Accelerated Modulated Fractionation (SIB-IMRT) for Head and Neck District (FAMOSO)

June 27, 2023 updated by: European Institute of Oncology

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

  1. 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.

  2. 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 Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
10

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Italy
    • MI
      • Milan, MI, Italy, 20141
        • Recruiting
        • Division of Radiotherapy European Institute of Oncology
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Arm 1

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).
Drug: Cetuximab plus Radiotherapy
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.
Other Names:
  • Radiotherapy, IMRT

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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.
up to 7 days during RT treatment

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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
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.
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

Clinical assessment will be performed through:

  1. Otolaryngology examination and laryngoscopy

    Radiological assessment will be performed through:

  2. Facial skeleton and neck MRI with and without contrast or CT with and without contrast if MRI is unfeasible.
up to 6-8 weeks after treatment completion and then up to 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
European Institute of Oncology

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Director: Roberto Orecchia, Prof, European Institute of Oncology

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2014

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 1, 2018

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 12, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 20, 2016

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 23, 2016

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 28, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 27, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • European Institute of Oncology

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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