Study of Ulevostinag (MK-1454) Alone or in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Solid Tumors or Lymphomas (MK-1454-001)

NCT ID: NCT03010176

Last Updated: 2025-10-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 156 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-02-03
• Study Completion Date: 2022-04-21

Brief Summary

The purpose of this study is to identify a maximum tolerated dose (MTD) or maximum administered dose (MAD) of ulevostinag alone and of ulevostinag in combination with pembrolizumab in participants with advanced/metastatic solid tumors or lymphomas in Part 1, and to evaluate the safety and efficacy of ulevostinag via intratumoral (IT) injection in combination with pembrolizumab in selected solid tumors in Part 2.

Ulevostinag will be administered IT; pembrolizumab (pembro) will be administered via intravenous (IV) infusion. In Part 1, participants will be allocated to one of three treatment arms: ulevostinag monotherapy (cutaneous/subcutaneous [cut/subcut] lesions), ulevostinag +pembro (cut/subcut lesions), or ulevostinag +pembro (visceral lesions).

In Part 2, participants with head and neck squamous cell carcinoma (HNSCC) who are anti-programmed cell death-protein 1 or anti-programmed cell death-ligand 1 (anti-PD-1/PD-L1) refractory or with anti-PD-1/PD-L1 treatment (TrT)-naïve triple-negative breast cancer (TNBC) or with anti-PD-1/PD-L1 TrT-naïve solid tumors with liver metastases/lesions will receive ulevostinag via IT injection at the preliminary Recommended Phase 2 Dose (RP2D) determined in Part 1 PLUS pembrolizumab via IV infusion for up 35 cycles (up approximately 2 years).

Detailed Description

Participants will receive either ulevostinag monotherapy or ulevostinag in combination with pembrolizumab for up to 35 cycles (approximately 2 years). Participants will undergo at least a 24-hour inpatient observation period following the first dose administration of ulevostinag on Cycle 1 Day 1 in Part 1. For Part 2, the length of the observation period following administration of the first dose of ulevostinag on Cycle 1 Day 1 is at least 8 hours.

Conditions

Solid Tumors; Lymphoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions)

Participants with cutaneous (cut) or subcutaneous (subcut) lesions will receive escalating doses of ulevostinag monotherapy via IT injection on Days 1, 8, and 15 of each 21-day cycle for Cycles 1, 2, and 3 and then on Day 1 of each 21-day cycle for Cycles 4 and beyond for up to 35 cycles (up to approximately 2 years).

Group Type: EXPERIMENTAL

Ulevostinag

Intervention Type: DRUG

IT injection

Part 1 Arm 2: Ulevostinag +Pembro (Cut/Subcut Lesions)

Participants with cut or subcut lesions will receive escalating doses of ulevostinag via IT injection on Days 1, 8, and 15 of each 21-day cycle for Cycles 1, 2, and 3 and then on Day 1 of each 21-day cycle for Cycles 4 and beyond PLUS pembrolizumab (pembro) via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years).

Group Type: EXPERIMENTAL

Ulevostinag

Intervention Type: DRUG

IT injection

Pembrolizumab

Intervention Type: BIOLOGICAL

IV infusion

Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions)

Participants with visceral lesions will receive escalating dose frequencies of ulevostinag via IT injection at escalating dose frequencies (Day 1 of each 21-day cycle for up to 35 cycles, then Days 1 and 8 of each 21-day cycle for two cycles, then Day 1 of each 21 day cycle up to 35 cycles, then Days 1, 8, and 15 of each 21-day cycle for two cycles followed by Day 1 of each 21-day cycle up to 35 cycles, PLUS pembrolizumab IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (approximately 2 years).

Group Type: EXPERIMENTAL

Ulevostinag

Intervention Type: DRUG

IT injection

Pembrolizumab

Intervention Type: BIOLOGICAL

IV infusion

Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory

Participants with HNSCC who are anti-programmed cell death-1 or anti-programmed cell death-ligand 1 refractory will receive ulevostinag at the preliminary Recommended Phase 2 Dose (RP2D) determined by dose escalation in Part 1 Arm 1 and 2 via IT injection on Days 1, 8, and 15 of Cycles 1 and 2 and on Day 1 of each 21-day cycle from Cycle 3 onward (up to a total of 35 cycles) PLUS pembrolizumab via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years).

Group Type: EXPERIMENTAL

Ulevostinag

Intervention Type: DRUG

IT injection

Pembrolizumab

Intervention Type: BIOLOGICAL

IV infusion

Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC

Participants with TNBC who are anti-PD-1/PD-L1 treatment-naïve or who have refractory unresectable locally advanced or metastatic TNBC will receive ulevostinag at the preliminary RP2D determined by dose escalation in Part 1 via IT injection on Days 1, 8, and 15 of Cycles 1 and 2 and on Day 1 of each 21-day cycle from Cycle 3 onward (up to a total of 35 cycles) PLUS pembrolizumab via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years).

