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)

Study Overview
=================
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 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.

Official Title
-----------------
Phase 1 Open-label, Multicenter Study of MK-1454 Administered by Intratumoral Injection as Monotherapy and in Combination With Pembrolizumab for Patients With Advanced/Metastatic Solid Tumors or Lymphomas

Conditions
-----------------
Solid Tumors, Lymphoma

Intervention / Treatment
-----------------
* Drug: Ulevostinag
* Biological: Pembrolizumab


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions)<br>Participants with cutaneous (cut) or subcutaneous (subcut) lesions 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<br>* IT injection<br>* Other names: MK-1454;|
| Experimental: Part 1 Arm 2: Ulevostinag +Pembro (Cut/Subcut Lesions)<br>Participants with cut or subcut lesions 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) 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years). | Drug: Ulevostinag<br>* IT injection<br>* Other names: MK-1454;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: Keytruda®;|
| Experimental: Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions)<br>Participants with visceral lesions 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 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (approximately 2 years). | Drug: Ulevostinag<br>* IT injection<br>* Other names: MK-1454;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: Keytruda®;|
| Experimental: Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory<br>Participants with HNSCC who are anti-programmed cell death-1 or anti-programmed cell death-ligand 1 refractory 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 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years). | Drug: Ulevostinag<br>* IT injection<br>* Other names: MK-1454;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: Keytruda®;|
| Experimental: Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC<br>Participants with TNBC who are anti-PD-1/PD-L1 treatment-naïve or who have refractory unresectable locally advanced or metastatic TNBC 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 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years). | Drug: Ulevostinag<br>* IT injection<br>* Other names: MK-1454;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: Keytruda®;|
| Experimental: Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver<br>Participants with solid tumors with liver metastases/lesions who are anti-PD-1/PD-L1 treatment-naïve 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 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years). | Drug: Ulevostinag<br>* IT injection<br>* Other names: MK-1454;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: Keytruda®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Percentage of Participants Who Experience a Dose-limiting Toxicity (DLT) Per Common Terminology Criteria for Adverse Events, Version 4.0 (CTCAE 4.0) | DLTs will be 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. | Up to 3 weeks at each dose level | 
| Parts 1 and 2: Percentage of Participants Who Discontinue Study Drug Due to an Adverse Event (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. The percentage of participants who discontinue study treatment due to an AE will be presented. | Up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1 and 2: Ulevostinag Area Under the Plasma Drug Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) | The AUC0-24 of ulevostinag when administered as monotherapy and as combination therapy with pembrolizumab will be determined. | 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 is 21 days. | 
| Parts 1 and 2: Ulevostinag Minimum Plasma Concentration (Cmin) | The observed Cmin of ulevostinag when administered as monotherapy and as combination therapy with pembrolizumab will be determined. | 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 is 21 days. | 
| Parts 1 and 2: Ulevostinag Maximum Plasma Concentration (Cmax) | The observed Cmax of ulevostinag when administered as monotherapy and as combination therapy with pembrolizumab will be determined. | 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 is 21 days. | 
| Parts 1 and 2: Pembrolizumab Minimum Plasma Concentration (Cmin) | The Cmin of pembrolizumab when administered as combination therapy with ulevostinag will be determined. | 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 is 21 days. | 
| Part 2: Objective Response Rate (ORR) As Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 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. ORR for the three Part 2 cohorts will be reported. | Up to approximately 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), Intratumoral (IT)