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)

Phase 2

Completed

Conditions: Head and Neck Squamous Cell Carcinoma (HNSCC)

Interventions: Drug: Ulevostinag
Biological: Pembrolizumab

Registration Number: NCT04220866

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 18

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ulevostinag+Pembrolizumab	Ulevostinag	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.
Ulevostinag+Pembrolizumab	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.
Pembrolizumab	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.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	Up to 913.0 days	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.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	Up to 913.0 days	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.
Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	Up to 913.0 days	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.
Overall Survival (OS)	Up to 913.0 days	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.
Number of Participants Who Experienced an Adverse Event (AE)	Up to 913.0 days	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.
Number of Participants Discontinuing Study Treatment Due to an AE	Up to approximately 715.0 days	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.

Trial Locations

Locations (34): IUCT - Oncopole ( Site 0069)
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Toulouse, Haute-Garonne, France
Instituto do Cancer do Estado de Sao Paulo - ICESP ( Site 0058)
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Sao Paulo, Brazil
Washington University ( Site 0021)
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Saint Louis, Missouri, United States
Hospital Clinico de Barcelona ( Site 0116)
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Barcelona, Spain
Centre Leon Berard ( Site 0072)
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Lyon, Auvergne, France
Hadassah Medical Center. Ein Kerem ( Site 0078)
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Jerusalem, Israel
Haukeland Universitetssykehus, Klinisk forskningspost voksne ( Site 0086)
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Bergen, Hordaland, Norway
Centro Regional Integrado de Oncologia ( Site 0062)
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Fortaleza, Ceara, Brazil
Centre Oscar Lambret ( Site 0071)
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Lille, Nord, France
Calvary Central Districts Hospital ( Site 0042)
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Elizabeth Vale, South Australia, Australia
H.U. Vall de Hebron ( Site 0112)
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Barcelona, Spain
Allgemeines Krankenhaus der Stadt Wien ( Site 0049)
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Vienna/Wien, Wien, Austria
Real e Benemerita Associacao Portuguesa de Beneficencia ( Site 0064)
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Sao Paulo, Brazil
Oslo Universitetssykehus Radiumhospitalet ( Site 0085)
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Oslo, Norway
Royal Marsden Hospital Sutton-Surrey ( Site 0032)
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Sutton, Surrey, United Kingdom
Royal Marsden NHS Foundation Trust ( Site 0031)
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London, London, City Of, United Kingdom
Hospital Universitario Ramon y Cajal ( Site 0115)
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Madrid, Spain
Severance Hospital ( Site 0103)
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Seoul, Korea, Republic of
Hospital de Caridade de Ijui ( Site 0061)
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Ijui, Rio Grande Do Sul, Brazil
University of California at San Francisco ( Site 0006)
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San Francisco, California, United States
Henry Ford Hospital ( Site 0012)
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Detroit, Michigan, United States
UCLA Hematology & Oncology ( Site 0005)
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Los Angeles, California, United States
Sanford Cancer Center Oncology Clinic ( Site 0014)
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Sioux Falls, South Dakota, United States
Chris OBrien Lifehouse ( Site 0040)
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Camperdown, New South Wales, Australia
Huntsman Cancer Institute ( Site 0004)
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Salt Lake City, Utah, United States
Ordensklinikum Linz Gmbh - Barmherzige Schwestern ( Site 0051)
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Linz, Oberosterreich, Austria
Monash Health-Monash Medical Centre ( Site 0041)
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Clayton, Victoria, Australia
SCRI-CCCIT GesmbH ( Site 0050)
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Salzburg, Austria
Centre Antoine Lacassagne ( Site 0070)
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Nice, Alpes-Maritimes, France
Rambam Medical Center ( Site 0077)
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Haifa, Israel
Gustave Roussy ( Site 0068)
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Villejuif, Val-de-Marne, France
Chaim Sheba Medical Center ( Site 0076)
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Ramat Gan, Tel Aviv, Israel
Asan Medical Center ( Site 0104)
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Seoul, Korea, Republic of
Hospital Universitario Virgen de la Victoria ( Site 0114)
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Malaga, Spain