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)

Phase 1

Completed

Conditions: Solid Tumors
Lymphoma

Interventions: Drug: Ulevostinag
Biological: Pembrolizumab

Registration Number: NCT03010176

Lead Sponsor: Merck Sharp & Dohme LLC

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 156

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.

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
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)	Cycle 1 (21-day cycle)	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.
Parts 1 and 2: Number of Participants Who Experienced One or More Adverse Events (AEs)	Up to approximately 2 years	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.
Parts 1 and 2: Number of Participants Who Discontinued Study Drug Due to an AE	Up to approximately 2 years	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.

Secondary Outcome Measures

Name	Time	Method
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.	The AUC0-24 is a measure of the amount of drug in the blood over time for 0 hours to 24 hours. The AUC0-24 of ulevostinag administered via IT injection as monotherapy and the AUC0-24 of ulevostinag administered via IT injection as combination therapy with pembrolizumab IV infusion were evaluated.
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.	Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. The Cmax of ulevostinag administered via IT injection as monotherapy and the Cmax of ulevostinag administered via IT injection as combination therapy with pembrolizumab IV infusion were evaluated.
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.	Cmin is a measure of the minimum amount of drug in the plasma after the dose is given. The Cmin of ulevostinag administered via IT injection as monotherapy and the Cmin of ulevostinag administered via IT injection as combination therapy with pembrolizumab IV infusion were evaluated.
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.	Cmin is a measure of the minimum amount of drug in the plasma after the dose is given. The Cmin of pembrolizumab IV infusion in combination with MK-1454 administered via IT injection was evaluated.
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	ORR is 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, taking as reference the baseline sum diameters) per RECIST 1.1. The ORR of ulevostinag at the preliminary RP2D in combination with pembrolizumab will be assessed by RECIST 1.1 modified to follow a maximum of 10 target lesions with a maximum of 5 target lesions per organ.

Trial Locations

Locations (19): Huntsman Cancer Institute ( Site 0004)
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Salt Lake City, Utah, United States
Mount Sinai Hospital ( Site 0002)
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New York, New York, United States
UCSF ( Site 0015)
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San Francisco, California, United States
Asan Medical Center ( Site 0104)
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Seoul, Korea, Republic of
Sheba Medical Center ( Site 0040)
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Ramat Gan, Israel
University of Alabama ( Site 0009)
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Birmingham, Alabama, United States
Mary Crowley Cancer Research Center ( Site 0001)
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Dallas, Texas, United States
UCLA Medical Center ( Site 0005)
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Santa Monica, California, United States
Institut Gustave Roussy ( Site 0049)
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Villejuif, Val-de-Marne, France
Institut Claudius Regaud ( Site 0051)
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Toulouse Cedex 9, Haute-Garonne, France
Institut Curie ( Site 0050)
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Paris, France
Rambam Medical Center ( Site 0041)
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Haifa, Israel
University of California San Francisco ( Site 0007)
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San Francisco, California, United States
UPMC Hillman Cancer Center ( Site 0013)
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Pittsburgh, Pennsylvania, United States
Henry Ford Health System ( Site 0014)
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Detroit, Michigan, United States
Columbia University ( Site 0003)
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New York, New York, United States
Severance Hospital ( Site 0103)
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Seoul, Korea, Republic of
The Royal Marsden Foundation Trust ( Site 0031)
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London, London, City Of, United Kingdom
The Royal Marsden NHS Foundation Trust. ( Site 0032)
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Sutton, Surrey, United Kingdom