Clinical Trials List
Protocol NumberMK-3475-669/ ECHO-304
NCT Number(ClinicalTrials.gov Identfier)NCT03358472
2017-11-20 - 2022-11-21
Phase III
Terminated5
ICD-10C44.42
Squamous cell carcinoma of skin of scalp and neck
ICD-9195.0
Malignant neoplasm of other and ill-defined sites of head, face and neck
A Phase 3 Randomized, Open-Label Clinical Study to Evaluate the Efficacy and Safety of Pembrolizumab Plus Epacadostat, Pembrolizumab Monotherapy, and the EXTREME Regimen as First Line Treatment for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (KEYNOTE-669/ECHO-304)
-
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
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- 林敬薇 Division of Radiation Therapy
- 陳建志 Division of Radiation Therapy
- 李權 Division of Radiation Therapy
- YI-CHUN LIU Division of Radiation Therapy
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Ching Yun Hsieh Division of Hematology & Oncology
- Wei-Ching Lin Division of Radiology
- Ming-Hung Tsai Division of Hematology & Oncology
- Ming-Yu Lien Division of Hematology & Oncology
- Chi-Ching Chen Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Principal Investigator
Co-Principal Investigator
- Su-Peng Yeh 未分科
Audit
None
Principal Investigator
Co-Principal Investigator
- Chia-Jui Yen 未分科
Audit
None
Co-Principal Investigator
- Chi-Ting Liau Division of Hematology & Oncology
- 廖俊達 Division of Hematology & Oncology
- Chia-Hsun Hsieh Division of Hematology & Oncology
- Shu-Hang Ag Division of Radiology
- Cheng-Lung Hsu Division of Hematology & Oncology
- Li-Yu Lee Division of Others -
- Tung-Chieh Chang Division of Radiation Therapy
- Tzu-Chen Yen Division of Nuclear Medicine
The Actual Total Number of Participants Enrolled
0 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
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
Condition/Disease
Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
Objectives
-To compare overall survival (OS) for the combination of pembrolizumab + epacadostat versus EXTREME regimen (cetuximab +
platinum [cisplatin or carboplatin] + 5-fluorouracil).
-To compare progression-free survival (PFS) for the combination of pembrolizumab + epacadostat versus the EXTREME
regimen.
Test Drug
Pembrolizumab (MK-3475); Epacadostat (INCB024360)
Active Ingredient
Pembrolizumab (Humanized anti-PD-1 mAb); Epacadostat (inhibitor of the enzyme IDO1)
Dosage Form
Solution ; Tablet
Dosage
25; 100, 25
Endpoints
1) OS is defined as the time from randomization to death due to any cause.
2) PFS is defined as the time from randomization to the first documented radiographic progressive disease (PD) or death due to any cause, whichever occurs first. For H2, PD will be assessed per RECIST 1.1 by BICR.
2) PFS is defined as the time from randomization to the first documented radiographic progressive disease (PD) or death due to any cause, whichever occurs first. For H2, PD will be assessed per RECIST 1.1 by BICR.
Inclution Criteria
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following
criteria apply:
Type of Participant and Disease Characteristics
1. Male/female participants who are at least 18 years of age on the day of signing
informed consent with histologically or cytologically-confirmed R/M HNSCC
that is considered incurable by local therapies will be enrolled in this study.
Note: The eligible primary tumor locations are oropharynx, oral cavity,
hypopharynx, and larynx.
Male participants:
2. A male participant must agree to use contraception as detailed in Appendix 5 of
this protocol during the treatment period and for at least 120 days after the last
dose of pembrolizumab and epacadostat, or pembrolizumab alone, and for at
least 180 days after the last dose of the EXTREME regimen, whichever is
longer. He must also refrain from donating sperm during this period. Note:
Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the participant.
Female participants:
3. A female participant is eligible to participate if she is not pregnant (see Protocol Appendix 5), not breastfeeding, and at least one of the following
conditions applies:
a.) Not a woman of childbearing potential (WOCBP) as defined in Protocol
Appendix 5 OR
b.) A WOCBP who agrees to follow the contraceptive guidance in Protocol
Appendix 5 during the treatment period and for at least 120 days after the last
dose of pembrolizumab and epacadostat, or pembrolizumab alone, and for at
least 180 days after last dose of the EXTREME regimen, whichever is longer.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the participant.
