Phase III Randomized Study of Pembrolizumab and Stereotactic Ablative Radiotherapy in Oligometastatic Squamous Cell Carcinoma of the Head and Neck

Trial ID: 2023-504478-39-00
Protocol: 2014-HNCG
Sponsor: Europese Organisatie Voor Onderzoek En Behandeling Van Kanker Organisation Europeenne Pour La Recherche Et Le Traitement Du Cancer European Organi

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Diseases & Conditions

Squamous cell carcinoma of head and neck

Objectives

The primary objective of this study is to evaluate whether the addition of **Stereotactic Ablative Body Radiotherapy (SABR)** to **pembrolizumab** enhances progression-free survival in patients with **squamous cell carcinoma of the head and neck** who have a PD-L1 Combined Positive Score (CPS) of ≥1 and present with 1-5 metastatic lesions, classified as oligometastatic disease. This is clinically relevant as it aims to determine the potential benefit of combining radiotherapy with immunotherapy in improving disease control in this patient population.

Secondary objectives include:

Assessing whether SABR combined with pembrolizumab improves overall survival, disease-specific survival, time to disease progression, time to development of new metastatic lesions, and time to progression in initially present oligometastatic lesions.
Evaluating the safety and tolerability of the SABR and pembrolizumab combination according to CTCAE v5.0 criteria.
Establishing the patient-reported tolerability profile of both treatment arms.
Comparing the patient-reported benefit between the two treatment arms.

Participants

The clinical trial involves a total of **40 participants** diagnosed with **squamous cell carcinoma of the head and neck**. The study population includes both male and female subjects who are at least 18 years of age. Participants are required to have a measurable disease based on RECIST 1.1 and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. The trial population was selected based on specific inclusion criteria, including the recovery from treatment-related toxicities and adequate organ function laboratory values. Participants must not require corticosteroids for managing treatment-related side effects. The study also considers lifestyle factors, such as the use of highly effective birth control measures for participants of childbearing potential during the study treatment period and for at least 4 months after the last dose. The trial includes individuals with histologically confirmed squamous cell carcinoma of the head and neck, with or without oligometastatic disease, and those eligible for treatment with pembrolizumab. The study population is characterized by a PD-L1 CPS of at least 1, and all metastases must be amenable to SABR. The trial does not exclude vulnerable populations, and the staging of the disease must not be older than 12 weeks before enrolment.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **pembrolizumab** in combination with stereotactic ablative body radiotherapy (SABR) for patients with **squamous cell carcinoma of the head and neck**. This is a randomized, double-blind, controlled phase III study. The primary objective is to assess whether the addition of SABR to pembrolizumab improves progression-free survival compared to pembrolizumab alone. The trial is expected to commence recruitment in December 2024 and conclude by December 2030, with a maximum treatment period of 24 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, measurable disease, and adequate organ function. Following successful screening, participants will be randomized to receive either pembrolizumab alone or in combination with SABR. The study drug, pembrolizumab, will be administered intravenously, with a maximum daily dose of 400 mg and a total dose not exceeding 6800 mg over the treatment period.

Follow-up visits will be scheduled regularly to monitor the participants' health status, assess treatment efficacy, and record any adverse events. These visits will include evaluations based on RECIST 1.1 criteria and assessments of overall survival, disease-specific survival, and time to disease progression. Patient-reported outcomes will also be collected using standardized questionnaires to evaluate tolerability and perceived benefits of the treatment.

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include significant adverse events, disease progression, or withdrawal of consent. Participants are expected to be involved in the study for the entire duration unless early termination criteria are met. The trial aims to provide robust data on the potential benefits of combining pembrolizumab with SABR in treating oligometastatic squamous cell carcinoma of the head and neck.

Treatment

The clinical trial involves the administration of **pembrolizumab**, an experimental medication, to evaluate its efficacy in patients with oligometastatic squamous cell carcinoma of the head and neck. **Pembrolizumab** is provided in the form of a **solution for infusion**. The active substance, **pembrolizumab**, is a protein-based therapeutic agent. The medication is administered **intravenously**. The dosing regimen includes a maximum daily dose of **400 mg** and a cumulative maximum dose of **6800 mg** over the course of the treatment. The treatment period is set to a maximum of **24 months**. The trial aims to determine the impact of adding stereotactic ablative body radiotherapy (SABR) to pembrolizumab on progression-free survival compared to pembrolizumab alone.

