European Larynx Organ Preservation Study (ELOS): Induction chemotherapy with Docetaxel and Cisplatin (TP) followed by radiation compared to additional PD-1 inhibition in CPS ≥1 advanced laryngeal and hypopharyngeal cancer suitable for laryngectomy selected after short induction early response evaluation
- Trial ID
- 2022-502751-61-00
- Sponsor
- Universitaet Leipzig
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the European Larynx Organ Preservation Study (ELOS) is to evaluate the impact of adding **pembrolizumab** to standard treatment on laryngectomy-free survival (LFS) in patients with advanced laryngeal and hypopharyngeal squamous cell carcinoma (LHNSCC) that is curable by total laryngectomy. The study aims to determine whether the inclusion of PD-1 inhibition with pembrolizumab enhances LFS compared to the standard treatment as per the DeLOS-II protocol. This is clinically relevant as it may offer a treatment option that preserves the larynx, potentially improving the quality of life for patients by avoiding laryngectomy.
Secondary objectives include comparing the Quality of Swallowing (QoS) assessed by Fiberoptic Endoscopic Evaluation of Swallowing (FEES), event-free survival (EFS), and overall survival (OS) between the treatment groups. The focus is on improving the quality and degree of larynx organ preservation, with particular attention to late functional outcomes such as swallowing. The study utilizes FEES for a direct and objective assessment of swallowing, avoiding less specific health-related quality of life (hrQoL) questionnaires, to better address the main outcome of functional larynx organ preservation.
Participants
The clinical trial involves participants diagnosed with **advanced stage II, III, IVA/B head and neck squamous cell carcinoma** of the larynx or hypopharynx, specifically those for whom a total laryngectomy is a curative option. The study population includes both male and female subjects aged 18 years and older, with a confirmed histological diagnosis of squamous cell carcinoma. Participants are required to have a PD-L1 expression within the tumor biopsy, calculated as CPS ≥ 1, and must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria emphasize adequate organ function and the ability to provide a newly obtained excisional biopsy of a tumor lesion not previously irradiated. Lifestyle considerations such as diet and physical activity are not specified, but male participants must agree to use contraception during the treatment period and for a specified duration afterward, while female participants must not be pregnant or breastfeeding and must adhere to contraceptive guidance if of childbearing potential.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, controlled, two-armed parallel group, multicenter study, focusing on advanced stage II, III, IVA/B head and neck **squamous cell carcinoma** of the larynx or hypopharynx. The primary objective is to compare laryngectomy-free survival (LFS) by adding **pembrolizumab** to standard treatment versus standard treatment alone. The trial will assess the efficacy of pembrolizumab in improving LFS over a period of 24 to 48 months, with laryngectomy or death from any cause considered as events. The study will involve a flexible follow-up period until 24 months after the randomization of the last patient.
Participants will be enrolled based on specific inclusion criteria, including a histologically confirmed diagnosis of squamous cell carcinoma suitable for total laryngectomy, and PD-L1 expression within the tumor biopsy. The trial will commence with a screening visit to confirm eligibility, followed by randomization into one of the two treatment arms. The treatment period will last up to 12 months, with pembrolizumab administered via **intravenous administration**. Participants will undergo regular follow-up visits to monitor treatment response and adverse events, with assessments including quality of swallowing and overall survival.
The expected duration of participant involvement is up to 48 months, including follow-up. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any condition that, in the investigator's opinion, would make continued participation detrimental to the participant's health. The end-of-study visit will occur at the conclusion of the follow-up period, where final assessments will be conducted to evaluate the primary and secondary endpoints. The trial is estimated to end by October 2025, with recruitment starting in October 2023.
Treatment
The clinical trial involves the administration of **pembrolizumab**, marketed as KEYTRUDA, which is a **concentrate for solution for infusion**. This experimental medication is administered via **intravenous administration**. The dosage is set at a maximum of 200 mg per day, with a total maximum dose of 3400 mg over a treatment period of up to 12 months. Pembrolizumab is a protein-based therapeutic agent, specifically a PD-1 inhibitor, and is utilized in this study to evaluate its efficacy in improving laryngectomy-free survival in patients with advanced laryngeal and hypopharyngeal cancer.
**Clindamycin** is used as a non-experimental treatment in the study. It is provided in the form of **film-coated tablets** and administered **orally**. The maximum daily dose is 600 mg, with a total maximum dose of 18,000 mg over a 10-day treatment period. Clindamycin serves as an antibiotic to manage potential infections during the trial.
**Docetaxel** is another non-experimental treatment, administered as a **concentrate for solution for infusion**. The route of administration is **infusion**, with a maximum daily dose of 75 mg/m² and a total maximum dose of 225 mg/m² over a 10-day period. Docetaxel is a chemotherapeutic agent used in the induction chemotherapy phase of the study.