Informed Consent
4. The participant (or legally acceptable representative if applicable) provides
written informed consent for the study.
Diagnostic Assessments
5. Have measurable disease by CT or MRI based on RECIST 1.1 as determined
by site radiology. Lesions situated in a previously irradiated area are
considered measurable if progression has been demonstrated in such lesions
following radiation therapy.
6. Have an ECOG PS of 0 or 1 within 7 days prior to randomization.
7. Have adequate organ function as defined in the following table (Table 1).
Specimens must be collected within ≤10 days prior to the start of study
treatment. (Participants may be enrolled based on local laboratory results
pending central laboratory results).
8. Have documentation of results from 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.
9. Have a baseline archival tumor specimen available or is willing to undergo a
pre-study treatment tumor core or excisional biopsy of a tumor lesion not
previously irradiated, to obtain the specimen. Fine needle aspirate (FNA) and
bone metastases samples are not acceptable.
Participants are eligible to be included in the study only if all of the following
criteria apply:
Type of Participant and Disease Characteristics
1. Male/female participants who are at least 18 years of age on the day of signing
informed consent with histologically or cytologically-confirmed R/M HNSCC
that is considered incurable by local therapies will be enrolled in this study.
Note: The eligible primary tumor locations are oropharynx, oral cavity,
hypopharynx, and larynx.
Male participants:
2. A male participant must agree to use contraception as detailed in Appendix 5 of
this protocol during the treatment period and for at least 120 days after the last
dose of pembrolizumab and epacadostat, or pembrolizumab alone, and for at
least 180 days after the last dose of the EXTREME regimen, whichever is
longer. He must also refrain from donating sperm during this period. Note:
Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the participant.
Female participants:
3. A female participant is eligible to participate if she is not pregnant (see Protocol Appendix 5), not breastfeeding, and at least one of the following
conditions applies:
a.) Not a woman of childbearing potential (WOCBP) as defined in Protocol
Appendix 5 OR
b.) A WOCBP who agrees to follow the contraceptive guidance in Protocol
Appendix 5 during the treatment period and for at least 120 days after the last
dose of pembrolizumab and epacadostat, or pembrolizumab alone, and for at
least 180 days after last dose of the EXTREME regimen, whichever is longer.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the participant.
Informed Consent
4. The participant (or legally acceptable representative if applicable) provides
written informed consent for the study.
Diagnostic Assessments
5. Have measurable disease by CT or MRI based on RECIST 1.1 as determined
by site radiology. Lesions situated in a previously irradiated area are
considered measurable if progression has been demonstrated in such lesions
following radiation therapy.
6. Have an ECOG PS of 0 or 1 within 7 days prior to randomization.
7. Have adequate organ function as defined in the following table (Table 1).
Specimens must be collected within ≤10 days prior to the start of study
treatment. (Participants may be enrolled based on local laboratory results
pending central laboratory results).
8. Have documentation of results from 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.
9. Have a baseline archival tumor specimen available or is willing to undergo a
pre-study treatment tumor core or excisional biopsy of a tumor lesion not
previously irradiated, to obtain the specimen. Fine needle aspirate (FNA) and
bone metastases samples are not acceptable.
Exclusion Criteria
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has carcinoma of the nasopharynx, salivary gland, unknown primary origin,
or nonsquamous histologies as primary tumors.
2. Has disease progression within 6 months of completion of curatively intended
systemic treatment for locoregionally advanced HNSCC.
3. Has a life expectancy of less than 3 months and/or has rapidly progressing
disease (eg tumor bleeding, uncontrolled tumor pain) in the opinion of the
treating investigator.
4. Has a history of bleeding requiring a medical intervention (eg, embolization
procedure, RBC transfusion, or hospitalization) within 30 days of study
enrollment.
