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

ConditionsSquamous Cell Carcinoma of Head and NeckHypopharyngeal Squamous Cell CarcinomaLaryngeal Squamous Cell Carcinoma Stage IIILaryngeal Squamous Cell Carcinoma Stage IVSquamous Cell Carcinoma of LarynxSquamous Cell Carcinoma of the LarynxSquamous Cell Carcinoma of the Larynx Stage IIISquamous Cell Carcinoma of the Larynx Stage IVLaryngeal Squamous Cell CarcinomaLaryngectomy; StatusLaryngeal CancerLaryngeal Neoplasms
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age18-70
SponsorUniversity of Leipzig

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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

Disqualifiers

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.

Trial design

Design model

Parallel

Treatments tested in this trial

  • KEYTRUDA®

    Biological/Vaccine

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

Treatment groups

140 Participants
are divided into 2 treatment groups
Group A: A - ControlNo intervention 0 interventions
Group B: B - KEYTRUDA®Experimental treatment 1 intervention

Trial outcomes

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.

Time frame
24 to 48 months (flexible follow-up)

Secondary outcomes

1

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.

Time frame
24 to 48 months (flexible follow-up)
2

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.

Time frame
24 to 48 months (flexible follow-up)
3

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.

Time frame
24 to 48 months (flexible follow-up)
4

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.

Time frame
24 to 48 months (flexible follow-up)

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

University of Leipzig

Lead sponsor

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

Source ClinicalTrials.gov
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