Squamous Cell Carcinoma of Head and NeckPhase 2ELOSNCT06137378
European Larynx Organ Preservation Study (ELOS) [MK-3475-C44]
A Phase 2 study testing KEYTRUDA® in people with Squamous Cell Carcinoma of Head and Neck and Hypopharyngeal Squamous Cell Carcinoma, run by University of Leipzig at 9 sites in Germany.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Squamous Cell Carcinoma of Head and Neck, Hypopharyngeal Squamous Cell Carcinoma, Laryngeal Squamous Cell Carcinoma Stage III
- What is being tested?
- KEYTRUDA®
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 140 participants
- Where
- 9 sitesGermany
- Study dates
- 17 Apr 2024to Dec 2030
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
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- 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.
Who cannot join
- 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.
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- 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.
- 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. antibiotics, antiemetics, etc. or any other component of concurrent auxiliary medication.
Trial locations and contacts
9 sites in 1 country. Contact the study team or a site near you to ask about taking part.
9 sites in 1 country
Germany9 sites, 9 recruiting
- Not yet recruiting
Universitätsklinikum Köln, Klinik für Hals-, Nasen-, Ohrenheilkunde, Kerpener Str. 62
Cologne, North Rhine-Westphalia, 50937
Shachi Sharma, Dr. med., 0049221-478 4750, shachi.sharma@uk-koeln.de
Jens Peter Klußmann, Prof. Dr., 0221-478 51660, jens.klussmann@uk-koeln.de
- Not yet recruiting
Universitätsklinikum Jena Klinik für Hals-, Nasen- und Ohrenheilkunde, Am Klinikum 1
Jena, Thuringia
Orlando Guntinas-Lichius, Prof. Dr., 00493641-9329301, orlando.guntinas@med.uni-jena.de
Thomas Bitter, PD Dr., 00493641-9329300, thomas.bitter@med.uni-jena.de
- Recruiting
University of Leipzig, Department für Kopf- und Zahnmedizin, Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde, Liebigstrasse 12
Leipzig, Saxon, 04103
Andreas Dietz, Prof. Dr., +493419721700, andreas.dietz@medizin.uni-leipzig.de
Markus Pirlich, PD Dr., 03419721700, markus.pirlich@medizin.uni-leipzig.de
- Recruiting
Universitätsklinikum Mannheim, Klinik für Hals-Nasen-Ohrenheilkunde Theodor-Kutzer-Ufer 1-3
Mannheim, Baden-Würtemberg, 68167
Annette Affolter, PD Dr., +49 621 383 3965, Annette.Affolter@umm.de
Nicole Rotter, Prof. Dr., +49 621 383 3965, nicole.rotter@umm.de
- Not yet recruiting
Klinikum rechts der Isar der TU München, Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde, Ismaninger Straße 22
München, Bavaria, 81675
Barbara Wollenberg, Prof. Dr., 004989-4140 2370, barbara.wollenberg@tum.de
Markus Wirth, PD Dr., 004989-4140 2370, Markus.Wirth@tum.de
- Not yet recruiting
Klinikum Ernst von Bergmann, Klinik für Hämatologie, Onkologie und Palliativmedizin, Charlottenstr. 72
Potsdam, Brandenburg, 14467
Grzegorz Kofla, Dr. med., 0049331-241 35702, Grzegorz.Kofla@klinikumevb.de
Karin Jordan, Prof. Dr., 0049331-241 35700, Karin.Jordan@klinikumevb.de
- Recruiting
Universität Regensburg, Klinik und Poliklinik für Strahlentherapie Franz-Josef-Strauss-Allee 11
Regensburg, Bavaria, 93053
Christoph Süß, Dr. med., +49 941 944-9400, Christoph.Suess@ukr.de
Felix Kajetan Steger, Dr. med., +49 941 944-9400, Felix.Steger@ukr.de
- Recruiting
Universitätsklinikum Ulm / Ulm University Medical Center, Klinik für Hals- Nasen-Ohrenheilkunde und Kopf-Halschirurgie, Frauensteige 12
Ulm, Baden-Würtemberg, 89075
Simon Laban, Prof. Dr., +49 731 50059500, Simon.Laban@uniklinik-ulm.de
Thomas Hoffmann, Prof. Dr., +49 731 50059500, t.hoffmann@uniklinik-ulm.de
- Recruiting
Universitätsklinikum Würzburg, Klinik für Hals-, Nasen-, Ohrenheilkunde, Josef-Schneider-Straße 8
Würzburg, Bavaria, 97080
Thomas Gehrke, PD Dr., 0049931-201 21757, Gehrke_T@ukw.de
Matthias Scheich, PD Dr., 0049931-201 21707, Scheich_M@ukw.de
About this study
Official title: ELOS - Induction Chemotherapy With Docetaxel and Cisplatin Followed by Radiation Compared to Additional PD-1 Inhibition in CPS ≥1 Advanced Laryngeal/Hypopharyngeal Cancer Suitable for Laryngectomy Selected After Early Response Evaluation
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.
