Phase 3 Evaluation of Dostarlimab Sequential Therapy Post-Chemoradiation in Locally Advanced Unresected Head and Neck Squamous Cell Carcinoma
- Trial ID
- 2023-508613-17-00
- Protocol
- 221530
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of dostarlimab as sequential therapy following chemoradiation therapy (CRT) compared to placebo in participants with PD-L1 positive locally advanced unresected head and neck squamous cell carcinoma (HNSCC) as per blinded independent central review (BICR). This is clinically relevant as it aims to determine the potential of dostarlimab to improve treatment outcomes in a specific subset of HNSCC patients, potentially offering a new therapeutic option for those with limited treatment alternatives.
Secondary objectives include:
- Estimating the difference in overall survival (OS) for participants treated with dostarlimab as sequential therapy following CRT compared to placebo in participants with locally advanced unresected HNSCC.
- Evaluating the efficacy of dostarlimab as sequential therapy following CRT compared to placebo in participants with PD-L1 positive locally advanced unresected HNSCC as per investigator assessment.
- Evaluating the safety and tolerability of dostarlimab compared to placebo.
- Describing the pharmacokinetics of dostarlimab administered after CRT in participants with locally advanced unresected HNSCC that has not been previously treated.
- Determining the immunogenicity of dostarlimab administered after CRT in participants with locally advanced unresected HNSCC that has not been previously treated.
Participants
The clinical trial involves a total of **509 participants** diagnosed with **head and neck neoplasms**. The study population includes both male and female subjects, aged 18 years and older, who have been newly diagnosed with locally advanced, unresected head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, hypopharynx, or larynx. Participants have completed cisplatin plus radiotherapy with curative intent and exhibit no evidence of distant metastatic disease. The trial population was selected based on specific inclusion criteria, including a confirmed PD-L1 positive tumor status and, for oropharyngeal carcinoma, HPV results defined by p16 IHC testing. Participants with known HIV infection are eligible if they meet certain virological and immunological criteria, such as a plasma HIV-1 RNA level persistently below 50 copies/mL and a CD4 cell count of at least 350 cells/mm³. The study does not include a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled Phase 3 study** to evaluate the efficacy of **dostarlimab** as sequential therapy following chemoradiation in participants with locally advanced unresected head and neck squamous cell carcinoma. The trial aims to assess the efficacy of dostarlimab compared to placebo in participants with PD-L1 positive tumors, with the primary endpoint being event-free survival. The study is expected to commence recruitment on May 7, 2024, and conclude by July 13, 2029, with a maximum treatment period of 12 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, diagnosis, and previous treatment history. Following successful screening, participants will be randomized to receive either dostarlimab or placebo via **intravenous infusion**. The study will include regular follow-up visits to monitor the participants' health, assess the treatment's efficacy, and record any adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement is up to 12 months, with conditions for early termination including the occurrence of significant adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The trial will adhere to rigorous safety and efficacy assessments, ensuring that all data collected is in line with the study's objectives and regulatory requirements.
Treatment
The clinical trial involves the administration of **dostarlimab**, marketed under the name JEMPERLI, which is a **concentrate for solution for infusion**. This experimental medication is provided in a dosage of 500 mg and is administered via **intravenous use**. The dosing schedule allows for a maximum daily dose of 1000 mg, with a total maximum dose of 9000 mg over the course of the treatment period. The treatment period is set for a maximum of 12 months. Dostarlimab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF07. The solution is prepared at a concentration of 50 mg/mL and is compatible with closed system transfer devices for clinical administration. The product is manufactured and supplied by GlaxoSmithKline (Ireland) Limited.
In addition to the experimental treatment, the study utilizes a **placebo** control, which consists of locally sourced sterile 0.9% (w/v) sodium chloride. This placebo is used to maintain the double-blind nature of the trial, ensuring unbiased results. The sodium chloride solution serves as a comparator treatment and is administered in a manner consistent with the experimental drug to ensure blinding. The placebo does not contain any active pharmaceutical ingredients and is used solely for the purpose of comparison in the study.