5. Has a history of peripheral neuropathy ≥ Grade 2 for participants who may
receive cisplatin.
6. Has a history of dihydropyrimidine dehydrogenase (DPD) deficiency
(homozygous or heterozygous mutations).
7. Has a history of any contraindication or has a severe hypersensitivity to any components of epacadostat, pembrolizumab (≥Grade 3), cisplatin or
carboplatin, cetuximab, and 5-FU.
Note: Sites are instructed to refer to the approved product labeling for these
therapies for information on contraindications or precautions for use.
Refer to Protocol Appendix 9 for Cisplatin Marketing authorization (for sites
conducting study in France only).
8. Had an allogeneic tissue/solid organ transplant.
9. Has a history of gastrointestinal condition or procedure that may affect drug
absorption.
Note: Participants with feeding tubes are eligible.
10. Any history of Serotonin Syndrome after receiving serotonergic drugs.
11. A WOCBP who has a positive urine pregnancy test within 72 hours before the
first dose of study treatment (see Protocol Appendix 5). If the urine test
cannot be confirmed as negative, a serum pregnancy test is required. In such
cases, the participant must be excluded from participation if the serum
pregnancy result is positive.
Note, in the event that 72 hours have elapsed between the screening
pregnancy test and the first dose of study treatment, another pregnancy test
(urine or serum) must be performed and must be negative in order for the
participant to start receiving study treatment.
Prior/Concomitant Therapy
12. Has received prior systemic therapy (as part of multimodal treatment) for
HNSCC administered in the recurrent and/or metastatic setting for incurable
disease.
Note: Systemic therapy (as part of multimodal treatment) which was
completed more than 6 months prior to signing consent if given as part of
multimodal treatment for locally advanced disease is allowed.
13. Has not fully recovered (ie, ≤Grade 1 or at baseline) from AEs due to a
previously administered treatment.
Note: Participants with ≤Grade 2 alopecia are an exception to this criterion
and may qualify for the study.
Note: If participants have received major surgery, they must have recovered
adequately from the toxicity and/or complications from the intervention prior
to starting study treatment.
14. Has received prior palliative radiotherapy within 2 weeks of start of study
treatment. Participants must have recovered from all radiation-related
toxicities, not require corticosteroids, and not have had radiation pneumonitis.
15. Has received prior therapy with epacadostat or any IDO1 inhibitor, an anti-PD-1, anti-PD-L1, or anti PD-L2 agent, or any agent directed to another
stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
16. Has received a live vaccine within 30 days prior to the first dose of study
treatment. Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow
fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine.
Seasonal influenza vaccines for injection are generally killed virus vaccines
and are allowed; however, intranasal influenza vaccines are live attenuated
vaccines and are not allowed.
17. Has received therapy with an MAOI, melatonin supplement, or UGT1A9
inhibitor within 21 days prior to starting treatment, or anticipates requiring
one of these prohibited medications during the treatment phase. Examples of
medications in these classes are found in Protocol Section 7.7.3.
18. Current use of any prohibited medication as described in Protocol Section
7.7.3.
Prior/Concurrent Clinical Study Experience
19. 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 treatment.
Note: Participants who have entered the Post-treatment Follow-up Phase of an
investigational study may participate as long as it has been 4 weeks after the
last dose of the previous investigational agent.
Diagnostic assessments
20. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid
therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any
other form of immunosuppressive therapy within 7 days prior to the first dose
of study treatment. Corticosteroid use as pre-medication for allergic reactions
(eg IV contrast) is permitted.
21. Has a known additional malignancy that is progressing or has required active
systemic treatment within the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical
cancer in situ) that have undergone potentially curative therapy are not
excluded. Participants with low-risk early stage prostate cancer defined as
follows are not excluded; Stage T1c or T2a with a Gleason score ≤ 6 and
prostatic-specific antigen (PSA) < 10 ng/mL either treated with definitive
intent or untreated in active surveillance that has been stable for the past year
prior to study enrollment. Other exceptions may be considered after consultation with the MSD Clinical Director.
