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Protocol NumberMK3475-181
NCT Number(ClinicalTrials.gov Identfier)NCT02564263

2016-01-06 - 2024-01-24

Phase III

Terminated3

ICD-10C15.9

Malignant neoplasm of esophagus, unspecified

A Phase III Randomized Open-label Study of Single Agent Pembrolizumab vs Physicians' Choice of Single Agent Docetaxel, Paclitaxel, or Irinotecan in Subjects with Advanced/Metastatic Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus that have Progressed after First-Line Standard Therapy (KEYNOTE-181)

  • 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

Principal Investigator Hsien-Kun Chang Division of Hematology & Oncology
Linkou Chang Gung Medical Foundation

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Principal Investigator Chia-Jui Yen Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Audit

None

Principal Investigator Chih-Hung Hsu Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Audit

None

Condition/Disease

Advanced/Metastatic Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus

Objectives

In this study, participants with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the esophagogastric junction (EGJ) that had progressed after first-line standard therapy were randomized to receive either pembrolizumab (MK-3475) OR the Investigator's choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan. The primary study hypothesis was that treatment with pembrolizumab would prolong overall survival (OS) as compared to treatment with standard chemotherapy.

Test Drug

KEYTRUDA

Active Ingredient

Pembrolizumab

Dosage Form

Injection

Dosage

100 mg/ 4 mL/ vial

Endpoints

Primary Outcome Measures :
1. Overall Survival (OS) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus [ Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months) ]
OS was defined as the time from randomization to death due to any cause. Median OS in participants with SCC of the esophagus is presented.

2. Overall Survival (OS) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10) [ Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months) ]
OS was defined as the time from randomization to death due to any cause. Median OS in participants with a PD-L1 CPS ≥10 is presented.

3. Overall Survival (OS) in All Participants [ Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months) ]
OS was defined as the time from randomization to death due to any cause. Median OS in all participants is presented.


Secondary Outcome Measures :
1. Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants [ Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months) ]
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by blinded independent central review per RECIST 1.1 in all participants is presented.

2. Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants [ Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months) ]
ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. The percentage of all participants who experienced a CR or PR is presented.

3. Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus [ Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months) ]
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by blinded independent central review per RECIST 1.1 is presented for participants with SCC of the esophagus.

4. Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10) [ Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months) ]
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by blinded independent central review per RECIST 1.1 is presented for participants with a PD-L1 CPS ≥10.

5. Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus [ Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months) ]
ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. The percentage of participants with SCC of the esophagus who experienced a CR or PR is presented.

6. Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10) [ Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months) ]
ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. The percentage of participants with a PD-L1 CPS ≥10 who experienced a CR or PR is presented.

7. Number of Participants Experiencing an Adverse Event (AE) [ Time Frame: Through End-of-Trial Analysis data cutoff date of 31-Dec-2020 (up to approximately 5 years) ]
An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who experienced ≥1 AE will be presented.

8. Number of Participants Discontinuing Study Treatment Due an Adverse Event (AE) [ Time Frame: Through End-of-Trial Analysis data cutoff date of 31-Dec-2020 (up to approximately 5 years) ]
An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE will be presented.

