Pembrolizumab or placebo in combination with chemoradiation (CRT) in subjects with locally advanced HNSCC

• Register: EUCTR
• Last refreshed on: 20 February 2017
• Main ID: EUCTR2016-003934-25-ES
• Date of registration: 04/01/2017
• Prospective Registration: Yes
• Primary sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
• Public title: Pembrolizumab or placebo in combination with chemoradiation (CRT) in subjects with locally advanced HNSCC
• Scientific title: A Randomized Phase III study of pembrolizumab given concomitantly with chemoradiation and as maintenance therapy versus chemoradiation alone in subjects with locally advanced head and neck squamous cell carcinoma (KEYNOTE-412) - Pembrolizumab or placebo in combination with chemoradiation in subjects with locally advanced HNSCC
• Date of first enrolment: 10/02/2017
• Target sample size: 780
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003934-25
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, Brazil, Canada, Colombia, Czech Republic, France, Germany, Ireland, Israel, Italy, Japan, Korea, Republic of, Netherlands, New Zealand, Poland, Spain, Taiwan, Turkey, United Kingdom, United States

Contacts

• Name: Investigación Clínica
• Affiliation: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

• Name: Investigación Clínica
• Affiliation: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Have a pathologically proven new diagnosis of squamous cell carcinoma of:
a. Oropharyngeal p16 positive
i. T4 (N0-N3), M0 ; or
ii. N3 (T1-T4), M0
OR
b. Oropharyngeal p16 negative
i. any T3-4 (N0-N3), M0 ; or
ii. any N2a-3 (T1-T4), M0
OR
c. Larynx/hypopharynx/oral cavity (independent of p16)
i. any T3-4 (N0-N3), M0 ; or
ii. any N2a-3 (T1-T4), M0
Note: Subjects with oral cavity tumors need to have unresectable disease
2. Be willing and able to provide written informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
3. Have results from (local) testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using CINtec® p16 Histology assay and a 70% cutoff point. If HPV status was previously tested using this method, no additional testing is required.
Note: Tumor p16 expression must be evaluated by assessment of IHC
analysis with CINtec® p16 Histology assay (Ventana Medical Systems Inc., Tucson AZ) using ‘Benchmark Ultra’ autostainer (Ventana, Tucson, AZ) and standard protocol. Positive p16 expression is defined as strong and diffuse nuclear and cytoplasmic staining in 70% or more of the tumor cells.
Note: HPV stratification in this trial will be performed using local testing of HPV status in subjects with oropharynx cancer using the specified method.
Note: If local p16 testing results are not available, or cannot be assessed
locally by the specified method, a tumor tissue sample may be submitted for p16 testing at the designated central laboratory.
Note: Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV testing by p16 IHC as by convention these tumor locations are assumed to be HPV-negative.
4. Have provided adequate tissue in terms of quality and quantity for PD-L1 biomarker analysis from a core or excisional biopsy (fine needle aspirate [FNA] is not adequate). Repeat samples may be required if adequate tissue is not provided.
Note: Central pathological review for p16 or PD-L1 will not be performed
before inclusion. Formalin-fixed paraffin embedded (FFPE) tumor tissue
sample blocks are preferred. If submitting unstained cut slides, freshly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut.
5. Be =18 years of age on day of signing informed consent.
6. Have evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by CT scan or MRI, based on RECIST version 1.1.
7. Be eligible for definitive CRT and not considered for primary surgery based on investigator decision.
8. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 performed within 10 days of treatment initiation.
9. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of trial treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
10. Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in the protocol, for the course of the study through 180 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
11. Male subjects of childbearing potential must agree to use an adequate method of contra
Exclusion criteria:
1. Has current participation or treatment with an investigational agent or use of an investigational device within 4 weeks of the first dose of trial treatment.
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137 or other immune checkpoint inhibitors) or has previously participated in Merck MK-3475 clinical trials.
3. Has received a live vaccine within 30 days prior to the first dose of study treatment.
4. Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity, such as nasopharyngeal, sinus, other para-nasal, or other unknown primary HNC.
5. Has had prior systemic therapy, targeted therapy, radiotherapy treatment or radical surgery for head and neck cancer under study.
6. Has Grade =2 audiometric hearing loss (25 decibels in 2 consecutive wave ranges).
7. Has Grade =2 neuropathy.
8. Has Grade 3-4 bleeding due to the underlying malignancy.
9. If subject has received major surgery, the subject must have recovered adequately form the toxicity and/or complications form the intervention prior to starting trial treatment.
10. Has known active Hepatitis B (e.g., HBsAg reactive) or C (e.g., HCV RNA [qualitative] is detected).
11. Has known history of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies).
12. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Corticosteroid use as pre-medication for allergic reactions (e.g. IV contrast), or as a prophylactic management of adverse events related to the chemotherapies specified in the protocol is allowed. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
13. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
14. Has an 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.
15. Has history of a diagnosed and/or treated hematologic or primary solid tumor malignancy, unless in remission for at least 5 years prior to randomization. A T1-2 prostatic cancer Gleason score =6, superficial bladder cancer, non melanomatous skin cancer or carcinoma in situ of the cervix is eligible. Other exceptions may be considered with Sponsor consultation.
16. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
17. Has had previous allogeneic tissue/solid organ transplant.
18. Has active infection requiring systemic therapy.
19. Has a history of severe hypersensitivity reaction (e.g., generalized rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to pembrolizumab, cisplatin or radiotherapy or their analogs.
20. Is a female patient who is pregnant or breast feeding or expecting to conceive or father children within the projected treatment phase of the trial, starting with the screening visit through 180 days after the last dose of trial treatment.
21. Have severe comorbidities that, in the opinion of the Investigator, might hamper participation in the study and/or the treatment administration.
22. Has

