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Study of Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-3475-012/KEYNOTE-012)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01848834
Recruitment Status : Completed
First Posted : May 8, 2013
Results First Posted : June 26, 2017
Last Update Posted : June 28, 2021
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Tracking Information
First Submitted Date  ICMJE May 3, 2013
First Posted Date  ICMJE May 8, 2013
Results First Submitted Date  ICMJE April 7, 2017
Results First Posted Date  ICMJE June 26, 2017
Last Update Posted Date June 28, 2021
Actual Study Start Date  ICMJE May 7, 2013
Actual Primary Completion Date April 26, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 28, 2021)
  • Number of Participants Experiencing Adverse Events (AEs) [ Time Frame: Serious AEs: Up to 90 days after last dose of treatment (Up to 28 months); nonserious AEs: Up to 30 days after last dose of treatment (Up to 26 months) - through final analysis (FA) cutoff date 26 Apr 2016 (Cohorts: A, B, B2, D) & 01 Sep 2015 (Cohort C) ]
    An AE was defined as any untoward medical occurrence in a participant administered a study treatment which did not necessarily have to have a causal relationship with this treatment. An AE could be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE was presented for the first course pembrolizumab treatment per protocol.
  • Number of Participants Discontinuing From Study Treatment Due to an AE [ Time Frame: Up to last dose of study treatment (Up to approximately 25 months) - through FA cutoff date 26 Apr 2016 (Cohorts: A, B, B2, D) & 01 Sep 2015 (Cohort C) ]
    An AE was defined as any untoward medical occurrence in a participant administered a study treatment which did not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. Some cases of clinical progression that led to discontinuation of study treatment were captured as AEs that led to discontinuation of study treatment. The number of participants who discontinued study treatment due to an AE was presented for the first course pembrolizumab treatment per protocol.
  • Overall Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Response Rate Based on Blinded Independent Central Radiology (BICR) Review (Cohorts A, B, C, and D) [ Time Frame: Every 8 weeks until disease progression (Cohorts A, B, D: Up to ~ 35 months; Cohort C: Up to ~ 28 months) - through FA cutoff date 26 Apr 2016 (Cohorts: A, B, D) & 01 Sep 2015 (Cohort C) ]
    Overall Response Rate (ORR) was defined as the percentage of participants who experienced a Complete Response (CR; disappearance of all target lesions) or a Partial Response (PR; at least a 30% decrease in the sum of diameters of target lesions) and was assessed using RECIST 1.1 based on BICR evaluation. The percentage of participants who experienced a CR or PR for Cohorts A, B, C and D participants was presented for the first course of pembrolizumab treatment per protocol. Cohorts A, B, C and D enrolled participants with programmed cell death-ligand 1 (PD-L1) positive tumors.
  • Overall RECIST 1.1 Response Rate Based on BICR Review for Participants in Cohort B2 [ Time Frame: Every 8 weeks until disease progression (Up to ~ 35 months) - through FA cutoff date 26 Apr 2016 ]
    ORR was defined as the percentage of participants in the analysis population who experienced a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) and was assessed using RECIST 1.1 based on BICR evaluation. The percentage of participants who experienced a CR or PR in Cohort B2 was presented for the first course of pembrolizumab treatment per protocol.
Original Primary Outcome Measures  ICMJE
 (submitted: May 3, 2013)
  • Number of participants experiencing adverse events [ Time Frame: From first dose to 90 days after last dose of study treatment (up to 2 years) ]
  • Number of participants discontinuing from study treatment due to adverse events [ Time Frame: From first dose up to last dose of study treatment (up to 2 years) ]
  • Number of participants with TNBC, head and neck, or urothelial cancer who achieve a clinically meaningful overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria [ Time Frame: Baseline and every 8 weeks, up to 2 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 28, 2021)
  • Overall RECIST 1.1 Response Rate Based on BICR Review, Cohorts B and B2 Human Papilloma Virus (HPV)-Positive Participants [ Time Frame: Every 8 weeks until disease progression (Up to ~ 35 months) - through FA cutoff date 26 Apr 2016 ]
    ORR was defined as the percentage of participants in the analysis population who experienced a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) and was assessed using RECIST 1.1 based on BICR evaluation. The percentage of participants who had tumors which were HPV positive and who experienced a CR or PR in the combined Cohorts B2 and B2 was presented for the first course of pembrolizumab treatment per protocol.
  • Overall RECIST 1.1 Response Rate Based on BICR Review, Cohort D Asia-Pacific (AP) Participants [ Time Frame: Every 8 weeks until disease progression (Up to ~ 35 months) - through FA cutoff date 26 Apr 2016 ]
    ORR was defined as the percentage of participants in the analysis population who experienced a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) and was assessed using RECIST 1.1 based on BICR evaluation. The percentage of participants who were from the Asia Pacific region and experienced a CR or PR in Cohort D was presented for the first course of pembrolizumab treatment per protocol.
  • Overall RECIST 1.1 Response Rate Based on BICR Review, for Participants Previously Treated With Cetuximab and Platinum in Cohorts B and B2 [ Time Frame: Every 8 weeks until disease progression (Up to ~ 35 months) - through FA cutoff date 26 Apr 2016 ]
    ORR was defined as the percentage of participants in the analysis population who experienced a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) and was assessed using RECIST 1.1 based on BICR evaluation. The percentage of participants who were previously treated with cetuximab and platinum and experienced a CR or PR in the Cohorts B and B2 was presented for the first course of pembrolizumab treatment per protocol.
  • Overall RECIST 1.1 Response Rate Based on Investigator Assessment for Cohorts A, B, C and D [ Time Frame: Every 8 weeks until disease progression (Cohorts A, B, D: Up to ~ 35 months; Cohort C: Up to ~ 28 months) - through FA cutoff date 26 Apr 2016 (Cohorts: A, B, D) & 01 Sep 2015 (Cohort C) ]
    ORR was defined as the percentage of participants in the analysis population who experienced a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) and was assessed by Investigator evaluation. The percentage of participants who experienced a CR or PR in Cohorts A, B, C and D based on investigator assessment was presented for the first course of pembrolizumab treatment per protocol. ORR per RECIST 1.1 based on investigator assessment was presented for Cohort B2 in a separate outcome measure.
  • Overall RECIST 1.1 Response Rate Based on Investigator Assessment for Cohort B2 [ Time Frame: Every 8 weeks until disease progression (Up to ~ 35 months) - through FA cutoff date 26 Apr 2016 ]
    ORR was defined as the percentage of participants in the analysis population who experienced a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) and was assessed by Investigator evaluation. The percentage of participants who experienced a CR or PR in Cohort B2 based on investigator assessment was presented for the first course of pembrolizumab treatment per protocol. ORR per RECIST 1.1 based on investigator assessment was presented for the other cohorts in a separate outcome measure.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 3, 2013)
  • Number of participants with head and neck cancer and who are human papilloma virus (HPV)-positive who achieve a clinically meaningful ORR per RECIST 1.1 criteria [ Time Frame: Baseline and every 8 weeks, up to 2 years ]
  • Number of participants with log fold change from baseline in cytokines >1 [ Time Frame: Baseline and Week 8 ]
  • Number of participants with TNBC, head and neck, or urothelial cancer who achieve a clinically meaningful ORR per immune-related response criteria (irRC) [ Time Frame: Baseline and every 8 weeks, up to 2 years ]
Current Other Pre-specified Outcome Measures
 (submitted: April 7, 2017)
Number of Participants With Log Fold Change From Baseline in Cytokines (Interleukin 10 [IL-10]) >1 [ Time Frame: Baseline and Week 8 ]
IL-10 is an anti-inflammatory cytokine. The number of participants with a log fold change from Baseline in IL-10 >1 was to be presented. Protocol Amendment 03 (26 May 2015) removed the secondary objective of investigating the relationship between programmed cell death 1 (PD-1) inhibition and up-regulation of cytokines biomarkers predicting response (e.g. IL-10) from the protocol. No data were collected for this outcome measure.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-3475-012/KEYNOTE-012)
Official Title  ICMJE A Phase Ib Multi-Cohort Study of MK-3475 in Subjects With Advanced Solid Tumors
Brief Summary