In addition to the experimental treatment, the study may include standard-of-care therapies as deemed necessary by the clinical investigators. The trial does not utilize a placebo or comparator treatment. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol. The trial is designed to assess the therapeutic potential of pembrolizumab in combination with SABR, with a focus on improving outcomes for patients with PD-L1 CPS ≥1 and 1-5 metastatic lesions.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the measurement of **progression-free survival** (PFS) using RECIST 1.1 criteria, as evaluated by the local investigator. This primary endpoint aims to determine whether the addition of SABR to pembrolizumab improves PFS in patients with squamous cell carcinoma of the head and neck, specifically those with PD-L1 CPS ≥1 and 1-5 metastatic lesions, compared to pembrolizumab alone.

Secondary endpoints include overall survival, disease-specific survival, time to disease progression, time to development of new metastatic lesions, and time to progression in oligometastatic lesions initially present at enrollment. Additionally, adverse events will be recorded according to CTCAE version 5.0. Patient-reported outcomes will be assessed using the QLQ-C15-PAL and EORTC IL243 questionnaires, focusing on tolerability aspects such as dyspnoea, pain, insomnia, and other symptoms, as well as perceived benefits in physical functioning and burden of illness.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male/female participants who are at least 18 years of age on the day of signing informed consent
Histologically confirmed squamous cell carcinoma of the head and neck of the oral cavity, oropharynx, hypopharynx, larynx or cervical primary occult and histologically or radiologically confirmed oligometastatic disease. Histological characterization of one metastatic lesion is strongly recommended
Patients with synchronous or metachronous oligometastatic disease according to the ESTRO/EORTC consensus (1-5 metastatic lesions, with or without primary/recurrent primary tumour and/or regional disease c/rcN1-N3 present)
Amenable to first-line systemic treatment for R/M SCCHN
For patients with oropharyngeal cancer: HPV status using p16 IHC evaluated locally
PD-L1 CPS of at least 1 as evaluated locally
Staging not older than 12 weeks before enrolment
All the 1-5 metastases must be amenable to SABR
Eligible for treatment with pembrolizumab
Measurable disease based on RECIST 1.1
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
Recovered from the treatment-related toxicities, such as from previous radiotherapy, systemic treatment or surgery, that otherwise would preclude the treatment with pembrolizumab or SABR, and not requiring corticosteroids for managing treatment-related side effects such as oedema, pneumonitis, pain
Adequate Organ Function Laboratory Values
Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 72 hours prior to enrolment and, the test must be repeated within 72 hours prior to the first dose of study treatment
Patients of childbearing / reproductive potential should use highly effective birth control measures, as defined by the investigator, during the study treatment period and for at least 4 months after the last dose of treatment. Male participant must refrain from donating sperm during this period. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. For women such methods include: • Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) • Intrauterine device (IUD) • Intrauterine hormone-releasing system (IUS) • Bilateral tubal occlusion • Vasectomized partner • Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)
Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment
Before patient registration/enrolment, written informed consent must be given according to ICH/GCP, and national/local regulations

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Exclusion Criteria

Nasopharynx, sino-nasal, and salivary gland cancers are excluded
In-field progression in < 6 months after curative intended locoregional irradiation of the head and neck
Lesions larger than 6 cm in the largest dimension as measured in the diagnostic CT or MRI scan for lesions outside the brain. Note: bone metastases over 6 cm may be included if in the opinion of the local radiation oncologist they can be treated safely (e.g., rib, scapula, pelvis) and no inner organ is affected
Brain metastases only
Non resected brain metastases > 4cm diameter
Any previous radiotherapy to any of the 1-5 metastases that would be subject to SABR in the experimental arm unless the investigator agrees to treat only after discussion with the RTQA team.
Received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of inactivated vaccines is allowed
Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 12 weeks prior to the first dose of study intervention
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer) that have undergone potentially curative therapy are not excluded, neither patient treated with adjuvant hormonal therapy (e.g., breast cancer)
Previously treated brain metastases that are radiologically non-stable. Patients with previously treated brain metastases, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention, can participate
Known contraindications to both PET-CT and CT scan or, in the sites with only one of the two methods available, known contraindication to the available method (either PET CT or CT scan)
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
Is expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
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 enrolment in the trial