European Larynx Organ Preservation Study (ELOS) [MK-3475-C44]

NCT06137378 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 2022-502751-61-00P_00432
• Study Type: interventional
• Target: 140
• Locations: 1 country
• Sites: 9

Brief Summary

ELOS is a prospective, randomized, open-label, controlled, two-armed parallel group, phase II multicentre trial in local advanced stage III, IVA/B head and neck squamous cell carcinoma of the larynx or hypopharynx (LHNSCC) with PD-L1-expression within tumor tissue biopsy, calculated as CPS ≥ 1 curable by total laryngectomy. Induction chemotherapy (IC) with Docetaxel and Cisplatin (TP) followed by radiation will be compared to additional PD-1 inhibition. Patients will be selected after short induction early response evaluation after the first cycle IC (IC-1) aiming on larynx organ-preservation by additional 2 cycles IC followed by radiotherapy (69.6 Gy) for responders achieving endoscopic estimated tumor surface shrinkage (ETSS) ≥ 30%. Nonresponders (ETSS \< 30% or progressing disease) will receive total laryngectomy and selective neck dissection followed by postoperative radiation or chemoradiation according to the recommendation of the clinics multidisciplinary tumor board. However, Patients randomized into the intervention arm starting day 1 will receive 200 mg Pembrolizumab (MK-3475) i.v. in 3-week cycle (q3w) for 17 cycles (12 months). Treatment with pembrolizumab will continue in the experimental arm regardless of ETSS status after IC-1 in both responders and laryngectomized nonresponders, independent from subsequent decision on adjuvant therapy after TL.

Conditions

Squamous Cell Carcinoma of Head and Neck; Hypopharyngeal Squamous Cell Carcinoma; Laryngeal Squamous Cell Carcinoma Stage III; Laryngeal Squamous Cell Carcinoma Stage IV; Squamous Cell Carcinoma of Larynx; Squamous Cell Carcinoma of the Larynx; Squamous Cell Carcinoma of the Larynx Stage III; Squamous Cell Carcinoma of the Larynx Stage IV; Laryngeal Squamous Cell Carcinoma; Laryngectomy; Status; Laryngeal Cancer; Laryngeal Neoplasms

Keywords

induction chemotherapy; neoadjuvant treatment; immune checkpoint inhibitor; pembrolizumab; KEYNOTE; larynx organ preservation; laryngectomy-free survival; overall survival; event-free survival

Outcome Measures

Primary Outcomes (1)

• laryngectomy-free survival (LFS)

  Laryngectomy-free survival (LFS) is the survival of the patient with larynx at place aka survival without laryngectomy, in the intent-to-treat population (follow-up of the total cohort until 24 months after randomization of the last patient accrued). Laryngectomy or death from any cause count as event. We measure LFS in the intent-to-treat population as the survival time of patients with larynx at place, which is the time interval from date of randomization until date of LFS event (follow-up of the total cohort until 24 months after randomization of the last patient accrued). Laryngectomy or death from any cause count as LFS event. Patients lost to follow-up will be censored at date of last visit with larynx at place. Recruitment will be over 2 years and all patients will be followed up for at least 2 years, resulting in a maximum follow-up time of 4 years.

  24 to 48 months (flexible follow-up)

Secondary Outcomes (4)

• overall-survival (OS)

  24 to 48 months (flexible follow-up)

• quality of swallowing (QoS) and freedom from laryngoesophageal dysfunction (FFLED)

  24 to 48 months (flexible follow-up)

• event-free survival (EFS)

  24 to 48 months (flexible follow-up)

• event-free survival (EFS), alternative definition

  24 to 48 months (flexible follow-up)

Study Arms (2)

