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)

NCT03010176 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: 1454-001MK-1454-0012016-003160-40
• Study Type: interventional
• Target: 156
• Locations: 5 countries
• Sites: 19

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).

Conditions

Solid Tumors; Lymphoma

Keywords

Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1); Intratumoral (IT)

Outcome Measures

Primary Outcomes (3)

• Part 1: Percentage of Participants Who Experienced a Dose-limiting Toxicity (DLT) Per Common Terminology Criteria for Adverse Events, Version 4.0 (CTCAE 4.0)

  DLTs were assessed during the first cycle (21 days) \& are defined as: Grade (Gr) 4 nonhematologic toxicity; Gr 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia, Gr 4 thrombocytopenia, Gr 3 thrombocytopenia (if associated with clinically significant bleeding); nonhematologic adverse event (AE) ≥ Gr 3 (with exceptions); Gr 3 or 4 nonhematologic lab abnormality (if medical intervention is required, leads to hospitalization, or persists for \>1 week); Gr 3 or 4 febrile neutropenia; drug-related toxicity that causes treatment discontinuation or dose delay \>7 days between consecutive doses during Cycle 1; drug-related toxicity that causes a \>2 week delay in Cycle 2 initiation; elevated aspartate aminotransferase or alanine aminotransferase lab value that is ≥3× upper limit of normal (ULN) \& an elevated total bilirubin value ≥2× ULN \& an alkaline phosphatase value \<2× ULN, in which no alternative reasons can be found; ≥Gr 2 immune-mediated uveitis; or Gr 5 toxicity.

  Cycle 1 (21-day cycle)

• Parts 1 and 2: Number of Participants Who Experienced One or More Adverse Events (AEs)

  AEs are defined as any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the study treatment, is also an AE.

  Up to approximately 2 years

• Parts 1 and 2: Number of Participants Who Discontinued Study Drug Due to an AE

  AEs are defined as any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the study treatment, is also an AE.

  Up to approximately 2 years

Secondary Outcomes (5)

• Parts 1 and 2: Ulevostinag Area Under the Plasma Drug Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24)

  Cycle 1 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, 6, 12, and 24 hours postdose. Each cycle was 21 days.

• Parts 1 and 2: Ulevostinag Minimum Plasma Concentration (Cmin)

  Cycle 1 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, 6, 12, and 24 hours postdose; Cycle 2 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, and 6 hours postdose. Each cycle was 21 days.

• Parts 1 and 2: Ulevostinag Maximum Plasma Concentration (Cmax)

  Cycle 1 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, 6, 12, and 24 hours postdose; Cycle 2 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, and 6 hours postdose. Each cycle was 21 days.

• Parts 1 and 2: Pembrolizumab Minimum Plasma Concentration (Cmin)

  Predose on Day 1 of Cycles 1, 2, and 4, and every 4 cycles thereafter up to Cycle 35 (up to 2 years). Each cycle was 21 days.

• Parts 1 and 2: Objective Response Rate (ORR) As Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

  Up to approximately 2 years

Study Arms (6)

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

EXPERIMENTAL

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).

Drug: Ulevostinag

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

EXPERIMENTAL

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).

Drug: Ulevostinag; Biological: Pembrolizumab

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

EXPERIMENTAL

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).

Drug: Ulevostinag; Biological: Pembrolizumab

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

EXPERIMENTAL

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).

Drug: Ulevostinag; Biological: Pembrolizumab

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

EXPERIMENTAL

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).

Drug: Ulevostinag; Biological: Pembrolizumab

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

EXPERIMENTAL

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).

Drug: Ulevostinag; Biological: Pembrolizumab

Interventions

Ulevostinag DRUG

IT injection

Also known as: MK-1454

Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions); Part 1 Arm 2: Ulevostinag +Pembro (Cut/Subcut Lesions); Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions); Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory; Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC; Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver

Pembrolizumab BIOLOGICAL

IV infusion

Also known as: MK-3475, Keytruda®

Part 1 Arm 2: Ulevostinag +Pembro (Cut/Subcut Lesions); Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions); Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory; Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC; Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver

Eligibility Criteria

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

You may qualify if:

• 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:

You may not qualify if:

• 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.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (19)

University of Alabama ( Site 0009)

Birmingham, Alabama, 35294, United States

Location

University of California San Francisco ( Site 0007)

San Francisco, California, 94143, United States

Location

UCSF ( Site 0015)

San Francisco, California, 94158, United States

Location

UCLA Medical Center ( Site 0005)

Santa Monica, California, 90404, United States

Location

Henry Ford Health System ( Site 0014)

Detroit, Michigan, 48202, United States

Location

Mount Sinai Hospital ( Site 0002)

New York, New York, 10029, United States

Location

Columbia University ( Site 0003)

New York, New York, 10032, United States

Location

UPMC Hillman Cancer Center ( Site 0013)

Pittsburgh, Pennsylvania, 15232, United States

Location

Mary Crowley Cancer Research Center ( Site 0001)

Dallas, Texas, 75230, United States

Location

Huntsman Cancer Institute ( Site 0004)

Salt Lake City, Utah, 84112, United States

Location

Institut Claudius Regaud ( Site 0051)

Toulouse, Haute-Garonne, 31059, France

Location

Institut Gustave Roussy ( Site 0049)

Villejuif, Val-de-Marne, 94805, France

Location

Institut Curie ( Site 0050)

Paris, 75005, France

Location

Rambam Medical Center ( Site 0041)

Haifa, 3109601, Israel

Location

Sheba Medical Center ( Site 0040)

Ramat Gan, 5265601, Israel

Location

Severance Hospital ( Site 0103)

Seoul, 03722, South Korea

Location

Asan Medical Center ( Site 0104)

Seoul, 05505, South Korea

Location

The Royal Marsden Foundation Trust ( Site 0031)

London, London, City of, SW3 6JJ, United Kingdom

Location

The Royal Marsden NHS Foundation Trust. ( Site 0032)

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 40499147 RESULT

• 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.

  PMID: 32823563 DERIVED

MeSH Terms

Conditions

Lymphoma; Parkinson Disease 4, Autosomal Dominant Lewy Body

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Results Point of Contact

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

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: January 3, 2017
• First Posted: January 4, 2017
• Study Start: February 3, 2017
• Primary Completion: April 21, 2022
• Study Completion: April 21, 2022
• Last Updated: October 29, 2025
• Results First Posted: February 26, 2024

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will share

Locations

IL (2); US (10); KR (2); FR (3); GB (2)