Read the detailed description
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.
The primary objective of ELOS is to compare laryngectomy-free survival (LFS) achieved by adding KEYTRUDA® (pembrolizumab) to standard treatment and LFS after standard treatment according to the DeLOS-II protocol in advanced LHNSCC curable by laryngectomy.
Hypothesis: Adding PD-1 inhibition by pembrolizumab to organ-preservation chemoradiation treatment improves laryngectomy-free survival (LFS) compared to standard treatment according to the DeLOS-II protocol.
The secondary objectives are to compare Quality of Swallowing (QoS) assessed by FEES, event free survival (EFS) and overall survival (OS) achieved by adding KEYTRUDA® (pembrolizumab) to standard treatment and QoS, EFS and OS after standard treatment according to the DeLOS-II protocol in advanced LHNSCC. In general, the main interest in trials focusing on improving quality and degree of larynx organ preservation is late functional (in particular "swallowing") outcome. Current instruments assessing hrQoL are less meaningful than direct objective assessment of swallowing utilizing physical examination like FEES. FEES is a well approved and reliable method and allows clear scoring of quality of swallowing for instance by applying the Rosenbek Scale. Therefore, the investigators decided to avoid any questionnaires for this assessment including those approved for use in head and neck cancer, as they fail to specifically address the main study outcome, functional larynx organ preservation.
Hypothesis: Adding PD-1 inhibition by KEYTRUDA® (pembrolizumab) to organ-preservation chemoradiation treatment improves QoS, EFS and OS compared to standard treatment according to the DeLOS-II protocol. EFS events are defined as any event either in interfering with proper larynx organ function (independent of the cause, tumor- or treatment related), relapse (local, loco-regional, or distant), or death.
- 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
- Being tested
- KEYTRUDA®
- Keywords
- induction chemotherapy, neoadjuvant treatment, immune checkpoint inhibitor, pembrolizumab, KEYNOTE, larynx organ preservation, laryngectomy-free survival, overall survival, event-free survival
- Medical subject headings
- Squamous Cell Carcinoma of Head and Neck, Laryngeal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
KEYTRUDA®Biological
Also called Pembrolizumab, MK-3475
200 mg KEYTRUDA® i. v. in 3-week cycle (q3w)
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Biological: KEYTRUDA® |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 24 to 48 months (flexible follow-up)
Secondary outcomes (4)
overall-survival (OS)
Overall survival (OS) is the survival of the patient without death from any cause, in the intent-to-treat population (follow-up of the total cohort until 24 months after randomization of the last patient accrued).
We measure OS in the intent-to-treat population as the survival time of patients as the time interval from date of randomization until date of death from any cause (follow-up of the total cohort until 24 months after randomization of the last patient accrued). Patients lost to follow-up will be censored at date of last visit. 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.