22. Has known active central nervous system metastases and/or carcinomatous
meningitis. Participants with previously treated brain metastases may
participate provided they are radiologically stable, ie, 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 steroid treatment for at least 14 days prior to first dose
of study treatment.
23. Has an active autoimmune disease that has required systemic treatment in past
2 years (ie, with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment and is
allowed.
24. Has a history of (non-infectious) pneumonitis that required steroids or has
current pneumonitis.
25. Has an active infection requiring systemic therapy.
26. Has a known history of human immunodeficiency virus (HIV) infection. No
HIV testing is required unless mandated by local health authority.
27. Has a known history of or is positive for active hepatitis B (defined as
hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (defined as HCV
RNA [qualitative] is detected). Note: Testing must be performed to determine
eligibility.
a. HBV DNA must be undetectable and HBsAg negative at
Screening Visit.
b. Hepatitis C Ab testing is allowed for screening purposes in
countries where HCV RNA is not part of SoC. In these cases,
HCV antibody positive patients will be excluded.
c. Participants who have had definitive treatment for HCV are
permitted if HCV RNA is undetectable at Screening Visit.
28. Has known psychiatric or substance abuse disorders that would interfere with
cooperating with the requirements of the study.
29. 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 treating
investigator.
30. 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 pembrolizumab and epacadostat or
pembrolizumab monotherapy and up to 180 days after the last dose of
EXTREME regimen.
Other Exclusions
31. Screening corrected QT (QTc) interval >480 milliseconds is excluded
(Fridericia formula is the preferred method. Bazett formula is acceptable). In
the event that a single QTc is >480 milliseconds, the participant may enroll if
the average QTc for the 3 electrocardiograms (ECGs) is <480 milliseconds.
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has carcinoma of the nasopharynx, salivary gland, unknown primary origin,
or nonsquamous histologies as primary tumors.
2. Has disease progression within 6 months of completion of curatively intended
systemic treatment for locoregionally advanced HNSCC.
3. Has a life expectancy of less than 3 months and/or has rapidly progressing
disease (eg tumor bleeding, uncontrolled tumor pain) in the opinion of the
treating investigator.
4. Has a history of bleeding requiring a medical intervention (eg, embolization
procedure, RBC transfusion, or hospitalization) within 30 days of study
enrollment.
5. Has a history of peripheral neuropathy ≥ Grade 2 for participants who may
receive cisplatin.
6. Has a history of dihydropyrimidine dehydrogenase (DPD) deficiency
(homozygous or heterozygous mutations).
7. Has a history of any contraindication or has a severe hypersensitivity to any components of epacadostat, pembrolizumab (≥Grade 3), cisplatin or
carboplatin, cetuximab, and 5-FU.
Note: Sites are instructed to refer to the approved product labeling for these
therapies for information on contraindications or precautions for use.
Refer to Protocol Appendix 9 for Cisplatin Marketing authorization (for sites
conducting study in France only).
8. Had an allogeneic tissue/solid organ transplant.
9. Has a history of gastrointestinal condition or procedure that may affect drug
absorption.
Note: Participants with feeding tubes are eligible.
10. Any history of Serotonin Syndrome after receiving serotonergic drugs.
11. A WOCBP who has a positive urine pregnancy test within 72 hours before the
first dose of study treatment (see Protocol Appendix 5). If the urine test
cannot be confirmed as negative, a serum pregnancy test is required. In such
cases, the participant must be excluded from participation if the serum
pregnancy result is positive.
Note, in the event that 72 hours have elapsed between the screening
pregnancy test and the first dose of study treatment, another pregnancy test
(urine or serum) must be performed and must be negative in order for the
participant to start receiving study treatment.
Prior/Concomitant Therapy
12. Has received prior systemic therapy (as part of multimodal treatment) for
HNSCC administered in the recurrent and/or metastatic setting for incurable
disease.
Note: Systemic therapy (as part of multimodal treatment) which was
completed more than 6 months prior to signing consent if given as part of
multimodal treatment for locally advanced disease is allowed.
13. Has not fully recovered (ie, ≤Grade 1 or at baseline) from AEs due to a
previously administered treatment.
