A Phase 2 interventional study of KEYTRUDA® in Squamous Cell Carcinoma of Head and Neck, Hypopharyngeal Squamous Cell Carcinoma and Laryngeal Squamous Cell Carcinoma Stage III, sponsored by University of Leipzig. Recruiting at 9 sites in Germany. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2024-09-20.
Sponsored by University of Leipzig · Phase 2, Interventional, and Treatment
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.
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.
1,711 studies on the registry are indexed under Squamous Cell Carcinoma of Head and Neck; 544 are open to participants now.
This study's planned enrollment of 140 is above the median of 50 across 1,456 interventional studies indexed under Squamous Cell Carcinoma of Head and Neck.
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Participants are eligible to be included in the study only if all of the following criteria apply:
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:
Exclusion Criteria:
Participants are excluded from the study if any of the following criteria apply:
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
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®
200 mg KEYTRUDA® i. v. in 3-week cycle (q3w)
Also known as: Pembrolizumab, MK-3475
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)
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)
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)
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)
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)
Plan to share: No
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Studies of the drug tested here: Pembrolizumab
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