Measured: 24 to 48 months (flexible follow-up)
quality of swallowing (QoS) and freedom from laryngoesophageal dysfunction (FFLED)
QoS will be assessed by fiber-endoscopic estimation of swallowing (FEES) at time of randomization and 6 and 24 months after first cycle induction chemo using the Rosenbek Scale (RS). De novo dysphagia (RS for aspiration and airway invasion/penetration >1) or exacerbation of existing dysphagia RS 2-5 to RS ≥6 (aspiration), is loss of freedom from laryngo-esophageal dysfunction (FFLED; event). An event might also be persistence of either tracheostoma or gastric tube at 24 months (event at 24 months) or total laryngectomy or death from any cause.
We measure FFLED in the intent-to-treat population as time interval from date of randomization until date of event (follow-up of the total cohort until 24 months after randomization of the last patient accrued). Patients lost to follow-up will be censored at date of last visit without event. Recruitment will be over 2 years and all patients will be followed up for at least 2 years, resulting in maximum follow-up of 4 years.
Measured: 24 to 48 months (flexible follow-up)
event-free survival (EFS)
Event-free survival (EFS) is the survival of the patient without any event. Total laryngectomy (TL), progressing disease, occurrence of new lesions, local or nodal relapse, distant metastases or death from any cause count as event.
We measure EFS in the intent-to-treat population as the time interval from date of randomization until date of any event (follow-up of the total cohort until 24 months after randomization of the last patient accrued). Patients lost to follow-up will be censored at date of last visit without event. 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.
Measured: 24 to 48 months (flexible follow-up)
event-free survival (EFS), alternative definition
Event-free survival (EFS) is the survival of the patient without any event. As early total laryngectomy (TL) of nonresponders with ETSS <30% assessed by early response evaluation in week 4 is per-protocol therapy of LHSCC patients, which according to insufficient response to IC-1 cannot be selected for further 2 cycles TP followed by RT to achieve larynx organ-preservation, the alternative analysis of EFS will not consider early TL of nonresponders as event. However, progressing disease, occurrence of new lesions, local or nodal relapse, distant metastases or death from any cause and TL >2 months after IC-1 or loss of FFLED count as event.
We measure EFS in the intent-to-treat population as the time interval from date of randomization until date of event. Patients lost to follow-up will be censored at date of last visit without event. 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.
Measured: 24 to 48 months (flexible follow-up)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Nov 2023
- Study start17 Apr 2024
- Primary completionDec 2028 (estimated)
- Study completionDec 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Squamous Cell Carcinoma of Head and NeckStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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
- Masking
- None (open label)
- Enrolment
- 140 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Leipzig
- Sponsor type
- University, hospital or other
- Collaborators
- University of Göttingen, University of Jena, University of Cologne, University of Ulm, University of Regensburg, Wuerzburg University Hospital, Technical University of Munich, Ernst von Bergmann Hospital, Universitätsmedizin Mannheim, University of Kiel
- Responsible party
- Principal investigator, Andreas Dietz, University of Leipzig
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06137378
- Sponsor's protocol ID
- 2022-502751-61-00
- Other IDs
- 2022-502751-61-00, P_00432
- Acronym
- ELOS
- Status last verified
- Sep 2024
- First submitted
- 13 Nov 2023
- Last updated
- 20 Sep 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 30412221Bindewald 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.
PubMed 17654777Rosenbek JC, Robbins JA, Roecker EB, Coyle JL, Wood JL. A penetration-aspiration scale. Dysphagia. 1996 Spring;11(2):93-8. doi: 10.1007/BF00417897.
PubMed 8721066Wichmann 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.