Efficacy
The efficacy of **dostarlimab** as sequential therapy following chemoradiation therapy (CRT) in participants with locally advanced unresected head and neck squamous cell carcinoma (HNSCC) will be assessed through a randomized, double-blind, placebo-controlled Phase 3 study. The primary endpoint for evaluating efficacy is Event Free Survival (EFS), which is defined by the first record of locoregional progression or recurrence, distant metastasis per RECIST 1.1 as per blinded independent central review (BICR), salvage surgery at the primary tumor site when invasive cancer is present, neck dissection or surgery performed more than 20 weeks after completion of CRT when invasive cancer is present, or death from any cause.
Secondary endpoints include overall survival (OS), defined as the time from randomization to death from any cause, and EFS as assessed by the investigator. Additional secondary endpoints involve the frequency and severity of treatment-emergent adverse events (TEAEs), immune-mediated TEAEs, serious adverse events (SAEs), and TEAEs/SAEs leading to dose delays, withdrawal, or death. Clinically significant changes in laboratory parameters, vital signs, and safety assessments will also be monitored. Pharmacokinetic parameters such as serum concentrations of dostarlimab and the incidence of anti-drug antibodies (ADA) against dostarlimab will be evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Is at least 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of signing the informed consent form (ICF).
- Has newly diagnosed unresected LA histologically confirmed HNSCC of the oral cavity, oropharynx, hypopharynx or larynx and completed cisplatin plus radiotherapy (termed “CRT” in this protocol) with curative intent and has no evidence of distant metastatic disease.
- Disease defined as: a) Oropharyngeal p16 positive: T4 (N0-N3), M0; N3 (T1-T4), M0 b) Oropharyngeal p16 negative: Any T3-T4 (N0-N3), M0; Any N2a-N3 (T1-T4), M0 c) Larynx/hypopharynx/oral cavity (independent of p16): Any T3-T4 (N0-N3), M0; Any N2a-N3 (T1-T4), M0. NOTE: Tumors to be staged according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual (Amin, 2017). NOTE: Participants with distant metastases (defined as new tumor identified at a site distant from the head and neck anatomic region or draining lymph nodes), including central nervous system (CNS) metastases and/or carcinomatosis, are not eligible, either pre-CRT, or in the screening period post-CRT. NOTE: For eligibility assessment: TNM stage for oropharyngeal HNSCC must be based on p16 status as determined by CINtec assay.
- Participants must have met the following minimum requirements for CRT delivered as part of local SoC: a. For Cisplatin: Minimum cumulative exposure of 200 mg/m2 as part of CRT, delivered as either Q3W (e.g., 100 mg/m2 cycles), or Q1W (e.g., 40 mg/m2) cycles. Dose delays and dose modification are permitted per local practice providing all other requirements are met. It is recommended that concurrent cisplatin and RT be started and completed as close to each other as possible. b. Total Radiation dose of 65 Gy to 72 Gy over 6 – 7 weeks (up to +7 days if required) to the high-risk disease site.
- Has provided acceptable core or excisional biopsy obtained prior to CRT (see Laboratory Manual for detail) demonstrating: a. PD-L1 positive tumor status as defined by CPS ≥ 1 using the Agilent 22C3 assay performed at central laboratory. b. If the primary tumor site is oropharyngeal carcinoma, the participant must have HPV results defined as p16 IHC testing using the CINtec p16 histology assay and a ≥70% cutoff point (p16 IHC positive is ≥70% of carcinoma TC(s) with nuclear and cytoplasmic moderate to strong staining; see Section 8.1.5 for details). If HPV status was previously tested locally using the CINtec assay (compliant to applicable local regulation), no additional central lab testing will be required.