Inclution Criteria

Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. 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.
2. Be ≥ 18 years of age on day of signing informed consent (or acceptable age
according to local regulations, whichever is older).
3. Have histologically or cytologically-confirmed diagnosis of adenocarcinoma or
squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of
the EGJ (defined as adenocarcinomas of the lower esophagus with the center
located within 1cm to 5cm above the anatomic EGJ).
4. Have metastatic disease or locally advanced, unresectable disease.
5. Have a life expectancy of greater than 3 months.
6. Have measurable disease based on RECIST 1.1 as determined by the local site
investigator/radiology assessment. Target lesions situated in a previously
irradiated area are considered measurable if progression has been demonstrated
in such lesions.
Note: The same image acquisition and processing parameters should be used
throughout the study for a given subject.
7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology
Group (ECOG) Performance Scale.
8. Have experienced documented objective radiographic or clinical disease
progression during or after first-line locally or globally recommended therapy.
9. Provide a tissue sample for intratumoral immune-related GEP analysis.
Newly-obtained tissue is preferred (no intervening treatment [local or systemic]
involving the site of tissue biopsy once tissue biopsy is obtained up to the time
of study enrollment). Formalin-fixed, paraffin-embedded (FFPE) block
specimens are preferred to slides. Repeat samples may be required if adequate
tissue is not provided
10. Demonstrate adequate organ function as defined in Table 1.
11. Female subjects of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study
medication. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.
12. Female subjects of childbearing potential must be willing to use an adequate
method of contraception – Contraception, for the course of the study through
120 days after the last dose of pembrolizumab or through 180 days after the last
dose of paclitaxel, docetaxel or irinotecan.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
13. Male subjects of childbearing potential must agree to use an adequate method of
contraception - Contraception, and not to donate sperm starting with the first
dose of study therapy through 120 days after the last dose of pembrolizumab or
through 180 days after the last dose of paclitaxel, docetaxel or irinotecan.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.

Exclusion Criteria

Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating and receiving study therapy or has participated in a
study of an investigational agent and received study therapy or used an
investigation device within 4 weeks of the first dose of treatment.
Note: Subjects who have entered the follow-up phase of an investigational
study may participate as long as it has been 4 weeks since the last dose of the
previous investigational agent or device.
2. Has active autoimmune disease that has required systemic treatment in 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.
3. 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. The use of physiologic doses of corticosteroids may be
approved after consultation with the Sponsor.
4. Has known active central nervous system (CNS) metastases and/or
carcinomatous meningitis. Subjects with previously treated brain metastases
may participate provided they have stable brain metastases for at least four
weeks prior to the first dose of trial treatment; also, any neurologic symptoms
must have returned to baseline.
5. Has had prior anti-cancer monoclonal antibody (mAb), chemotherapy, targeted
small molecule therapy, or radiation therapy within 2 weeks prior to study Day
1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
due to a previously administered agent.
Note: Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an
exception to this criterion and may qualify for the study.
Note: If subject received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy.
6. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent,
or if the subject has previously participated in Merck pembrolizumab
(MK-3475) clinical trials.
7. Has a diagnosed additional malignancy within 5 years prior to treatment
allocation with the exception of curatively treated basal cell carcinoma of the
skin, squamous cell carcinoma of the skin and/or curatively resected in situ
cervical and/or breast cancers.
8. Has received a live vaccine within 30 days of planned start of study therapy.
Note: The killed virus vaccines used for seasonal influenza vaccines for
injection are allowed; however intranasal influenza vaccines (e.g.,
FluMist® ) are live attenuated vaccines, and are not allowed.
9. 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.
10. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2
antibodies).
11. Has known active Hepatitis B (e.g., Hepatitis B surface Antigen reactive) or
Hepatitis C (e.g., HCV RNA [qualitative] is detected).
12. Has known history of, or any evidence of interstitial lung disease or active,
non-infectious pneumonitis.
13. Has an active infection requiring systemic therapy.
14. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
15. Is pregnant or breastfeeding, or expecting to conceive or father children within
the projected duration of the trial, starting with the screening visit through 120
days after the last dose of pembrolizumab or through 180 days after the last
dose of paclitaxel, docetaxel or irinotecan.
16. Has a known allergy, hypersensitivity, or contraindication to paclitaxel,
docetaxel, or irinotecan or any components used in their preparation or has a
contraindication to taxane therapy.
17. Is or has an immediate family member (e.g., spouse, parent/legal guardian,
sibling or child) who is investigational site or sponsor staff directly involved
with this trial, unless prospective IRB approval (by chair or designee) is given
allowing exception to this criterion for a specific subject.

The Estimated Number of Participants

  • Taiwan

    23 participants

  • Global

    628 participants

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