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Locally advanced head and neck squamous cell carcinoma (LA HNSCC)
MedDRA version: 19.0 Level: PT Classification code 10067821 Term: Head and neck cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Trade Name: Keytruda
Product Name: Pembrolizumab
Product Code: MK-3475
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Pembrolizumab
CAS Number: 1374853-91-4
Current Sponsor code: MK-3475
Other descriptive name: Anti-PD-1 monoclonal antibody
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Solution for infusion
Route of administration of the placebo: Intravenous use

Trade Name: Cisplatin Teva® 1mg/ml
Product Name: Cisplatin
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: cisplatin
CAS Number: 15663-27-1
Other descriptive name: Cisplatin
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: •The interim efficacy analyses will be performed when 75% of the final required EFS events (or approximately 214 events) have accrued, which is expected approximately 33 months after study start
•The final analysis will be performed when 286 EFS events have accrued, which is estimated to be 48 months after study start.
•The interim safety analysis will be performed when the first 30 subjects have completed CRT. The eDMC will also review safety data periodically in the study.

Secondary Objective: -To compare Overall Survival (OS) in subjects treated with pembrolizumab in combination with CRT and subjects treated with placebo in combination with CRT.
-To evaluate and compare the safety and tolerability profile of pembrolizumab in combination with CRT and subjects treated with placebo in combination with CRT.
- To compare mean change from baseline in Global health status/quality of life (QoL) using the EORTC QLQ-C30, and swallowing, speech and pain symptoms using the EORTC QLQ-H&N35 in subjects treated with pembrolizumab in combination with CRT and subjects treated with placebo in combination with CRT.

Main Objective: To compare Event-free survival (EFS) per RECIST (Response Evaluation
Criteria in Solid Tumors) 1.1 by blinded independent central review (BICR) in subjects treated with pembrolizumab in combination with CRT and subjects treated with placebo in combination with CRT.

Primary end point(s): Event-free survival (EFS)

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: The OS in all subjects will be evaluated at the interim or final analysis if the statistical criterion for success is met for the primary EFS hypothesis in all subjects.

Secondary end point(s): Overall survival

Secondary ID(s)

MK-3475-412

Source(s) of Monetary Support

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.,Inc.