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AF CRT +/- Nimorazole in HNSCC

Primary Purpose

Locally Advanced Head and Neck HPV Negative Squamous Cell Cancers

Status
Active
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Cisplatin
Radiotherapy
Placebo
Nimorazole
Sponsored by
European Organisation for Research and Treatment of Cancer - EORTC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Locally Advanced Head and Neck HPV Negative Squamous Cell Cancers

Eligibility Criteria

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

Inclusion Criteria:

  • Newly diagnosed tumors classified as stage III-IV located in the larynx, oropharynx and hypopharynx (unknown primary should be excluded; oral cavity are not eligible)
  • Human papillomavirus(HPV)/p16 negative (≤70% positively stained cells), assessed locally for tumors of the oropharynx
  • Tumors of the larynx and hypopharynx regardless of the HPV status
  • Histopathological diagnosis of invasive squamous cell carcinoma in the primary tumor
  • World Health Organization (WHO) performance 0-2
  • All Hematology and biochemical investigations, should be done within 4 weeks before randomization (maximum 6 weeks before treatment starts)
  • Normal bone marrow function based on routine blood samples, i.e. neutrophils ≥ 1.0 x 109/L, platelets ≥ 75 x 109/L, hemoglobin ≥ 10.0 g/dL or 6.2 mmol/L
  • Normal kidney function creatinine clearance ≥ 60ml/min, and Electrolyte balance: calcium ≤ 11.5 mg/dl or 2.9 mmol/l, magnesium ≥ 1.2 mg/dl or 0.5 mmol/l
  • Normal liver function assessed by routine laboratory examinations, i.e. bilirubin < 1.5 x Upper Limit of Normal (ULN), Aspartate aminotransferase (AST)< 3 x ULN, alkaline phosphatases < 3 x ULN
  • No prior or current anticancer treatment to the head and neck area (e.g. radical attempted or tumor reductive surgery, neo-adjuvant chemotherapy, Epidermal Growth Factor Receptor (EGFR) inhibitors or radiotherapy).
  • Patients must be candidate for curative intent external beam chemo-radiotherapy, and must be expected to complete the treatment.
  • All patients should have an oral and dental examination including preferably clinical and radiological examination. Whenever indicated, extraction of dental elements should be carried out at least 10 days before treatment start;for 1-2 (max 2) monoradicular single tooth extractions (if not continous a max of 4) without bone resection 5 days (as a minimum) are allowed.
  • Radiotherapy planned to start within acceptable delay (preferably within 2 weeks and a maximum of 4 weeks from randomization).
  • Radiotherapy planned to start within 8 weeks from baseline imaging tumor assessment.
  • Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before randomization in the trial
  • All subjects must agree to abstain from donating blood while receiving therapy and for four weeks following discontinuation of therapy.
  • All subjects must agree not to share study medication with another person and to return all unused study drug to the investigator.
  • Before patient registration, written informed consent must be given according to International Conference on Harmonisation /Good Clinical Practice (ICH/GCP), and national/local regulations (including material acquisition for central testing of the hypoxic signature)

Exclusion Criteria:

  • Patients who have received treatment with any investigational drug substance within 4 weeks prior to randomization;
  • Current participation in any other interventional clinical study;
  • Pregnant or breast-feeding female patient. Pregnancy test should be done within 72 hours from treatment start;
  • Female subjects of childbearing potential (defined as a sexually mature woman who 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally post-menopausal (amenorrhoea following cancer therapy does not rule out childbearing potential) for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months)) not willing to use adequate contraception during study and for 6 month after last dose of study drug;
  • Male subjects not willing to use condoms throughout study drug therapy, and for 6 months after cessation of study therapy if their partner is of childbearing potential and has no contraception;
  • Known or suspected HIV infection;
  • Second malignancies in the 3 years prior to study entry with the exception of surgically cured carcinoma in situ of the cervix, in situ breast cancer, incidental finding of stage T1a or T1b prostate cancer, and basal/squamous cell carcinoma of the skin;
  • Uncontrolled or chronic bacterial, fungal or viral infection;
  • Known or suspected hypersensitivity to component(s) of investigational product or cisplatin contraindication;
  • All indicated timelines and absolute values requested by the eligibility criteria must be adhered to. However, a maximum of +/- 10% of the reference value for laboratory parameters and a maximum of +/- 3 days for timelines may be acceptable. Discussion with EORTC Headquarters and study coordinator is encouraged.