PubMed 39239277
Study at a glance
From the registry record, last updated by the sponsor on 20 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- ELOS - Induction Chemotherapy With Docetaxel and Cisplatin Followed by Radiation Compared to Additional PD-1 Inhibition in CPS ≥1 Advanced Laryngeal/Hypopharyngeal Cancer Suitable for Laryngectomy Selected After Early Response Evaluation
- ClinicalTrials.gov ID
- NCT06137378
- Acronym / sponsor ID
- ELOS / 2022-502751-61-00
- 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
- Keywords
- induction chemotherapy, neoadjuvant treatment, immune checkpoint inhibitor, pembrolizumab, KEYNOTE, larynx organ preservation, laryngectomy-free survival, overall survival
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 140 participants (estimated)
- Lead sponsor
- University of LeipzigUniversity, hospital or other
- Collaborators
- University of Göttingen, University of Jena, University of Cologne, University of Ulm, University of Regensburg, Wuerzburg University Hospital, Technical University of Munich, Ernst von Bergmann Hospital, Universitätsmedizin Mannheim, University of Kiel
- Study start
- 17 Apr 2024 (actual)
- Primary completion
- Dec 2028 (estimated)
- Study completion
- Dec 2030 (estimated)
- First posted
- 18 Nov 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
The primary objective of ELOS is to compare laryngectomy-free survival (LFS) achieved by adding KEYTRUDA® (pembrolizumab) to standard treatment and LFS after standard treatment according to the DeLOS-II protocol in advanced LHNSCC curable by laryngectomy.
Hypothesis: Adding PD-1 inhibition by pembrolizumab to organ-preservation chemoradiation treatment improves laryngectomy-free survival (LFS) compared to standard treatment according to the DeLOS-II protocol.
The secondary objectives are to compare Quality of Swallowing (QoS) assessed by FEES, event free survival (EFS) and overall survival (OS) achieved by adding KEYTRUDA® (pembrolizumab) to standard treatment and QoS, EFS and OS after standard treatment according to the DeLOS-II protocol in advanced LHNSCC. In general, the main interest in trials focusing on improving quality and degree of larynx organ preservation is late functional (in particular "swallowing") outcome. Current instruments assessing hrQoL are less meaningful than direct objective assessment of swallowing utilizing physical examination like FEES. FEES is a well approved and reliable method and allows clear scoring of quality of swallowing for instance by applying the Rosenbek Scale. Therefore, the investigators decided to avoid any questionnaires for this assessment including those approved for use in head and neck cancer, as they fail to specifically address the main study outcome, functional larynx organ preservation.
Hypothesis: Adding PD-1 inhibition by KEYTRUDA® (pembrolizumab) to organ-preservation chemoradiation treatment improves QoS, EFS and OS compared to standard treatment according to the DeLOS-II protocol. EFS events are defined as any event either in interfering with proper larynx organ function (independent of the cause, tumor- or treatment related), relapse (local, loco-regional, or distant), or death.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- 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
| Arm | Type | Receives |
|---|---|---|
| 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 | Biological: KEYTRUDA®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. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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
Key exclusion criteria (22 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| KEYTRUDA®Also: Pembrolizumab, MK-3475200 mg KEYTRUDA® i. v. in 3-week cycle (q3w) | Biological | B - KEYTRUDA® |
Primary outcome
laryngectomy-free survival (LFS)
Time frame: 24 to 48 months (flexible follow-up)
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.
4 secondary outcomes
overall-survival (OS)
Time frame: 24 to 48 months (flexible follow-up)
quality of swallowing (QoS) and freedom from laryngoesophageal dysfunction (FFLED)
Time frame: 24 to 48 months (flexible follow-up)
event-free survival (EFS)
Time frame: 24 to 48 months (flexible follow-up)
event-free survival (EFS), alternative definition
Time frame: 24 to 48 months (flexible follow-up)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Sep 2024.
- Background: PubMed 30412221Dietz 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.
- Background: PubMed 17654777Bindewald 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.
- Background: PubMed 8721066Rosenbek JC, Robbins JA, Roecker EB, Coyle JL, Wood JL. A penetration-aspiration scale. Dysphagia. 1996 Spring;11(2):93-8. doi: 10.1007/BF00417897.
- Derived from this study: PubMed 39239277Wichmann 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
9 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing KEYTRUDA® in people with Squamous Cell Carcinoma of Head and Neck and Hypopharyngeal Squamous Cell Carcinoma, run by University of Leipzig at 9 sites in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 20 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Andreas Dietz, MD PhD (+493419721700, Andreas.Dietz@medizin.uni-leipzig.de), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
laryngectomy-free survival (LFS) (time frame: 24 to 48 months (flexible follow-up)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06137378, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Sep 2024.