This study is being done to investigate the safety, tolerability and anti-tumor activity of pembrolizumab (MK-3475) in participants with advanced triple negative breast cancer (TNBC) (Cohort A), advanced head and neck cancer (Cohorts B and B2), advanced urothelial cancer (Cohort C), or advanced gastric cancer (Cohort D). Additionally, for Cohort D, data is presented for Asian Pacific (AP) participants. Only participants with programmed cell death-ligand 1 (PD-L1) expressing tumors were enrolled in Cohorts A, B, C and D. Participants in Cohort B2 were enrolled irrespective of PD-L1 status.

The primary study hypothesis is that pembrolizumab is safe and well-tolerated.

Detailed Description

Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (approximately up to 2 years) for reasons other than disease progression or intolerability, may be eligible for a second course of pembrolizumab for up to approximately 1 additional year at the investigator's discretion. Per protocol, response during this second course will not count towards the efficacy outcome measures and adverse events during this second course will not count towards the safety outcome measures.

Protocol Amendment 01 (08 Aug 2013) included a new study arm (Cohort D) for approximately 32 participants with advanced gastric cancer. Of these 32 participants, 16 will be from sites in the Asia Pacific (AP) region and the other 16 will be from sites outside the AP region.

Protocol Amendment 02 (07 Apr 2014) added a new study arm (Cohort B2) for approximately 110 participants with advanced head and neck cancer who will receive a lower dose of pembrolizumab every three weeks (Q3W). Both programmed cell death ligand 1 (PD-L1)- positive and PD-L1-negative participants will be enrolled into this cohort.

Protocol Amendment 03 (26 May 2015) removed the secondary objective of investigating the relationship between programmed cell death 1 (PD-1) inhibition and up-regulation of cytokines biomarkers predicting response (e.g. Interleukin-10 [IL-10]) from the protocol.