Sites / Locations

  • Royal Brisbane And Women's Hospital
  • Princess Alexandra Hospital - University Of Queensland
  • Royal North Shore Hospital
  • Hopitaux Universitaires Bordet-Erasme - Institut Jules Bordet
  • Cliniques Universitaires Saint-Luc
  • U.Z. Leuven - Campus Gasthuisberg
  • Centre Georges-Francois-Leclerc
  • CHU de Tours - Hopital Bretonneau
  • Institut Gustave Roussy
  • Charite - Universitaetsmedizin Berlin - Campus Virchow-Klinikum
  • Ludwig-Maximilians-Universitaet Muenchen - Klinikum der Universitaet Muenchen - Campus Grosshadern
  • Vrije Universiteit Medisch Centrum
  • Radboud University Medical Center Nijmegen
  • Medical University Of Gdansk
  • The Great Poland Cancer Centre
  • Maria Sklodowska-Curie Memorial Cancer Centre
  • Lower Silesian Oncology Centre
  • Hôpitaux universitaires de Genève - HUG - site de Cluse-Roseraie
  • UniversitaetsSpital Zurich

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Radiotherapy+ Cisplatin+ Placebo

Radiotherapy+ Cisplatin+ Nimorazole

Arm Description

Accelerated radiotherapy (Therapeutic Planning Target Volume (PTV): 70 Gray (Gy), 6 fractions/week, 35 fractions of 2 Gy, prophylactic PTV: 54.25 Gy, 6 fractions/week, 35 fractions of 1.55 Gy) + concomitant cisplatin (weekly schedule of 40mg/m2 (delivered on day 1, 8, 15, 22, 29) Patients will receive placebo (1.2 g/m2) 90 min (+/- 30 min) prior to each radiotherapy fraction but no more than 5 times a week (If the 6th radiotherapy fraction in a week is given on a separate day from the 5th fraction of radiotherapy, no nimorazole/placebo dose is received that day. If the 6th fraction of radiotherapy is given on the same day as the 5th fraction, nimorazole/placebo is given 90 minutes before the 5th radiotherapy fraction, only).

Accelerated radiotherapy (Therapeutic PTV: 70 Gy, 6 fractions/week, 35 fractions of 2 Gy, prophylactic PTV: 54.25 Gy, 6 fractions/week, 35 fractions of 1.55 Gy) + concomitant cisplatin (weekly schedule of 40mg/m2 (delivered on day 1, 8, 15, 22, 29) . Patients will receive nimorazole (1.2 g/m2) 90 min (+/- 30 min) prior to each radiotherapy fraction but no more than 5 times a week (If the 6th radiotherapy fraction in a week is given on a separate day from the 5th fraction of radiotherapy, no nimorazole/placebo dose is received that day. If the 6th fraction of radiotherapy is given on the same day as the 5th fraction, nimorazole/placebo is given 90 minutes before the 5th radiotherapy fraction, only).

Outcomes

Primary Outcome Measures

locoregional control rate

Secondary Outcome Measures

Time to distant metastasis
Time to second cancer
Overall survival
Disease-specific free survival
Acute and late morbidity

Full Information

First Posted
June 12, 2013
Last Updated
May 9, 2022
Sponsor
European Organisation for Research and Treatment of Cancer - EORTC
Collaborators
Danish Head and Neck Cancer Group
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1. Study Identification

Unique Protocol Identification Number
NCT01880359
Brief Title
AF CRT +/- Nimorazole in HNSCC
Official Title
A Blind Randomized Multicenter Study of Accelerated Fractionated Chemo-radiotherapy With or Without the Hypoxic Cell Radiosensitizer Nimorazole (Nimoral), Using a 15-gene Signature for Hypoxia in the Treatment of Squamous Cell Carcinoma of the Head and Neck.
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 25, 2014 (Actual)
Primary Completion Date
September 6, 2019 (Actual)
Study Completion Date
January 9, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
European Organisation for Research and Treatment of Cancer - EORTC
Collaborators
Danish Head and Neck Cancer Group

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The drug nimorazole belongs to a class of chemicals known as 5-nitroimidazoles. Drugs from this class are used against infection. In addition, nimorazole makes tumor cells more sensitive to radiotherapy. Therefore, the investigators want to find out whether the addition of nimorazole to the standard treatment with radiotherapy in combination with chemotherapy with cisplatin shows activity against your type of head and neck cancer and is safe. Furthermore the investigators will investigate if a specific examination done with your tumor tissue will help to predict whether the treatment will work or not. To find out if the activity observed with this treatment is not caused by chance alone, the investigators need to obtain data from patients who receive this treatment and from patients who receive other treatments. The data from these two groups of patients will be compared to see which treatment is better. Participants will be split into 2 groups. Each group will receive different treatments. The treatment each group receives is determined by chance using a computer program. This works like flipping a coin and is called randomization. This helps to make sure that groups of patients are similar when the study starts. Neither you, your study doctor, nor the study staff can influence in which group you will be placed or which treatment you will receive. If allocated to group 1, Patient will receive radiotherapy in combination with chemotherapy with cisplatin and nimorazole as a pill. This is considered the 'experimental' treatment. If allocated to group 2, patient will receive radiotherapy in combination with chemotherapy with cisplatin and a so called 'placebo' as a pill. The placebo is a dummy treatment. It looks like the real one, but it is not. It contains no active ingredient/medicine.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Locally Advanced Head and Neck HPV Negative Squamous Cell Cancers