**Cisplatin** is also administered as a **concentrate for solution for infusion** via **infusion**. The dosing schedule mirrors that of docetaxel, with a maximum daily dose of 75 mg/m² and a total maximum dose of 225 mg/m² over 10 days. Cisplatin is a chemotherapeutic agent used in combination with docetaxel during the induction phase.
**Dexamethasone** is provided in **tablet** form and administered **orally**. The maximum daily dose is 4 mg, with a total maximum dose of 12 mg over a 12-day treatment period. Dexamethasone is an anti-inflammatory agent used to manage inflammation and potential side effects associated with chemotherapy.
**Ibuprofen** is included as an auxiliary treatment, available in **tablet** form and administered **orally**. The maximum daily dose is 800 mg, with a total maximum dose of 13,600 mg over a 12-day period. Ibuprofen serves as an anti-inflammatory and analgesic to manage pain and inflammation during the trial.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the measurement of **laryngectomy-free survival (LFS)** over a period of 24 to 48 months. This endpoint is defined as the duration of survival without undergoing a laryngectomy, with laryngectomy or death from any cause being considered as events. Patients who are lost to follow-up will be censored at the date of their last visit where the larynx was intact. The trial aims to compare the LFS achieved by adding pembrolizumab to the standard treatment regimen against the LFS obtained with the standard treatment alone, as per the DeLOS-II protocol, in patients with advanced laryngeal and hypopharyngeal squamous cell carcinoma (SCC) that is suitable for laryngectomy.
Secondary efficacy endpoints include event-free survival and overall survival, both measured over the same 24 to 48-month period. Additionally, the quality of swallowing (QoS) will be evaluated using Fiberoptic Endoscopic Evaluation of Swallowing (FEES) at the time of randomization, and subsequently at 6 months and 24 months following the initial chemotherapy cycle. These assessments will provide a comprehensive evaluation of the treatment's impact on both survival and functional outcomes in the patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male and female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of squamous cell carcinoma (SCC) of the larynx (T3 or T4a) or hypopharynx (T2, T3 or T4a) according to the decision of the multidisciplinary tumor board suitable for total laryngectomy can be enrolled in this study.
- Stage III, IVA, IVB laryngeal or II, III, IVA, IVB hypopharyngeal SCC, whenever clear resection margins R0 >5 mm can be achieved.
- Have provided newly obtained excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
- PD-L1-expression* within the tumor biopsy, CPS ≥1. *Assessment of PD-L1 status will be performed according to the guidelines for first line treatment with Pembrolizumab using a clinically established and CE-certified test, for example: PD-L1 IHC 22C3 pharmDx (Agilent), VENTANA PD-L1 (SP263) Assay (Roche), or PD-L1 IHC 28-8 pharmDx (Agilent) etc.). The PD-L1 testing has to be performed in a certified pathology institute (Round-robin certificate).
- Male participants: A male participant must agree to use contraception (Appendix 3 of this protocol) during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.
- Female participants: A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: a) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR b) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 120 days after the last dose of study treatment.
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of allocation/randomization.
- Have adequate organ function as defined in the Table 1 of this Protocol. Specimens must be collected within 10 days prior to the start of study treatment.
Exclusion Criteria
- A WOCBP who has a positive urine pregnancy test within 72 hours prior to receiving the first dose of study medication (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory receptor on T or NK cells (e.g., CTLA-4, OX 40, CD137).
- Has received prior systemic anti-cancer therapy including investigational agents.
- Has received prior radiotherapy in the head and neck region.
- Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
- Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 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 history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. Note: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in-situ cancers.
- Has known distant metastases including active CNS metastases and/or carcinomatous meningitis. Participants with radiological findings suspect for potentially being distant metastasis may participate, provided these findings are radiologically stable, 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 any treatment for at least 14 days prior to first dose of study intervention.
- Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients or intolerance to any drug administered during treatment.
- Has 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, etc.) is not considered a form of systemic treatment and is allowed.
- Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
- Has an active infection requiring systemic therapy.
- Has a known history of Human Immunodeficiency Virus (HIV) infection. Note: No HIV testing is required unless mandated by local health authority.
- Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
- Has a known history of active TB (Bacillus Tuberculosis).
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Is pregnant or breastfeeding or 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.
- Has had an allogenic tissue/solid organ transplant.
- Has a known intolerance to one of the substances administered during treatment including e.g. antiemetics, etc. or any other component of concurrent auxiliary medication.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 01 Oct 2023 | 140 |
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 |
|---|---|---|---|---|---|---|
CISPLATIN | Other | — | INFUSION | 75 | 10 | SUB07483MIG |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS ADMINISTRATION | 200 | 12 | PRD4323105 |
DEXAMETHASONE | Other | — | ORAL | 4 | 12 | SUB07017MIG |
DOCETAXEL | Other | — | INFUSION | 75 | 10 | SUB12492MIG |