Participants who stopped study treatment without progression (e.g. completed 2 years) may have been eligible for up to 1 year of retreatment upon subsequently experiencing disease progression.

With Amendment 05 (11 Dec 2017), once study participants have achieved the study objective or the study has ended, participants will be discontinued from this study and enrolled in an extension study (KEYNOTE-587; NCT03486873) to continue protocol-defined assessments and treatment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Cancer
  • Solid Tumor
Intervention  ICMJE Biological: Pembrolizumab
IV infusion
Other Names:
  • MK-3475
  • SCH 900475
  • KEYTRUDA®
Study Arms  ICMJE
  • Experimental: Cohort A: Triple Negative Breast Cancer
    Participants receive pembrolizumab, 10 mg/kg, intravenously (IV) once every 2 weeks, and continue to receive drug until disease progression, death, withdrawal of consent, Investigator decision, or end of study (up to 2 years).
    Intervention: Biological: Pembrolizumab
  • Experimental: Cohort B: Head & Neck Cancer
    Participants receive pembrolizumab, 10 mg/kg, IV once every 2 weeks, and continue to receive drug until disease progression, death, withdrawal of consent, Investigator decision, or end of study (up to 2 years).
    Intervention: Biological: Pembrolizumab
  • Experimental: Cohort C: Urothelial Cancer
    Participants receive pembrolizumab, 10 mg/kg, IV once every 2 weeks, and continue to receive drug until disease progression, death, withdrawal of consent, Investigator decision, or end of study (up to 2 years).
    Intervention: Biological: Pembrolizumab
  • Experimental: Cohort D: Gastric Cancer
    Participants receive pembrolizumab, 10 mg/kg, IV once every 2 weeks, and continue to receive drug until disease progression, death, withdrawal of consent, Investigator decision, or end of study (up to 2 years).
    Intervention: Biological: Pembrolizumab
  • Experimental: Cohort B2: Head & Neck Cancer Expansion
    Participants receive pembrolizumab, 200 mg, IV once every 3 weeks, and continue to receive drug until disease progression, death, withdrawal of consent, Investigator decision, or end of study (up to 2 years).
    Intervention: Biological: Pembrolizumab
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 24, 2015)
297
Original Estimated Enrollment  ICMJE
 (submitted: May 3, 2013)
90
Actual Study Completion Date  ICMJE June 30, 2020
Actual Primary Completion Date April 26, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically or cytologically-confirmed diagnosis of tumor that is recurrent, metastatic, or persistent:

    • For Cohort A - triple negative breast cancer (estrogen, progesterone, and human epidermal growth factor receptor 2 [HER2] negative)
    • For Cohort B - squamous cell carcinoma of the head and neck (including human papilloma virus (HPV)-positive head and neck squamous cell cancer).
    • For Cohort C - urothelial tract cancer of the renal pelvis, ureter, bladder, or urethra (transitional cell or non-transitional cell histology)
    • For Cohort D - adenocarcinoma of the stomach or gastroesophageal junction
    • For Cohort B2 - squamous cell carcinoma of the head and neck (both HPV-positive and -negative head and neck squamous cell cancer)
  • Any number of prior treatment regimens
  • Measurable disease
  • Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1
  • Female participants of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study treatment
  • Male participants 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 treatment

Exclusion Criteria:

  • Currently participating in/has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of study treatment
  • Diagnosis of immunosuppression or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
  • Anti-cancer monoclonal antibody treatment within 4 weeks prior to study Day 1 or not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Chemotherapy, targeted small molecule therapy or radiation therapy within 2 weeks prior to study Day 1 or not recovered from adverse events due to a previously administered agent
  • Known additional malignancy that is progressing or requires active treatment excepting basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
  • Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
  • Active autoimmune disease requiring systemic treatment within the past 3 months or documented history of clinically severe autoimmune disease, or syndrome that requires systemic steroids or immunosuppressive agents
  • Evidence of interstitial lung disease
  • Active infection requiring systemic therapy
  • Known psychiatric or substance abuse disorders
  • Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
  • Prior therapy with an anti-programmed cell death 1 (PD-1), anti-PD-L1, anti-PD-L2, anti-CD137 antibody, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody
  • Known history of human immunodeficiency virus (HIV)
  • Known active Hepatitis B or Hepatitis C
  • Received live vaccine within 30 days prior to start of study treatment
  • 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 Independent Review Board (IRB) approval (by Chair or Designee) is given allowing exception to this criterion for a specific participant
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries Belgium,   Canada,   France,   Israel,   Japan,   Korea, Republic of,   Taiwan,   United States
 
Administrative Information
NCT Number  ICMJE NCT01848834
Other Study ID Numbers  ICMJE 3475-012
2012-005771-14 ( EudraCT Number )
142453 ( Registry Identifier: JAPIC_CTI )
MK-3475-012 ( Other Identifier: Merck )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Current Responsible Party Merck Sharp & Dohme LLC
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Merck Sharp & Dohme LLC
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme LLC
PRS Account Merck Sharp & Dohme LLC
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP