Clinical Trials List
Protocol NumberMK3475-426
Active
2016-09-01 - 2020-05-31
Phase III
Terminated3
ICD-10C64
Malignant neoplasm of kidney, except renal pelvis
ICD-9189.0
Malignant neoplasm of kidney, except pelvis
A Phase III Randomized, Open-label Study to Evaluate Efficacy and Safety of Pembrolizumab (MK-3475) in Combination with Axitinib versus Sunitinib Monotherapy as a First-line Treatment for Locally Advanced or Metastatic Renal Cell Carcinoma (mRCC) (KEYNOTE-426)
-
Trial Applicant
Merck Sharp & Dohme (I.A.) LLC
-
Sponsor
-
Trial scale
Multi-Regional Multi-Center
-
Update
2026/03/01
Investigators and Locations
Co-Principal Investigator
- Tzu-chun Wei Division of Urology
- Yi-Hsiu Huang Division of Urology
- Tzu-Ping Lin Division of Urology
- Yen-Hwa Chang Division of Urology
- 潘競成 Division of Others
- 沈書慧 Division of Radiology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
Audit
None
Linkou Chang Gung Medical Foundation
Taiwan National PI
張文震
Co-Principal Investigator
- See-Tong Pang Division of Hematology & Oncology
- Mengting Peng Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
4 Terminated
Audit
None
Co-Principal Investigator
- Su-Peng Yeh Division of Hematology & Oncology
- 陳冠亨 Division of Urology
- Po-Fan Hsieh Division of Urology
- Hsi-Chin Wu Division of Urology
- Ching-Chan Lin Division of Hematology & Oncology
- Chi-Ping Huang Division of Urology
- Chi-Rei Yang Division of Urology
The Actual Total Number of Participants Enrolled
0 Terminated
Condition/Disease
Locally Advanced or Metastatic Renal Cell Carcinoma (mRCC)
Objectives
Primary Objective(s) & Hypothesis(es)
(1) Objective: To evaluate and compare PFS per RECIST 1.1 as assessed by BICR in
subjects treated with pembrolizumab plus axitinib versus sunitinib monotherapy.
Hypothesis: The combination therapy of pembrolizumab plus axitinib is superior to
sunitinib monotherapy with respect to PFS as assessed by BICR per RECIST 1.1.
(2) Objective: To evaluate and compare OS in subjects treated with pembrolizumab plus
axitinib versus sunitinib monotherapy.
Hypothesis: The combination therapy of pembrolizumab plus axitinib is superior to
sunitinib monotherapy with respect to OS.
Test Drug
Pembrolizumab(MK-3475)
Active Ingredient
Pembrolizumab
Dosage Form
Injection
Dosage
100 mg/4 mL
Endpoints
The study includes 2 primary objectives: 1) to compare progression-free survival (PFS)
between the 2 treatment arms per Response Evaluation Criteria in Solid Tumors version 1.1
(RECIST 1.1) [1] as assessed by blinded independent central imaging review (BICR) and 2)
to compare overall survival (OS) between the 2 treatment arms. Key secondary objectives
include comparison of objective response rate (ORR), duration of response (DOR), and
disease control rate (DCR) per RECIST 1.1 as assessed by BICR, patient reported outcomes
(PROs), and safety and tolerability between the two treatment arms.
The safety objective is to characterize the safety and tolerability of pembrolizumab in
combination with axitinib in subjects with advanced mRCC as a first-line treatment. The
following safety parameters will be analyzed: AEs and SAEs graded per NCI CTCAE,
Version 4.0 criteria with time to onset/recovery, causality and outcome; changes in
laboratory values, vital signs since baseline, treatment discontinuations and reason for
discontinuation, death and cause of death, etc. Concomitant medications will be collected
with time and reasons for use. These are routine safety parameters collected and analyzed in
Phase II/III oncology trials.
between the 2 treatment arms per Response Evaluation Criteria in Solid Tumors version 1.1
(RECIST 1.1) [1] as assessed by blinded independent central imaging review (BICR) and 2)
to compare overall survival (OS) between the 2 treatment arms. Key secondary objectives
include comparison of objective response rate (ORR), duration of response (DOR), and
disease control rate (DCR) per RECIST 1.1 as assessed by BICR, patient reported outcomes
(PROs), and safety and tolerability between the two treatment arms.
The safety objective is to characterize the safety and tolerability of pembrolizumab in
combination with axitinib in subjects with advanced mRCC as a first-line treatment. The
following safety parameters will be analyzed: AEs and SAEs graded per NCI CTCAE,
Version 4.0 criteria with time to onset/recovery, causality and outcome; changes in
laboratory values, vital signs since baseline, treatment discontinuations and reason for
discontinuation, death and cause of death, etc. Concomitant medications will be collected
with time and reasons for use. These are routine safety parameters collected and analyzed in
Phase II/III oncology trials.
