Cetuximab will be administered with standard schedule: charge dose of 400mg/mq a week before the beginning of concurrent treatment, then weekly doses of 250mg/mq intravenous for 7 administration. This schedule to obtain the same biological efficacy on tumour with lower toxicity on healthy tissues. | Drug | Arm 1 |
Primary outcome
Number of patients who experienced acute toxicity with Grade 3 or Grade 4 adverse events according to Scala CTCAE v4.0 toxicity criteria and scale Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG / EORTC)
Time frame: up to 7 days during RT treatment
During radiotherapy, patients will be assessed weekly for acute toxicity using validated international scales.acute toxicity will be assessed with CTCAE V 4.03 (Common Terminology Criteria of Adverse Events Version 4.03) scale. Furthermore pain (NRS pain scale) nutritional assessment (weight in kilograms ) will be performed.
2 secondary outcomes
Number of patients who experienced late toxicity with Grade 3 or Grade 4 adverse events according to Scala CTCAE v4.0 toxicity criteria and scale RTOG / EORTC
Time frame: up to 6-8 weeks after treatment completion and then up to 2 years
Number of patients who experienced local or distance recurrence of disease assessed through clinical and radiological controls
Time frame: up to 6-8 weeks after treatment completion and then up to 2 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Jun 2023.
- Individual participant dataSharing planned: No
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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.
Roberto Orecchia, Prof. contact
Daniela Alterio, MD contact
Roberto Orecchia, Prof study director
European Institute of Oncology
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Cetuximab plus Radiotherapy in people with Carcinoma of the Head and Neck, run by European Institute of Oncology at 1 site in Italy.
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 7 inclusion and 7 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 28 Jun 2023. 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 Italy. 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.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
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 Roberto Orecchia, Prof. (roberto.orecchia@ieo.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of patients who experienced acute toxicity with Grade 3 or Grade 4 adverse events according to Scala CTCAE v4.0 toxicity criteria and scale Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG / EORTC) (time frame: up to 7 days during RT treatment). 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 28 Jun 2023.