A - Control

NO INTERVENTION

Standard-Arm: Short Induction (IC-1): T = Docetaxel 75 mg/m\^2 i.v. day 1 P = Cisplatin 75 mg/m\^2 i.v. day 1 Response evaluation will be performed in week 4 after IC-1 by endoscopic estimation of tumor-surface shrinkage (ETSS) to select nonresponders for early total laryngectomy (TL). Responders receive further 2 cycles TP followed by radiotherapy (RT) starting week 11. ETSS \< 30% (Nonresponder): \- TL + adjuvant RT or chemo-radiotherapy (CRT) according the decision of the tumor board ETSS \>=30% (Responder): 2 further TP cycles (IC-2 in week 5-7 and IC-3 in week 8-10; same doses as IC-1) Radiotherapy (RT) is accelerated IMRT with concomitant boost with total dose of 69.6 Gy applied over 5.5 weeks to all tumor localizations; clinically non-affected neck levels receive 51.6 Gy. \* protocol is according exactly to the DeLOS-II protocol arm A in Dietz et al. Ann Oncol. 2018 Oct 1;29(10):2105-2114

B - KEYTRUDA®

EXPERIMENTAL

Intervention arm aka Experimental-Arm: Treatment same as for patients randomized into the standard arm A + application of KEYTRUDA® (pembrolizumab), i.v., in 3-week cycle (q3w) 200 mg, starting day 1; for 17 cycles (12 months). Treatment with pembrolizumab will continue in the experimental arm regardless of ETSS status after IC-1 in both responders and laryngectomized nonresponders, independent from subsequent decision on adjuvant therapy after TL.

Biological: KEYTRUDA®

Interventions

KEYTRUDA® BIOLOGICAL

200 mg KEYTRUDA® i. v. in 3-week cycle (q3w)

Also known as: Pembrolizumab, MK-3475

B - KEYTRUDA®

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants are eligible to be included in the study only if all of the following criteria apply:
• 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 or hypopharynx according to the decision of the multidisciplinary tumor board suitable for total laryngectomy can be enrolled in this study.
• Stage III, IVA or IVB, whenever clear resection margins R0 \>5 mm can be achieved and no radiologic signs of extranodal extension of neck nodes are present.
• 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
• Male participants:
• A male participant must agree to use a contraception as detailed in 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:
• Not a woman of childbearing potential (WOCBP) OR
• A WOCBP who agrees to follow the contraceptive guidance 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 4) of the protocol. Specimens must be collected within 10 days prior to the start of study treatment.

You may not qualify if:

• Participants are excluded from the study if any of the following criteria apply:
• 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.
• 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.
• Has known distant metastases including active CNS metastases and/or carcinomatous meningitis.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• 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.

Sponsors & Collaborators

• University of Leipzig: lead
• University of Göttingen: collaborator
• University of Jena: collaborator
• University of Cologne: collaborator
• University of Ulm: collaborator
• University of Regensburg: collaborator
• Wuerzburg University Hospital: collaborator
• Technical University of Munich: collaborator
• Ernst von Bergmann Hospital: collaborator
• Universitätsmedizin Mannheim: collaborator
• University of Kiel: collaborator

Study Sites (9)

Universitätsklinikum Mannheim, Klinik für Hals-Nasen-Ohrenheilkunde Theodor-Kutzer-Ufer 1-3

Mannheim, Baden-Würtemberg, 68167, Germany

RECRUITING

Universitätsklinikum Ulm / Ulm University Medical Center, Klinik für Hals- Nasen-Ohrenheilkunde und Kopf-Halschirurgie, Frauensteige 12

Ulm, Baden-Würtemberg, 89075, Germany

RECRUITING

Klinikum rechts der Isar der TU München, Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde, Ismaninger Straße 22

München, Bavaria, 81675, Germany

NOT YET RECRUITING

Universität Regensburg, Klinik und Poliklinik für Strahlentherapie Franz-Josef-Strauss-Allee 11

Regensburg, Bavaria, 93053, Germany

RECRUITING

Universitätsklinikum Würzburg, Klinik für Hals-, Nasen-, Ohrenheilkunde, Josef-Schneider-Straße 8

Würzburg, Bavaria, 97080, Germany

RECRUITING

Klinikum Ernst von Bergmann, Klinik für Hämatologie, Onkologie und Palliativmedizin, Charlottenstr. 72

Potsdam, Brandenburg, 14467, Germany

NOT YET RECRUITING

Universitätsklinikum Köln, Klinik für Hals-, Nasen-, Ohrenheilkunde, Kerpener Str. 62

