European Larynx Organ Preservation Study (ELOS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University of Leipzig

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Apr 2024 → ongoing

Decision date (initial)

2023-11-10

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

MSD

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Objective: To compare laryngectomy-free survival (LFS) achieved by adding pembrolizumab to standard treatment and LFS after standard treatment according to the DeLOS-II protocol in advanced LHNSCC curable by laryngectomy.

Primary hypothesis: Adding PD-1 inhibition by pembrolizumab to larynx-organ preservation chemo-radiation treatment improves laryngectomy-free survival (LFS) compared to standard treatment according to the DeLOS-II protocol.

Endpoint: 24-month to 48-month laryngectomy-free survival, the survival of the patient 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. Patients lost to follow-up will be censored at date of last visit with larynx at place.

Secondary objectives 1

1. Objective: To compare Quality of Swallowing (QoS) assessed by FEES, event free survival (EFS) and overall survival (OS) achieved by adding 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 [2,3]. FEES is a well approved and reliable method and allows clear scoring of quality of swallowing for instance by applying the Rosenbek Scale (Appendix 4 [3]). Therefore, we 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.

Conditions and MedDRA coding

Advanced stage III, IVA, IVB laryngeal or II, III, IVA, IVB hypopharyngeal squamous cell carcinoma (SCC) curable by total laryngectomy. Note: PD-L1-expression within tumor tissue biopsy, calculated as CPS ≥ 1, is mandatory.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 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.
2. Stage III, IVA, IVB laryngeal or II, III, IVA, IVB hypopharyngeal SCC, whenever clear resection margins R0 >5 mm can be achieved.
3. Have provided newly obtained excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
4. 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).
5. 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.
6. 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.
7. 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.
8. 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 21

1. 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.
2. 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).
3. Has received prior systemic anti-cancer therapy including investigational agents.
4. Has received prior radiotherapy in the head and neck region.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients or intolerance to any drug administered during treatment.
11. 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.
12. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
13. Has an active infection requiring systemic therapy.
14. Has a known history of Human Immunodeficiency Virus (HIV) infection. Note: No HIV testing is required unless mandated by local health authority.
15. 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.
16. Has a known history of active TB (Bacillus Tuberculosis).
17. 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.
18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
19. 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.
20. Has had an allogenic tissue/solid organ transplant.
21. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 24-month to 48-month laryngectomy-free survival, the survival of the patient without laryngectomy, in the intent-to-treat population (flexible 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. Patients lost to follow-up will be censored at date of last visit with larynx at place.

Secondary endpoints 3

1. 24-months to 48-months event-free survival (flexible follow-up)
2. 24-months to 48-months overall survival (flexible follow-up)
3. Quality of swallowing (QoS) assessed by FEES at time of randomization, 6 months and 24 months after IC-1

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University of Leipzig

Sponsor organisation

University of Leipzig

Address

Ritterstraße 26, Zentrum Zentrum

City

Leipzig

Postcode

04109

Country

Germany

Scientific contact point

Organisation

University of Leipzig

Contact name

Coordinating Investigator

Public contact point

Organisation

University of Leipzig

Contact name

Coordinating Investigator

Locations

1 EU/EEA country · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications