MK-3475 (SCH 9000475) as neoadjuvant and adjuvant therapy in Stage III-IVA resectable LA HNSCC (Locoregionally Advanced Head and Neck Squamous Cell Carcinoma)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

13 Dec 2018 → ongoing

Decision date (initial)

2022-12-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2022-500254-41-00

EudraCT number

2017-001139-38

WHO UTN

U1111-1274-2398

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenomic, Pharmacogenetic, Efficacy, Safety, Pharmacoeconomic

1. To compare pembrolizumab as neoadjuvant therapy and in combination with radiotherapy (RT) ± cisplatin as adjuvant therapy to only RT ± cisplatin as adjuvant therapy with respect to the event-free survival (EFS), per RECIST 1.1, as assessed by blinded independent central review (BICR) in participants whose tumors express PD-L1 CPS≥10, CPS≥1, and in all participants, regardless of CPS status.

Secondary objectives 5

1. To compare pembrolizumab neoadjuvant therapy to no neoadjuvant therapy with respect to the rate of major pathological response (mPR) as assessed by the central pathologist at the time of definitive surgery in participants whose tumors express PD-L1 CPS≥10, CPS≥1, and in all participants regardless of CPS status.
2. To compare pembrolizumab as neoadjuvant therapy and in combination with radiotherapy (RT) ± cisplatin as adjuvant therapy to only RT ± cisplatin as adjuvant therapy with respect to overall survival (OS) in participants whose tumors express PD-L1 CPS≥10, CPS≥1, and in all participants, regardless of CPS status.
3. To evaluate the rate of pathological complete response (pCR), as assessed by the central pathologist at the time of definitive surgery, in participants whose tumors express PD-L1 CPS≥10, CPS≥1, and in all participants regardless of CPS status.
4. To evaluate global health status/quality of life (QoL) and physical functioning scores using the European Organisation for Research and Treatment of Cancer (EORTC) QoL questionnaire (QLQ)-C30, and swallowing, speech and pain symptoms using the EORTC Head and Neck–Specific QoL questionnaire (EORTC QLQ-H&N35) in participants whose tumors express PD-L1 CPS≥10, CPS≥1, and in all participants, regardless of CPS status.
5. To determine the safety and tolerability of pembrolizumab as neoadjuvant therapy and in combination with RT ± cisplatin as adjuvant therapy.

Conditions and MedDRA coding

Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Has histologically confirmed new diagnosis of resectable, non-metastatic, squamous cell carcinoma that is either: Stage III Human Papillomavirus (HPV) positive oropharyngeal primary that is tumor size (T) 4, lymph node involvement (N) 0-2, no distant metastases (M0); Stage III or IVA oropharyngeal HPV negative; or Stage III or IVA larynx/hypopharynx/oral cavity primaries.
2. Is eligible for primary surgery based on investigator decision and per local practice.
3. Female and male participants of reproductive potential must agree to use adequate contraception throughout the study period and for up to 180 days after the last dose of study therapy.
4. Male participants must refrain from donating sperm throughout the study period and for up to 180 days after the last dose of study therapy.
5. Female participant that is not pregnant or breastfeeding.
6. Has evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on RECIST version 1.1.
7. Has provided newly obtained core or excisional biopsy of a tumor lesion not previously irradiated.
8. Has results from (local) testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using CINtec® p16 Histology assay.
9. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days of randomization.

Exclusion criteria 23

1. Has Stage T4B and/or N3 locoregionally advanced head and neck squamous cell carcinoma (LA HNSCC) and/or distant metastases.
2. Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity, such as nasopharyngeal, sinus, other para-nasal, or other unknown primary head and neck cancer (HNC).
3. Female participant who has a positive urine pregnancy test within 72 hours prior to study start or within 24 hours prior to the start of radiotherapy with or without cisplatin.
4. Has received prior therapy with an anti-programmed cell death receptor 1(PD-1), anti-programmed cell death receptor ligand 1(PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor.
5. Has received prior radiotherapy treatment or systemic anti-cancer therapy including investigational agents for the HNC under study prior to study start.
6. Has received a live vaccine within 30 days prior to randomization.
7. 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 randomization.
8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization.
9. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. in situ cervical cancer or breast carcinoma) that have undergone potentially curative therapy.
10. Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system metastases and/or carcinomatous meningitis.
11. Has Grade ≥2 audiometric hearing loss.
12. Has Grade ≥2 neuropathy.
13. Has Grade 3-4 bleeding due to the underlying malignancy.
14. Has received major surgery or has not recovered adequately from the toxicity and/or complications from the intervention prior to study start.
15. Has had previous allogeneic tissue/solid organ transplant.
16. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients, radiotherapy, cisplatin or their analogs.
17. Has an active autoimmune disease that has required systemic treatment in past 2 years.
18. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
19. Has an active infection requiring systemic therapy.
20. Has a known history of human immunodeficiency virus (HIV) infection.
21. Has a known history of or is positive for Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C (defined as Hepatitis C virus [HCV] ribonucleic acid is detected.
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the investigator.
23. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Event-free Survival (EFS)

Secondary endpoints 8

1. Major Pathological Response (mPR)
2. Overall Survival (OS)
3. Pathological Complete Response (pCR)
4. Change From Baseline in Global Health Status/Quality of Life Scale (GHS/QoL)
5. Change From Baseline in Global Health Status/Physical Functioning Scales
6. Change from Baseline in Swallowing, Speech, and Pain Symptoms
7. Percentage of Participants Experiencing an Adverse Event (AEs)
8. Percentage of Participants Discontinuing Study Drug Due to AEs

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue, P. O. Box 2000 P. O. Box 2000

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Kimberly Benjamin

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Kimberly Benjamin

Third parties 6

Locations

9 EU/EEA countries · 40 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 102 files

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

Application history

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