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

NCT01848834 | Completed Phase 1 Results FDA Drug

• 4 other identifiers: 3475-0122012-005771-14142453MK-3475-012
• Study Type: interventional
• Target: 297
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Cancer; Solid Tumor

Keywords

PD-1; PD1; PD-L1; PDL1

Outcome Measures

Primary Outcomes (4)

• Number of Participants Experiencing Adverse Events (AEs)

  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.

  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)

• Number of Participants Discontinuing From Study Treatment Due to an AE

  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.

  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)

• 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)

  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.

  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 RECIST 1.1 Response Rate Based on BICR Review for Participants in Cohort B2

  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.

  Every 8 weeks until disease progression (Up to ~ 35 months) - through FA cutoff date 26 Apr 2016

Secondary Outcomes (5)

• Overall RECIST 1.1 Response Rate Based on BICR Review, Cohorts B and B2 Human Papilloma Virus (HPV)-Positive Participants

  Every 8 weeks until disease progression (Up to ~ 35 months) - through FA cutoff date 26 Apr 2016

• Overall RECIST 1.1 Response Rate Based on BICR Review, Cohort D Asia-Pacific (AP) Participants

  Every 8 weeks until disease progression (Up to ~ 35 months) - through FA cutoff date 26 Apr 2016

• Overall RECIST 1.1 Response Rate Based on BICR Review, for Participants Previously Treated With Cetuximab and Platinum in Cohorts B and B2

  Every 8 weeks until disease progression (Up to ~ 35 months) - through FA cutoff date 26 Apr 2016

• Overall RECIST 1.1 Response Rate Based on Investigator Assessment for Cohorts A, B, C and D

  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 RECIST 1.1 Response Rate Based on Investigator Assessment for Cohort B2

  Every 8 weeks until disease progression (Up to ~ 35 months) - through FA cutoff date 26 Apr 2016

Other Outcomes (1)

• Number of Participants With Log Fold Change From Baseline in Cytokines (Interleukin 10 [IL-10]) >1

  Baseline and Week 8

Study Arms (5)

Cohort A: Triple Negative Breast Cancer

EXPERIMENTAL

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

Cohort B: Head & Neck Cancer

EXPERIMENTAL

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

Cohort C: Urothelial Cancer

EXPERIMENTAL

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

Cohort D: Gastric Cancer

EXPERIMENTAL

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

Cohort B2: Head & Neck Cancer Expansion

EXPERIMENTAL

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

Interventions

Pembrolizumab BIOLOGICAL

IV infusion

Also known as: MK-3475, SCH 900475, KEYTRUDA®

Cohort A: Triple Negative Breast Cancer; Cohort B2: Head & Neck Cancer Expansion; Cohort B: Head & Neck Cancer; Cohort C: Urothelial Cancer; Cohort D: Gastric Cancer

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (9)

• 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.

  PMID: 27157491 RESULT

• 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.

  PMID: 27138582 RESULT

• 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.

  PMID: 27247226 RESULT

• 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.

  PMID: 28081914 RESULT

• 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.

  PMID: 27646946 RESULT

• 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.

  PMID: 35217573 DERIVED

• 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.

  PMID: 35101941 DERIVED

• 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.

  PMID: 31395089 DERIVED

• 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.

  PMID: 29284202 DERIVED

MeSH Terms

Conditions

Neoplasms

Interventions

pembrolizumab

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 3, 2013
• First Posted: May 8, 2013
• Study Start: May 7, 2013
• Primary Completion: April 26, 2016
• Study Completion: June 30, 2020
• Last Updated: June 28, 2021
• Results First Posted: June 26, 2017

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will share