Note: Participants with ≤Grade 2 alopecia are an exception to this criterion
and may qualify for the study.
Note: If participants have received major surgery, they must have recovered
adequately from the toxicity and/or complications from the intervention prior
to starting study treatment.
14. Has received prior palliative radiotherapy within 2 weeks of start of study
treatment. Participants must have recovered from all radiation-related
toxicities, not require corticosteroids, and not have had radiation pneumonitis.
15. Has received prior therapy with epacadostat or any IDO1 inhibitor, an anti-PD-1, anti-PD-L1, or anti PD-L2 agent, or any agent directed to another
stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
16. Has received a live vaccine within 30 days prior to the first dose of study
treatment. Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow
fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine.
Seasonal influenza vaccines for injection are generally killed virus vaccines
and are allowed; however, intranasal influenza vaccines are live attenuated
vaccines and are not allowed.
17. Has received therapy with an MAOI, melatonin supplement, or UGT1A9
inhibitor within 21 days prior to starting treatment, or anticipates requiring
one of these prohibited medications during the treatment phase. Examples of
medications in these classes are found in Protocol Section 7.7.3.
18. Current use of any prohibited medication as described in Protocol Section
7.7.3.
Prior/Concurrent Clinical Study Experience
19. 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 treatment.
Note: Participants who have entered the Post-treatment Follow-up Phase of an
investigational study may participate as long as it has been 4 weeks after the
last dose of the previous investigational agent.
Diagnostic assessments
20. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid
therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any
other form of immunosuppressive therapy within 7 days prior to the first dose
of study treatment. Corticosteroid use as pre-medication for allergic reactions
(eg IV contrast) is permitted.
21. Has a known additional malignancy that is progressing or has required active
systemic treatment within the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical
cancer in situ) that have undergone potentially curative therapy are not
excluded. Participants with low-risk early stage prostate cancer defined as
follows are not excluded; Stage T1c or T2a with a Gleason score ≤ 6 and
prostatic-specific antigen (PSA) < 10 ng/mL either treated with definitive
intent or untreated in active surveillance that has been stable for the past year
prior to study enrollment. Other exceptions may be considered after consultation with the MSD Clinical Director.
22. Has known active central nervous system metastases and/or carcinomatous
meningitis. Participants with previously treated brain metastases may
participate provided they are radiologically stable, ie, 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 steroid treatment for at least 14 days prior to first dose
of study treatment.
23. Has an active autoimmune disease that has required systemic treatment in past
2 years (ie, with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment and is
allowed.
24. Has a history of (non-infectious) pneumonitis that required steroids or has
current pneumonitis.
25. Has an active infection requiring systemic therapy.
26. Has a known history of human immunodeficiency virus (HIV) infection. No
HIV testing is required unless mandated by local health authority.
27. Has a known history of or is positive for active hepatitis B (defined as
hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (defined as HCV
RNA [qualitative] is detected). Note: Testing must be performed to determine
eligibility.
a. HBV DNA must be undetectable and HBsAg negative at
Screening Visit.
b. Hepatitis C Ab testing is allowed for screening purposes in
countries where HCV RNA is not part of SoC. In these cases,
HCV antibody positive patients will be excluded.
c. Participants who have had definitive treatment for HCV are
permitted if HCV RNA is undetectable at Screening Visit.
28. Has known psychiatric or substance abuse disorders that would interfere with
cooperating with the requirements of the study.
29. 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 treating
investigator.
30. 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 pembrolizumab and epacadostat or
pembrolizumab monotherapy and up to 180 days after the last dose of
EXTREME regimen.
Other Exclusions
31. Screening corrected QT (QTc) interval >480 milliseconds is excluded
(Fridericia formula is the preferred method. Bazett formula is acceptable). In
the event that a single QTc is >480 milliseconds, the participant may enroll if
the average QTc for the 3 electrocardiograms (ECGs) is <480 milliseconds.
The Estimated Number of Participants
-
Taiwan
40 participants
-
Global
625 participants