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
640 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Radiotherapy+ Cisplatin+ Placebo
Arm Type
Placebo Comparator
Arm Description
Accelerated radiotherapy (Therapeutic Planning Target Volume (PTV): 70 Gray (Gy), 6 fractions/week, 35 fractions of 2 Gy, prophylactic PTV: 54.25 Gy, 6 fractions/week, 35 fractions of 1.55 Gy) + concomitant cisplatin (weekly schedule of 40mg/m2 (delivered on day 1, 8, 15, 22, 29) Patients will receive placebo (1.2 g/m2) 90 min (+/- 30 min) prior to each radiotherapy fraction but no more than 5 times a week (If the 6th radiotherapy fraction in a week is given on a separate day from the 5th fraction of radiotherapy, no nimorazole/placebo dose is received that day. If the 6th fraction of radiotherapy is given on the same day as the 5th fraction, nimorazole/placebo is given 90 minutes before the 5th radiotherapy fraction, only).
Arm Title
Radiotherapy+ Cisplatin+ Nimorazole
Arm Type
Experimental
Arm Description
Accelerated radiotherapy (Therapeutic PTV: 70 Gy, 6 fractions/week, 35 fractions of 2 Gy, prophylactic PTV: 54.25 Gy, 6 fractions/week, 35 fractions of 1.55 Gy) + concomitant cisplatin (weekly schedule of 40mg/m2 (delivered on day 1, 8, 15, 22, 29) . Patients will receive nimorazole (1.2 g/m2) 90 min (+/- 30 min) prior to each radiotherapy fraction but no more than 5 times a week (If the 6th radiotherapy fraction in a week is given on a separate day from the 5th fraction of radiotherapy, no nimorazole/placebo dose is received that day. If the 6th fraction of radiotherapy is given on the same day as the 5th fraction, nimorazole/placebo is given 90 minutes before the 5th radiotherapy fraction, only).
Intervention Type
Drug
Intervention Name(s)
Cisplatin
Intervention Type
Radiation
Intervention Name(s)
Radiotherapy
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Type
Drug
Intervention Name(s)
Nimorazole
Primary Outcome Measure Information:
Title
locoregional control rate
Time Frame
9 years after first patient in
Secondary Outcome Measure Information:
Title
Time to distant metastasis
Time Frame
9 years after first patient in
Title
Time to second cancer
Time Frame
9 years after first patient in
Title
Overall survival
Time Frame
9 years after first patient in
Title
Disease-specific free survival
Time Frame
9 years after first patient in
Title
Acute and late morbidity
Time Frame
9 years after first patient in