Cologne, North Rhine-Westphalia, 50937, Germany

NOT YET RECRUITING

University of Leipzig, Department für Kopf- und Zahnmedizin, Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde, Liebigstrasse 12

Leipzig, Saxon, 04103, Germany

RECRUITING

Universitätsklinikum Jena Klinik für Hals-, Nasen- und Ohrenheilkunde, Am Klinikum 1

Jena, Thuringia, Germany

NOT YET RECRUITING

Related Publications (4)

• Dietz A, Wichmann G, Kuhnt T, Pfreundner L, Hagen R, Scheich M, Kolbl O, Hautmann MG, Strutz J, Schreiber F, Bockmuhl U, Schilling V, Feyer P, de Wit M, Maschmeyer G, Jungehulsing M, Schroeder U, Wollenberg B, Sittel C, Munter M, Lenarz T, Klussmann JP, Guntinas-Lichius O, Rudack C, Eich HT, Foerg T, Preyer S, Westhofen M, Welkoborsky HJ, Esser D, Thurnher D, Remmert S, Sudhoff H, Gorner M, Bunzel J, Budach V, Held S, Knodler M, Lordick F, Wiegand S, Vogel K, Boehm A, Flentje M, Keilholz U. Induction chemotherapy (IC) followed by radiotherapy (RT) versus cetuximab plus IC and RT in advanced laryngeal/hypopharyngeal cancer resectable only by total laryngectomy-final results of the larynx organ preservation trial DeLOS-II. Ann Oncol. 2018 Oct 1;29(10):2105-2114. doi: 10.1093/annonc/mdy332.

  PMID: 30412221 BACKGROUND

• Bindewald J, Herrmann E, Dietz A, Wulke C, Meister E, Wollbruck D, Singer S. [Quality of life and voice intelligibility in laryngeal cancer patients--relevance of the "satisfaction paradox"]. Laryngorhinootologie. 2007 Jun;86(6):426-30. doi: 10.1055/s-2007-966167. German.

  PMID: 17654777 BACKGROUND

• Rosenbek JC, Robbins JA, Roecker EB, Coyle JL, Wood JL. A penetration-aspiration scale. Dysphagia. 1996 Spring;11(2):93-8. doi: 10.1007/BF00417897.

  PMID: 8721066 BACKGROUND

• Wichmann G, Wald T, Pirlich M, Napp J, Munter I, Asendorf T, Tostmann R, Vogt J, Vogel K, Meuret S, Stoehr M, Zebralla V, Nicolay NH, Kuhnt T, Hambsch P, Guntinas-Lichius O, Klussmann JP, Wiegand S, Dietz A. The European Larynx Organ Preservation Study [MK-3475-C44]. Front Oncol. 2024 Aug 22;14:1433238. doi: 10.3389/fonc.2024.1433238. eCollection 2024.

  PMID: 39239277 DERIVED

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck; Laryngeal Neoplasms

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site; Otorhinolaryngologic Neoplasms; Laryngeal Diseases; Respiratory Tract Diseases; Respiratory Tract Neoplasms; Otorhinolaryngologic Diseases

Central Study Contacts

Andreas Dietz, MD PhD

CONTACT

+493419721700; Andreas.Dietz@medizin.uni-leipzig.de

Susanne Wiegand, MD PhD

CONTACT

+493419721700; susanne.wiegand@medizin.uni-leipzig.de

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: There will be no masking
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Univ.-Prof. Dr. med. Andreas Dietz, Chairman, Clinic of Otolaryngology, Head and Neck Surgery & Dept. Head Medicine and Oral Health

Model Details: Prospective, randomized, open-label, controlled, two-armed parallel group, phase II multicenter larynx organ-preservation trial with randomization in a 1:1 ratio into standard arm vs. investigational arm with a flexible follow-up of 24-48 months

Study Record Dates

• First Submitted: November 13, 2023
• First Posted: November 18, 2023
• Study Start: April 17, 2024
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2030
• Last Updated: September 20, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

DE (9)