PembroMetaRT: Study on the Efficacy of Treatment by Radiotherapy and Pembrolizumab in Newly Diagnosed Metastatic Head & Neck Cancers

Sponsor

UNICANCER (Other)

Overall Status

Recruiting

CT.gov ID

NCT04747054

Collaborator

GORTEC (Other), National Cancer Institute, France (Other)

148

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Study to evaluate the efficacy of treatment by radiotherapy and pembrolizumab in newly diagnosed metastatic head & neck cancers

Condition or Disease	Intervention/Treatment	Phase
Squamous Cell Carcinoma of Head and Neck	Drug: Pembrolizumab Radiation: Loco-regional radiotherapy Drug: Chemotherapy	Phase 3

Detailed Description

Comparative interventional prospective phase 3, randomised, open-label, multicentric trial comparing the combination of radiotherapy and pembrolizumab alone or with chemotherapy to systemic treatment as first line treatment of patients with newly diagnosed head and neck squamous cell carcinoma with synchronous metastases.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

148 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Randomized Trial of Loco-regional Radiotherapy Added to Pembrolizumab Alone or With Chemotherapy Versus Systemic Treatment Alone for Patients With Newly Diagnosed Head and Neck Squamous Cell Carcinoma With Synchronous Metastases

Actual Study Start Date :

Dec 1, 2021

Anticipated Primary Completion Date :

Oct 1, 2025

Anticipated Study Completion Date :

Oct 1, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Radiotherapy added to systemic treatment Pembrolizumab 200 mg every 3 weeks until disease progression or unacceptable toxicity. Loco-regional radiotherapy will start at D8 after the first administration of pembrolizumab (D1) with 54 Gy/18 fractions in the head and neck region. If the investigator decides before randomization to add chemotherapy with pembrolizumab, the chemotherapy will start from cycle 3 or 4 of pembrolizumab (after radiotherapy administration) and will combine carboplatin AUC 5 mg/mL/min or cisplatin 100 mg/m² every 3 weeks with 5-FU 1000 mg/m²/day during 4 days every 3 weeks for a maximum of 6 cycles	Drug: Pembrolizumab Pembrolizumab 200 mg every 3 weeks until disease progression (as confirmed according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1)) or unacceptable toxicity. The treatment of pembrolizumab should not be delayed because of radiotherapy planning. Other Names: KEYTRUDA Radiation: Loco-regional radiotherapy The loco-regional radiotherapy will start at D8 after the first administration of pembrolizumab (D1) (if delayed, RT should be started no later than three weeks after the first administration of pembrolizumab, i.e. before the second administration of pembrolizumab if possible), with 54 Gy/18 fractions in the head and neck region. The volume of RT will include only involved loco-regional tumor region and no prophylactic neck volume will be necessary. Drug: Chemotherapy If the investigator decides before randomization to add chemotherapy with pembrolizumab, the chemotherapy will be composed of carboplatin AUC 5 mg/mL/min or cisplatin 100 mg/m² every 3 weeks with 5-FU 1000 mg/m²/day during 4 days every 3 weeks for a maximum of 6 cycles
Active Comparator: Systemic treatment Pembrolizumab 200 mg every 3 weeks until disease progression or unacceptable toxicity. If the investigator decides before randomization to add chemotherapy with pembrolizumab, the chemotherapy will be composed of carboplatin AUC 5 mg/mL/min or cisplatin 100 mg/m² every 3 weeks with 5-FU 1000 mg/m²/day during 4 days every 3 weeks for a maximum of 6 cycles	Drug: Pembrolizumab Pembrolizumab 200 mg every 3 weeks until disease progression (as confirmed according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1)) or unacceptable toxicity. The treatment of pembrolizumab should not be delayed because of radiotherapy planning. Other Names: KEYTRUDA Drug: Chemotherapy If the investigator decides before randomization to add chemotherapy with pembrolizumab, the chemotherapy will be composed of carboplatin AUC 5 mg/mL/min or cisplatin 100 mg/m² every 3 weeks with 5-FU 1000 mg/m²/day during 4 days every 3 weeks for a maximum of 6 cycles

Arm

Intervention/Treatment

Experimental: Radiotherapy added to systemic treatment

Pembrolizumab 200 mg every 3 weeks until disease progression or unacceptable toxicity. Loco-regional radiotherapy will start at D8 after the first administration of pembrolizumab (D1) with 54 Gy/18 fractions in the head and neck region. If the investigator decides before randomization to add chemotherapy with pembrolizumab, the chemotherapy will start from cycle 3 or 4 of pembrolizumab (after radiotherapy administration) and will combine carboplatin AUC 5 mg/mL/min or cisplatin 100 mg/m² every 3 weeks with 5-FU 1000 mg/m²/day during 4 days every 3 weeks for a maximum of 6 cycles

Drug: Pembrolizumab

Pembrolizumab 200 mg every 3 weeks until disease progression (as confirmed according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1)) or unacceptable toxicity. The treatment of pembrolizumab should not be delayed because of radiotherapy planning.