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Newly diagnosed tumors classified as stage III-IV located in the larynx, oropharynx and hypopharynx (unknown primary should be excluded; oral cavity are not eligible) Human papillomavirus(HPV)/p16 negative (≤70% positively stained cells), assessed locally for tumors of the oropharynx Tumors of the larynx and hypopharynx regardless of the HPV status Histopathological diagnosis of invasive squamous cell carcinoma in the primary tumor World Health Organization (WHO) performance 0-2 All Hematology and biochemical investigations, should be done within 4 weeks before randomization (maximum 6 weeks before treatment starts) Normal bone marrow function based on routine blood samples, i.e. neutrophils ≥ 1.0 x 109/L, platelets ≥ 75 x 109/L, hemoglobin ≥ 10.0 g/dL or 6.2 mmol/L Normal kidney function creatinine clearance ≥ 60ml/min, and Electrolyte balance: calcium ≤ 11.5 mg/dl or 2.9 mmol/l, magnesium ≥ 1.2 mg/dl or 0.5 mmol/l Normal liver function assessed by routine laboratory examinations, i.e. bilirubin < 1.5 x Upper Limit of Normal (ULN), Aspartate aminotransferase (AST)< 3 x ULN, alkaline phosphatases < 3 x ULN No prior or current anticancer treatment to the head and neck area (e.g. radical attempted or tumor reductive surgery, neo-adjuvant chemotherapy, Epidermal Growth Factor Receptor (EGFR) inhibitors or radiotherapy). Patients must be candidate for curative intent external beam chemo-radiotherapy, and must be expected to complete the treatment. All patients should have an oral and dental examination including preferably clinical and radiological examination. Whenever indicated, extraction of dental elements should be carried out at least 10 days before treatment start;for 1-2 (max 2) monoradicular single tooth extractions (if not continous a max of 4) without bone resection 5 days (as a minimum) are allowed. Radiotherapy planned to start within acceptable delay (preferably within 2 weeks and a maximum of 4 weeks from randomization). Radiotherapy planned to start within 8 weeks from baseline imaging tumor assessment. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before randomization in the trial All subjects must agree to abstain from donating blood while receiving therapy and for four weeks following discontinuation of therapy. All subjects must agree not to share study medication with another person and to return all unused study drug to the investigator. Before patient registration, written informed consent must be given according to International Conference on Harmonisation /Good Clinical Practice (ICH/GCP), and national/local regulations (including material acquisition for central testing of the hypoxic signature) Exclusion Criteria: Patients who have received treatment with any investigational drug substance within 4 weeks prior to randomization; Current participation in any other interventional clinical study; Pregnant or breast-feeding female patient. Pregnancy test should be done within 72 hours from treatment start; Female subjects of childbearing potential (defined as a sexually mature woman who 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally post-menopausal (amenorrhoea following cancer therapy does not rule out childbearing potential) for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months)) not willing to use adequate contraception during study and for 6 month after last dose of study drug; Male subjects not willing to use condoms throughout study drug therapy, and for 6 months after cessation of study therapy if their partner is of childbearing potential and has no contraception; Known or suspected HIV infection; Second malignancies in the 3 years prior to study entry with the exception of surgically cured carcinoma in situ of the cervix, in situ breast cancer, incidental finding of stage T1a or T1b prostate cancer, and basal/squamous cell carcinoma of the skin; Uncontrolled or chronic bacterial, fungal or viral infection; Known or suspected hypersensitivity to component(s) of investigational product or cisplatin contraindication; All indicated timelines and absolute values requested by the eligibility criteria must be adhered to. However, a maximum of +/- 10% of the reference value for laboratory parameters and a maximum of +/- 3 days for timelines may be acceptable. Discussion with EORTC Headquarters and study coordinator is encouraged.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jens Overgaard
Organizational Affiliation
Aarhus University Hospital
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Vincent Grégoire
Organizational Affiliation
Cliniques Universitaires St. Luc
Official's Role
Study Chair
Facility Information:
Facility Name
Royal Brisbane And Women's Hospital
City
Brisbane
ZIP/Postal Code
QLD 4029
Country
Australia
Facility Name
Princess Alexandra Hospital - University Of Queensland
City
Brisbane
ZIP/Postal Code
QLD 4102
Country
Australia
Facility Name
Royal North Shore Hospital
City
St Leonards
ZIP/Postal Code
NSW 2065
Country
Australia
Facility Name
Hopitaux Universitaires Bordet-Erasme - Institut Jules Bordet
City
Brussels
ZIP/Postal Code
1000
Country
Belgium
Facility Name
Cliniques Universitaires Saint-Luc
City
Brussels
ZIP/Postal Code
1200
Country
Belgium
Facility Name
U.Z. Leuven - Campus Gasthuisberg
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Centre Georges-Francois-Leclerc
City
Dijon
ZIP/Postal Code
21079
Country
France
Facility Name
CHU de Tours - Hopital Bretonneau
City
Tours
ZIP/Postal Code
37044
Country
France
Facility Name
Institut Gustave Roussy
City
Villejuif
ZIP/Postal Code
94805
Country
France
Facility Name
Charite - Universitaetsmedizin Berlin - Campus Virchow-Klinikum
City
Berlin
Country
Germany
Facility Name
Ludwig-Maximilians-Universitaet Muenchen - Klinikum der Universitaet Muenchen - Campus Grosshadern
City
Muenchen
ZIP/Postal Code
81377
Country
Germany
Facility Name
Vrije Universiteit Medisch Centrum
City
Amsterdam
ZIP/Postal Code
7007MB
Country
Netherlands
Facility Name
Radboud University Medical Center Nijmegen
City
Nijmegen
ZIP/Postal Code
6500 H
Country
Netherlands
Facility Name
Medical University Of Gdansk
City
Gdansk
ZIP/Postal Code
80 211
Country
Poland
Facility Name
The Great Poland Cancer Centre
City
Poznan
Country
Poland
Facility Name
Maria Sklodowska-Curie Memorial Cancer Centre
City
Warsaw
Country
Poland
Facility Name
Lower Silesian Oncology Centre
City
Wrocław
Country
Poland
Facility Name
Hôpitaux universitaires de Genève - HUG - site de Cluse-Roseraie
City
Geneva
ZIP/Postal Code
1211
Country
Switzerland
Facility Name
UniversitaetsSpital Zurich
City
Zurich
ZIP/Postal Code
8091
Country
Switzerland

12. IPD Sharing Statement

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AF CRT +/- Nimorazole in HNSCC

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