- Participants with known HIV infection are allowed with the following requirements: a) Documented evidence of plasma HIV-1 RNA levels persistently <50 c/mL confirmed ≤3 months prior to AND at screening; Plasma HIV-1 RNA consistently <50 c/ml required; if single increase >50 c/ml occurred, they cannot have been persistent nor associated with antiretroviral resistance per investigator assessment unless undetectable viral load is defined differently by local guidelines and agreed with the sponsor’s Central Study Team. In the 3 to 12 months prior to screening, plasma HIV-1 RNA levels consistently <50 c/mL are required; if single/isolated increases ≥50 c/mL occurred and are thought to be neither persistent nor associated with antiretroviral resistance per investigator assessment, the participant would be eligible if entry criteria are otherwise met. AND b) CD4 cell count ≥350 cells/mm3 over the 12 months prior to AND at screening (and no measurement <350cells/mm3 during that time period) AND c) Is on an uninterrupted combination antiretroviral therapy (ART) regimen for at least 3 months prior to screening, with a combination ART regimen consistent with locally recommended guidelines. NOTE: Participants who test as HIV positive during Screening will not be eligible for the study by default, owing to insufficient time to meet the safety requirements described in inclusion criteria 6, a, b, and c (above).
- No history of HIV-associated non-Hodgkin lymphoma ≤5 years prior to study entry and no history of HIV- associated invasive cervical cancer.
- No treatment with an HIV-1 immunotherapeutic vaccine within 90 days of screening.
Exclusion Criteria
- Has received prior radiation therapy, systemic therapy, targeted therapy, or surgery for management of head and neck cancer not considered part of CRT. Participants receiving induction chemotherapy are excluded. CRT combinations with components other than cisplatin and RT (e.g., experimental agents, including radiosensitizers/radioprotectants, cetuximab) are not eligible.
- Has cancer outside of the oropharynx, larynx, hypopharynx or oral cavity, such as nasopharyngeal, sinus, other para-nasal, or other unknown primary head and neck cancer. Has more than one primary HNSCC tumor
- Any unresolved toxicity CTCAE >Grade 2 from the prior CRT.
- Has a known additional malignancy that progressed or required active treatment within the past 2 years.
- Has Grade 3-4 bleeding due to underlying malignancy or has high risk of bleeding (examples include but not limited to tumors encasing or infiltrating a major vessel (i.e., carotid artery, jugular vein) and/or other high-risk features such as an arteriovenous fistula.
- Is immunocompromised in the opinion of the investigator.
- Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
- Has any history of interstitial lung disease or pneumonitis (past or current).
- Has experienced any of the following with prior immunotherapy: any imAE of Grade ≥3, immune-mediated severe neurologic events of any grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis, Guillain-Barré Syndrome, or transverse myelitis), exfoliative dermatitis of any grade (Stevens-Johnson Syndrome, toxic epidermal necrolysis, or DRESS syndrome), or myocarditis of any grade. Non-clinically significant laboratory abnormalities are not exclusionary.
- Has documented presence of HBsAg at Screening or within 3 months prior to randomization. Participants with a negative HBsAg and positive HBcAb result are eligible only if HBV DNA is negative.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 07 May 2024 | 21 |
 Czechia | Recruiting | 07 May 2024 | 21 |
 France | Recruiting | 07 May 2024 | 36 |
 Germany | Not Recruiting | 07 May 2024 | 21 |
 Greece | Recruiting | 07 May 2024 | 25 |
 Hungary | Recruiting | 07 May 2024 | 12 |
 Italy | Recruiting | 07 May 2024 | 43 |
 Norway | Recruiting | 07 May 2024 | 12 |
 Poland | Recruiting | 07 May 2024 | 34 |
 Portugal | Recruiting | 07 May 2024 | 40 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Locally sourced sterile 0.9% (w/v) sodium chloride | Placebo | N/A | — | — | — | N/A |
JEMPERLI 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1000 | 12 | PRD8877508 |