Other Names:

KEYTRUDA

Radiation: Loco-regional radiotherapy

The loco-regional radiotherapy will start at D8 after the first administration of pembrolizumab (D1) (if delayed, RT should be started no later than three weeks after the first administration of pembrolizumab, i.e. before the second administration of pembrolizumab if possible), with 54 Gy/18 fractions in the head and neck region. The volume of RT will include only involved loco-regional tumor region and no prophylactic neck volume will be necessary.

Drug: Chemotherapy

If the investigator decides before randomization to add chemotherapy with pembrolizumab, the chemotherapy will be composed of carboplatin AUC 5 mg/mL/min or cisplatin 100 mg/m² every 3 weeks with 5-FU 1000 mg/m²/day during 4 days every 3 weeks for a maximum of 6 cycles

Active Comparator: Systemic treatment

Pembrolizumab 200 mg every 3 weeks until disease progression or unacceptable toxicity. If the investigator decides before randomization to add chemotherapy with pembrolizumab, the chemotherapy will be composed of carboplatin AUC 5 mg/mL/min or cisplatin 100 mg/m² every 3 weeks with 5-FU 1000 mg/m²/day during 4 days every 3 weeks for a maximum of 6 cycles

Drug: Pembrolizumab

Other Names:

KEYTRUDA

Drug: Chemotherapy

Outcome Measures

Primary Outcome Measures

Progression-free survival (PFS) [From randomization to disease progression or death, up to 3 years.]
The progression-free survival is the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse.

Secondary Outcome Measures

Overall survival (OS) [From randomization to death from any cause, up to 5 years.]
The overall survival is the length of time from randomization that patients enrolled in the study are still alive. The outcome is to evaluate whether the radiotherapy improves overall survival compared to standard of care.
Quality of life questionnaire - Core 30 (QLQ-C30) [At baseline, 4 months, 6 months, 12 months, 18 months, 2 years, 3 years, and 4 years]
Developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials. The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.
Quality of Life Questionnaire - Head & Neck Cancer Module (QLQ-H&N35) [At baseline, 4 months, 6 months, 12 months, 18 months, 2 years, 3 years, and 4 years]
The head & neck cancer module is a 35-item questionnaire designed for use among a wide range of patients with head & neck cancer, varying in disease stage and treatment modality. It includes 7 multi-item scales that assess pain (4 items), swallowing (4 items), senses (2 items), speech (3 items), social eating (4 items), social contact (5 items), and sexuality (2 items). There are also 11 single items. Using a 4-point Likert scale (1 = "not at all", 2 = "a little", 3 = "quite a bit", and 4 = "very much"), patients indicate the degree to which they have experienced symptoms. For all items and scales, high scores indicate more problems.
Objective response rate (ORR) [At 18 weeks and 21 weeks]
The Objective response rate is defined as the presence of a partial response (PR) or complete response (CR) observed at week 18. The investigator will evaluate the objective response using RECIST v1.1.
Loco-regional progression [From randomization to loco-regional progression, up to 5 years.]
Locoregional disease progression is defined as the time from randomization to the first documented locoregional progression evaluated by RECIST v1.1.
Distant progression [From randomization to distant progression, up to 5 years.]
Distant progression is defined as the time from randomization to the first documented distant disease progression evaluated by RECIST v1.1.
Progression-free survival 2 (PFS2) [Up to 5 years after randomization.]
Progression-free survival 2 is defined as time from randomization to a second tumor progression (according to RECIST V1.1) on next-line treatment (given after a first progression) or death from any cause. Patients who did not have a progression after the initial treatment are counted as an event at the time of death if they died whatever the cause of death or are censored at the time of last news if they are alive. Patients who had a progression after the initial treatment are counted as an event when they progressed again under or after the treatment of the first progression (if they start a new treatment, i.e. a third treatment, they are also counted as an event) or when they died whatever the cause of death or they are censored at the time of last news if they are alive without new progression after the first progression.
Incidence of Treatment Adverse Events [Throughout study completion, up to 5 years.]
The tolerance and safety will be evaluated by toxicity (acute [<1 months after the end of pembrolizumab] and late [≥1 month after the end of pembrolizumab]), assessed using the Common terminology criteria for adverse events version 5.0 (CTCAE v5.0).
Compliance to treatment [Throughout study treatment, up to 5 years]
Compliance to treatment is defined by the difference on recieved study regimen compared to the planned study regimen.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient must have signed a written informed consent form prior to any study specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient's consent.
Newly diagnosed histologically confirmed squamous cell carcinoma of head and neck (oral cavity, oropharynx, hypopharynx, and larynx) with histologically confirmed distant metastases at presentation (T1-4 N0-3 M1)
Eligible for treatment by pembrolizumab according to the European Marketing Authorization
Patient ≥18 years old
Performance status: 0-1 (WHO)
Combined Positive Score (CPS) ≥1 for primary tumor (as determined per local practice)
Subjects must have at least one measurable lesion as per RECIST v1.1 to assess efficacy
Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to randomization:
Absolute neutrophil count ≥1.5 × 10⁹/L
Platelet ≥100 × 10⁹/L
Hemoglobin ≥90 g/L
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT), ≤3 × upper limit of normal (ULN), (unless documented liver metastases where ≤5 x ULN is permitted)
Bilirubin ≤1.5 × ULN.
Serum albumin ≥25 g/L
Creatinine clearance ≥30 mL/min (calculated per institutional guidelines or by Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formula)
Corrected serum calcium of ≤11.5 mg/dL or ≤2.6 mmol/L.
Patient must agree to use adequate contraception methods for the duration of the study treatment and up to 4 months after the last dose of pembrolizumab administration
Patients must be affiliated to a Social Security System (or equivalent)