Inclution Criteria
In order to be eligible for participation in this trial, the subject must:
1. Provide written informed consent/assent 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.
3. Have histologically confirmed diagnosis of RCC with clear cell component
with or without sarcomatoid features.
4. Have locally advanced/metastatic disease (i.e., Stage IV RCC per American
Joint Committee on Cancer) or have recurrent disease.
5. Have measurable disease per RECIST 1.1 as assessed by the investigator
/site radiologist. Target lesions situated in a previously irradiated area are
considered measurable if progression has been demonstrated in such lesions.
6. Have received no prior systemic therapy for advanced RCC.
7. Have provided archival tumor tissue sample or newly obtained core or
excisional biopsy of a tumor lesion not previously irradiated.
Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to
slides.
Note: Tumor 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).
8. Have Karnofsky performance status (KPS) ≥70% as assessed within 10 days
prior to randomization (see Section 12.4 for KPS description).
9. Subjects receiving bone resorptive therapy (including but not limited to
bisphosphonate or RANK-L inhibitor) must have been on stable doses for 4
weeks prior to randomization.
10. Demonstrate adequate organ function as defined in Table 1 and all screening
laboratory tests should be performed within 10 days prior to randomization.
11. Female subjects of childbearing/reproductive 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 for the course of the study through 120 days after
the last dose of study medication.
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 starting with the first dose of study therapy through
120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject
1. Provide written informed consent/assent 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.
3. Have histologically confirmed diagnosis of RCC with clear cell component
with or without sarcomatoid features.
4. Have locally advanced/metastatic disease (i.e., Stage IV RCC per American
Joint Committee on Cancer) or have recurrent disease.
5. Have measurable disease per RECIST 1.1 as assessed by the investigator
/site radiologist. Target lesions situated in a previously irradiated area are
considered measurable if progression has been demonstrated in such lesions.
6. Have received no prior systemic therapy for advanced RCC.
7. Have provided archival tumor tissue sample or newly obtained core or
excisional biopsy of a tumor lesion not previously irradiated.
Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to
slides.
Note: Tumor 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).
8. Have Karnofsky performance status (KPS) ≥70% as assessed within 10 days
prior to randomization (see Section 12.4 for KPS description).
9. Subjects receiving bone resorptive therapy (including but not limited to
bisphosphonate or RANK-L inhibitor) must have been on stable doses for 4
weeks prior to randomization.
10. Demonstrate adequate organ function as defined in Table 1 and all screening
laboratory tests should be performed within 10 days prior to randomization.
11. Female subjects of childbearing/reproductive 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 for the course of the study through 120 days after
the last dose of study medication.
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 starting with the first dose of study therapy through
120 days after the last dose of study therapy.
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 in or has participated in a study of an
investigational agent or has used an investigational device within 4 weeks
prior to randomization.
2. Has had major surgery within 4 weeks prior to randomization or radiation
therapy within 2 weeks prior to randomization, or who has not recovered
(i.e., ≤ Grade 1 or at baseline) from AEs due to prior treatment.
3. Has had prior treatment with any anti-PD-1, or PD-L1, or PD-L2 agent or an
antibody targeting any other immune-regulatory receptors or mechanisms.
Examples of such antibodies include (but are not limited to) antibodies
against IDO, PD-L1, IL-2R, and GITR.
4. Has received prior therapy with VEGF/VEGFR or mTOR targeting agents.
Note: Prior neoadjuvant/adjuvant therapy of these targeted agents is
acceptable if completed > 12 months prior to randomization.
5. Has a history of severe hypersensitivity reaction (e.g., generalized
rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to
axitinib or sunitinib.
6. Has a diagnosis of immunodeficiency or is receiving systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior
to randomization, except in the case of central nervous system (CNS)
metastases (see exclusion 9). The use of physiologic doses of
corticosteroids may be approved after consultation with the Sponsor.
7. Has an active autoimmune disease requiring systemic treatment within the
past 3 months or a documented history of clinically severe autoimmune
disease, or a syndrome that requires systemic or immunosuppressive agents.
Subjects with vitiligo, diabetes Type I, or resolved childhood asthma/atopy
will not be excluded from the study. Subjects requiring intermittent use of
bronchodilators, inhaled steroids, or local steroid injections would not be
excluded from the study. Subjects with hypothyroidism stable on hormone
replacement or Sjøgren’s syndrome will not be excluded from the study.
8. Has a known additional malignancy that has progressed or has required
active treatment in the last 3 years.
Note: Subjects with basal cell carcinoma of the skin, squamous cell
carcinoma of the skin that has undergone potentially curative therapy or
carcinoma in situ are not excluded.