Group Type: EXPERIMENTAL

Ulevostinag

Intervention Type: DRUG

IT injection

Pembrolizumab

Intervention Type: BIOLOGICAL

IV infusion

Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver

Participants with solid tumors with liver metastases/lesions who are anti-PD-1/PD-L1 treatment-naïve will receive ulevostinag at the preliminary RP2D based on Part 1: ulevostinag + pembro (visceral lesions) treatment arm via IT injection in a to-be-determined dose and frequency, based on data from Arm 3, PLUS pembrolizumab via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years).

Group Type: EXPERIMENTAL

Ulevostinag

Intervention Type: DRUG

IT injection

Pembrolizumab

Intervention Type: BIOLOGICAL

IV infusion

Interventions

Ulevostinag

IT injection

Intervention Type: DRUG

Pembrolizumab

IV infusion

Intervention Type: BIOLOGICAL

Other Intervention Names

MK-1454; MK-3475; Keytruda®

Eligibility Criteria

Inclusion Criteria

All Arms and Cohorts (Parts 1 and 2):

• Has ≥1 injectable lesion which is measurable and amenable to injection and biopsy.
• Has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
• Demonstrates adequate organ function within 7 days prior to treatment initiation.
• Female participants of childbearing potential must be using a contraceptive method that is highly effective or be abstinent from heterosexual intercourse (on a long-term and persistent basis) during the intervention period and for at least 130 days after the last dose of study intervention and agrees not to donate eggs to others or freeze/store for personal use for the purpose of reproduction during this period. Male participants must agree to refrain from donating sperm PLUS either be abstinent from heterosexual intercourse (on a long-term and persistent basis) OR agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse contraception, unless confirmed to be azoospermic (vasectomized) during the intervention period and for at least 130 days after the last dose of study intervention.
• Human Immunodeficiency (HIV)-infected participants must meet these additional criteria: a) Has laboratory-test-documented HIV-1 infection; b) Has well-controlled HIV on anti-retroviral therapy (ART), defined as: 1) must have a cluster of differentiation (CD4+) T-cell count >350 cells/mm^3 at time of screening; 2) must have achieved and maintained virologic suppression defined as confirmed HIV ribonucleic acid (RNA) level below 50 or the lower limit of quantification (LLOQ) using the locally available assay at the time of screening and for ≥12 weeks prior to screening; and, 3) must have been on a stable regimen, without changes in drugs or dose modification, for ≥4 weeks prior to study entry (Day 1).

All Part 1 Arms:

-Has ≥1 distant, discrete non-injected lesion which is amenable to biopsy. This lesion must be measurable as defined by the response criteria used to assess the participant (RECIST 1.1 for solid tumors or revised International Working Group [IWG] criteria for lymphomas).

Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions) and Part 1 Arm 2: Ulevostinag+Pembro (Cut/Subcut Lesions):

• Has a histologically- or cytologically-confirmed advanced/metastatic solid tumor or lymphoma by pathology report and who has received, or been intolerant to, all treatment known to confer clinical benefit. Solid tumors and lymphomas of any type are eligible for enrollment.
• Has stage III or stage IV disease that is not surgically resectable. Stage IIB (T3N0M0B0-1) cutaneous T cell lymphoma (CTCL) participants are eligible.

Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions):

• Has stage III or stage IV disease that is not surgically resectable.
• Has metastatic liver involvement that does not exceed one third of the total liver volume in participants to be treated by liver IT injection. Hepatocellular carcinoma participants are excluded from eligibility of IT liver injection.

All Part 2 Expansion Cohorts:

Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory:

• Has HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; anti-PD-1/PD-L1 refractory metastatic or recurrent. Participants may not have a primary tumor site of the nasopharynx (any histology).
• Has histologically confirmed Stage III, IVa, or IVb disease per TNM (Tumor, Nodes, Metastasis) staging, American Joint Committee on Cancer (AJCC, 8th edition), with recurrent or persistent disease after definitive chemoradiation, deemed unresectable and considered refractory to both platinum-based combination chemotherapy and anti-programmed cell death-ligand 1 (anti-PD-1/PD-L1) antibody therapy.

OR

• Has histologically confirmed Stage IVc disease per TNM staging, AJCC 8th edition, considered refractory to platinum-based combination chemotherapy and anti-PD-1/PD-L1 antibody therapy.

Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC:

• Has confirmed unresectable locally advanced or metastatic TNBC as locally determined according to the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) guidelines on a newly obtained core or excisional biopsy from a metastatic, not previously irradiated, tumor lesion.
• Has received at least one prior systemic treatment for metastatic breast cancer and has intolerance to, or documented disease progression on or after their most recent therapy.
• Has been previously treated with an anthracycline and/or taxane in the (neo)adjuvant or metastatic setting unless there was a medical contraindication to this treatment regimen.
• Have lactate dehydrogenase (LDH) <2.5 × upper limit of normal (ULN)

Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver:

• Has histologically or cytologically confirmed Stage IV solid tumor that is not surgically resectable.
• Complete resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or baseline (except alopecia). If participant received major surgery or radiation therapy of >30 Gray (Gy), they must have recovered from the toxicity and/or complications from the intervention.