Exclusion Criteria:

Symptomatic central nervous system (CNS) metastases and / or carcinomatous meningitis
History of another malignancy within 2 years prior to study inclusion, with the exception of completely resected basal or squamous cell skin cancer, or successfully treated in-situ carcinoma
Prior radiotherapy in the head and neck region
Any prior or current treatment for invasive head and neck cancer. This will include but is not limited to: prior tyrosine kinase inhibitors, any monoclonal antibody, chemotherapy, anti-PD-1/PD-L1 and CTLA-4, prior radiotherapy (RT), or use of any investigational agent
Known Acquired Immune Deficiency Syndrome (AIDS)
Known currently active infection including hepatitis B or hepatitis C
Patient having received live attenuated vaccine within 28 days prior to enrolment
Pregnant or breast feeding woman
Active autoimmune disease except vitiligo, type-1 diabetes, hypothyroid stabilized with hormonal substitution, or psoriasis which do not require systemic treatment
Active immunodeficiency or ongoing immunosuppressive therapy
Active symptomatic interstitial lung disease
Significant disease which, in the judgment of the investigator, as a result of the medical interview, physical examinations, or screening investigations would make the patient inappropriate for entry into the trial
Any social, personal, medical, geographic and/or psychologic factor(s) that could interfere with the observance of the patient to the protocol and/or the follow-up and/or the signature of the informed consent
Prior organ transplantation including allogenic stem-cell transplantation
Other severe acute or chronic medical conditions including colitis, pneumonitis, pulmonary fibrosis or psychiatric conditions including active suicidal ideation; or laboratory abnormalities that may increase the risk associated with study participation and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
Person deprived of their liberty or under protective custody or guardianship
Patient who have taken any investigational medicinal product or have used an investigational device within 30 days prior to study inclusion

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Institut Sainte Catherine	Avignon	France	84000
2	CHU Bordeaux	Bordeaux	France	33075
3	Institut Bergonié	Bordeaux	France
4	Centre François Baclesse	Caen	France	14076
5	CH Carcassonne	Carcassonne	France	1A810
6	Centre Jean Perrin	Clermont-Ferrand	France	63011
7	Centre Georges François Leclerc	Dijon	France
8	Centre Guillaume le Conquérant	Le Havre	France
9	Centre Jean Bernard - Clinique Victor Hugo	Le Mans	France
10	Centre Oscar Lambret	Lille	France	59020
11	Groupe Hospitalier Bretagne Sud	Lorient	France
12	Centre Léon Bérard	Lyon	France
13	Hopital de la Timone	Marseille	France
14	Hopital Nord Franche Comté - Site de Mittan	Montbéliard	France	25209
15	Centre Antoine Lacassagne	Nice	France
16	Institut Jean Godinot	Reims	France	51726
17	Centre Henri Becquerel	Rouen	France	76038
18	Institut de Cancérologie Strasbourg-Europe	Strasbourg	France
19	Institut Claudius Regaud	Toulouse	France	31059
20	Institut de Cancérologie de Lorraine	Vandoeuvre les nancy	France	54519
21	Gustave Roussy	Villejuif	France