Study of Intratumoral (IT) Ulevostinag (MK-1454) in Combination With Intravenous (IV) Pembrolizumab (MK-3475) Compared to IV Pembrolizumab Alone as the First Line Treatment of Metastatic or Unresectable, Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) (MK-1454-002)

A Phase 2 Study in First Line Metastatic or Unresectable, Recurrent Head and Neck Squamous Cell Carcinoma to Evaluate Intratumoral MK-1454 in Combination With IV Pembrolizumab vs IV Pembrolizumab Monotherapy

The purpose of this study is to assess the efficacy and safety of intratumoral (IT) ulevostinag PLUS pembrolizumab (MK-3475) compared to pembrolizumab alone as a first line treatment of adults with metastatic or unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

The primary study hypotheses are that IT ulevostinag in combination with pembrolizumab results in a superior Objective Response Rate (ORR), per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), compared to pembrolizumab alone:

1. In participants with a tumor that has a programmed cell death-ligand 1 (PD-L1) Combined Positive Scoring (CPS) ≥ 1, and
2. In participants with a tumor that has a PD-L1 CPS ≥ 20.

Study Overview

• Status: Completed
• Conditions: Head and Neck Squamous Cell Carcinoma (HNSCC)
• Intervention / Treatment: Biological: Pembrolizumab; Drug: Ulevostinag

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Chris OBrien Lifehouse ( Site 0040)
  • South Australia
    • Elizabeth Vale, South Australia, Australia, 5112
      • Calvary Central Districts Hospital ( Site 0042)
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Health-Monash Medical Centre ( Site 0041)
• Austria
  • Salzburg, Austria, 5020
    • SCRI-CCCIT GesmbH ( Site 0050)
  • Oberosterreich
    • Linz, Oberosterreich, Austria, 4010
      • Ordensklinikum Linz Gmbh - Barmherzige Schwestern ( Site 0051)
  • Wien
    • Vienna/Wien, Wien, Austria, 1090
      • Allgemeines Krankenhaus der Stadt Wien ( Site 0049)
• Brazil
  • Sao Paulo, Brazil, 01246-000
    • Instituto do Cancer do Estado de Sao Paulo - ICESP ( Site 0058)
  • Sao Paulo, Brazil, 01321-001
    • Real e Benemerita Associacao Portuguesa de Beneficencia ( Site 0064)
  • Ceara
    • Fortaleza, Ceara, Brazil, 60336-232
      • Centro Regional Integrado de Oncologia ( Site 0062)
  • Rio Grande Do Sul
    • Ijui, Rio Grande Do Sul, Brazil, 98700-000
      • Hospital de Caridade de Ijui ( Site 0061)
• France
  • Alpes-Maritimes
    • Nice, Alpes-Maritimes, France, 06189
      • Centre Antoine Lacassagne ( Site 0070)
  • Auvergne
    • Lyon, Auvergne, France, 69373
      • Centre Leon Berard ( Site 0072)
  • Haute-Garonne
    • Toulouse, Haute-Garonne, France, 31059
      • IUCT - Oncopole ( Site 0069)
  • Nord
    • Lille, Nord, France, 59000
      • Centre Oscar Lambret ( Site 0071)
  • Val-de-Marne
    • Villejuif, Val-de-Marne, France, 94800
      • Gustave Roussy ( Site 0068)
• Israel
  • Haifa, Israel, 3109601
    • Rambam Medical Center ( Site 0077)
  • Jerusalem, Israel, 9112001
    • Hadassah Medical Center. Ein Kerem ( Site 0078)
  • Tel Aviv
    • Ramat Gan, Tel Aviv, Israel, 5265601
      • Chaim Sheba Medical Center ( Site 0076)
• Korea, Republic of
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital ( Site 0103)
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center ( Site 0104)
• Norway
  • Oslo, Norway, 0379
    • Oslo Universitetssykehus Radiumhospitalet ( Site 0085)
  • Hordaland
    • Bergen, Hordaland, Norway, 5021
      • Haukeland Universitetssykehus, Klinisk forskningspost voksne ( Site 0086)
• Spain
  • Barcelona, Spain, 08035
    • H.U. Vall de Hebron ( Site 0112)
  • Barcelona, Spain, 08036
    • Hospital Clinico de Barcelona ( Site 0116)
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal ( Site 0115)
  • Malaga, Spain, 29010
    • Hospital Universitario Virgen de la Victoria ( Site 0114)
• United Kingdom
  • London, City Of
    • London, London, City Of, United Kingdom, SW3 6JJ
      • Royal Marsden NHS Foundation Trust ( Site 0031)
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Royal Marsden Hospital Sutton-Surrey ( Site 0032)
• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Hematology & Oncology ( Site 0005)
    • San Francisco, California, United States, 94158
      • University of California at San Francisco ( Site 0006)
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital ( Site 0012)
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University ( Site 0021)
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Cancer Center Oncology Clinic ( Site 0014)
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute ( Site 0004)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has histologically or cytologically confirmed diagnosis of metastatic or unresectable, recurrent head and neck squamous cell carcinoma (HNSCC) that is considered incurable by local therapies
• Has not had prior systemic therapy administered in the recurrent or metastatic setting
• Has tumor PD-L1 expression of CPS ≥1. Tumor tissue must be provided for PD-L1 biomarker analysis
• Has measurable disease per RECIST 1.1, as assessed by BICR
• Has at least 1 measurable lesion which is amenable to injection
• Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Demonstrates adequate organ function within 7 days prior to treatment initiation
• Male participants of reproductive potential must agree to refrain from donating sperm and use a male condom plus partner use of an additional contraceptive method during sexual contact with females of childbearing potential during the intervention period with ulevostinag and for at least 120 days after the last dose of ulevostinag
• Female participants of childbearing potential who are not pregnant or breastfeeding must be willing to use a highly effective method of birth control or be surgically sterile or abstain from heterosexual activity during the intervention period and for at least 120 days after the last dose of study intervention, and agree not to donate eggs (ova, oocytes) to others or freeze/store for personal use

