Clinical Trials List
Protocol NumberMK3475-412
NCT Number(ClinicalTrials.gov Identfier)NCT03040999
2017-01-20 - 2025-08-15
Phase III
Terminated10
ICD-10C44.42
Squamous cell carcinoma of skin of scalp and neck
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)
-
Trial Applicant
Merck Sharp & Dohme (I.A.) LLC
-
Sponsor
Merck Sharp & Dohme Corp.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- 劉奕廷 Division of Hematology & Oncology
- Shang-Yin Wu Division of Hematology & Oncology
- 蔡牧宏 Division of Radiation Therapy
- 吳沅樺 Division of Radiation Therapy
- 薛尉廷 Division of Radiation Therapy
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
The Actual Total Number of Participants Enrolled
0 Terminated
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Tsung-Lun Lee Division of Otolaryngology
- 胡育文 Division of Radiation Therapy
- 戴世光 Division of Otolaryngology
- Yuan-Hung Wu Division of Radiation Therapy
- Mu-Hsin Chang Division of Radiation Therapy
- Ling-Wei Wang Division of Radiology
- 羅文良 Division of Oral and Maxillofacial Surgery
- 朱本元 Division of Otolaryngology
- 黃品逸 Division of Radiation Therapy
The Actual Total Number of Participants Enrolled
5 Terminated
Audit
None
The Actual Total Number of Participants Enrolled
0 Terminated
Linkou Chang Gung Medical Foundation
Taiwan National PI
王宏銘
Co-Principal Investigator
- Li-Yu Lee 無
- 謝家訓 Division of Hematology & Oncology
- Chia-Hsun Hsieh 無
- Tung-Chieh Chang 無
- 黃炳勝 無
- Cheng-Lung Hsu 無
- Shu-Hang Ag 無
- 廖俊達 無
- Tzu-Chen Yen 無
- Chi-Ting Liau 無
- 范綱行 無
The Actual Total Number of Participants Enrolled
5 Terminated
Audit
None
Co-Principal Investigator
- 廖斌志 Division of Hematology & Oncology
- Hsiang-Fong Kao Division of Hematology & Oncology
- YA-FANG CHEN Division of Radiology
- HUAI-CHENG HUANG Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Shang-Yin Wu Division of Hematology & Oncology
- 吳沅樺 Division of Radiation Therapy
- 薛尉廷 Division of Radiation Therapy
- 劉奕廷 Division of Hematology & Oncology
- 蔡牧宏 Division of Radiation Therapy
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- 廖斌志 Division of Hematology & Oncology
- HUAI-CHENG HUANG Division of Hematology & Oncology
- Hsiang-Fong Kao Division of Hematology & Oncology
- YA-FANG CHEN Division of Radiology
The Actual Total Number of Participants Enrolled
0 Terminated
Condition/Disease
Locally Advanced Head and Neck Squamous Cell Carcinoma
Objectives
All objectives and hypotheses apply to male/female adult subjects (≥18 years of
age) with LA HNSCC.
1. Primary Objective(s) & Hypothesis(es)
(1) 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.
Hypothesis: Pembrolizumab in combination with CRT is superior to
placebo in combination with CRT with respect to EFS per RECIST 1.1 by
BICR.
2. Secondary Objective(s) & Hypothesis(es)
(1) Objective: To compare Overall Survival (OS) in subjects treated with
pembrolizumab in combination with CRT and subjects treated with
placebo in combination with CRT.
Hypothesis: Pembrolizumab in combination with CRT is superior to
placebo in combination with CRT with respect to OS.
(2) Objective: To evaluate and compare the safety and tolerability profile of
pembrolizumab in combination with CRT and subjects treated with
placebo in combination with CRT.
(3) Objective: 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.
Test Drug
Keytruda
Active Ingredient
Pembrolizumab (MK-3475)
Dosage Form
IV Infusion
Dosage
100 mg/4 mL
Endpoints
Primary Endpoint(s)
Event-free survival (EFS)
Key Secondary Endpoints
Overall survival (OS)
Event-free survival (EFS)
Key Secondary Endpoints
Overall survival (OS)
Inclution Criteria
Diagnosis/Condition for Entry into the Trial
Male and female subjects with LA HNSCC who are at least 18 years of age
will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
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 (please see Section 7.1.5, Tumor Tissue Collection for
details). 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
(details pertaining to tumor tissue submission can be found in
the Procedures Manual).
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 (Section 5.9.2) must be willing
to use an adequate method of contraception as outlined in Section 5.9.2 –
Contraception, 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 (Section 5.9.2) must agree to use
an adequate method of contraception as outlined in Section 5.9.2-
Contraception, starting with the first dose of study therapy through 180
days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and
preferred contraception for the subject.
12. Demonstrate adequate organ function as defined in Table 1. All screening
labs should be performed within 10 days of treatment initiation.
Male and female subjects with LA HNSCC who are at least 18 years of age
will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
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 (please see Section 7.1.5, Tumor Tissue Collection for
details). 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
(details pertaining to tumor tissue submission can be found in
the Procedures Manual).
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 (Section 5.9.2) must be willing
to use an adequate method of contraception as outlined in Section 5.9.2 –
Contraception, 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 (Section 5.9.2) must agree to use
an adequate method of contraception as outlined in Section 5.9.2-
Contraception, starting with the first dose of study therapy through 180
days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and
preferred contraception for the subject.
12. Demonstrate adequate organ function as defined in Table 1. All screening
labs should be performed within 10 days of treatment initiation.
Exclusion Criteria
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
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 premedication 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 a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
subject’s participation for the full duration of the trial, or is not in the best
interest of the subject to participate, in the opinion of the treating
investigator.
23. Has known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the trial.
The subject must be excluded from participating in the trial if the subject:
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 premedication 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 a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
subject’s participation for the full duration of the trial, or is not in the best
interest of the subject to participate, in the opinion of the treating
investigator.
23. Has known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the trial.
The Estimated Number of Participants
-
Taiwan
33 participants
-
Global
780 participants
