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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT01848834
First received: May 3, 2013
Last updated: April 7, 2017
Last verified: April 2017
  Purpose

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.


Condition Intervention Phase
Cancer Solid Tumor Biological: Pembrolizumab Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase Ib Multi-Cohort Study of MK-3475 in Subjects With Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Number of Participants Experiencing Adverse Events (AEs) [ Time Frame: Serious AEs: Up to 90 days after last dose of study treatment (Up to 34 months); nonserious AEs: Up to 30 days after last dose of study treatment (Up to 32 months) ]
    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 is presented.

  • Number of Participants Discontinuing From Study Treatment Due to an AE [ Time Frame: Up to last dose of study treatment (Up to approximately 31 months) ]
    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 discontinued study treatment due to an AE is presented. Some cases of clinical progression that led to discontinuation of study treatment were captured as AEs that led to discontinuation of study treatment.

  • 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 & B2, C, and D) [ Time Frame: Every 8 weeks until disease progression (Up to approximately 34 months) ]
    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 percentages of participants who experienced a CR or PR for Cohort A, Cohorts B and B2 participants, Cohort C and Cohort D are presented. Cohorts A, B, C and D enrolled participants with programmed cell death-ligand 1 (PD-L1) positive tumors; Cohort B2 enrolled participants regardless of PD-L1 expression.

  • 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 approximately 14 months) ]
    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 is presented. ORR per RESIST 1.1 based on BICR review is presented for the other cohorts in a separate outcome measure.


Secondary Outcome Measures:
  • Overall RECIST 1.1 Response Rate Based on BICR Review, Cohorts B and B2 HPV-positive Participants [ Time Frame: Every 8 weeks until disease progression (Up to approximately 27 months) ]
    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 is presented. ORR per RESIST 1.1 based on BICR review is presented for the other cohorts in a separate outcome measure.

  • 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 approximately 30 months) ]
    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 is presented. ORR per RESIST 1.1 based on BICR review is presented for the other cohorts in separate outcome measures.

  • 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 approximately 27 months) ]
    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 is presented. ORR per RESIST 1.1 based on BICR review is presented for the other cohorts in separate outcome measures.

  • 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 (Up to approximately 34 months) ]
    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 percentages of participants who experienced a CR or PR in Cohorts A, B, C and D based on Investigator assessment are presented. ORR per Investigator assessment is 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 approximately 14 months) ]
    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 percentages of participants who experienced a CR or PR in Cohorts A, B, C and D based on Investigator assessment are presented. ORR per Investigator assessment is presented for the other cohorts in a separate outcome measure.


Other Outcome Measures:
  • 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.


Enrollment: 297
Actual Study Start Date: May 7, 2013
Estimated Study Completion Date: January 17, 2018
Primary Completion Date: April 26, 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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).
Biological: Pembrolizumab
IV infusion
Other Names:
  • MK-3475
  • SCH 900475
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).
Biological: Pembrolizumab
IV infusion
Other Names:
  • MK-3475
  • SCH 900475
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).
Biological: Pembrolizumab
IV infusion
Other Names:
  • MK-3475
  • SCH 900475
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).
Biological: Pembrolizumab
IV infusion
Other Names:
  • MK-3475
  • SCH 900475
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).
Biological: Pembrolizumab
IV infusion
Other Names:
  • MK-3475
  • SCH 900475

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01848834

Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  More Information

Publications:
Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng J, Karantza V, Buisseret L. Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol. 2016;[e-pub 2May2016]. doi: 10.1200/JCO.2015.64.8931

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01848834     History of Changes
Other Study ID Numbers: 3475-012
2012-005771-14 ( EudraCT Number )
142453 ( Registry Identifier: JAPIC_CTI )
P21477 ( Other Identifier: Merck Protocol Number )
Study First Received: May 3, 2013
Results First Received: April 7, 2017
Last Updated: April 7, 2017
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description:

http://www.merck.com/clinical-trials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final_Updated%20July_9_2014.pdf

http://engagezone.msd.com/ds_documentation.php


Keywords provided by Merck Sharp & Dohme Corp.:
PD-1
PD1
PD-L1
PDL1

Additional relevant MeSH terms:
Pembrolizumab
Antineoplastic Agents

ClinicalTrials.gov processed this record on June 26, 2017