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

• 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: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Cancer; Solid Tumor	Biological: Pembrolizumab	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 297 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib Multi-Cohort Study of MK-3475 in Subjects With Advanced Solid Tumors
• Actual Study Start Date: May 7, 2013
• Actual Primary Completion Date: April 26, 2016
• Actual Study Completion Date: June 30, 2020

Arms and Interventions

Arm	Intervention/treatment
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; KEYTRUDA®
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; KEYTRUDA®
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; KEYTRUDA®
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; KEYTRUDA®
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; KEYTRUDA®

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.

Other Outcome Measures:

1. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• 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 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

Contacts and Locations

Sponsors and Collaborators

Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme LLC:

Study Protocol and Statistical Analysis Plan  [PDF] December 11, 2017

More Information

Publications of Results:

Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, Eder JP, Golan T, Le DT, Burtness B, McRee AJ, Lin CC, Pathiraja K, Lunceford J, Emancipator K, Juco J, Koshiji M, Bang YJ. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016 Jun;17(6):717-726. doi: 10.1016/S1470-2045(16)00175-3. Epub 2016 May 3.

Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, Karantza V, Buisseret L. Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol. 2016 Jul 20;34(21):2460-7. doi: 10.1200/JCO.2015.64.8931. Epub 2016 May 2.

Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, Heath K, McClanahan T, Lunceford J, Gause C, Cheng JD, Chow LQ. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016 Jul;17(7):956-965. doi: 10.1016/S1470-2045(16)30066-3. Epub 2016 May 27.

Plimack ER, Bellmunt J, Gupta S, Berger R, Chow LQ, Juco J, Lunceford J, Saraf S, Perini RF, O'Donnell PH. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. Lancet Oncol. 2017 Feb;18(2):212-220. doi: 10.1016/S1470-2045(17)30007-4. Epub 2017 Jan 10.

Chow LQM, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, Berger R, Eder JP, Burtness B, Lee SH, Keam B, Kang H, Muro K, Weiss J, Geva R, Lin CC, Chung HC, Meister A, Dolled-Filhart M, Pathiraja K, Cheng JD, Seiwert TY. Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort. J Clin Oncol. 2016 Nov 10;34(32):3838-3845. doi: 10.1200/JCO.2016.68.1478. Epub 2016 Sep 30.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Haddad RI, Seiwert TY, Chow LQM, Gupta S, Weiss J, Gluck I, Eder JP, Burtness B, Tahara M, Keam B, Kang H, Muro K, Albright A, Mogg R, Ayers M, Huang L, Lunceford J, Cristescu R, Cheng J, Mehra R. Influence of tumor mutational burden, inflammatory gene expression profile, and PD-L1 expression on response to pembrolizumab in head and neck squamous cell carcinoma. J Immunother Cancer. 2022 Feb;10(2):e003026. doi: 10.1136/jitc-2021-003026.

Cristescu R, Aurora-Garg D, Albright A, Xu L, Liu XQ, Loboda A, Lang L, Jin F, Rubin EH, Snyder A, Lunceford J. Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors. J Immunother Cancer. 2022 Jan;10(1):e003091. doi: 10.1136/jitc-2021-003091.

van Vugt MJH, Stone JA, De Greef RHJMM, Snyder ES, Lipka L, Turner DC, Chain A, Lala M, Li M, Robey SH, Kondic AG, De Alwis D, Mayawala K, Jain L, Freshwater T. Immunogenicity of pembrolizumab in patients with advanced tumors. J Immunother Cancer. 2019 Aug 8;7(1):212. doi: 10.1186/s40425-019-0663-4.

Tahara M, Muro K, Hasegawa Y, Chung HC, Lin CC, Keam B, Takahashi K, Cheng JD, Bang YJ. Pembrolizumab in Asia-Pacific patients with advanced head and neck squamous cell carcinoma: Analyses from KEYNOTE-012. Cancer Sci. 2018 Mar;109(3):771-776. doi: 10.1111/cas.13480. Epub 2018 Feb 8.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT01848834
• Other Study ID Numbers: 3475-012; 2012-005771-14 ( EudraCT Number ); 142453 ( Registry Identifier: JAPIC_CTI ); MK-3475-012 ( Other Identifier: Merck )
• First Posted: May 8, 2013
• Results First Posted: June 26, 2017
• Last Update Posted: June 28, 2021
• Last Verified: May 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme LLC:

PD-1; PD1; PD-L1; PDL1

Additional relevant MeSH terms:

Neoplasms; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action