9. Has known active CNS metastases and/or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate provided
they are stable, i.e. without evidence of progression for at least 4 weeks by
repeat imaging (note that the repeat imaging should be performed during
study screening), without requirement of steroid treatment for at least 4
weeks prior to randomization and with any neurologic symptoms resolved or have returned to baseline of prior treatment for brain metastasis.
10. Has a history of (non-infectious) pneumonitis that required steroids or
current pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has a known history of Human Immunodeficiency Virus (HIV) infection
(HIV ½ antibodies).
Note: HIV ½ antibodies testing is required when the investigator has reason
to suspect the subject has HIV infection or is otherwise mandated per local
guidance.
13. Has known active Hepatitis B (e.g., Hepatitis B surface antigen [HBsAg]
reactive) or Hepatitis C virus (e.g., HCV RNA [qualitative] is detected).
Note: HCV RNA testing is not required in those countries where local
standard of care uses only Hepatitis C antibody testing as evidence of status
of Hepatitis C.
14. Has received a live virus vaccine within 30 days of randomization.
15. Has a clinically significant gastrointestinal (GI) abnormality including:
Inability to take oral medication
Requirement for IV alimentation
Prior surgical procedures affecting absorption including total gastric
resection
Treatment for active peptic ulcer within the past 6 months
Active GI bleeding, as evidenced by hematemesis, hematochezia or
melena in the past 3 months without evidence of resolution
documented by endoscopy or colonoscopy
Intraluminal metastatic lesion with suspected bleeding, inflammatory
bowel disease, ulcerative colitis or other GI condition associated with
increased risk of perforation, or history of GI perforation
Malabsorption syndromes
Inflammatory bowel disease
16. Has QT interval corrected for heart rate (QTc) ≥ 480 msec.
17. Has a history of any of the following cardiovascular conditions within 12
months of screening:
Myocardial infarction
Unstable angina pectoris
Cardiac angioplasty or stenting
Coronary/peripheral artery bypass graft
Class III or IV congestive heart failure per New York Heart
Association
Cerebrovascular accident or transient ischemic attack
18. Has a history of deep vein thrombosis or pulmonary embolism within 6
months of screening.
19. Has poorly controlled hypertension defined as systolic blood pressure (SBP)
≥ 150 mm Hg and/or diastolic blood pressure (DBP) ≥ 90 mm Hg.
Note: measurement of screening blood pressure (BP) reading is based on an
average of 3 readings at least 2 minutes apart. Subjects with initial screening
BP ≥150/90 mm Hg can be treated with anti-hypertensive medication to
achieve a well-controlled status and are eligible with reassessed SBP/DBP
of <150/90 mm Hg.
20. Has evidence of inadequate wound healing.
21. Has active bleeding disorder or other history of significant bleeding
episodes within 30 days of randomization.
22. Has hemoptysis within 6 weeks prior to randomization.
23. Has current use or anticipated need for treatment with drugs or foods that
are known strong cytochrome P450 (CYP3A4/5) inhibitors including but
not limited to atazanavir, clarithromycin, indinavir, itraconazole,
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin,
troleandomycin, voriconazole, and grapefruit or grapefruit juice.
NOTE: The topical use of these medications, such as 2% ketoconazole
cream, is allowed.
24. Has current use or anticipated need for treatment with drugs that are known
strong CYP3A4/5 inducers, including but not limited to carbamazepine,
phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s wort.
25. 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.
26. Has known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the trial.
27. Has had a prior solid organ transplant.
28. 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 trial treatment.
29. Is, at the time of signing informed consent, a known regular user (including
"recreational use") of any illicit drugs or had a recent history (within the last
year) of drug or alcohol abuse.
The subject must be excluded from participating in the trial if the subject:
1. 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.
2. Has had major surgery within 4 weeks prior to randomization or radiation
therapy within 2 weeks prior to randomization, or who has not recovered
(i.e., ≤ Grade 1 or at baseline) from AEs due to prior treatment.
3. Has had prior treatment with any anti-PD-1, or PD-L1, or PD-L2 agent or an
antibody targeting any other immune-regulatory receptors or mechanisms.
Examples of such antibodies include (but are not limited to) antibodies
against IDO, PD-L1, IL-2R, and GITR.
4. Has received prior therapy with VEGF/VEGFR or mTOR targeting agents.
Note: Prior neoadjuvant/adjuvant therapy of these targeted agents is
acceptable if completed > 12 months prior to randomization.
5. Has a history of severe hypersensitivity reaction (e.g., generalized
rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to
axitinib or sunitinib.