Exclusion Criteria

All Arms and Cohorts (Parts 1 and 2):

• Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or has not recovered to Baseline or Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 from the adverse events due to cancer therapeutics administered >4 weeks earlier.
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and has received study therapy or has used an investigational device within 28 days of administration of ulevostinag. Note: Prior exposure to immunotherapeutics is allowed, including PD-1 and PD-L1 inhibitors
• Is expected to require any other form of antineoplastic therapy while on study.
• Is on chronic systemic steroid therapy in excess of replacement doses (prednisone ≤ 10 mg/day is acceptable), or on any other form of immunosuppressive medication.
• Has a history of a second malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 2 years.
• Has clinically active central nervous system metastases and/or carcinomatous meningitis.
• Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody.
• Has an active autoimmune disease that has required systemic treatment in the past 2 years.
• Has a history of vasculitis.
• Has an active infection requiring therapy.
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years.
• Has Hepatitis B or C infection(s).
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
• Has not fully recovered from any effects of major surgery, and is free of significant detectable infection.
• Has received a live vaccine within 30 days prior to first dose of study drug.
• Has a history of re-irradiation for squamous cell carcinoma of the head & neck (HNSCC) at the projected injection site.
• Has a tumor(s) in direct contact or encases a major blood vessel, and has ulceration and/or fungation onto the skin surface at the projected injection site.
• HIV-infected participants with history of Kaposi's sarcoma and/or multicentric Castleman's disease
• HIV-infected participants who have had an HIV-related opportunistic infection within 6 months
• Has been treated with a Stimulator of Interferon Genes (STING) agonist (e.g. ulevostinag, ADU-S100).

All Part 2 Expansion Cohorts:

• Has experienced weight loss >10% over 2 months prior to first dose of study treatment.
• Has clinically relevant ascites at baseline (defined as requiring paracentesis) or with moderate radiographic ascites. A minimal amount of radiographic ascites is allowed.
• Has a history of interstitial lung disease.
• For Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver, participants with MSI-H CRC are excluded.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Merck Sharp & Dohme LLC

Locations

University of Alabama ( Site 0009)

Birmingham, Alabama, United States

University of California San Francisco ( Site 0007)

San Francisco, California, United States

UCSF ( Site 0015)

San Francisco, California, United States

UCLA Medical Center ( Site 0005)

Santa Monica, California, United States

Henry Ford Health System ( Site 0014)

Detroit, Michigan, United States

Mount Sinai Hospital ( Site 0002)

New York, New York, United States

Columbia University ( Site 0003)

New York, New York, United States

UPMC Hillman Cancer Center ( Site 0013)

Pittsburgh, Pennsylvania, United States

Mary Crowley Cancer Research Center ( Site 0001)

Dallas, Texas, United States

Huntsman Cancer Institute ( Site 0004)

Salt Lake City, Utah, United States

Institut Claudius Regaud ( Site 0051)

Toulouse, Haute-Garonne, France

Institut Gustave Roussy ( Site 0049)

Villejuif, Val-de-Marne, France

Institut Curie ( Site 0050)

Paris, , France

Rambam Medical Center ( Site 0041)

Haifa, , Israel

Sheba Medical Center ( Site 0040)

Ramat Gan, , Israel

Severance Hospital ( Site 0103)

Seoul, , South Korea

Asan Medical Center ( Site 0104)

Seoul, , South Korea

The Royal Marsden Foundation Trust ( Site 0031)

London, London, City of, United Kingdom

The Royal Marsden NHS Foundation Trust. ( Site 0032)

Sutton, Surrey, United Kingdom

Countries

United States; France; Israel; South Korea; United Kingdom

References

Harrington KJ, Champiat S, Brody JD, Cho BC, Romano E, Golan T, Hyngstrom JR, Strauss J, Oh DY, Popovtzer A, Gomez-Roca C, Perets R, Kim SB, Wong DJ, Powell SF, Khilnani A, Jemielita T, Zhao Q, Zhao R, Ingham M. Phase I and II Clinical Studies of the STING Agonist Ulevostinag with and without Pembrolizumab in Participants with Advanced or Metastatic Solid Tumors or Lymphomas. Clin Cancer Res. 2025 Aug 14;31(16):3400-3411. doi: 10.1158/1078-0432.CCR-24-3630.

Reference Type: RESULT

PMID: 40499147 (View on PubMed)

Gogoi H, Mansouri S, Jin L. The Age of Cyclic Dinucleotide Vaccine Adjuvants. Vaccines (Basel). 2020 Aug 13;8(3):453. doi: 10.3390/vaccines8030453.

Reference Type: DERIVED

PMID: 32823563 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

MK-1454-001

Identifier Type: OTHER

Identifier Source: secondary_id

2016-003160-40

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1454-001

Identifier Type: -

Identifier Source: org_study_id