• Human immunodeficiency virus (HIV)-infected participants must meet these additional criteria:

  1. Has HIV-1 infection documented by using any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry (Day 1)
  2. Has well-controlled HIV on anti-retroviral therapy (ART)

Exclusion Criteria:

• Has disease that is suitable for local therapy administered with curative intent
• Has progressive disease (PD) within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC
• Has had chemotherapy or biological cancer therapy in the recurrent or metastatic setting for the treatment of HNSCC
• Has had radiation therapy (or other non-systemic therapy) within 2 weeks prior to randomization or participant has not fully recovered from adverse events (AEs) due to a previously administered treatment
• Is expected to require any other form of antineoplastic therapy while on study
• Has a history of a second malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for at least 2 years
• Has clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has an active autoimmune disease that has required systemic treatment in the past 2 years
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
• Has had an allogenic tissue/solid organ transplant
• Has a history of vasculitis
• Has a history of interstitial lung disease
• Has an active infection requiring systemic therapy
• Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Has had a severe hypersensitivity reaction to treatment a monoclonal antibody/components of the study treatment
• Has known Hepatitis B virus or Hepatitis C virus infections
• Has received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-programmed cell death-ligand 2 (anti-PD-L2) agent or if the participant has previously participated in Merck Sharp & Dohme (MSD) MK-3475 clinical trials
• HIV infected participant who has had an HIV-related opportunistic infection within 6 months
• HIV infected participants who have a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
• Is pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
• Has not fully recovered from any effects of major surgery without significant detectable infection
• Has a history of re-irradiation for HNSCC at the projected injection site in the head and neck
• Has received a live-virus vaccine within 30 days of planned study treatment start
• Has been treated with a stimulator of interferon genes (STING) agonist (e.g. ulevostinag, ADU-S100)
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy, or used an investigational device, any of which occurred within 4 weeks of the first dose of study treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ulevostinag+Pembrolizumab; Participants receive ulevostinag 540 ug via intratumoral (IT) injection on Day 1 of every week for two 3-week cycles (Cycles 1-2), then on Day 1 of each 3-week cycle for up 33 cycles (Cycles 3-35), for a total of 35 cycles PLUS pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment is up to approximately 2 years.	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475; KEYTRUDA®; Drug: Ulevostinag; IT injection; Other Names: MK-1454
Active Comparator: Pembrolizumab; Participants receive pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment is up to approximately 2 years.	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475; KEYTRUDA®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	ORR was defined as the percentage of participants in the analysis population who have 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) per RECIST 1.1. ORR was assessed by blinded independent central review (BICR), and the 95% confidence interval (CI) was based on the exact method for binomial data.	Up to 913.0 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	PFS was defined as the time from randomization to the first documented progressive disease (PD) or death from any cause, whichever occurs first. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. PFS was assessed by BICR and was based on the product-limit (Kaplan-Meier) method for censored data.	Up to 913.0 days
Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	DOR was defined as the time from the first documented evidence of 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) per RECIST 1.1 until Progressive Disease (PD) or death due to any cause, whichever occurs first, in participants demonstrating a CR or PR. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR was based on the product-limit (Kaplan-Meier) method for censored data.	Up to 913.0 days
Overall Survival (OS)	OS is defined as the time from randomization to the date of death from any cause, and is based on the product-limit (Kaplan-Meier) method for censored data.	Up to 913.0 days
Number of Participants Who Experienced an Adverse Event (AE)	An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.	Up to 913.0 days
Number of Participants Discontinuing Study Treatment Due to an AE	An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.	Up to approximately 715.0 days

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• McIntosh JA, Liu Z, Andresen BM, Marzijarani NS, Moore JC, Marshall NM, Borra-Garske M, Obligacion JV, Fier PS, Peng F, Forstater JH, Winston MS, An C, Chang W, Lim J, Huffman MA, Miller SP, Tsay FR, Altman MD, Lesburg CA, Steinhuebel D, Trotter BW, Cumming JN, Northrup A, Bu X, Mann BF, Biba M, Hiraga K, Murphy GS, Kolev JN, Makarewicz A, Pan W, Farasat I, Bade RS, Stone K, Duan D, Alvizo O, Adpressa D, Guetschow E, Hoyt E, Regalado EL, Castro S, Rivera N, Smith JP, Wang F, Crespo A, Verma D, Axnanda S, Dance ZEX, Devine PN, Tschaen D, Canada KA, Bulger PG, Sherry BD, Truppo MD, Ruck RT, Campeau LC, Bennett DJ, Humphrey GR, Campos KR, Maddess ML. A kinase-cGAS cascade to synthesize a therapeutic STING activator. Nature. 2022 Mar;603(7901):439-444. doi: 10.1038/s41586-022-04422-9. Epub 2022 Mar 16.

Helpful Links

• Merck Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2020
• Primary Completion (Actual): September 30, 2022
• Study Completion (Actual): September 30, 2022

Study Registration Dates

• First Submitted: January 6, 2020
• First Submitted That Met QC Criteria: January 6, 2020
• First Posted (Actual): January 7, 2020

Study Record Updates

• Last Update Posted (Actual): October 27, 2023
• Last Update Submitted That Met QC Criteria: October 25, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: metastatic; Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1); pembrolizumab; recurrent; unresectable; intratumoral (IT); ulevostinag
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Neoplasms, Squamous Cell; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: 1454-002; MK-1454-002 (Other Identifier: Merck); 2019-003060-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No