6. Has a diagnosis of immunodeficiency or is receiving systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior
to randomization, except in the case of central nervous system (CNS)
metastases (see exclusion 9). The use of physiologic doses of
corticosteroids may be approved after consultation with the Sponsor.
7. Has an active autoimmune disease requiring systemic treatment within the
past 3 months or a documented history of clinically severe autoimmune
disease, or a syndrome that requires systemic or immunosuppressive agents.
Subjects with vitiligo, diabetes Type I, or resolved childhood asthma/atopy
will not be excluded from the study. Subjects requiring intermittent use of
bronchodilators, inhaled steroids, or local steroid injections would not be
excluded from the study. Subjects with hypothyroidism stable on hormone
replacement or Sjøgren’s syndrome will not be excluded from the study.
8. Has a known additional malignancy that has progressed or has required
active treatment in the last 3 years.
Note: Subjects with basal cell carcinoma of the skin, squamous cell
carcinoma of the skin that has undergone potentially curative therapy or
carcinoma in situ are not excluded.
9. Has known active CNS metastases and/or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate provided
they are stable, i.e. without evidence of progression for at least 4 weeks by
repeat imaging (note that the repeat imaging should be performed during
study screening), without requirement of steroid treatment for at least 4
weeks prior to randomization and with any neurologic symptoms resolved or have returned to baseline of prior treatment for brain metastasis.
10. Has a history of (non-infectious) pneumonitis that required steroids or
current pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has a known history of Human Immunodeficiency Virus (HIV) infection
(HIV ½ antibodies).
Note: HIV ½ antibodies testing is required when the investigator has reason
to suspect the subject has HIV infection or is otherwise mandated per local
guidance.
13. Has known active Hepatitis B (e.g., Hepatitis B surface antigen [HBsAg]
reactive) or Hepatitis C virus (e.g., HCV RNA [qualitative] is detected).
Note: HCV RNA testing is not required in those countries where local
standard of care uses only Hepatitis C antibody testing as evidence of status
of Hepatitis C.
14. Has received a live virus vaccine within 30 days of randomization.
15. Has a clinically significant gastrointestinal (GI) abnormality including:
Inability to take oral medication
Requirement for IV alimentation
Prior surgical procedures affecting absorption including total gastric
resection
Treatment for active peptic ulcer within the past 6 months
Active GI bleeding, as evidenced by hematemesis, hematochezia or
melena in the past 3 months without evidence of resolution
documented by endoscopy or colonoscopy
Intraluminal metastatic lesion with suspected bleeding, inflammatory
bowel disease, ulcerative colitis or other GI condition associated with
increased risk of perforation, or history of GI perforation
Malabsorption syndromes
Inflammatory bowel disease
16. Has QT interval corrected for heart rate (QTc) ≥ 480 msec.
17. Has a history of any of the following cardiovascular conditions within 12
months of screening:
Myocardial infarction
Unstable angina pectoris
Cardiac angioplasty or stenting
Coronary/peripheral artery bypass graft
Class III or IV congestive heart failure per New York Heart
Association
Cerebrovascular accident or transient ischemic attack
18. Has a history of deep vein thrombosis or pulmonary embolism within 6
months of screening.
19. Has poorly controlled hypertension defined as systolic blood pressure (SBP)
≥ 150 mm Hg and/or diastolic blood pressure (DBP) ≥ 90 mm Hg.
Note: measurement of screening blood pressure (BP) reading is based on an
average of 3 readings at least 2 minutes apart. Subjects with initial screening
BP ≥150/90 mm Hg can be treated with anti-hypertensive medication to
achieve a well-controlled status and are eligible with reassessed SBP/DBP
of <150/90 mm Hg.
20. Has evidence of inadequate wound healing.
21. Has active bleeding disorder or other history of significant bleeding
episodes within 30 days of randomization.
22. Has hemoptysis within 6 weeks prior to randomization.
23. Has current use or anticipated need for treatment with drugs or foods that
are known strong cytochrome P450 (CYP3A4/5) inhibitors including but
not limited to atazanavir, clarithromycin, indinavir, itraconazole,
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin,
troleandomycin, voriconazole, and grapefruit or grapefruit juice.
NOTE: The topical use of these medications, such as 2% ketoconazole
cream, is allowed.
24. Has current use or anticipated need for treatment with drugs that are known
strong CYP3A4/5 inducers, including but not limited to carbamazepine,
phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s wort.
25. 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.
26. Has known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the trial.
27. Has had a prior solid organ transplant.
28. 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 trial treatment.
29. Is, at the time of signing informed consent, a known regular user (including
"recreational use") of any illicit drugs or had a recent history (within the last
year) of drug or alcohol abuse.
The Estimated Number of Participants
-
Taiwan
19 participants
-
Global
840 participants
